BMJ OpenCV risk9-12. Many of these abnormalities are indeed already evident in patients with only mild abnormalities of kidney function (estimated glomerular filtration rates [eGFR]:

For peer review only

Results and lessons from the Spironolactone To Prevent Cardiovascular Events In Early Stage Chronic Kidney

Disease (STOP-CKD) Randomised Controlled Trial

Journal: BMJ Open

Manuscript ID bmjopen-2015-010519

Article Type: Research

Date Submitted by the Author: 10-Nov-2015

Complete List of Authors: Ng, Khai Ping; Queen Elizabeth Hospital Birmingham, Renal Medicine Jain, Poorva; University of Birmingham, Primary Care Clinical Sciences Gill, Paramjit; University of Birmingham, Primary Care Clinical Sciences

Heer, Gurdip; University of Birmingham, Primary Care Clinical Sciences Townend, Jonathan; University Hospitals Birmingham NHS Foundation Trust, Cardiology Freemantle, Nick; University College London, Dept Primary Care and Population Health Greenfield, Sheila; University of Birmingham, Primary Care Clinical Sciences McManus, Richard; University of Oxford, Dept of Primary Care Health Sciences Ferro, Charles; Queen Elizabeth Hospital, Nephrology

<b>Primary Subject Heading</b>:

Renal medicine

Secondary Subject Heading: Cardiovascular medicine, General practice / Family practice, Research methods

Keywords: cardiovascular, chronic kidney disease, mineralocorticoid receptor antagonist, PRIMARY CARE, randomised trial, research recruitment

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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1

Results and lessons from the Spironolactone To Prevent Cardiovascular

Events In Early Stage Chronic Kidney Disease (STOP-CKD) Randomised

Controlled Trial

Authors:

Khai P Ng MBChB1

Poorva Jain MBChB 2

Paramjit S Gill FRCGP FHEA2

Gurdip Heer BSc(Hons) RGN2

Jonathan N Townend MD3

Nick Freemantle PhD4

Sheila Greenfield PhD 2

Richard J McManus PhD FRCGP5

Charles J Ferro MD1

Affiliation: 1Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, Birmingham, B15

2WB, UK 2Primary Care Clinical Sciences, School of Health and Population Sciences, University of

Birmingham, Birmingham, B15 2TT, UK 3Department of Cardiology, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2WB,

UK 4Department of Primary Care and Population Health, UCL Medical School, Rowland Hill

Street, London, NW3 2PF, UK 5Nuffield

Department of Primary Care Health Sciences, University of Oxford, Woodstock

Rd, Oxford, OX2 6GG, UK

Corresponding author:

Dr Charles Ferro

Department of Renal Medicine,

Queen Elizabeth Hospital Birmingham,

Mindelsohn Way,

Birmingham,

B15 2WB, UK

Email: [email protected] Tel: +44 121 3715842 Fax: +44 121 3715858

Keywords:

Cardiovascular; chronic kidney disease; mineralocorticoid receptor antagonist; primary care;

randomised trial

Word count: 3257 words (abstract 259)

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ABSTRACT

Objectives

To determine whether low-dose spironolactone can safely lower arterial stiffness in patients

with chronic kidney disease stage 3 in the primary care setting.

Design

A multi-centre, prospective, randomised, placebo-controlled, double-blinded study.

Setting

Eleven primary care centres in South Birmingham, England.

Participants

Adult patients with stage 3 chronic kidney disease. Main exclusion criteria were diagnosis of

diabetes mellitus, chronic heart failure, atrial fibrillation, severe hypertension, systolic blood

pressure < 120 mmHg or baseline serum potassium ≥ 5 mmol/L.

Intervention

Eligible participants were randomised to receive either spironolactone 25 mg once daily or

matching placebo for an intended period of 40 weeks.

Outcome measures

The primary endpoint was the change in arterial stiffness as measured by pulse wave

velocity. Secondary outcome measures included the rate of hyperkalaemia, deterioration of

renal function, barriers to participation and expected recruitment rates to a potential future

hard-endpoint study.

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Results

From the 11 practices serving a population of 112,462, there were 1,598 (1.4%) patients

identified as being eligible and invited to participate. Of these, 134 (8.4%) attended the

screening visit of which only 16 (1.0%) were eligible for randomisation. The main reasons

for exclusion were low systolic blood pressure (< 120 mmHg: 40 patients) and high estimated

glomerular filtration rate (≥ 60 ml/min/1.73m2: 38 patients). The trial was considered

unfeasible and was terminated early.

Conclusion

We highlight some of the challenges in undertaking research in primary care including

patient participation in trials. This study not only challenged our preconceptions, but also

provided important learning for future research in this large and important group of patients.

Strength and limitations of this study

� This is the first reported randomised, placebo-controlled interventional trial of

patients with stage 3 chronic kidney disease in the primary care setting in England.

� The strengths of the study are the original study design, setting and populations.

� The review of the list of potential participants by their corresponding general

practitioners might have resulted in selection bias.

� The major limitation to this study was the poor recruitment which ultimately led to

early termination of study.

� Critical analysis and transparent reporting of research recruitment failure provide

important learning for future research in this large and important group of patients.

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Trial registration number: Current Controlled Trial ISRCTN80658312

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INTRODUCTION

Chronic kidney disease (CKD) is increasingly recognised as an independent risk factor for

cardiovascular (CV) morbidity and mortality1-4

. Although the increased CV risk observed in

dialysis patients is considerable, the global health burden of CV disease in the earlier stages

of CKD is likely to be much greater given the high reported prevalence of up to 13% in

developed countries5 6

. In addition to an increased risk of vasculo-occlusive events such as

myocardial infarction, patients with CKD also have an increased risk of cardiac arrhythmias

and heart failure7 8

. Increased arterial stiffness, leading to myocardial hypertrophy and

fibrosis is thought to be a key mechanistic pathway in this pathophysiology of this increased

CV risk9-12

. Many of these abnormalities are indeed already evident in patients with only mild

abnormalities of kidney function (estimated glomerular filtration rates [eGFR]: 30 – 90

ml/min/1.73m2)12 13

.

Activation of the renin-angiotensin-aldosterone system (RAAS) is a key mediator of the

arterial and cardiac changes observed in patients with CKD as well as the increased CV risk

associated with this condition11 14

. Aldosterone is a mineralocorticoid that is a key effector of

the RAAS. The mineralocorticoid receptor antagonist (MRA), spironolactone, used in low

dose, has been shown to significantly lower arterial stiffness and left ventricular mass in

patients with stage 3 CKD managed by nephrologists in secondary care15

. However, the

majority (>90%) of patients with this level of kidney function are managed in primary care

by their general practitioners (GPs)2 16

. These patients tend to be older and have non-

proteinuric renal diseases probably as a consequence of hypertension, reno-vascular disease

and possibly normal ageing17

. Furthermore, concerns about MRAs causing hyperkalaemia

and worsening renal function might limit their future use in the primary care setting.

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We therefore undertook a feasibility study to examine the actions of low dose spironolactone

on arterial stiffness in non-diabetic patients with stage 3 CKD managed in primary care.

Secondary objectives included the rate of hyperkalaemia, deterioration of renal function,

barriers to participation and expected recruitment rates to a potential future hard-endpoint

study.

SUBJECTS AND METHODS

The study design has previously been described in detail (Appendix 1)18

. In brief, it was a

multicentre, prospective, randomised, placebo-controlled, double-blind, parallel trial in non-

diabetic patients with confirmed stage 3 CKD over 18 years of age in primary care. Patients

with diabetes mellitus were excluded given that the pathophysiology of arterial stiffness is

likely to be different and they have a higher risk of hyperkalaemia19

. Diabetes would be

expected to affect 20-30% of a community sample of CKD, and hence would form a large

subgroup within the trial. Thus, although diabetes is an important issue in CKD, we

considered that this would be best explored in a separate study.

The GFR was estimated by the four-variable Modification of Diet in Renal Disease (MDRD)

formula with serum creatinine recalibrated to be traceable to an isotope-derived mass

spectroscopy method20

. The full inclusion and exclusion criteria are detailed in Table 1. The

UK National Institute for Health and Care Excellence (NICE) guidelines on CKD

recommended systolic BP (SBP) target range of 120-139 mmHg and diastolic BP (DBP) <

90mmHg for patients with CKD19

. As spironolactone is known to have a BP-lowering effect,

patients with SBP <120 mmHg or postural hypotension were excluded from the study.

Patients with uncontrolled severe hypertension (BP ≥ 180/110 mmHg)21

and patients with a

serum potassium ≥ 5 mmol/L19

.

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Table 1: Inclusion and exclusion criteria of STOP-CKD study

Abbreviations: ACEi: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blocker; BP:

blood pressure; CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; GP: general

practitioner; uACR: urine albumin:creatinine ratio.

Practices’ electronic patient records (EPR) were screened to identify all patients whose latest

eGFR were 30-59 ml/min/1.73m2 in the preceding 12 months and satisfied the study

inclusion and exclusion criteria. Following review by individual patient’s GPs to determine

suitability for participation, potential participants were sent postal invitations. Non-

responders were sent a second invitation two weeks later. Those expressing a willingness to

participate were invited to attend a screening visit at their own general practice to confirm

eligibility. Following this screening visit, eligible participants attended a randomisation visit

within two weeks and if still eligible were assigned 1:1 to receive either spironolactone

Inclusion criteria

Age over 18 years

Diagnosis of CKD Stage 3 (MDRD eGFR 30-59 ml/min/1.73m2, sustained for at least 90 days)

Exclusion criteria

Diabetes Mellitus

Terminal disease or considered otherwise unsuitable by GP

Clinical diagnosis of chronic heart failure

Atrial fibrillation

Alcohol or drug abuse

Inability to comply with trial medication and follow-up

Documented previous hyperkalaemia or intolerance of spironolactone

Documented Addisonian crisis or taking fludrocortisone

Severe hypertension: BP ≥ 180/110 mmHg

Systolic BP < 120 mmHg

Recent acute kidney injury or hospital admission (within previous 6 weeks)

Chronic diarrhoea

Urine albumin:creatinine ratio (uACR) ≥ 70 mg/mmol

Serum potassium ≥ 5 mmol/L on screening visit

Concomitant co-trimoxazole medication

Concomitant ACEi and ARB medication

Concomitant lithium medication

Concomitant warfarin medication

Pregnancy

Breastfeeding

Planned major surgical intervention within 46 weeks of recruitment

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25 mg once daily orally or identical placebo for 40 weeks using a web-based randomisation

system (Appendix 1). Investigator, outcome assessors, data analysts and participants were all

blinded to the treatment allocation. Patients were given a prescription to collect their study

medication from their local community pharmacy. Arterial stiffness, as determined by

carotid-femoral pulse wave velocity (cfPWV) was measured using the Vicorder

system (Skidmore, Bristol, UK)21

at randomisation visit and 40 weeks. Blood pressure was

measured using the BpTRU™ BPM-100 automated BP monitor, which was set to obtain six

serial BP readings, at one-minute intervals22

. The mean office BP was derived from the 2nd

and 3rd

BP readings, whereas the mean BpTRU reading was derived from the 2nd

- 6th

readings23

. Postural hypotension was defined as a drop of SBP >20 mmHg after a minute on

standing.

Ethical approval for the study was given by the National Research Ethics Service (Reference

No 12/WM/0168) and clinical trial authorization was granted by the Medicine and Healthcare

Products Regulatory Agency (Reference No 21761/0274/001-0001). The Primary Care

Clinical Research and Trials Unit (PC-CRTU) at the University of Birmingham coordinated

the study. (Trial registration number: ISRCTN80658312).

Sample size calculation

In a previous study of the effect of spironolactone, the standard deviation (SD) of the change

in cfPWV was 1.0 m/s in the active treatment group and 0.9 m/s in the control group24

.

Hence, 100 subjects in each arm would provide 90% power with an α value of 0.05 to detect a

difference in change of cfPWV of 0.5 m/s between the active treatment and control groups.

The study therefore intended to recruit 240 patients to account for an approximate dropout

rate of 20%, which would result in at least 200 evaluable patients completing this trial.

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Statistical analysis

Statistical analyses were performed using SPSS version 20 (SPSS Inc, Chicago, IL), and SAS

version 9.4 (SAS Institute; Cary, NC). Numerical values are expressed as mean (SD) for

parametric data or median (interquartile range [IQR]) for non-parametric data. Normality of

the distribution of data was assessed by visual inspection of histogram and normal probability

plot. Non-parametric data were loge-transformed before comparative analyses. Continuous

data were compared using Student t-tests.

Exploratory analyses were performed to identify any potential factors influencing patients’

willingness to participate. The information available on invited patients invited was limited to

their age, gender, ethnicity, general practice and last recorded eGFR. These five factors were

therefore assessed by binary logistic regression using a forced enter method with regard to

their impact on patient’s research participation. Patients who expressed interest in

participating were categorised as ‘willing invitees’ whereas patients who either did not

respond to the invitation or replied but declined participation were grouped together as ‘non-

willing invitees’. Patients’ gender (male/female) and ethnicity (white/others) were analysed

as dichotomous data whereas age and last recorded eGFR were analysed as continuous data.

Supplementary analyses were performed with eGFR being dichotomised either into CKD

stage 3a (eGFR: 45- 59 ml/min/1.73m2) and stage 3b (eGFR: 30- 44 ml/min/1.73m

2) or into

categories above or below the median of eGFR (54 ml/min/1.73m2). Non-linearity of age and

eGFR were examined using restricted cubic spline models. Models were selected on

achieving a significant improvement in Akaike’s Information Criterion. Statistical

significance was defined as a two-tailed p value < 0.05.

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RESULTS

All 71 primary care practices within the former South Birmingham Primary Care Trust with

more than 3,000 patients registered were invited to participate. Eleven practices (15%) agreed

to take part, with a total population of 112,462 (Table 2). Electronic database searches

identified 2,044 potentially eligible patients. A further 446 (21.8%) patients were excluded by

their GPs with the proportion excluded varying considerably (2.3 – 52.6%). Five of the 11

practices were known to be ‘research-active’. There was no statistically significant difference

in regards to proportions of patients excluded between ‘research-active’ practices compared

to their counterparts (median: 19 [IQR: 10-47] vs 11 [IQR: 4-28] %, p=0.2).

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Table 2: Eleven recruiting practices’ population, prevalence of stage 3-5 chronic kidney disease, numbers of patients invited, screened and

randomised for STOP-CKD study.

Practice Practice

population

Prevalence

of stage 3-5

CKD*

Patients

eligible from

computerised

search (%)

Patients

excluded by

GP (%)**

Patients

invited (%)

Patients

replying

(%)***

Patients

expressing

interest (%)†

Patients

attending

screening visit

(%)†

Patients

randomized

(%)†

#1R 7,501 4.72 % 260 (3.5) 49 (18.8) 211 (2.8) 105 (49.8) 37 (17.5) 22 (10.4) 3 (1.4)

#2R 3,838 1.86 % 38 (1.0) 20(52.6) 18 (0.5) 7 (38.9) 3 (16.7) 3 (16.7) 0

#3 27,025 4.82 % 360 (1.3) 183 (50.8) 177 (0.6) 102 (57.6) 21 (11.9) 15 (8.5) 1 (0.6)

#4 7,113 3.58 % 179 (2.5) 7 (3.9) 172 (2.4) 81 (47.1) 20 (11.6) 12 (7.0) 2 (1.2)

#5 24,553 2.97 % 478 (1.9) 97 (20.3) 381 (1.6) 152 (39.9) 41 (10.8) 29 (7.6) 5 (1.3)

#6 R

8,729 4.19 % 157 (1.8) 17 (10.8) 140 (1.6) 61 (43.6) 20 (14.3) 16 (11.4) 3 (2.1)

#7 R

5,817 4.69 % 129 (2.2) 13 (10.1) 116 (2.0) 44 (37.9) 15 (12.9) 10 (8.6) 1 (0.9)

#8 4,824 3.58 % 114 (2.4) 13 (11.4) 101 (2.1) 44 (43.6) 11 (10.9) 10 (9.9) 0

#9 9,436 6.67 % 236 (2.5) 25 (10.6) 211 (2.2) 97 (46.0) 19 (9.0) 12 (5.7) 0

#10 7,104 2.75 % 43 (0.6) 1 (2.3) 42 (0.6) 27 (64.3) 6 (14.3) 3 (7.1) 1 (2.4)

#11 R

6,522 2.97 % 50 (0.8) 21 (42.0) 29 (0.4) 13 (44.8) 3 (10.3) 2 (6.9) 0

Total 112,462 2,044 446 1,598 733 196 134 16

Mean % 3.89% 1.82% 21.8% 1.42%

R Signify general practices which were research-active and had dedicate on-site practice research nurses.

*Data obtained from Quality and Outcomes Framework 2013/2014 report

(%) indicates percentage of total practice population

** indicates percentage of potentially eligible patients excluded by their general practitioner

†indicates percentage of patients invited

Abbreviations: CKD, chronic kidney disease; GP, general practitioner

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Invitation to study participation

The trial commenced in July 2013. A total of 1,598 invitation letters were sent out to all

potentially eligible patients (Figure 1). Sixty-three percent were female with a mean age of 71

(SD: 12) years and a median eGFR of 53 (IQR: 48-57) ml/min/1.73m2. Most patients’ (84%)

last eGFR readings were within the range of 45-59 ml/min/1.73m2. The ethnicity was 83.4%

white British, 3.4% black British, 3.3% South Asian, 1% mixed or other ethnicity and 8.9%

unknown.

Patients’ response to study invitation letter

Responses were received from 733 patients (46%) who had a mean age of 73 (SD: 11) years.

Of these, 196 (12%) expressed interest in participating in the study. Percentages of those who

were interested in participation ranged from 9% to 18% across the 11 practices (Table 2).

Of the 537 patients who responded declining participation, 295 (55%) did not wish to take a

new medication, 220 (41%) did not wish to be part of a research trial, 134 (25%) indicated

that they did not have time to take part in the study, 86 (16%) did not wish to have further

blood tests, 48 (9%) were unable to attend the surgery, 21 (4%) believed kidney problems

were of no concern to them and 80 (15%) did not give a reason. Other reasons for non-

participation detailed in the free-text area on the research reply slip included old age, poor

mobility, presence of other health issues, concerns regarding the side effects of

spironolactone, reluctance to take additional medication, work commitments, being carer for

other family members, being away from home during trial period as well as unawareness of

CKD diagnosis.

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In a logistic regression model, age, male gender and coming from research-active practices

were associated with a greater willingness to participate in the trial, whereas ethnicity and

levels of eGFR were not predictive (Table 3). Age was noticeably non-linear in relation to

recruitment, with younger and older age associated with a lower likelihood of agreeing to

participate in the study (Figure 2).

Table 3: Logistic regression demonstrating factors associated with increased likelihood of

patients’ willingness to participate in the trial. (Age as Restricted Cubic Spline)

Variable Odds Ratio Lower 95% CI Upper 95% CI P

Intercept 0.01931 0.00095 0.394 0.0103

eGFR 1.00513 0.98076 1.030 0.6827

Male gender 1.36905 1.00544 1.864 0.0461

White Ethnicity 1.51474 0.96679 2.373 0.0699

Research Active Practice 1.42223 1.04079 1.943 0.0270

AGE 1.02677 0.97659 1.080 0.3014

AGE1 0.93568 0.79398 1.103 0.4275

AGE2 0.79572 0.15232 4.157 0.7865

AGE3 3.30525 0.10044 108.771 0.5024

P for non-linearity for Age 0.0111

P for overall effect of Age 0.0003

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Screening visit

Of the 196 patients who initially expressed an interest in participating in the study, 134

patients (69%) actually attended the screening visit. The characteristics of these patients are

presented in Table 4. The cause of CKD was unclear in the majority of the patients and only

17 patients (13%) had a documented cause of CKD. The median last-recorded MDRD eGFR

was 55 (IQR: 51-57) ml/min/1.73m2 with 88% within the range of 45-59 ml/min/1.73m

2.

In total, 52 (39%) patients were found to be ineligible for the study during the screening visit.

The reasons for exclusion are listed in Figure 1. The main cause for exclusion was low BP.

Thirty-two patients had an office SBP lower than 120 mmHg with 16 patients receiving at

least one anti-hypertensive agent, although five of these patients were known to have

ischaemic heart disease and thus another potential indication for treatment with these agents

other than hypertension. Of the 79 remaining eligible patients, a further 46 were excluded

after the screening blood test (Figure 1). The main reason for exclusion (31 patients) was

having an eGFR greater than 60 ml/min/1.73m2.

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Table 4: Baseline demographics, clinical characteristics, blood pressure measurements and

biochemistry profiles of patients attended screening visit and patients randomised to receive

trial medication.

Attended screening

visit

Randomised into STOP-

CKD study

Number of patients 134 16

Male gender, n. (%) 62 (46) 7 (44)

White ethnicity, n. (%) 125 (93) 16 (100)

Mean age (SD), years 68 (10) 71 (7)

Medical history, n. (%)

• Hypertension

• Hypercholesterolaemia

• Coronary heart disease

• Coronary artery bypass graft/angioplasty

• Stroke/transient ischaemic attack

• Peripheral vascular disease

Total number of comorbidities, median (IQR)

62 (46)

42 (31)

17 (13)

13 (10)

11 (8)

8 (6) 1 (0-2)

5 (31)

3 (19)

1 (6)

0

1 (6)

0 0 (0-1)

Medications, n. (%)

Anti-platelet agents

Lipid lowering agents

Use of anti-hypertensive agents

• Diuretics

• β-blockers

• ACEi/ARB

• Nitrates

• Calcium channel blockers

• α channel blockers

Patients not receiving any anti-hypertensive agents

34 (25)

54 (40)

74 (55)

20 (15)

20 (15)

48 (36)

5 (4)

21 (16)

11 (8)

60 (45)

4 (25)

4 (25)

9 (56)

1 (6)

2 (13)

5 (31)

0

4 (25)

0

7 (44)

Smoking history, n (%)

• Current smoker

• Ex-smoker

• Never smoker

8 (6)

55 (41)

71 (53)

1 (6)

7 (44)

8 (50)

BP Measurements

• Office systolic BP, mean (SD), mmHg

• Office diastolic BP, mean (SD), mmHg

• Office systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, n.

(%)

• Office BP within NICE CKD targets, n. (%)

• Office systolic BP <120 mmHg, n. (%)

132 (19) 79 (10)

47 (35)

54 (40)

34 (25)

133 (10) 78 (8)

10 (62)

6 (38)

0


Na+, mmol/L 141 (3) 142 (2) K+, mmol/L 4.5 (0.6) 4.5 (0.4)

Urea, mg/dL 6.8 (2.0) 6.9 (1.4)

Creatinine, median (IQR), µmol/L 98 (85-112) 101 (86-121)

MDRD eGFR (median, IQR), ml/min/1.73m2 57 (51-65) 54 (48-57)

CKD EPI eGFR (mean, SD), ml/min/1.73m2 59 (12) 53 (7)

Urine ACR (median, IQR), mg/mmol

• < 3 mg/mmol, n. (%)

• 3-30 mg/mmol, n. (%)

• > 30 mg/mmol, n. (%)

0.9 (0-2.0) 62 (79)

16 (20)

1 (1)

0.85 (0.08- 1.95) 13 (81)

3 (19)

0

Ca+2, mmol/L 2.38 (0.10) 2.38 (0.13)

Albumin, g/L 46 (2) 45 (1)

Total protein, g/L 72 (4) 71 (3) Alkaline phosphatase, U/L 78 (25) 79 (17)

Alanine Aminotransferase, U/L 20 (8) 19 (7)

Abbreviations: ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BP, blood

pressure,; Ca+2,serum calcium; eGFR, estimated glomerular filtration rate; IQR, interquartile range; K

+, serum

potassium; Na+, serum sodium; n., number of patients; SD, standard deviation.

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Randomisation visit

Of the 33 remaining eligible patients, 28 (85%) attended the randomisation visit (Figure 1). A

further 12 patients were excluded at this point. Eight had an office SBP less than 120 mmHg,

three had postural hypotension and one had uncontrolled hypertension. Sixteen patients were

randomised and their baseline characteristics were shown in Table 4.

Early termination of study

In May 2014, the STOP-CKD study was terminated early because of futility. In order to

achieve the original planned sample size of 240 patients, the projected number of primary

care practices required to be involved in the study would be 145 practices covering a

population of more than 1.5 million. After thorough discussion, the trial Data Monitoring and

Ethics Committee and the Trial Steering Committee collectively agreed that the study was

not feasible with the allocated resources.

DISCUSSION

In the UK, as indeed in many countries, most patients with early-stage CKD are managed in

primary care. Many observational studies have established that these patients have several

differences compared with patients managed in secondary care25

. They tend to be older with a

lower prevalence of proteinuria and more preserved eGFR25

. These differences are important

if any intervention shown to be effective for the treatment of CKD in the minority of patients

treated in secondary care is rolled out to the community. The STOP-CKD trial was an attempt

to establish whether low-dose spironolactone, a treatment shown to be safe and effective in

improving surrogate markers of CV risk in patients with CKD managed in secondary care,

was equally safe and effective in patients with CKD managed in primary care. Although the

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study proved not to be feasible, there are several important findings and lessons that can be

learnt from it to inform future interventional studies in this population.

Estimating the number of patients needed

Assessing the number of patients needed to invite in order to recruit to the sample size is an

essential but challenging requirement in planning any study. Recently, a Japanese study

explored the use of information technology in predicting the success or failure of study

recruitment26

. The study derived the eligible EPR index by dividing the number of eligible

patients identified from the EPR by the target sample size. An EPR index of more than 1.7

was reported to have a sensitivity and specificity of approximately 70% and 100%,

respectively in predicting recruitment success. However, in spite of a much higher EPR index

of 6.7 that should have predicted successful recruitment, the STOP-CKD study failed to reach

its target sample size, suggesting that other recruitment issues were involved.

Following the EPR search, the number of patients eligible for invitation reduced considerably

after GP review. The variation observed in the proportion of patients excluded by GPs across

the practices suggests that there were large elements of subjectivity and inconsistency in this

assessment. It is likely that many patients fulfilling the inclusion criteria were excluded at this

stage. While the review of the list of potential participants by their corresponding GPs was

well intentioned, significant selection-bias might have occurred during the process and we

suggest that in future studies, this step requires revision with clear and transparent criteria.

Prevalence of chronic kidney disease

In the UK, primary care physicians are required to keep a register of patients with stages 3-5

CKD2 26

. Published data from the participating practices showed the average percentage of

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total patients on the CKD register was 3.89%, which is lower than the recently published

reports from UK research databases of 5.15%27

and 5.9%28

and marginally lower than that

reported for all English practices over 2010-2012 of 4.3%29

. Nevertheless, it appears that the

observed prevalence of CKD is much lower than the 10% figure which was the finding in

previous epidemiological work in the UK29

and globally30

. It has been suggested that the

prevalence of CKD has been significantly overestimated by using a single serum creatinine

measurement to define CKD31

and this has been confirmed in a recent UK study using two

creatinine measurements which reported a CKD prevalence of 3.9%32

.

In order to increase patient inclusivity and bypass the issues of un-coded or mis-coded CKD5,

we searched and short-listed all patients with a latest recorded eGFR of 30-59 ml/min/1.73m2

in the preceding 12 months. The eGFR test performed at the screening visit served as a

confirmation of CKD diagnosis. Despite having an eGFR within 30-59 ml/min/1.73m2

previously, 40% of such patients were excluded due to an eGFR greater than 60

ml/min/1.73m2 at screening, and therefore, by definition did not have CKD stage 3. Of those

who fulfilled the biochemical eligibility criteria, most had only modest reduction in eGFR

with a median eGFR of 54 ml/min/1.73m2 and none were found to have significant levels of

albuminuria33 34

.

Blood pressure

The treatment of hypertension is still the cornerstone of management of CKD, both in terms

of CKD progression and the reduction of CV risk31 35

. In agreement with other studies, we

found less than half of the patients attending the screening visit achieved both the SBP and

DBP target recommended by the NICE CKD guidelines1. Amongst those with SBP ≥ 140

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mmHg or DBP ≥ 90 mmHg, more than 40% were in fact not receiving any anti-hypertensive

medication.

It has long been believed that lowering office/clinic BP to levels lower than 120/80 mmHg is

associated with worse outcomes and increased mortality, especially in the elderly4. This is

reflected in recent guidelines on the management of CKD that recommend BP not be lowered

below these levels32 33

. The results of the recent SPRINT trial challenge these guidelines36

and future studies might consider the inclusion of such patients.

Primary Care Practice Recruitment strategies

Though we designed the STOP-CKD study to minimize any extra workload on the

participating primary care practices, most practices declined the initial approach and it took a

lot of effort from the investigators to recruit the 11 practices that participated. In order to

improve the quality and quantity of primary care research in the UK, a ‘research ready self-

accreditation’ initiative to support general practices in meeting the legal requirements of the

UK for carrying out research5. Thus far, there are more than 1,000 research-ready general

practices in the UK5. Our study demonstrated a significant positive influence of research-

active practices on patients’ participation providing further support for these measures.

Patient recruitment strategies

Although the need for a robust evidence base for any intervention before it becomes accepted

practice is now well established, there is surprisingly little evidence on how best to conduct

an RCT37 38

. Regulatory and ethical issues compelled us to contact potentially eligible

patients by mailshot through their GPs. This is a notoriously inefficient and costly process

with large number of invitations needing to be sent to recruit the target number of patients.

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Two key reviews previously explored the value of various strategies in improving

participants’ recruitment in research studies6 39

. The STEPS study suggested that being

flexible and robust in adapting to unexpected issues was important to ensure trials success40

whilst in the systematic review by Treweek et al, telephone reminders to non-responders, opt-

out rather than opt-in system of being contacted about the study, financial incentives and

open designs all appeared to be effective strategies40

. We suggest that an initial approach

using telephone, text or email may yield better results and that further research examining the

acceptability and efficacy of initial recruitment strategies is of major importance. Our logistic

regression model showed that younger and older patients were significantly less likely to

participate. Thus, although we designed the study with broad inclusivity criteria we still did

not manage to recruit the “real-life CKD population”, which may reflect patients’ self-

selection bias. Strategies to recruit these patients therefore need developing and testing in

future studies.

CONCLUSIONS

The STOP-CKD study was a non-age restricted, investigator-led, feasibility RCT designed to

inform a future larger, hard end-point study in patients with CKD in primary care. The study

highlighted the unique characteristics of the CKD population in primary care, which

challenged our preconceived knowledge about the appropriate intervention and management

of this sizeable group of patients. With the majority of interventional studies on patients with

CKD thus far based in secondary care, there remains an urgent need to optimise the

generalisability of future CKD research, especially in primary care. The experience and

lessons learnt from this study provide important information for all CKD researchers to

meticulously reflect on their future research aims, study design, choices of intervention and

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most importantly recruitment strategies. As Henry Ford once said, ‘failure is only the

opportunity to begin again, only this time more wisely’.

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Authors’ contributions

PJ, PSG, JNT, NF, SG, RJM and CJF were responsible for the study conception and design.

KPN, PJ and GH were involved in patient recruitment. KPN drafted the manuscript. NF was

the study statistician. All authors have critically reviewed the manuscript and given final

approval of the version to be published.

Acknowledgements

We would like to acknowledge the support of the staff at the PC-CRTU at the University of

Birmingham, especially Val Redman and Dr Odette Chagoury; research nurses and clinical

trials pharmacists at the Birmingham and Black Country Comprehensive Local Research

Network, especially Sandeep Pahal and Claire Norton; all community pharmacists involved

in the STOP-CKD study; Mona Koshkouei and Alison Perry at Lloyds pharmacy; Alan

Wong and Sabina Melander in the pharmacy production department at the Royal Free

Hospital as well as the patient and public involvement representatives, DMEC, TSC, funders

and sponsor of this study. Importantly, we would also like to acknowledge the support of the

patients, staff and GPs at the eleven recruiting practices;

Declaration

This paper presents independent research funded by the NIHR under the Research for Patient

Benefit programme (PB-PG-0010-21226). The views expressed in this publication are those

of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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Funding

The STOP-CKD study was funded by a project grant from the NIHR Research for Patient

Benefit programme (PB-PG-0110-21226), a personal Fellowship awarded to CJF from the

NIHR Fellowship scheme and the Birmingham and Black Country Comprehensive Local

Research Network strategic fund. RJM holds an NIHR Professorship.

Sponsor

The STOP-CKD study was sponsored by the University of Birmingham (Dr Sean Jennings,

Research Governance and Ethics Manager, Research Support Group, University of

Birmingham, Edgbaston, Birmingham, B15 2TT, UK). The University of Birmingham holds

public liability (negligent harms) and clinical trial (negligent harm) insurance policies, which

apply to this trial.

Competing Interests

RJM has received BP monitors from Omron and Lloyds Pharmacies. NF has received

funding for research, consulting and travel from Sanofi Aventis, Novo Nordisk, Eli Lilly,

Ipsen, Roche and Intermune. The other authors declare that they have no relevant financial

interests.

Data Sharing Statement

Data sharing is not in place.

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38. Treweek S, Altman DG, Bower P, et al. Making randomised trials more efficient: report

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Legends of Figures

Figure 1: The CONSORT flow diagram of STOP-CKD study

* Some patients had multiple reasons of ineligibility

**multiple adverse reaction to anti-hypertensive in the past and previous endovascular aortic aneurysm repair which would

affect PWV measurements

Figure 2: Relative odds and 95% confidence interval of recruitment by age using restricted

cubic spline.

NB: Solid line = estimate, dotted lines = 95% CIs.

Supplementary File

Appendix 1: STOP-CKD study protocol

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Figure 1: The CONSORT flow diagram of STOP-CKD study 210x297mm (200 x 200 DPI)

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Figure 2: Relative odds and 95% confidence interval of recruitment by age using restricted cubic spline. 210x297mm (200 x 200 DPI)

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PROTOCOL FOR CTIMP

STOP-CKD

Spironolactone to Prevent Cardiovascular Events in

Early Stage Chronic Kidney Disease:

A Pilot Trial

Version 3.0

26th July 2012

Sponsor: University of Birmingham

Chief Investigator: Dr Charles Ferro

Study Co-ordination Centre: Primary Care Clinical Research and Trials

Unit (PC-CRTU)

EudraCT Number: 2012-000654-55

ISRCTN Number:

PC-CRTU Number: CVD-001

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STOP-CKD Protocol Version 3.0- 26th July 2012

Page 2 of 70

Sponsor

University of Birmingham

Edgbaston

Birmingham

B15 2TT

Chief Investigator

Dr Charles Ferro

Consultant Nephrologist and Senior Lecturer

Renal Unit

Queen Elizabeth Hospital Birmingham

Mindelsohn Way

Birmingham

B15 2WB

Tel: +44 (0) 121 3715839

Fax: +44 (0) 121 3715858

E-mail: [email protected]

Co-Investigators

Prof Richard McManus

Professor of Primary Care Cardiovascular Research

Department of Primary Care Health

Sciences

University of Oxford

2nd Floor

23-38 Hythe Bridge Street

Oxford

OX1 2ET

Tel: + 44 (0)1865 617834

Fax: + 44 (0)1865 289287

Email: [email protected]

Dr Paramjit Gill

Reader in Primary Care Research

Primary Care Clinical Sciences Tel: + 44 (0)121 414 3758

School of Health and Population Sciences

College of Medical and Dental Sciences

University of Birmingham Email: [email protected]

Edgbaston, Birmingham

B15 2TT

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Page 3 of 70

Dr John Townend

Consultant Cardiologist and Senior Lecturer

Cardiology Department

Queen Elizabeth Hospital

Birmingham

Mindelsohn Way

Birmingham

B15 2WB

Tel: + 44 (0) 121 6978476


Dr Sheila Greenfield

Senior Lecturer in Medical Sociology

Primary Care Clinical Science


Edgbaston

Birmingham

B15 2TT

Tel: + 44 (0) 121 414 6493


Dr Poorva Jain

Renal Medicine Research Fellow/Registrar in Nephrology

Primary Care Clinical Science


Edgbaston

Birmingham

B15 2TT

Tel: + 44 (0) 121 414 5643


Research Fellow

For general queries, supply of trial documentation and collection of data, please contact:

Dr Khai Ping Ng

Renal Medicine Research Fellow

Queen Elizabeth Hospital Birmingham

Edgbaston

Mindelsohn Way

Birmingham

B15 2WB

Tel: + 44 (0) 800 9230329

Fax: + 44 (0) 121 414 8616

E-mail: [email protected]

Research Nurse

Gurdip Heer

Primary Care Research Nurse Tel: +44 (0) 121 4146046 Primary Care Clinical Science


Edgbaston Emails: [email protected]

Birmingham

B15 2TT

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Page 4 of 70

Study Administrator/Coordinator

Details to be confirmed

Statistician

Prof Nick Freemantle

Professor of Clinical Epidemiology & Biostatistics

Primary Care Clinical Sciences

University College London

Gower Street

London

WC1E 6BT

Tel: +44 (0)20 7794 0500 ex34756

Fax: +44 (0) 20 7794 1224

Email:

[email protected]

Coordinating Centre Primary Care Clinical Research and Trials Unit (PC-CRTU)

University of Birmingham, UK

Funding

National Institute for Health Research

Grant ID.: PB-PG-0110-21226

This protocol describes the STOP CKD study and provides information about procedures for entering participants: it should

not be used as a guide for the treatment of other participants. Every care has been taken in the drafting of this protocol, but

corrections or amendments may be necessary. These will be circulated to investigators in the study, but centres entering

participants for the first time are advised to contact the trials centre to confirm they have the most recent version. Problems

relating to this trial should be referred, in the first instance, to the Study Co-ordinator.

This study will adhere to Good Clinical Practice and will be conducted in compliance with this protocol, the Data Protection

Act, and other regulatory requirements, as appropriate.

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Table of Contents

1 TRIAL SUMMARY ........................................................................................................ 8

1.1 Title .................................................................................................................................... 8

1.2 Aims .................................................................................................................................. 8

1.3 Outcome Measures .......................................................................................................... 8

1.4 Population ........................................................................................................................ 9

1.5 Number Of Sites .............................................................................................................. 9

1.6 Eligibility .......................................................................................................................... 9

1.7 Treatment .......................................................................................................................... 9

1.8 Duration ............................................................................................................................ 9

1.9 Reference Diagram ........................................................................................................ 10

2 INTRODUCTION ........................................................................................................ 11

2.1 Background .................................................................................................................... 11

2.2 Rationale For Current Trial .......................................................................................... 13

3 TRIAL OBJECTIVES ................................................................................................... 14

4 TRIAL DESIGN ............................................................................................................ 14

4.1 Plan Of Investigation .................................................................................................... 14

4.2 Trial Outcome Measures .............................................................................................. 17

4.3 Study Timetable ............................................................................................................. 18

5 PARTICIPANT ENTRY .............................................................................................. 19

5.1 Pre-Randomisation Evaluations .................................................................................. 19

5.2 Sample Size ..................................................................................................................... 19

5.3 Inclusion Criteria ........................................................................................................... 19

5.4 Exclusion Criteria .......................................................................................................... 19

5.5 Withdrawal Criteria ...................................................................................................... 20

6 STUDY PROCEDURES ............................................................................................... 22

7 RANDOMISATION AND ENROLMENT PROCEDURE ................................... 25

7.1 Randomisation Or Registration Practicalities ........................................................... 25

7.2 Unblinding ..................................................................................................................... 25

8 TREATMENTS ............................................................................................................. 26

8.1 Treatment Arms ............................................................................................................. 26

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8.2 Dose Modifications For Toxicity ................................................................................. 26

8.3 Pre-Medication ............................................................................................................... 28

8.4 Interaction With Other Drugs ...................................................................................... 28

8.5 Dispensing And Accountability .................................................................................. 30

9 TRIAL MANAGEMENT ............................................................................................. 31

9.1 Roles And Responsibilities ........................................................................................... 31

9.2 Trial Steering Committee ............................................................................................. 31

9.3 Data Monitoring Committee ........................................................................................ 31

10 PHARMACOVIGILANCE ......................................................................................... 32

10.1 Definitions ...................................................................................................................... 32

10.2 Causality ......................................................................................................................... 33

10.3 Reporting Procedures ................................................................................................... 33

11 ASSESSMENT AND FOLLOW-UP .......................................................................... 35

11.1 Loss To Follow-Up ........................................................................................................ 35

11.2 Trial Closure ................................................................................................................... 35

12 STATISTICS AND DATA ANALYSIS.................................................................... 36

12.1 Statistical Plan ................................................................................................................ 36

12.2 Analysis Plan .................................................................................................................. 36

12.3 Data Handling, Record Keeping And Retention ...................................................... 36

12.4 Data Access and Quality Assurance ........................................................................... 36

12.5 Case Report Forms ........................................................................................................ 41

13 MONITORING ............................................................................................................. 42

13.1 Risk Assessment ............................................................................................................ 42

13.2 Monitoring At Study Co-ordination Centre .............................................................. 42

13.3 Monitoring At Local Site .............................................................................................. 43

14 REGULATORY ISSUES .............................................................................................. 44

14.1 Clinical Trial Authorisation (CTA) ............................................................................. 44

14.2 Ethics Approval ............................................................................................................. 44

14.3 Patient Consent .............................................................................................................. 44

14.4 Confidentiality ............................................................................................................... 45

14.5 Indemnity ....................................................................................................................... 45

14.6 Sponsor ........................................................................................................................... 45

14.7 Funding ........................................................................................................................... 45

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14.8 Audits .............................................................................................................................. 45

15 FINANCIAL ARRANGEMENTS .............................................................................. 46

15.1 Participant Payments .................................................................................................... 46

15.2 GP Payments .................................................................................................................. 46

16 PUBLICATION ............................................................................................................. 47

17 REFERENCES ................................................................................................................ 48

18 PROTOCOL AMENDMENTS ................................................................................... 52

Appendix A: STOP- CKD Hyperkalaemia Management Protocol

Appendix B: Patient Information Sheet

Appendix C: Consent Form

Appendix D: Low Potassium Diet Information Sheet

Appendix E: EQ5D-5L Form

Appendix F: Side Effect Questionnaire

Appendix G: Spironolactone medicine information

Appendix H: Role and responsibility

Appendix I: Trial Personnel Contact Sheet

Appendix J: Pharmacovigilance Flowchart

Appendix K: Serious Adverse Event Reporting Form

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1 TRIAL SUMMARY

1.1 Acronym

STOP- CKD

Title Spironolactone to Prevent Cardiovascular Events in Early Stage Chronic

Kidney Disease (CKD): A Pilot Trial

1.2 Aims Spironolactone, a mineralocorticoid receptor blocker (MRB) has been shown

in double-blind, prospective, placebo-controlled trial in the secondary care

setting to be associated with improved arterial stiffness and left ventricular

mass and function. This suggests that spironolactone may reduce

cardiovascular events in people with CKD. However, prior to a larger trial,

further feasibility work is required to test procedures and outcomes in a

primary care setting. This pilot study aims to examine:

Patient and professionals’ attitudes to spironolactone in CKD in a community

setting and potential barriers exist to its use.

The recruitment rate to the trial.

The effect of spironolactone on arterial stiffness measured, by pulse wave

velocity and pulse wave analysis, in primary care.

The rate of spironolactone related hyperkalaemia and renal dysfunction in

primary care and if it is affected by the method of analysis.

1.3 Outcome Measures

Primary end-point:

Change in carotid-femoral pulse wave velocity between baseline and 40

weeks

Secondary end-points:

Incidence of hyperkalaemia

Change in blood pressure

Change in estimated Glomerular Filtration Rate (eGFR)

Incidence of hypotension (<100mmHg or >20mmHg systolic drop on

standing)

Incidence of side-effects

Incidence of other adverse events or adverse reaction defined by the

Medicines and Healthcare products Regulatory Agency (MHRA)

Health status as measured by EQ5D

Change in urinary albumin to creatinine ratio (ACR)

Change of pulse wave analysis

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1.4 Population

Patients registered in participating primary care practices within South

Birmingham will be screened with a view to recruit 240 eligible patients with

CKD stage 3 to this randomised controlled pilot study.

1.5 Number of Sites

Up to ten primary care practices within the South Birmingham will be

involved in STOP-CKD trial.

1.6 Eligibility

Inclusion Criteria:

Age over 18 years

Diagnosis of CKD stage 3

Exclusion Criteria:

Diabetes Mellitus

Terminal disease or felt otherwise unsuitable by their general practitioner

(GP)

Chronic heart failure i.e. a clinical diagnosis or known ejection fraction (EF)

<55%

Atrial fibrillation




Documented Addisonian crisis and/or on fludrocortisone

Severe hypertension: blood pressure ≥ 180/110 mmHg

Systolic blood pressure < 120mmHg

Recent acute kidney injury or hospital admission (within past 6 weeks)

Chronic diarrhoea

ACR ≥ 70mg/mmol (will require specialist referral if not already made)

Serum potassium ≥ 5 mmol/L on screening blood test

Concomittant co-trimoxazole medication

Concomittant angiotensin-converting enzyme inhibitor AND angiotensin II

receptor blocker medication

Pregnancy

1.7 Treatment

240 patients will be recruited into the study and randomised between placebo

and spironolactone 25mg daily.

1.8 Duration

All recruited patients will be receiving either placebo or spironolactone for 40

weeks. Patients will be followed-up during the duration of treatment and 6

weeks after discontinuation of trial medication (wash-out period). The total

trial duration is 46 weeks.

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1.9 Reference Diagram

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2 INTRODUCTION

2.1 Background Chronic Kidney disease (CKD) is a common but poorly recognised risk factor

for cardiovascular disease in the community. CKD is defined and categorised

in terms of estimated glomerular filtration rate (eGFR) and affects more than

10% of the population. In primary care, the largest group (>50%) is CKD stage

3 defined as eGFR 30 to 59 ml/min/1.73m2 [1-4]. This issue is magnified in

patients aged 65 or over where up to 35% of these patients will have eGFR of

less than 60 ml/min/1.73m2. CKD prevalence appears to be increasing with a

rise from 10 to 13.1% over the last decade in the US [2].

Only 1.3% of patients with CKD stage 3 are likely to require renal

replacement therapy after five years but they are far more likely to suffer

from a range of adverse cardiovascular events such as stroke or heart failure

[5-9]. The risk of cardiovascular disease is between 2 and 4 times that of

control populations and even greater in young patients [10-13]. The presence

of proteinuria increases this risk a further two- to four-fold [14, 15].

Cardiovascular disease in CKD differs from that of the general population.

Traditional risk factors such as cholesterol and blood pressure are poorly

predictive of risk while markers of inflammation, anaemia,

hypoalbuminaemia and bone mineral disorder are much more important

than in the general population [16, 17]. Although CKD patients have more

atherosclerotic disease, two further phenotypes exist:

• Left ventricular hypertrophy accompanied by systolic and diastolic

dysfunction;

• Arterial wall thickening, stiffening and calcification (arteriosclerosis).

We and others have shown that these abnormalities are present in patients

with early (stage 2 and 3) CKD [18, 19] despite good blood pressure control

[20]. The importance of increased arterial stiffness in CKD is evidenced by the

strong independent association of this parameter with mortality in patients

with CKD [21, 22].

Despite the CV risk, there is a paucity of information on how to treat patients

with early CKD as most large studies exclude these patients [23]. The only

useful evidence is from post hoc or subgroup analysis of patients with CKD

often not known to have this at inclusion [24-28].

The Renin-Angiotensin-Aldosterone System (RAAS) is an attractive target for

intervention and inhibitors of this system have been used effectively to

reduce hypertension and proteinuria in CKD patients [29-31]. In addition,

retrospective analyses of the HOPE (Ramipril in high cardiovascular risk

patients) and PROGRESS (perindopril protection against recurrent stroke

study) suggested that angiotensin converting enzyme (ACE) inhibitors may

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be even more effective in reducing cardiovascular risk in patients with

evidence of CKD than in individuals with normal renal function [18, 27].

However prolonged use of ACE inhibitors and angiotensin receptor blockers

(ARB) can lead to aldosterone ‘escape’ and their efficacy in non-proteinuric

CKD is less certain [29].

Aldosterone is a mineralocorticoid that is a key effector of the RAAS. In vitro,

it is implicated in numerous cardiovascular effects including endothelial

dysfunction, transmural arterial inflammation, myocardial and vascular

hypertrophy and fibrosis independent of blood pressure control [32-35]. In

humans high aldosterone levels have been associated with higher left

ventricular mass, increased arterial stiffness, reduced exercise capacity and a

more rapid decline in renal function. Treatment with MRBs conferred a

powerful prognostic benefit in heart failure in the RALES and EPHESUS

studies [36, 37] and was confirmed in a meta-analysis [38]. In CKD patients

they are associated with significant decreases in proteinuria [39, 40].

We have been investigating the problem of high cardiovascular morbidity

and mortality in CKD for the last four years. We have recently completed and

published a double blind, randomised placebo controlled study showing that

the addition of the MRB, spironolactone to background ACE or ARB therapy

in patients with stage 2 and 3 CKD in a specialist setting effectively and safely

reduced LV mass and improved parameters of LV systolic and diastolic

function measured by echocardiography and magnetic resonance imaging

[41]. Arterial stiffness, measured by pulse wave velocity, was also

significantly reduced.

A trial testing whether these changes in intermediate end points are

translated into gains in terms of reduced cardiovascular events is required

and would need to include many patients recruited from a primary care

setting where most CKD stage 3 patients are managed. However, our pilot

work suggests that many patients with CKD in primary care are not

prescribed ACE inhibitors, do not have controlled blood pressure, are almost

20 years older and have less well defined phenotypes than the patients

included in our hospital based study. In addition, concerns on spironolactone

resulting in hyperkalaemia and worsened renal function amongst the

primary and secondary healthcare professionals have also limited the

widespread use of spironolactone, especially in the primary care setting. The

incidence of hyperkalaemia related to spironolactone was reported to be

between 2 to 17.5% [36, 37, 42-44]. This diverse variation is likely to be due to

the difference of the age, prevalence of diabetes mellitus, and use of beta-

blocker in the studied population. Similarly, the long-term effect of

spironolactone on renal function is uncertain, especially in the chronic kidney

disease population. Therefore, before undertaking a large and expensive,

appropriately powered clinical trial, further feasibility and safety work is

required in primary care.

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2.2 Rationale for Current Trial

The aim is to carry out preliminary development work for, and to test the

feasibility of, a randomised controlled trial (RCT). The ultimate purpose of

the RCT is to determine whether cardiovascular events might safely be

reduced with the use of spironolactone in addition to standard management

for chronic kidney disease (CKD) in a primary care setting.

The questions that need to be addressed are:

1) What are patient and primary care physician’s attitudes to spironolactone

in CKD in a community setting and what potential barriers exist to its use?

Spironolactone is currently uncommonly used in this population (pilot work

suggests that <5% are prescribed it) and given the potential number of

patients that would be eligible for treatment should the trial be successful it is

important that potential barriers to implementation of a large trial are

explored with both patients and physicians.

2) What is the recruitment rate to the trial?

In order to determine the likely cost and feasibility of a definitive trial, we

need to know how many patients per practice are likely to be recruited into

the trial over a given period of time.

3) Are similar effects in intermediate outcome (pulse wave velocity) as seen in

a secondary care population achievable with a more pragmatic design in

primary care?

This information will underpin the power calculation for a subsequent

substantive trial. Key differences in study design between a community

population and previous specialist setting are: Lack of run in period, the

concomitant medication prescribed, baseline blood pressure control and the

characterisation of patients’ phenotypes.

4) What rates of hyperkalaemia are seen with the use of spironolactone in a

primary care setting and are there differences in potassium measured either

in plasma and serum, sent by standard transport to the laboratory from

primary care versus samples centrifuged on site and rapid transport?

Spironolactone is well documented to cause hyperkalaemia and in primary

care this is complicated by the fact that spuriously high potassium levels may

occur due to delays in transport to the laboratory. Information regarding

hyperkalaemia in a community setting is an important feature in the design

of the larger trial.

In addition to addressing the above questions, a further aim of this project is

to pilot all the procedures that will be used in the proposed definitive trial.

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3 TRIAL OBJECTIVES

The primary objective is to determine the effect of spironolactone on arterial stiffness

in CKD Stage 3 population

The secondary objectives are to:

o Determine the safety of spironolactone in CKD stage 3 in primary care

setting, in regards to the incidence of hyperkalaemia and worsened renal

function.

o Examine whether the different methods of serum analysis affect the rate of

hyperkalaemia seen in primary care.

o Assess the effect of low dose spironolactone on blood pressure and

albuminuria in CKD 3.

o Examine patients’ and healthcare professionals’ attitudes towards CKD as

well as research in CKD in the community setting.

o Explore patients’ and healthcare professionals’ attitudes towards the use of

spironolactone in CKD in a community setting and the potential barriers

which may that might exist to its use.

4 TRIAL DESIGN

4.1 Plan of Investigation This is a randomised controlled trial aiming to examine the effect of

spironolactone on arterial stiffness outcome in patients with CKD stage 3 and

its safety in the community setting. This study is a double- blinded and

placebo- controlled trial involving 240 patients. The study period is 46 weeks.

The plan of investigation is as followed:

Up to ten primary care practices within South Birmingham will be

recruited to take part in this study.

Potential subjects within these practices will be identified by general

practitioners by searching computerised primary care clinical records

for patients with biochemical evidence of CKD stage 3 (eGFR 30-

59ml/min/1.73m2).

Invitation to participate in STOP-CKD together with Patient

information Sheet (PIS) will be sent out to potentially eligible patients.

Potentially eligible patients will be invited to attend research

‘screening clinic’ at their own practice where the trial will be further

explained verbally and written information supplied.

Written consent will be obtained for willing participants.

Clinical history, examination, blood pressure measurement and blood

and urine tests will be performed during the ‘screening clinic’.

Blood test on ‘screening clinic’ will confirm the diagnosis of CKD 3:

eGFR 30-59 ml/min/1.73m2 using the MDRD (Modification of Diet in

Renal Disease) equation. Urine test (urine ACR) will exclude patients

who have ACR > 70mg/mmol.

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Willing and eligible patients will then be invited back no more than

two weeks after their initial visit (screening clinic) to attend for

randomisation clinic (randomisation clinic).

During ‘randomisation visit’, informed consent will be sought again

before randomisation to commence on trial medication. They will be

given time and opportunity with the research clinician or research

nurse to discuss or ask the clinician or the research nurse questions

regarding their participation in the study. All questions or concerns

about the trial should be answered to the satisfaction of the patient. It

should be explained that they are free to refuse to take part and

informed about their right to withdraw from the trial at any time. If

the patient agrees to take part in the trial they should be asked to sign

and date the approved Informed Consent Form, which should also be

signed and dated by the Investigator. A copy of the Informed Consent

Form should be given to the patient, a copy filed in the hospital notes

and a copy filed in the Investigator Site File.

Patients who agree to be enrolled into the study will have their pulse

wave velocity (PWV), pulse wave analysis (PWA) and blood pressure

measured. Patients will complete the EQ5D (quality of life survey)

and medication monitoring questionnaires. They will be randomised

between inactive placebo and spironolactone 25 mg daily for 40

weeks.

Frequent checks of electrolytes, BP measurement and drug monitoring

questionnaire will be undertaken at 2, 4, 8, 16 and 28 weeks after the

randomisation visit. (See section 6. Study Procedure for details).

Patients with persistently elevated BP > 150/90 mmHg will be referred

to their corresponding general practitioner for blood pressure

management as per NICE guidelines.

Subjects with hyperkalaemia or renal function deterioration on the

follow-up blood tests during the study period will be managed

according to ‘STOP-CKD hyperkalaemia and renal dysfunction

management protocol’ (see Appendix A).

Subjects with an increment of serum creatinine ≥ 30% or reduction of

eGFR ≥ 25% from baseline (screening visit eGFR) will be withdrawn

from the trial medication.

Subject with >20 mmHg systolic postural drop in blood pressure

during the trial and/or the systolic blood pressure drops to below 100

mmHg will be withdrawn from the trial medication.

All subjects will have repeat blood and urine test as well as blood

pressure, PWV, PWA measurements performed at 40 weeks after the

randomisation visit. They will also complete the EQ5D and drug

monitoring questionnaires at 40 weeks.

All subjects will stop trial medication at 40 week after the

randomisation visit.

There will be a wash-out period of trial medication for 6 weeks. All

subjects will have repeat blood and urine tests as well as blood

pressure, PWV and PWA measurements performed again at 46 weeks.

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Other aspects of this study:

Quality Control of Laboratory tests

o We will audit time from blood sampling to analysis of sample

in the biochemistry laboratory in the Queen Elizabeth Hospital

Birmingham.

o Up to 100 patients enrolled in this trial will have laboratory

tests sent both in standard fashion utilising routine transport

of samples as well as being centrifuged on site (recruited GP

surgeries) and transport them rapidly to laboratory. We aim to

compare the serum potassium results processed via these two

methods.

Qualitative analysis to address development and feasibility issues

The pilot RCT will answer research questions 2-4 and additional

qualitative work will focus on research questions:

1. What are patients’ and general practitioners’ attitudes to CKD?

2. What are patients’ and general practitioners’ attitudes to research in

CKD in a community setting and what potential barriers exist for

participation?

3. What are general practitioners’ and patients’ attitudes to

spironolactone in CKD in a community setting and what potential

barriers exist to its use?

General Practitioners (GPs) and patients who have been invited to

participate in the STOP-CKD randomised control trial will also be invited

to participate in the qualitative interview study. GPs and patients will

receive information sheet on the interview study. Informed, written

consent for interview study will be obtained prior to their participation in

this qualitative research study.

This interview study aims to understand GPs’ and patients’ views on

CKD, research in CKD as well as the use of spironolactone in CKD in the

community setting. The outcome of this qualitative study will contribute

to how trial procedures might be modified for a future definitive trial and

improve our understanding of the factors which may limit the

prescription of spironolactone in the community settings.

A grounded theory approach will be used to guide sampling, data

collection and analysis. Purposive sampling will allow for maximum

variety of patient and GP characteristics. Up to 30 patients and 30 GPs

will be selected for interview. Patient sampling will ensure representation

of views from different ages, ethnicity, socio-economic status and gender.

We will aim to include both patients who withdraw from the trial after it

has started and patients who participate in the complete trial. GP

sampling will ensure representation of different ages of GP, practice

location and practice size. Interviewing will continue till data saturation

has been achieved.

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Data sampling technique includes one to one interview as well as focus

group. The interviews will be confidential and face to face using a topic

prompt which will be refined over the course of the initial interviews.

They will be undertaken by research fellow (KN), supervised by SG. The

interviews will be carried out in a place convenient to the interviewees

(home or GP surgery).

All interviews will be audio-taped and transcribed verbatim.

Transcriptions will be read and checked for accuracy by the researcher

and the text entered into a computerised database using the NVivo

qualitative software package. Interviewees will be sent a copy of their

interview summary, asked whether they agree with it and whether they

have any additional comments. Constant comparative analysis will be

used to interpret the data. Data collection and analysis will be iterative

with new data being used to confirm or challenge the emerging concept.

4.2 Trial Outcome Measures Primary end point

o Change in carotid-femoral pulse wave velocity between

baseline and 40 weeks

Secondary end-points

o Incidence of hyperkalaemia

o Change in blood pressure (systolic and diastolic)

o Change in eGFR

o Change in ACR

o Change in pulse wave analysis

o Tolerability of spironolactone

Incidence of hyperkalaemia with serum potassium

above 5.5mmol/L

Incidence of hyperkalaemia with serum potassium

above 6mmol/L

Incidence of increment of creatinine by more than 30%

or reduction of eGFR by more than 25% from baseline

Incidence of other side effects leading to withdrawal of

spironolactone

Incidence of other adverse reactions or events defined

by the Medicines and Healthcare products Regulatory

Agency (MHRA)

Health related quality of life as measured by EQ5D

Difference in serum potassium reading using two different methods

of transport and analysis

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Qualitative data outcome on patients’ and primary care physicians’

attitudes towards spironolactone in CKD in community setting and

the potential barriers exist to its use.

Qualitative data outcome on patients’ and primary care physicians’

attitudes to CKD and research in CKD in a community setting and the

potential barriers exist for participation.

4.3 Study Timetable

Trial Task Month: 1-3 4-6 7-9 10-12 13-15 16-18 19-21 22-24

Ethics, practice recruitment

Practice visits, training of staff and identify

eligible patients

Patient recruitment and randomisation, data

collection

Data entry and follow up

Data cleaning and verification and analysis

Final write-up

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5 PARTICIPANT ENTRY

5.1 Pre-Randomisation Evaluations Potential subjects will be identified by searching computerised primary care

clinical records for patients with biochemical evidence of CKD stage 3 (eGFR

30-59 ml/min/1.73m2). Potentially eligible patients will receive invitation to

participate in STOP-CKD study and patient information sheet. They will be

invited to attend a baseline clinic at their own practice where the trial will be

explained verbally and written information supplied. Written consent will be

obtained prior to enrolment into the study.

5.2 Sample Size

We aim to recruit 240 patients to account for a drop-out rate of 20%, which

will result in at least 200 patients completing this randomised control trial

with 100 patients in each arm (inactive placebo versus spironolactone).

Power calculation: The primary end point on which sample size and power has been

calculated is pulse wave velocity (PWV). Using the data from our recent study of the

effect of spironolactone, the standard deviation (SD) of the change in PWV was

1.0m/s in the active treatment group and 0.9m/s in the control group. Hence, 100

subjects in each arm will provide 90% power with an alpha value of 0.05 to

demonstrate a change in PWV of 0.5m/s.

5.3 Inclusion Criteria Age over 18 years

Diagnosis of CKD Stage 3 (eGFR 30-59 ml/min/1.73m2) using the MDRD

(Modification of Diet in Renal Disease) equation.

5.4 Exclusion Criteria Diabetes Mellitus

Terminal disease or felt otherwise unsuitable by their general practitioner

(GP)

Chronic heart failure i.e. a clinical diagnosis or known ejection fraction (EF)

<55%

Atrial fibrillation




Documented Addison’s disease and/or on fludrocortisone

Severe hypertension: blood pressure ≥ 180/110 mmHg

Systolic blood pressure less than 120mmHg

Recent acute kidney injury or hospital admission (within past 6 weeks)

Chronic diarrhoea

Pregnancy

ACR>70 mg/mmol (will require specialist referral if not already made)

Serum potassium ≥ 5 mmol/L on screening blood test

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Concomitant angiotensin-converting enzyme inhibitor AND angiotensin II

receptor blocker medication

5.5 Withdrawal Criteria

Subjects will be withdrawn from the trial if they choose not to continue or if

their GPs feel that continued participation in the trial is inappropriate or if they

are no longer eligible due to:

a. Hypotension:

If there is >20 mmHg systolic postural drop in blood pressure during the trial

and/or the systolic blood pressure drops to below 100 mmHg then the trial

medication will be discontinued.

b. Hyperkalaemia: (see also Appendix A: STOP-CKD hyperkalaemia

management protocol)

If the potassium is between 5.5-6.0 mmol/L, patient will have urgent repeat

sampling at the GP surgery. If repeat potassium is below 5.5 mmol/L, patient

will continue with the trial medication. If the repeat potassium is in fact

between 5.5- 6.0 mmol/L, the trial medication will be reduced to alternate

days and patient will receive low potassium diet advice (see appendix D).

Repeat blood test will be performed after one week.

If the potassium is at or above 6.0 mmol/L, urgent repeat sampling will be

performed at QEHB. If the repeat potassium is in fact at or above 6.0 mmol/L,

the trial medication will be discontinued immediately.

c. Deterioration of renal function: (see also Appendix A: STOP-CKD

hyperkalaemia management protocol)

If plasma creatinine increase is ≥ 30% or eGFR decrease is ≥25% from the

baseline at any time point, the trial medication will be discontinued and the

GP will be advised to refer the patient to specialist care.

d. Serum sodium < 130 mEq/L on 2 occasions:

To withdraw trial medication.

e. Gynaecomastia, impotence, diminished libido in male or hirsutism,

oligomenorrhoea, amenorrhoea, menorrhagia, breast tenderness in female:

To withdraw trial medication if patient is intolerant of the side effect/effects.

f. Headache or Lethargy:

To withdraw trial medication if symptom persists for >1 week.

g. Confusion, ataxia or drowsiness:


h. Rash, Lichen planus or lupus-like syndrome:

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Page 21 of 70

To withdraw trial medication immediately.

i. General abdominal discomfort:

To withdraw trial medication if persistent discomfort for > 1 week.

j. Diarrhoea or vomiting:

To withdraw trial medication if symptoms persist for > 3 days.

k. Gastric/ duodenal ulcer or bleeding:


l. Agranulocytosis:

To withdraw trial medication

m. Hepatitis:


n. Benign adenoma or thyroid, testes, malignant breast tumours,

hepatocellular carcinoma or leukemia:


Full details of the reason(s) for withdrawal should be recorded on the Case Report

Forms (CRFs) if healthcare professionals-initiated, otherwise a simple statement

reflecting patient preference will suffice. Patients who withdraw from trial treatment

but continue with on-going follow-up and data collection should be followed-up in

accordance with the protocol.

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6 STUDY PROCEDURES The schedule of assessments and investigations required is described below and

summarised in Figure 1. This information should be recorded in the patient notes

where not explicitly required in the Case Report Forms.

Screening Visit

o Valid Informed Consent gained.

o Full demographic details including age, self-assigned race and postcode.

o Relevant medical history taken.

o Concomitant medication (description of other medication prescribed for more

than 7 days and taken within one month of randomisation).

o Screening blood tests: full blood count; urea + creatinine + electrolytes; liver

function tests, bone profile, random serum glucose, pro-

thrombotic/fibrotic/inflammatory markers.

o Urinalysis using albumin: creatinine ratio (ACR).

Refer to patients’ General Practitioner (GP) if:

BP ≥ 180/11mmHg

ACR ≥ 70 mg/mmol: to refer to GP to consider referral to nephrology

specialist if patients have not been reviewed by nephrologist in the past 5

years since the diagnosis.

ACR= 30-69 mg/mmol and BP ≥ 140/90 mmHg and NOT on either

angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor

blocker (ARB): to refer to GP to consider for ACEI/ARB. Patients will be re-

invited to participate in STOP-CKD study after they have been on ACEI/ARB

for at least 6 weeks.

ACR= 30-69 mg/mmol with haematuria: to refer to GP for review.

Eligible and willing patients will be invited back to Randomisation Visit within 2

weeks after Screening Visit.

Randomisation Visit (Week 0)

o Valid Informed Consent gained for randomisation.

o Relevant medical history taken.

o Medication Monitoring Questionnaire. (see appendix F)

o Quality of Life Questionnaire (EQ5D-5L). (see appendix E)

o Weight, height and waist/hip ratio measurements.

o Office blood pressure measurement using a validated automated device after 5

minutes rest plus after one minute of standing.

o Pulse wave velocity and pulse wave analysis measured using Vicorder Device

with added cardiovascular software. This device is simple to use in a primary

care setting and has recently been assessed and validated against the most

commonly used applanation tonometry device.

o Patients will then be randomised to treatment with spironolactone 25mg once

daily or inactive placebo. (please refer to Section 7: Randomisation for details)

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Week 2, 4, 8, 16, 28 after Randomisation visit

o Medication Monitoring Questionnaire.

o Record of compliance to trial medication.

o Office blood pressure measurement using a validated automated device.

o Patients with persistently elevated BP > 150/90 mmHg at both week 2 and week

4 will be referred to their corresponding general practitioner for blood pressure

management as per NICE guidelines.

o Blood Sample – full blood count, renal, hepatic profile.

o Hyperkalaemia and deterioration of renal function will be managed according

to STOP-CKD hyperkalaemia and renal dysfunction management protocol

(Appendix A).

o If there is >20 mmHg systolic postural drop in blood pressure during the trial

and/or the systolic blood pressure drops to below 100 mmHg, the trial

medication will be discontinued.

Week 40 after Randomisation Clinic

o Medication Monitoring Questionnaire.

o Record Compliance to trial medication.

o Quality of Life Questionnaire: EQ5D-5L.



with added cardiovascular software.

o Blood Sample – full blood count, renal, hepatic and bone profile as well as pro-


o Urinalysis for urine ACR.

o Discontinue all trial medication.

o Patients should not have any change of antihypertensive medication between

week 40 and week 46.

Week 46 after Randomisation Clinic



with added cardiovascular software.

o Blood Sample – full blood count, renal, hepatic and bone profile as well as pro-


o Urinalysis for urine ACR.

o Trial closes.

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Page 24 of 70

Figure 1: Flowchart of Assessments

This table provides a summary of the trial-related procedures required; refer also to full text in section

4.2

Treatment and Follow-up

Visit: Screening Randomisation Week

2

Week

4

Week

8

Week

16

Week

28

Week

40

Week

46

Valid informed consent gained X X

Full demographic details X

Relevant medical history taken X X

Concomitant medications X

Weight, Height, Waist/Hip ratio

measurements X

Blood pressure measurement X X X X X X X X

Pulse Wave Velocity and pulse

wave analysis measurement X X X

Routine Blood sampling:

FBC, renal, hepatic, bone profile X X X X X X X X

Pro-

thrombotic/fibrotics/Inflammatory

Markers

X X X

Urine ACR X X X

EQ5D-5L Questionnaire X X

Medication Monitoring

Questionnaire X X X X X X X X

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7 RANDOMISATION AND ENROLMENT PROCEDURE

7.1 Randomisation or Registration Practicalities All investigators, practice staff and patients will be blinded to treatment.

Randomisation will be undertaken using the Primary Care Clinical Research

and Trials Unit (PC-CRTU, fully accredited by the NIHR as a trials unit)

secured web-based randomisation system. Randomisation assignment will be

computer generated and stratified by practice, patient’s blood pressure (on

target or not on target) and presence of albuminuria. Patients will then be

randomised to treatment with spironolactone 25 mg once daily or inactive

placebo.

7.2 Unblinding All investigators will be unblinded after the completion of 46 weeks follow-

up of all subjects and closure of the trial. The practice staff and all patients

involved in the study, including those who withdraw, will also be informed

of their trial medications (spironolactone or inactive placebo).

During the trial, codebreak should be avoided whenever possible. If

emergency unblinding is deemed to be appropriate, all STOP-CKD research

team members have access to break the randomisation code in emergency

situations. When assessing SAEs it should be assumed that the patient

received spironolactone (not inactive placebo). If the event is thought to be

related, unblinding will be performed by the coordinating centre.

To report serious adverse event/reaction

OR

To break the randomisation code for a patient:

STOP-CKD hotline on:

0 800 9230329

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8 TREATMENTS

8.1 Treatment Arms STOP -CKD is a double-blinded randomised controlled trial involving

two treatment arms:

Spironolactone 25mg orally, once daily.

Inactive placebo, orally, once daily.

During the trial, subjects may reduce the trial medication to once,

every two days according to STOP-CKD hyperkalaemia and renal

dysfunction management protocol.

The trial medication will be supplied by Royal Free Hospital and

funded via NIHR RfPB grant for this study. The trial medication will

be labelled and packaged by Royal Free Hospital prior to delivery to

the local Lloyd Pharmacy closest to the recruited general practice for

participant to collect.

8.2 Dose Modifications for Toxicity

Information on side effects of spironolactone is derived from British National

Formulary [45].

Common Terminology Criteria for Adverse Events (CTCAE) v4.0 is used to

classified frequency of undesirable effects of the medication.

Very common: ≥1/10

Common: ≥1/100; < 1/10

Uncommon: ≥ 1/1,000; < 1/100

Rare: ≥ 1/10,000; < 1/1,000

Very rare: < 1/10,000

Unknown: cannot be estimated from the available data

Metabolic Common Hyperkalaemia [46]

To be managed according to

STOP-CKD hyperkalaemia

and renal dysfunction

protocol (Appendix A)

Common Hyponatremia To withdraw trial medication

if serum Na+ <130 mEq/L on 2

occasions

Renal Very common/

common

Renal Dysfunction To be managed according to

STOP-CKD hyperkalaemia

and renal dysfunction

protocol (Appendix A)

Endocrine Very common/

common

Male: Gynaecomastia,

impotence, diminished


if patient is intolerant of the

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Page 27 of 70

libido.

Female: hirsutism,

oligomenorrhoea,

amenorrhoea, menorrhagia,

breast tenderness

side effect/effects.

Nervous system Common Headache To withdraw trial medication

if symptom persists for >1

week.

Unknown Confusion, ataxia,

drowsiness

Lethargy

To rule out electrolyte

disturbance leading to

symptoms. To withdraw trial

medication.


if symptom persists for > 1

week.

Dermatologic Common Rash To withdraw trial medication

Rare Lichen planus, lupus-like

syndrome


Hypersensitivity Uncommon Anaphylaxis, contact

dermatitis, eosinophilia


immediately

Gastrointestinal Common General abdominal

discomfort

Diarrhoea, vomiting


if persistent discomfort for > 1

weeks


if persistent diarrhoea or

vomiting for >3 days.

Very rare Gastric/ duodenal ulcer or

bleeding


Haematologic Rare Agranulocytosis


Hepatic Rare Hepatitis


Oncologic Unknown Animal studies suggested

association between

spironolactone with benign

adenoma of the thyroid and

testes, malignant breast

tumours, hepatocellular

carcinoma and leukemia.


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Page 28 of 70

8.3 Pre-Medication

Not required

8.4 Interaction with Other Drugs [45, 47, 48]

Angiotensin Converting Enzyme (ACE) inhibitors or Angiotensin II

Receptor Blocker (ARB): Concomitant administration of ACE

inhibitors and/o

r ARB with potassium-sparing diuretics is associated with increased

risk of hyperkalaemia. Serum K+ and renal function should be

monitored carefully and on regular basis.

Antihypertensives - potentiation of the effect of antihypertensive

drugs occurs and their dosage may need to be reduced when

spironolactone is added to the treatment regime, and then adjusted as

necessary.

Anti-diabetics: Administration with chlorpropamide may increase

risk of hyponatraemia.

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic

hypotension may occur.

Aspirin: May reduce the diuretic effect of spironolactone.

Ciclosporin: Co-administration of potassium-sparing diuretics with

ciclosporin may result in hyperkalaemia. Avoid concurrent use of

spironolactone and ciclosporin. If concurrent therapy is necessary,

monitor serum potassium levels for persistent elevations in patients.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly

hypokalemia, may occur.

Coumarins: In patients receiving oral anticoagulant therapy with

warfarin, the prothrombin time ratio or INR (international normalised

ratio) should be monitored with the addition and withdrawal of

treatment with spironolactone, and should be reassessed periodically

during concurrent therapy. Adjustments of the warfarin dose may be

necessary in order to maintain the desired level of anticoagulation.

Digoxin: Spironolactone has been shown to increase the half-life of

digoxin. This may result in increased serum digoxin levels and

subsequent digitalis toxicity. It may be necessary to reduce the

maintenance and digitalization doses when Spironolactone is

administered, and the patient should be carefully monitored to avoid

over or under-digitalization.

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Drug/Laboratory test interactions: Several reports of possible interference

with digoxin radioimmunoassay by Spironolactone, or its metabolites, have

appeared in the literature. Neither the extent nor the potential clinical

significance of its interference (which may be assay-specific) has been fully

established.

Diuretics: Spironolactone should not be administered concurrently

with other potassium- sparing diuretics as this may induce

hyperkalaemia. Potassium canrenoate, a metabolite of spironolactone,

has been shown to cause myeloid leukaemia in rats.

Lithium: Concurrent use of lithium and spironolactone may result in

increased lithium concentrations and lithium toxicity (weakness,

tremor, excessive thirst, and confusion) due to decreased lithium

excretion. If concomitant therapy is necessary monitor serum lithium

levels within the first five to seven days of adding or discontinuing

spironolactone and periodically thereafter. Lower lithium doses may

be required with concomitant spironolactone therapy.

Nonsteroidal anti-inflammatory drugs (NSAIDs): Combination of

NSAIDs, e.g., indomethacin, with potassium-sparing diuretics has

been associated with severe hyperkalemia and should be avoided in

CKD Stage 3 population.

Potassium salts: Potassium supplements are contraindicated except in

cases of initial potassium depletion. If potassium supplementation is

considered essential, serum electrolytes should be monitored.

Pregnancy: Teratogenic effects. Pregnancy Category C.

Sympathomimetics: Spironolactone reduces vascular responsiveness

to noradrenaline (norepinephrine); caution should be exercised in the

management of patients subjected to regional or general anaesthesia.

Tacrolimus: Spironolactone should not be used in patients

undergoing therapy with tacrolimus as concomitant use has resulted

in mild to severe hyperkalaemia.

Trimethoprim-sulfamethoxazole: Among older patients receiving

spironolactone, treatment with trimethoprim-sulfamethoxazole was

associated with a major increase in the risk of admission to hospital

for hyperkalaemia. This drug combination should be avoided when

possible [48].

Ulcer healing drugs: As carbenoxolone may cause sodium retention

and thus decrease the effectiveness of spironolactone, concurrent use

of the two agents should be avoided.

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Page 30 of 70

8.5 Dispensing and Accountability

As STOP-CKD is a double-blinded randomised controlled trial, FP10

prescriptions are therefore not suitable. Royal Free Hospital will manufacture

and package the drug and placebo. These trial packs will then be delivered to

local Lloyd pharmacy closest to the recruited general practice and dispensed

from there.

It is very important that accurate drug dispensing, schedule and compliance

data are recorded. The trial will therefore utilise the expertise of a named Lloyd

pharmacist to assist with completion of such records.

Accurate collection of this data will not only support toxicity and quality of life

evaluations being conducted as part of the study but may be pivotal to the

overall success of this trial. Any problems relating to pharmacy issues should

be addressed to the Study Pharmacy Advisor.

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Page 31 of 70

9 TRIAL MANAGEMENT

STOP-CKD will be coordinated by the Primary Care Clinical Research and Trials Unit

(PC-CRTU, fully accredited by NIHR as a trials unit) at the University of Birmingham

according to the current guidelines for Good Clinical Practice. Conduction of the study

may be monitored by research team to confirm compliance with the protocol and the

protection of patients’ rights as detailed in the Declaration of Helsinki.

9.1 Roles and Responsibilities

The CI takes overall responsibility for the conduct of study. Any delegated or

devolved responsibility will be documented on the delegation log. It is the CI’s

responsibility to ensure that staffs are appropriately trained to perform the tasks

that they are delegated to and that it is appropriately documented on the

delegation log. (See Appendix H for the roles and responsibilities of trial staff).

9.2 Trial Steering Committee

A Trial Steering Committee (TSC) will be appointed and will provide the

overall supervision for the trial, in particular: trial progress, protocol

compliance, patient safety and review of updated information.

The TSC will include the Trial Management Group (namely the CI, co-

investigators, study manager, and statistician), two lay representatives (Paul

Cornick and Nick Flint) and Dr Robert Cramb, Consultant Biochemist who

provide expertise in the collection and analysis of laboratory samples and an

independent Consultant Nephrologist. The TSC will meet 3-6 monthly

depending on the phase of the study. An investigators group will meet

monthly to provide oversight of the developing trial with more frequent

operational meeting of the CI, trial manager and trial team as required.

9.3 Data Monitoring Committee

An independent Data Monitoring Committee for the trial will be responsible

for the regular monitoring of trial data. The committee will consist of a clinician

not entering patients into the trial, an academic general practitioner and an

independent statistician who will also chair the committee.

The DMC will assess the progress of the trial and give advice on whether the

accumulated data from the trial, together with the results from other relevant

trials, justifies the continuing recruitment of further patients. The committee

will meet in person or by teleconference prior to the trial commencing and then

three and six months after initiation of trial. The DMC will make confidential

recommendations to the TSC as the decision-making Committee for the trial.

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10 PHARMACOVIGILANCE

10.1 Definitions

Adverse Event (AE): any untoward medical occurrence in a patient or clinical

trial subject administered a medical product, and which does not necessarily

have a causal relationship with the treatment. An AE can therefore be any

unfavourable and unintended sign (including an abnormal laboratory finding),

symptom or disease temporarily associated with use of an investigational medicinal

product (IMP), whether or not considered related to the IMP.

Adverse Reaction (AR): all untoward and unintended responses to an IMP,

related to any dose administered. All AEs judged by the reporting investigator or

sponsor as having a reasonable causal relationship to an IMP qualify as adverse

reactions. The expression ‘reasonable causal relationship’ means to convey in general

that there is evidence or argument to suggest a causal relationship.

Unexpected Adverse Reaction: an AR, the nature or severity of which is not

consistent with the applicable product information (eg. Investigator’s Brochure

for an unapproved investigational product, or a Summary of Product

Characteristics (SmPC) for an authorised product). When the outcome of the

adverse reaction is not consistent with the applicable product information, this adverse

reaction should be considered as unexpected. Side effects documented in the SmPC

which occur in a more severe form than anticipated are also considered to be

unexpected.

Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR): any

untoward medical occurrence or effect that at any dose:

• Results in death

• Is life-threatening – an event in which the subject was at risk of death at the time of

event, not an event that hypothetically might have caused death if it were more severe

• Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation

• Results in persistent or significant disability or incapacity

• Is a congenital anomaly or birth defect

Medical judgement should be exercised in deciding whether an AE/AR is serious in

other situations. Important AE/ARs that are not immediately life-threatening or do

not result in death or hospitalisation but may jeopardise the subject or require

intervention to prevent one of the other outcomes listed above, should also be

considered serious.

Suspected Unexpected Serious Adverse Reaction (SUSAR): any suspected

adverse reaction related to an IMP that is both unexpected and serious.

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Page 33 of 70

10.2 Causality

Most AE/ARs that occur in this trial, whether they are serious or not, will be

expected treatment-related toxicities due to the drugs used in this trial. The

assignment of the causality should be made by the Investigator responsible for

the care of the participant using the definitions in the table below.

If any doubt about the causality exists, the Local Investigator should inform the

Study Co-ordination Centre, who will notify the Chief Investigator. The

pharmaceutical companies and/or other clinicians may be asked to advice in

some cases.

In the case of discrepant views on causality between the Investigator and

others, all parties will discuss the case. In the event that no agreement is made,

the MHRA will be informed of both points of view.

Relationship Description

Unrelated There is no evidence of any causal relationship.

Unlikely

There is little evidence to suggest a causal relationship (eg. the event did not

occur within a reasonable time after administration of the trial medication).

However, the influence of other factors may have contributed to the event (eg.

the participant’s clinical condition, other concomitant treatments).

Possible

There is some evidence to suggest a causal relationship (eg. because the event

occurs within a reasonable time after administration of the trial medication).

However, the influence of other factors may have contributed to the event (eg.

the participant’s clinical condition, other concomitant treatments).

Probable There is evidence to suggest a causal relationship and the influence of other

factors is unlikely.

Definitely There is clear evidence to suggest a causal relationship and other possible

contributing factors can be ruled out.

Not assessable There is insufficient or incomplete evidence to make a clinical judgement of the

causal relationship.

10.3 Reporting Procedures

All AEs should be reported. Depending on the nature of the event, the

reporting procedures below should be followed. Any questions concerning AE

reporting should be directed to the Chief Investigator, in the first instance. A

flowchart is provided (Appendix J) to aid in the reporting procedures.

10.3.1 Non-Serious AE/ARs

All such events, whether expected or not, should be recorded in the toxicity

section of the relevant Case Report Form and sent to the Study Co-ordination

Centre within one month of the form being due.

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10.3.2 SAEs and SARs

An SAE form (QCD 09-04) should be completed and faxed to the Study Co-

ordination Centre for all SAEs and SARs immediately. However,

hospitalisations for elective treatment of pre-existing condition do not need

reporting as SAEs.

Fatal or life-threatening SAEs and SARs should be reported on the day that the

local site is aware of the event, by means of the SAE form. Any additional

information relating to the event should be sent within 5 days if the reaction

has not resolved at the time of reporting.

10.3.3 SUSARs

Complete the SAE form and send it immediately (preferably by fax), signed

and dated to the Study Co-ordination Centre, together with relevant treatment

forms and anonymised copies of all relevant investigations.

OR

Contact the Study Co-ordination Centre by telephone and then send the

completed SAE form to the Study Co-ordination Centre immediately, as above.

The Study Co-ordination Centre will notify the MHRA and main REC of any

SUSARs occurring during the study (fatal and life-threatening SUSARs within

7 days of notification, and non-life-threatening within 15 days). All

investigators will be informed of all SUSARs occurring throughout the study.

Local investigators should report any SUSARs and/or SAEs/SARs as required

by their Local Research Ethics Committee and/or R&D Office.

Contact Details for Reporting SAEs/SARs and SUSARs

Fax 0121 414 3050, attention of Dr Charles Ferro

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11 ASSESSMENT AND FOLLOW-UP

Subjects will be receiving blinded treatment (inactive placebo or spironolactone) for 40

weeks and followed-up for 46 weeks after randomisation. (Please refer to Section 6:

Study Procedure for the details of each assessment)

11.1 Loss to Follow-Up We plan to recruit an extra 20 patients into each treatment arm in the hope that

this will allow for any participants that are lost to follow-up.

If participants miss week 2 or week 4 trial follow-up, we will inform the

practice, contact the patients and re-invite the participants to the next follow-up

clinic within a week.

If participants missed week 8, 16, 28, 40 or 46 trial follow-up, we will inform the

practice, contact the patients and re-invite the participants to the next follow-up

clinic within 2 weeks.

If participants fail to attend clinic on 2 occasions, we will aim to establish the

reason of failure to attend. If participants are deemed not suitable to continue

with the study or decide to withdraw from the study, we will withdraw

participants from the study and ensure participants return the rest of the

unused trial medications.

11.2 Trial Closure

For the purposes of Clinical Trial Authorisation (CTA) under the European

Union Directive 2001/20/EC, the study is deemed to have ended 30 days after

the last patient undergoes the final assessment at 46 weeks.

For the purposes of Multicentre Research Ethics Committee approval, the study

end date is deemed to be the date of last data capture.

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12 STATISTICS AND DATA ANALYSIS

12.1 Statistical Plan

The statistical plan has been developed through advice of Prof Nick

Freemantle. He will also supervise statistical analysis of this trial.

Power Calculation: The primary end point on which sample size and power

has been calculated is PWV. Using the data from our recent study of the effect

of spironolactone the SD of the change in PWV was 1.0 m/s in the active

treatment group and 0.9 m/s in the control group. Thus, 100 subjects per group

will provide 90% power at with an alpha value of 0.05 to demonstrate a change

in PWV of 0.5 m/s. We will recruit 240 patients to account for a drop-out rate of

20%.

12.2 Analysis Plan Difference in the primary outcome between experimental conditions will be

assessed using generalised mixed models. Repeated measures within a

subject will be characterised as R side residual overdispersion parameters,

accounting for baseline values. Frequency differences will be tested by

Fisher’s Exact test. A pre-specified multivariable analysis will examine the

influence of change in systolic BP and other relevant factors on changes in the

primary end point.

12.3 Data Handling, Record Keeping and Retention To enable monitoring, peer review and/or audits from Health Authorities, the

Investigator must agree to keep records, including the identity of all

participating subjects (sufficient information to link records e.g. CRFs and GP

notes), all original signed Informed Consent Forms, copies of all CRFs and

detailed records of drug disposition.

To comply with international regulations these records should be retained by

the Investigator for at least 5 years.

12.4 Data Access and Quality Assurance The STOP-CKD database system will be located within PC-CRTU.

The security of the System is governed by the following relevant policies of the

University of Birmingham:

• Data Protection Policy

• Conditions of Use of Computing and Network Facilities (version 2.01

17/12/07)

• Information Security Policy of the University of Birmingham (version 1.01

17/12/07)

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• Code of Practice on Access to Computing Facilities (version 1.0 15/12/08) –

restricted document

• BS7799 compliance

• ISO 27001/2 compliance

The University’s Data Protection Policy and the Conditions of Use of

Computing and Network Facilities set out the security arrangements under

which sensitive data should be processed and stored. The University has

designated Mrs Carolyn Pike (Director of Legal Services) to act as Data

Controller and as Data Protection Officer. Any queries should be directed to

the Information Compliance Manager Mrs D Jeynes on 0121 414 3196. The

University of Birmingham maintains an Information Security Policy which has

specifically been designed to be compliant with the ISO 27001/2 standards, and

references the existing Conditions of Use of Computing and Network Facilities

and New Codes of Practice encompassing use of computers, data use and

security. These policies have been approved by Council, the University’s

governing body, and have been implemented across the whole University. The

Study Centre has arrangements in place for the secure storage and processing

of the study data which comply with the above policies.

The System shall incorporate the following security countermeasures:

Physical security measures:

Access to the Study Centre is restricted to members of the department using a

swipe card system. Any repairs to the System will be carried out on-site and

under supervision. A burglar alarm is in operation at times when no members

of staff are present. Full backups take place daily and tapes/disks are stored in

a fire-proof safe.

Logical measures for access control and privilege management:

The System will only be accessible to persons authorised by the CI. Electronic

data are stored on access controlled servers. New requests for access to the

system, e.g. for newly appointed staff, have to be approved by the Trial

Manager. Patient identifiable data are stored separately from non-identifiable

data when they are no longer required for linkage or quality checking. All

members of the research team are trained in the appropriate use of confidential

information. The data received will be separately archived after personal data

has been deleted. The CI will have responsibility for access to the archived

material.

All staff members are required to sign an undertaking of confidentiality which

if broken would be likely to lead to dismissal.

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Network security measures:

The University of Birmingham maintains a ‘front door’ site firewall to protect

the network from external threats. Antivirus software is used on all servers

and desktops. The database application and server are hosted on a separate

secure network protected by a further hardware firewall. This network can

only be accessed via our Citrix Access Gateway SSL VPN appliances.

System Management

The System shall be developed by the PC-CRTU Programming Team.

The System shall be implemented and maintained by the PC-CRTU

Programming Team in conjunction with the IT Manager who is responsible for

the implementation of security configurations and the CI. In case of disposal or

replacement of the System any media that may contain patient identifiable data

will be securely wiped. Equipment will then be physically destroyed by a

University of Birmingham approved contractor. The System will have a three

year standard limited warranty with on-site service.

System Design

The System shall comprise of a database and a data entry application.

Data entry is via a Windows application hosted on a PC-CRTU database. The

database server is only accessible from within the university network and the

firewall is configured to allow access from specific machines only.

Administrative access is restricted to PC-CRTU but some read only access can

be enabled for study staff based at the Study Centre. SQL server allows us to

specify access at a table level to view, add, edit and delete. This acts as

additional security on top of that enforced by the application.

The application server is accessible over the internet via PC-CRTU database.

All traffic to and from the application is automatically encrypted using SSL

(128 bit). All users are required to log on to the system using a username and

strong password. The application and the database itself use role based

security controls. Users can only edit and view data that they have been given

access to (via their role).

Operational Processes

The patient identifiable/sensitive data will be collected from a combination of

sources including directly from participants (onto paper), from medical records

(onto paper or secure database). All identifiable data will be collected

following patient consent. Paper records will be kept securely in locked filing

cabinets within secure areas.

The data will be processed and stored within the Study Centre (University of

Birmingham), in accordance the Conditions of Use of Computing and Network

Facilities (version 2.01 Dec 2007), the Information Security Policy of the

University of Birmingham (version 1.01 dated 17th December 2007).

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Processing of all patient identifiable data received for this part of the study

takes place in the Study Centre. For back-up, encrypted copies of the data are

stored in a secure area of the departmental file server and are backed up tape

nightly. Access is limited to authorised study staff and the PC-CRTU IT

Manager.

Patient data are stored in secure SQL server database. Data entry is facilitated

by a secure application designed and developed by the PC-CRTU

programming team in conjunction with the Trial Manager.

We will allocate study identity numbers for the records of all patients enrolled

within this project. Patient identifiable data will be kept confidentially and can

be separated from the rest of the data.

Data processing

Statisticians will only have access to anonymised data.

Staffs handling of patient identifiable/sensitive data are trained by the CI, in

order to ensure that they comply with university policy. See Section 5.3.4 of

University of Birmingham Information Security Policy Document (version 1.01

17 December 2007): All employees are required to be made aware of the risk of

breaching confidentiality associated with the copying (including photocopying

or other duplication) of confidential or sensitive documents. Authorisation for

copying such documents should be obtained from the document owner where

documents are classified as highly confidential or above.

Disposal

When the System or its data has completed its purpose/has become redundant

or is no longer needed, the following methods will be adopted to dispose of

equipment, back-up media or other stored data:

Commercially available data shredder software will be used to electronically

shred the file and any external hard drives used for back-up. Any DVDs

containing data will be destroyed by physically shredding the DVD.

Any study paper data will be retained in a locked room/filing cabinet within

the study centre for a minimum of 15 years after the end of the study for

research governance purposes, or securely archived. All paper records will be

shredded or securely disposed of at this point.

System Audit

The System shall benefit from the following internal/external audit

arrangements:

Internal audit of the system can be carried out at any time by the PC-CRTU, an

expert central facility for co-ordinating community based studies. Day-to-day

monitoring and assurance of the security of the system is the responsibility of

the CI, Trial Manager and IT Team Leader.

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An annual IT risk assessment is conducted within Primary Care Clinical

Sciences. This is conducted by the departments IT manager. The aim of the

risk assessment is to ensure identification and evaluation of risks, and to

regularly reassess strategies to deal with any possible threats to the security of

the System. The scope of the audit includes, but is not limited to, assessing the

design and operation of controls to ensure:

• Necessary policies and procedures are in place

• Access control i.e. network and system security is appropriately

implemented, restricted and reviewed to safeguard unauthorised access to or

modification of programs and data

• Procedures are in place for secure disposal or destruction of storage media

when no longer required.

• Security of data

Data is retained in accordance with laws and university policies to enable

retrieval when needed.

System Protection

The System shall benefit from the following resilience/contingency/disaster

recovery arrangements:

The databases are all backed up incrementally hourly with a full backup once a

day. This allows us to do a ‘point in time restore’ if required. This means that

we can revert to a previous version of the database if needed. The daily

backup is encrypted and then copied to the university file server where it is

then backed up to tape. Tapes are retained for 20 weeks in a fire proof safe,

after which they are reused for subsequent backups. They are then physically

destroyed at the end of their useful life.

Both application and database servers also have a disk image taken regularly

meaning that if the hardware was to fail then we could restore the servers as

they were at that time very quickly.

In anticipation of hardware failures the servers use multiple hard disks in

RAID configuration meaning that if one was to fail then no data would be lost.

The servers also have dual power units and are protected from power failures

and surges by a UPS. The servers are under warranty with next business day

support for repairs.

In the event of serious disruption, total system failure, or major incident the

System can be restored using the files from the tapes.

In the event of a security or confidentiality breach both the University’s Legal

Services and the IT Security Manager (IT Services) will be informed so that it

can be investigated if appropriate.

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Please also refer to Conditions of Use of Computing and Network Facilities

(version 2.01 17/12/07) - Section 9.9 Access to Data:

Anyone who wilfully and knowingly acts to impede a security, disciplinary or

operational investigation commits a disciplinary offence. This includes the

removal or destruction of relevant data or hardware and the withholding of

passwords and encryption keys.

System Level Security Policy Ownership

This SLSP shall be the responsibility of CI, Chief Investigator and shall be

reviewed on an annual basis.

Data Protection Registration

The University of Birmingham has Data Protection Registration to cover the

purposes of analysis and for the classes of data requested. The University’s

Data Protection Registration number is Z6195856.

12.5 Case Report Forms (CRFs)

The CRFs must be completed and signed/dated by the Investigator or one of

their authorised staff members as soon as the required information is

available. The completed originals should be sent to the STOP-CKD Study

Office, with a copy held by the Investigator at site. In all cases it remains the

responsibility of the Investigator to ensure that they have been completed

correctly and that the data are accurate. Entries should be made in ballpoint

pen preferably in black ink and must be legible. Any errors should be crossed

out and with a single stroke, the correction inserted and the change initialled

and dated. If it is not clear why a change has been made, an explanation

should be written next to the change. Typing correction fluid should not be

used. Data reported on each CRF should be consistent with the source data or

the discrepancies should be explained. All sections are to be completed before

returning to the STOP-CKD Study Office. If information is not known, this

must be clearly indicated by entering NK on the form. All missing and

ambiguous data will be queried.

Trial CRFs may be amended as appropriate; this will not constitute a protocol

amendment. Revised CRFs should be used by all participating sites with

immediate effect.

Case report forms will include:

Screening Visit Form

Randomisation Visit Form

Week 2, 4, 8, 16, 28 Visit Forms

Week 40 Visit Form

Week 46 Visit Form

Withdrawal form

Adverse Event (AE)/Serious Adverse Event (SAE) Form

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13 MONITORING

13.1 Risk Assessment The study has undergone Peer Review by the National Institute for Health

Research.

We have previously completed Chronic Renal Impairment in Birmingham II

(CRIB II) study, which was a single-centre (secondary care setting),

prospective, double-blind, placebo-controlled, randomised interventional trial

examining the effect of spironolactone on left ventricular function and arterial

stiffness in 112 patients with CKD Stage 2 or Stage 3, who were already

receiving an angiotensin converting enzyme (ACE) inhibitor and/or

angiotensin receptor blocker (ARB) for at least 6 months [41]. STOP-CKD study

employs similar methodology and safety monitoring as CRIB II, except that

STOP-CKD study population is confined to CKD Stage 3 and managed in the

primary care setting.

In CRIB II, there was a 4-week open-label run-in phase of 25mg of

spironolactone once daily, after which patients were randomised to continue a

further 36 weeks of treatment with either 25mg of spironolactone or to receive

placebo. During the open-label run-in phase, CRIB II reported 1 case of serious

hyperkalaemia (potassium 6.5 mmol/L), 1 patient with hypotension and acute

deterioration in renal function (eGFR decreased from 31 to 24 ml/min/1.73m2).

Spironolactone was withdrawn from all the above 3 patients. 6 (5%) patients

had potassium levels between 5.5 and 5.9 mmol/L requiring reduction of

spironolactone dosage. During blinded treatment between week 4 and 40, 4

patients had potassium levels between 5.5 and 5.9 mmol/L that required a dose

reduction to alternate day treatment. Two of these 4 patients were found to

have been on placebo after unblinding. No patients were withdrawn due to

hyperkalaemia after randomisation, and there were no reported side effects,

including gynaecomastia [41].

CRIB II study evidently demonstrated relatively few adverse events associated

with the use low dose spironolactone 25mg once daily in CKD Stage 2 and

Stage 3 patients in the secondary care setting, provided there was careful

monitoring plan in place. Hence, by using the same dose of spironolactone and

identical adverse reaction/events monitoring regime, this pilot trial will

provide crucial information to ascertain if similar safety profile of

spironolactone 25mg once daily can be achieved in the primary care setting in

CKD Stage 3 patients.

13.2 Monitoring At Study Co-ordination Centre

The study coordinator will be in regular contact with the recruited practice

staffs, research nurse and trial administrator (by phone or email) to check on

progress and answer any queries that they may have. Trial staff will check

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incoming CRFs for compliance with the protocol, consistent data, missing data

and timing.

Research team have engaged with quality assurance at PC-CRTU at

consultancy level. Research team will be advised in terms of monitoring plan

for the study. Monitoring will be conducted both centrally and on-site while

research team visits the general practices.

13.3 Monitoring At Local Site Monitoring will be done according to the PC-CRTU policy and the STOP-CKD

Monitoring Plan. Investigators will allow the trial monitors access to source

documents as requested. If a monitoring visit is required, the STOP-CKD Study

Office will contact the site to arrange a date for the proposed visit. Data to be

verified will include:

Informed Consent

Eligibility

Adverse Events

Any major problems identified during monitoring will be reported to the

STOP-CKD Steering Committee. All records will be maintained in accordance

with local regulations and in a manner that ensures security and

confidentiality. The completed original CRFs are the sole property of the

STOP-CKD Steering Committee and should not be made available in any

form to third parties (except for authorised representatives of appropriate

Health/Regulatory Authorities) without written permission from the STOP-

CKD Steering Committee.

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14 REGULATORY ISSUES

14.1 Clinical Trial Authorisation (CTA)

This study has Clinical Trial Authorisation from the UK competent authority,

MHRA: reference: 21761/0274/001-0001

14.2 Ethics Approval

The Study Co-ordination Centre has obtained approval from the West

Midlands- Coventry and Warwickshire Research Ethics Committee. The trial

must be submitted for Site Specific Assessment (SSA) at each participating

NHS Trust. The Chief Investigator will require a copy of the SSA approval

letter before accepting participants into the trial. The trial will be conducted in

accordance with the recommendations for physicians involved in research on

human subjects adopted by the 18th World Medical Assembly, Helsinki 1964

and later revisions.

14.3 Patient Consent It is the responsibility of the research clinician or research nurse to obtain fully

Informed Written Consent from each patient prior to evaluation of the patient's

suitability for the trial as well as enrolment into the trial.

Suitable volunteers will be identified from their medical records by their

general practitioner to be invited to attend the Health Centre. The approved

Patient Information Sheet will be send out to the identified patients with the

invitation to attend the first research clinic (‘screening visit’). The volunteers

will be given ample time to read the information sheet at home, given time to

discuss their participation with others outside of the clinical trials team in order

for the patient to reach a decision. During the ‘screening visit’, volunteers will

have the opportunity to discuss about the risks and benefits of participation in

the study and chance to ask any question. Informed consent will be sought by

the Clinical Staff (Medical or Nursing) and where obtained, will be followed by

initial screening blood samples.

Volunteers who are suitable for entry into the study based on the evaluation of

the screening visit will then be invited back to the Health Centre within 2

weeks of the initial visit, whereby informed consent will be sought again before

randomisation to commence on trial medication. They will be given time and

opportunity with the research clinician or research nurse to discuss or ask the

clinician or the research nurse questions regarding their participation in the

study. All questions or concerns about the trial should be answered to the

satisfaction of the patient. It should be explained that they are free to refuse to

take part and informed about their right to withdraw from the trial at any time.

If the patient agrees to take part in the trial they should be asked to sign and

date the approved Informed Consent Form, which should also be signed and

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dated by the Investigator. A copy of the Informed Consent Form should be

given to the patient, a copy filed in the hospital notes and a copy filed in the

Investigator Site File.

Throughout the study the patient will have the opportunity to ask questions

about the trial and any new information that may be relevant to the patient’s

willingness to continue participation in the trial should be shared with the

patient in a timely manner.

A copy of the Informed Consent Form and Patient Information Sheet is

included in Appendices (Appendix B and Appendix C).

14.4 Confidentiality

Participants’ identification data will be required for the registration process.

The Study Co-ordination Centre will preserve the confidentiality of

participants taking part in the trial, and is registered under the Data Protection

Act. Confidentiality will be monitored and consent will be sought from

patients for members of the study team, regulatory authorities and the PCT to

have direct access to patient medical records. If data is to be transferred

outside of the EU, consent must also be sought for this.

14.5 Indemnity

University of Birmingham holds Public Liability (negligent harm) and Clinical

Trial (negligent harm) insurance policies, which apply to this trial.

14.6 Sponsor

University of Birmingham will act as the main sponsor for this trial.

14.7 Funding

The National Institute for Health Research, Research for Patient Benefit Scheme

is funding this trial.

14.8 Audits

The trial may be subject to inspection and audit by MHRA and University of

Birmingham under their remit as sponsor, the Study Co-ordination Centre and

other regulatory bodies, to ensure adherence to GCP.

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15 FINANCIAL ARRANGEMENTS

15.1 Participant Payments Participants will be reimbursed for travel expenses where required if requested

15.2 GP Payments

GP practices will be reimbursed for work done in supporting the trial via

service support costs.

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16 PUBLICATION

The overall question being addressed by this study – is a randomised controlled trial

of spironolactone in CKD the community feasible and likely to result in similar effects

to those seen in hospital settings? – will be of relevance to the renal research

community and the primary care research community. If the answer is yes, a trial is

feasible, then we will be actively disseminating the results to general practices and

renal colleagues nationwide with the aim of recruiting them to the definitive trial. An

obvious mechanism to do this is via the renal speciality group of the Comprehensive

Research Network and the Primary Care Research Network. This will be

supplemented by meetings that we will organise to explain the trial to interested renal

specialists and GPs in their catchment areas. If the answer is no, a trial is not feasible,

then the lessons learnt will remain of considerable interest to the research community,

and we would present our findings to both a primary care audience (e.g at scientific

meetings of the Society for Academic Primary Care and the Confederation of Primary

Care Research Organisations) and a renal audience (e.g. at the Renal Association and

American Society of Nephrology).

We would anticipate publishing the findings in peer-reviewed journals on the overall

results of the pilot study. We will disseminate our results to all participants and via

our website and local media plus through patient groups (see above).

All publications and presentations relating to the trial will be authorised by the Trial

Steering Committee. The first publication of the trial results will be in the name of

Trial Steering Committee, if this does not conflict with the journal’s policy. If there are

named authors, these will include at least the Chief Investigator, Statistician and Trial

Co-ordinator. Members of the Trial Steering Committee and Data Monitoring

Committee will be listed and contributors will be cited by name if published in a

journal where this does not conflict with the journal’s policy. Authorship of parallel

studies initiated outside of the Trial Steering Committee will be according to the

individuals involved in the project, but must acknowledge the contribution of the Trial

Steering Committee and Study Co-ordination Centre.

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17 REFERENCES

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17. Kestenbaum, B., et al., Serum phosphate levels and mortality risk among people

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the American Society of Nephrology : JASN, 2004. 15(6): p. 1640-7.

20. Edwards, N.C., et al., Aortic distensibility and arterial-ventricular coupling in early

chronic kidney disease: a pattern resembling heart failure with preserved ejection

fraction. Heart, 2008. 94(8): p. 1038-43.

21. Blacher, J., et al., Impact of aortic stiffness on survival in end-stage renal disease.

Circulation, 1999. 99(18): p. 2434-9.

22. Ilyas, B., et al., Renal function is associated with arterial stiffness and predicts

outcome in patients with coronary artery disease. QJM : monthly journal of the

Association of Physicians, 2009. 102(3): p. 183-91.

23. Coca, S.G., et al., Underrepresentation of renal disease in randomized controlled

trials of cardiovascular disease. JAMA : the journal of the American Medical

Association, 2006. 296(11): p. 1377-84.

24. Mann, J.F., et al., Renal insufficiency as a predictor of cardiovascular outcomes and

the impact of ramipril: the HOPE randomized trial. Annals of internal medicine,

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25. Rahman, M., et al., Renal outcomes in high-risk hypertensive patients treated with

an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a

diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to

Prevent Heart Attack Trial (ALLHAT). Archives of internal medicine, 2005.

165(8): p. 936-46.

26. Sever, P.S., et al., Prevention of coronary and stroke events with atorvastatin in

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27. Tonelli, M., et al., Effect of pravastatin on cardiovascular events in people with

chronic kidney disease. Circulation, 2004. 110(12): p. 1557-63.

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20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet, 2002.

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29. Jafar, T.H., et al., Proteinuria as a modifiable risk factor for the progression of non-

diabetic renal disease. Kidney international, 2001. 60(3): p. 1131-40.

30. Barnett, A.H., et al., Angiotensin-receptor blockade versus converting-enzyme

inhibition in type 2 diabetes and nephropathy. The New England journal of

medicine, 2004. 351(19): p. 1952-61.

31. Kunz, R., et al., Meta-analysis: effect of monotherapy and combination therapy with

inhibitors of the renin angiotensin system on proteinuria in renal disease. Annals of

internal medicine, 2008. 148(1): p. 30-48.

32. Di Zhang, A., et al., Cross-talk between mineralocorticoid and angiotensin II

signaling for cardiac remodeling. Hypertension, 2008. 52(6): p. 1060-7.

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34. Delcayre, C. and B. Swynghedauw, Molecular mechanisms of myocardial

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35. Young, M.J., Mechanisms of mineralocorticoid receptor-mediated cardiac fibrosis and

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37. Pitt, B., et al., Eplerenone, a selective aldosterone blocker, in patients with left

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38. Ezekowitz, J.A. and F.A. McAlister, Aldosterone blockade and left ventricular

dysfunction: a systematic review of randomized clinical trials. European heart

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39. Bomback, A.S., et al., Change in proteinuria after adding aldosterone blockers to

ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review.

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40. Navaneethan, S.D., et al., Aldosterone antagonists for preventing the progression of

chronic kidney disease: a systematic review and meta-analysis. Clinical journal of

the American Society of Nephrology : CJASN, 2009. 4(3): p. 542-51.

41. Edwards, N.C., et al., Effect of spironolactone on left ventricular mass and aortic

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42. Heshka, J., et al., Spironolactone for difficult to control hypertension in chronic

kidney disease: an analysis of safety and efficacy. Journal of the American Society

of Hypertension : JASH, 2010. 4(6): p. 295-301.

43. Svensson, M., et al., How prevalent is hyperkalemia and renal dysfunction during

treatment with spironolactone in patients with congestive heart failure? Journal of

cardiac failure, 2004. 10(4): p. 297-303.

44. Tamirisa, K.P., K.D. Aaronson, and T.M. Koelling, Spironolactone-induced renal

insufficiency and hyperkalemia in patients with heart failure. American heart

journal, 2004. 148(6): p. 971-8.

45. Committee, J.F., ed. British National Formulary. 62 ed. September 2011, BMJ

Group and Pharmaceutical Press: London.

46. Wei, L., et al., Spironolactone use and renal toxicity: population based longitudinal

analysis. BMJ, 2010. 340: p. c1768.

47. Compendium, E.M. Electronic Medicines Compendium on Spironolactone tablets

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ets+25mg/.

48. Antoniou, T., et al., Trimethoprim-sulfamethoxazole induced hyperkalaemia in

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p. d5228.

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18 PROTOCOL AMENDMENTS

Version 1.0 Approved on 22nd March 2012

Version 2.0 Approved on 18th June 2012

Version 3.0 Approved on 26th July 2012

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Appendix A

STOP- CKD Hyperkalaemia and Renal Dysfunction Management Protocol

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Appendix B: Patient Information Sheet

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Appendix C: Consent form

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Appendix D

Low Potassium Diet Information Sheet

Potassium is a mineral found in the blood. The level of potassium in the blood should be kept

between 3.5-5.5 mmol/L. The trial medication you are receiving may increase the potassium level in

your body. High potassium level can be dangerous and affect your heart.

To reduce the level of potassium in your blood, you may need to cut down on certain foods which are

high in potassium. This table gives a simple guide on some of the foods to limit and provides tips on

alternatives that can be used.

Limit or Avoid Alternatives you can choose from

Fruit:

Bananas, strawberries, mango, fresh grapefruit,

pineapple, grapes, rhubarb, oranges, kiwi,

prunes, ALL dried fruit

(limit to 2 portions per day)

Apples, pears, Satsuma, tinned fruit drained of

juice.

Vegetables:

Tomatoes, mushrooms, spinach, sweet corn,

beetroot, plantains, parsnips, aubergine, broccoli,

avocado, baked beans.

(limit to 2 portions per day)

ALL boiled vegetables, carrots, cabbage,

cauliflower, onion, turnip, asparagus, lettuce,

cucumber, courgette, celery.

Potatoes and alternatives: (see below)

Roast, baked or chips (unless the potatoes have

been boiled first)

Boiled potatoes, rice, noodles, bread

Drinks:

Fruit and vegetables juices, smoothies, fruit-juice-

based squashes (i.e.: Ribena, Hi-Juice etc).

Coffee

Beer, cider, lager, sherry, port.

Fizzy drinks without fruit juice and some

squashes.

Tea

Spirits (Gin, Whisky, Vodka, etc).

Snacks:

ALL potato crisps. ALL nuts.

Chocolate, marzipan, liquorice, toffee.

Snacks made from wheat, corn or rice (i.e.: rice

crackers, popcorn, Doritos, Wotsits, Skips). Plain

biscuits and cakes, crumpets.

Boiled sweets, fruit pastilles, mints, chewing

gum.

Others:

Lo-salt and other salt substitutes

Use other herbs and spices

Milk: limit to ½ pint per day

Potatoes: Potatoes are high in potassium and should be prepared in the following way to reduce their

potassium content.

1. Cut in small pieces.

2. Boil in large volume of water.

3. May then be fried, roasted or creamed.

The water used to cook potatoes and vegetables should be discarded.

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Appendix E: EQ5D-5L Form

Under each heading, please tick the ONE box that best describes your health TODAY MOBILITY

I have no problems in walking about

I have slight problems in walking about

I have moderate problems in walking about

I have severe problems in walking about

I am unable to walk about

SELF-CARE

I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities)

I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN / DISCOMFORT

I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort

ANXIETY / DEPRESSION

I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed

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Appendix F

Medication Monitoring Questionnaire:

Side Effect Yes No

Nausea

Vomiting

Abdominal Discomfort

Diarrhoea

Black Discoloured Stool

Tiredness

Headache

Confusion

Drowsiness

Dizziness/ Imbalance

Breast swellings

Breast pain

Menstrual (period) disturbance

Change in libido

Excessive hair growth

Unwanted hair growth

Hair loss

Leg cramps

Rash

Joint pain

Others: (Please comment)

Have you missed any trial medication since the last visit? Yes / No

If Yes, how many tablets have you missed?

To be completed by healthcare professional

Side Effect Yes No

Hyperkalaemia

Hyponatremia

Increment of serum creatinine ≥ 30% from

baseline

or reduction of eGFR ≥ 25% from baseline

Leucopenia

Agranulocytosis

Thrombocytopenia

Hepatotoxicity

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Appendix G:

Spironolactone Medicine Information Summary of Product Characteristics last updated on the eMC: 02/02/2011

Contraindications

Spironolactone therapy is contraindicated in the following:

• Anuria (patients are at greater risk of developing hyperkalaemia)

• Active renal insufficiency, rapidly progressing or severe impairment of renal function (spironolactone may aggravate

electrolyte imbalance and the risk of developing hyperkalaemia is increased)

• Hyperkalaemia (spironolactone may further increase serum potassium concentrations)

• Addison's disease

• Hypersensitivity to spironolactone or any of the ingredients in the product

• Diabetes mellitus, especially in patients with confirmed or suspected renal insufficiency

• Diabetic nephropathy (increased risk of hyperkalaemia. Spironolactone should be discontinued at least 3 days prior to a

glucose tolerance test because of the risk of severe hyperkalaemia).

Special warnings and precautions for use

• Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose – galactose

malabsorption should not take this medicine.

• Patients receiving spironolactone should be carefully evaluated for possible disturbances of fluid and electrolyte

balance, particularly in the elderly and in those with significant renal and hepatic impairment.

• Hyperkalaemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac

irregularities which may be fatal. Should hyperkalaemia develop, spironolactone should be discontinued, and if

necessary, active measures taken to reduce the serum potassium to normal. Dilutional hyponatraemia may be induced

especially when spironolactone is concurrently administered with other diuretics.

• Care should be taken in patients suffering from hyponatraemia.

• Reversible increases in blood urea have been reported with spironolactone therapy, particularly in the presence of

impaired renal function.

• Reversible hyperchloraemic metabolic acidosis, usually in association with hyperkalaemia has been reported to occur

in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.

• Caution is required in severely ill patients and those with relatively small urine volumes who are at greater risk of

developing hyperkalaemia.

• Caution is required in patients with a predisposition to metabolic or respiratory acidosis. Acidosis potentiates the

hyperkalaemic effects of spironolactone and spironolactone may potentiate acidosis.

• Spironolactone has been shown to produce tumours in rats when administered at high doses over a long period of

time. The significance of these findings with respect to clinical use is not certain. However, the long-term use of

spironolactone in young patients requires careful consideration of the benefits and the potential hazard involved.

• Caution should be exercised in patients diagnosed with porphyria as spironolactone is considered unsafe in these

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patients.

• Care should be taken in patients suffering from menstrual abnormalities or breast enlargement.

Interaction with other medicinal products and other forms of interaction

• ACE inhibitors - since ACE inhibitors decrease aldosterone production they should not routinely be used with

spironolactone, particularly in patients with marked renal impairment.

• Angiotensin-II receptor antagonists – concurrent administration of angiotensin-II receptor antagonists, e.g. valsartan,

losartan, and spironolactone may result in an increase in serum potassium levels. If concurrent use is necessary, monitor

serum potassium levels.

• Antihypertensives - potentiation of the effect of antihypertensive drugs occurs and their dosage may need to be

reduced when spironolactone is added to the treatment regime, and then adjusted as necessary.

• Anti-diabetics – administration with chlorpropamide may increase risk of hyponatraemia.

• Aspirin - may reduce the diuretic effect of spironolactone.

• Cardiac glycosides - spironolactone has been reported to increase serum digoxin concentration and to interfere with

certain serum digoxin assays. In patients receiving digoxin and spironolactone, the digoxin response should be

monitored by means other than serum digoxin concentrations, unless the digoxin assay used has been proven not be

affected by spironolactone therapy. If it proves necessary to adjust the dose of digoxin, patients should be carefully

monitored for evidence of enhanced or reduced digoxin effect.

• Ciclosporin - co-administration of potassium-sparing diuretics with ciclosporin may result in hyperkalaemia. Avoid

concurrent use of spironolactone and ciclosporin. If concurrent therapy is necessary, monitor serum potassium levels for

persistent elevations in patients.

• Corticosteroids - co-administration of spironolactone with fludrocortisone may result in a paradoxical dose-related

increase in urinary potassium excretion. If concomitant administration is necessary, closely monitor serum potassium

levels.

• Coumarins - in patients receiving oral anticoagulant therapy with warfarin, the prothrombin time ratio or INR

(international normalised ratio) should be monitored with the addition and withdrawal of treatment with spironolactone,

and should be reassessed periodically during concurrent therapy. Adjustments of the warfarin dose may be necessary in

order to maintain the desired level of anticoagulation.

• Diuretics - spironolactone should not be administered concurrently with other potassium- sparing diuretics as this may

induce hyperkalaemia. Potassium canrenoate, a metabolite of spironolactone, has been shown to cause myeloid

leukaemia in rats.

• Lithium - concurrent use of lithium and spironolactone may result in increased lithium concentrations and lithium

toxicity (weakness, tremor, excessive thirst, and confusion) due to decreased lithium excretion. If concomitant therapy is

necessary monitor serum lithium levels within the first five to seven days of adding or discontinuing spironolactone and

periodically thereafter. Lower lithium doses may be required with concomitant spironolactone therapy.

• NSAIDs - may attenuate the natriuretic efficacy of diuretics due to inhibition of intrarenal synthesis of prostaglandins.

There may be an increased risk of nephrotoxicity and hyperkalaemia when NSAIDs, notably indometacin are used with

spironolactone.

Indometacin and mefenamic acid, inhibit the excretion of canrenone reducing the diuretic effect.

• Potassium salts – potassium supplements are contraindicated except in cases of initial potassium depletion. If

potassium supplementation is considered essential, serum electrolytes should be monitored.

• Sympathomimetics - spironolactone reduces vascular responsiveness to noradrenaline (norepinephrine); caution

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should be exercised in the management of patients subjected to regional or general anaesthesia.

• Tacrolimus - spironolactone should not be used in patients undergoing therapy with tacrolimus as concomitant use has

resulted in mild to severe hyperkalaemia.

• Ulcer healing drugs - as carbenoxolone may cause sodium retention and thus decrease the effectiveness of

spironolactone, concurrent use of the two agents should be avoided.

• In fluorimetric assays spironolactone may interfere with the estimation of compounds with similar fluorescence

characteristics.

• Liver function tests – spironolactone may enhance the metabolism of antipyrine used in liver function tests.

Pregnancy and lactation

Spironolactone or its metabolites may cross the placental barrier. With spironolactone feminisation has been observed in

male rat foetuses. Spironolactone should be used with caution in pregnant women, weighing the potential risk to the

mother and foetus against the possible benefits. Canrenone, a metabolite of spironolactone, appears in breast milk,

therefore an alternative method of infant feeding should be instituted.

Effects on ability to drive and use machines

Patients should be warned that they may experience dizziness or drowsiness when taking this medicine. They should

make sure they are not affected before driving or operating machinery.

Undesirable effects

• Blood and lymphatic system disorders: agranulocytosis, eosinophilia and thrombocytopenia have been reported rarely.

Spironolactone may cause transient elevations in blood urea nitrogen (BUN) especially in patients with renal impairment.

Hyponatraemia has been reported rarely.

• Hypersensitivity: these occur rarely and are usually mild but very occasionally may be severe causing swelling, shock

and collapse. Shortness of breath, skin rash or itching has been reported rarely.

• Metabolism and nutrition disorders: hyperkalemia and hyponatraemia has been reported rarely. Electrolyte disturbances.

• Nervous system disorders: ataxia, drowsiness, dizziness, headache and clumsiness have been reported although these are

less common.

• Psychiatric disorders: lethargy.

• Cardiac disorders: severe hyperkalaemia may result in paralysis, flaccid paraplegia and cardiac arrhythmias with

subsequent cardiovascular collapse. This can be fatal in patients with impaired renal function.

• Hepato – biliary disorders: hepatotoxicity has been reported.

• Gastrointestinal disorders: gastritis, gastric bleeding, stomach cramps, diarrhoea, vomiting and ulceration are more

frequent effects.

• Skin and subcutaneous tissue disorders: urticaria and alopecia has been reported rarely. Skin rashes have also been

reported.

• Musculoskeletal, connective tissue and bone disorders: osteomalacia.

• Renal and urinary disorders: acute renal failure, particularly in those with pre-existing renal impairment.

• Reproductive system and breast disorders: gynaecomastia may develop in association with the use of spironolactone.

Development appears to be related to both dosage level and duration of therapy and is usually reversible once therapy is

discontinued. In rare instances some breast enlargement may persist. Alteration in voice pitch may also occur on rare

occasions which may not be reversible. Impotence and decreased sexual ability has been reported. This is usually

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reversible on discontinuation of spironolactone. Breast tenderness and increased hair growth in females, irregular

menstrual periods and sweating have been reported.

Overdose

Toxic effects of overdosage are drowsiness, mental confusion, nausea, vomiting, dizziness or diarrhoea. Hyponatraemia

or hyperkalaemia may be induced but these effects are unlikely to be associated with acute overdosage. Symptoms of

hyperkalaemia may manifest as paraesthesia, lassitude and muscular weakness, flaccid paralysis or muscle spasm and

may be difficult to distinguish clinically from hypokalaemia.

No specific antidote has been identified. Improvement may be expected on cessation of therapy. Electrocardiographic

changes are the earliest specific signs of potassium disturbances. General supportive measures include replacement of

fluids and electrolytes may be indicated. For hyperkalaemia, reduce potassium intake, administer potassium-excreting

diuretics, intravenous glucose with regular insulin, or oral ion-exchange resins.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

ATC CODE C03D A01

Spironolactone is a steroid with a structure resembling that of the natural adrenocorticoid hormone, aldosterone. It acts

as a competitive inhibitor of aldosterone and acts on the distal portion of the renal tubule thereby increasing sodium and

water excretion and reducing potassium excretion. It is classed as a potassium sparing diuretic or aldosterone antagonist.

Pharmacokinetic properties

Absorption – Spironolactone is incompletely but fairly rapidly absorbed from the gastrointestinal tract and the extent of

absorption will depend on the particle size and formulation and is improved after food. Bioavailability is estimated from

60 to 90%. Time to peak plasma concentration is approximately one hour.

Distribution – Although the plasma half life of spironolactone itself is short (1.3 hours) the half lives of the active

metabolites are longer (ranging from 2.8 to 11.2 hours).

Spironolactone is estimated to be 90% protein bound. Volume of distribution, extent of tissue accumulation and ability to

cross the blood brain barrier are not known. Spironolactone or its metabolites may cross the placental barrier and

canrenone is secreted breast milk. Spironolactone is known to have a slow onset of action two to three days and a slow

diminishment of action.

Metabolism – The main site of biotransformation is the liver where it is metabolised, to 80% sulphur containing

metabolities such as 7 alpha- thiomethylspironolactone and canrenone (20%). Many of these metabolities also have a

diuretic-activity. Canrenone, which is an active metabolite, has a biphasic plasma half life of about 4 - 17 hours.

Elimination – Spironolactone is excreted in the urine and faeces in the form of metabolites.

The renal action of a single dose of spironolactone reaches its peak after 7 hours, and activity persists for at least 24 hours.

Preclinical safety data

Carcinogenicity spironolactone has been shown to produce tumours in rats when administered at high doses over a long

period of time. The significance of these findings with respect to clinical use in not certain. However the long term use of

spironolactone in young patients requires careful consideration of the benefits and the potential hazard involved.

Spironolactone or its metabolities may cross the placental barrier. With spironolactone, feminisation has been observed in

male rat foetuses. The use of spironolactone in pregnant women requires that the anticipated benefit be weighed against

the possible hazards to the mother and foetus.

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Appendix H: Role and Responsibilities

Brief Study Title: STOP-CKD

Study Start Date: May 2012

Trial Role Name Responsibilities Signature and Date

Chief

Investigator Dr Charles Ferro

Lead investigator

Responsible for the design,

conduct, analyses and

reporting of STOP-CKD.

Co

Investigator

Prof Richard

McManus

Expert Primary care input

Provide advice in the design

and conduct of the study.

Dr Paramjit Gill

Expert Primary care input

Provide advice in the design

and conduct of the study.

Dr John Townend Specialist cardiology input

Dr Sheila

Greenfield

Sociology input.

Supervision of qualitative

study.

Dr Poorva Jain Specialist nephrology input

Statistician Prof Nick

Freemantle

Provide statistical advice and

supervise statistical analysis

Research

Fellow Dr Khai Ping Ng

Trial Management

Day to day renal advice

Training research nurses and

trial administrator.

Research Nurse Gurdip Heer Day to day running of STOP-

CKD study

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Study

Administrator/

coordinator

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STOP-CKD Protocol Appendix A

Appendix I: TRIAL PERSONNEL CONTACT SHEET

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Brief Study Title: STOP-CKD

Study Start Date: May 2012

Personnel Name Address Telephone E-mail

Sponsor Brendan Laverty


Edgbaston

Birmingham

B15 2TT

0121 414 7618 [email protected]

Chief

Investigator Dr Charles Ferro

Consultant Nephrologist

University Hospital

Birmingham

Mindelsohn Way

Birmingham

B15 2WB

0121 3715839 [email protected]

Co

Investigator

Prof Richard

McManus

Professor of Primary Care

Cardiovascular Research

Department of Primary Care

Health Sciences

University of Oxford

2nd Floor

23-38 Hythe Bridge Street

Oxford

OX1 2ET.

01865 617834

[email protected].

ac.uk

Dr Paramjit Gill

Reader in Primary Care

Research

Primary Care Clinical

Sciences

School of Health and

Population Sciences

College of Medical and

Dental Sciences


0121 414 3758 [email protected]

Dr John Townend

Consultant Cardiologist/

Senior Lecturer

University Hospital

Birmingham

Mindelsohn Way

Birmingham

B15 2WB.


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Dr Sheila

Greenfield

Senior Lecturer in Medical

Sociology


Science


Edgbaston

Birmingham

B15 2TT


Dr Poorva Jain

Renal Medicine Research

Fellow/Registrar in

Nephrology


Science


Edgbaston

Birmingham

B15 2TT


Statistician Prof Nick

Freemantle

Professor of Clinical

Epidemiology and

Biostatistics

Primary care clinical sciences

University College London

Gower Street

London

WC1E 6BT

020 77940500

Ext 34756

[email protected]

k

Research

Fellow Dr Khai Ping Ng

Renal Medicine Research

Fellow/Registrar in

Nephrology

University Hospital

Birmingham

Mindelsohn Way

Birmingham

B15 2WB


Research Nurse

Gurdip Heer

Primary Care Research

Nurse


Science


Edgbaston

Birmingham

B15 2TT

0 121 4146046

[email protected]

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Study

Administrator/

coordinator

To be confirmed

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CONSORT 2010 checklist Page 1

CONSORT 2010 checklist of information to include when reporting a randomised trial*

Section/Topic Item No Checklist item

Reported on page No

Title and abstract

1a Identification as a randomised trial in the title 1

1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) 2,3

Introduction

Background and

objectives

2a Scientific background and explanation of rationale 5

2b Specific objectives or hypotheses 6

Methods

Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 6,7

3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons N/A

Participants 4a Eligibility criteria for participants Table 1

4b Settings and locations where the data were collected 6

Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were

actually administered

7,8

Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they

were assessed

8

6b Any changes to trial outcomes after the trial commenced, with reasons N/A

Sample size 7a How sample size was determined 8

7b When applicable, explanation of any interim analyses and stopping guidelines N/A

Randomisation:

Sequence

generation

8a Method used to generate the random allocation sequence 8

8b Type of randomisation; details of any restriction (such as blocking and block size) 8

Allocation

concealment

mechanism

9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers),

describing any steps taken to conceal the sequence until interventions were assigned

Appendix 1

Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to

interventions

8

Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those 8

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assessing outcomes) and how

11b If relevant, description of the similarity of interventions 8

Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 9

12b Methods for additional analyses, such as subgroup analyses and adjusted analyses 9

Results

Participant flow (a

diagram is strongly

recommended)

13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and

were analysed for the primary outcome

Figure 1

13b For each group, losses and exclusions after randomisation, together with reasons Figure 1

Recruitment 14a Dates defining the periods of recruitment and follow-up 12,16

14b Why the trial ended or was stopped 16

Baseline data 15 A table showing baseline demographic and clinical characteristics for each group Table 4

Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was

by original assigned groups

12, 13

Outcomes and

estimation

17a For each primary and secondary outcome, results for each group, and the estimated effect size and its

precision (such as 95% confidence interval)

N/A

17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended N/A

Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing

pre-specified from exploratory

12,13

Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) Figure 1

Discussion

Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 3, 17-20

Generalisability 21 Generalisability (external validity, applicability) of the trial findings 3, 17-20

Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence 20

Other information

Registration 23 Registration number and name of trial registry 4,8

Protocol 24 Where the full trial protocol can be accessed, if available 6, Appendix 1

Funding 25 Sources of funding and other support (such as supply of drugs), role of funders 23

*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also

recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials.

Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.

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Results and lessons from the Spironolactone To Prevent Cardiovascular Events In Early Stage Chronic Kidney

Disease (STOP-CKD) Randomised Controlled Trial

Journal: BMJ Open

Manuscript ID bmjopen-2015-010519.R1

Article Type: Research

Date Submitted by the Author: 05-Jan-2016

Complete List of Authors: Ng, Khai Ping; Queen Elizabeth Hospital Birmingham, Renal Medicine Jain, Poorva; University of Birmingham, Primary Care Clinical Sciences Gill, Paramjit; University of Birmingham, Primary Care Clinical Sciences

Heer, Gurdip; University of Birmingham, Primary Care Clinical Sciences Townend, Jonathan; University Hospitals Birmingham NHS Foundation Trust, Cardiology Freemantle, Nick; University College London, Dept Primary Care and Population Health Greenfield, Sheila; University of Birmingham, Primary Care Clinical Sciences McManus, Richard; University of Oxford, Dept of Primary Care Health Sciences Ferro, Charles; Queen Elizabeth Hospital, Nephrology

<b>Primary Subject Heading</b>:

Renal medicine

Secondary Subject Heading: Cardiovascular medicine, General practice / Family practice, Research methods

Keywords: cardiovascular, chronic kidney disease, mineralocorticoid receptor antagonist, PRIMARY CARE, randomised trial, research recruitment


BMJ Open on D

ecember 4, 2020 by guest. P

rotected by copyright.http://bm

jopen.bmj.com

/B

MJ O

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ebruary 2016. Dow

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1

Results and lessons from the Spironolactone To Prevent Cardiovascular

Events In Early Stage Chronic Kidney Disease (STOP-CKD) Randomised

Controlled Trial

Authors:

Khai P Ng MBChB1

Poorva Jain MBChB 2

Paramjit S Gill FRCGP FHEA2

Gurdip Heer BSc(Hons) RGN2

Jonathan N Townend MD3

Nick Freemantle PhD4

Sheila Greenfield PhD 2

Richard J McManus PhD FRCGP5

Charles J Ferro MD1

Affiliation: 1Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, Birmingham, B15

2WB, UK 2Primary Care Clinical Sciences, School of Health and Population Sciences, University of

Birmingham, Birmingham, B15 2TT, UK 3Department of Cardiology, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2WB,

UK 4Department of Primary Care and Population Health, UCL Medical School, Rowland Hill

Street, London, NW3 2PF, UK 5Nuffield

Department of Primary Care Health Sciences, University of Oxford, Woodstock

Rd, Oxford, OX2 6GG, UK

Corresponding author:

Dr Charles Ferro

Department of Renal Medicine,

Queen Elizabeth Hospital Birmingham,

Mindelsohn Way,

Birmingham,

B15 2WB, UK

Email: [email protected] Tel: +44 121 3715842 Fax: +44 121 3715858

Keywords:

Cardiovascular; chronic kidney disease; mineralocorticoid receptor antagonist; primary care;

randomised trial

Word count: 3797 words (abstract 259)

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ABSTRACT

Objectives

To determine whether low-dose spironolactone can safely lower arterial stiffness in patients

with chronic kidney disease stage 3 in the primary care setting.

Design

A multi-centre, prospective, randomised, placebo-controlled, double-blinded study.

Setting

Eleven primary care centres in South Birmingham, England.

Participants

Adult patients with stage 3 chronic kidney disease. Main exclusion criteria were diagnosis of

diabetes mellitus, chronic heart failure, atrial fibrillation, severe hypertension, systolic blood

pressure < 120 mmHg or baseline serum potassium ≥ 5 mmol/L.

Intervention

Eligible participants were randomised to receive either spironolactone 25 mg once daily or

matching placebo for an intended period of 40 weeks.

Outcome measures

The primary endpoint was the change in arterial stiffness as measured by pulse wave

velocity. Secondary outcome measures included the rate of hyperkalaemia, deterioration of

renal function, barriers to participation and expected recruitment rates to a potential future

hard-endpoint study.

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Results

From the 11 practices serving a population of 112,462, there were 1,598 (1.4%) patients

identified as being eligible and invited to participate. Of these, 134 (8.4%) attended the

screening visit of which only 16 (1.0%) were eligible for randomisation. The main reasons

for exclusion were low systolic blood pressure (< 120 mmHg: 40 patients) and high estimated

glomerular filtration rate (≥ 60 ml/min/1.73m2: 38 patients). The trial was considered

unfeasible and was terminated early.

Conclusion

We highlight some of the challenges in undertaking research in primary care including

patient participation in trials. This study not only challenged our preconceptions, but also

provided important learning for future research in this large and important group of patients.

Strength and limitations of this study

� This is the first reported randomised, placebo-controlled interventional trial of

patients with stage 3 chronic kidney disease in the primary care setting in England.

� The strengths of the study are the original study design, setting and populations.

� The review of the list of potential participants by their corresponding general

practitioners might have resulted in selection bias.

� The major limitation to this study was the poor recruitment which ultimately led to

early termination of study.

� Critical analysis and transparent reporting of research recruitment failure provide

important learning for future research in this large and important group of patients.

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4

Trial registration number: Current Controlled Trial ISRCTN80658312

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5

INTRODUCTION 1

Chronic kidney disease (CKD) is increasingly recognised as an independent risk factor for 2

cardiovascular (CV) morbidity and mortality1-4

. Although the increased CV risk observed in 3

dialysis patients is considerable, the global health burden of CV disease in the earlier stages 4

of CKD is likely to be much greater given the high reported prevalence of up to 13% in 5

developed countries5 6

. In addition to an increased risk of vasculo-occlusive events such as 6

myocardial infarction, patients with CKD also have an increased risk of cardiac arrhythmias 7

and heart failure7 8

. Increased arterial stiffness, leading to myocardial hypertrophy and 8

fibrosis is thought to be a key mechanistic pathway in this pathophysiology of this increased 9

CV risk7 9-11

. Many of these abnormalities are indeed already evident in patients with only 10

mild abnormalities of kidney function (estimated glomerular filtration rates [eGFR]: 30 – 90 11

ml/min/1.73m2)12-14

. 12

13

Activation of the renin-angiotensin-aldosterone system (RAAS) is a key mediator of the 14

arterial and cardiac changes observed in patients with CKD as well as the increased CV risk 15

associated with this condition15 16

. Aldosterone is a mineralocorticoid that is a key effector of 16

the RAAS. The mineralocorticoid receptor antagonist (MRA), spironolactone, used in low 17

dose, has been shown to significantly lower arterial stiffness and left ventricular mass in 18

patients with stage 3 CKD managed by nephrologists in secondary care17

. However, the 19

majority (>90%) of patients with this level of kidney function are managed in primary care 20

by their general practitioners (GPs)18 19

. These patients tend to be older and have non-21

proteinuric renal diseases probably as a consequence of hypertension, reno-vascular disease 22

and possibly normal ageing20 21

. Furthermore, concerns about MRAs causing hyperkalaemia 23

and worsening renal function might limit their future use in the primary care setting. 24

25

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6

We therefore undertook a feasibility study to examine the actions of low dose spironolactone 26

on arterial stiffness in non-diabetic patients with stage 3 CKD managed in primary care. 27

Secondary objectives included the rate of hyperkalaemia, deterioration of renal function, 28

barriers to participation and expected recruitment rates to a potential future hard-endpoint 29

study. 30

31

SUBJECTS AND METHODS 32

The study design has previously been described in detail (Appendix 1)22

. In brief, it was a 33

multicentre, prospective, randomised, placebo-controlled, double-blind, parallel trial in non-34

diabetic patients with confirmed stage 3 CKD over 18 years of age in primary care. Patients 35

with diabetes mellitus were excluded given that the pathophysiology of arterial stiffness is 36

likely to be different and they have a higher risk of hyperkalaemia23

. Diabetes would be 37

expected to affect 20-30% of a community sample of CKD, and hence would form a large 38

subgroup within the trial. Thus, although diabetes is an important issue in CKD, we 39

considered that this would be best explored in a separate study. 40

41

The GFR was estimated by the four-variable Modification of Diet in Renal Disease (MDRD) 42

formula with serum creatinine recalibrated to be traceable to an isotope-derived mass 43

spectroscopy method24

. The full inclusion and exclusion criteria are detailed in Table 1. The 44

UK National Institute for Health and Care Excellence (NICE) guidelines on CKD 45

recommended systolic BP (SBP) target range of 120-139 mmHg and diastolic BP (DBP) < 46

90mmHg for patients with CKD25

. As spironolactone is known to have a BP-lowering effect, 47

patients with SBP <120 mmHg or postural hypotension were excluded from the study26

. In 48

addition, due to the increased risk of hyperkalaemia associated with the use of 49

spironolactone, patients with a serum potassium ≥ 5 mmol/L or those already receiving both 50

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7

angiotensin converting enzyme inhibitor (ACEi) and angiotensin II receptor blocker (ARB) 51

were also excluded from the study27

. Patients with uncontrolled severe hypertension (BP ≥ 52

180/110 mmHg) were deemed inappropriate for the study as they required urgent anti-53

hypertensive treatment26

and so were patients with urine albumin:creatinine ratio (uACR) ≥ 54

70 mg/mmol who should be referred and managed in secondary care setting. 55

56

Table 1: Inclusion and exclusion criteria of STOP-CKD study 57

Inclusion criteria

Age over 18 years

Diagnosis of CKD Stage 3 (MDRD eGFR 30-59 ml/min/1.73m2, sustained for at least 90 days)

Exclusion criteria

Diabetes Mellitus

Terminal disease or considered otherwise unsuitable by GP

Clinical diagnosis of chronic heart failure

Atrial fibrillation




Documented Addisonian crisis or taking fludrocortisone

Severe hypertension: BP ≥ 180/110 mmHg

Systolic BP < 120 mmHg

Recent acute kidney injury or hospital admission (within previous 6 weeks)

Chronic diarrhoea

Urine albumin:creatinine ratio (uACR) ≥ 70 mg/mmol

Serum potassium ≥ 5 mmol/L on screening visit


Concomitant ACEi and ARB medication (dual-angiotensin blockade)

Concomitant lithium medication

Concomitant warfarin medication

Pregnancy

Breastfeeding

Planned major surgical intervention within 46 weeks of recruitment

58 Abbreviations: ACEi: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blocker; BP: 59 blood pressure; CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; GP: general 60 practitioner; uACR: urine albumin:creatinine ratio. 61 62

63

Practices’ electronic patient records (EPR) were screened to identify all patients whose latest 64

eGFR were 30-59 ml/min/1.73m2 in the preceding 12 months and satisfied the study 65

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inclusion and exclusion criteria. Following review by individual patient’s GPs to determine 66

suitability for participation, potential participants were sent postal invitations addressed from 67

their GPs (Appendix 2). Non-responders were sent a second invitation two weeks later. Those 68

expressing a willingness to participate were invited to attend a screening visit at their own 69

general practice to confirm eligibility. Following this screening visit, eligible participants 70

attended a randomisation visit within two weeks and if still eligible were assigned 1:1 to 71

receive either spironolactone 25 mg once daily orally or identical placebo for 40 weeks using 72

a web-based randomisation system (Appendix 1). Investigator, outcome assessors, data 73

analysts and participants were all blinded to the treatment allocation. Patients were given a 74

prescription to collect their study medication from their local community pharmacy. Arterial 75

stiffness, as determined by carotid-femoral pulse wave velocity (cfPWV) was measured using 76

the Vicorder system (Skidmore, Bristol, UK)28

at randomisation visit and 40 weeks. Blood 77

pressure was measured using the BpTRU™ BPM-100 automated BP monitor, which was set 78

to obtain six serial BP readings, at one-minute intervals29

. The mean office BP was derived 79

from the 2nd

and 3rd

BP readings, whereas the mean BpTRU reading was derived from the 2nd

80

- 6th

readings30

. Postural hypotension was defined as a drop of SBP >20 mmHg after a minute 81

on standing. 82

83

Ethical approval for the study was given by the National Research Ethics Service (Reference 84

No 12/WM/0168) and clinical trial authorization was granted by the Medicine and Healthcare 85

Products Regulatory Agency (Reference No 21761/0274/001-0001). The Primary Care 86

Clinical Research and Trials Unit (PC-CRTU) at the University of Birmingham coordinated 87

the study. (Trial registration number: ISRCTN80658312). 88

89

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Sample size calculation 90

In a previous study of the effect of spironolactone, the standard deviation (SD) of the change 91

in cfPWV was 1.0 m/s in the active treatment group and 0.9 m/s in the control group31

. 92

Hence, 100 subjects in each arm would provide 90% power with an α value of 0.05 to detect a 93

difference in change of cfPWV of 0.5 m/s between the active treatment and control groups. 94

The study therefore intended to recruit 240 patients to account for an approximate dropout 95

rate of 20%, which would result in at least 200 evaluable patients completing this trial. 96

97

Statistical analysis 98

Statistical analyses were performed using SPSS version 20 (SPSS Inc, Chicago, IL), and SAS 99

version 9.4 (SAS Institute; Cary, NC). Numerical values are expressed as mean (SD) for 100

parametric data or median (interquartile range [IQR]) for non-parametric data. Normality of 101

the distribution of data was assessed by visual inspection of histogram and normal probability 102

plot. Non-parametric data were loge-transformed before comparative analyses. Continuous 103

data were compared using Student t-tests. 104

105

Exploratory analyses were performed to identify any potential factors influencing patients’ 106

willingness to participate. The information available on invited patients invited was limited to 107

their age, gender, ethnicity, general practice and last recorded eGFR. These five factors were 108

therefore assessed by binary logistic regression using a forced enter method with regard to 109

their impact on patient’s research participation. Patients who expressed interest in 110

participating were categorised as ‘willing invitees’ whereas patients who either did not 111

respond to the invitation or replied but declined participation were grouped together as ‘non-112

willing invitees’. Patients’ gender (male/female) and ethnicity (white/others) were analysed 113

as dichotomous data whereas age and last recorded eGFR were analysed as continuous data. 114

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Supplementary analyses were performed with eGFR being dichotomised either into CKD 115

stage 3a (eGFR: 45- 59 ml/min/1.73m2) and stage 3b (eGFR: 30- 44 ml/min/1.73m

2) or into 116

categories above or below the median of eGFR (54 ml/min/1.73m2). Non-linearity of age and 117

eGFR were examined using restricted cubic spline models. Models were selected on 118

achieving a significant improvement in Akaike’s Information Criterion. Statistical 119

significance was defined as a two-tailed p value < 0.05. 120

121

RESULTS 122

All 71 primary care practices within the former South Birmingham Primary Care Trust with 123

more than 3,000 patients registered were invited to participate. Eleven practices (15%) agreed 124

to take part, with a total population of 112,462 (Table 2). Electronic database searches 125

identified 2,044 potentially eligible patients. A further 446 (21.8%) patients were excluded by 126

their GPs with the proportion excluded varying considerably (2.3 – 52.6%). Five of the 11 127

practices were known to be ‘research-active’. There was no statistically significant difference 128

in regards to proportions of patients excluded between ‘research-active’ practices compared 129

to their counterparts (median: 19 [IQR: 10-47] vs 11 [IQR: 4-28] %, p=0.2). 130

131

132

133

134

135

136

137

138

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Table 2: Eleven recruiting practices’ population, prevalence of stage 3-5 chronic kidney disease, numbers of patients invited, screened and 139

randomised for STOP-CKD study. 140

Practice Practice

population

Prevalence

of stage 3-5

CKD*

Patients

eligible from

computerised

search (%)

Patients

excluded by

GP (%)**

Patients

invited (%)

Patients

replying

(%)***

Patients

expressing

interest (%)†

Patients

attending

screening visit

(%)†

Patients

randomized

(%)†

#1R 7,501 4.72 % 260 (3.5) 49 (18.8) 211 (2.8) 105 (49.8) 37 (17.5) 22 (10.4) 3 (1.4)

#2R 3,838 1.86 % 38 (1.0) 20(52.6) 18 (0.5) 7 (38.9) 3 (16.7) 3 (16.7) 0

#3 27,025 4.82 % 360 (1.3) 183 (50.8) 177 (0.6) 102 (57.6) 21 (11.9) 15 (8.5) 1 (0.6)

#4 7,113 3.58 % 179 (2.5) 7 (3.9) 172 (2.4) 81 (47.1) 20 (11.6) 12 (7.0) 2 (1.2)

#5 24,553 2.97 % 478 (1.9) 97 (20.3) 381 (1.6) 152 (39.9) 41 (10.8) 29 (7.6) 5 (1.3)

#6 R

8,729 4.19 % 157 (1.8) 17 (10.8) 140 (1.6) 61 (43.6) 20 (14.3) 16 (11.4) 3 (2.1)

#7 R

5,817 4.69 % 129 (2.2) 13 (10.1) 116 (2.0) 44 (37.9) 15 (12.9) 10 (8.6) 1 (0.9)

#8 4,824 3.58 % 114 (2.4) 13 (11.4) 101 (2.1) 44 (43.6) 11 (10.9) 10 (9.9) 0

#9 9,436 6.67 % 236 (2.5) 25 (10.6) 211 (2.2) 97 (46.0) 19 (9.0) 12 (5.7) 0

#10 7,104 2.75 % 43 (0.6) 1 (2.3) 42 (0.6) 27 (64.3) 6 (14.3) 3 (7.1) 1 (2.4)

#11 R

6,522 2.97 % 50 (0.8) 21 (42.0) 29 (0.4) 13 (44.8) 3 (10.3) 2 (6.9) 0

Total 112,462 2,044 446 1,598 733 196 134 16

Mean % 3.89% 1.82% 21.8% 1.42% 141 R Signify general practices which were research-active and had dedicate on-site practice research nurses. 142 *Data obtained from Quality and Outcomes Framework 2013/2014 report 143 (%) indicates percentage of total practice population 144 ** indicates percentage of potentially eligible patients excluded by their general practitioner 145 †indicates percentage of patients invited 146 Abbreviations: CKD, chronic kidney disease; GP, general practitioner147

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Invitation to study participation 148

The trial commenced in July 2013. A total of 1,598 invitation letters were sent out to all 149

potentially eligible patients (Figure 1). Sixty-three percent were female with a mean age of 71 150

(SD: 12) years and a median eGFR of 53 (IQR: 48-57) ml/min/1.73m2. Most patients’ (84%) 151

last eGFR readings were within the range of 45-59 ml/min/1.73m2. The ethnicity was 83.4% 152

white British, 3.4% black British, 3.3% South Asian, 1% mixed or other ethnicity and 8.9% 153

unknown. 154

155

Patients’ response to study invitation letter 156

Responses were received from 733 patients (46%) who had a mean age of 73 (SD: 11) years. 157

Of these, 196 (12%) expressed interest in participating in the study. Percentages of those who 158

were interested in participation ranged from 9% to 18% across the 11 practices (Table 2). 159

160

Of the 537 patients who responded declining participation, 295 (55%) did not wish to take a 161

new medication, 220 (41%) did not wish to be part of a research trial, 134 (25%) indicated 162

that they did not have time to take part in the study, 86 (16%) did not wish to have further 163

blood tests, 48 (9%) were unable to attend the surgery, 21 (4%) believed kidney problems 164

were of no concern to them and 80 (15%) did not give a reason. Other reasons for non-165

participation detailed in the free-text area on the research reply slip included old age, poor 166

mobility, presence of other health issues, concerns regarding the side effects of 167

spironolactone, reluctance to take additional medication, work commitments, being carer for 168

other family members, being away from home during trial period as well as unawareness of 169

CKD diagnosis. 170

171

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In a logistic regression model, age, male gender and coming from research-active practices 172

were associated with a greater willingness to participate in the trial, whereas ethnicity and 173

levels of eGFR were not predictive (Table 3). Age was noticeably non-linear in relation to 174

recruitment, with younger and older age associated with a lower likelihood of agreeing to 175

participate in the study (Figure 2). 176

177

Table 3: Logistic regression demonstrating factors associated with increased likelihood of 178

patients’ willingness to participate in the trial. (Age as Restricted Cubic Spline) 179

180

Variable Odds Ratio Lower 95% CI Upper 95% CI P

Intercept 0.01931 0.00095 0.394 0.0103

eGFR 1.00513 0.98076 1.030 0.6827

Male gender 1.36905 1.00544 1.864 0.0461

White Ethnicity 1.51474 0.96679 2.373 0.0699

Research Active Practice 1.42223 1.04079 1.943 0.0270

AGE 1.02677 0.97659 1.080 0.3014

AGE1 0.93568 0.79398 1.103 0.4275

AGE2 0.79572 0.15232 4.157 0.7865

AGE3 3.30525 0.10044 108.771 0.5024

P for non-linearity for Age 0.0111

P for overall effect of Age 0.0003

181

182

183

184

185

186

187

188

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Screening visit 189

Of the 196 patients who initially expressed an interest in participating in the study, 134 190

patients (69%) actually attended the screening visit. The characteristics of these patients are 191

presented in Table 4. The cause of CKD was unclear in the majority of the patients and only 192

17 patients (13%) had a documented cause of CKD. The median last-recorded MDRD eGFR 193

was 55 (IQR: 51-57) ml/min/1.73m2 with 88% within the range of 45-59 ml/min/1.73m

2. 194

195

In total, 52 (39%) patients were found to be ineligible for the study during the screening visit. 196

The reasons for exclusion are listed in Figure 1. The main cause for exclusion was low BP. 197

Thirty-two patients had an office SBP lower than 120 mmHg with 16 patients receiving at 198

least one anti-hypertensive agent, although five of these patients were known to have 199

ischaemic heart disease and thus another potential indication for treatment with these agents 200

other than hypertension. Of the 79 remaining eligible patients, a further 46 were excluded 201

after the screening blood test (Figure 1). The main reason for exclusion (31 patients) was 202

having an eGFR greater than 60 ml/min/1.73m2. 203

204

205

206

207

208

209

210

211

212

213

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Table 4: Baseline demographics, clinical characteristics, blood pressure measurements and 214

biochemistry profiles of patients attended screening visit and patients randomised to receive 215

trial medication. 216

Attended screening

visit

Randomised into STOP-

CKD study


Male gender, n. (%) 62 (46) 7 (44)

White ethnicity, n. (%) 125 (93) 16 (100)

Mean age (SD), years 68 (10) 71 (7)

Medical history, n. (%)

• Hypertension

• Hypercholesterolaemia

• Coronary heart disease

• Coronary artery bypass graft/angioplasty

• Stroke/transient ischaemic attack

• Peripheral vascular disease

Total number of comorbidities, median (IQR)

62 (46)

42 (31)

17 (13)

13 (10)

11 (8)

8 (6) 1 (0-2)

5 (31)

3 (19)

1 (6)

0

1 (6)

0 0 (0-1)

Medications, n. (%)

Anti-platelet agents

Lipid lowering agents

Use of anti-hypertensive agents

• Diuretics

• β-blockers

• ACEi/ARB

• Nitrates

• Calcium channel blockers

• α channel blockers

Patients not receiving any anti-hypertensive agents

34 (25)

54 (40)

74 (55)

20 (15)

20 (15)

48 (36)

5 (4)

21 (16)

11 (8)

60 (45)

4 (25)

4 (25)

9 (56)

1 (6)

2 (13)

5 (31)

0

4 (25)

0

7 (44)

Smoking history, n (%)

• Current smoker

• Ex-smoker

• Never smoker

8 (6)

55 (41)

71 (53)

1 (6)

7 (44)

8 (50)

BP Measurements

• Office systolic BP, mean (SD), mmHg

• Office diastolic BP, mean (SD), mmHg

• Office systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, n.

(%)

• Office BP within NICE CKD targets, n. (%)

• Office systolic BP <120 mmHg, n. (%)

132 (19) 79 (10)

47 (35)

54 (40)

34 (25)

133 (10) 78 (8)

10 (62)

6 (38)

0


Na+, mmol/L 141 (3) 142 (2) K+, mmol/L 4.5 (0.6) 4.5 (0.4)

Urea, mg/dL 6.8 (2.0) 6.9 (1.4)

Creatinine, median (IQR), µmol/L 98 (85-112) 101 (86-121)

MDRD eGFR (median, IQR), ml/min/1.73m2 57 (51-65) 54 (48-57)

CKD EPI eGFR (mean, SD), ml/min/1.73m2 59 (12) 53 (7)

Urine ACR (median, IQR), mg/mmol

• < 3 mg/mmol, n. (%)

• 3-30 mg/mmol, n. (%)

• > 30 mg/mmol, n. (%)

0.9 (0-2.0) 62 (79)

16 (20)

1 (1)

0.85 (0.08- 1.95) 13 (81)

3 (19)

0

Ca+2, mmol/L 2.38 (0.10) 2.38 (0.13)

Albumin, g/L 46 (2) 45 (1)

Total protein, g/L 72 (4) 71 (3) Alkaline phosphatase, U/L 78 (25) 79 (17)

Alanine Aminotransferase, U/L 20 (8) 19 (7)

217 Abbreviations: ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BP, blood 218 pressure,; Ca

+2,serum calcium; eGFR, estimated glomerular filtration rate; IQR, interquartile range; K

+, serum 219

potassium; Na+, serum sodium; n., number of patients; SD, standard deviation. 220

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Randomisation visit 221

Of the 33 remaining eligible patients, 28 (85%) attended the randomisation visit (Figure 1). A 222

further 12 patients were excluded at this point. Eight had an office SBP less than 120 mmHg, 223

three had postural hypotension and one had uncontrolled hypertension. Sixteen patients were 224

randomised and their baseline characteristics were shown in Table 4. 225

226

Early termination of study 227

In May 2014, the STOP-CKD study was terminated early because of futility. In order to 228

achieve the original planned sample size of 240 patients, the projected number of primary 229

care practices required to be involved in the study would be 145 practices covering a 230

population of more than 1.5 million. After thorough discussion, the trial Data Monitoring and 231

Ethics Committee and the Trial Steering Committee collectively agreed that the study was 232

not feasible with the allocated resources. 233

234

DISCUSSION 235

In the UK, as indeed in many countries, most patients with early-stage CKD are managed in 236

primary care. Many observational studies have established that these patients have several 237

differences compared with patients managed in secondary care32

. They tend to be older with a 238

lower prevalence of proteinuria and more preserved eGFR32

. These differences are important 239

if any intervention shown to be effective for the treatment of CKD in the minority of patients 240

treated in secondary care is rolled out to the community. The STOP-CKD trial was an attempt 241

to establish whether low-dose spironolactone, a treatment shown to be safe and effective in 242

improving surrogate markers of CV risk in patients with CKD managed in secondary care, 243

was equally safe and effective in patients with CKD managed in primary care. Although the 244

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study proved not to be feasible, there are several important findings and lessons that can be 245

learnt from it to inform future interventional studies in this population. 246

247

Estimating the number of patients needed 248

Assessing the number of patients needed to invite in order to recruit to the sample size is an 249

essential but challenging requirement in planning any study. Recently, a Japanese study 250

explored the use of information technology in predicting the success or failure of study 251

recruitment33

. The study derived the eligible EPR index by dividing the number of eligible 252

patients identified from the EPR by the target sample size. An EPR index of more than 1.7 253

was reported to have a sensitivity and specificity of approximately 70% and 100%, 254

respectively in predicting recruitment success. However, in spite of a much higher EPR index 255

of 6.7 that should have predicted successful recruitment, the STOP-CKD study failed to reach 256

its target sample size, suggesting that other recruitment issues were involved. 257

258

Following the EPR search, the number of patients eligible for invitation reduced considerably 259

after GP review. The variation observed in the proportion of patients excluded by GPs across 260

the practices suggests that there were large elements of subjectivity and inconsistency in this 261

assessment. It is likely that many patients fulfilling the inclusion criteria were excluded at this 262

stage. While the review of the list of potential participants by their corresponding GPs was 263

well intentioned, significant selection-bias might have occurred during the process and we 264

suggest that in future studies, this step requires revision with clear and transparent criteria. 265

266

Prevalence of chronic kidney disease 267

In the UK, primary care physicians are required to keep a register of patients with stages 3-5 268

CKD34 35

. Published data from the participating practices showed the average percentage of 269

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total patients on the CKD register was 3.89%, which is lower than the recently published 270

reports from UK research databases of 5.15%34

and 5.9%36

and marginally lower than that 271

reported for all English practices over 2010-2012 of 4.3%37

. Nevertheless, it appears that the 272

observed prevalence of CKD is much lower than the 10% figure which was the finding in 273

previous epidemiological work in the UK38

and globally6 39

. It has been suggested that the 274

prevalence of CKD has been significantly overestimated by using a single serum creatinine 275

measurement to define CKD40

and this has been confirmed in a recent UK study using two 276

creatinine measurements which reported a CKD prevalence of 3.9%34

. 277

278

In order to increase patient inclusivity and bypass the issues of un-coded or mis-coded 279

CKD34

, we searched and short-listed all patients with a latest recorded eGFR of 30-59 280

ml/min/1.73m2 in the preceding 12 months. The eGFR test performed at the screening visit 281

served as a confirmation of CKD diagnosis. Despite having an eGFR within 30-59 282

ml/min/1.73m2 previously, 40% of such patients were excluded due to an eGFR greater than 283

60 ml/min/1.73m2 at screening, and therefore, by definition did not have CKD stage 3. Of 284

those who fulfilled the biochemical eligibility criteria, most had only modest reduction in 285

eGFR with a median eGFR of 54 ml/min/1.73m2 and none were found to have significant 286

levels of albuminuria. 287

Blood pressure 288

The treatment of hypertension is still the cornerstone of management of CKD, both in terms 289

of CKD progression and the reduction of CV risk41 42

. In agreement with other studies, we 290

found less than half of the patients attending the screening visit achieved both the SBP and 291

DBP target recommended by the NICE CKD guidelines32 38

. Amongst those with SBP ≥ 140 292

mmHg or DBP ≥ 90 mmHg, more than 40% were in fact not receiving any anti-hypertensive 293

medication. 294

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295

It has long been believed that lowering office/clinic BP to levels lower than 120/80 mmHg is 296

associated with worse outcomes and increased mortality, especially in the elderly43

. This is 297

reflected in recent guidelines on the management of CKD that recommend BP not be lowered 298

below these levels25 44

. The results of the recent SPRINT trial challenge these guidelines45

299

and future studies might consider the inclusion of such patients. 300

301

Widening inclusion criteria 302

Faced with persistent recruitment difficulties, consideration to widen the STOP-CKD study 303

eligibility criteria had been suggested. However, the eligibility criteria remained unchanged 304

as each was believed to be essential not only in safeguarding patients’ safety, but also 305

ensuring validity of the research study. 306

307

Patients with diabetes represent a significant subgroup of the CKD population. It is possible 308

that as such patients have more regular contact with the healthcare professionals; they might 309

potentially be more aware of their disease label and more willing to participate in the study. 310

However, as patients with diabetes are known to have higher risk of hyperkalaemia and the 311

pathophysiology of their increased arterial stiffness is likely to be different to those without, 312

the inclusion of this subgroup of patients in this pilot study would result in a small study 313

population too heterogeneous to effectively address the primary research question. Though 314

the STOP-CKD study was unable to include patients with diabetes, the challenges faced by 315

the study and lessons learnt from it have thus far been used to inform the ongoing BARACK 316

D study46

, a large prospective, randomised, open blinded end-point trial aiming to determine 317

the effect of low-dose spironolactone on mortality and CV outcomes in patients with stage 3b 318

CKD in primary care. Encompassing stage 3b CKD population with a minimal SBP of 100 319

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mmHg, and including those with Type 2 DM; the participants’ criteria of BARACK D study 320

therefore varies somewhat from that of the STOP-CKD. Its findings, assuming the trial 321

successfully recruits, are therefore eagerly anticipated. 322

323

Primary care practice recruitment strategies 324

Though we designed the STOP-CKD study to minimise any extra workload on the 325

participating primary care practices, most practices declined the initial approach and it took a 326

lot of effort from the investigators to recruit the 11 practices that participated. In order to 327

improve the quality and quantity of primary care research in the UK, a ‘research ready self-328

accreditation’ initiative to support general practices in meeting the legal requirements of the 329

UK for carrying out research47

. Thus far, there are more than 1,000 research-ready general 330

practices in the UK48

. Our study demonstrated a significant positive influence of research-331

active practices on patients’ participation providing further support for these measures. 332

In addition, an integrated system which allows researchers to run complex searchers over 333

anonymised population-level health record, such as FARSITE, has proven to be a rapid 334

method in testing research feasibility, providing accurate selection of large patient population 335

from greater number of GP practices, facilitating administrative processes and importantly, 336

minimising research work-load for the practices49

. Innovative set-up of a more cohesive 337

health informatics system looks to be the key in supporting and delivering faster and more 338

effective research evidence of the real-world for the future50

. 339

Patient recruitment strategies 340

Although the need for a robust evidence base for any intervention before it becomes accepted 341

practice is now well established, there is surprisingly little evidence on how best to conduct 342

an RCT51 52

. Regulatory and ethical issues compelled us to contact potentially eligible 343

patients by mailshot through their GPs. This is a notoriously inefficient and costly process 344

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with large number of invitations needing to be sent to recruit the target number of patients. 345

Two key reviews previously explored the value of various strategies in improving 346

participants’ recruitment in research studies51 53

. The STEPS study suggested that being 347

flexible and robust in adapting to unexpected issues was important to ensure trials success53

348

whilst in the systematic review by Treweek et al, telephone reminders to non-responders, opt-349

out rather than opt-in system of being contacted about the study, financial incentives and 350

open designs all appeared to be effective strategies51

. 351

352

We suggest that an initial approach using telephone, text or email may yield better results and 353

that further research examining the acceptability and efficacy of initial recruitment strategies 354

is of major importance. In addition, the effects of shortening patients’ information sheet54

, 355

using computer pop-ups on patients’ electronic health records to highlight potential 356

participants, minimising frequency of research visits and optimising the use of healthcare 357

informatics for research data collection also worth exploring. Importantly, it is plausible that 358

the issue of low awareness of CKD diagnosis among the patients55

might have negatively 359

impacted on the recruitment of the STOP-CKD study. Efforts in developing wider 360

recruitment strategies which focus on increasing potential participants’ awareness and 361

understanding of CKD should therefore be considered56

. Suggested methods to improve CKD 362

research recruitment in primary care are listed in Table 5. 363

364

Our logistic regression model showed that younger and older patients were significantly less 365

likely to participate. Thus, although we designed the study with broad inclusivity criteria we 366

still did not manage to recruit the “real-life CKD population”, which may reflect patients’ 367

self-selection bias. Strategies to recruit these patients therefore need developing and testing in 368

future studies. 369

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370

Table 5: Suggested methods to improve CKD research recruitment in primary care 371

� Open design

� Concise patient information sheet

� Minimise frequency of research visit

� Optimise use of routinely collected data via healthcare informatics

� Telephone, text or email as initial approach and reminder for non-responder

� Financial incentives/eliminating financial disincentives

� Computer pop-ups on healthcare records

� Increase disclosure of CKD diagnosis from healthcare providers to patients

� Improve patients’ understanding of CKD and its implications.

372

CONCLUSIONS 373

The STOP-CKD study was a non-age restricted, investigator-led, feasibility RCT designed to 374

inform a future larger, hard end-point study in patients with CKD in primary care. The study 375

highlighted the unique characteristics of the CKD population in primary care, which 376

challenged our preconceived knowledge about the appropriate intervention and management 377

of this sizeable group of patients. With the majority of interventional studies on patients with 378

CKD thus far based in secondary care, there remains an urgent need to optimise the 379

generalisability of future CKD research, especially in primary care. The experience and 380

lessons learnt from this study provide important information for all CKD researchers to 381

meticulously reflect on their future research aims, study design, choices of intervention and 382

most importantly recruitment strategies. As Henry Ford once said, ‘failure is only the 383

opportunity to begin again, only this time more wisely’. 384

385

386

387

388

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389

Authors’ contributions 390

PJ, PSG, JNT, NF, SG, RJM and CJF were responsible for the study conception and design. 391

KPN, PJ and GH were involved in patient recruitment. KPN drafted the manuscript. NF was 392

the study statistician. All authors have critically reviewed the manuscript and given final 393

approval of the version to be published. 394

395

Acknowledgements 396

We would like to acknowledge the support of the staff at the PC-CRTU at the University of 397

Birmingham, especially Val Redman and Dr Odette Chagoury; research nurses and clinical 398

trials pharmacists at the Birmingham and Black Country Comprehensive Local Research 399

Network, especially Sandeep Pahal and Claire Norton; all community pharmacists involved 400

in the STOP-CKD study; Mona Koshkouei and Alison Perry at Lloyds pharmacy; Alan 401

Wong and Sabina Melander in the pharmacy production department at the Royal Free 402

Hospital as well as the patient and public involvement representatives, DMEC, TSC, funders 403

and sponsor of this study. Importantly, we would also like to acknowledge the support of the 404

patients, staff and GPs at the eleven recruiting practices; 405

406

Declaration 407

This paper presents independent research funded by the NIHR under the Research for Patient 408

Benefit programme (PB-PG-0010-21226). The views expressed in this publication are those 409

of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. 410

411

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Funding 412

The STOP-CKD study was funded by a project grant from the NIHR Research for Patient 413

Benefit programme (PB-PG-0110-21226), a personal Fellowship awarded to CJF from the 414

NIHR Fellowship scheme and the Birmingham and Black Country Comprehensive Local 415

Research Network strategic fund. RJM holds an NIHR Professorship. 416

417

Sponsor 418

The STOP-CKD study was sponsored by the University of Birmingham (Dr Sean Jennings, 419

Research Governance and Ethics Manager, Research Support Group, University of 420

Birmingham, Edgbaston, Birmingham, B15 2TT, UK). The University of Birmingham holds 421

public liability (negligent harms) and clinical trial (negligent harm) insurance policies, which 422

apply to this trial. 423

424

Competing Interests 425

RJM has received BP monitors from Omron and Lloyds Pharmacies. NF has received 426

funding for research, consulting and travel from Sanofi Aventis, Novo Nordisk, Eli Lilly, 427

Ipsen, Roche and Intermune. The other authors declare that they have no relevant financial 428

interests. 429

430

431

Data sharing 432

No additional data available. 433

434

435

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Legends of Figures 585

Figure 1: The CONSORT flow diagram of STOP-CKD study 586

* Some patients had multiple reasons of ineligibility 587 **multiple adverse reaction to anti-hypertensive in the past and previous endovascular aortic aneurysm repair which would 588 affect PWV measurements 589 590

Figure 2: Relative odds and 95% confidence interval of recruitment by age using restricted 591

cubic spline. 592

NB: Solid line = estimate, dotted lines = 95% CIs. 593

594

595

Supplementary File 596

Appendix 1: STOP-CKD study protocol 597

Appendix 2: STOP-CKD research invitation letter 598

599

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Figure 1: The CONSORT flow diagram of STOP-CKD study * Some patients had multiple reasons of ineligibility

**multiple adverse reaction to anti-hypertensive in the past and previous endovascular aortic aneurysm

repair which would affect PWV measurements. 220x271mm (600 x 600 DPI)

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Figure 2: Relative odds and 95% confidence interval of recruitment by age using restricted cubic spline. NB: Solid line = estimate, dotted lines = 95% CIs.

180x188mm (600 x 600 DPI)

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CONSORT 2010 checklist of information to include when reporting a randomised trial*

Section/Topic Item No Checklist item

Reported on page No

Title and abstract

1a Identification as a randomised trial in the title 1

1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) 2,3

Introduction

Background and

objectives

2a Scientific background and explanation of rationale 5

2b Specific objectives or hypotheses 6

Methods

Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 6,7

3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons N/A

Participants 4a Eligibility criteria for participants Table 1

4b Settings and locations where the data were collected 6

Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were

actually administered

7,8

Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they

were assessed

8

6b Any changes to trial outcomes after the trial commenced, with reasons N/A

Sample size 7a How sample size was determined 8

7b When applicable, explanation of any interim analyses and stopping guidelines N/A

Randomisation:

Sequence

generation

8a Method used to generate the random allocation sequence 8

8b Type of randomisation; details of any restriction (such as blocking and block size) 8

Allocation

concealment

mechanism

9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers),

describing any steps taken to conceal the sequence until interventions were assigned

Appendix 1

Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to

interventions

8

Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those 8

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assessing outcomes) and how

11b If relevant, description of the similarity of interventions 8

Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 9

12b Methods for additional analyses, such as subgroup analyses and adjusted analyses 9

Results

Participant flow (a

diagram is strongly

recommended)

13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and

were analysed for the primary outcome

Figure 1

13b For each group, losses and exclusions after randomisation, together with reasons Figure 1

Recruitment 14a Dates defining the periods of recruitment and follow-up 12,16

14b Why the trial ended or was stopped 16

Baseline data 15 A table showing baseline demographic and clinical characteristics for each group Table 4

Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was

by original assigned groups

12, 13

Outcomes and

estimation

17a For each primary and secondary outcome, results for each group, and the estimated effect size and its

precision (such as 95% confidence interval)

N/A

17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended N/A

Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing

pre-specified from exploratory

12,13

Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) Figure 1

Discussion

Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 3, 17-20

Generalisability 21 Generalisability (external validity, applicability) of the trial findings 3, 17-20

Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence 20

Other information

Registration 23 Registration number and name of trial registry 4,8

Protocol 24 Where the full trial protocol can be accessed, if available 6, Appendix 1

Funding 25 Sources of funding and other support (such as supply of drugs), role of funders 23

*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also

recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials.

Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.

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BMJ OpenCV risk9-12. Many of these abnormalities are indeed already evident in patients with only mild abnormalities of kidney function (estimated glomerular filtration rates [eGFR]: