ATTACG: Anakinra versus Treatment as usual in the ... · 9/19/2017 · Research Protocol NL52526.044.15 / ATTACG 7 List of abbreviations MSU Monosodium urate NSAIDs Non-steroidal

Research Protocol

ATTACG: Anakinra versus Treatment as

usual in the Treatment of ACute Gout

Version 11: 19 September 2017

Research Protocol NL52526.044.15 / ATTACG

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Project Information

Study title: Anakinra versus treatment as usual in the treatment of acute

gout

Short title: ATTACG

Dutch title: Anakinra versus standaardbehandeling bij acute jicht

Protocol ID: NL52526.044.15

EudraCT number: 2015-000696-27

Version: 11

Date: 19 September 2017

Coordinating investigator: C.A. (Carly) Janssen MSc

Principal investigator: Prof. dr. M.A.F.J. (Mart) van de Laar

Multicenter research (investigator

per site):

1. Medisch Spectrum Twente, Enschede (Principal site):

M.A.F.J. van de Laar & H.E. Vonkeman

2. Rijnstate, Velp/Arnhem: H. Visser

3. VieCuri Medical Centre, Venlo: T. Jansen

4. Medisch Center Leeuwarden, Leeuwarden: R. Bos

5. Ziekenhuisgroep Twente, Almelo/Hengelo: H. Baan

6. Röpcke-Zweers Ziekenhuis, Hardenberg: C. Lebrun

7. Bernhoven Ziekenhuis, Uden: P.L.C.M. van Riel

8. Maastricht Universitair Medisch Centrum,

Maastricht: A.E.R.C.H. Boonen

9. Maasstad Ziekenhuis, Rotterdam, M.R. Kok

Sponsor (in Dutch

verrichter/opdrachtgever):

Prof. dr. M.A.F.J (Mart) van de Laar (University of Twente,

UT)

Subsidizing parties: ZonMw, Sobi

Independent physician: Dr. W.M. Smit (Department of Internal Medicine, Medisch

Spectrum Twente, Enschede)

Pharmacy: Slotervaart Hospital

Department of Pharmacy & Pharmacology

Louwesweg 6

1066 EC Amsterdam, the Netherlands


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Table of Contents

1. INTRODUCTION AND RATIONALE............................................................................................................. 9

2. STUDY AIMS ........................................................................................................................................... 10

PRIMARY OBJECTIVE ............................................................................................................................................... 10

SECONDARY OBJECTIVES .......................................................................................................................................... 10

3. STUDY DESIGN ....................................................................................................................................... 11

DURATION AND DESIGN .......................................................................................................................................... 11

MULTI-CENTER RESEARCH ....................................................................................................................................... 11

COORDINATING PHARMACY ..................................................................................................................................... 11

4. STUDY POPULATION .............................................................................................................................. 12

POPULATION ......................................................................................................................................................... 12

INCLUSION CRITERIA ............................................................................................................................................... 12

EXCLUSION CRITERIA ............................................................................................................................................... 12

5. TREATMENT OF SUBJECTS ...................................................................................................................... 14

INVESTIGATIONAL TREATMENT.................................................................................................................................. 14

COMPARATOR TREATMENT ...................................................................................................................................... 14

NON-ACTIVE PLACEBOS ........................................................................................................................................... 14

URATE LOWERING THERAPY (ULT) ............................................................................................................................ 14

RESCUE MEDICATION ............................................................................................................................................. 14

REFRACTORY GOUT ATTACK ..................................................................................................................................... 15

6. INVESTIGATIONAL TREATMENT ............................................................................................................. 16

NAME AND DESCRIPTIVE .......................................................................................................................................... 16

SUMMARY OF FINDINGS FROM PRE-CLINICAL STUDIES ................................................................................................... 16

SUMMARY OF FINDINGS FROM CLINICAL STUDIES .......................................................................................................... 16

SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS ........................................................................................... 17

DESCRIPTION AND JUSTIFICATION OF ROUTE OF ADMINISTRATION AND DOSAGE ................................................................. 17

PREPARATION AND LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCT ......................................................................... 18

DRUG ACCOUNTABILITY ........................................................................................................................................... 18

7. NON-INVESTIGATIONAL TREATMENT .................................................................................................... 19

NAME AND DESCRIPTION OF AVAILABLE SOC TREATMENTS ............................................................................................. 19

Colchicine ...................................................................................................................................................... 19

NSAID, naproxen ........................................................................................................................................... 19

Systemic corticosteroid, prednisolon ............................................................................................................ 19

URATE LOWERING THERAPY .................................................................................................................................... 19

NON-ACTIVE SOC PLACEBOS .................................................................................................................................... 19

DOSAGE AND METHOD OF ADMINISTRATION ............................................................................................................... 19

PREPARATION AND LABELLING OF NON-INVESTIGATIONAL MEDICINAL PRODUCT ................................................................. 20

DRUG ACCOUNTABILITY ........................................................................................................................................... 20

8. METHODS .............................................................................................................................................. 21

STUDY ENDPOINTS ................................................................................................................................................. 21

Primary endpoint .......................................................................................................................................... 21

Secondary endpoints of 3 month randomized controlled trial ..................................................................... 21


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Secondary endpoints of 9 month open label study extension ...................................................................... 21

DATA COLLECTION ................................................................................................................................................. 21

DATA COLLECTION TOOLS ........................................................................................................................................ 23

Patient numbering ........................................................................................................................................ 23

Baseline characteristics ................................................................................................................................ 23

Uric acid and CRP measurement .................................................................................................................. 23

Patient flare diary ......................................................................................................................................... 23

Patient reported outcomes (PROs) ............................................................................................................... 23

Side effects , AE and SAE .............................................................................................................................. 24

Direct and indirect costs ............................................................................................................................... 25

Study drop-out or completion ....................................................................................................................... 25

DISTRIBUTION OF MEDICINES TO PARTICIPATING CENTERS .............................................................................................. 25

RANDOMIZATION, BLINDING AND TREATMENT ALLOCATION............................................................................................ 25

WITHDRAWAL OF INDIVIDUAL SUBJECTS FROM THE STUDY ............................................................................................. 26

REPLACEMENT OF INDIVIDUAL SUBJECTS AFTER WITHDRAWAL FROM THE STUDY ................................................................. 26

FOLLOW-UP OF SUBJECTS WITHDRAWN FROM STUDY .................................................................................................... 26

FOLLOW-UP OF SUBJECTS WITHDRAWN FROM TREATMENT ............................................................................................ 26

PREMATURE TERMINATION OF THE STUDY................................................................................................................... 26

9. SAFETY REPORTING................................................................................................................................ 27

SECTION 10 WMO EVENT ...................................................................................................................................... 27

SAFETY MONITORING .............................................................................................................................................. 27

AE REPORTING ...................................................................................................................................................... 27

SAE REPORTING .................................................................................................................................................... 28

SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS REPORTING ................................................................................. 28

FOLLOW-UP OF AE AND SAE ................................................................................................................................... 29

ANNUAL SAFETY REPORT ......................................................................................................................................... 29

DATA SAFETY MONITORING BOARD .......................................................................................................................... 29

10. DATA ANALYSES ................................................................................................................................ 30

POPULATIONS ....................................................................................................................................................... 30

PRIMARY EFFICACY ANALYSES ................................................................................................................................... 30

MISSING DATA ...................................................................................................................................................... 31

SECONDARY ANALYSES ............................................................................................................................................ 31

SAFETY ANALYSES .................................................................................................................................................. 31

COST EFFECTIVENESS ANALYSES ................................................................................................................................ 32

SAMPLE SIZE CONSIDERATIONS ................................................................................................................................. 32

11. ETHICAL CONSIDERATIONS ................................................................................................................ 33

REGULATORY AND ETHICAL COMPLIANCE .................................................................................................................... 33

RECRUITMENT AND INFORMED CONSENT PROCEDURES .................................................................................................. 33

COMPENSATION FOR INJURY .................................................................................................................................... 33

12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .......................................................... 34

HANDLING DATA AND DOCUMENTS ........................................................................................................................... 34

MONITORING AND QUALITY ASSURANCE ..................................................................................................................... 34

PROTOCOL ADHERENCE AND AMENDMENTS ................................................................................................................ 34

ANNUAL PROGRESS REPORT ..................................................................................................................................... 35

END OF STUDY REPORT ............................................................................................................................................ 35


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PUBLIC DISCLOSURE AND PUBLICATION POLICY ............................................................................................................. 35

13. STRUCTURED RISK ANALYSIS ............................................................................................................. 36

POTENTIAL RISKS AND CONCERNS RELATED TO THIS STUDY.............................................................................................. 36

Summary anakinra and gout studies ............................................................................................................ 36

Risks and concerns related to anakinra ........................................................................................................ 36

Other risks and concerns .............................................................................................................................. 37

REDUCING AND MANAGING THE POTENTIAL RISKS AND CONCERNS ................................................................................... 37

14. REFERENCE LIST ................................................................................................................................. 39

15. APPENDICES ...................................................................................................................................... 43

I. CRF INFORMATION ....................................................................................................................................... 43

II. PATIENT FLARE DIARY ..................................................................................................................................... 43

III. PROS QUESTIONNAIRES ................................................................................................................................. 43

IV. DSMB CHARTER .......................................................................................................................................... 43


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List of abbreviations

MSU Monosodium urate

NSAIDs Non-steroidal anti-inflammatory drugs

SoC Standard of Care

ULT Urate lowering therapy

IL Interleukin

TNF Tumor necrosis factor

NI Non-inferiority

NVR Dutch Society for Rheumatology (in Dutch: Nederlandse Vereniging voor Reumatologie)

SPC Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-tekst)

IB Investigator’s Brochure

METC Medical Ethical Testing Committee (in Dutch: Medisch Ethische Toetsingscommissie)

RA Rheumatoid arthritis

SC Subcutaneous

CRP C-reactive protein

AE Adverse Event

SAE Serious Adverse Event

HR-QOL Health related quality of life

QOL Quality of life

EDC Electronic data capture

CRF Case report form

PROs Patient Reported Outcomes

NRS Numeric rating scale

HAQ-DI Health Assessment Questionnaire Disability Index

SF-36 Short form-36

WPAI 18 Work productivity and activity impairment questionnaire

Sobi Swedish Orphan Biovitrum Ltd

IMPD Investigational Medicinal Product Dossier

DSMB Data Safety Monitoring Board

SUSAR Suspected Unexpected Serious Adverse Reaction

ITT Intent-to-treat

PP Per-protocol

CI Confidence interval

QALDs Quality adjusted life days

ICUR Incremental cost-utility ratio

WMO Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch Wetenschappeljik Onderzoek)

Wbp Dutch Personal Data Protection Act (in Dutch: de Wet bescherming persoonsgegevens)


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Summary

Background: Gout is a common form of inflammatory arthropathy, with hyperuricemia being the

predominant risk factor. The close relationship between gout and hyperuricemia has led to treatment

strategies wherein both the acute gout flare and hyperuricemia are targeted simultaneously. Currently

available treatment options for gout flares (colchicine, corticosteroids and non-steroidal anti-

inflammatory drugs; referred to as standard of care (SoC)) are frequently contra-indicated or poorly

tolerated by gout patients due to presence of significant multi-morbidity. Anakinra (Kineret) is an IL-

1 receptor antagonist presently indicated for the treatment of rheumatoid arthritis (RA) and Cryopyrin-

Associated Periodic Syndromes. At present, anakinra has been studied in a handful of case series and

small open label studies for its clinical efficacy and safety in acute gout.

Objective: To demonstrate non-inferiority (NI) of anakinra compared with the SoC in the treatment of

acute gout flares. Also, to compare the safety and cost per quality-adjusted life day between anakinra

and SoC and to compare the 3 and 12 months clinical outcome of patients initially treated with

anakinra versus SoC and starting ULT.

Study design: A 3 month multi-center randomized, double (dummy)-blinded, placebo controlled NI

trial, followed by a 9 month open label follow-up study.

Study population: 200 patients with an acute gout flare.

Intervention: Patients will be randomized to 5 consecutive days of daily a 100mg injection of anakinra

+ SoC pill placebo or SoC treatment + 5 consecutive days of anakinra injection placebo. SoC treatment

dosage and duration is according to standard procedures. Both arms will receive urate lowering

therapy according to standard procedures.

Main study endpoints: The main study endpoint is the change in patient-reported pain in the index

joint from baseline to the average of pain values at 24, 48 and 72 hours after initiating treatment.

Secondary endpoints include (in-) direct costs, quality of life (QOL), physical functioning, treatment

side effects, changes in joint swelling & tenderness, C-reactive protein (CRP), uric acid level, patient

perceived treatment response and number of recurrent flares.

Burden, risks and benefits: Patients will have to visit the treating rheumatologist at day 1, 7 and at

month 3 during the study period. At 6 time points over the course of the study patients will have to fill

in a survey questionnaire. During the first 7 days after starting the study (or by onset of a new gout

attack), patients will additionally be required to fill in a survey on patient reported outcomes,

medication intake and experienced side effects. Main risks associated with using anakinra are the

possible physical discomfort of subcutaneous (SC) treatment injections, headache, local (skin) injection

site reaction, increased total blood cholesterol levels, thrombocytopenia, serious (respiratory or skin)

reactions, neutropenia or/and allergic reactions. Relapse of a gout flare might occur sooner in patients

receiving anakinra or prednisolone compared to patients receiving prophylactics. The potential risks

and concerns associated with this study are managed due to strict inclusion and exclusion criteria and

the establishment of a Data Safety Monitoring Board (DSMB) and through active safety monitoring.

Any remaining risks are considered acceptable since the risks are not considered severe or life

threatening.


1 Throughout the entire protocol these standard treatment options, colchicine, NSAIDs and corticosteroids, will be referred to as standard of care (SoC) 9

1. Introduction and Rationale

Gout is a common form of inflammatory arthropathy most frequently seen in men and in women

primarily after menopause (1–3). Studies in various geographic locations have shown the prevalence

of gout to be increasing over time, which is frequently attributed to the increasing longevity of the

population and the accumulation of gout risk factors in older age (1,4–9). Individuals with gout often

present with multiple comorbid conditions, including metabolic syndrome (including hypertension,

diabetes mellitus and obesity), cardiovascular disease and kidney disease (3,4,10). Hyperuricemia is

the predominant risk factor for gout and possibly also for many of its most common comorbidities (1).

When left untreated, elevated serum uric acid levels can lead to precipitation of monosodium urate

(MSU) crystals in and around the joints, initiating and stimulating a local inflammatory response.

Although many individuals with chronic hyperuricemia remain asymptomatic, the risk for gout is

greater than when serum uric acid levels are kept within the clinical desired range (0.30 - 0.35 mmol/L).

The clinical manifestation of an acute gout flare is recognized for causing excruciating pain. It can have

its onset in any joint in the body, however, primarily the lower joints in the legs are affected.

The close relationship between gout and hyperuricemia has led to treatment strategies wherein both

the acute gout flare and hyperuricemia are targeted simultaneously (11–13). Three standard options

are available to treat pain and inflammation associated with acute gout, including colchicine, non-

steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids1. In the Netherlands, allopurinol,

febuxostat and benzbromaron are currently available for the treatment of hyperuricemia by

normalizing uric acid levels in the body, also referred to as urate lowering therapy (ULT). Reduction of

serum uric acid levels following initiation of ULT may induce acute gout flares. To prevent the onset of

these flares, NSAIDS and colchicine are, additionally, recommended as prophylactics agents when

initiating ULT (14–18). Although gout is a well understood rheumatic disease, currently available

treatment options are frequently contra-indicated or poorly tolerated by gout patients, which

frequently presents in the presence of significant multi-morbidity.

Since the discovery of the inflammasome, the crucial role of interleukin (IL) - 1 in initiating and

maintaining gouty inflammation has become well recognized (3,19). Precipitated MSU crystals at

inflamed joint sites get phagocytized by macrophages or monocytes, leading to intracellular activation

of the NALP3 inflammasome. This system subsequently activates caspase-1, promoting the maturation

of Pro-IL-1β and extracellular excretion of pro-inflammatory IL-1β (19,20). Secreted IL-1β then binds

to the IL-1 receptor on local endothelial cells and macrophages, signaling them to produce further pro-

inflammatory cytokines and chemokines, including tumor necrosis factor (TNF)-α, IL-6, and neutrophil

chemo attractants (21). These amplify the inflammatory response, attracting other inflammatory cells,

including neutrophils, into the area.

For complex gout patients presenting with multiple comorbidities, IL-1 antagonists may be of great

significance. In 2013, the European Medicines Agency approved the medicinal product canakinumab,

a fully human monoclonal anti-human IL-1β antibody, for the treatment of acute gout flares. Due to

very high costs per treatment, this agent is reimbursed only for patients with frequent gout flares (>2

per year) who cannot tolerate any of the three standard treatments, to a maximum of 2.5 Million euros

per year in the Netherlands.


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Anakinra (Kineret) is a DNA recombinant IL-1 receptor antagonist currently registered for the

treatment of rheumatoid arthritis and Cryopyrin-Associated Periodic Syndromes. It acts by

competitively inhibiting the binding of IL-1α and IL-1β to IL-1 type I receptors, causing the biological

activity of these interleukins to be neutralized. The clinical efficacy and safety of anakinra in acute gout

have been investigated and reported on in a few case series or small open label studies (22–45).

Although these studies provide a proof of concept for the plausibility and clinical importance of

anakinra as a treatment option for acute gout, no large scale clinical trial has yet been performed. The

primary goal of the proposed study is to demonstrate the non-inferiority (NI) of anakinra versus

treatment as usual in patients with acute gout. Secondary goals are to compare the cost-effectiveness

of anakinra to treatment as usual, to evaluate the safety of anakinra and to compare the 3 and 12

months clinical outcome of gout patients initially treated with anakinra or treatment as usual starting

ULT.

2. Study Aims

Primary objective

To demonstrate the NI of anakinra compared with the SoC in the treatment of acute gout flares.

Secondary objectives

To compare the cost per quality-adjusted life day between anakinra and SoC.

To evaluate the safety of anakinra in the treatment of acute gout flares.

To compare the 3 and 12 months clinical outcome of patients initially treated with anakinra versus

SoC and starting ULT.


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3. Study Design

Duration and design

The total study duration is 12 months. The initial 3 month study is a multi-center randomized, double

(dummy)-blinded, placebo controlled NI trial, followed by a 9 month open label extension study.

200 patients with crystal proven acute gout will be randomly allocated in the ratio 1:1 to either 1) 5

consecutive days of 100 mg daily anakinra injection and SoC pill placebo or 2) one of the SoC treatment

options and 5 consecutive days of 100 mg anakinra injection placebo. SoC treatment allocation, dosage

and duration are in line with the national guidelines for gout setup by the Dutch Society of

Rheumatology (Dutch: Nederlandse Vereniging voor Reumatologie, NVR) (16). In line with these

guidelines, when tolerable, patients will be appointed SoC treatment with colchicine or NSAID which

will then be continued prophylactically for 90 days when initiating ULT. Patients in both arms will also

receive ULT according to recommendations as stated in the national guidelines for gout by the NVR

(16).

Multi-center research

Subjects will be included into the study by rheumatologists working in different medical centers in the

Netherlands. Between 4-10 centers will participate in this study. General practitioners in the region of

the participating medical centers will be informed and asked to refer patients with suspected gout to

the closest study center.

Coordinating pharmacy

The following pharmacy will function as pharmacy for the production, labelling and distribution of

study medicines in this study:

Slotervaart Hospital

Department of Pharmacy & Pharmacology

Louwesweg 6

1066 EC Amsterdam, the Netherlands


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4. Study Population

Population

The study population will include both male and female patients with an acute gout flare.

Inclusion criteria

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

At least 18 years of age

Signed written informed consent

Identification of intracellular MSU crystals in primary joint through aspiration of joint

Exclusion criteria

A potential subject who meets any of the following criteria will be excluded from participation in this

study in case of:

Absolute contra-indication for all available types of ULT (allopurinol, febuxostat and

benzbromaron)

Contra-indications allopurinol: Hypersensitivity to the active substance or to any of the

excipients (see for the excipients the official SPC for the brand given).

Contra-indications febuxostat: Hypersensitivity to the active substance or to any of the

excipients (see for the excipients the official SPC for the brand given).

Contra-indications benzbromaron: Hypersensitivity to the active substance or to any of the

excipients (see for the excipients the official SPC for the brand given). Patients with known liver

disease. Concomitant use of hepatotoxic drugs, particularly antituberculosis agents. Hepatic

porphyia. Severe renal impairment (clearance < 30 ml/min.). Patients with secretion of urate

higher than 700 mg/24 hours (= 4.2 mmol/24 hour). Urolithiasis. Acute gout flare

Absolute contra-indication for anakinra

Contra-indications anakinra: Hypersensitivity to the active substance or to any of the excipients

(citric acid anhydrous, sodium chloride, disodium edetate dihydrate, polysorbate 80, sodium

hydroxide, water for injections) or to E. coli derived proteins. Kineret must not be used in

patients with severe renal impairment (creatinine clearance rate < 30 ml/minute). Kineret

treatment must not be initiated in patients with neutropenia (absolute neutrophil count <1.5 x

109 /l).

Presence of liver disease that according to the treating physician precludes participation

in the study

Absolute contra-indication for all three of the possible SoC treatments (colchicine,

naproxen, prednisolon)

Contra-indications colchicine: Hypersensitivity to the active substance or to any of the

excipients (microcrystalline cellulose (E460), lactose, sodium carboxy starch, magnesium

stearate (E470b)). Women of childbearing age, unless effective contraceptive measures are

taken. Colchicine should not be used in patients with severe renal impairment or severe hepatic

impairment.

Contra-indications naproxen: Hypersensitivity to the active substance or to any of the

excipients (potato starch, lactose, hydroxypropyl cellulose (200 CP), magnesium stearate,

colloidal anhydrous silicon dioxide). Naproxen is contra-indicated in patients who have


13

previously shown allergic reactions (e.g. asthma, rhinitis or urticaria) in response to

acetylsalicylic acid or other prostaglandin-synthesis inhibitors. Severe anaphylactoid reactions

have been reported in these patients. In principle, naproxen must not be administered to

patients with gastrointestinal ulcerations, congestive gastritis or atrophic gastritis,

gastrointestinal bleeding or other bleeding such as cerebrovascular bleeding. Severe renal

impairment.

Contra-indications prednisolon: Hypersensitivity to the active substance or to any of the

excipients (lactose, magnesium stearate (E470b), silicon dioxide (E551), potato starch,

pregelatinized potato starch, sodium (potato) starch glycolate, magnesium stearate (E572),

erythrosine (E127)). Gastric and duodenal ulcers. Acute infectious processes, particularly viral

infections and systemic fungal infections. Tropical worm infections. Administration after

vaccination with a live attenuated virus. Ocular herpes simplex.

Known history of allergy or sensitivity to latex

Current use of any ULT (ULT therapies are allopurinol, febuxostat and benzbromaron)

Concurrent use of other IL-1 agents (to this category belong: canakinumab and rilonacept)

Patient reports no to mild gout related pain

Pregnancy or lactation

Women who are planning on becoming pregnant within the study period (12 months)

Patients with active or recurrent bacterial, fungal or viral infection

Patients using TNF inhibitors (to this category belong: Certolizumab, Golimumab,

Adalimumab, Etanercept, Infliximab)

Patient has insufficient knowledge of the Dutch language for completing questionnaires

independently


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5. Treatment of subjects

Investigational treatment

Patients allocated to the investigational treatment group will receive Kineret (active substance

anakinra). For specific information regarding the product characteristics, safety, therapeutic

indications, dosage and duration, etcetera, please see Chapter 6: Investigational treatment of this

protocol.

Comparator treatment

Subjects allocated to the active comparator group will receive colchicine, naproxen (NSAIDS) or

prednisolon (systemic corticosteroids). These treatments are standard medicinal products currently

registered for treating acute gouty arthritis. Per specific case, the treating rheumatologist will decide

on the SoC treatment the patient may receive, according to their medical history, contraindications,

intolerances, etcetera. This is in line with the guidelines for gout treatment as setup by the NVR (16).

All the participating centers will receive medication for all three of the SoC treatments, making the

rheumatologists free to choose the best tolerable SoC treatment for the patient. For specific

information (e.g. dosage and duration) on the standard treatments, please see Chapter 7: Non-

investigational treatment of this research protocol.

Non-active placebos

To ensure blinding, patients will receive non-active placebos. Subjects in the investigational anakinra

treatment group will receive a non-active placebo resembling the SoC treatments. Subjects in the

comparator group will receive a non-active anakinra injection placebo (NaCl 0.9%, 0.67 ml) resembling

the anakinra treatment injection. For details on the blinding of study medication see Chapter 8:

Methods, section Randomization, Blinding and treatment allocation of this research protocol.

Urate lowering therapy (ULT)

All subjects included in either treatment arm will start ULT at baseline. ULT is part of standard

prophylaxis in the treatment of recurrent acute gout flares according to the NVR treatment guidelines

for gout (16). When tolerable, patients will be appointed ULT with allopurinol. When allopurinol cannot

be tolerated, alternatively benzbromaron or febuxostat will be appointed. Please see Chapter 7: Non-

investigational treatment of this research protocol for further details.

Rescue Medication

No rescue medication will be prescribed during the first 7 days after starting the study (baseline – day

7). Patients may use over the counter medicines as NSAIDs and acetaminophen during this time.

Patients will be asked to report the use of any over the counter medicines, as well as other medication

in the patient flare diary. During the rest of the study period, patients can use over the counter

medication and will be asked to rapport the use in the flare diary during the occurrence of refractory

gout attacks.


15

Refractory gout attack

Patients will return to their treating rheumatologist 7 days after starting the study medication for their

initial acute gout flare. In case of an ongoing or new gout flare between day 7 until the end of the

study, the treating rheumatologist will decide on the gout treatment to give the patient. Treatment

options will be according to standard clinical care. Anakinra treatment will not be available as

treatment option for refractory gout attacks. Patients will be instructed to contact their treating

rheumatologist in case a new gout flare arises during the study period. The treating rheumatologist

can, together with the sponsor, decide if breaking the treatment randomization code is needed in

order to provide the best optimal care for the patient.


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6. Investigational treatment

For a detailed description of the investigational product characteristics, therapeutic indications,

dosages, pharmaceutical properties, side effects, etcetera, please see the Summary of Product

Characteristics (SPC) and Investigator’s Brochure (IB) submitted as part of the dossier for the Medical

Ethical Testing Committee (in Dutch: Medisch Ethische Toetsingscommissie, METC). A short summary

of general information regarding anakinra and studies with anakinra for gout is given below.

Name and descriptive

Kineret contains the active substance anakinra. It is a recombinant, nonglycosylated form of the

human IL-1 receptor antagonist (r-metHuIL-1ra). Besides the inclusion of a single methionine residue

at its amino terminus, it is identical to the naturally present human IL-1 receptor antagonist. Anakinra

is produced by means of recombinant DNA technology in Escherichia coli cells. Currently, Kineret is

registered for treating adults with signs and symptoms of rheumatoid arthritis (RA) and for cryopyrin-

associated periodic syndromes.

Summary of findings from pre-clinical studies

Pre-clinical information regarding anakinra is listed in the SPC. One animal study has been done with

anakinra and gout by So et al. 2007 (34). The effectiveness of IL-1 inhibition in relieving inflammatory

manifestations associated with gout was studied in in-vivo MSU crystal-induced inflammation BALB/c

mice. The mice were given anakinra injections, anti-IL-1R1 monoclonal antibodies or anti-TNF

monoclonal antibodies and the level of neutrophil recruitment was determined. Both anakinra and the

anti-IL-1R1 monoclonal antibody showed comparable inhibitory effects on neutrophil recruitment. The

results were statistically significant compared to a positive MSU control. Another in-vitro study has

been done that aimed to prove that IL-1β is the main inflammatory component present in macrophage

supernatants, that promotes MSU crystal-induced neutrophil extracellular traps release (46).This was

tested by using anakinra to determine the inhibition of the release. The results showed that anakinra

has anti-inflammatory mechanisms.

Summary of findings from clinical studies

In total, the clinical effectiveness of anakinra in gout has been documented in 22 case reports and/or

series, 1 small open-label study and 1 survey study (updated 4 August 2017) (22–45). The patients

included in these studies were all complex gouty arthritis patients with severe comorbidities and/or

intolerance to conventional therapies, with the exception of one study, Petite et al. 2016 (45).

Treatment with anakinra was, therefore, used as an alternative agent in all studies. In general, in the

22 case reports and/or series, anakinra demonstrated to rapidly and effectively alleviate the pain

associated with gout in the majority of the patients. Dosage regimes differed between patients, with

some taking 100 mg anakinra daily for three to five consecutive days, whilst others took anakinra daily

or every other day for up to six months. In this population, observed side effects included (amongst

others) one injection site reaction, neutropenia in another patient, one case of leukopenia, seven

infectious complications, once the worsening of encephalopathy in a liver failure patient, and twice

the occurrence of a H1N1 Influenza infection after initiating anakinra therapy. One critically ill case

developed an infectious complication (herpes zoster) one day after completing a 6-day anakinra

treatment, possibly related to the anakinra treatment. One patient developed a postoperative wound


17

infection, whereby the site was possibly already infected before anakinra treatment was initiated. Four

patients could not discontinue anakinra treatment without getting an acute flare within several days

after stopping. One case developed tuberculous cervical lymphadenitis after long-term anakinra

therapy (4 years every 2-3 days), though unclear if this was due to anakinra. One open-label clinical

trial has been documented, including 10 patients taking 100 mg subcutaneous (SC) anakinra for 3

consecutive days (34). Patients responded rapidly to anakinra, with the most rapid onset observed

within 24 hours. The subjective symptoms of gout were greatly relieved 48 hours after the first

injection in all patients. No side effects were observed during the study period, and there were no

infectious complications. Only one patient had a minor flare at one month follow-up. For anakinra in

gout, no randomized-controlled clinical trials have been reported. One national survey study has been

done on the off-label use of anakinra among French physicians in order to estimate its efficacy and

safety (41). The main proportion of the gout patients (22/28) who used anakinra off-label reached total

clinical remission. In general, the documented studies show the possible efficacy of anakinra for the

treatment and rapid relief of acute gout flares in severe and complex comorbid gout patients, not able

to take or tolerate conventional therapies.

Summary of known and potential risks and benefits

The potential risks associated with using anakinra for the treatment of acute gouty arthritis are:

Physical discomfort of SC treatment injection

Local (skin) injection site reaction (pain, inflammation, erythema, or ecchymoses, rashes)

Increased total blood cholesterol levels

Serious infections (respiratory and skin infections, Influenza infections)

Allergic reaction and anaphylaxis (angioedema, urticarial and pruritus) to anakinra or other

constituents, including latex

Decreased neutrophil count, leading to neutropenia

Thrombocytopenia (low level of blood platelets)

Drug interaction between ULT and anakinra

Elevated levels of liver enzymes

Gastrointestinal disturbances related to liver disorders (yellow skin and eyes, nausea, loss of

appetite, dark-colored urine, light-colored stools)

Headaches

The potential benefits associated with the use of anakinra for the treatment of acute gout arthritis are

alleviation of inflammation, pain and disease burden.

Description and justification of route of administration and Dosage

Active and placebo Kineret will be administered by SC injection once daily. Each syringe contains

100mg anakinra or non-active anakinra (NaCL 0.9%, 0.67 ml) placebo. The route of administration will

be identical to current standard procedures applied for RA patients. To prevent and avoid discomfort

at the site of injection, it is recommended to change the injection site location regularly. Current

recommendations as listed in the SPC for the method of administration for anakinra, will also be

applicable and followed in this study.


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Preparation and labelling of investigational medicinal product

Finished products of anakinra and anakinra placebo injections will be delivered by Swedish Orphan

Biovitrum AB (Sobi) to the coordinating pharmacy before the start of the study. The coordinating

pharmacy is responsible for preparing and re-labeling these medicinal products. During preparation

and labeling of anakinra and anakinra placebos, the coordinating pharmacy will comply with the GMP

guidelines.

Drug accountability

The allocation of anakinra and anakinra placebo to the local pharmacy of each participating sites will

be done under strict supervision of the central coordinating pharmacy and the proper environmental

settings. The study medication will be delivered to, accepted by and stored at the local pharmacy of

each participating site. The nurse/treating rheumatologist is responsible for retrieving these packages

and handing these over to the patient or the patient can retrieve the medication package and return

to the treating rheumatologist/nurse who will further guide the patient. If during the trial any of the

products are not fit for use or are not being used, these will be retoured to the central coordinating

pharmacy and replaced if needed and possible. The treating rheumatologist/nurse should together

with the local pharmacy ensure proper sending of the unusable medication to the coordinating

pharmacy in case of retouring products.


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7. Non-investigational treatment

Name and description of available SoC treatments

Colchicine

Colchicine is indicated for treating acute gouty arthritis in patients who cannot tolerate, or who have

contra-indications for, NSAIDs. It is also used as a prophylaxis for gout flares when initiating ULT in

patients who cannot tolerate, or who have contra-indications for, NSAIDs.

NSAID, naproxen

Therapeutic indications for naproxen include many inflammatory musculoskeletal diseases, including

gouty arthritis. Naproxen is a prostaglandin synthetase inhibitor and belongs to the group of NSAIDs,

which are used to control pain and inflammation.

Systemic corticosteroid, prednisolon

Prednisolon is used to treat rheumatic conditions and other bodily disorders. Prednisolon is a

corticosteroid which primarily acts as a glucocorticosteroid. The therapeutic effect of

glucocorticosteroids is mostly through two mechanisms; an anti-inflammatory or immunosuppressive

(anti-allergic) mechanism.

Urate Lowering Therapy

Different ULT treatments are available; allopurinol, febuxostat and benzbromaron. All are aimed at

lowering the urate/uric acid levels in the blood serum, however, the mechanism of action differs

between the three. Allopurinol and febuxostat work by inhibiting the action of the enzyme xanthine

oxidase, which plays a role by the conversion from hypoxanthine into uric acid. Benzbromaron acts as

a uricosuric agent, which causes the excretion of uric acid in the urine to be increased.

Non-active SoC placebos

Oral SoC placebo medication will be provided in capsules, identical in size, shape color and appearance

to the active SoC treatment. For details about the blinding of study medication, see Chapter 8:

Methods, section Randomization, Blinding and treatment allocation.

Dosage and method of administration

For all SoC treatments and placebos and ULT treatments, the dosage, duration and method of

administration will be in line with the Gout Guidelines of the NVR and standard care procedures (16).

For colchicine (placebo) this is 3 daily dosages of 0.5 mg for 90 days, for naproxen (placebo) twice a

day 500 mg for 90 days and for prednisolone (placebo) 35 mg daily dosage for 5 days. Colchicine and

naproxen will be continued for 90 days as these are given as prophylaxes when initiating ULT. Patients

receiving naproxen will be prescribed antacids in line with the standard procedure when receiving

NSAID for longer periods of time. For ULT treatment the first choice will be allopurinol 100 mg daily for

1 week followed by 300 mg. Alternatively benzbromaron or febuxostat will be used. Dosage will be

adjusted according to treating to target of urate serum concentration below 0.30 mmol/L. ULT will be

initiated at baseline.


20

Preparation and labelling of non-investigational medicinal product

The central coordinating pharmacy will ensure the proper number of SoC treatments and placebos will

be acquired before the start of the study. During the preparation and labeling of SoC treatment and

SoC placebos the coordinating pharmacy will comply with the GMP guidelines.

Drug accountability

The allocation of SoC and SoC placebo to the local pharmacy of each participating sites will be done

under strict supervision of the central coordinating pharmacy and the proper environmental settings.

The study medication will be delivered to, accepted by and stored at the local pharmacy of each

participating site. The nurse/treating rheumatologist is responsible for retrieving these packages and

handing these over to the patient or the patient can retrieve the medication package and return to the

treating rheumatologist/nurse who will further guide the patient. If during the trial any of the products

are not fit for use or are not being used, these will be retoured to the central coordinating pharmacy

and replaced if needed and possible. The treating rheumatologist/nurse should together with the local

pharmacy ensure proper sending of the unusable medication to the coordinating pharmacy in case of

retouring products.


21

8. Methods

Study endpoints

Primary endpoint

Change in patient-reported pain in the index joint from baseline to the average of pain values

at 24, 48 and 72 hours

Secondary endpoints of 3 month randomized controlled trial

Time to 50% reduction in pain in the primary affected joint

Time to remission of pain

Time to first reoccurrence of flare

number of new flares

Decrease of primary joint swelling according to patient across day 2-5

Decrease of primary joint tenderness according to patient across day 2-5

Decrease in C-reactive protein (CRP) levels after 7 days of treatment

Decrease of serum uric acid concentration after 3 months

Treatment response according to patient across day 2 -7

% dropout due to adverse events (AE)

% dropout due to serious adverse events (SAE)

physical function

Health related quality of life (HR-QOL)

Experienced side effects

Direct and indirect costs

Secondary endpoints of 9 month open label study extension

Time to first reoccurrence of flare

number of new flares

% patients starting with canakinumab treatment

% patients with serum uric acid concentration ≤ 0.36 mmol/l

Physical function

HR-QOL

Experienced side effects


Data collection

All data will be collected using an electronic case report form (CRF). The electronic data capture (EDC)

system used is ROMA2, currently also being used for different clinical trials within the field of

rheumatology. Within ROMA2 a study specific template will be developed. All data will be collected

and entered by the participating sites directly into the EDC system. The sites will be fully trained for

using the EDC system. The data which is to be collected from the patients directly (e.g. questionnaires)

will also be collected using the EDC system. The data will be saved in a secure database.


22

Patient data collection and follow-up will take place at baseline, days 2-7, month 3 and thereafter at

month 6, 9 and 12. In case of recurrence of gout flares, patients are asked to contact the treating

rheumatologist and to keep a flare diary for 7 consecutive days. Treating rheumatologists are asked to

document any side effects, AE and SAE in the CRF. Decisions regarding treatment of recurrent flares

are at the discretion of the attending physician and the patient. See schedule below for follow-up

moments:

* Laboratory results that become available during the routine clinical care during the course of the study will be

collected.

**Patients lost during follow-up will be recorded in the CRF

Baseline (day 1)

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Month 3

follow-up

(month 6, 9)

Study end

(month 12)

Onset new flare

Eligibility criteria (e.g. aspiration of joint fluid)

X

Informed consent

X

Demographics X

Patient medical status

X

Serum uric acid X X X X* X*

CRP level X X X X* X*

Flare diary X X X X X X X X

Physical functioning

X X X X X

HR-QOL X X X X X

Work productivity & health care volumes

X X X X X

AE and SAE X X X

Study drop-out/ completion

X**

Table 1. Patient follow-up scheme.


23

Data collection tools

Patient numbering

Each patient is identified by a unique 5 character patient identification number, assigned by the EDC

system. The first two numbers will index the center number at which the patient is included and the

final three numbers index the patient’s order of inclusion at the study site.

Baseline characteristics

At baseline, demographic characteristics including sex, age, weight, length, blood pressure will be

collected. A patient medical status including gout status, comorbidities and other medication usage

will also be obtained at baseline and updated throughout the study. Whether the patient entered the

study through primary or secondary health care will also be noted. See Appendix I for the specific CRF

information gathered by the treating rheumatologist.

Uric acid and CRP measurement

At baseline, serum uric acid and CRP level will be determined. During the course of the study, CRP and

serum uric acid levels will be recorded according to the data collection scheme in Table 1. Whenever

laboratory results on CRP levels and serum uric acid levels become available during routine/regular

clinical care, these results will also be collected during the course of this study.

Patient flare diary

A digital (or if needed pen and paper) flare diary will be filled in at home during the occurrence of acute

gout flares for 7 consecutive days upon flare onset. The following will be recorded daily: pain intensity,

swelling, tenderness, treatment response, global assessment of overall wellbeing, study medication

intake, other medication intake and experienced side effects. The side effects will be reported to the

treating rheumatologist, who will register these effects along with potential AE and SAE. Study

medication intake will be noted for determining the compliance of patients to the study medication.

See Appendix II for the patient flare diary.

Patient reported outcomes (PROs)

PROs will be measured using standardized instruments available, at baseline and during follow-up

according to the data collection scheme in Table 1. PROs are made available to the patients on the

computer and if needed a paper and pencil version will be available as well. The patient reported

domains measured are pain intensity, amount of swelling, tenderness of joint, treatment response,

physical functioning, health related quality of life, work productivity. See for all PROs questionnaires

and flare diary Appendix III and II. Below a specific explanation of the specific tool used to measure

each specific PRO:

Pain intensity: Pain intensity at the primary joint during treatment follow-up time will be

assessed using a 5-point Likert scale (1 = none; 2 = mild; 3 = moderate; 4 = severe; 5 = extreme)

and a 100mm visual analog scale (0 = no pain, 100 = worst imaginable pain). Also a numeric

rating scale (NRS) will be used to measure pain intensity (0 = no pain at all until 10 = worst

imaginable pain).


24

Swelling: The amount of swelling of the primary joint will be measured using a 5-point Likert

scale (1 = none; 2 = mild; 3 = moderate; 4 = severe; 5 = extreme).

Tenderness: The tenderness of the primary joint will be determined using 5-point Likert scale

(1 = none; 2 = mild; 3 = moderate; 4 = severe; 5 = extreme).

Treatment response: Treatment response according to the patient will be assessed using a 9-

point Likert scale (1=fully disappeared; 2=very much improved; 3=much improved; 4=slightly

improved; 5=no changes; 6=slightly worse; 7=much worse; 8=very much worse; 9=not

applicable).

Global assessment of overall wellbeing: The global assessment of overall wellbeing will be

assessed using a 10 point NRS (0 = worst imaginable health until 10 = best imaginable

wellbeing).

Physical functioning: Disability will be assessed using the Stanford Health Assessment

Questionnaire Disability Index (HAQ-DI) (47). HAQ-DI assesses disability using 20 questions

regarding dressing and grooming, arising, eating, walking, hygiene, reach, grip and activities.

Individual item scores can be adjusted for the use of aids or help from others in completing

the activities referred to in the item. Category scores represent the highest individual item

score in each category and an overall disability score is obtained by averaging the category

scores. Higher scores indicated more disability.

HR-QOL: HR-QOL will be assessed using the medical outcomes survey short form 36 (SF-36)

(48). The SF-36 assesses the 8 HR-QOL domains of: bodily pain, physical role function, physical

function, general health, emotional role function, vitality, and social function. For each domain

a summary score is obtained ranging from 0-100, with higher scores representing better

health.

Work productivity and health care volumes: Work productivity will be assessed using the Work

Productivity and Activity Impairment Questionnaire (WPAI) (49). The WPAI includes questions

about employment: time lost from work, reduced productivity at work and reduced

productivity while engaged in regular activities in the previous week. Patients will also be asked

to report the volume of hospital related care using a standardized questionnaire.

Side effects , AE and SAE

Side effects, AEs and SAEs will be obtained during follow-up according to the data collection scheme

in Table 1. Patients are asked to report any side effects experienced in the daily flare diary and

subsequently report this to their treating rheumatologist at follow-up moments. At each visit

rheumatologists will be requested to state whether or not patients experience specific side effects

potentially related to IL-1 suppression including: serious infections, malignancy, opportunistic

infections, drug induced liver injury, major adverse cardiovascular events, severe injection site

reactions, AEs related to immunogenicity/allergincity, worsening uric acid levels, disorders of

lipoprotein metabolism, worsening kidney function, potential vaccine interactions and pregnancy. All

AE – including SAE irrespective of causality and safety endpoints (where relevant) – will be collected

and recorded in the CRF, irrespective of causal association. If an AE or SAE occurs in between follow-

up moments this should be reported to the treating rheumatologist and be reported in the CRF.

Patients can report side effects through the online web portal. For details regarding the safety

monitoring during this study, see Chapter 9: Safety reporting, section Safety monitoring of this

protocol.


25


The direct and indirect costs will be calculated from the work productivity and health care volumes

questionnaire filled in by the patient. Volumes of hospital related care, i.e. consultations with the

rheumatologist and the rheumatology nurse, hospital admissions, as well as medication use (exact

dose of gout medication and administration period) will be prospectively registered in the electronic

CRF. Direct costs will be calculated by multiplying volumes of care by their respective costs. The

standard cost prices from the 2016 Dutch Guideline for Cost Analyses will be used for hospital related

care. Cost prices for medication will be retrieved from the 2016 Dutch national tariff list provided by

the Dutch Board of Health Insurances.

Study drop-out or completion

Information about patients that decide to stop with the study prematurely will be documented in the

CRF. In the CRF will be noted when a patient has completed the study.

Distribution of medicines to participating centers

The distribution of the study medication to each of the participating sites will be done in 1-2 shifts. The

first shift will consist out of small batches and aims to determine the speed of inclusion at each

participating site. Depending on these findings, the study medication will be allocated a second time.

The central coordinating pharmacy is responsible for proper distribution of the study medication to

each site, including the proper environmental settings (e.g. temperature). The study medication will

be delivered to and accepted by the local pharmacy of each participating site. The study medication

will be stored at the local pharmacy of the participating site.

Randomization, blinding and treatment allocation

Patients will be asked to participate in this study, be given additional information and asked informed

consent by their treating rheumatologist. At times, a research nurse can give additional information or

ask for patient informed consent when asked to do so by the rheumatologist. When patients have

signed the written informed consent, the treating rheumatologist will give the patient a prescription

wherein states which one of the three SoC treatments the patient can be given. As the packages are

stored at the local pharmacy, the patient self or the nurse/treating rheumatologist can retrieve these

packages and hand it over to the patient. Depending on the tolerable SoC treatment, patients will be

appointed randomly to either the anakinra treatment or the patients’ tolerable SoC treatment. The

randomization is based on a previous computer-generated randomization list (anakinra or SoC) per

SoC treatment. No stratification will be carried out. When the patient has received the medication

package he/she will be instructed by the nurse on how to properly inject themselves with the syringe

as well as other baseline characteristics will be gathered. The research nurse will register the new

patient in the EDC, which will assign the patient an automated unique 5 character patient identification

number. See Chapter 8: Methods, section Patient numbering for details regarding this number. The

treatment packages will also each be identified by a number, which will be linked to the patient

identification number in the EDC. Each treatment package will contain either anakinra injections along

with the tolerable SoC placebo medication, or anakinra placebo injections with the tolerable active SoC

treatment. Oral SoC medication and placebos will be provided in capsules, identical in size, shape color

and appearance. For details on SoC treatments and placebos see the Investigational Medicinal Product


26

Dossier (IMPD) submitted as part of the dossier for the METC. Anakinra and anakinra placebo are a

solution for injection, available in pre-filled syringes ready for SC use. Treating rheumatologists/nurses

do not have access to the randomization (treatment) code except in case of a SAE and/or SUSAR. In

this case, the code may be broken only in circumstances when knowledge of the study medication is

essential for treating the patient. In case of a SAE or SUSARs, the local responsible investigator will

contact the sponsor directly (see Chapter 9: Safety Reporting, section SAE reporting). The sponsor and

local head investigator will together decide if the code needs to be broken. If needed, the sponsor may

contact the Data Safety Monitoring Board (DSMB) for further advice regarding the specific matter.

Withdrawal of individual subjects from the study

Subjects are free to quit the study at any time for any reason if they wish to do so without any further

consequences to their medical treatment. The treating rheumatologist and/or study investigator can

decide to withdraw a subject from the study for urgent medical reasons or because of serious protocol

violation.

Replacement of individual subjects after withdrawal from the study

If subjects are withdrawn from the study, no replacement of the subject will occur. In the total sample

size calculation a dropout rate of 10-13% was included.

Follow-up of subjects withdrawn from study

The data retrieved from subjects who were withdrawn from the study will be used for data analyses.

Follow-up of subjects withdrawn from treatment

Patients who will be withdrawn form treatment due to intolerable side effects or due to lack of efficacy,

will be instructed by their physician to continue to fill in questionnaires until the end of the study.

Premature termination of the study

The sponsor and/or DSMB may decide to prematurely end the study when feels the health of the

subjects are put at jeopardy. For details on the DSMB see Chapter 9: DSMB of this protocol.


27

9. Safety reporting

Section 10 WMO event

In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and

the reviewing accredited METC if anything occurs, on the basis of which it appears that the

disadvantages of participation may be significantly greater than was foreseen in the research proposal.

The study will be suspended pending further review by the accredited METC, except insofar as

suspension would jeopardise the subjects’ health. The investigator will take care that all subjects are

kept informed.

Safety monitoring

Patients will be informed to contact their treating rheumatologist when severe side effects (e.g.

infections) occur and asked to report side effects during the entire study period directly to their

treating rheumatologist and by reporting this through the web portal and/or in the flare diary during

gout attacks. All AE/SAE will be collected and recorded in the electronic CRF and database, irrespective

of causal association. All AE/SAE directly observed or reported by the patient or caregiver to the

treating rheumatologist or other site personnel, from the time of prescribing anakinra or SoC and

entering this study, should be evaluated by the site and assessed for seriousness and relatedness to

anakinra or SoC, as defined below in the section ‘AE reporting’.

AE reporting

An AE is the appearance or worsening of any undesirable sign, symptom, or medical condition

occurring after starting anakinra or SoC even if the event is not considered to be related to anakinra or

SoC. Medical conditions/diseases present before starting anakinra or SoC are only considered AEs if

they worsen after starting anakinra or SoC. Abnormal laboratory values or test results constitute AEs

only if they induce clinical signs or symptoms, are considered clinically significant, or require therapy.

All AE reported spontaneously by the subject or observed by the investigator or the staff are to be

recorded regardless of whether considered related to anakinra or SoC. In addition, all reports of the

following special scenarios are considered an AE irrespective if a clinical event has occurred:

Drug-drug or drug-food interaction

Drug exposure during pregnancy

Lack of effectiveness

Overdose

Drug abuse and misuse

Drug maladministration or accidental exposure

Dispensing errors / medication errors

Off-label use

Withdrawal or rebound symptoms

All AEs recorded on the adverse event CRF in the EDC system should include the following information:

The severity grade

Relationship to medicinal product being studied

Duration (start and end date, if applicable)


28

Whether it constitutes a SAE (if so, follow rules for SAE reporting)

Whether the AE is treated

SAE reporting

A SAE is any untoward medical occurrence or effect that:

Results in death;

Is life threatening (at the time of the event);

Requires hospitalisation or prolongation of existing inpatients’ hospitalisation;

Results in persistent or significant disability or incapacity;

Is a congenital anomaly or birth defect;

Any other important medical event that may not result in death, be life threatening, or require

hospitalization, may be considered a serious adverse event when, based upon appropriate

medical judgement, the event may jeopardize the subject or may require an intervention to

prevent one of the outcomes listed above.

Information about all SAEs (and SUSAR, see below) is collected and recorded on the adverse event CRF

in the EDC system and should include information as mentioned in the previous subsection AE

Reporting.

In case a (S)AE arises (or SUSAR, see below) occurs within the first 30 days after start of the study, the

responsible investigator at that participating site should report this to the sponsor directly (within 24

hours; email: [email protected] / tel: 053 – 487 2450). The sponsor will report the SAEs (or SUSAR)

through the web portal ToetsingOnline to the accredited METC that approved the protocol, within 15

days after the sponsor has first knowledge of the SAE. SAEs (or SUSARs) that result in death or are life

threatening should be reported expedited. The expedited reporting will occur not later than 7 days

after the responsible investigator has first knowledge of the adverse event. This is for a preliminary

report with another 8 days for completion of the full report. After the first 30 days after starting the

study, the occurrence of any (S)AE and/or SUSAR will not need to be reported (expeditely) as

mentioned above, but will need to be summarized in a line listing which will be made available to the

accrediting METC periodically.

Documented SAEs (and SUSARs) as a result of anakinra injection during the duration of the trial,

independent of causality, will be reported to Sobi within 24 hours of first awareness. This can be done

by sending an email to the Sobi Drug Safety Department ([email protected]). The sponsor and

investigator shall assist Sobi in obtaining follow-up information for any reported serious adverse

events.

Suspected unexpected serious adverse reactions reporting

Adverse reactions are all untoward and unintended responses to an investigational product related to

any dose administered. Unexpected serious adverse reactions are Suspected unexpected serious

adverse reactions (SUSARs) if the following three conditions are met:

1. the event must be serious;


29

2. there must be a certain degree of probability that the event is a harmful and an undesirable

reaction to the medicinal product under investigation, regardless of the administered dose;

3. the adverse reaction must be unexpected, that is to say, the nature and severity of the adverse

reaction are not in agreement with the product information as recorded in:

SPC for an authorised medicinal product;

Investigator’s Brochure for an unauthorised medicinal product.

When, within the first 30 days after start of the study, the head investigator at a participating centre

has first knowledge of any (S)AE, independent of whether it might be a SUSAR, he/she will report this

immediately to the sponsor (within 24 hours; email: [email protected] / tel: 053 – 487 2450). The

sponsor will decide, depending on the assessment of the head investigator, if the (S)AE is a SUSAR. The

recording of SUSARS in the CRF and reporting of SUSARs to Sobi and the METC will be done by the

sponsor and follow the same procedure as for the reporting of SAE (see previous section: SAE

reporting). The expedited reporting of SUSARs through the web portal ToetsingOnline is sufficient as

notification to the competent authority. The reporting of SUSARs occurring 30 days after start of the

study, will be reported in a line listing made available to the accrediting METC periodically.

Follow-up of AE and SAE

All AEs will be followed until they have abated, or until a stable situation has been reached. Depending

on the event, follow up may require additional tests or medical procedures as indicated, and/or

referral to the general physician or a medical specialist. AEs, SAEs and SUSARs need to be reported in

the CRF system till end of study within the Netherlands, as defined in the protocol.

Annual safety report

In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year throughout the

clinical trial, a safety report to the accredited METC and competent authority. The annual safety report

will be combined with the annual progress report. This safety report consists of:

1. A list of all suspected (unexpected or expected) serious adverse reactions, along with an

aggregated summary table of all reported serious adverse reactions, ordered by organ system,

per study;

2. A report concerning the safety of the subjects, consisting of a complete safety analysis and an

evaluation of the balance between the efficacy and the harmfulness of the medicine under

investigation.

Data Safety Monitoring Board

To perform ongoing safety surveillance of the study participants, an independent DSMB will be

established before the first participant starts the study. For further details regarding the DSMB, see

the DSMB charter in Appendix IV.


30

10. Data analyses

Populations

Primary efficacy analyses will be performed for both the intention-to-treat (ITT) and per-protocol (PP)

populations. The ITT population will consist of all randomized subjects who have been administered at

least one dose of study medication. The PP population will exclude all subjects in the ITT population

who meet any of the following criteria:

• Have taken any interfering concomitant medications during the first three days of the study.

• Have missing data for one or more assessments of the primary outcome.

Primary efficacy analyses

The primary outcome of this study is the difference between treatment arms in change in patient-

reported pain on a 5-point Likert scale in the index joint from baseline to the average of the patient-

reported pain values at 24, 48 and 72 hours (referred to hereafter as Δpain). In accordance with FDA,

EMA and consort guidelines, the NI-margin for this study was established after carefully considering

the maximum clinically tolerable loss of efficacy of anakinra compared with SoC and by estimating a

putative placebo effect from historical results of clinical studies in acute gout employing the 5-point

Likert pain scale as the primary outcome (50–53).

Previous NI studies in gout with the 5-point Likert scale have employed a difference of 0.5 points in

favor of the active comparator as a NI margin based on clinical reasoning only (i.e. the maximum

clinically tolerable loss of efficacy) (53–55).

A review of studies identified in a systematic search of the PubMed database revealed that all but one

of the previous clinical studies in acute gout compared different NSAIDs (53–55). No difference in

efficacy was found between treatment arms in any of the studies and mean Δpain ranged from -1.2 to

-1.4 (M=-1.4) in these studies. Although no placebo controlled trials had yet been performed, one

recent study randomized patients to SC rilonacept 320 mg at baseline plus the NSAID indomethacin 50

mg, oral TID for 3 days followed by 25 mg TID for up to 9 days (n = 74); SC placebo at baseline plus oral

indomethacin as above (n = 76); or SC rilonacept 320 mg at baseline plus oral placebo (n = 75)(56). No

significant difference in Δpain was observed between the rilonacept + indomethacin group and the

placebo + indomethacin group. From these results the authors concluded that rilonacept in

combination with indomethacin did not provide additional pain relief over 72 hours relative to

indomethacin alone in patients with acute gout flare. However, significant between group differences

were observed between the rilonacept + placebo group and the rilonacept + indomethacin group (Dif.

Δpain = -0.7, 95% CI = -0.4 -1.0).

Anakinra will be declared non-inferior to SoC in case it can be demonstrated that the difference

between anakinra and SoC does not exceed 0.4 points in favor of SoC on Likert pain. This NI margin

corresponds to the lower bound of the 95% CI for the difference between groups (indomethacin +

rilonacept vs placebo + rilonacept) observed in the study by Terkeltaub et al. 2013 (56). This NI margin

is slightly more stringent than employed in previous NI studies in acute gout and represents a

conservative estimate of the effect of anakinra relative to historical placebo, since the assumed


31

placebo effect corresponds to the historically observed effect of placebo plus single injection

rilonacept.

The hypotheses tested in this study are:

H0: ΔpainAnakinra - ΔpainSoC > 0.4

Ha: ΔpainAnakinra - ΔpainSoC ≤ 0.4

The study hypotheses will be tested in an analysis of covariance model (ANCOVA) with treatment group

as a fixed factor and baseline pain scores as a covariate. NI of anakinra compared with SoC will be

accepted if the upper bound of the 95% CI around the estimated difference in the primary endpoint

lies to the left of the NI margin of 0.4, both in the ITT analysis and the PP analysis. Non-compliance

may bias ITT analysis towards NI, a sensitivity analysis will be performed where non-compliant patients

will be excluded from the ITT analysis (57). For the purpose of this analysis, patients who report to

have missed 1 or more dosages of anakinra or SoC during the first three days and/or report having

taken any pain-relieving agent during the same period will be considered non-compliant.

In case NI of anakinra compared with SoC has been accepted, a superiority analysis will be performed

on the ITT population. Superiority of anakinra versus SoC will be concluded in case the upper bound of

the 95% CI around ΔpainAnakinra - ΔpainSoC < 0.

Missing Data

It will be assumed that any missing data will occur at random and missing values will be imputed for

the ITT population using multiple imputation by chained equations. The imputation models will be

specified to include the individual pain scores observed at days 1-7 and any available variable that has

a statistical association with the outcome to be imputed or with missingness, as identified in a logistic

regression analysis with missingness as the dependent variable (58). 20 datasets with imputed

plausible values will obtained, with 200 iterations between data sets. Rubin’s rules will be employed

to obtain pooled parameter estimates and their associated standard errors for all analyses. The results

of the analysis of the primary study hypothesis using the pooled results will be compared to the results

obtained on the observed data alone.

Secondary analyses

Secondary efficacy endpoints will be analyzed by specifying a series of linear mixed-effects models with

the endpoint as the dependent variable and time, treatment group and their interaction as fixed

effects. Continuous variables will be summarized with sample size, mean, standard deviation and

range. Frequency counts and percentage of subjects within each category will be provided for

categorical data.

Safety analyses

Safety will be evaluated by tabulations of AE/SAE and will be presented with descriptive statistics at

baseline and follow-up visits for each treatment group.


32

Cost effectiveness analyses

The primary utility measure of the study is quality adjusted life days (QALDs), and will be calculated

from the SF-36 scores (SF-6D). The incremental cost-utility ratio (ICUR) will be calculated by dividing

the difference in costs by the difference in the QALDs produced by the two groups. The ICUR is

expressed as costs per QALD gained.

Sample size considerations

A standard deviation of 0.94 will be assumed for Δpain, corresponding to the findings of previous studies

(53–56). Furthermore it is assumed that there is no difference in effectiveness between anakinra and

SoC. 87 patients per arm need to be included to be 80% sure that a 97.5 % CI for SoC - Anakinra does

not contain the NI limit of 0.4. Taking a 10-13% drop out rate into account, 100 patients per arm will

be included in the study to ensure sufficient power for the per protocol analyses.


33

11. Ethical considerations

Regulatory and ethical compliance

The study will be conducted in accordance with the ethical principles outlined in the Declaration of

Helsinki (version 2013) and the Medical Research Involving Human Subjects Act (in Dutch: Wet

Medisch Wetenschappeljik Onderzoek, WMO 2006)(59).

Recruitment and informed consent procedures

Adequate and complete oral and written information about the nature, purpose(s), risk(s) and

benefit(s) of the study will be made available to potential subjects by the treating

rheumatologist/nurse. The subjects will be informed about the opportunity to ask an independent

physician additional questions and are given a maximum of one day for making a decision. This

relatively short period of time is necessary, given that most gout attacks spontaneously resolve in 1 to

2 weeks. Eligible patients will only be included in the study after providing written (witnessed, where

required by law or regulation), METC approved informed consent. Informed consent must be obtained

before conducting any study procedures. The process of obtaining informed consent should be

documented in the patient source documents. Treating rheumatologists will be provided with an

informed consent form template that complies with the relevant guidelines and regulatory

requirements.

Compensation for injury

Each participating centre has a liability insurance (in Dutch: aansprakelijkheidsverzekering) which is in

accordance with article 7, subsection 9 of the WMO for the participants taking part in the study at that

centre.

The sponsor (linked to University of Twente, Enschede) has an insurance (in Dutch:

proefpersonenverzekering) which is in accordance with the legal requirements in the Netherlands

(Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical Research in Humans

2015). This insurance provides cover for damage to research subjects through injury or death caused

by the study. The insurance applies to the damage that becomes apparent during the study or within

4 years after the end of the study. All subjects at the different participating centres are covered by the

insurance.


34

12. Administrative aspects, Monitoring and Publication

Handling data and documents

Each patient’s data collected for this study will be stored under an assigned unique number. All patient

data will be stored in the ROMA database. The ROMA database is a secure environment that adheres

to all available international guidelines and fulfills NEN7510 and ISO 27001 regulations. Back-ups of

the entire database are made daily. Data protection and privacy regulations will be observed in

capturing, forwarding, processing and storing patient data. Patients must be informed accordingly, and

will be asked to give their consent on data-handling procedures in accordance with the Dutch Personal

Data Protection Act (in Dutch: De Wet bescherming persoonsgegevens, Wbp). The collected data will

be kept for 15 years after completion of the study. Data will be kept and stored in ROMA. Data and

official documents will also be stored at the University of Twente.

Monitoring and quality assurance

Monitoring before, during and after completion of the study will take place to ensure the rights and

safety of the patients, data integrity and validity of the study results. A DSMB is appointed before the

start of the study and the occurrence of any AEs, SAEs and/or SUSARs is reported in the electronic CRF

(see Chapter 9: Safety Reporting).

The coordinating investigator will contact and visit the participating sites whenever needed during the

course of the study. To minimize the onset of problems and to ensure the responsibilities and

procedures for data entry are well understood among the study staff, a pre-study initiation visit will be

conducted at each of the participating centres. Site monitoring visits will be done whenever needed to

sort out possible problems and to ensure data quality.

The study specific template within the EDC system ROMA2 will be pre-tested before study initiation.

During the course of the study the collected data in the electronic CRF will be checked regularly (once

per week) for missing data, entry faults, etc. If problems occur, the coordinating investigator will take

the necessary actions to reassure the quality of the data (e.g. visiting site, explanation using EDC

system, etc.). After study completion the data will be reviewed and analyses will be done as described

in Chapter 10: Data Analyses of this protocol.

Protocol adherence and amendments

Treating rheumatologists or other involved health care professionals will apply due diligence to avoid

protocol violations. The protocol will be amended and updated as needed throughout the course of

the study. A substantial amendment is defined as an amendment to the terms of the METC application,

or to the protocol or any other supporting documentation, that is likely to affect to a significant degree:

the safety or physical or mental integrity of the subjects of the trial;

the scientific value of the trial;

the conduct or management of the trial; or

the quality or safety of any intervention used in the trial.


35

All substantial amendments requires a written protocol amendment that must be notified to and

approved by the relevant METC, competent authority and Sobi before implementation. Non-

substantial amendments, affecting only typing errors and administrative aspects of the study, do not

need to be notified to the accredited METC and the competent authority; but the METC must be kept

informed of such administrative changes and the sponsor should record and file these changes.

Annual progress report

The sponsor/investigator will submit a summary of the progress of the trial to the accredited METC

once a year. Information will be provided on the date of inclusion of the first subject, numbers of

subjects included and numbers of subjects that have completed the trial, serious adverse events/

serious adverse reactions, other problems, and amendments. This report will be combined with the

annual safety report.

End of study report

The sponsor will notify the accredited METC and the competent authority of the end of the study

within a period of 90 days. The end of the study is defined as when the last patient has completed the

last questionnaires at month 12. In case the study is ended prematurely, the sponsor will notify the

accredited METC and the competent authority within 15 days, including the reasons for the premature

termination. Within one year after the end of the study, the sponsor will submit a final study report

with the results of the study, including any publications/abstracts of the study, to the accredited METC

and the competent authority.

Public disclosure and publication policy

Upon study completion and finalization of the study report, the results of the study may either be

submitted for publication and/or posted in a publicly accessible database of results. Publication will

follow the International Committee of Medical Journal Editors (ICMJE) guidelines. Analysis and

publication has to comply with the conditions described in the contract with Sobi underlying this

proposal.


36

13. Structured Risk Analysis

Potential risks and concerns related to this study

Summary anakinra and gout studies

Anakinra was registered for market use on March 8 2002 for treating RA. The exact mechanism of

action is known and can be found in the SPC. Pertaining to gout, anakinra has been tested in both

animals and humans, and even one in-vitro study wherein anakinra showed to have anti-inflammatory

mechanisms (46). Anakinra showed inhibitory effects on the peritoneal neutrophil recruitment in an

in-vivo mouse model (BALB/C mice) of MSU crystal-induced inflammation (34). In total, 24 (clinical)

studies have been documented for acute gout and the usage of anakinra as treatment therapy, of

which 15 single case reports, 7 case series, one controlled open label study and one survey study (22–

45). No randomized-controlled clinical trials have been reported. The patients included in the

documented studies were all complex gouty arthritis patients with severe comorbidities and/or

intolerance to conventional therapies, with the exception of one study, Petite et al. 2016 (45).

Treatment with anakinra was, therefore, used as an alternative agent. Dosage regime of anakinra

differed between studies, however, the dosage 100 mg anakinra was reported in all studies. Frequently

used dosage regime was once daily 100 mg anakinra for 3 consecutive days. However, some patients

with chronic tophaceous gout used daily treatment for up to a 6 months, without any observed adverse

effects. One patient used anakinra effectively every 2-3 days up to 4 years leading to disappearance of

clinical tophi and no recurrence of gouty arthritis. After 4 years, this patient got tuberculous cervical

lymphadenitis, yet it is unsure if this was due to long-term anakinra therapy. Rapid treatment response

to anakinra was observed in the majority of the patients in the reported clinical studies. Observed side

effects due to usage of anakinra were an injection site reaction by one patient, neutropenia by another

patient, one case of leukopenia, seven infectious complications and twice a H1N1 Influenza infection

occurred during anakinra treatment by a patient, although it is not clear whether this was caused by

anakinra treatment. One critically ill case developed an infectious complication (herpes zoster) one day

after completing a 6-day anakinra treatment, although it is not clear whether this was related to the

anakinra treatment. Also, one patient developed a postoperative wound infection, although it is not

clear whether the site was already infected before anakinra treatment was initiated. Four patients

could not discontinue anakinra treatment without getting an acute flare within 4 days of stopping and

one patient had a minor flare at one month follow-up. At last, one patient with decompensated liver

failure had worsening of encephalopathy. For specific details regarding these studies, see IB.

Risks and concerns related to anakinra

The potential risks associated with anakinra for the treatment of acute gouty arthritis are:

Physical discomfort of SC treatment injection

Local (skin) injection site reaction associated with pain, inflammation, erythema, or

ecchymoses, rashes

Increased total blood cholesterol levels

Serious infections including respiratory infections and skin infections, Influenza infections

Allergic reaction and anaphylaxis (angioedema, urticarial and pruritus) to anakinra or other

constituents, including latex


37

Decreased neutrophil count, potentially leading to neutropenia

Thrombocytopenia (low level of blood platelets)

Drug interaction between ULT and anakinra

Elevated levels of liver enzymes

Gastrointestinal disturbances related to liver disorders (yellow skin and eyes, nausea, loss of

appetite, dark-colored urine, light-colored stools)

Headaches

These risks are defined according to the documented information and side effects in the literature and

the concerns as listed in the SPC. For elaborate explanations regarding these side effects see SPC and

IB.

Other risks and concerns

NSAIDs and colchicine are intended as prophylactics for gout flares when initiating ULT. Patients

receiving anakinra treatment or prednisolone treatment (when allocated into the SoC group) will not

receive colchicine or NSAID prophylactics when initiating ULT. Relapse of a gout flare might occur

sooner in this population compared to the other study arm that will receive prophylactics.

Reducing and managing the potential risks and concerns

To ensure the risks associated with the injection of anakinra remain limited, the inclusion and exclusion

criteria of this study are strict. Eligible patients will be excluded from the study if there are

contraindications to the use of anakinra or any of its constituents. This will reduce the chance of allergic

reactions to anakinra in the study population. Additionally, patients with pre-existing neutropenia or

with untreated infections will not be included in the study. Also, pregnant, lactating women and

women who are planning on becoming pregnant within the study period (12 months) are not allowed

to participate in the study, as the effect of anakinra on unborn or nursed children is unknown. Patients

using TNF inhibitors are also excluded from this study, as concurrent use of anakinra with TNF

inhibitors has been shown to be associated with the development of severe infections and

neutropenia.

A DSMB will be established to ensure the safety of the participants. As no information is available on

the possible drug reaction between ULT and anakinra, any reported SAE or SUSAR will be evaluated

for possible interaction by the DSMB as well as the treating rheumatologist. Moreover, patients

experiencing any side effects or other AE will be instructed to immediately contact their treating

rheumatologist. The treating rheumatologist will give the patient the needed care and report any SAE

and/or SUSARs to the sponsor. The sponsor will report the events in accordance with Chapter 9: Safety

Reporting, of this protocol. If needed, the sponsor and/or DSMB will decide to prematurely terminate

the study if there is a possibility that the safety of the participants is being put in jeopardy.

Anakinra has been used for treating patients with RA since 2002. The long experience with this product

in RA patients has resulted in a good description of its safety profile and the possible side effects. Such

information has contributed to clearly defining the potential risks associated with using anakinra in the

present study. In addition, patients with chronic RA may use anakinra daily for long periods of time

(years if needed) to treat the disease. Therefore, it is expected that the risks associated with the 5 day

anakinra treatment in this study will be limited and is therefore judged an acceptable treatment


38

duration. Moreover, the applied daily dosage of 100mg anakinra in this study is the same as the

recommended dosage for treating RA patients and as used in other documented studies, suggesting

the dosage is acceptable.

When a new acute gout flare arises after the first study week (baseline – day 7), all patients should

contact their treating rheumatologist who will treat the patient with the best available care. The group

not receiving prophylactic agents will receive the same optimal care as patients receiving

prophylactics. In some cases it might be needed to break the randomization (treatment) code to be

able to provide the patient the best care. Patients will be instructed by the research nurse and/or their

treating rheumatologist on how to handle in case another flare arises. By applying the above, the

concerns associated with not taking prophylactics will remain limited.

The risks associated with this study have been evaluated and minimized by setting up strict inclusion

and exclusion criteria and by establishing a DSMB. Not all risks could however be eliminated. The

remaining risks are acceptable since the risks are not considered to be severe or life threatening.


39

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15. Appendices

I. CRF Information

II. Patient flare diary

III. PROs questionnaires

IV. DSMB Charter

ATTACG studie

CRF - TOELATINGSCRITERIA (Pagina 1/2)

1. Poliklinische patiënt met microscopisch kristalbewezengedocumenteerde jicht

2. Op moment van inclusie is de patiënt 18 jaar of ouder Ja Nee

Ja Nee

Ja Nee

INCLUSIECRITERIA

EXCLUSIECRITERIA

- -Datum(dd mm jjjj)

Patiëntcode/medicatiecode:

Initialenbehandelaar

3. Patiënt heeft de patiënteninformatie ondertekend Ja Nee

1. Patiënt heeft een absolute contra-indicatie voor alle beschikbare urinezuur verlagende therapie (allopurinol, febuxostat, benzbromaron)

Contra-indicaties allopurinol: Overgevoeligheid voor de werkzame stof (allopurinol) of voor één van de hulpstoffen (zie hiervoor de officiële productinformatie)

Contra-indicaties febuxostat: Overgevoeligheid voor de werkzame stof (febuxostat) of voor één van de hulpstoffen (zie hiervoor de officiële productinformatie).

Contra-indicaties benzbromaron: Overgevoeligheid voor het werkzaam bestanddeel(benzbromaron) of voor één van de hulpstoffen (zie hiervoor de officiële productinformatie).Patiënten met bekende leverziekte. Gelijktijdig gebruik van hepatotoxische geneesmiddelen,in het bijzonder anti-tuberculose agentia. Hepatische porfyrie. Ernstige nierinsufficiëntie(klaring < 30 ml/min). Patiënten met hyperuraturie hoger dan 700 mg/24 uur (= 4,2 mmol/24uur). Urolithiasis. Acute jichtaanval.

2. Patiënt heeft een absolute contra-indicatie voor anakinra

Contra-indicaties anakinra: Overgevoeligheid voor de werkzame stof (anakinra) of vooréén van de hulpstoffen (citroenzuur watervrij, natriumchloride, dinatriumedetaat-dihydraat,polysorbaat 80, natriumhydroxide, water voor injectie), of voor eiwitten geproduceerd metbehulp van E. coli. Anakinra (Kineret) mag niet worden gebruikt bij patiënten met ernstigenierfunctiestoornissen (CLcr < 30 ml/minuut). Er mag geen Kineret-behandeling wordenbegonnen bij patiënten met neutropenie (Absolute Neutrophil Count <1,5 x 109/l).

Ja Nee

Centrum (kies 1):MST VieCuri MC ZGT MCL Rijnstate Ropcke-Zweers Ziekenhuis

Locatie centrum:

3. Aanwezigheid van leveraandoeningen die volgens debehandelende arts deelname aan de studie onmogelijk maken

Ja Nee

Versie 3 - 09/02/2016

ATTACG studie

CRF - TOELATINGSCRITERIA (Pagina 2/2)

Ja Nee

10. Patiënt is een vrouw die binnen de studie periode zwanger denktte raken (12 maanden)

Is de patiënt toelaatbaar tot de studie volgens de bovengenoemdecriteria?(Een patiënt is alleen toelaatbaar als aan alle inclusie criteria voldaan is en niet aan hetexclusiecriteria)

Ja Nee

13. Patiënt beschikt over onvoldoende beheersing van deNederlandse taal om zelfstandig vragenlijsten in te vullen

7. Patiënt gebruikt andere interleukine-1 therapieënTot andere interleukine-1 therapieën behoren canakinumab en rilonacept.

11. Patiënt heeft een actieve of terugkerende bacteriële, schimmelof virale infectie

Ja Nee

Ja Nee

Ja Nee

Ja Nee

12. Patiënt gebruikt TNF-remmersTot TNF-remmers behoren: Certolizumab, Golimumab, adalimumab, etanercept, infliximab

Ja Nee

9. Patiënt is zwanger of geeft borstvoeding

Ja Nee6. Actueel gebruik van urinezuur verlagende therapie (UVT) Tot UVT behoren allopurinol, febuxostat en benzbromaron.

Ja Nee5. De patiënt heeft een verleden van latex sensitiviteit of allergie

4. Patiënt heeft een absolute contra-indicatie voor alle 3standaard jichtaanvalmiddelen; colchicine, naproxen en prednisolon

Ja Nee

Contra-indicaties colchicine: Overgevoeligheid voor de werkzame stof (colchicine) of voor één van dehulpstoffen (microkrystallijne cellulose (E460), magnesiumstearaat (E470b), lactose, natriumcarboxyzetmeel).Vrouwen in de vruchtbare leeftijd, tenzij doeltreffende anticonceptie-maatregelen worden genomen. Patiëntenmet ernstige nierfunctiestoornissen. Patiënten met ernstige leverfunctiestoornissen.

Contra-indicaties naproxen: Overgevoeligheid voor naproxen of voor één van de hulpstoffen

(aardappelzetmeel, lactose, hydroxypropylcellulose (200 CP), magnesiumstearaat, watervrij colloïdaalsiliciumdioxide). Naproxen mag ook niet toegediend worden aan patiënten, die na toediening vanacetylsalicylzuur of andere prostaglandinesynthetaseremmende middelen een allergische reactie vertoondhebben, zoals astma, rhinitis of urticaria. Ernstige anafylactoïde reacties zijn bij deze patiënten gerapporteerd. Naproxen mag in principe niet toegediend worden aan patiënten met ulceraties van het maagdarmkanaal, gastritis congestiva of gastritis atrophica, maagdarmbloedingen of andere bloedingen zoals cerebrovasculaire bloedingen. Ernstige nierinsufficiëntie

Contra-indicaties prednisolon: Overgevoeligheid voor prednisolon of één van de andere bestanddelen

van de tabletten (lactose, magnesiumstearaat (E470b), siliciumdioxide (E551), aardappelzetmeel,voorverstijfseld aardappelzetmeel, natrium (aardappel)zetmeelglycollaat. Ulcus ventriculi en ulcus duodeni. Acute infectieuze processen, met name virusinfecties en systemische schimmelinfecties.

Tropische worminfecties. Toediening na vaccinatie met levend verzwakt virus. Herpes simplex oculi.

Ja Nee8. Patiënt rapporteert geen tot milde jicht gerelateerde pijn

Versie 3 - 09/02/2016

ATTACG studie

CRF - PATIËNTKARAKTERISTIEKEN

5. Diastolische bloeddruk (mm/Hg)

6. Systolische bloeddruk (mm/Hg)

3. Lengte (cm)

4. Gewicht (kg)

Ja Nee

Ja Nee

Geschat?

1. Geslacht Man Vrouw

2. Leeftijd (jaren)

Eerstelijnszorg (via de huisarts, spoedeisende hulp)Tweedelijnszorg (via de polikliniek reumatologie)

Patiënt is binnengekomen via:

Biometrische kenmerken

Versie 3 - 09/02/2016

7. Hartslag (per minuut)

ATTACG studie

CRF - JICHT STATUS

1. Jicht diagnose datum(dd-mm-jjjj)

Diagnosedatum

- -

MonoarticulairOligoarticulairPolyarticulair

2. Jicht type

4. Beloop IntermitterendChronisch

Jicht status (1/4)

Bij monoarticulaire jicht is 1 gewricht aangedaan door jicht. Bij Oligoarticulaire jicht zijn er meer dan 1,maar minder dan 5 gewrichten aangedaan. Bij polyarticulaire jicht zijn er meer dan 5 gewrichtenaangedaan.

Dit is de datum waarop voor het eerst jicht werd gediagnosticeerd bij de patiënt. Dit kan zijn door dehuisarts, reumatoloog of iemand anders.

3. Topheuze jicht Ja Nee

5. Aantal jichtaanvallen.(Noteer het aantal jichtaanvallen sindshet vorige bezoek. Noteer bij heteerste bezoek het aantal aanvallenover de afgelopen 12 maanden)

Versie 3 - 09/02/2016

ATTACG studie

Jicht status (2/4)

Ja (ga door naar vraag 7)

Nee (je hoeft verder niets in te vullen voor jicht status, ga door naar sectie comborbiditeiten)

6. Voldoet de patiënt aan het volgende: Ten minste 1 episode van zwelling, pijn ofgevoeligheid in een perifeer gewricht of bursa (nu en/of ooit in het verleden)

7. Voldoet de patiënt aan het volgende: Aanwezigheid van urinezuurkristallen in eensymptomatisch gewricht of bursa (i.e. in gewrichtsvloeistof) of tophus

Ja (je hoeft verder niets in te vullen voor jicht status, ga door naar sectie comborbiditeiten)

Nee (ga door naar vraag 8)

8. Patroon van gewricht/bursa betrokkenheid tijdens symptomatische episode(n) nu en/ofooit in het verleden (1 antwoord mogelijk):Symptomatische episoden zijn periodes van symptomen inclusief alle soorten zwelling, pijn, gevoeligheid in

een perifeer gewricht of bursa.

Gewricht(en) of bursa(e) anders dan de enkel, middenvoet of MTP1 (of de betrokkenheidvan deze alleen als onderdeel van een polyarticulair voorval)

Enkel OF middenvoet (als onderdeel van een monoarticulaire of oligoarticulaire episodezonder de betrokkenheid van MTP1)

MTP1 (als onderdeel van een monoarticulaire of oligoarticulaire episode)

9. Kenmerken van symptomatische episode(n) (nu en/of ooit in het verleden) (1 antwoordmogelijk):

i. Erytheem rondom het aangetaste gewricht (patiënt-gerapporteerd of door de artswaargenomen)

ii. Aanraking of druk uitoefenen op het aangetaste gewricht wordt niet verdrageniii. Grote moeite met lopen of het onvermogen om aangetaste gewricht te gebruiken

Geen kenmerken

1 kenmerk

2 kenmerken

3 kenmerken

CRF - JICHT STATUS

Versie 3 - 09/02/2016

ATTACG studie

Jicht status (3/4)

10. Tijdsverloop van episode(n) nu en/of ooit in het verleden:Bij aanwezigheid (ooit) van 2 of meer is er sprake van een typische episode, ongeacht anti-inflammatoirebehandeling:i. Tijd tot maximaal bereikte pijn <24 uurii. Resolutie van symptomen is minder of gelijk dan 14 dageniii. Volledige resolutie (tot baseline niveau) tussen symptomatische episoden

11. Klinisch bewijs van tophi:Druipende of krijt - achtige subcutane knobbel onder transparante huid, vaak met bovenliggende vasculariteit,gelegen in typische locaties: gewrichten, oren, bursitis olecrani, vingertoppen, pezen (bijv. Achilles).

Geen typerende episode(n)

1 Typische episode

Terugkerende typerende episode(n)

Afwezig

Aanwezig

12. Urinezuurspiegel:Gemeten middels de uricase methode. Idealiter gemeten op een tijdstip wanneer er door de patiënt geenurinezuurverlagende therapie werd ingenomen en 4 weken na de start van de episode bij de patiënt (i.e.,tijdens interkritische periode); als praktisch uitvoerbaar, opnieuw testen onder dergelijke condities. Dehoogste waarde, onafhankelijk van wanneer gemeten, dient te worden gescoord.

<4 mg/dL (<0.24 mmol/L)

4 - <6 mg/dL (0.24 - <0.36 mmol/L)

6 - <8 mg/dL (0.36 - <0.48 mmol/L)

8 - <10 mg/dL (0.48 - <0.60 mmol/L)

groter of gelijk aan 10 mg/dL (groter of gelijk aan 0.6 mmol/L)

13. Analyse gewrichtsvloeistof van een symptomatisch (nu en/of ooit in het verleden)gewricht of bursa:Dient beoordeeld te worden door een getrainde waarnemer.

Niet gedaan

Urinezuurkristallen negatief

CRF - JICHT STATUS

Versie 3 - 09/02/2016

ATTACG studie

Jicht status (4/4)

14. Beeldvormend onderzoek van uraatafzetting in symptomatisch (nu en/of ooit in hetverleden) gewricht of bursa:Echografisch bewijs van dubbel contour sign (zie uitleg *) of DECT vertoont uraatafzetting (zie uitleg **).

Niet gedaan

Afwezig

Aanwezig (geldt voor beide technieken)

* Hyperechoische onregelmatige versterkingen die onafhankelijk zijn van de insonatie hoek van deultrasoon geluid bundel (noot: valspositief "dubbel contour sign"(artefact) zou kunnen verschijnen aan hethyaline kraakbeen oppervlak maar dienen te verdwijnen met een verandering van de insonatie hoek van desonde).

** Aanwezigheid van kleurgecodeerd uraat bij de articulaire of peri-articulaire plaatsen. Afbeeldingen zijnverkregen door het gebruik van een dual energy computer tomografie (DECT) scanner, met data verworvenbij 80 en 140kV en geanalyseerd met jicht-specifieke software met een twee materiaal decompositiealgoritme dat uraat kleur codeerd. Een positieve scan is gedefinieerd als de aanwezigheid vankleurgecodeerd uraat by articulaire of peri-articulaire plaatsen. Nagelbed, submillimeter, huid, 'motion','beam hardening' en vasculaire artefacten dienen niet te worden geïnterpreteerd als bewijs voor DECTuraatafzetting.

15. Beeldvormend onderzoek van jicht-gerelateerde gewrichtsschade:Conventionele radiografie van de handen en/of voeten toont ten minste één erosie (zie uitleg ***)

Niet gedaan

Afwezig

Aanwezig

*** Erosie wordt gedefinieerd als een corticale breuk met een sclerotische marge en overhangende rand;exclusief DIP gewrichten en zeemeeuw uiterlijk.

CRF - JICHT STATUS

Versie 3 - 09/02/2016

ATTACG studie

CRF - COMORBIDITEITEN

Hypertensie

Ja Nee

Lymfoproliferatieve maligniteit

Metabolisch syndroomsyndroom

Cardiovasculaire ziekte

Hyperlipidemie

Overige malignitieit

Overige comorbiditeiten

Ja Nee

Ja Nee

Ja Nee

Ja Nee

Ja Nee

Ja Nee

Ja Nee

Ja NeeObesitas

Nierinsufficientie

Indien ja, welke comorbiditeiten?

COMORBIDITEITEN

Versie 3 - 09/02/2016

ATTACG studie

CRF - LABORATORIUM

Serum urine zuur (mmol/l) ,

CRP (mg/l) ,

Versie 3 - 09/02/2016

CRF - JICHTMEDICATIE

Jichtmedicatie Noteer hier ALLE medicatie die voor JICHT gestart is op moment van inclusie of gestart is tijdens de studie op recept van de reumatoloog, zowel ontstekingsremmende als urinezuur verlagende therapieën. Voor codes zie onderaan de pagina. Laat het veld stopdatum leeg indien de medicatie voortgezet wordt.

- -- -Startdatum Stopdatum

Dosering Eenheden Frequentie

, per

Naam

Route



, per

Naam

Route

Codes route1. Intra-articluair 5. Oraal2. Intramusculair 6. Rectaal3. Intraveneus 7. Subcutaan4. Intranasaal 8. Overig

ATTACG studie

Reden van stoppen

Hersteld Niet effectief Last van Bijwerkingen

Indien last van Bijwerkingen, wat waren de bijwerkingen?

Reden van stoppen

Hersteld Niet effectief Last van Bijwerkingen

Indien last van Bijwerkingen, wat waren de bijwerkingen?

Versie 3 - 09/02/2016

CRF - OVERIGE MEDICATIE

Overige medicatie (Noteer hier alle medicatie die op dit moment voor aandoeningen anders dan jicht gebruikt worden of die in de afgelopen 12 maanden zijn gebruikt)

ATTACG studie

Naam

- -- -Startdatum Stopdatum (indien van toepassing)


, perRoute

Reden van stoppen:

Hersteld Niet effectief Last van bijwerkingen

Indien last van bijwerkingen, wat waren de bijwerkingen?

Codes route1. Intra-articluair 3. Intraveneus 5. Oraal 7. Subcutaan2. Intramusculair 4. Intranasaal 6. Rectaal 8. Overig



, per

Naam

Route

Reden van stoppen:Hersteld Niet effectief Last van bijwerkingen

Indien last van bijwerkingen, wat waren de bijwerkingen?

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CRF - BIJWERKINGEN

Infectieziekte

Leveraandoeningen na starten medicatie

Hart en vaataandoeningen

Verslechtering van serum urinezuur

Verslechtering nierfunctie

Tumor lysis

Zwanger

Overig

Ja Nee

Ja Nee

Ja Nee

Ja Nee

Ja Nee

Ja Nee

Ja Nee

Ja Nee

Indien ja, welke?

Versie 3 - 09/02/2016

CRF - ADVERSE EVENTS

ATTACG studie

1. Omschrijving van de bijwerking

2. Begindatum bijwerking (dd-mm-jjjj)

- -

4. Hoe is het met deze bijwerking afgelopen bij de patiënt?

Hersteld Hersteld met restverschijnselen Herstellende Overleden Onbekend

5. Is deze bijwerking behandeld?

Nee Onbekend Ja

Nee Onbekend Ja

7. Zijn er naast de studie medicatie mogelijk andere oorzaken of omstandigheden die debijwerking kunnen hebben veroorzaakt of verergerd?

8. Heeft de bijwerking geleid tot een van de volgende situaties?

OverlijdenLevensbedreigende situatieZiekenhuisopnameBlijvende arbeidsongeschiktheidAangeboren afwijkingOverige ernstige afwijkingen

3. Stopdatum bijwerking (dd-mm-jjjj)

- -

6. Relatie tot studie medicatie?

Verdacht Samengaand Interactie Geen / n.v.t. Anders

9. Welke actie is er ondernomen?

Geen

Bijvend gestaakt

Tijdelijk gestaakt

Dosering verlaagd

Dosering verhoogd

Dosering onveranderd

Onbekend

Anders / n.v.t.

Versie 3 - 09/02/2016

CRF - STUDIE UITVAL

ATTACG studie

1. Datum laatste dosis studie medicatie

- -

2. Datum studie uitval

- -

3. Belangrijkste reden voor uitval(Serious) Adverse events

SUSARBesluit van patiënt

Besluit behandelaarPatiënt overledenOverige reden, namelijk:

4. Specificeer de reden voor uitval hieronder nader

Versie 3 - 09/02/2016

ATTACG studie

Patiëntcode./medicatiecode

JICHTAANVAL DAGBOEK - DAG 1 (Pagina 1 van 3)

1. Wat is de datum waarop deze jichtaanval begon? (dd-mm-jjjj)

- -

3. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? (1 vakje volledig inkleuren)

1 2 3 4

veel pijngeen pijn

5. Hoe gezwollen zijn de delen van uw lichaam die door jicht zijn aangedaan vandaag?(1 vakje volledig inkleuren)

4. Hoe gevoelig voor aanraking zijn de delen van uw lichaam die door jicht zijnaangedaan vandaag? (1 vakje volledig inkleuren)

5

2. Wat is de datum vandaag? (dd-mm-jjjj)

- -

milde pijn matige pijn

1 2 3 4

nietgevoelig

5

lichtgevoelig

redelijk gevoelig

extreemgevoelig

1 2 3 4

niet gezwollen

5

enigszins gezwollen

redelijk gezwollen

heel gezwollen

extreem gezwollen

6. Wat vindt u van het beloop van uw klachten sinds het begin van deze jichtaanval? (1vakje volledig inkleuren)

1 2 3 4 5 6 7 8 9

enigszinsverbeterd

geheelverdwenen

zeer veelverbeterd

veelverbeterd

nietveranderd

ietsverslechterd

veelverslechterd

zeer veelverslechterd

niet vantoepassing

extreme pijn

heel gevoelig

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9. Heeft u last van bijwerkingen? Zo ja, noteer hieronder de bijwerkingen die u vandaagervaart: (1 letter per vakje)


0 10 1 2 3 4 5 6 7 8 9

Helemaal geen pijn

Ondraaglijkepijn

8. Als u denkt aan alle manieren waarop uw jicht u vandaag beïnvloedt, hoe gaat hetdan met u? (1 vakje volledig inkleuren)

Zeer slecht 0 10 1 2 3 4 5 6 7 8 9

Zeer goed

10. Heeft u vandaag uw studiemedicatie ingenomen? (1 vakje volledig inkleuren)

Nee

Ja, alle medicijnen zoals voorgeschreven

Ja, maar gedeeltelijk/niet alles zoals voorgeschreven

helemaalgeen pijn

ondraaglijkepijn

11. Hoeveel pijn heeft u vandaag als gevolg van uw jicht? Wilt u dit aangeven door eenverticaal streepje ( I ) te zetten op onderstaande lijn?

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12. Heeft u de afgelopen 24 uur naast uw onderzoeksmedicatie, nog andere medicijneningenomen om uw jichtaanval te bestrijden? Zo ja, noteer hieronder de medicatie die uheeft ingenomen. Hieronder valt ook paracetamol en ibuprofen gebruik: (1 letter pervakje).

Hoeveel tabletten/injecties heeft u in de afgelopen 24 uur gebruikt van dit medicijn?

Dosering volgens de verpakking (kruis aan of de dosering in microgram of milligram is)

Naam medicijn volgens de verpakking

Medicijn 1

,




Medicijn 2

,




Medicijn 3

,

Microgram

Milligram

Microgram

Milligram

Microgram

Milligram

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- -

1 2 3 4 5

1 2 3 4 5


1 2 3 4

niet gezwollen

5

enigszins gezwollen

redelijk gezwollen

heel gezwollen

extreem gezwollen


1 2 3 4 5 6 7 8

enigszinsverbeterd

geheelverdwenen

zeer veelverbeterd

veelverbeterd

nietveranderd

ietsverslechterd

veelverslechterd


9

niet vantoepassing

veel pijngeen pijn milde pijn matige pijn extreme pijn

nietgevoelig

lichtgevoelig

redelijk gevoelig

extreemgevoelig

heel gevoelig


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0 10 1 2 3 4 5 6 7 8 9

Helemaal geen pijn

Ondraaglijkepijn


Zeer slecht 0 10 1 2 3 4 5 6 7 8 9

Zeer goed



Nee



helemaalgeen pijn

ondraaglijkepijn


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Medicijn 1

,




Medicijn 2

,




Medicijn 3

,

Microgram

Milligram

Microgram

Milligram

Microgram

Milligram

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1 2 3 4 5

1 2 3 4 5


1 2 3 4

niet gezwollen

5

enigszins gezwollen

redelijk gezwollen

heel gezwollen

extreem gezwollen


1 2 3 4 5 6 7 8

enigszinsverbeterd

geheelverdwenen

zeer veelverbeterd

veelverbeterd

nietveranderd

ietsverslechterd

veelverslechterd


9

niet vantoepassing


nietgevoelig

lichtgevoelig

redelijk gevoelig

extreemgevoelig

heel gevoelig


- -


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0 10 1 2 3 4 5 6 7 8 9

Helemaal geen pijn

Ondraaglijkepijn


Zeer slecht 0 10 1 2 3 4 5 6 7 8 9

Zeer goed



Nee



helemaalgeen pijn

ondraaglijkepijn


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Medicijn 1

,




Medicijn 2

,




Medicijn 3

,

Microgram

Milligram

Microgram

Milligram

Microgram

Milligram

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1 2 3 4 5

1 2 3 4 5


1 2 3 4

niet gezwollen

5

enigszins gezwollen

redelijk gezwollen

heel gezwollen

extreem gezwollen

5. Wat vindt u van het beloop van uw klachten sinds het begin van deze jichtaanval? (1vakje volledig inkleuren) 1 2 3 4 5 6 7 8

enigszinsverbeterd

geheelverdwenen

zeer veelverbeterd

veelverbeterd

nietveranderd

ietsverslechterd

veelverslechterd


9

niet vantoepassing


nietgevoelig

lichtgevoelig

redelijk gevoelig

extreemgevoelig

heel gevoelig


- -


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0 10 1 2 3 4 5 6 7 8 9

Helemaal geen pijn

Ondraaglijkepijn


Zeer slecht 0 10 1 2 3 4 5 6 7 8 9

Zeer goed



Nee



helemaalgeen pijn

ondraaglijkepijn


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Medicijn 1

,




Medicijn 2

,




Medicijn 3

,

Microgram

Milligram

Microgram

Milligram

Microgram

Milligram

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1 2 3 4 5

1 2 3 4 5


1 2 3 4

niet gezwollen

5

enigszins gezwollen

redelijk gezwollen

heel gezwollen

extreem gezwollen


enigszinsverbeterd

geheelverdwenen

zeer veelverbeterd

veelverbeterd

nietveranderd

ietsverslechterd

veelverslechterd


9

niet vantoepassing


nietgevoelig

lichtgevoelig

redeijk gevoelig

extreemgevoelig

heel gevoelig


- -


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0 10 1 2 3 4 5 6 7 8 9

Helemaal geen pijn

Ondraaglijkepijn


Zeer slecht 0 10 1 2 3 4 5 6 7 8 9

Zeer goed



Nee



helemaalgeen pijn

ondraaglijkepijn


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Medicijn 1

,




Medicijn 2

,




Medicijn 3

,

Microgram

Milligram

Microgram

Milligram

Microgram

Milligram

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1 2 3 4 5

1 2 3 4 5


1 2 3 4

niet gezwollen

5

enigszins gezwollen

redelijk gezwollen

heel gezwollen

extreem gezwollen


enigszinsverbeterd

geheelverdwenen

zeer veelverbeterd

veelverbeterd

nietveranderd

ietsverslechterd

veelverslechterd


9

niet vantoepassing


nietgevoelig

lichtgevoelig

redelijk gevoelig

extreemgevoelig

heel gevoelig


- -


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0 10 1 2 3 4 5 6 7 8 9

Helemaal geen pijn

Ondraaglijkepijn

7. Als u denkt aan alle manieren waarop uw jicht u vandaag beïnvloedt, hoe gaat hetdan met u?

Zeer slecht 0 10 1 2 3 4 5 6 7 8 9

Zeer goed


Nee



helemaalgeen pijn

ondraaglijkepijn


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Medicijn 1

,




Medicijn 2

,




Medicijn 3

,

Microgram

Milligram

Microgram

Milligram

Microgram

Milligram

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1 2 3 4 5

1 2 3 4 5


1 2 3 4

niet gezwollen

5

enigszins gezwollen

redelijk gezwollen

heel gezwollen

extreem gezwollen


1 2 3 4 5 6 7 8

enigszinsverbeterd

geheelverdwenen

zeer veelverbeterd

veelverbeterd

nietveranderd

ietsverslechterd

veelverslechterd


9

niet vantoepassing


nietgevoelig

lichtgevoelig

redelijk gevoelig

extreemgevoelig

heel gevoelig


- -


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0 10 1 2 3 4 5 6 7 8 9

Helemaal geen pijn

Ondraaglijkepijn


Zeer slecht 0 10 1 2 3 4 5 6 7 8 9

Zeer goed



Nee



helemaalgeen pijn

ondraaglijkepijn


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Medicijn 1

,Microgram

Milligram




Medicijn 2

,Microgram

Milligram




Medicijn 3

,Microgram

Milligram

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VRAGENLIJST VOOR PATIËNTEN - FYSIEK FUNCTIONEREN 1/2

- Kunt u zichzelf aankleden, inclusiefveters strikken en knopendichtmaken?

zonder enigemoeite

met enigemoeite

met veelmoeite

onmogelijkuit te voeren

- Kunt u uw haren wassen?

- Kunt u opstaan vanuit een rechte stoel?

- Kunt u in en uit bed komen?

- Kunt u vlees snijden?

- Kunt u een vol kopje of glas naar demond brengen?

- Kunt u een nieuw pak melk openen?

- Kunt u buitenshuis op een vlakke grondwandelen?

- Kunt u vijf traptreden oplopen?

AANKLEDING EN VERZORGING

OPSTAAN

ETEN

LOPEN

Kruis aan welke HULPMIDDELEN u normaal gebruikt voor de bovenstaande activiteiten:

Wandelstok

Rollator / looprekje

Krukken

Rolstoel

Hulpmiddelen, gebruikt bij het aankleden (knoophaak,

ritssluiting-trekker, lange-steel schoenlepel, etc.)

Speciale of aangepaste hulpmiddelen bij eten of drinken

Speciale of aangepaste stoel

Kruis elke categorie aan waarvoor u normaal HULP VAN ANDEREN nodig heeft:

Aankleden / verzorging

Opstaan

Eten

Lopen

De volgende vragen gaan over de invloed van uw ziekte op het functioneren in het dagelijksleven. Kruis het antwoord aan dat het best beschrijft wat u meestal kon doen in deAFGELOPEN WEEK.

Overig, namelijk:

ATTACG studie

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VRAGENLIJST VOOR PATIËNTEN - FYSIEK FUNCTIONEREN 2/2

Kruis het antwoord aan dat het best beschrijft wat u meestal kon doen IN DE AFGELOPENWEEK.

zonder enigemoeite

met enigemoeite

met veelmoeite

onmogelijkuit te voeren

HYGIËNE

- Kunt u zelf uw lichaam wassen enafdrogen?

- Kunt u in en uit bad komen?

- Kunt u op en van het toilet?komen?

REIKEN

- Kunt u een 2,5 kg wegend voorwerp,zoals een pak suiker, bereiken enomlaaghalen van net boven uw hoofd?

- Kunt u voorover buigen om kleren van devloer op te rapen?

GRIJPKRACHT

- Kunt u auto-portieren openen?

- Kunt u deksels van potten, die al eensgeopend zijn, losdraaien?

- Kunt u een kraan openen dichtdraaien?

ACTIVITEITEN

- Kunt u boodschappen doen en winkelen?

- Kunt u in en uit een auto komen?

- Kunt u klusssen doen, zoals stofzuigen oftuinieren?

Kruis aan welke HULPMIDDELEN u normaal gebruikt voor de bovenstaande activiteiten:

Verhoogd toilet

Zitje in de badkuip

Lange-steel hulpmiddelen om iets te bereiken

Lange-steel hulpmiddelen in de badkamer

Overig, namelijk:Potdeksel-opener

Badkuip-muurstang

Kruis elke categorie aan waarvoor u normaal HULP VAN ANDEREN nodig heeft:

Wassen en toiletbezoek

Naar voorwerpen reiken

Voorwerpen pakken en openen

Boodschappen doen en klussen

ATTACG studie

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VRAGENLIJST VOOR PATIËNTEN - GEZONDHEIDSSTATUS 1/4

Deze vragenlijst gaat over uw standpunten t.a.v. uw gezondheid. Wilt u elke vraagbeantwoorden door het juiste hokje aan te kruisen. Wanneer u twijfelt over het antwoordop een vraag, probeer dan het antwoord te geven dat het meest van toepassing is.

uitstekend

zeer goed

goed

matig

slecht

Hoe beoordeelt u nu uw gezondheid over het algemeen, vergeleken met een jaar geleden?

veel beter nu dan een jaar geleden

wat beter nu dan een jaar geleden

ongeveer hetzelfde nu als een jaar geleden

wat slechter nu dan een jaar geleden

veel slechter nu dan een jaar geleden

De volgende vragen gaan over bezigheden die u misschien doet op een doorsnee dag. Wordtu door uw gezondheid op dit moment beperkt bij deze bezigheden? Zo ja, in welke mate?

ja,ernstigbeperkt

ja, eenbeetje

beperkt

nee, hele-maal nietbeperkt

a. Forse inspanning, zoals hardlopen, tillenvan zware voorwerpen, een veeleisendesport beoefenen

b. Matige inspanning, zoals een tafelverplaatsen, stofzuigen, zwemmen of fietsen

c. Boodschappen tillen of dragen

d. Een paar trappen oplopen

e. Eén trap oplopen

f. Bukken, knielen of hurken

g. Meer dan een kilometer lopen

h. Een paar honderd meter lopen

i. Ongeveer honderd meter lopen

j. Uzelf wassen of aankleden

1.

2.

3.

Hoe zou u over het algemeen uw gezondheid noemen?

SF-36v2™ Health Survey 1992,2003 Health Assessment Lab, Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved.SF-36® is a registered trademark of Medical Outcomes Trust.(SF-36v2 Standard, Netherlands (Dutch))

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4. Hoe vaak heeft u in de afgelopen 4 weken, één van de volgende problemen bij uw werk ofandere dagelijkse bezigheden gehad, ten gevolge van uw lichamelijke gezondheid?

a. U besteedde minder tijd aan werkof andere bezigheden

b. U heeft minder bereikt dan u zou willen

c. U was beperkt in het soort werk ofandere bezigheden

d. U had moeite om uw werk of anderebezigheden uit te voeren (het kostteu bijvoorbeeld extra inspanning)

Hoe vaak heeft u in de afgelopen 4 weken, één van de volgende problemen ondervonden bijuw werk of andere dagelijkse bezigheden, ten gevolge van emotionele problemen (zoalsdepressieve of angstige gevoelens)?

5.

a. U besteedde minder tijd aan werk

of andere bezigheden

b. U heeft minder bereikt dan u zou willen

c. U deed uw werk of andere bezighedenniet zo zorgvuldig als gewoonlijk

In hoeverre hebben uw lichamelijke gezondheid of emotionele problemen u gedurende deafgelopen 4 weken gehinderd in uw normale omgang met familie, vrienden of buren, of bijactiviteiten in groepsverband?

6.

helemaal niet

enigszins

nogal

veel

heel erg veel

meestal soms zelden nooitaltijd

altijd meestal soms zelden nooit


ATTACG studie

9373


Hoeveel lichamelijke pijn heeft u de afgelopen 4 weken gehad?7.

geen

heel licht

licht

nogal

ernstig

heel ernstig

8. In welke mate bent u de afgelopen 4 weken door pijn gehinderd in uw normale werk (zowelwerk buitenshuis als huishoudelijk werk)?

helemaal niet

enigszins

nogal

veel

heel erg veel

9. Deze vragen gaan over hoe u zich voelt en hoe het met u ging in de afgelopen 4 weken. Wiltu alstublieft bij elke vraag het antwoord geven dat het best benadert hoe u zich voelde?

Hoe vaak gedurende de afgelopen 4 weken...

a. Voelde u zich levenslustig?

b. Was u erg zenuwachtig?

c. Zat u zo in de put dat niets u konopvrolijken?

d. Voelde u zich rustig en tevreden?

e. Had u veel energie?

f. Voelde u zich somber en neerslachtig?

g. Voelde u zich uitgeput?

h. Voelde u zich gelukkig?

i. Voelde u zich moe?

altijd meestal soms zelden nooit


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10. Hoe vaak hebben uw lichamelijke gezondheid of emotionele problemen u gedurende deafgelopen 4 weken gehinderd bij uw sociale activiteiten (zoals vrienden of familie bezoeken,etc.)?

altijd

meestal

soms

zelden

nooit

11. Hoe JUIST of ONJUIST is elk van de volgende uitspraken voor u?

volkomenjuist

groten-deelsjuist

weetik niet

volkomenonjuist

groten-deels

onjuist

a. Ik lijk wat gemakkelijker ziek te wordendan andere mensen

b. Ik ben even gezond als andere mensendie ik ken

c. Ik verwacht dat mijn gezondheid achteruitzal gaan

d. Mijn gezondheid is uitstekend


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9373

VRAGENLIJST VOOR PATIËNTEN - ZORGGEBRUIK (1/2)

1. Heeft u een bezoek gebracht aan een van onderstaandegezondheidsmedewerkers SINDS UW VORIGE BEZOEK BIJ DEREUMATOLOOG? Zo ja, geef aan hoe vaak u geweest bent.

Reumatoloog

Verpleegkundig consulent /

Physician assistant /

Huisarts

Bedrijfsarts

Gynaecoloog

Psycholoog

Maatschappelijk werker

Uroloog

Kaakchirurg

Maagdarmlever arts

Vaatchirurg

Neuroloog

Chirurg

Cardioloog

Psychotherapeut

Hydrotherapeut

Oefentherapeut

Ergotherapeut

Fysiotherapeut

Psychiater

Plastisch chirurg

Longarts

Internist

Dermatoloog

Hematoloog

KNO arts

Podotherapeut

Revalidatie arts

Orthop. schoenmaker

Orthopeed

OogartsAnestesioloog

Oncoloog

Nefroloog

ATTACG studie

onderzoeksverpleegkundige

verpleegkundige specialist

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VRAGENLIJST VOOR PATIËNTEN - ZORGGEBRUIK (2/2)

2. Heeft u sinds uw vorige bezoek bij dereumatoloog professionele hulp gekregen in verbandmet persoonlijke verzorging of verpleging? Zo ja,hoeveel uur gemiddeld per week?

3. Heeft u sinds uw vorige bezoek bij dereumatoloog gebruik gemaakt van betaaldehuishoudelijke hulp, bijvoorbeeld alfa hulp? Zo jahoeveel uur gemiddeld per week?

4. Heeft u sinds uw vorige bezoek bij dereumatoloog hulp gekregen van uw partner, familie ofvrienden in verband met persoonlijke verzorging of hethuishouden als gevolg van jicht? Zo ja hoeveel uurgemiddeld per week?

6. Heeft u een van onderstaande behandelingen ondergaansinds uw vorige bezoek bij de reumatoloog? Zo ja, geefhet aantal aan

Maken van een röntgen foto

Maken van een echo

Het maken van een MRI

Het maken van een CT-scan

7. Bent u sinds uw vorige bezoek bij de reumatoloog ineen van onderstaande zorginstellingen opgenomen geweest?Zo ja, geef de duur van de opname dan in dagen. Het is nietnodig om dagopnames voor de toediening van medicatie tenoteren

Academisch ziekenhuis

Algemeen ziekenhuis

Revalidatiecentrum

Intensive care algemeen ziekenhuis

Intensive care academisch ziekenhuisDagen

Dagen

Dagen

Dagen

Dagen

DagenVerpleeghuis

5. Wat is uw arbeidssituatie (meerdere antwoorden mogelijk)

Betaald werk

VUT/pensioen

WAO/WIA

Vrijwilligerswerk

Geen van bovenstaande

ATTACG studie

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VRAGENLIJST VOOR PATIËNTEN - WERK PRODUCTIVITEIT (1/1)

2. Hoeveel uur was u tijdens de afgelopen zeven dagen afwezig vanuw werk in verband met uw jicht? Reken hierbij de uren die u gemisthebt op dagen waarop u ziek was, later op het werk kwam, vroegerwegging enz. Reken hier de tijd die u gemist hebt omdat u aandeze studie meedoet niet bij

Ja Nee1. Hebt u op dit moment een baan (werkt u tegen betaling)? Indiennee, kies nee en ga verder naar vraag 6

4. Hoeveel uur hebt u in de afgelopen 7 dagen daadwerkelijkgewerkt? (indien 0, ga door naar vraag 6)

5. Hoezeer heeft uw jicht in de afgelopen 7 dagen uw productiviteitbeïnvloed TERWIJL U AAN HET WERK WAS? (denk aan de dagenwaarop u beperkt werd in de hoeveelheid of het soort werk dat u kondoen, minder bereikte dan u gewild had of niet zo zorgvuldig konwerken als gewoonlijk.)

uur

uur

6. Hoezeer heeft uw jicht tijdens de afgelopen 7 dagen uwvermogen beïnvloed uw normale dagelijkse activiteiten, buiten uwbaan, uit te voeren? Met normale bezigheden bedoelen weactiviteiten die u gewoonlijk uitvoert zoals werk in en rondom hethuis, winkelen, voor de kinderen zorgen, lichaamsbeweging,studeren, enz. Denk aan de momenten waarop u beperkt werd inde hoeveelheid of soort activiteiten die u kon doen of minderbereikte dan u gewild had.

Jicht had geeninvloed opmijn werk 0 10 1 2 3 4 5 6 7 8 9

Jicht heeftmij volledig

belet mijnwerk te doen

Jicht had geeninvloed opmijnactiviteiten

0 10 1 2 3 4 5 6 7 8 9

Jicht heeftmij volledig

belet mijnactiviteiten

te doen

ATTACG studie

uur3. Hoeveel uur bent u tijdens de afgelopen 7 dagen afweziggeweest van uw werk vanwege een andere reden, zoals vakantie,feestdagen, tijd die u vrij hebt genomen om aan deze studie deel tenemen?

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DSMB Charter

“ATTACG: Anakinra versus treatment as usual in the treatment of acute gout”

Dossier: NL52526.044.15 / EudraCT number: 2015-000696-27

Introduction

This charter is for the Data Safety Monitoring Board (DSMB) which will act in advisory capacity to

prof. dr. M.A.F.J. van de Laar, Medisch Spectrum Twente, Ariënsplein 1 7511 JX, Enschede,

conducting the ATTACG study funded by ZonMw. The purpose of this document is to describe the

roles and responsibilities of the DSMB, describe board processes and describe the method of

reporting.

DSMB Roles and Responsibilities

The DSMB roles and responsibilities are:

- To perform ongoing safety surveillance of the study participants

- To advise prof. dr. M.A.F.J. van de Laar on if breaking the randomization (treatment) code is

needed if cases of SAE or SUSARs arise during the trial

- To report to prof. dr. M.A.F.J. van de Laar on the safety of anakinra during the trial

- To decide to prematurely stop the study if felt the safety of the patients is being jeopardized

The DSMB will discharge itself from its duties when the last participant completes the study.

Membership

The DSMB will consist of 3 advisory members:

1. Prof. dr. Rene Westhovens, rheumatologist, Universiteit Ziekenhuis Leuven, Belgium.

2. Dr. Mark Reinders, hospital pharmacist, Atrium Medisch Centrum, Heerlen, the Netherlands.

3. Prof. dr. Thomas Bardin, rheumatologist, Hôpital Lariboisière, Paris, France / professor of

rheumatology, Université Paris VII.

There are no financial, scientific, or other conflict of interest with the study.

Before the trial

The DSMB will be informed about its duties and the study before the start of the trial by means of

this DSMB charter and the final study protocol. If needed, the principal investigator (tel. 053-487

2450 / email: [email protected]) or coordinating investigator (tel. 06-2855-4650 email:

[email protected]) may be contacted if any aspects of the study and duties of the DSMB are

not clear.

During the trial

The DSMB will review safety data when 50 patients allocated to the anakinra treatment study group

have been included in the study. At this point in time the committee will review the safety data on

the documented and frequency of side effects and/or AE/SAE among patients using anakinra. The

coordinating investigator will provide the necessary data to the DSMB. A recommendation regarding

the outcome of this evaluation will be made available to the principal investigator.

At any point in time an emergency evaluation of the safety data may be called upon (by DSMB

chairman or principal investigator) should safety issues or other unanticipated problems arise. In

cases of SAE or SUSARs and the sponsor feels breaking the randomization (treatment) code may

need to be broken in order to treat the patient, the sponsor may decide to contact the DSMB for

advice regarding this matter.

A recommendation to terminate the study may be made by the DSMB at any time. The DSMB should

communicate such a recommendation to the principal investigator immediately by telephone and

confirmed by email (tel. 053 – 487 2450 / email: [email protected]).

Reporting

A formal report, including an advice and/or recommendation for continuation or modification of the

study will be prepared by the DSMB and when finalized be submitted to the principal investigator.

The principal investigator is responsible for distributing the DSMB recommendations to all other

study investigators. A copy of all the DSMB recommendations will be sent to the authorizing METC.

When the principal investigator decides not to implement the recommendations, besides the copy, a

clear and convincing reasoning for why the advice has not been followed should be included and sent

to the authorizing METC as well.

Confidentiality

All materials, discussions and proceedings of the DSMB are completely confidential. Members and

other participants in the DSMB meetings are expected to maintain confidentiality.

Documents

ATTACG: Anakinra versus Treatment as usual in the ... · 9/19/2017 · Research Protocol NL52526.044.15 / ATTACG 7 List of abbreviations MSU Monosodium urate NSAIDs Non-steroidal