Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Walker J, Hansen CH, Martin P, et al, for the SMaRT (Symptom Management Research Trials) Oncology-3 Team. Integrated collaborative care for major depression comorbid with a poor prognosis cancer (SMaRT Oncology-3): a multicentre randomised controlled trial in patients with lung cancer. Lancet Oncol 2014; published online Aug 28. http://dx.doi.org/10.1016/S1470-2045(14)70343-2.

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Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to:

Integrated collaborative care for major depression comorbid with a poor prognosis cancer (SMaRT

Oncology-3): a multicentre randomised controlled efficacy trial in patients with lung cancer.

Jane Walker, Christian Holm Hansen, Paul Martin, Stefan Symeonides, Charlie Gourley, Lucy Wall, David

Weller, Gordon Murray and Michael Sharpe.

for the SMaRT (Symptom Management Research Trials) Oncology-3 Team

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CONTENT

Study Team and Collaborators

Trial Steering Committee and Data Monitoring Committee

Supplementary Text

Suppl. Text 1 Trial governance

Suppl. Text 2 Quality control

Suppl. Text 3 Depression screening service

Suppl. Text 4 Derivation of the primary outcome

Suppl. Text 5 Social deprivation scores

Supplementary Tables

Suppl. Table 1 Comorbid diagnoses at baseline

Suppl. Table 2 Minimum effective doses of antidepressants

Suppl. Table 3 Selected participant quotes about DCPLC

Supplementary Figures

Suppl. Figure 1 Derivation of trial sample

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Study Team and Collaborators

Trial Management: Michael Sharpe, Gordon Murray, David Weller, Jane Walker, Christian Holm Hansen,

Paul Martin, Kerry McElhinney, Susan Stratton, Charlie Gourley, Lucy Wall, Stefan Symeonides, Alan

Wigglesworth, Elspeth Currie, Laura Hodges, Colin Steen, Lewis Harpin.

Principal Investigators and number of participants recruited from each site: Jim Cassidy (NHS Greater

Glasgow and Clyde; 68), Michael Sharpe (NHS Lothian; 28), Rosie Harrand (NHS Lanarkshire; 24), Lucy Wall

(NHS Fife; 11), Nicola Steele (NHS Forth Valley; 5), Hannah Lord (NHS Tayside; 4), Douglas West and Alan

Kirk (NHS Waiting Times Directive; 2).

DCPLC Delivery: Michael Sharpe, Jane Walker, Parvez Thekkumpurath, Mark O’Connor, Neelom Sharma,

Chloe Beale, Anne Byrne, Aarti Sawhney, Geraldine Hamilton, Linda Russell, Fiona Murdoch, Margaret

Russell, Lorraine Petrie, Michael Loynd, Sarah Hunter, Lisa Veitch, Ann McCulloch.

Data Collection: Stefan Symeonides, Michele Macnab, Sam Ruddell, Laura Dickson, Susan Dewar, Joelle

Cowie, Emma Witt.

Health Economics: Mark Sculpher, Gerry Richardson, Simon Walker, Ana Duarte.

External Academic Advice: Wayne Katon, Kurt Kroenke.

Depression Screening Service: Jan Irvine, Maria Breslin, Kate Randell, Lynda Russell, Paul Watson, Ashleigh

Macdougall, Jennifer Petrie, Veronica Cumming, Timothy Chan, Melanie Russell, Dawn Lindsay, Emma

Geddes, Stuart Cooney, Alison McCusker, Hazel Smillie, Kathryn Cunningham, Megan White, Heather

Coventry, Julie Wallace, Leanne Stephen, Niall Brennan, Frieda Brookmann, Alanna Perratt, Louise

Colquhoun, Karen Maybury, Anthony Shek, Kim Williamson, Nicola Kennedy, Petra Wynne.

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Trial Steering Committee and Data Monitoring Committee

Trial Steering Committee: Amanda Ramirez (Chair), Michael Bennett, David Cameron,

Graham Dunn, Simon Gilbody, Peter Rainey, Alison Richardson, Galina Velikova.

Data Monitoring Committee: John Geddes (Chair), Ed Juszczak, Dan Stark.

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Supplementary Text 1: Trial governance

The day to day running of the trial was led by a Trial Management Group (TMG), members of which met

weekly. The Trial Manager oversaw all aspects of the trial and was accountable to the Chief Investigator. Two

Trial Site Co-ordinators managed the trial centres and all seven recruitment sites (NHS health boards) had a

Principal Investigator.

The trial was overseen by an independent Trial Steering Committee (TSC) which provided overall supervision

of the trial.

The trial Data Monitoring Committee (DMC) comprised members who acted independently of the TMG, TSC

and trial funder. The purpose of the DMC was to monitor interim trial data and make recommendations to the

TSC regarding any ethical or safety concerns regarding the trial’s continuation.

Following an initial joint meeting of the TSC, DMC and TMG in March 2008, the DMC met annually during

recruitment. DMC meetings began with an open session attended by the Chief Investigator, Trial Manager,

Trial Statistician and Trial Data Manager, during which pooled data on recruitment, data quality and adverse

events were presented and discussed. The DMC members then met separately in a closed session to review

unmasked primary outcome and safety data, prepared by an independent statistician. The DMC Chair provided

initial recommendations to the Trial Manager immediately after this closed session and written

recommendations were made to the TSC.

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Supplementary Text 2: Quality control

Quality control of trial procedures

All trial staff were trained in the use of the trial protocol and the standard operating procedures applicable to

their role. In addition, trial staff attended regular updates on good clinical research practice and received regular

supervision from senior members of the trial team. As well as the generic standard operating procedures of the

local research and development office, standard operating procedures were developed and used for the following

trial processes and occurrences:

1. Trial master file

2. Trial site files

3. Participant information, informed consent and eligibility assessment

4. Trial entry

5. Baseline data collection

6. Protocol violations

7. DCPLC delivery

8. DCPLC quality assurance

9. DCPLC quality control

10. Commencing outcome data collection

11. Collection of outcome data

12. Participant withdrawal

13. Adverse events

14. End of trial participation

15. Data recording, storage, transfer and archiving

16. Participant deaths

17. Suicide risk assessment

18. Suicide risk assessment during data collection

19. Suicide review

20. Contacting primary care providers during data collection

21. Detecting adverse events during data collection

22. Data collection quality checks

Quality control of DCPLC

DCPLC nurses were registered medical nurses with experience of working with cancer patients and were trained

over a whole time equivalent of two to three months. Training emphasised the achievement of competency in

specific clinical areas (basic oncology, basic psychiatry, advanced communication skills, depression assessment

and treatment, suicide risk assessment, problem solving therapy, use of the DCPLC treatment manual) and

nurses were required to demonstrate competency by passing assessments before treating trial participants.

Training comprised: tutorials, directed reading, role plays and simulated patient treatment sessions. Assessments

were both written and practical.

DCPLC psychiatrists were board certified consultation-liaison psychiatrists. Two senior (UK consultant level)

psychiatrists led the treatment supervision throughout the trial. At any time during the trial two other (UK

registrar level) psychiatrists also assisted with supervision, with each of these working on the trial for at least

one year. Supervising psychiatrists met regularly to ensure a consistent approach and based their supervision on

the DCPLC supervisors’ manual.

Treatment sessions were video-recorded with participants’ permission. A supervising psychiatrist watched the

video-recordings of each nurse’s early (first two months) treatment sessions and gave detailed feedback. We

also developed standardised rating sheets for each treatment session type (first session, second session,

subsequent sessions, penultimate session, final session, booster treatment sessions). These were used by the

nurses to rate their own sessions and by the supervisors in order to determine whether the nurses were adhering

to the treatment approach. The rating sheets specified the behaviours that the nurse was expected to carry out in

each session type (e.g. introduction, discussion of antidepressant medication) as well as proscribed behaviours

(e.g. counselling).

An independent researcher also used these standardised sheets to rate approximately 10% (60) of all DCPLC

sessions. In 97% of these sessions the care manager covered all the areas expected. The independent researcher

also rated each session for overall quality on a 0-10 scale (with 0 representing ‘very poor’ and 10 representing

‘very good’); the results of these ratings were a mean score of 8.4, median 8 and range 7-10.

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Supplementary Text 3: Depression screening service

This clinical service was delivered by a team of screening assistants (psychology graduates and general nurses)

supervised by consultation-liaison psychiatrists. The service identified patients with major depression using a

two-stage procedure: In the first stage, patients completed the Hospital Anxiety and Depression Scale (HADS)

using touchscreen computers whilst waiting for their oncology appointment. A screening assistant helped

patients to do this and ensured that the oncology clinician received the patient’s questionnaire results. In the

second stage the screening team telephoned at home those patients who had scored high on the HADS (total

score ≥15) and conducted diagnostic depression interviews (the depression section of the Structured Clinical

Interview for DSMIV). For patients who were found to have major depression, the screening team sent a report

to the PCP and oncologist and, during the period of trial recruitment, offered referral to the trial team. The flow

of patients though the screening service during the trial period is shown in Figure S1.

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Supplementary Text 4: Derivation of the primary outcome

The primary outcome was an average of the participant’s available depression scores (using the SCL-20 scale)

during the time they were in the trial. This was calculated in two steps: In the first step, we calculated the area

under the curve (AUC) formed by connecting the participant’s available post-baseline SCL-20 depression scores

using straight lines. In the second step, to disassociate the unit of measurement from the time the participant was

in the trial, the AUC was divided by the time between the first and the last post-baseline measurement (i.e. the

length of the AUC). The calculation of the primary outcome for one of the participants in the trial is illustrated

in the figure below.

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Join the available scores collected during follow-up

Compute the area under the curve (AUC)

Divide the AUC by its length to obtain the average depression severity

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For the eight participants in the trial with only one available post-baseline measurement, the SCL-20 depression

score from this single assessment was used in the analysis as their average depression score in accordance with

the pre-specified analysis plan.

Mathematically the average depression severity was defined for participants with two or more available follow-

up measurements as

1

1

1

)1()1(21

iin

n

j

ijjiijji

tt

ttyy

i

i

In the expression above, yij is the observed SCL-20 depression score for patient i on the jth observed

measurement (j =1,…, ni), ni is the number of observed follow-up measurements for patient i, and tij is the time

(measured in days since randomisation) of the jth measurement for patient i.

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Supplementary Text 5: Social deprivation scores

Social deprivation was calculated using the Scottish Index of Multiple Deprivation (SIMD) 2009. The SIMD

divides Scotland into 6,505 small geographical divisions (datazones) and ranks these from the most deprived

(ranked 1) to the least deprived (ranked 6,505).

We used participants’ home address postcodes to calculate their social deprivation index.

The median deprivation index for trial participants was 1727, which lies in the third most deprived decile of the

SIMD.

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Supplementary Table 1: Comorbid diagnoses at baseline

DCPLC

(n=68)

UC

(n=74)

Major depression 68 (100%) 74 (100%)

Cancer 68 (100%) 74 (100%)

GI disease1 46 (68%) 40 (54%)

Pulmonary disorders2 37 (54%) 37 (50%)

Musculoskeletal disorders3 26 (38%) 32 (43%)

Hypertension 31 (46%) 32 (43%)

Cardiac disease4 29 (43%) 30 (41%)

Diabetes 7 (10%) 10 (14%)

Thyroid disorders 4 (6%) 6 (8%)

Neurological disorders5 7 (10%) 7 (10%)

Genito-urinary disorders6 6 (9%) 4 (5%)

Cerebrovascular disease 10 (15%) 1 (1%)

Patients with ≥3 diagnoses 61 (90%) 66 (89%)

Number of diagnoses, mean (median); range 5 (5); 1-11 5 (5); 1-10

Data are number (percentage) unless otherwise specified.

Most common examples of diagnoses: 1 gastro-oesophageal reflux disease

2 asthma, chronic obstructive airways disease

3 osteoarthritis, osteoporosis, back pain

4 ischaemic heart disease

5 peripheral neuropathy, migraine, epilepsy

6 urinary incontinence

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Supplementary Table 2: Minimum effective doses of antidepressants

Taylor D, Paton C, Kapur N. Maudsley Hospital Prescribing Guidelines. 10th ed. London: Informa Healthcare;

2011.

Antidepressant Dose (mg/day)

citalopram 20

escitalopram 10 fluoxetine 20

fluvoxamine 50

paroxetine 20 sertraline 50

nortriptyline 75

amitiptyline 75 clomipramine 75

dosulepin 75

dothiepin 75 lofepramine 140

venlafaxine 75 duloxetine 60

mirtazapine 30

trazodone 150

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Supplementary Table 3: Selected participant quotes about DCPLC

Quotes regarding the helpfulness of treatment

Well, I got the DVD and the book and I was reading it and I said “well, that’s how I feel” and that was definitely how I felt and I

thought “well, they’re right”

It was a lot more informal than I thought which is very, very good. It was really nice.

Just a happy smiling face coming into see you, you know, not doing you off for anything.

Well, I’m very grateful to have had the attention and the help, and I feel so much better for it all.

Honestly, I thought it was all very nicely, very considerately done Thank you for giving me the opportunity; it was wonderful, it really did help.

Quotes regarding recommending DCPLC to a friend

I think everybody should get it. See once you’ve had your operation and you’ve had your chemo and you’re through the end of it, well

that’s it. You’re just left .. I was .. I just felt as if I was left.

Just that I would recommend to people and not to be frightened of it, there’s nothing to be ashamed of, stigma because you’re

depressed. There are different levels of depression; I didn’t know I was depressed, and I now I know I was.

No I thought the treatment nurse was quite good and if someone else had depression I think it would be a good idea.

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Supplementary Figure 1: Derivation of the trial sample from lung cancer clinic attendance to referral to

trial team

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N indicates number of screening events, n indicates number of individual patients

Referred to trial team N=490

(n=479)

Appointments N=21,678

(n=6,348)

HADS≥15 N=3,351 (n=2,324)

Depressed N=671

(n=629)

Excluded N=181 Depression duration > 2 years N=53 Receiving other psychiatric treatment N=11 Excluded by psychiatrist N=19 Poor prognosis N=57 Refused to have details passed to trial team N=41

Depression interview not completed N=1,215 Ineligible for interview (recently diagnosed N=373 major depression, recently interviewed) Unable to carry out interview (cognitive, N=176 impairment, communication problems) Patient preferred not to carry out interview N=173 Clinician/family member advised against N=126 interview Too unwell N=115 Could not contact N=109 Deceased N=59 Other N=84

HADS not completed N=12,008 Ineligible for screening (unclear diagnosis, N=5351 recently screened, under 18) Missed N=1793 Patient preferred not to use screening N=1423 system Administrative (clinic cancelled, list changed, N=1414 attending different clinic) Too unwell N=636 Unable to use screening (cognitive N=427 impairment, communication problems) Clinician advised not to screen N=312 Too distressed N=91 Screening interrupted N=489 Other N=72

HADS<15 N=6,319

Not depressed N=1,465