Evaluating the clinical and cost effectiveness of behavioural activation therapy for depression after stroke (BEADS): a feasibility randomised controlled trial Shirley A. Thomas1*, Avril E. R. Drummond2, Nadina B. Lincoln1, Rebecca L. Palmer3, Roshan dasNair1, Nicholas R. Latimer3, Gemma L. Hackney4, Laura Mandefield4, Stephen J. Walters3, Rachael D. Hatton3, Cindy L. Cooper4, Timothy F. Chater4, Timothy J. England1, Patrick Callaghan2, Elizabeth Coates4, Katie E. Sutherland4, Sarah Jacob Eshtan4, and Gogem Topcu1 1School of Medicine, University of Nottingham, UK 2School of Health Sciences, University of Nottingham, UK 3School of Health and Related Research, University of Sheffield, UK 4Sheffield Clinical Trials Research Unit, University of Sheffield, UK * Corresponding author: Dr Shirley Thomas, Associate Professor, Division of Rehabilitation & Ageing, School of Medicine, University of Nottingham, B Floor, Medical School, Queens Medical Centre, Nottingham, NG7 2UH. Email: [email protected] Declared competing interests of authors: Shirley Thomas and Avril Drummond report grants from NIHR, and The Stroke Association, outside the submitted work. Rebecca Palmer is an author of the Consent Support Tool, which was piloted in the work and discussed in the report. Roshan das Nair is a member of the HS&DR Board. Stephen Walters is a member of the HTA Clinical Trials Board and HTA Funding Boards Policy Group and he reports grants from NIHR HTA Programme, during the conduct of the study; personal fees from Royalties, research grants from NIHR and the Medical Research Council, personal fees from external examining fees, and book royalties outside the submitted work. Cindy Cooper is a member of the NIHR CTU Standing Advisory Committee. i Keywords: Stroke, Depression, Cost-Benefit analysis, Psychotherapy, Research Design Word Count: 48,856 ii Funding Acknowledgement: This project was funded by the National Institute for Health Research Health Technology Assessment Programme (project number 13/14/01). This report presents independent research commissioned by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the Health Technology Assessment Programme or the Department of Health. The views and opinions expressed by the interviewees in this publication are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, MRC, CCF, NETSCC, the Health Technology Assessment programme or the Department of Health. iii Abstract Background There is currently insufficient evidence for the clinical and cost-effectiveness of psychological therapies for post-stroke depression. Objective To evaluate the feasibility of undertaking a definitive trial to evaluate the clinical and cost effectiveness of behavioural activation (BA) compared to usual stroke care for treating post-stroke depression. Design Parallel group, feasibility, multicentre, RCT with nested qualitative research and economic evaluation. Setting Acute and community stroke services in three sites in England. Participants Community dwelling adults 3 months to 5 years post-stroke, depressed as determined by the Patient Health Questionnaire-9 (PHQ-9) or Visual Analog Mood Scales Sad. Exclusions: blind, deaf, dementia, unable to communicate in English, without mental capacity to consent, receiving treatment for depression at the time of stroke onset, currently receiving psychological intervention. Randomisation and blinding Participants were randomised (1:1 ratio) to BA or usual stroke care. Randomisation was conducted using a computer-generated list with random permuted blocks of varying sizes, stratified by site. Participants and therapists were aware of the allocation, outcome assessors were blind. Interventions The intervention arm received up to 15 sessions of BA over 4 months. BA aims to iv improve mood by increasing people’s level of enjoyable or valued activities. The control arm received usual care only. Outcomes Primary: feasibility of recruitment to the main trial, acceptability of research procedures and measures, appropriateness of baseline and outcome measures, retention of participants, potential value of conducting the definitive trial. Secondary feasibility outcomes concerned delivery of the intervention. Primary clinical outcome 6 months post-randomisation: PHQ-9. Secondary clinical outcomes: Stroke Aphasic Depression Questionnaire-Hospital, Nottingham Leisure Questionnaire, Nottingham Extended Activities of Daily Living, Carer Strain Index, EuroQol EQ-5D-5L, healthcare resource use questionnaire. Results Forty-eight participants were recruited in 27 centre-months of recruitment; a recruitment rate of 1.8 participants per centre per month. The 25 participants randomised to receive BA attended a mean of 8.5 (SD 4.4) therapy sessions; 23 participants were allocated to usual care. Outcome assessments were completed by 39 (81%) participants (18 BA, 21 usual care). Mean PHQ-9 scores at 6-months follow-up were 10.1 (SD 6.9) and 14.4 (SD 5.1) in the BA and control groups respectively, a difference of -3.8 (95% CI: -6.9 to -0.6) after adjusting for baseline PHQ-9 score and centre, representing a reduction in depression in the BA arm. Therapy was delivered as intended. BA was acceptable to participants, carers and therapists. Value of information analysis indicates that the benefits of conducting a definitive trial would be likely to outweigh the costs. We estimate that a sample size between 580 and 623 would be needed for a definitive trial. Limitations Target recruitment was not achieved although we identified methods to improve recruitment. v Conclusions BEADS was feasible with regarding to the majority of outcomes. The outstanding issue is whether a sufficient number of participants could be recruited within a reasonable timeframe for a definitive trial. Future work Identify whether there are sufficient sites able to deliver the services required for a definitive trial. Trial registration ISRCTN: 12715175 Funding NIHR Health Technology Assessment programme (13/14/01). Word count: 500 vi Contents Abstract ..................................................................................................................... iv Scientific summary ................................................................................................. xvi Plain English Summary .......................................................................................... xxv 1 Introduction ............................................................................................................ 1 1.1 Post-stroke depression ..................................................................................... 1 1.2 Current service provision ................................................................................ 2 1.3 Behavioural activation..................................................................................... 4 1.4 Rationale and objectives.................................................................................. 6 2 Methods ................................................................................................................. 8 2.1 The feasibility trial .......................................................................................... 8 2.1.1 Trial design .............................................................................................. 8 2.1.2 Ethical approval ....................................................................................... 8 2.1.3 Important changes to the methods after feasibility trial commencement 8 2.1.4 Participants and eligibility criteria ........................................................... 9 2.1.5 Settings and locations where the data were collected ............................ 16 2.1.6 Interventions .......................................................................................... 16 2.1.7 Feasibility criterion ................................................................................ 21 2.1.8 Changes to trial outcomes after the trial commenced, with reasons ...... 24 2.1.9 Sample size ............................................................................................ 24 2.1.10 Explanation of any interim analyses and stopping guidelines ............... 25 2.1.11 Method used to generate the random allocation sequence ..................... 25 2.1.12 Type of randomisation; details of any restriction (such as blocking and block size) ............................................................................................................ 25 2.1.13 Allocation concealment mechanism ...................................................... 26 2.1.14 Blinding.................................................................................................. 26 2.1.15 Statistical methods ................................................................................. 26 2.1.16 Analysis populations .............................................................................. 27 2.1.17 Patient and public involvement (PPI) .................................................... 30 2.2 Fidelity assessment ........................................................................................ 31 2.3 Health Economic Methods ............................................................................ 32 2.3.1 Background ............................................................................................ 32 2.3.2 Overview ................................................................................................ 33 vii 2.3.3 Resource use .......................................................................................... 34 2.3.4 Unit costs ............................................................................................... 35 2.3.5 Outcomes ............................................................................................... 35 2.3.6 Analysis.................................................................................................. 35 2.4 The qualitative research ................................................................................ 38 2.4.1 Interviewer characteristics ..................................................................... 39 2.4.2 Relationship with participants................................................................ 39 2.4.3 Theoretical and thematic framework ..................................................... 39 2.4.4 Participant Selection .............................................................................. 40 2.4.5 Data collection ....................................................................................... 41 2.4.6 Data analysis .......................................................................................... 41 3 Results of the feasibility trial ............................................................................... 43 3.1 Implementation of intervention and trial ....................................................... 43 3.1.1 Implementation summary ...................................................................... 43 3.2 Recruitment and participant flow .................................................................. 43 3.2.1 Recruitment to the trial .......................................................................... 43 3.2.2 Protocol non-compliances ...................................................................... 52 3.2.3 Losses and exclusions after randomization ............................................ 53 3.2.4 Dates defining the periods of recruitment and follow-up ...................... 54 3.3 Baseline data ................................................................................................. 56 3.4 Clinical Outcomes and estimation................................................................. 61 3.4.1 Decision on the primary endpoint and sample size for a definitive trial72 3.4.2 Delivery and receipt of the intervention ................................................ 74 3.4.3 Number of missing values/incomplete cases ......................................... 77 3.5 Adverse events .............................................................................................. 78 3.6 Challenges with implementation ................................................................... 79 3.6.1 Challenges with the delivery of the intervention ................................... 79 3.6.2 Challenges with recruitment and data collection ................................... 79 4 Fidelity assessment results ................................................................................... 86 5 Health economic results ....................................................................................... 92 5.1 Feasibility Outcomes ..................................................................................... 92 5.2 Within trial analysis ...................................................................................... 93 5.3 Model-based analysis .................................................................................. 102 viii 5.3.1 Model Inputs ........................................................................................ 102 5.3.2 Value of information ............................................................................ 111 5.4 Summary of health economics findings ...................................................... 115 5.5 Discussion of health economics findings .................................................... 117 5.6 Limitations of the health economics analysis ............................................. 118 6 Qualitative research results ................................................................................ 120 6.1 Patient views of the interventions and trial ................................................. 120 6.1.1 Gains and changes................................................................................ 120 6.1.2 Therapy-specific experiences (intervention group only) ..................... 124 6.2 Therapist views of delivering the therapy ................................................... 129 6.2.1 Experiences of delivering the therapy .................................................. 129 6.2.2 Challenges ............................................................................................ 130 6.2.3 Improvements needed/suggestions ...................................................... 132 6.2.4 Experiences of participants from therapist perspective ....................... 132 6.3 Practical aspects of delivering the therapy from therapists’ perspective .... 134 6.3.1 Support provided to therapists ............................................................. 134 6.3.2 Experience of working on trial within therapists’ department ............. 138 6.3.3 Integrating the trial practice into wider service ................................... 138 6.4 Participant views on the trial procedures .................................................... 139 6.4.1 Rationale of the study .......................................................................... 139 6.4.2 Motivation and reason to participate.................................................... 140 6.4.3 Understanding the research process ..................................................... 141 6.4.4 Participant views of the outcome measures ......................................... 144 6.5 Therapist views on the trial procedures....................................................... 150 6.5.1 Recruitment .......................................................................................... 150 6.5.2 Study procedures .................................................................................. 151 6.5.3 Measures .............................................................................................. 152 6.6 Qualitative summary ................................................................................... 153 7 Discussion .......................................................................................................... 155 7.1 Summary of findings ................................................................................... 155 7.2 Evidence of feasibility and implications for a future definitive trial .......... 157 7.2.1 Population/recruitment ......................................................................... 157 7.3 Generalisability ........................................................................................... 161 ix 7.3.1 Intervention .......................................................................................... 163 7.3.2 Outcomes ............................................................................................. 164 7.3.3 Adverse event reporting ....................................................................... 166 7.4 Strengths and limitations ............................................................................. 166 7.4.1 The feasibility trial ............................................................................... 166 7.4.2 Fidelity assessment .............................................................................. 168 7.4.3 Health economics ................................................................................. 169 7.4.4 The qualitative research ....................................................................... 170 7.5 Results in the context of other studies of psychological interventions for post-stroke depression ............................................................................................ 171 7.6 Patient and public involvement (PPI) ......................................................... 171 8 Conclusions ........................................................................................................ 172 Acknowledgements .................................................................................................... 176 References .................................................................................................................. 180 9 Appendices ......................................................................................................... 192 List of Tables Table 1 PHQ-9 Depression Categories ........................................................................ 28 Table 2 Summary recruitment flow - by screening route ............................................ 48 Table 3 Number identified by screening routea ........................................................... 49 Table 4 Participants randomised by centre and by montha .......................................... 49 Table 5 Number recruited by the recruitment route ..................................................... 49 Table 6 Number of carers recruited to BEADS trial by treatment arm and site .......... 50 Table 7 Reasons for non consent given by carers ........................................................ 50 Table 8 Non compliances reported in the trial ............................................................. 52 Table 9 Attrition presented by treatment arm, site and time since stroke. .................. 53 Table 10 Number of participants who completed follow up by home visit and postal pack. ............................................................................................................................ 54 Table 11 Baseline demographics by treatment arm ..................................................... 56 Table 12 Baseline outcome measures by treatment arm .............................................. 57 Table 13 Stroke characteristics by treatment arm ........................................................ 58 Table 14 Stroke history by treatment arm.................................................................... 59 x