Confidential: For Review Only Computerised cognitive behaviour therapy (cCBT) as a treatment for depression in primary care (The REEACT trial): a …

Confidential: For Review O

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Computerised cognitive behaviour therapy (cCBT) as a

treatment for depression in primary care (The REEACT trial): a large scale pragmatic randomised controlled trial

Journal: BMJ

Manuscript ID BMJ.2015.026474.R2

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 21-Aug-2015

Complete List of Authors: Gilbody, Simon; University of York, Health Sciences Littlewood, Elizabeth; University of York, Department of Health Sciences Hewitt, Catherine; University of York, Department of Health Sciences; University of York, Health Sciences Brierley, Gwen; University of Cambridge School of Clinical Medicine, Tharmanathan, Puvan; University of York, Health Sciences Araya, Ricardo; LSHTM, Barkham, Michael; University of Sheffield, Centre for Psychological Services Research Bower, Peter; University of Manchester, Cooper, Cindy; University of Sheffield, Paediatric Endocrinology Gask, Linda; University of Manchester, PsychiatryPrimary Care

Kessler, David; University of Bristol, Academic Unit of Psychiatry, School of Social and Community Medicine Lester, Helen; School of Health and Population Sciences, Primary care Lovell, Karina; University of Manchester, School of Nursing, Midwifery and Social Work Parry, Glenys; University of Sheffield, School of Health & Related Research Richards, David; University of Exeter, Medical School Andersen, Phil; University of York, Health Sciences Brabyn, Sally; University of York, Health Sciences Knowles, Sarah; University of Manchester, Health Sciences Research Group Shepherd, Charles; University of Hull, Tallon, Debbie; University of Bristol, Academic Unit of Psychiatry, School of

Social and Community Medicine White, David; University of Sheffield, School of Health & Related Research

Keywords: Depression, CBT, computer, primary care

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Confidential: For Review OnlyCONSORT 2010 checklist Page 1

CONSORT 2010 checklist of information to include when reporting a randomised trial*

Section/Topic Item No Checklist item

Reported on page No

Title and abstract

1a Identification as a randomised trial in the title 1

1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) 3-4

Introduction

Background and

objectives

2a Scientific background and explanation of rationale 7-8

2b Specific objectives or hypotheses 8

Methods

Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 8

3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons NA

Participants 4a Eligibility criteria for participants 8-9

4b Settings and locations where the data were collected 9

Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were

actually administered

10-11

Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they

were assessed

11

6b Any changes to trial outcomes after the trial commenced, with reasons NA

Sample size 7a How sample size was determined 12

7b When applicable, explanation of any interim analyses and stopping guidelines NA

Randomisation:

Sequence

generation

8a Method used to generate the random allocation sequence 9

8b Type of randomisation; details of any restriction (such as blocking and block size) 9

Allocation

concealment

mechanism

9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers),

describing any steps taken to conceal the sequence until interventions were assigned

9

Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to

interventions

9

Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those 9

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Confidential: For Review OnlyCONSORT 2010 checklist Page 2

assessing outcomes) and how

11b If relevant, description of the similarity of interventions NA

Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 13

12b Methods for additional analyses, such as subgroup analyses and adjusted analyses 14

Results

Participant flow (a

diagram is strongly

recommended)

13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and

were analysed for the primary outcome

Fig 1 & p14

13b For each group, losses and exclusions after randomisation, together with reasons Fig 1

Recruitment 14a Dates defining the periods of recruitment and follow-up 14

14b Why the trial ended or was stopped NA

Baseline data 15 A table showing baseline demographic and clinical characteristics for each group Table 1

Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was

by original assigned groups

P15 and

tables 2 and 3

Outcomes and

estimation

17a For each primary and secondary outcome, results for each group, and the estimated effect size and its

precision (such as 95% confidence interval)

P15 16

17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended P15 16

Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing

pre-specified from exploratory

P15 16

Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) P16

Discussion

Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 17-19

Generalisability 21 Generalisability (external validity, applicability) of the trial findings 17-19

Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence 18

Other information

Registration 23 Registration number and name of trial registry 6

Protocol 24 Where the full trial protocol can be accessed, if available 22

Funding 25 Sources of funding and other support (such as supply of drugs), role of funders 21-22

*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also

recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials.

Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.

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Page 1 of 37 10/12/2012 Trial Protocol – Version 12

Trial Protocol

The Randomised Evaluation of the Effectiveness and

Acceptability of Computerised Therapy (REEACT) Trial

Protocol Number: 250101 ISRCTN91947481

Sponsor: University of York

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Signature Page: Chief Investigator: Professor Simon Gilbody Alcuin C Block Department of Health Sciences University of York York YO10 5DD Tel: 01904 321370 Email: [email protected]

10th December 2012

Signature Date

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Co-Investigators (Site Principal Investigators in Bold) Bristol Professor Ricardo Araya Professor of Psychiatry Academic Unit of Psychiatry University of Bristol Cotham House Cotham Hill Bristol BS6 6JL Tel: 0117 331 4028 Email: [email protected]

Dr David Kessler Senior Research Fellow in Primary Care Academic Unit of Primary Health Care University of Bristol Cotham House Cotham Hill Bristol BS6 6JL Tel: 0117 331 4031 Email: [email protected]

Manchester

Dr Peter Bower Reader National Primary Care Research and Development Centre University of Manchester Manchester M13 9PL Tel: 0161 275 7638 Email: [email protected]

Professor Linda Gask Professor of Primary Care Mental Health National Primary Care Research and Development Centre University of Manchester Manchester M13 9PL Tel: 0161 275 7638 Email: [email protected]

Professor Helen Lester Professor of Primary Care Primary Care Clinical Sciences Building University of Birmingham Edgbaston Birmingham B15 2TT Tel: 0121 414 2684 Email: [email protected]

Professor Karina Lovell Professor of Mental Health School of Nursing, Midwifery and Social Work University of Manchester Manchester M13 9PL Tel: 0161 306 7853 Email: [email protected]

Nicola Lidbetter Manager, National Phobics’ Society Zion CRC 339 Stretford Road Hulme Manchester M15 4ZY Tel: 08444 775774 Email:[email protected]

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Sheffield Professor Michael Barkham Professor of Clinical Psychology Director, Centre for Psychological Services Research Clinical Psychology Unit/ScHARR Department of Psychology Western Bank University of Sheffield Sheffield S10 2TP Tel: +44(0)114 222 6527 Email: [email protected]

Dr Cindy Cooper Senior Research Fellow: Clinical Trials ScHARR University of Sheffield Regent Court 30 Regent Street Sheffield S1 4DA Tel: 0114 222 0743 Email: [email protected]

Professor Glenys Parry Professor of Psychological Therapies ScHARR University of Sheffield Regent Court 30 Regent Street Sheffield S1 4DA Tel: 0114 222 5454 Email: [email protected]

York Professor Simon Gilbody Department of Health Sciences Alcuin C Block University of York York YO10 5DD Tel: 01904 321370 Email: [email protected]

Mr Steven Palmer Senior Research Fellow Centre for Health Economics University of York York YO10 5DD Tel: 01904 321401 Email: [email protected]

Professor David Torgerson Director, York Trials Unit ARRC Department of Health Sciences University of York York YO10 5DD Tel: 01904 321340 Email: [email protected]

Professor Mark Sculpher Professor of Health Economics Centre for Health Economics University of York York YO10 5DD Tel: 01904 321401 Email: [email protected]

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Mrs Rachel Richardson Research Fellow Department of Health Sciences University of York York YO10 5DD Tel: 01904 321863 Email: [email protected]

Exeter Professor David Richards Professor of Mental Health Services Research School of Psychology University of Exeter Room 118, Washington Singer Building Perry Road Exeter EX4 4QG Tel: 01392 264615 Email: [email protected]

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1. Background Cognitive behaviour therapy (CBT) has emerged as the leading evidence-supported form of brief psychotherapy for people with depression. [1][2]However, it is unfeasible that demand for CBT can be met from existing therapist resources. [3] Primary care doctors therefore have relatively few treatment options other than antidepressant medication and/or referral to specialist psychology services where long waiting lists are likely. Computerised CBT represents an alternative form of therapy delivery that has the potential to enhance access to psychological care. Existing research into computerised CBT has most recently been summarised by Kaltenthaler et al in their 2006 review of clinical and cost effectiveness. [4]With respect to depression, three commercially-produced computerised packages available to the NHS were considered – Beating the Blues (BtB), Cope and Overcoming Depression. Of these only one, BtB, had been evaluated in a randomised controlled trial. [5] However, this research was conducted by those who owned and held intellectual copyright to BtB. Amongst internet-based free-to-use packages, only one, MoodGYM, has been evaluated in a randomised trial, also conducted by the package developers. [6] The overall conclusion of the HTA review was that ‘the efficacy but not effectiveness of Beating the Blues had been established in comparison with treatment as usual’. [4] However, several caveats applied and specific recommendations for further research were made that are important with respect to the present trial protocol.

1. The cost effectiveness of computerised packages is unclear. More importantly, the cost effectiveness from the perspective of the UK NHS has not been sufficiently established and the longer term cost effectiveness beyond the brief time horizon of existing trials is essentially unknown. This is important since commercial packages (such as BtB) will need to be purchased at substantial cost to the NHS. The major burden of costs associated with depression have been highlighted by Layard, [7] and are at a societal level (lost employment and increased welfare costs). The cost effectiveness of computerised CBT from a societal perspective is unknown.

2. Existing trials use highly selected populations who are necessarily comfortable with information technology and willing to be randomised to computerised therapy as a treatment option. The acceptability of the replacement of the therapist with a machine-interface is largely unknown.

3. There are no trials of free-to-use computerised CBT packages versus commercial computerised CBT. Similarly, there are no trials of computerised CBT versus therapist-led CBT. This is important since the effectiveness of free-to-use computerised CBT would need to be comparable to pay-per-use CBT or therapist-led CBT if it were to be a viable alternative within a stepped care pathway. [8]

4. Evaluations of all the commercially available and free to use packages of computerised CBT have been conducted by companies or

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researchers responsible for their development. Whilst this does not invalidate the results, it does raise concerns that a truly independent evaluation of the clinical and cost effectiveness of computerised CBT is needed to inform NHS decision making. Kaltenthaler et al make this a core research recommendation, where they state: ‘Research needs to be carried out by independent researchers. It should be carried out by those who are not associated with commercial or product gains.’ [4]

The present trial is designed to address these recommendations. Two products (MoodGYM and BtB) have demonstrated efficacy in a primary care setting. This study will represent Phase III of the MRC Complex Interventions Framework [9] and will be a definitive evaluation of computerised CBT in a trial that is adequately controlled and has appropriate statistical power. The post trial modelling phase corresponds to Phase IV of the MRC framework. In this phase we plan to answer important questions regarding generalisability and long term cost effectiveness. We will also conduct a qualitative process evaluation of the acceptability of this new technology to users and to the NHS.

2. Research Objectives This will be a fully randomised trial of usual GP care for depression versus the addition of one of two computerised CBT packages to usual GP care. We will include a concurrent economic and qualitative evaluation to meet the following specific aims:

1. To establish the clinical and cost effectiveness of the addition of computerised CBT to usual GP care over a two year trial follow-up period, and to assemble a primary care depression cohort of trial patients with a follow-up period of up to 10 years.

2. To establish the acceptability (to patients and clinicians) of computerised CBT.

3. To establish the differential clinical and cost effectiveness of a free-to-use computerised package, in comparison to a commercial pay-to-use computerised CBT package over a two year and longer-term time horizon.

3. Methods

3.1 Design

3.1.1 Trial-based clinical and economic evaluation: This will be a fully randomised controlled trial to evaluate the clinical and cost effectiveness of computerised CBT packages when added to usual GP care. Patients who meet our pragmatic inclusion criteria will be individually randomised into one of three treatment groups: (1) usual GP care PLUS a commercial pay-to-use computerised CBT package (BtB); (2) usual GP care PLUS a free-to-use computerised CBT package (MoodGYM) and (3) usual GP care. All patients

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will therefore receive usual GP care, and we anticipate that the majority of patients in the usual care group will receive antidepressants in line with NICE guidance. Our evaluation is therefore a pragmatic trial. The key comparison will be in the additional benefits that might be expected through the early addition of computerised CBT to usual care. There will be a concurrent economic evaluation whereby we will collect patient-level resource and service-use data to determine the comparative cost effectiveness of commercial versus free-to-use CBT – each in comparison with usual GP care. The issue of patient preference for either computerised therapy or usual care may well be important in determining their relative effectiveness. [4][10] Computerised CBT offers the potential of greater access to therapy, since it is not constrained by finite therapist numbers. However, a key dimension in the clinical effectiveness of computerised CBT will be the acceptability of therapy delivered by computer. Conversely, successful computerised CBT requires a level of time and commitment on the part of the patient, whereas usual GP care (focussed mainly on drug therapy) may be more acceptable for patients (who may not be sufficiently motivated to engage in computerised CBT). The research into the acceptability of and preference for computerised CBT in general is scarce. [10] Conventional trial designs ignore the issue of patient preference, giving an ‘average’ treatment effect for all those who are willing to undergo randomisation. The REEACT trial will use a ‘fully randomised preference approach’[11] to examine the issue of patient preference and the differential impact of preference on the relative effectiveness of usual care versus computerised CBT. Participants will each be asked about their baseline preference for either usual care plus computerised CBT or usual care prior to randomisation, and this will be further examined within a planned subgroup analysis. This strategy preserves the advantages of randomisation (unconfounded estimates of effect and the ability to draw causal inference from our trial), whilst still studying the impact of patient preference. [11] Patient preference designs are rarely employed in mental health, [12] and an important output of the REEACT trial will be to fully integrate the use of preference designs in a new and innovative area of research. 3.1.2 Concurrent process evaluation of the acceptability and implementation of computerised CBT: There has been little previous qualitative work exploring issues of the acceptability of computerised CBT, particularly from a primary care perspective. A systematic review by Waller and Gilbody of barriers to computerised CBT found only five relevant qualitative papers, all of relatively poor quality. [10] The review highlighted practical issues such as the substantial numbers of potential participants lost prior to trials commencing, the generally positive views of GPs about the introduction of computerised CBT and problems created by variable patient computer literacy. Drop out rates of up to 25% were also an issue in a previous evaluation of computerised CBT. [6] The impact of computerised therapies with or without internet support will, however, become an increasingly important issue both within and beyond the arena of mental

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health[10] and therefore this process evaluation of the REEACT trial will provide important generalisable information for the wider health community. We will use May’s ‘normalization process model’ [13] as our guiding theoretical framework to help us understand the conditions necessary to support the introduction of computerised CBT both within the home and community locations. This practical model has been developed to assist the assessment and evaluation of complex interventions in health care and facilitates our use of the MRC framework, [9] enabling us to understand better how they can be embedded and integrated as routine elements of care. May suggests, for example, that a complex intervention such as computerised CBT is more likely to become part of routine clinical practice if it improves patient-professional interactions and confers an advantage on the organisation in terms of managing workload. For the qualitative analysis, we will conduct semi-structured interviews with patients. Patients will be sampled based on their expressed preference for computerised CBT prior to randomisation, and whether they completed the course of computerised CBT or not. We expect to recruit between 36-40 patients, with the group reflecting a roughly equal balance of preference and completion. Patient interview topic guides will contain core questions developed from a literature review by Waller and Gilbody, [10] including computer literacy; changes in views about therapy pre and post-treatment; and views on using computerised CBT in future without consulting a health practitioner.Interviews will be held at the end of treatment and will be run throughout the duration of the data collection period. We will also sample from patients who choose not to participate in the trial prior to randomization, if those patients indicate their primary reason for refusal is due to concerns over using computerised CBT. We expect to recruit between 8-10 patients in this group. Health professional and managerial views on their experience of incorporating computerised CBT into primary care will be explored through individual semi-structured interviews with a purposive sample of GPs and practice managers. Topic guides will explore how this complex intervention is normalised within primary care. For GPs, this means, for example, that we will seek their views on potential changes to the doctor-patient relationship and for practice managers on issues of resources and risk. Interviews will continue in each group until data saturation is complete although we expect this may mean approximately 25 interviews with both GPs and managers. 3.1.3 Post trial modelling exercise: Decision modelling is increasingly used in the examination of clinical and cost effectiveness within health technology assessment; [15] often to enhance the relevance and applicability of randomised data and to allow additional economic and policy-related questions to be addressed (MRC complex interventions phase IV). Our post-trial modelling phase will enhance the results of the REEACT trial in the

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following three ways: (1) costs and outcomes will be extrapolated beyond the 2-year time horizon of the trial to fully account for the longer term impact of the different interventions; (2) we will consider the results of the trial alongside other evidence that has emerged in the interim (computerised CBT is a rapidly evolving technology); (3) we will be able to provide an indirect comparison with therapist-led CBT. Emergence and integration of additional interim evidence: Since the REEACT trial will not report longer term outcomes for four years, it is possible that the results of our trial will become supplanted by either new evidence or by the emergence of new products or costs. For example, if several trials of similar products emerge, it would be important to consider the results of the REEACT trial along with these other data. We will use meta-analysis and meta-regression to consider the clinical and cost effectiveness results from our own trial in comparison with other evidence. [16] Any new data can be entered as new input parameters and probabilistic sensitivity analyses within a simple decision model. [17] Indirect comparison with face to face CBT: If computerised CBT were to be clinically equivalent or not markedly inferior to full therapist-delivered CBT, then there would be substantial benefits in adopting computerised CBT more widely within a stepped care framework; [8] given the potential lower costs, and increased accessibility. To date, there are no definitive trials of computerised CBT versus therapist-led CBT, and the ideal design to evaluate computerised CBT versus full CBT would be by adding a further treatment arm to the REEACT trial. However, in line with the research brief, we have proposed a three arm design (usual care vs free-to-use computerised CBT plus usual care vs pay-to-use computerised CBT plus usual care). We propose however, to address the comparative clinical and cost effectiveness of computerised CBT versus therapist CBT versus usual care alone using newly developed methods of indirect and mixed treatment comparisons. [18] This method uses a hierarchical Bayesian evidence synthesis to simulate head-to-head comparisons when these are not available directly from randomised evidence. This will be of substantial use to decision makers in implementing computerised CBT within a stepped care framework, when traditional models of face to face therapy remain the dominant model of CBT delivery. 3.2 Inclusion/Exclusion Criteria 3.2.1 Inclusion criteria: Our target population will be adult patients, aged 18 and above with depression who are not currently in receipt of computerised CBT or specialist psychological therapy. Our inclusion threshold will be a score of >=10 on the PHQ9 depression severity instrument. [19] This cut point is known to detect clinical depression (major depression) in a UK primary care population[20] with sensitivity = 91.7% and specificity = 78.3%. We will also include patients with either co-morbid physical illness or co-morbid non-psychotic functional disorders, such as anxiety. We will include both incident and prevalent cases. In line with the pragmatic nature of this trial, we will

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reflect usual GP care and participants will be eligible to participate whether they are in receipt of antidepressant medication or not. 3.2.2 Exclusion criteria: We will exclude patients who are actively suicidal; suffering psychotic symptoms; depressed in the post-natal period; or have recently suffered bereavement. Patients with previous treatment experience of CBT will not be excluded. We will exclude cases of psychotic depression, since computerised therapy is not recommended within NICE guidance, [21] and are also unlikely to be recruited or randomised by general practitioners to receive computerised CBT, since they are unlikely to have sufficient equipoise in this case. We will also exclude patients who have alcohol or drug abuse as a primary diagnosis and patients who are not able to read and write in English. 3.3 Recruitment and Randomisation We plan to use four main recruitment routes, as follows:

1. GP-initiated recruitment. When a GP identifies a potential trial participant, the GP will inform them about the trial. If the patient is immediately interested in participating, the GP will ask them to complete a ‘Permission for Release of Personal Details’ form that will include their contact details. The GP will also complete a referral form, stating that the patient matches the study criteria and give the patient a cover letter and a Patient Information Sheet. The GP or representative will then fax the referral form and the Permission for Release of Personal Details form to the local researcher. The researcher will then contact the patient to pre-screen for eligibility using the PHQ9 and, if appropriate, arrange a visit as soon as possible. Some patients may wish to consider participation over a longer period and the GP will give them the information pack and a letter that explains how to contact the research team. If the patient contacts the researcher he or she will then make an arrangement to visit the patient as soon as possible. When the researcher visits he or she will answer any questions about the trial, make sure that the patient has read the information sheet and obtain consent to be screened for eligibility (Part 1 of Patient Consent Form). The researcher will then check eligibility and obtain informed consent to participate in the study, if eligible (Part 2 of Patient Consent Form). The researcher will then take baseline measurements (Biographical Questionnaire, CIS-R, CORE-OM, SF-36 v2, EQ5D, adapted CSRI) and ascertain treatment preference. He or she will then contact the secure randomisation line to determine treatment allocation, whilst still with the patient. The researcher will then immediately inform the patient of the allocation and make arrangements to initiate computerised CBT if this is the allocation. A letter will also be faxed to the GP informing them of the outcome of the interview, together with the PHQ-9 score, if obtained. Researchers will also make arrangements to collect follow-up measurements after four months. This could mean arranging a follow-up visit or telephone call;

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alternatively it may be preferable to the patient to receive and return the questionnaires by post. The researcher will also contact the patient shortly before the follow-up is due to confirm the arrangements, and re-arrange if necessary.

2. Recruitment initiated by health professionals attached to a GP

Practice. We anticipate that practice-attached nurses and mental health professionals attached to GP Practices (‘primary care mental health workers’) will see people with depression who may be potential trial participants. They will be able to introduce the trial to the patient, give the patient relevant information and ask the patient to complete the ‘Permission to Contact’ form in the same way that a GP would. They will also be able to complete a referral form and fax both the ‘Permission to Contact’ form and the referral form to the local researcher. They will inform the patient’s GP that they have made a referral. The local researcher will proceed in a similar way to receiving a referral from a GP. The local researcher will let both the GP and the referrer know of the outcome of the referral.

3. Record screening. Where a GP agrees, we will ask practice staff to

review patient records to identify any potential participants from previously recorded PHQ9 scores (collected in line with the Quality and Outcomes Framework). These prevalent cases will be contacted by post with the GP’s permission, or the GP can then consider the patient for the trial at their next appointment.

4. Waiting room screening. Where a GP practice agrees we will screen patients in the waiting room with a simple two question screening instrument. [23] If a patient screens positive for a possible depression, we will notify the GP immediately so that the GP can consider entering them into the trial.

Our trial will recruit in four centres – York and Gateshead (CI Gilbody), Bristol (investigators Araya and Kessler), Manchester (investigators Lovell, Gask, Bower, and Lester) and Sheffield (investigators, Barkham, Parry and Cooper). Each of these centres has an established recruiting network of practices. We have made a conservative assumption based on nationally available data that each GP with an average list size of 2,100 will see 2 new cases of depression per week. If we assume that GPs invite 25% of these incident patients to participate in the trial and that 25% of these patients meet our inclusion criteria and consent to participate, then each GP potentially contributes 10 patients during the two-year recruitment period. We have previously used waiting room screening methods and scrutiny of computerised records as described above to supplement this GP referral route, with an overall acceptance & randomisation rate of 25%. Our researchers will use active GP engagement with poorly recruiting practices and each of the investigators will provide participating practices with a series of mental health educational events to raise the profile of the REEACT study and as a participation

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incentive. In line with recommendations by Peveler and colleagues from a HTA-funded primary care depression trial, we have included a service support cost to GPs and practices to compensate for additional time involved in recruitment. [24] A further GP incentive will be the use of the Quality and Outcomes Framework (QOF). [22] By participating in our trial, each practice will ensure that patients recruited into the trial also complete the PHQ9, - a validated assessment measure now incentivised for the Depression 2 indicator in the QOF. Finally, to be sure that we will recruit to time and on target, we have enlisted the help of one of the Improving Access to Psychological Therapies (IAPT) programmes being coordinated by the Care Services Improvement Partnership (CSIP). This programme is assisting a number of PCT-based clinical sites to reconfigure their management of non-psychotic depression within a stepped care framework. Investigator Richards is an advisor to both the regional and national programmes. CSIP and the programme participants have agreed to allow eligible referred patients to be considered for inclusion in this trial. We will then follow the procedure for practice nurse initiated recruitment. Subsequent to funding being secured, the REEACT trial has been adopted by the Mental Health Research Network (MHRN). New sites will be added and resources made available to help recruitment within NHS hub sites. The MHRN covers 60% of the population of England, and will be an invaluable resource for recruitment within the broad recruitment strategies specified in this protocol. The precise location of specific sites cannot be specified at this point in time. Eligible participants who have consented to be in the trial will be randomised to treatment group using the computer-based York Trials Unit telephone randomisation service. In view of the large numbers enrolled in the study, further stratification by depression severity will not be needed. Stratification improves treatment precision in trials with less than 50 participants. However, for larger trials simple randomisation followed by analysis of covariance produces equally precise results[25] and eliminates any possible subversion associated with restricted randomisation methods. 3.4 Interventions

This is a pragmatic trial[26][27] and we will impose no restrictions on routine care, including the use of antidepressant drugs or the addition of drug treatment to computerised CBT in the intervention arms. 3.4.1 Experimental interventions: The intervention groups will each receive computerised therapy in addition to usual care. The control intervention will be usual GP care alone, with no specific encouragement to provide computerised CBT. Computerised therapy will be offered in one of three locations according to patient choice and local availability: (1) in the GP surgery (provided the patient’s GP practice is able to provide a broadband-connected

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computer and private room on a fixed weekly basis); (2) a central location close to the patients’ own home e.g. in a psychotherapy department or a large GP practice, (where a stand alone computer in a private room operating on a weekly booking system will be provided); or (3) the patients’ own homes (if they already have a computer and a broadband connection). This will maximise patient access and flexibility whilst respecting the importance of patient choice. All patients in the two intervention groups will receive support in the form of regular phone calls to encourage them to engage with the computerised therapy. We will record these phone calls in order to supervise the support worker. We will obtain informed consent to do this, but if participants do not consent to this, they can still participate in the trial. Experimental group 1: Beating the Blues (©Ultrasis, http://www.ulltrasis.com) is an interactive, multimedia, computerised CBT package comprising a 15 minute introductory video followed by 8 therapy sessions of approximately 50 minutes duration each. There are homework exercises between the sessions. BtB has been shown to be effective in reducing symptoms of depression. [5] The usual purchase cost of this package is £800 per patient and it can be used on a stand-alone computer or via the Internet in the patient’s own home. Experimental group 2: MoodGYM (©ANU http://moodgym.anu.edu.au) is a free-to-use web-based CBT programme for depression developed and copyrighted at the Australian National University Centre for Mental Health Research. It consists of five interactive modules, which are made available sequentially weekly, with revision of all aspects of the programme in the sixth week. MoodGYM has been shown to be effective in reducing symptoms of depression. [6] MoodGYM is used in the UK with 20.5% of the registrants on MoodGYM being from the UK (Professor Kathy Griffiths - personal communication). 3.4.2 Control intervention: Participants allocated to the control condition will receive usual care by their general practitioner. In line with the overall pragmatic approach of the trial, we will replicate ‘normal GP practice’ by making no specific patient-level recommendation or requirement to alter usual care by participating in the trial. We will however remind GPs of the existence of NICE guidance on the management of depression, including the prescription of antidepressants, where this is indicated 3.5 Outcome Measures 3.5.1 Primary outcome measure: our primary outcome will be depression severity and symptomatology as measured by a validated self-report measure (the Patient Health Questionnaire-9) [19] at four months. The PHQ9 is a nine-item questionnaire, which records the core symptoms of depression. There are extensive US and non-US validation and sensitivity to change data. It has most recently been validated in a UK primary care population[20] and

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has become the instrument of choice in UK primary care, [29] in the fulfilment of QOF routine depression measurement. It has the added advantage that it can be reliably administered over the phone. [30]

3.5.2: Secondary outcome measures: PHQ9 at 12 and 24 months; generic and global mental health (Clinical Outcomes in Routine Evaluation-Outcome Measure – CORE-OM); [31] Health Related Quality of Life (SF-36 v2); [32]

health-state utility (EuroQol - EQ5D); adapted CSRI; Preference Questionnaire; each all at 4, 12 and 24 month. [33]. We will measure antidepressant use in all three arms to assess whether participants randomised to the CCBT arms are subject to differing prescription rates of antidepressants. We will do this by accessing the GP notes. 3.5.3: Outcome measures for primary care depression cohort: PHQ9; CORE-OM; a self-report measure of anxiety (GAD-7) [34], Health Related-Quality of Life (SF-12) [35]; EQ5D; adapted CSRI; ; each all at three, five, seven and ten years. We will also measure aspects of service use, concurrent physical health problems; and prescription of medication, by accessing GP notes.

4. Statistical Considerations We will recruit a minimum of 690 patients with depression - 230 participants per arm. We need to know whether computerised CBT represents a useful addition to usual GP care, and whether the free to use computerised packages do not represent a poor second choice for patients. In this sense we will need to establish whether the clinical effectiveness of free to use computerised therapy is similar and NOT SUBSTANTIALLY INFERIOR to commercially produced CBT. Accordingly, we have powered our trial on the basis of non-inferiority, and will analyse our data in line with specific adjustments and recommendations that are needed in a non-inferiority trial. [36][37] We have based our sample size on the usual care arm of our own recent primary care trial of collaborative care for depression, where the proportion of patients responding to usual care according to a SCID diagnosis (major depression, yes/no) in a usual care arm was in the region of 0.6 (similar rate found in a UK HTA trial of anti-depressants in primary care, [24] and US pragmatic depression trial. [368). We would regard a response rate not more than 0.15 below this rate as being acceptable, given the additional care options that are available to patients who do not initially respond to computerised CBT, within a stepped care framework. Our proposed sample size of 690 (230 participants per arm) will have in excess of 90% power to detect non-inferiority with a 5% probability. We have made an assessment of loss to follow up of 35% based upon our early recruitment in the trial, and by recruiting no fewer than 690 we will retain 80% power to detect non-inferiority.

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In addition, our trial will also have 84% power to detect a difference of 0.15 between usual care arms and either of the computerised CBT arms using a conventional power analysis (alpha = 0.05; two sided)

5. Analysis 5.1 Statistical analysis of clinical data We will analyse the data on an intention to treat basis. The primary outcome, depressed/not depressed (at four months) will be used in a logistic regression model to compare each of the computerised packages with usual care alone. The analysis will be adjusted for baseline depression severity (measured by PHQ9) and co-morbidity with anxiety (established by diagnosis using the CIS-R). [28] Odds ratios and the corresponding 95% confidence intervals will be presented for the two comparisons (BtB vs usual care and MoodGYM vs usual care). Two-sided 95% confidence intervals for the odds ratio will be calculated. Using this method, the experimental treatment is not inferior to the control treatment at a 5% level if the upper boundary is below our pre-specified margin of non-inferiority. [39] For each outcome measure the number of non-responders will be calculated for each treatment group and response rates compared. Appropriate sensitivity analyses will be used to examine the effects of missing data on outcomes. All secondary analyses will be conducted using linear or logistic regression, depending on the outcome measure, adjusting for the same covariates as the primary analysis. The influence of preference will be ascertained by including this as a predictive co-variate in a planned sub-group analysis.

5.2 Analysis of economic data

The cost-effectiveness of computerised CBT will be evaluated in two phases. Phase 1 will comprise a within-trial economic analysis using prospectively collected clinical and resource-use data within the trial, over a two-year time horizon. Individual patient-level data will be used to quantify costs during the study and quality of life will be assessed by the EuroQoL-5D (EQ-5D) questionnaire. Phase 2 will address two related issues: (a) the need to extrapolate individual costs and quality of life data beyond the trial study period, and (b) the need to assess the cost effectiveness of the treatment strategies being investigated in the trial within the broader perspective of the NHS. Phase 2 of the study will, therefore, require the development of an economic model to (a) predict long term costs and effects and (b) synthesise available evidence regarding the effectiveness of alternative treatment strategies in order that the full range of possible treatment options and related evidence is evaluated in terms of cost-effectiveness. Overall cost-effectiveness for the 2 phases will be expressed in terms of the additional cost per quality-adjusted life-year (QALY) gained. Uncertainty in cost-effectiveness will be presented in terms of the probability that the alternative

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forms of management are most cost-effective given a range of maximum values the NHS might be willing to pay for an additional QALY. [40] Phase 1 Economic evaluation: Cost estimation under alternative treatment strategies will be done according to a two-stage process. The first stage is to measure resource use in physical units as used by trial patients. The second stage is to ‘cost’ these resource use data using prices or unit costs. Costs will be assessed from an NHS and Personal Social Service perspective. A separate analysis of costs from a wider perspective will also be undertaken, reflecting the societal perspective of the recent Layard report. [7] The wider social costs will be presented separately to avoid double counting with the QALY measure. Resource utilisation will be assessed from case records and patient self-report using an adapted version of the Client Service Receipt Inventory (CSRI). [41] The study will aim to estimate representative national unit costs. Intervention costs will be based on delivery costs within the trial and include supervision and appropriate capital costs. In this study the main outcome for the cost-effectiveness analysis will be the QALY, assessed using EQ-5D, [33] which consists of five health dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has three levels of severity (no problems, moderate problems and severe problems) that generate 245 unique health states into which a patient can be classified. In addition to providing a description of the health states, the EQ-5D also provides a single preference weight (also described as a utility or value) for each health state. The use of generic, validated quality of life measures and general population weights in the application of cost-effectiveness analysis has been recommended for policy level decision-making and now form part of the Reference Case for cost-effectiveness studies submitted to NICE.

Phase 2 Economic evaluation: The trial data will provide estimates of costs and effects that initially follow the clinical outcome data. However, cost-effectiveness analysis should adopt a time-horizon over which the costs and benefits of alternative treatments may vary. To fully account for the longer-term costs and benefits of the alternative treatments it will be necessary to extrapolate beyond the trial period. Statistical and decision-modelling methods will be used to undertake extrapolation, which will apply to costs as well as effects. This will take the form of a cohort state transition model which will reflect, for each treatment being evaluated: (i) the intervention costs of the study treatments; (ii) mortality rates and impact on quality of life of the therapies; (iii) rates of response and relapse over time; and (iv) costs and quality of life of response and relapse. The model will estimate long-term quality-adjusted survival and costs for each intervention. In order to provide a policy-relevant analysis to provide an input into decision-making, it is important for Phase 2 of the project to draw evidence from sources other than just the REEACT trial. In particular, we will seek to incorporate published data from all relevant trials relating to the use of computerised CBT into the long-term model. Furthermore we will seek to

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combine these data with other trial data to facilitate a direct comparison of the cost-effectiveness of computerised CBT compared to therapist-led CBT. To inform future research priorities in the NHS, the model will also be used to undertake analyses of the expected value of information. [42] Bayesian value of information analysis can used to determine the expected costs of decision uncertainty predicted by the model and the maximum value that can be placed on additional research aimed at reducing this uncertainty. This analysis will be used as the basis to inform policy decisions relating to future research priorities in this area. 5.3 Qualitative analysis of process data All focus groups and semi-structured interviews will be audio taped and fully transcribed. Transcripts and notes will be read and re-read independently by two of the research team (Lester and Gask). The data will then be organised into initial codes and higher codes that provide insight into emergent themes. Key concepts and categories will be identified using an open coding method by deconstructing each interview sentence by sentence. Main categories will then be compared across interviews / focus groups and reintegrated into common themes, The focus group data analysis will also seek issues with strong group-to-group validation and “sensitive moments” within group interactions that indicated difficult but important issues. [43]Reliability will be enhanced by identifying issues that are consistent between groups and validated using ‘sensitive moments’ within focus group interactions that indicate difficult but important issues. [44] A computer software package (QSR NVivo) will be used to manage the data and to increase the transparency of the analysis. Deviant cases will be actively sought throughout the analysis and emerging ideas and themes modified in response. [45]

6. Ethical Issues We are aware that people with depression represent a vulnerable group. However, we do not anticipate any major ethical issues with the proposed study since both experimental treatments are in use in the NHS or are recommended in recent guidance issued by the National Institute of Clinical Excellence. [21] However, computerised therapy is not routinely available in primary care at the current time (i.e. it is subject to constrained access and geographical variations in availability). We therefore have some concern that there may be insufficient individual equipoise amongst GPs and patients to consider randomisation to a treatment (computerised CBT) with which they have little experience. We have addressed this issue in the pragmatic design of our study. Patients allocated to computerised therapy will still receive usual care (including antidepressants where the GP decides this is necessary). We will report antidepressant use as an outcome of interest. The issue of patient preference will be ascertained at study entry and we will carry out a planned subgroup analysis. We will explore the issue of clinician equipoise in qualitative interviews.

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6.1 Risks and anticipated benefits for trial participants and society All participants will receive usual GP care, and therefore no treatment will be withheld by participating in this trial. This trial may in fact benefit individual participants, since computerised therapy is not routinely available despite NICE recommendations. By participating in this trial, patients will also receive a more intensive level of monitoring than that normally received in primary care. Patients who fail to respond to computerised therapy; deteriorate rapidly or become suicidal will be more readily identified and directed to appropriate care. 6.2 Informing potential participants of possible benefits and known risks The patient information leaflets will provide potential participants with information about the possible benefits and any known risks of taking part in the trial. Participants will be given the opportunity to discuss this issue with either their GP or trial coordinator prior to consenting to participate. The trial coordinator will inform the participant if new information comes to light that may affect the participant’s willingness to participate in the trial.

6.3 Obtaining informed consent from participants

Potential participants will receive an information pack about the trial. The pack will contain an invitation letter and patient information leaflet., The researcher will assess them for eligibility and then discuss the trial and answer any questions. Written informed consent will then be obtained prior to the patient being randomised.

6.4 Proposed time period of retention of relevant trial documentation All data will be stored for a minimum of 20 years after the end of final analysis of the study and will be accessed by the Trial Statistician. All paper records will be stored in a secure storage facilities. Personal identifiable paper records will be stored separate from anonymised paper records. All electronic records will be stored on a password protected server within York Trials Unit and the University of Manchester. All contact information will be destroyed securely immediately at the end of the trial.

7. Service User Involvement Service-user input into the design, conduct and dissemination of the REEACT trial comes from Nicky Lidbetter, who is a named co-applicant. Nicky is both a mental health service user and is involved in the delivery and implementation of computerised self-help packages within NHS primary care. Nicky has been a non-executive director of Manchester Mental Health & Social Care NHS Trust since 2002 where she had responsibility for chairing the Trust’s Research & Development Committee. Very recently, Nicky has established

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the first user-led primary care mental health service in Central Manchester and is soon to launch a new user-led computerised Cognitive Behavioural Therapy project in conjunction with Manchester PCT and CSIP North West. Service users will also be invited to join the trial steering group and we will follow good practice in terms of ensuring their ability to contribute to discussions. We will also work with our service user applicant to ensure that our dissemination strategies are inclusive and accessible to people who use services.

8. Research Governance The trial will be conducted to protect the human rights and dignity of the participant as reflected in the 1996 version of the Helsinki Declaration. Patients will not receive any financial inducement to participate. In order to protect the trial participants the following provisions will be made/upheld; the trial has been designed to minimise pain, discomfort and fear and any foreseeable risk in relation to the treatments involved, the explicit wishes of the participant will be respected including the right to withdraw from the trial at any time, the interest of the patient will prevail over those of science and society, provision will be made for indemnity by the investigator and sponsor and a contact name for further information will be provided.

8.1 Trial sponsorship The University of York have agreed to act as sponsors for the trial. 8.2 Monitoring and reporting adverse events We will have no influence on the prescription of medications by the GP for participants in this trial. We propose no experimental manipulation to directly influence choice or dose of medication. This trial will not therefore be subject to any additional restrictions, such as being Clinical Trial of an Investigational Medicinal Product (CTIMP). We have sought and received guidance on this from the MHRA in October 2008 Monitoring: Researchers will ask participants about any health-related adverse events at each follow-up visit (4, 12 and 24 months). For any events that are judged to be serious, the researcher will complete a Serious Adverse Event/Reaction (SAE/R) form (Appendix 1). We will also ask GPs involved in the trial to complete one of these forms if they identify that a trial participant has experienced a serious adverse event. For non-serious adverse events (NSAEs), the researcher will complete a NSAE form. Reporting: Reporting of SAE/Rs should take place as soon as the GP or local researcher becomes aware of the event. GPs will be asked to immediately fax SAE/R forms to the local trial centre. The local researcher/PI should immediately report all SAE/Rs to the Trial Manager by telephone. The SAE/R form should be faxed to the Trial Manager within 48 hours. A copy of

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the form should be kept by the local trial centre. If a SAE/R is reported and the paperwork completed by someone other than the PI, it is important that this person discusses the event with the PI as soon as possible. The Trial Manager will then inform the Chief Investigator and at least 2 members of the Trial Management Group will decide whether the event is related to the trial treatment. The DMEC and TSC will immediately see all SAE/Rs thought by the Trial Management Group to be treatment-related. All SAE/Rs will be reported to the main REC within 15 days of the CI becoming aware of the event where the event is related to administration of any of the research procedures and is unexpected. Local researchers should inform the Trial Manager of any NSAEs within 5 days of becoming aware of the event. He or she should also complete a NSAE form which should be sent to the Trial Manager and a copy kept at the local trial centre. The CI and Trial Manager will review NSAE forms to check the assessment of seriousness and of relatedness to the treatment. The DMEC/TSC will review the following at their next scheduled meeting

SAEs not thought to be treatment related by the Trial Management Group

NSAEs thought to be related to the treatment

NSAEs thought to be unrelated to the treatment Suicide Inherent in the nature of the condition under scrutiny (depression) is the risk of suicide and deliberate self-harm. All participants will be subject to usual GP care, and the primary care physician will be responsible for the day to day management of depression – and will ultimately be responsible for all patient-level treatment/management decisions – including prescribing, referral and assessment of risk. This arrangement is made clear to all clinicians who refer patients to this trial. The pragmatic nature of this trial means that we will not seek to influence this arrangement. However, we will follow good clinical practice in monitoring for suicide risk during all researcher encounters with trial participants. Where any risk to patients due to expressed thoughts of self-harm is encountered, we will follow the trial suicide protocol (see Appendix II).

9. Study Organisational Structure 9.1 Trial Steering Committee (TSC)

A TSC will be set up and will include an independent chair and at least two other independent members, including a service user, along with the chief investigator and the other study investigators. They will meet at least annually.

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9.2 Data Monitoring and Ethics Committee (DMEC) A DMEC will be set up and will include an independent statistician and mental health professional. The role of the DMEC is to immediately see all serious adverse events thought to be treatment related and look at the outcome data from an ethical standpoint. They will meet at least annually. The membership of our TSC and DMEC is detailed in appendix III. 9.3 Trial management The Trial Management Group will consist of the CI, other investigators, Trial Manager, Data Manager and Trial Statistician and will consider day-to-day management issues and the overall progress of the trial They will meet quarterly. The York-based trial manager will be responsible for the day-to-day running of the trial, obtaining ethical and research and development approval, designing trial documentation, recruitment of GPs and participants and trial centre co-ordination, collection of data, assisting the statistician clean and analyse data, writing the initial draft of research papers and disseminating the study’s findings. The trial secretary will assist the trial co-ordinator with these tasks whilst the data manager will validate and manage the data prior to analysis. The trial statistician will be responsible for cleaning the data, conducting the statistical analysis and sending the data to the DMEC. Professors Lester and Gask will be responsible for the process evaluation element of the trial. The Chief Investigator will be in charge of the overall management of the trial. Each trial site (York, Manchester, Sheffield, Bristol) will have a research fellow/trial coordinator to facilitate recruitment; liaise with GPs; to introduce and monitor computerised therapy; and to ensure patient follow up and outcome assessment. They will be aided by a part time secretary/admin worker who will co-ordinate patient computer appointments. Clinical supervision and GP liaison will be undertaken by a research active clinician with specific experience in CBT (York - Gilbody & Richards; Manchester - Lovell and Gask; Sheffield - Parry; Bristol - Araya and Kessler). For years 3 & 4, site research fellows will ensure patient follow up and scrutiny of GP records to establish service utilisation and antidepressant prescriptions and conduct post-intervention qualitative interviews. The research fellow in Manchester will, after appropriate training, also assist Professors Lester and Gask in undertaking the focus groups with patients and in interviewing GPs and practice managers. The economic analysis will require the specialist input of Dr Palmer and Professor Sculpher (main analysis in year 5).

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10. Project Timetable and Milestones 1st April 2008 Apply for ethics, research and development (R & D) approval

for all sites as required and for adoption onto the MHRN.

May 2009-May 2011 Start patient recruitment at York, Manchester, Bristol and Sheffield, plus sites from MHRN/CSIP collaborators as soon as Ethics/ R & D approval are received for a 24-month period.

May 2013 – End of Trial Final follow-up interview with last participant.

May 2013 to end October 2013 Data cleaning and statistical analysis and writing up study findings.

Jan 2013 to 2021 Extended follow-up interviews with consenting trial participants (Primary Care Depression Cohort)

11. Statement of Indemnity Normal NHS Indemnity procedures will apply. The University of York will also provide relevant cover.

12. Dissemination We will publish papers relating to this trial that will include (as a minimum) the results of the clinical and cost effectiveness comparisons and the results of the qualitative analysis. Professor Gilbody is an editor of the Cochrane Depression, Anxiety and Neurosis Group and can thus ensure that the results of this trial are incorporated in relevant Cochrane reviews. We will also publish in professional journals to ensure that clinicians have prompt access to our findings. We will produce a short summary of the results that can be distributed to all trial participants, including patients and GPs, as well as relevant patient and other interest groups. Finally, we will aim to ensure coverage of our findings in the wider media by issuing a press release. This will serve to bring the public and clinicians’ attention to our findings.

13. References 1. Roth, A. and P. Fonagy, What works for whom?: a critical review of psychotherapy

research. 1996, New York: Guilford Press. 2. Department of Health, A review of strategic policy on NHS psychotherapy services in

England. 1996, London: HMSO. 3. Lovell, K. and D. Richards, Multiple Access Points and Levels of Entry (MAPLE):

Ensuring choice, accessibility and equity for CBT services. Behavioural and Cognitive Psychotherapy, 2000. 28: p. 379-391.

4. Kaltenthaler, E., et al., Computerised cognitive behaviour therapy for depression and anxiety update: a systematic review and economic evaluation. Health Technology Assessment, 2006. 10: p. 33.

5. Proudfoot, J., et al., Computerised, interactive, multimedia cognitive behavioural therapy for anxiety and depression in general practice. Psychological Medicine, 2003. 33: p. 217-227.

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6. Christensen, H., K.M. Griffiths, and A.F. Jorm, Delivering interventions for depression by using the internet: randomised controlled trial. BMJ, 2004. 328: p. 265.

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effectiveness and efficiency. Narrative literature review. Br J Psychiatry, 2005. 186: p. 11-7.

9. Campbell, M., et al., Framework for design and evaluation of complex interventions to improve health. British Medical Journal, 2000. 321: p. 694-696.

10. Waller, R. and S. Gilbody, Barriers to the uptake of computerised cognitive behavioural therapy: A systematic review of the quantitative and qualitative evidence. Psychological Medicine, 2008. In press.

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14. Morgan, D.L., Focus groups as qualitative research. 1997, London: Sage. 15. Claxton, K., M. Sculpher, and M. Drummond, A rational framework for decision

making by the National Institute For Clinical Excellence (NICE). Lancet, 2002. 360: p. 711-5.

16. Thompson, S.G. and J.P. Higgins, How should meta-regression analyses be undertaken and interpreted? Stat Med, 2002. 21: p. 1559-73.

17. Sculpher, M., M. Drummond, and M.J. Buxton, The iterative use of economic evaluation as part of the process of health technology assessment. J Health Serv Res Policy, 1997. 2: p. 26-30.

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43. Barbour, R. and J. Kitzinger, Developing focus group research. Politics, theory and practice. 1999, London: Sage.

44. Barbour, R., Checklist for improving rigour in qualitative research: case of the tail wagging the dog? BMJ, 2001. 322: p. 115-7.

45. Silverman, D., Interpreting qualitative data. Methods for analysing talk, text and interaction. 1997, London: Sage.

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Appendix I

Serious Adverse Event/ Reaction Form

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SERIOUS ADVERSE EVENT/REACTION FORM Computerised Cognitive Behaviour Therapy for Depression

REEACT is required to report quickly to our main Research Ethics Committee any serious adverse events that may be related to the trial treatment. We also need to know about serious adverse events that are not related to the trial treatment. To enable us to do this, please let us know as soon as possible of any serious events experienced by trial participants so that we can judge if they are trial related.. Please complete this form as fully as you can and fax to your local REEACT centre on xxxxx.

Serious events/reactions are defined as fatal, life-threatening, resulting in persistent or significant disability or incapacity, resulting in or prolonging hospitalisation, resulting in a congenital anomaly or birth defect, or those which are deemed by the reporter as medically significant.

Patient Details REEACT ID Number:

GP Patient Number:

Sex (please circle): M / F

Date of Birth:

Patient Initials

Weight (kgs) Height (cms)

Event Details

Relationship of Event to Treatment (tick one box only) Unrelated Unlikely to Possibly Probably Definitely Not able to be related related related related assess if related

Trial Medicine Details Name of medicinal product

Relationship of Event to Treatment (tick one box only) Unrelated Unlikely to Possibly Probably Definitely Not able to be related related related related assess if related

Please describe the event, any treatment given and the outcome Date event started………………………… Date event stopped (if applicable)…………………... Please indicate why you consider this event to be serious (please tick all that apply)

Patient died Involved inpatient hospitalisation

Life-threatening Involved persistent or significant disability or incapacity

Resulted in a congenital anomaly or birth defect

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Your Details Name, position and professional address …………………………………………………………………………………………………………. …………………………………………………………………………………………………………. …………………………………………………………………………………………………………. Tel No: ……………………………. Profession (Specialty) …………………………………….. Signature ......................................................... Date……………………………………………

Please FAX this form to REEACT on XXXXXXX Thank You

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Appendix II

Suicide Protocol

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If at any time you believe that there is a significant suicide risk with a patient who is participating in the study that has not been communicated to their GP, you must contact Professor Simon Gilbody (an honorary consultant psychiatrist), or the relevant designated centre psychiatrist or psychologist in Bristol, Sheffield or Manchester, if Professor Gilbody is not available. Professor Gilbody, or designated psychologist/psychiatrist, will then assess the patient and if he / she believes it necessary and if there is a significant risk, he / she will notify the patient’s GP with or without their consent. However Professor Gilbody or the designated psychologist/psychiatrist would contact the GP without first assessing the patient for himself/herself if the situation was urgent, again with or without the patient’s consent.

The PHQ9 questionnaire asks if the patient has had “Thoughts that you would be better off dead or of hurting yourself in some way” (Question 9). If participants indicate a response of 3 for this item, then you should ask whether the patient has talked to their GP about these feelings. If the patient has spoken of these thoughts to their GP then no action is required. If not, you should ask the patient whether it is OK for you to contact their GP and inform them of the situation. If the patient refuses, contact Professor Gilbody, or the relevant designated psychiatrist/psychologist. If the patient agrees, you should immediately get in touch with the appropriate GP. If unable to contact Professor Gilbody or any of the designated centre psychologists/psychologists, contact the Trial Co-ordinator, Dr Liz Littlewood, or any other of the Co-investigators who will advise further. You should follow the same procedure if the results of the CIS-R indicate that the patient has had suicidal plans in the past week. The diagram below illustrates this procedure. Please also complete the attached Suicidal Intent Form, if the patient agrees to you contacting their GP, and inform the Trial Co-ordinator. If relevant, Professor Gilbody or the relevant designated centre psychiatrist/psychologist should also complete the Suicidal Intent Form: Psychiatrist/Psychologist. These forms should then be stored with the patient’s trial records. Suicide Risk Identified on a Postal Questionnaire Some patients may choose to receive and return the follow-up questionnaires by post at any of the follow-up points (4 months, 12 months or 24 months). If you receive a PHQ9 in which the patient has indicated a score of 3 for Question 9, you will also need to follow the suicide protocol. Contact the patient by telephone and say that you are concerned by their response to this

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question. Ask if they have discussed these feelings with their GP. If the patient has spoken of these thoughts to their GP then no action is required. If not, you should ask the patient whether it is OK for you to contact their GP and inform them of the situation. If the patient refuses, contact Professor Gilbody, or the relevant designated psychiatrist/psychologist. If the patient agrees, you should immediately get in touch with the appropriate GP. If unable to contact Professor Gilbody or any of the designated centre psychologists/psychologists, contact the Trial Co-ordinator, Dr Liz Littlewood, or any other of the Co-investigators who will advise further. If any other written responses on the questionnaires give you cause for concern, raise this with Professor Gilbody, or the relevant designated psychiatrist/psychologist. If you are unable to contact the patient within 24 hours, contact the patient’s GP. Inform the GP of the patient’s questionnaire response and that you have been unable to contact the patient to assess the situation further. At this point also check that the patient’s contact telephone number is correct. It may be that we have an out of date telephone number. If an alternative telephone number is provided and the GP agrees, attempt to contact the patient again. If still unable to contact the patient or if no alternative contact number is available confirm with the GP that they will follow up with the patient as they feel appropriate based on their clinical knowledge of the patient. Inform Professor Gilbody, or the relevant designated psychiatrist/psychologist of the patient’s questionnaire response and details of contact with the GP. Complete the appropriate forms as for a face-to-face/ telephone interview.

If, at any time, you have any concerns surrounding this, speak to Professor Gilbody or the designated centre psychiatrist/psychologist.

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Has patient discussed these suicidal thoughts with their GP?

YES NO

No Action “I am concerned that you are having these thoughts. Do you agree for me to pass on this information to your GP?”

YES NO

Researcher to contact patient’s GP or Duty Dr.

“As you’ve had these thoughts, I need to let my clinical colleague know who will telephone you.”

If no objection raised

Inform Professor Gilbody (or designated centre psychiatrist/psychologist) who will contact patient to assess risk or decide to break confidentiality and contact patient’s GP if appropriate. If unable to contact any relevant centre clinician, contact the Trial Co-ordinator, or any of the other Co-Investigators

Patient refuses contact by clinician

NB. If situation arises during pre-trial assessment, continue with gaining consent and take action

as necessary afterwards.

Complete attached forms and

inform Trial Co-ordinator

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SUICIDAL INTENT FORM

The patient below has shown thoughts of suicidal intent on the PHQ9 or CIS-R and

has agreed for their GP to be contacted by the researcher

Name of participant: ……………………………………………

REEACT Participant ID: ……………………………

Suicidal intent revealed on PHQ9 CIS-R

Action taken

Date GP contacted: …………………… Name of GP contacted: ……………………………… Outcome of contact with GP/Comments

………………………………………………………………………………………

………………………………………………………………………………………

………………………………………………………………………………………

………………………………………………………………………………………

………………………………………………………………………………………

………………………………………………………………………………………

……………………………………………………………………………………..

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SUICIDAL INTENT FORM: PSYCHIATRIST/PSYCHOLOGIST

Name of participant: ……………………………………………

REEACT Participant ID: ……………………………

Name of Psychiatrist/Psychologist notified: ………………………….

Date notified: …………………………

Action taken

Patient contacted: Yes No GP contacted: Yes No If Yes, GP contacted with patient’s consent Yes No Name of GP contacted: ……………………………… Date of contact: ……………………..

Comments

………………………………………………………………………………………

………………………………………………………………………………………

………………………………………………………………………………………

………………………………………………………………………………………

………………………………………………………………………………………

………………………………………………………………………………………

……………………………………………………………………………………..

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Appendix III

DMEC and TSC membership

REEACT Trial Steering Committee Professor Joe Reilly (Chair): Clinical Director for R&D (Tees, Esk and Wear Valleys NHS Trust), Director, Mental Health Research Centre (Durham University), Deputy Lead (Mental Health Research Network North East Hub) [email protected] Dr Mike Slade: Reader in Health Services Research, Head of Section of Community Mental Health, Consultant Clinical Psychologist in Rehabilitation (Institute of Psychiatry) [email protected] Professor Shirley Reynolds: Professor of Clinical Psychology (University of East Anglia) [email protected] Professor Robbie Foy: Professor of Primary Care (University of Leeds) [email protected] Mr Nic Seccombe: (Anxiety UK) – service user representative cCBT Manager SELF HELP SERVICES Zion Community Centre 339 Stretford Road Hulme, Manchester, M15 4ZY [email protected] Mrs Lina Gega: Lecturer in Mental Health (University of East Anglia) [email protected] PLUS members of the REEACT co-investigators REEACT Data Monitoring and Ethics Committee Professor Mike Lucock (Chair): Professor of Clinical Psychology,,University of Huddersfield. [email protected] Dr Chris Roberts: Reader in Biostatistics,University of Manchester. [email protected] Dr Paul Blenkiron: Consultant Psychiatrist & Cognitive Therapist (North Yorkshire and York PCT) [email protected]

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REEACT 24 month effectiveness paper (revised) BMJ

1

Computerised cognitive behaviour therapy (cCBT) as a treatment for

depression in primary care (The REEACT trial): a large scale pragmatic

randomised controlled trial

Simon Gilbody, Elizabeth Littlewood, Catherine Hewitt, Gwen Brierley, Puvan Tharmanathan, Ricardo

Araya, Michael Barkham, Peter Bower, Cindy Cooper, Linda Gask, David Kessler, Helen Lester*, Karina

Lovell, Glenys Parry, David A Richards, Phil Andersen, Sally Brabyn, Sarah Knowles, Charles Shepherd,

Debbie Tallon, David White on behalf of the REEACT Team

Simon Gilbody, Professor of Psychological Medicine and Health Services Research, Department of

Health Sciences, University of York, York, YO10 5DD

Elizabeth Littlewood, Research Fellow, Department of Health Sciences, University of York, York, YO10

5DD

Catherine Hewitt, Professor of Trials and Statistics, York Trials Unit, Department of Health Sciences,

University of York, York, YO10 5DD

Gwen Brierley, Clinical Research Manager, MRC Epidemiology Unit, University of Cambridge School

of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus,

Cambridge, CB2 0QQ

Puvan Tharmanathan, Research Fellow, York Trials Unit, Department of Health Sciences, University

of York, York, YO10 5DD

Ricardo Araya, Professor of Global Mental Health, Department of Population Health, London School

of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT

Michael Barkham, Professor of Clinical Psychology, Centre for Psychological Services Research,

Department of Psychology, The University of Sheffield, Sheffield, S10 2TP

Peter Bower, Professor of Health Services Research, NIHR School for Primary Care Research,

Manchester Academic Health Science Centre, The University of Manchester, Manchester, M13 9NT

Cindy Cooper, Professor of Health Services Research and Clinical Trials, Clinical Trials Research Unit,

School of Health and Related Research, The University of Sheffield, 30 Regent Street, Sheffield, S1

4DA

Linda Gask, Emerita Professor of Primary Care Psychiatry, NIHR School for Primary Care Research,

Manchester Academic Health Science Centre, The University of Manchester, Manchester, M13 9NT

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2

David Kessler, Senior Lecturer in Primary Care & General Practitioner, Centre for Academic Primary

Care, School of Social & Community Medicine, University of Bristol, Oakfield House, Oakfield Grove,

Bristol, BS8 2BN

Helen Lester, Professor of Primary Care, Primary Care Clinical Sciences Building, University of

Birmingham, Edgbaston, Birmingham, B15 2TT

Karina Lovell, Professor of Mental Health, School of Nursing, Midwifery and Social Work, The

University of Manchester, Jean McFarlane Building, Oxford Road, Manchester, M13 9PL

Glenys Parry, Professor of Psychological Therapies, School of Health and Related Research, The

University of Sheffield, 30 Regent Street, Sheffield, S1 4DA

David A Richards, Professor of Mental Health Services, University of Exeter Medical School, Haighton

Building, University of Exeter, St Luke’s Campus, Heavitree Road, Exeter, EX1 2LU

Phil Andersen, Telephone Support Worker, Department of Health Sciences, University of York, York,

YO10 5DD

Sally Brabyn, Research Fellow, Department of Health Sciences, University of York, York, YO10 5DD

Sarah Knowles, Research Fellow, NIHR School for Primary Care Research, Manchester Academic

Health Science Centre, The University of Manchester, Manchester, M13 9NT

Charles Shepherd, Research Nurse, Faculty of Health & Social Care, University of Hull, Hull, HU6 7RX

Debbie Tallon, Trial Manager, Centre for Academic Mental Health, School of Social & Community

Medicine, University of Bristol Oakfield House, Oakfield Grove, Bristol, BS8 2BN

David White, Study Co-ordinator, Clinical Trials Research Unit, School of Health and Related

Research, The University of Sheffield, 30 Regent Street, Sheffield, S1 4DA

Correspondence to Simon Gilbody [email protected]

Department of Health Sciences, University of York, York, YO10 5DD.

*In memoriam

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3

PICO <suggested accompanying figure 2>

Study question: what is the clinical effectiveness of free-to-use and commercially-developed

computer-delivered cognitive behaviour therapy (cCBT) for people with depression in primary care?

Summary answer: over a 24 month period (including a primary outcome at four months) computer-

delivered CBT with weekly telephone support was no more effective than usual GP care in improving

depression symptoms. A commercial product offered no additional benefit compared to a free-to-

use product.

What is known and what this paper adds: computerised CBT is widely offered in primary care for

people with depression and is recommended by NICE. Previous trials have demonstrated the

efficacy of computer-delivered CBT, but there have been no large-scale independent pragmatic

evaluations of this technology conducted in primary care. This study shows that engagement with

the technology is low in primary care, despite regular supportive telephone calls. A widely used commercially-developed cCBT programme (Beating the Blues) and a free-to-use cCBT programme

(MoodGYM) produced no additional benefit when added to usual GP care for depression.

Design: Pragmatic, multicentre, three arm, parallel randomised controlled trial of two cCBT products

plus usual GP care versus GP care alone. Treatment allocation was not blinded.

Participants and setting: The study included 691 adults with symptoms of depression (PHQ9>=10)

who were identified in United Kingdom primary care.

Primary outcomes: The primary outcome was depression severity, assessed using the PHQ9 at four months. Participants were judged to have improved if their PHQ9 score fell below 10 at follow up.

Secondary outcomes included health-related quality of life (measured by the SF-36) and

psychological wellbeing (measured by the CORE-OM) at four, 12 and 24 months, and depression at

12 and 24 months.

Main results and role of chance: By intention to treat, participants offered commercial or free-to-

use cCBT experienced no additional improvement in depression compared to usual GP care at four

months (Beating the Blues versus usual GP care OR 1.19, 95% CI 0.75 to 1.88; MoodGYM versus

usual GP care OR 0.99, 95% CI 0.62 to 1.56). Across all time points there was no statistical evidence

of an overall difference between Beating the Blues or MoodGYM compared to usual GP care (OR 0.99, 95% CI 0.57 to 1.70 and OR 0.68, 95% CI 0.42 to 1.10, respectively). Commercially-provided

cCBT conferred no additional benefit over free-to-use cCBT or usual GP care at any follow up point.

Uptake and usage of cCBT was low despite regular telephone support.

Harms: 49 adverse events were recorded. All were judged unrelated to the trial intervention except

one where there was insufficient information.

Bias, confounding and other reasons for caution: There was 24% drop-out at 4 months. The trial

was powered to detect a small clinical effect size (in line with other low intensity psychological

interventions) but we had insufficient power to detect a very small effect size and we cannot exclude

this.

Generalisability to other populations: the results of the REEACT trial are generalizable to the broad

range of patients with depression who are managed in primary care. We cannot generalise the

results of this trial to cCBT, where this is offered with a much higher level of guidance and support.

However this is not routinely offered in UK primary care.

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4

Study funding and potential competing interests: Commissioned and funded by the UK National

Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme (project

number 06/43/05). The authors have no competing interests.

Trial registration number: Current Controlled Trials ISRCTN91947481.

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5

Abstract

Objective: To investigate the effectiveness of supported computerised cognitive behaviour therapy

(cCBT) as an adjunct to usual primary care for adults with depression.

Design: Pragmatic, multicentre, three arm, parallel randomised controlled trial using simple

randomisation. Treatment allocation was not blinded.

Setting: Primary care.

Participants: Adults with symptoms of depression (PHQ9>=10).

Interventions: Participants were randomised to receive either a commercially-produced cCBT

programme (‘Beating the Blues’) or a free-to-use cCBT programme (MoodGYM) in addition to usual

GP care. Participants were supported and encouraged to complete the programme via weekly

telephone calls.

Control participants were offered usual GP care, with no constraints on the range of treatments that

could be accessed.

Main outcome measures: The primary outcome was depression severity, assessed using the PHQ9

at four months. Secondary outcomes included health-related quality of life (measured by the SF- 36)

and psychological wellbeing (measured by the CORE-OM) at four, 12 and 24 months, and depression

at 12 and 24 months.

Results: 691 participants were randomised (210 to Beating the Blues plus usual GP care, 242 to

MoodGYM plus usual GP care, and 239 to usual GP care). Analyses used intention-to-treat.

Participants offered commercial or free-to-use cCBT experienced no additional improvement in

depression compared to usual GP care at four months (Beating the Blues versus usual GP care OR

1.19, 95% CI 0.75 to 1.88; MoodGYM versus usual GP care OR 0.99, 95% CI 0.62 to 1.56). In a

repeated measures multilevel logistic regression model across all time points there was no statistical

evidence of an overall difference between Beating the Blues or MoodGYM compared to usual GP

care (OR 0.99, 95% CI 0.57 to 1.70 and OR 0.68, 95% CI 0.42 to 1.10, respectively). Commercially-

provided cCBT conferred no additional benefit over free-to-use cCBT or usual GP care at any follow

up point. Uptake and usage of cCBT was low despite regular telephone support.

Conclusions: Supported cCBT did not substantially improve depression outcomes compared with

usual GP care alone, although confidence intervals were wide and there was 24% drop-out at 4

months. Short-term clinical efficacy demonstrated in previous trials conducted by product

developers was not found in this pragmatic trial. Commercially available products were no more

effective than those which are free-to-use and the additional cost to services through providing

these products may not be justified. Guidelines for the treatment of depression may need to be

revised in the light of these trial results.

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6

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7

‘What this paper adds’ box:

What is already known:

• There is an increasing interest in the delivery cognitive behaviour therapy (CBT) via computer

(cCBT), which is a potentially effective and efficient mode of delivery for the large numbers of

people with depression in primary care.

• Computer-delivered CBT is endorsed in evidence-supported NICE guidelines and forms a component of Improving Access to Psychological Therapy services, but research is generally

conducted in specialist centres and by researchers who have also developed computer

programmes.

• There are no independent large scale pragmatic evaluations of cCBT conducted in primary

care settings.

What this paper adds

• We present the results of the largest independent evaluation of the effectiveness of

commercial and free to use cCBT in UK primary care

• Despite the provision of telephone support to use the cCBT programmes, there was limited

uptake by people with clinical depression.

• Commercially developed and free to use cCBT programmes conferred little or no clinical

benefit when offered in addition to usual primary care for depression.

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8

Trial registration Current Controlled Trials ISRCTN91947481

Commissioned by the UK National Institute for Health Research (NIHR) Health Technology

Assessment (HTA) Programme.

This project was funded by the NIHR Health Technology Assessment programme (project number

06/43/05).

The views and opinions expressed therein are those of the authors and do not necessarily reflect

those of the HTA programme, NIHR, NHS or the Department of Health.

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9

Background

Depression is one of the most common reasons for consulting with a general practitioner (GP) and

its associated personal and economic burden is considerable.1 Whilst antidepressants remain an

important treatment option, many patients and healthcare professionals would like to access

psychological therapy as an alternative or adjunct to drug therapy.2 3

Cognitive behaviour therapy (CBT) has emerged as a leading evidence-supported form of brief

psychological therapy for people with depression.4 5 However, demand for CBT cannot be met from

existing therapist resources.6 One alternative to therapist-delivered CBT is the provision of therapy

via computer.7 A number of interactive programmes have been developed which enable CBT to be

delivered by computer. National Institute of Health and Care Excellence (NICE) guidelines

recommend the provision of computerised CBT (cCBT) as an initial lower-intensity treatment for

depression as part of a ‘stepped care’ approach in primary care,5 and forms one of a range of

psychological interventions that are offered in many Improving Access to Psychological Therapy

services.8 If effective, such programmes have the potential to expand access to psychological

therapy in primary care and may represent an efficient non-pharmacological intervention for

depression or adjunct to pharmacological treatments.9

For those who decide to use (or commission the provision of) computerised CBT there are a number

of interactive internet-based products; some commercially produced and others free-to-use.7 In the

first category, commercial products have been marketed to bodies such as the NHS. The alternative

free-to-use products comprise a range of programmes which have been developed by the public

sector or by research institutes. These can be accessed at no direct cost to healthcare providers or

patients.

Research evidence in support of cCBT (both commercial and free-to-use) has generally been

supportive,7 9 10 with claims of effectiveness comparable to that seen in therapist-delivered CBT.9 11

Meta-analysis of the effectiveness of cCBT has demonstrated larger effect sizes where a level of

professional support or guidance is offered to accompany the computer-mediated treatment

programme.12 A concern is the degree to which patients find it acceptable to receive psychological

therapy via a computer rather than from a trained therapist. Many patients offered cCBT do not

access the material or make minimal use of it.13 Non randomised studies have also demonstrated

higher dropout rates14 than that seen in summaries of developer-led trials.9 There has been limited

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10

qualitative research into the acceptability of cCBT.14 Previous systematic reviews have also

highlighted the need for studies which (1) recruit participants in primary care settings (rather than

academic centres or secondary care), (2) use a standardised diagnostic assessment, and (3) the need

for longer term follow up beyond one year.12

A United Kingdom technology appraisal of computerised treatments published in 2006 gave cautious

support to the use of a commercially-developed cCBT package for depression, but also

recommended that an independent evaluation of the acceptability and effectiveness of cCBT be

undertaken as a matter of priority.7 In 2008 the REEACT trial (Randomised Evaluation of the

Effectiveness and Acceptability of Computerised Therapy) was commissioned by the United Kingdom

National Institute of Health Research (NIHR) Health Technology Assessment (HTA) Programme as an

independent evaluation. In 2009 the earlier technology appraisal was superseded when cCBT,

meeting the stated quality criteria, was generically endorsed in NICE clinical guidelines for the initial

treatment of depression.

Our primary aim was to establish the effectiveness and acceptability of supported cCBT as an adjunct

to usual GP care for depression. We also judged that it would be informative to commissioners of

services and to public mental health provision if we examined whether free-to-use computerised

CBT products were no less effective than commercially developed computerised packages. We

therefore designed a trial to test the effectiveness of supported cCBT when added to usual GP care,

and also to test the non-inferiority of free-to-use cCBT compared to commercially developed cCBT.

In this paper we present the clinical effectiveness results of the REEACT trial. We report in a

companion paper the results of a concurrent process evaluation using qualitative methods of the

acceptability of supported computerised CBT.

Methods

The REEACT study was a pragmatic, multicentre, three arm, parallel, randomised controlled trial.

Adults presenting with depressive symptoms in primary care were randomised 1:1:1 to receive

either usual care from their GP or usual care from their GP plus one of two interventions: (1) a

commercially-produced cCBT intervention (‘Beating the Blues’) or (2) a free-to-use cCBT intervention

(MoodGYM). Each of these products had previously been endorsed in a technology appraisal7 and

NICE guidelines,5 and had been shown to be effective in developer-led trials.15 16

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11

Recruitment of participants and baseline assessment

We wished to evaluate the use of supported cCBT in the broad population of patients in primary

care who were eligible and appropriate for this intervention. We set a minimum eligibility criterion

based on a widely-used measure of depression severity (score of 10 or above on the Patient Health

Questionnaire nine item scale – PHQ9) since this has been well-validated against standardised

criteria17 and is also the measure commonly used to assess depression and to inform treatment

decisions in United Kingdom primary care.18 We recruited adults (18+ years) presenting in primary

care with new or existing depressive symptoms (ascertained by the PHQ9), who were not in receipt

of cCBT or specialist psychological therapy at the time of recruitment. Potential participants were

recruited either directly by their GP or by letter of invitation if their clinical records noted that they

had depression. We checked participant access to the internet at baseline (pre-randomisation).

Participants either had access to the internet at home or via a close friend or relative. Some

participants were happy to access the internet in a central location including a local library, local

MIND, GP practice (although few participants accessed the internet via these locations).

We excluded patients who were known by their GP to be actively suicidal; suffering psychotic

symptoms; depressed in the post-natal period; or had recently suffered bereavement. Patients with

previous treatment experience of CBT were not excluded.

All participants completed a pre-randomisation baseline assessment using a number of self-report

questionnaires. Participants also completed a diagnostic gold standard, self-report, computer-based

interview (the Clinical Interview Schedule – Revised, CIS-R)19 which assesses depression severity and

diagnosis, along with other common mental health disorders, according to the International

Classification of Disease (ICD-10) criteria.20

Participants gave written informed consent before taking part in the study. Recruitment for the trial

took place between August 2009 and March 2011 in general practices in York, Manchester, Sheffield,

Bristol, Hull and the North-East of England. Ethical approval was granted by Leeds East Research

Ethics Committee (Ref 08/H1306/77). Patient safety was monitored by systematic monitoring of

adverse events and serious adverse events, each reviewed by a clinical member of the team for

relatedness to trial interventions (in line with an extension to the CONSORT statement – see 21).

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Randomisation, concealment, and blinding

Participants were allocated by simple randomisation to one of three groups without any restrictions

placed on the sequence (i.e. no blocking or stratification were included in the randomisation

procedure). Treatment allocation was concealed from the study researchers at the point of

recruitment using an automated computer data entry system. This was administered remotely by

the York Trials Unit and employed a computer-generated code. Owing to the nature of the

intervention, none of the participants, general practices or clinicians could be blinded to treatment

allocation. GPs were informed by letter of participant treatment allocation.

Follow-up

Collection of follow-up data took place between December 2009 and April 2013. Participants were

asked to provide data at four, 12 and 24 months post-randomisation using a series of self-completed

questionnaires. Four month follow-up was chosen as the primary outcome endpoint as it

represented the period at which we expected to observe the largest between-group effect.12 Data

were collected at 12 and 24 months to investigate any longer term outcomes that could be

attributed to the intervention.

To maximise retention, researchers arranged telephone or face-to-face interviews to facilitate data

collection at four, 12 and 24 month follow-up points. Participants were sent the questionnaire by

post if a telephone or face-to-face contact was not possible. Researchers performing the outcome

assessments were not blind to treatment allocation, however observer bias was minimised by the

use of self-report questionnaires. A monetary voucher was offered to study participants in

recognition of time spent in completing follow up, and was non-contingent on response in line with

evidence to enhance retention.22

Intervention and comparator (usual GP care)

This was a pragmatic trial. We imposed no constraints on usual GP care in the control or

intervention groups and participants were therefore free during the trial to access any treatment

usually available in primary care, including the use of antidepressants, counselling, psychological

services (including Improving Access to Psychological Therapy services, which were present in most

sites during the course of the trial), or secondary care mental health services.

Supported cCBT intervention groups: Participants in the intervention groups were each offered

supported cCBT in addition to usual GP care. Participants were encouraged to access their allocated

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cCBT packages in their own home or at that of a friend/relative with a broadband internet

connection. To ensure those without computer access were not denied participation in the REEACT

trial, we also gave information on the location of free-to-use internet connected computers

(although few participants used this mode of access).

The cCBT packages were supported by weekly telephone calls, in order to exceed or replicate (via

the telephone) a level of support offered in earlier developer-led trials (e.g. 16 15) and in view of the

evidence that professionally supported treatment was more likely to be effective than unsupported

computer self-help programmes.12 We also offered a level of support which replicated or exceeded

the support offered in routine NHS primary care psychological therapy services to ensure the results

of the REEACT study were generalizable to UK NHS services. The telephone support was delivered

by trained technicians. Participants in the two intervention groups were encouraged via the phone

to engage with the course of computerised therapy, and technical issues relating to computers and

the online programmes were also resolved. With the participants’ consent we recorded these

phone calls in order to supervise the telephone support staff and to ensure fidelity to this model of

technical/motivational support. As part of quality assurance, tapes were scrutinised by an

experienced trial clinician to ensure technical support in line with the treatment protocol was

delivered.

Experimental group 1: Beating the Blues (©Ultrasis, http://www.ulltrasis.com) is an interactive,

multimedia, cCBT package comprising a 15 minute introductory video followed by eight therapy

sessions of approximately 50 minutes duration each. The programme is entirely online and there is

no interaction with clinicians or individualised feedback on computer sessions. There are homework

exercises between the sessions. Beating the Blues has been shown to be efficacious in developer-

led trials in reducing symptoms of depression.15

Experimental group 2: MoodGYM (©ANU http://moodgym.anu.edu.au) is a free-to-use web-based

CBT programme for depression developed and copyrighted at the Australian National University

Centre for Mental Health Research. It consists of five interactive modules, which are made available

sequentially on a weekly basis, with revision of all aspects of the programme in the sixth week. The

programme is entirely online and there is no interaction with clinicians or individualised feedback on

computer sessions. MoodGYM has been shown to be efficacious in reducing symptoms of

depression in developer led-trials.16

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We were able to check uptake and online use of each computer programme with reference to

computer usage records and by self-report. The number and duration of telephone support calls

that were offered and utilised was also recorded.

Outcomes

The primary outcome was the PHQ9 at the four month follow-up. The PHQ9 is a self-report measure

which includes the cardinal cognitive and somatic symptoms of depression as defined by the

American Psychiatric Association Diagnostic and Statistical Manual – version four (DSM-IV).23 Scores

can range from zero to 27, with a recommended cut point of ≥10 which is indicative of the need for

treatment and has been validated against standardised diagnosis of clinical depression.17 Depression

severity was reported as continuous PHQ9 scores and as a dichotomous outcome according to the

proportion of participants who were improved with PHQ9 scores <10. The dichotomised PHQ9 score

was set as the primary outcome and sample size was ascertained on the basis of the ability of the

trial to detect differences in the proportion of participants who were improved.

Secondary outcomes included the Short Form 36 (SF36) as a measure of health-related quality of

life. The SF36 scoring algorithm produces a physical component scale (PCS) and mental component

scale (MCS).24 25 We also recorded health state utility using the EQ-5D,26 and general psychological

wellbeing using the Clinical Outcomes in Routine Evaluation-Outcome Measure – (CORE-OM). This

instrument measures a range of domains including well-being, psychological symptoms, function and

risk. 27

Patient involvement

Patient and members of the public were involved at several stages of the trial, including the design,

management and conduct of the trial. We received input from patients with lived experience of

depression and common mental health problems in the design of the trial materials, and

management oversight via membership of the Trial Steering Committee. A user-led organisation

(Anxiety UK and Self-Help Services) acted as co-applicant (via its Chief Executive) and collaborator.

We carefully assessed the burden of the trial interventions on patients. We intend to disseminate

the main results to trial participants and will seek patient and public involvement in the

development of an appropriate method of dissemination.

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Sample size

The REEACT trial was designed to test whether computerised CBT represented a clinically effective

addition to usual GP care, and whether the free-to-use computerised package did not represent a

less effective (non-inferior) choice of therapy for patients. We powered our trial to both capture any

benefit of computerised CBT over usual GP care alone and test the non-inferiority of free-to-use

cCBT. We based our sample size calculation on the usual care arm of primary care depression trials,

where the proportion of patients responding to usual care was in the region of 0.6.28 This proportion

is similar to that found in a UK HTA trial of antidepressants in primary care.29 We regarded a figure of

not more than 0.15 below this proportion as being acceptable, given the additional care options that

are available to patients who do not initially respond to computerised CBT within a stepped care

framework. In our original sample size calculation, to detect non-inferiority using the percentage

success in both groups as 60% and a non-inferiority margin of 15%, with over 80% power and

assuming 25% attrition required 200 participants in each of the three arms. Recruitment to the trial

went better than expected and the trial could have finished recruitment early but there were slightly

higher levels of attrition so sample sizes were re-estimated. In order to retain similar levels of power

to detect non-inferiority between the free-to-use and commercial computerised CBT programmes,

whilst allowing for 35% attrition, 690 participants were sought (230 participants in each of the three

arms). The trial was also powered to detect a difference of 15% between the usual GP care arm and

either of the two computerised CBT arms using a conventional power analysis. Assuming 80% power

(5% two sided significance) to show a difference in the proportion participants improved (PHQ-9<10)

of 0.6 versus 0.75 (equivalent to an odds ratio of 2 for not depressed or an odds ratio of 0.5 for

depressed) at 4 months required a sample size of 149 in each group or 230 after allowing for 35%

attrition (i.e. 690 in total).

Statistical analysis

Outcome measures were compared separately between the following groups of participants:

1. Beating the Blues versus Usual GP Care (superiority)

2. MoodGYM versus Usual GP Care (superiority)

3. MoodGYM versus Beating the Blues (non-inferiority)

For each group comparison, similar analyses were applied depending on type of comparison

(superiority or non-inferiority) and the inclusion of potentially important covariates. All analyses

were performed in Stata 13, following a pre-specified analysis plan approved by the trial steering

committee. All analyses were conducted on an intention-to-treat basis, including all participants in

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the groups to which they were randomised, using two-sided significance tests at the 5% significance

level for superiority comparisons. All baseline data were summarised by treatment group and

reported descriptively, with no formal statistical comparisons.

Primary analysis

Groups were compared using a logistic regression model of dichotomised PHQ9 scores with

adjustments for gender, age, baseline depression severity, depression duration and level of anxiety.

Odds ratios (OR) and corresponding 95% confidence intervals (CI) were obtained from this model.

To assess non-inferiority between Beating the Blues and MoodGYM, we computed two sided 90%

confidence intervals. Using this method, the free-to-use cCBT programme MoodGYM would not be

inferior to the commercial pay-to-use cCBT programme Beating the Blues at the 5% level if the upper

boundary was below the pre-specified margin of non-inferiority (15% difference in proportions

which corresponded with 1.44 for the odds ratio).

Secondary analyses

The primary analysis was repeated for the 12 and 24 month dichotomised PHQ-9 data using the

same methods as outlined above. We also analysed all time points in one model rather than

individual analyses at each time point using a repeated measures multilevel logistic regression

model. The values at four, 12 and 24 months were the outcome measures, and the baseline PHQ-9

score, age, gender, depression duration, level of anxiety, treatment group and time were included as

fixed effects, an interaction between treatment and time was also included in the model.

Participants were treated as random effects (to allow for clustering of data within each participant).

Different covariance patterns were assessed for the repeated measurements within participants:

unstructured, independent, exchangeable and identity. Overall odds ratios and corresponding 95%

(or 90% for non-inferiority) confidence intervals as well as individual odds ratios at each time point

(four, 12 and 24 months) were estimated from these models. The PHQ-9 in its continuous form,

CORE-OM and SF36 component scores were analysed using a multilevel linear mixed model

following a similar procedure to those outlined above for the dichotomised PHQ-9 scores. The model

made adjustments for the same covariates. For continuous outcomes we also reported standard

effect sizes (Hedges G).

The statistical analysis and reporting of the REEACT trial followed the Consolidated Standards of

Reporting Trial (CONSORT) guidelines.30

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Results

One hundred GP practices agreed to take part in the study with participants being recruited from a

total of 83 of these practices. Potential participants were either referred or responded to a letter

inviting them to participate in the trial between August 2009 and March 2011. Of 1273 people

assessed, 691 eligible and consenting participants were successfully randomised (CONSORT diagram

figure 1). At baseline, 242 people were allocated to the MoodGYM intervention arm, 210 to the

Beating the Blues intervention arm and 239 to the usual GP care arm (unequal numbers were

expected by chance under conditions of simple randomisation). Follow up was achieved at the four

month primary outcome for 526 (76%) participants; for 484 (70%) at 12 -months; and for 461 (67%)

at 24 months.

<Figure 1> consort diagram

The randomised groups were well-balanced and similar on entry to the trial in terms of age, gender,

severity of depression, duration of depression, anti-depressant use and educational attainment

(Table 1). The median depression severity across all groups was 17 which broadly equated with a

moderate severity of depression.31 Depression had been present for more than one year in more

than one third of participants. When diagnosis according to the CISR was applied, 81% of

participants were found to have a confirmed depressive episode according to ICD criteria, with no

difference between groups (82.2% of participants in the Beating the Blues group, 81.1% of

participants in the usual GP care group and 79.9% of participants in the MoodGYM group).

<Table 1>

Primary analysis

At four months, 83 of the 165 (50.30%) participants in the Beating the Blues group, 78 of the 179

(43.58%) participants in the usual GP care group and 89 of the 182 (48.90%) participants in the

MoodGYM group remained depressed by the criterion of 10 or more on the PHQ-9 (Table 2). Results

from the logistic regression (Table 3) showed that there was no statistical evidence of a difference

between Beating the Blues and usual GP care at four months (OR 1.19, 95% CI 0.75 to 1.88) or

between MoodGYM and usual GP care at four months (OR 0.99, 95% CI 0.62 to 1.56; Table 3). For

the non-inferiority comparison between MoodGYM and Beating the Blues, the odds ratio at four

months was 0.91 and 90% CI 0.62 to 1.34, p=0.69. The upper limit of the 90% confidence interval for

the odds ratio was 1.34, thus satisfying statistical criteria for non-inferiority of MoodGYM compared

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to Beating the Blues (Table 3). Results of the sensitivity analyses were consistent when adjustments

were made for centre, and when the impact of drop-outs was assessed under best (missing=not

depressed) and worst case (missing=depressed) scenarios (Table 3).

<Tables 2 and 3>

Secondary analyses

Results from the PHQ9 logistic regression highlighted that there was no statistical evidence of a

difference between Beating the Blues and usual GP care across any of the time points (12 months OR

0.77, 95% CI 0.47 to 1.26; 24 months OR = 1.00, 95% CI 0.60 to 1.68; Table 3 and Figure 2). There

was some statistical evidence of a difference in favour of MoodGYM versus usual GP care at 12

months (OR 0.56, 95% CI 0.34 to 0.93) but this was no longer evident at 24 months (OR 0.68, 95% CI

0.41 to 1.15; Table 3 and Figure 2). For the non-inferiority comparison, the upper limit of the 90%

confidence interval for the odds ratio at 12 and 24 months was below the pre-specified margin, thus

satisfying statistical criteria for non-inferiority (12 months OR 0.77, 90% CI 0.50 to 1.18; 24 months

OR 0.72, 90% CI 0.47 to 1.11). The results from the multilevel logistic regression model were similar

to those from the logistic regression models at each individual time-point (Table 3). However, the

results for the non-inferiority comparison between MoodGYM and Beating the Blues at four months

do change, the upper limit of the 90% confidence interval for the odds ratio was above the pre-

specified margin, thus no longer satisfying statistical criteria for non-inferiority with Beating the

Blues inferior to MoodGYM (OR 0.94, 90% CI 0.57 to 1.55).

<Figure 2 and Table 4>

There was no statistical evidence of a difference on the overall (including all time points) mean

depression scores, CORE-OM scores, and MCS and PCS quality of life scores of Beating the Blues

when compared to usual GP care alone. The standard effect size (Hedges G) across all time points

for Beating the Blues versus usual GP care alone showed no statistical evidence of a difference (-

0.02, 95% CI -0.22 to 0.19) (Table 4). There was no statistical evidence of a difference on the overall

(including all time points) mean depression scores and PCS quality of life scores of MoodGYM when

compared to usual GP care alone. The standard effect size (Hedges G) across all time points for

MoodGYM versus usual GP care alone was small and statistically non-significant (0.09, 95% CI -0.11

to 0.28). However, there was statistical evidence of a difference in favour of MoodGYM for

depression scores at 12 months (Table 4). There was also statistical evidence of a difference in

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favour of MoodGYM on the overall (including all time points) mean CORE-OM scores and MCS

quality of life scores when compared to usual GP care alone; with statistical evidence of a difference

in CORE-OM scores at 12 months and MCS quality of life scores at 12 and 24 months.

<Table 4>

Participant safety

In total, 302 participants reported 745 non-serious adverse events: 93 participants (264 events) in

the Beating the Blues group, 110 participants (241 events) in the usual GP care group and 99

participants (240 events) in the MoodGYM group. Table 5 summarises the non-serious and serious

adverse events by trial arm. Across all participants, 49 serious adverse events were recorded from

39 participants. Of these, 39 were judged to be unrelated and 9 unlikely to be related to the trial

intervention. We were unable to make a judgement of relatedness to the trial intervention for one

serious adverse event reported due to limited information provided. Five of the serious adverse

events were referred to the DMEC for discussion and two were referred to REC. Of the 49 serious

adverse events, 40 (81.6%) involved inpatient hospitalisation, seven were life-threatening and two

resulted in participants dying.

<Table 5>

Uptake and usage of computerised CBT and telephone support

After allocation, 83% (n=175) of Beating the Blues participants and 77% (n=186) of MoodGYM

participants accessed the programmes (as ascertained by computer login records). When asked at

four months post-randomisation, 19% of the usual GP care group reported having used

computerised CBT; either on the recommendation of their GP, by self-referral or at the

recommendation of a mental health professional.

From computer-verified records, we ascertained that the median number of sessions completed for

Beating the Blues was 2 (inter-quartile range IQR 0 to 5) and the most commonly used (median)

number of sessions was 1 (out of eight computer sessions). For MoodGYM the median number of

sessions completed was 1 (IQR 0 to 2) and the most frequently used number of sessions was 1 (out

of six computer sessions). Of those participants who started the programmes, a total of 31

participants (18%) completed all eight sessions of Beating the Blues, and 29 participants (16%)

completed all six sessions of MoodGYM.

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A median of 13 contact attempts were made to both Beating the Blues (IQR 11-16) and MoodGYM

(IQR 10-16) participants. A total mean of 6.0 (IQR 3-8) technical telephone support calls were made

to Beating the Blues participants. A total mean of 6.8 (IQR 4-9) technical telephone support calls

were made to MoodGYM participants. Of the technical telephone support calls made, the mean

number of calls answered by participants was 3.1 (IQR 1-5) for Beating the Blues participants. For

MoodGYM participants, the mean number of technical support calls answered by participants was

3.3 (IQR 1-5). The total mean number of minutes of technical support calls delivered to participants

was 6.2 (IQR 2-8) minutes for Beating the Blues participants and 6.5 minutes (IQR 2-9) for MoodGYM

participants. The mean number of emails sent were 5.3 (IQR 2-8) for Beating the Blues participants

and 5.0 (IQR 1-8) for MoodGYM participants. Texts were rarely sent (mean of <0.1 texts sent to both

Beating the Blues and MoodGYM participants).

Usual care received

Examination of GP medical records revealed that participants received a range of treatments as part

of the usual care from their GP. Participants received a range of anti-depressant medications and

access to various mental health services, including referral to Improving Access to Psychological

Therapy (IAPT) services, Community Mental Health Teams, psychiatrists, psychologists and

counsellors. Such services were used by similar proportions of participants across each of the three

groups. In addition, participants visited their GP to a comparable extent across the three groups. We

present the results of a full economic evaluation elsewhere.32

<Table 6>

Discussion

Principal findings

The main finding from the REEACT trial is that for the primary outcome of depression severity at four

months there was no significant benefit for supported cCBT in addition to usual GP care. Confidence

intervals were wide for these estimates and there was 24% drop-out at four months. The estimates

and 95% confidence intervals at our primary time point of interest were all below our original

sample size estimate (OR=0.5). This negative finding was true for both a free-to-use package

(MoodGYM) and commercially-produced cCBT (Beating the Blues). A statistically significant benefit

for cCBT was found in a secondary analysis for mental health quality of life and generic psychological

wellbeing at 12 months post-treatment. These secondary outcomes favoured the free to use

package, but no effect was seen for commercially-produced cCBT at any time point or for any

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outcome. It is questionable whether this would be seen as clinically significant and was not

observed for the primary outcome of four months and was not evident at longer term follow up.

The REEACT trial is to our knowledge the largest pragmatic independent evaluation of the

effectiveness of supported cCBT in primary care. The REEACT trial is novel in that we addressed a

question that is important to commissioners of services by comparing packages which were free-to-

use versus commercially available products. Both these products were recommended in depression

guidelines issued by NICE at the time of design of the REEACT trial, and they both remain NICE-

endorsed treatments at the time of publication of this trial.5 Our main finding is therefore that

whilst cCBT has been shown to be efficacious in developer-led trials, it was not effective in usual NHS

care settings. The main reason for this was low adherence and engagement with treatment, rather

than lack of efficacy.

The REEACT trial included an extended follow up to 24 months. Neither of the supported cCBT

interventions showed any benefit over usual GP care when all time points were taken into account in

a repeated measures analysis, although there was a small but statistically significant benefit for

MoodGYM at 12 months follow up. By 24 months there was no statistical evidence of a difference

between intervention and control. The small benefit for MoodGYM at 12 months is therefore

difficult to interpret, and is not in keeping with other research in this area where benefit is usually

only observed in the short term.33

Comparison with other studies

The results of the REEACT trial are different from developer-led trials which have recently been

summarised in systematic reviews9 10 and technology appraisals.7 Aside from the independence of

the REEACT evaluation from those who have developed cCBT, there are a number of differences in

design which are worthy of note. The first is that the REEACT trial was purposely conducted entirely

within primary care, which is the setting in which the majority of people with depression receive

treatment.34 This contrasts with a number of trials which have recruited their target population via

the internet, or in specialist (secondary care) referral centres or in centres which have developed

specialist clinics where participants are directly supervised whilst they use a computer package. We

would argue that this enhances the degree to which the REEACT results can be applied to primary

care and to primary care-led mental health services.

The second difference is the level of support that was offered. In the REEACT trial participants were

proactively offered a high level of technical support, and weekly encouragement to use the

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computer packages, but we purposely did not augment structured psychological therapy over the

telephone using trained psychological therapists. Telephone support in the REEACT trial did not

involve detailed explanations of cognitive behavioural therapy and did not involve detailed review of

homework or between-session tasks. The cCBT was therefore a form of supported self-help, but was

not one which was guided by a clinician. Unsupported self-help treatment (including unsupported

computer-delivered self-help) has been shown in systematic reviews to have minimal effects and a

relatively small effect size.12 35 In contrast, more intensively supported treatments have generally

been found in efficacy trials to have moderate effect sizes claimed to be comparable with face to

face therapy.11 The level of support in the REEACT trial is one that is at least as intensive as that

offered in many NHS care settings and is in line with (or in the case of MoodGYM exceeds) the level

of support that is generally offered.16 The REEACT trial therefore represents an evaluation of a

supported intervention which replicates the use of cCBT in routine primary care settings. However

the chosen level of support was less intense than other efficacy trials where computer usage has, for

example, been supervised on a 1:1 basis by therapists or where a healthcare professional has been

physically present to ensure the user interacts successfully with the computer (e.g.15). More

intensively supported cCBT might have been more likely to have resulted in a positive outcome, but

would have diluted the pragmatic evaluation of the effectiveness of cCBT as it is offered in primary

care. The presence of weekly pro-active telephone support meant that we anticipated there would

be some benefit demonstrated in this effectiveness trial; comparable to that observed in developer-

led guided self-help trials.12 Future research could explore whether the use of telephone-delivered

clinician support results in a higher level of engagement and a more effective form of computerised

treatment. An alternative mode of support is by the use of online therapist, which have shown

positive results in primary care.36

The other significant finding in this trial is that, despite the provision of a high level of telephone

support, there was relatively low uptake of computerised CBT. This finding is in line with other

lower intensity forms of intervention for depression when offered in primary care where dropout

and failure to engage with therapy are common.37 However, this finding contrasts with other

developer-led efficacy trials where good levels of engagement and uptake have been reported.37

Again we note that REEACT was a pragmatic study, where a feasible and representative primary care

intervention was replicated within the context of a randomised controlled trial. The REEACT trial is a

real world evaluation of supported computer-delivered CBT. The reasons for poor engagement and

barriers to the use of this technology in routine care have hitherto not been explored within the

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context of trials, and a companion paper (Knowles et al – also under submission) reports in depth

the reasons for poor engagement. We have found that participants offered cCBT were generally

unwilling to engage with computer programmes and highlighted the difficulty in repeatedly logging

on to computer systems when they are clinically depressed. Participants highlighted that they

desired a greater level of clinical support as an adjunct to therapy and in the absence of this support

they commonly disengaged with the computer programmes.

The REEACT study was also pragmatic in reflecting the degree to which GPs might offer cCBT for

people with a range of severities of depression. Though we set a minimum entry criterion (PHQ

>=10) we noted that the mean score was 17 and this is indicative of moderately severe depression.

This is a slightly higher level of severity than is recommended in NICE guidance and an important

finding is that GPs seem ready to offer cCBT as a treatment at a range of severities. This was often in

combination with anti-depressant therapy. Future research might seek to evaluate cCBT within a

more constrained range of severity of depression; though we noted that usage was low for people

with all severities of depression.

Limitations of the REEACT trial

There were limitations to the REEACT study. First, participants were selected using a definition of

depression based on a cut point drawn from a depression severity scale.17 We did not use a

diagnosis of depression based on a structured diagnostic interview schedule as the primary inclusion

criterion. However REEACT was a pragmatic randomised controlled trial and we deliberately

adopted a criterion drawn from an instrument that is widely used in UK primary care to guide

treatment.18 We did however concurrently use a diagnostic interview schedule and 81% or our

participants met the ICD criteria for depressive episode. Second, REEACT was powered at 80% to

detect a modest effect size which is comparable to other low intensity forms of psychological

therapy observed in primary care settings.37 We did not have sufficient statistical power to detect

much smaller effect sizes that have been observed in entirely unsupported cCBT.35 Nevertheless we

note that REEACT was a supported form of cCBT and our trial exceeded 80% statistical power to

detect the range of effect sizes that have been reported in systematic reviews of previous trials of

cCBT.12

We also note that there was potential crossover, with some reported access of computer based

treatment or support by 19% participants in the usual care arm of the REEACT trial. Unfortunately

we do no not know what form of support was accessed, and this could include a range of computer

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materials (including cCBT programmes). From the intervention arms, we were able to access the

computer records to ascertain actual usage of the technology and this was very low even for people

who self-reported accessing cCBT. As a pragmatic study, usual care was not constrained in REEACT

and this was a strength of the design. It is unlikely that cross-over and dilution of effect is a

sufficient explanation of the negative findings in REEACT and the more likely explanation is lack of

uptake of the intervention when this is offered, even with telephone support.

Conclusions and policy implications

Computerised CBT forms a core component of primary care psychological therapy services in the

United Kingdom and other health systems. The overall conclusion is therefore that supported

computerised cognitive behaviour therapy conferred modest or no benefit over usual GP care, and

would suggest that the routine promotion and commissioning of cCBT be reconsidered in light of the

findings of this trial. We would also conclude that commercially-developed computerised cognitive

behaviour therapy products confer little or no benefit over free-to-use products. This is an

important finding for those who commission services and purchase commercial products on behalf

of publicly funded health services. The routine use and purchase of computerised therapy is likely to

be an ineffective form of low intensity treatment for depression and an inefficient use of finite

healthcare resources. There are a range of treatments for depression which might be considered

instead of cCBT. These include telephone guided self-help, bibliotherapy, low intensity psychological

workers supporting self-help technologies and therapist-delivered cognitive behaviour therapy.5

There is a need to evaluate the clinical and cost effectiveness of such approaches. In relation to

cCBT there is, for example, an ongoing independent trial (REEACT 2) of the effectiveness of guided

computer therapy versus the effectiveness of guided bibliotherapy for depression.

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Contributions: SG was the chief investigator, initiated the collaborative project, designed the trial,

provided management oversight of the whole trial, chaired the trial management group (TMG) and

drafted and revised the paper. He is guarantor. EL was the trial manager, monitored data collection

for the whole trial and drafted and revised the paper. CH was the trial statistician, wrote the

statistical analysis plan, conducted all statistical analyses and drafted and revised the paper. GB was

the trial manager, monitored data collection for the whole trial and provided technical telephone

support to trial participants. PT was the trial manager and monitored data collection for the whole

trial. RA, MB, PB, CC, LG, DK, HL, KL, GP, and DR contributed to the trial design, assisted with the

conduct of the trial at their respective sites and were members of the TMG. PA provided technical

telephone support to trial participants. SB, SK, CS, DT and DW were site trial coordinators and

monitored data collection in their respective sites. All authors contributed to redrafts of the report.

Acknowledgements: We would like to extend our thanks first and foremost to the REEACT

participants for their valuable contribution to this study. We would also like to thank Rachel

Richardson who established and assisted with the management of the trial; the research teams at

each of our research sites; the GPs, research and support staff at all GP practices; the Primary Care

Research Network and the Mental Health Research Network, and members of the Trial Steering

Committee and Data Monitoring and Ethics Committee. We would like to thank Professor David

Torgerson for his valuable contribution to the design of the study and for his insightful advice

throughout the trial, and Stephen Palmer, Ana Duarte and Simon Walker for designing and

conducting the economic evaluation (to be reported in a separate publication). We also thank our

patient and public contributors for their valuable input throughout the trial. We would also like to

extend our gratitude to the developers of MoodGYM and Ultrasis for providing us with participant

log-ins and usage data.

The REEACT trial is dedicated to the memory of Professor Helen Lester (1961-2013) who contributed

time and wisdom at every stage of the REEACT trial.

Funding: This project was funded by the NIHR Health Technology Assessment programme (project

number 06/43/05).

The views and opinions expressed herein are those of the authors and do not necessarily reflect

those of the Department of Health or the National Institute of Health Research Health Technology

Assessment Programme. The funder played no role in the study design, in the collection, analysis or

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interpretation of the data, in the writing of the paper or in the decision to submit the article for

publication. All authors were independent from the funders. All authors had full access to all of the

study data and take responsibility for the integrity of the data and the accuracy of the data. The lead

author affirms that this manuscript is an honest, accurate, and transparent account of the study

being reported; that no important aspects of the study have been omitted; and that any

discrepancies from the study as planned (and if relevant registered) have been explained. A CC BY

licence is required.

Competing interests: All authors have completed the ICMJE uniform disclosure form

at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the

submitted work; no financial relationships with any organisations that might have an interest in the

submitted work in the previous three years; no other relationships or activities that could appear to

have influenced the submitted work.

Ethical approval: The Leeds (East) Research Ethics Committee approved the trial on 10 July 2008

(08/H1306/77). All participants provided written informed consent to participate in the trial. The full

trial protocol can be accessed at: http://www.nets.nihr.ac.uk/projects/hta/064305

“The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of

all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats

and media (whether known now or created in the future), to i) publish, reproduce, distribute, display

and store the Contribution, ii) translate the Contribution into other languages, create adaptations,

reprints, include within collections and create summaries, extracts and/or, abstracts of the

Contribution, iii) create any other derivative work(s) based on the Contribution, iv) to exploit all

subsidiary rights in the Contribution, v) the inclusion of electronic links from the Contribution to third

party material where-ever it may be located; and, vi) licence any third party to do any or all of the

above.”

Data sharing: reasonable requests for patient level data should be made to the corresponding

author and will be considered by the REEACT trial management group. Consent for data sharing was

not obtained but the presented data are anonymised and risk of identification is low.

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Figure 1: REEACT consolidated standards of reporting trials diagram

Figure 2: Depression status as measured using the PHQ9 across all follow up points

Note: Means are all predicted means and 95% CIs estimated from the mixed model with gender, age, baseline

PHQ-9 score, duration of depression, level of anxiety, month, treatment and an interaction between month

and treatment as fixed effects.

Table 1: Baseline characteristics

Table 2: PHQ summary (PHQ-9≥10) by duration of follow up and treatment group

Table 3: Results from the logistic regression and mixed models

Note: odds ratios are presented as “odds of being depressed”; Logistic model adjusted for gender, age,

baseline depression severity, depression duration and level of anxiety. Mixed model adjusted for gender, age,

baseline depression severity, depression duration, level of anxiety, month, treatment and an interaction

between month and treatment as fixed effects. *90% CI for the non-inferiority comparison.

Table 4: Result of the Linear Mixed Model for secondary analyses

Note: Means are all predicted means and 95% CIs estimated from the mixed model with gender, age, baseline

depression severity (alternatively MCS, PCS or CORE-OM), depression duration, level of anxiety, month,

treatment and an interaction between month and treatment as fixed effects.

Table 5: Summary of adverse events

Note: a Non-serious adverse events

b Serious Adverse Event

c Researcher was informed that the participant had recently been hospitalised but when contacted patient did

not provide further information and withdrew from the study d

One SAE was classed as both involving inpatient hospitalisation and life-threatening e

One SAE was class as both life-threatening and involving persistent or signification disability or incapacity

Table 6: Primary and secondary care services accessed by trial participants from baseline to 12

month follow-up (data obtained via GP medical records)

Note: * Improving Access to Psychological Therapies is a NHS service offering psychological

interventions to individuals with depression and anxiety disorders. + Community Mental Health Teams

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Table 1: Baseline characteristics

Characteristic at baseline

Beating the

Blues

(N= 210)

Control Usual

care

(N=239)

MoodGYM

(N=242) Total (N=691)

Age (years) (Mean, SD) 39.61 (12.34) 40.52 (12.64) 39.43 (12.96) 39.86 (12.65)

Over 65 (%) 6 (3) 11 (5) 12 (5) 29 (4)

Gender

Female 142 (68) 163 (68) 157 (65) 462 (67)

Depression severity

PHQ-9, Mean (SD)

Median (Min to Max)

16.78 (4.21)

17 (10 to 27)

16.32 (4.52)

16 (10 to 27)

16.87 (3.99)

17 (10 to 26)

16.65 (4.25)

17 (10 to 27)

Previous episodes of depression (%)

Yes 144 (69) 178 (75) 169 (70) 491 (71)

No 65 (31) 60 (25) 72 (30) 197 (29)

Don’t know 1 (0) 0 (0) 1 (1) 2 (0)

No response 0 (0) 1 (0) 0 (0) 1 (0)

Number of episodes of depression (%) (n=144) (n=178) (n=169) (n=491)

1 42 (29) 49 (28) 44 (26) 135 (27)

2 34 (24) 49 (28) 31 (18) 114 (23)

3 12 (8) 21 (12) 23 (14) 56 (11)

4 10 (7) 7 (4) 14 (8) 31 (6)

5+ 22 (15) 24 (13) 22 (13) 68 (14)

Chronically depressed 19 (13) 21 (12) 30 (18) 70 (14)

Don’t know 4 (3) 7 (4) 5 (3) 16 (3)

No response 1 (1) 0 (0) 0 (0) 1 (0)

Previously prescribed antidepressants (%) (n=144) (n=178) (n=169) (n=491)

Yes 129 (90) 152 (85) 149 (88) 430 (88)

No 14 (10) 26 (15) 20 (12) 60 (12)

Don’t know 1 (1) 0 (0) 0 (0) 1 (0)

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Seen anyone other than GP for depression

(%) (n=104) (n=129) (n=132) (n=365)

Psychiatrist 25 (24) 37 (28) 31 (23) 93 (25)

Psychologist 21 (20) 21 (16) 35 (26) 77 (21)

Counsellor 79 (76) 100 (76) 95 (70) 273 (75)

Community psychiatric nurse 15 (14) 26 (20) 19 (14) 60 (16)

Social worker 2 (2) 3 (2) 1 (1) 6 (2)

CAB 2 (2) 1 (1) 2 (1) 5 (1)

Other statutory/voluntary agency 11 (11) 18 (14) 9 (7) 9 (7)

Don’t know 1 (1) 1 (1) 2 (1) 3 (1)

Duration of depression

0 (no problem recorded) 9 (4) 13 (5) 14 (6) 36 (5)

1 (present for < 2 weeks) 3 (1) 0 (0) 2 (1) 5 (1)

2 (present for 2 weeks to 6 months) 67 (32) 96 (40) 79 (33) 242 (35)

3 (present for 6 months to 1 year) 49 (24) 46 (19) 43 (18) 138 (20)

4 (present for 1 to 2 years) 24 (12) 30 (13) 37 (15) 91 (13)

5 (present >2 years) 56 (27) 53 (22) 64 (27) 173 (25)

Duration of anxiety

0 (no problem recorded) 31 (15) 33 (14) 33 (14) 97 (14)

1 (present for < 2 weeks) 6 (3) 5 (2) 6 (3) 17 (2)

2 (present for 2 weeks to 6 months) 57 (27) 79 (33) 63 (26) 199 (29)

3 (present for 6 months to 1 year) 32 (15) 41 (17) 34 (14) 107 (16)

4 (present for 1 to 2 years) 24 (12) 21 (9) 32 (13) 77 (11)

5 (present >2 years) 58 (28) 59 (25) 71 (30) 188 (27)

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Table 2: PHQ summary (PHQ-9≥10) by duration of follow up and treatment group

Follow-up Beating the Blues Control usual care MoodGYM

Baseline (n=210) (n=239) (n=242)

Depressed n (%) 210 (100.00) 239 (100.00) 242 (100.00)

4 months (n=165) (n=179) (n=182)

Depressed n (%)≥10 83 (50.30) 78 (43.58) 89 (48.90)

12 months (n=153) (n=166) (n=165)

Depressed n (%) 54 (35.29) 66 (39.76) 50 (30.30)

24 months (n=143) (n=158) (n=160)

Depressed n (%) 60 (41.96) 61 (38.61) 55 (34.38)

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Table 3: Results from the logistic regression and mixed models

Comparison Odds Ratio 95% Confidence interval P-value

Logistic regression results

4 months

Beating the Blues vs. Usual GP care 1.19 0.75 1.88 0.46

MoodGYM vs. Usual GP care 0.98 0.62 1.56 0.95

MoodGYM vs. Beating the Blues 0.91 0.62* 1.34* 0.69

12 months




24 months




Sensitivity analyses 4 months

Adjusting for centre




Best case scenario (missing=not depressed)

Beating The Blues vs. Usual GP care 1.34 0.90 2.01 0.15



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Worst case scenario (missing=depressed)




Mixed model results

4 months




12 months




24 months




Note: odds ratios are presented as “odds of being depressed”; Logistic model adjusted for gender, age,

baseline depression severity, depression duration and level of anxiety. Mixed model adjusted for gender, age,

baseline depression severity, depression duration, level of anxiety, month, treatment and an interaction

between month and treatment as fixed effects. *90% CI for the non-inferiority comparison.

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6

Table 4: Result of the Linear Mixed Model for secondary analyses

Comparison Intervention

Mean 95% CI

Usual GP care

Mean 95% CI

Difference

(95% CI) p-value

Effect size 95% CI

PHQ-9 continuous

Overall

Beating the Blues vs. usual GP care 8.06 (6.92 to 9.20) 7.93 (6.74 to 9.13) 0.12 (-0.87 to 1.11) 0.81 -0.02 (-0.22 to 0.19)

MoodGYM vs. usual GP care 8.49 (7.26 to 9.72) 9.30 (8.00 to 10.60) -0.81 (-1.75 to 0.13) 0.09 0.09 (-0.11 to 0.28)

4 months


MoodGYM vs. usual GP care 9.86 (8.55 to 11.18) 9.80 (8.42 to 11.18) 0.06 (-1.09 to 1.22) 0.91 -0.01 (-0.20 to 0.19)

12 months

Beating the Blues vs. usual GP care 7.20 (5.94 to 8.46) 7.83 (6.53 to 9.13) -0.63 (-1.87 to 0.62) 0.33 0.07 (-0.13 to 0.27)

MoodGYM vs. usual GP care 7.63 (6.31 to 8.95) 9.22 (7.83 to 10.60) -1.59 (-2.75 to -0.42) 0.008 0.16 (-0.03 to 0.36)

24 months



Mental Component Score

Overall

Beating the Blues vs. usual GP care 38.52 (35.77 to 41.27) 37.50 (34.62 to 40.38) 1.02 (-1.34 to 3.37) 0.40 0.05 (-0.16 to 0.26)

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MoodGYM vs. usual GP care 38.98 (36.03 to 41.92) 35.99 (32.88 to 39.11) 2.98 (0.73 to 5.24) 0.009 0.14 (-0.06 to 0.34)

4 months

Beating the Blues vs. usual GP care 35.23 (32.28 to 38.17) 36.33 (33.29 to 39.37) -1.10 (-3.85 to 1.64) 0.43 -0.05 (-0.26 to 0.15)

MoodGYM vs. usual GP care 35.07 (31.90 to 38.23) 34.87 (31.54 to 38.20) 0.20 (-2.60 to 2.99) 0.89 0.01 (-0.19 to 0.21)

12 months

Beating the Blues vs. usual GP care 41.58 (38.55 to 44.60) 38.25 (35.11 to 41.39) 3.32 (0.37 to 6.28) 0.03 0.16 (-0.05 to 0.37)


24 months

Beating the Blues vs. usual GP care 38.76 (35.52 to 41.99) 37.92 (34.62 to 41.22) 0.84 (-2.49 to 4.17) 0.62 0.04 (-0.17 to 0.25)


Physical Component Score

Overall


MoodGYM vs. usual GP care 48.87 (47.11 to 50.63) 49.91 (48.05 to 51.76) -1.04 (-2.41 to 0.33) 0.14 -0.08 (-0.28 to 0.12)

4 months



12 months



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8

24 months



CORE-OM

Overall



4 months



12 months


MoodGYM vs. usual GP care 10.87 (9.25 to 12.48) 12.98 (11.28 to 14.68) -2.12 (-3.54 to -0.69) 0.004 0.18 (-0.02 to 0.38)

24 months



Means are all predicted means and 95% CIs estimated from the mixed model with gender, age, baseline depression severity (alternatively MCS, PCS or CORE-OM),

depression duration, level of anxiety, month, treatment and an interaction between month and treatment as fixed effects.

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Table 5: Summary of adverse events

Summary

Beating the

Blues

(N=210)

Usual GP

Care

(N=239)

MoodGYM

(N=242)

Total

(N=691)

Total number of NSAEsa

264 241 240 745

Number of participants with one or

more NSAEs 93 (44.3) 110 (46.0) 99 (40.9) 302 (43.7)

NSAEs per patient

1 27 (29.0) 49 (44.5) 36 (36.4) 112 (37.1)

2 30 (32.3) 31 (28.2) 21 (21.2) 82 (27.2)

3 14 (15.1) 13 (11.8) 22 (22.2) 49 (16.2)

4 6 (6.5) 7 (6.4) 12 (12.1) 25 (8.3)

5 5 (5.4) 6 (5.5) 6 (6.1) 17 (5.6)

6 or more 11 (11.8) 4 (3.6) 2 (2.0) 17 (5.6)

Total Number of SAEsb

19 19 11 49

Number of participants with one or

more SAEs 15 (7.1) 15 (6.3) 9 (3.7) 39 (5.6)

Events per patient

1 12 (80.0) 11 (73.3) 7 (77.8) 30 (76.9)

2 2 (13.3) 4 (26.7) 2 (22.2) 8 (20.5)

3 1 (6.7) 0 (0.0) 0 (0.0) 1 (2.6)

Relationship to treatment

Unrelated 18 (94.7) 15 (78.9) 6 (54.5) 39 (79.6)

Unlikely to be related 0 (0.0) 4 (21.1) 5 (45.5) 9 (18.4)

Possibly related 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Probably related 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Definitely related 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Unable to assessc 1 (5.3) 0 (0.0) 0 (0.0) 1 (2.0)

Number of Serious Adverse Events

referred to DMEC 0 (0.0) 3 (15.8) 2 (18.2) 5 (10.2)

Number of Serious Adverse Events

referred to REC 0 (0.0) 2 (10.5) 0 (0.0) 2 (4.1)

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10

Event details

Involved inpatient hospitalisationd 17 (89.5) 13 (68.4) 10 (90.9) 40 (81.6)

Life-threateningd e

0 (0.0) 6 (31.6) 1 (9.1) 7 (14.3)

Patient died 2 (10.5) 0 (0.0) 0 (0.0) 2 (4.1)

Involved persistent or significant

disability or incapacitye

0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Resulted in a congenital anomaly or

birth defect 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

a Non-serious adverse events

b Serious Adverse Event

c Researcher was informed that the participant had recently been hospitalised but when contacted patient did

not provide further information and withdrew from the study

d One SAE was classed as both involving inpatient hospitalisation and life-threatening

e One SAE was class as both life-threatening and involving persistent or signification disability or incapacity

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Table 6: Primary and secondary care services accessed by trial participants from baseline to 12

month follow-up (data obtained via GP medical records)

Service Beating the Blues

(n=173)

Usual GP Care (n=202) MoodGYM (n=205)

Mean

(SD)

Used by

(%)

Mean

(SD)

Used by

(%)

Mean

(SD)

Used by

(%)

Primary Care

GP 7.66

(5.48) 96.49

6.94

(4.82) 95.92

6.98

(4.62) 97.51

Nurse 1.60

(2.31) 57.89

1.86

(2.85) 62.76

2.03

(3.86) 61.19

Out of Hours 0.09

(0.33) 8.19

0.07

(0.31) 5.61

0.06

(0.26) 5.47

Medication

Depression-related N/A 81.55 N/A 83.94 N/A 76.77

Secondary Care

IAPT*

0.25

(1.23) 5.29

0.41

(1.25) 12.76

0.33

(1.46) 6.97

CMHT+

0.20

(1.58) 5.26

0.14

(0.70) 6.12

0.08

(0.41) 4.48

Counsellor 0.28

(1.65) 5.29

0.04

(0.29) 2.04

0.13

(0.86) 3.48

Psychiatric 0.17

(1.16) 4.68

0.13

(0.82) 3.06

0.11

(0.88) 1.99

Psychological 0.46

(2.95) 4.09

0.37

(2.26) 4.08

0.01

(0.21) 0.50

* Improving Access to Psychological Therapies is a NHS service offering psychological interventions to

individuals with depression and anxiety disorders.

+ Community Mental Health Teams

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Assessed for eligibility (n=1273)

Excluded (n=582)

Not meeting inclusion criteria (n=234)

Declined to participate (n=348)

Allocated to Beating the Blues &

usual GP care (n=210)

Received Beating the Blues (n=210)

Allocated to MoodGYM &


Received MoodGYM (n=242)

Allocation

Follow-Up

Randomised (n=691)

Enrollment

Allocated to Usual GP

Care (n=239)

Assessed for eligibility (n=1273) Enrollment

Excluded (n=582)




Allocation

Follow-Up


Follow-Up

Randomised (n=691)

Excluded (n=582)




Follow-Up


Follow-Up

Randomised (n=691)

Excluded (n=582)




Allocation

Enrollment




Allocation

Enrollment

Excluded (n=582)




Allocation

Enrollment

4 month follow-up (n=165; 79%)

Lost to follow-up (n=33)

Withdrawn from intervention

(n=15)

Full withdrawal (n=12)







Incomplete primary outcome (n=2)

(n=2)

4 month follow-up: (n=179; 75%)











Withdrawn from intervention

(n=9)








Analysis

Primary outcome analysis (n=165)

Analysis at 12 months (n=153)








Allocated to MoodGYM &


Received MoodGYM (n=242)

Allocated to Usual GP

Care (n=239)

Randomised (n=691)




Excluded (n=582)




Allocation

Enrollment

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Note: Means are all predicted means and 95% CIs estimated from the mixed model with gender, age, baseline PHQ-9 score, duration of depression, level of anxiety, month, treatment and an interaction between month and treatment as fixed effects.

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