Title: ACTIB (Assessing Cognitive behavioural Therapy in Irritable Bowel): A randomized controlled trial of clinical and cost effectiveness of therapist delivered cognitive behavioural therapy and web-based self-management in irritable bowel syndrome.
Funder: Department of Health and Social Care

Abstract: Design: A 3-arm multi-centre RCT. 495 patients with refractory IBS individually randomised to Therapist CBT (TCBT), low intensity behavioural therapy (LIBT) or TAU by an independent randomisation service (CTU) with block randomisation and stratification by centre. Assessors blind to treatment arm. TAU participants will have access to the WCBT website at trial end. A nested qualitative study will explore patients’ experiences of treatments: interviews at 3 and 12 mths with approx. 17 per arm; analysed inductively to identify factors that facilitate or impede adherence to treatment. Setting: Treatment at home via telephone and internet. Therapists based at King’s College London. Target population: Adults (18 yrs or over) with refractory IBS (on-going symptoms, IBS-SSS >75), fulfilling ROME III criteria and unresponsive to first-line therapies (eg anti-spasmodics or anti-depressants) with a continuing symptom profile >12 months. Exclusion: unexplained rectal bleeding or weight loss, IBD, coeliac disease, colorectal carcinoma. Blood tests: FBC, TTG, CRP taken prior to randomisation to exclude important differential diagnoses. Current medications maintained at a stable dose. Recording of: current and past medications, length of symptoms, sub-type of IBS (diarrhoea, constipation or alternating pattern), previous or current psychiatric diagnoses. Health Technologies being assessed: Therapist CBT and Lower intensity CBT (a web-based self-management programme). NICE recommends CBT for refractory IBS but cost is high and availability poor. We will compare 2 formats of CBT (TCBT and LIBT) for IBS against TAU in a high quality trial. The CBT is based on an empirical CB model of IBS (Spence, Moss-Morris. GUT 56,(8),2007). Key differences between arms: therapist contact time and interactive website access. Structured therapy sessions, based on a previous efficacious CBT trial for IBS, consist of education, behavioural and cognitive techniques, aimed at improving bowel habits, developing stable, healthy eating patterns, addressing unhelpful thoughts, managing stress, reducing symptom focussing and preventing relapse. TCBT: patient manual + 6, 60min telephone sessions + homework tasks with a CBT therapist at week 1, 2, 3, 5, 7, 9 and two 1 hr 'booster' CBT sessions at 4 and 8mths. WCBT: An interactive, tailored CBT self-management website developed with substantial patient input (MIBS trial). Participants access 8 online sessions and homework tasks, similar content to TCBT and receive weekly automated email reminders and minimal therapist support: 3, 30 minute telephone support calls at week 1, 3 and 5 and two, 30 min booster sessions at 4 and 8mths. ‘Booster’ sessions are included in both arms to discuss setbacks and to reinforce positive symptom management. Telephone CBT sessions rather than face to face are proposed, as they have similar efficacy, improve accessibility, are efficient, less costly and could be readily delivered across the NHS from a centralised service. Currently, IBS patients have minimal CBT access. Web CBT is effective in depression and recent small trials show promise for IBS but indicate some therapist input is needed. 73% households have internet connections with numbers rising. Therapists receive manuals, training and supervision to ensure quality and adherence to protocol. All sessions are taped to check treatment fidelity, length and number of phone sessions. Patients’ adherence is measured through number of phone sessions and automated count of web sessions accessed. Secure website passwording will ensure non-contamination of treatments. TAU is defined as continuation of current medications, and GP or consultant follow-up with no psychological therapy. All participants receive a standard information sheet on Lifestyle and Diet in IBS based on NICE. Measurement of cost and outcomes: Primary outcomes: IBS symptom Severity Scale (IBS-SSS) and Work and Social adjustment scale (WSAS). IBS SSS is widely used in IBS studies (50 point change from baseline deemed clinically significant). In this resistant symptom group, accounting for 15 point placebo response in TAU, a 35 point difference between groups at 12mths is relevant for less costly, more accessible LIBT compared to TAU. 12mths primary outcome, data collection at 3 and 6mths to assess effect over time. Data will be entered onto an online data entry system at CTU. Intention-to-treat analysis. Group differences will be assessed using mixed linear regression models accounting for repeated measurements. Covariates: baseline IBS-SSS, treatment group, therapist, IBS symptoms type, time and a time by treatment interaction term to extract differences at 3, 6, and 12mths. Therapist effects and treatment effect moderation by important baseline variables (treatment by variable interactions) will be explored. Mixed models account for missing outcome data under the missing at random assumption, the effect checked using sensitivity analyses. Secondary outcomes: Responder based on Subjects Global assessment of relief (SGA),(Qol (EQ-D5), Enablement, Hospital Anxiety and Depression Scale, adverse events, health care utilization - important to measure the wider IBS effects, will be analysed similarly. A complier average causal effect will be estimated if there is appreciable lack of compliance. Cost-effectiveness: Taking a health service and societal perspective. Intervention costs: based on number of therapy/support sessions, combined information on staff time (based on salaries and overheads) and (for web arm) development costs apportioned over estimated number of users. Other service use and lost employment: measured with a study schedule at baseline and each follow-up. Costs calculated by combining these data with national unit cost and average earnings information. Healthcare and societal costs at 12mths will be combined with the primary outcome measure, QALYs and incremental cost-effectiveness ratios computed for the two therapies compared to TAU and each other, indicating the extra cost of a unit-improvement on the IBS SSS, or the cost saved with unit-deterioration (relevant for therapy comparison). QALYs will be derived using area-under the curve methods from the EQ-5D (measured at baseline and each follow-up)- validated for IBS. Uncertainty around ICERs for each two-way comparison will be addressed using cost-effectiveness planes. Interpretation of the QALY-based cost-effectiveness results will use cost-effectiveness acceptability curves, with all 3 arms compared. Sample size: A mean (SD) IBS-SSS in TAU arm of 250(76) (as in MIBS study) was assumed. Based on a two-sided, two-sample t-test, to detect a mean difference of 35 points at 12 months between LIBT and TAU, (effect size 0.46), 90% power, type I error 0.025 (two primary outcomes), needs a sample size of 119 per arm. Accounting for clustering due to therapists, cluster size approx. 17(10 therapists), intraclass correlation coefficient of 0.02, an inflation factor of 1.32 is required; allowing for 20% attrition and a deflation factor of 0.84 for baseline IBS SSS correlation with outcome; a sample size of 495 is required (165 each arm). This is also sufficient to detect an SGA responder difference between LIBT and TAU of 22%, or an odds ratio of 2.9, with 90% power, assuming 20% responders in TAU arm. Project timetable: Pre-study: Ethics. 1-8mths: Complete R&D, register trial, publish protocol, prepare recruitment & assessment materials, update & test website, recruit & train therapists, design data collection forms and study database, set up randomisation service, 9-30mths: Recruitment, screening, intervention delivery, assessment. 31-42mths: Therapy booster sessions, 12mth follow-up assessments. 43-46mths: Data preparation, and analysis. 47-48mths: Final reports, dissemination. Recruitment: 495 participants over 22mths (23 randomised/mth), Approx. 30 NHS GP practices and Hospital based GI services in Hampshire (SUHT ± 500 IBS pts/yr) and London (GSTT, King’s College Hospital, LSL and S. London Healthcare, ± 1000 IBS pts/yr).

Lay abstract: Irritable bowel syndrome (IBS) is a common chronic gastrointestinal disorder that affects 10 – 22% of the UK population and costs the NHS over £200 million a year. Abdominal pain, bloating and altered bowel habit, affect quality of life, social functioning and time off work. Initial treatment relies on a positive diagnosis, reassurance, lifestyle advice, and drug therapies. However, many patients suffer ongoing symptoms. NICE guidelines recommend Cognitive Behavioural Therapy (CBT) for patients with IBS who continue to have symptoms after 12 months. CBT is a therapeutic approach which centres on the interaction of bodily symptoms, external triggers, thoughts and emotions. However, access to this therapy is limited due to the cost and availability of therapists and there is uncertainty regarding its clinical and cost-effectiveness. One way to make CBT accessible to larger numbers of patients is to provide a low-intensity form of the therapy. We have developed a CBT-based website which could be accessed by patients countrywide. This low-intensity behavioural therapy (LIBT) has the potential to be more accessible, because it is less expensive and requires less therapist-time than traditional therapist-delivered CBT. However, there is a lack of high quality evidence on the clinical effectiveness and cost-effectiveness of these approaches. We will compare both therapies plus treatment as usual (TAU), with treatment as usual alone – where patients continue with their current medications and GP or consultant care, but do not receive any psychological therapy. The Therapist delivered CBT arm will have 6, 1 hr telephone CBT sessions with trained therapists over 9 weeks. Therapists will provide information about IBS, and use behavioural and cognitive techniques aimed at improving bowel habits, addressing unhelpful thoughts, reducing heightened attention to symptoms and preventing relapse. Patients will complete tasks to reinforce the sessions. Previous trials of Therapist CBT have shown that the positive effect of CBT on IBS diminishes with time so we have added two booster CBT telephone sessions at 4 and 8 months to try and prolong the effect. The LIBT group will have access to the interactive, CBT based self-management website developed with substantial patient input in a previous study (MIBS). Participants undertake 8 web sessions over 9 weeks at home, which include similar content to the therapist CBT, homework on online and weekly email reminders. In a feasibility study of the website, patients found it user friendly and accessible and it appeared to enhance maintenance of symptom improvement compared to control. They also receive 3, 30 min telephone support calls from a therapist and 2 booster telephone calls at 4 and 8 months. Several small trials of web-based CBT for IBS show promising results but indicate that some therapist input is necessary to encourage patients to engage with and work through the website. This will be a multi-site trial. Participants will be recruited from London (by the research team at Kings) and the South coast of England (by the research team at Southampton). Hospital-based gastroenterology consultants and GPs will search their databases for patients with IBS and send out invitation letters. They will also recruit opportunistically patients presenting to clinic or the surgery. People interested in participating will return a reply slip to the research team and be contacted to complete a screening questionnaire to ensure they fulfil the entry criteria for the trial. Adults with IBS symptoms for at least 12 months that have not improved with initial treatments will be eligible. They will have a simple blood test to exclude other conditions (as in the MIBS study) and then they will be randomly assigned to one of the 3 groups, therapist CBT, LIBT, and TAU. The main outcomes are IBS symptom severity and the Work and Social Adjustment Scale (WSAS)which measures the effect of the IBS on the peoples people’s ability to work and manage at home, participate in social and private leisure activities and relationships, at 12 months. Data will also be collected on these outcomes at 3, 6 months. We will also assess cost-effectiveness and wider benefits (e.g. quality of life and mood) as these provide important additional ways of assessing the impact of IBS on people’s lives. The trial will be conducted in full accordance with current guidelines for ethical research conduct. Fair access to the treatments being tested is important. Participants need to have web access, which could exclude some people who would otherwise like to take part. However, three quarters of households have web access, this figure is rapidly increasing, and those without home access could use public computers (eg local library). Participants must not be aged over 60yrs, because colorectal cancer is more common in the over 60yrs and guidelines recommend that changes in bowel habit in this group require hospital tests beyond the scope of this trial. Participants in the TAU group will be given access to the website at the end of the trial, giving them access to CBT. The research team has substantial experience in running trials and working with patients with IBS. Hazel Everitt was principal investigator for the MIBS trial which developed and piloted the self-management website. She will lead overall trial management and recruitment at Southampton and manage the protocol for the TAU arm. Rona Moss-Morris developed a CBT model of IBS, conducted previous IBS trials, and developed the web-based programme on which the LIBT is based. She will lead the web therapy arm including website oversight, developing therapist manuals, training and supervision of web therapists and lead recruitment at Kings. Trudie Chalder has considerable trial and CBT experience and was involved in a leading research paper into CBT for IBS in primary care undertaken in London in 2005 and will lead the therapist arm including developing or revising, therapist/patient manuals and protocols, training and supervision of therapists for therapy arm. Co-applicants have significant experience to ensure a rigorously run trial: Paul Little, Southampton, is a GP and clinical trials expert; Paul McCrone, Kings, Health Economics has undertaken the health economics evaluation for a previous CBT for IBS trial; Sabine Landau, Kings, is an Statistician experienced in complex trials; Flis Bishop, Southampton, has qualitative methods expertise; Robert Logan and Nicholas Coleman, Consultant Gastroenterologists will provide expert advice and oversight of secondary care recruitment in London and Southampton respectively. Collaborators include: Caroline Murphy, Institute of Psychology, who will co-ordinate CTU support, Jane Hutton Clinical Psychologist, Kings, Clinical psychology advice and qualitative methods expertise; Brendon Delaney, Guys, GP, will assist with Primary Care recruitment in London.The budget includes overheads for running a large complex intervention trial across 2 centres, including salaries for a Trial Manager in Southampton (100%), trial co-ordinators in Southampton (50%) and London (100%); Randomisation, Database support supplied by the CTU (£30,000), Computer programming and website support; Statistical and Health Economic support; Travel, Equipment and Consumable costs. NHS costs include: 10 part-time therapists (20% for 28 months) to undertake the CBT sessions and GP and Consultant time to identify participants.

Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;7.3 MANAGEMENT AND DECISION MAKING
Health categories: ORAL AND GASTROINTESTINAL