Comparing the clinical and cost-effectiveness of COlesevelam for Bile Acid diarrhoea with colestyramine or Loperamide, including long Term follow-up (COBALT).

Research question

What is the clinical and cost-effectiveness of colesevelam as a first-line treatment for Primary bile acid diarrhoea (PBAD) compared with colestyramine or loperamide? Background

PBAD is a common condition with a substantial impact on quality of life, affecting patients’ daily activities, ability to work and socialise. PBAD can be diagnosed using the selenium-75-labelled homocholic acid conjugated taurine (SeHCAT) test, which measures bile acid retention over 7 days, and is widely available in the UK. There remains a lack of evidence for effective treatments with uncertainty regarding the medium and long-term clinical and economic benefits of colesevelam compared with commonly used treatments, such as colestyramine or loperamide.

We have designed a multi-centre, randomised, open-label, three-arm, parallel-group, superiority trial to address these issues. Aims and objectives

The aim is to determine the clinical and cost-effectiveness of colesevelam as a first-line treatment for PBAD compared with colestyramine or loperamide. The primary objective will be to compare the proportion of participants with PBAD who have a symptomatic response to colesevelam at 6 months compared with colestyramine or loperamide.

Methods

519 adults with a new diagnosis of PBAD based on a 7-day SeHCAT retention of = 20% will be randomised 1:1:1 to receive colesevelam, colestyramine, or loperamide for 6 months. Randomisation will use minimisation with the following variables SeHCAT retention and recruiting site. Participants will titrate their dose of study drug up or down during the trial as needed, guided by a standardised algorithm, depending on symptom response and side-effects.

At 6 months, participants will be offered the opportunity to continue their randomised treatment for a further 6 months and all participants will be followed up for 12 months to assess longer term outcomes.

Clinical effectiveness will be assessed using a diary of daily stool frequency and stool type according to the Bristol stool form scale (BSFS) completed by participants over a 1-week period at baseline, 6 weeks, 6 months, and 12 months. It will also capture symptoms of urgency, incontinence, abdominal pain and bloating. The primary outcome will measure the proportion of participants with PBAD who have a clinical response at 6 months in those randomised to colesevelam compared with colestyramine or loperamide.

Clinical response will be defined as a mean of <3 stools/day and <1 watery stools/day. The study will examine the role of SeHCAT testing for diagnosing PBAD by exploring treatment response according to different SeHCAT thresholds in a pre-defined subgroup analysis. The primary economic evaluation will assess the cost-effectiveness of colesevelam compared with colestyramine or loperamide at 6 months post-randomisation using costs per quality adjusted life year (QALY) as the outcome measure. Timelines for delivery The study is 51 months duration, with a 24-month recruitment period, 12-month follow-up and an 8-month internal pilot. Anticipated impact and dissemination

The results will help clinicians, patients, and health service policy makers to make better-informed decisions regarding the management of PBAD. We will present the results at national and international conferences and publish in open-access articles in high-impact journals. We will also use social media and involve our PPI group to ensure wide dissemination.