23/33 The clinical and cost-effectiveness of colesevelam for the treatment of bile acid diarrhoea commissioning brief

Introduction

The aim of the Health Technology Assessment (HTA) Programme is to ensure that high quality research information on the clinical effectiveness, cost-effectiveness and broader impact of healthcare treatments and tests are produced in the most efficient way for those who plan, provide or receive care from NHS and social care services. The commissioned workstream invites applications in response to calls for research on specific questions which have been identified and prioritised for their importance to the NHS, patients and social care.

Research question

What is the clinical and cost-effectiveness of colesevelam for the treatment of bile-acid diarrhoea?

1. Intervention: Colesevelam. 
2. Patient group: Patients diagnosed with bile acid diarrhoea, with applicants to specify and justify eligibility criteria and method of diagnosis. Applications are encouraged which include recruitment from geographic populations with high disease burden which have been historically underserved by research activity in this field. 
3. Setting: Gastroenterology services and any other suitable setting. 
4. Control and comparator: Applicants to specify and justify the control and comparator intervention(s). Applicants are strongly encouraged to study multiple drugs in a multi-arm trial, for example, including colesevelam, loperamide and other bile acid sequestrants.
5. Study design: A randomised controlled trial with an internal pilot phase to test key trial processes such as recruitment and adherence. Clear stop and go criteria should be provided to inform progression from pilot to full trial. 
6. Important outcomes: Severity of diarrhoea and associated symptoms, including urgency and anxiety; overall health-related quality of life. Other outcomes and outputs: Adverse effects; cost-effectiveness; patient experience, for example, how well the drug is tolerated and how it affects the severity of symptoms in the longer term; occupational and educational outcomes and related quality of life. Objective measures should be considered if appropriate and acceptable. Recommendations of the potential place of colesevelam in the patient pathway. Existing Core Outcomes should be included amongst the list of outcomes unless a good rationale is provided to do otherwise. Applicants are encouraged to report recruitment and findings disaggregated by sex, plus other demographic factors where relevant. 
7. Minimum duration of follow-up: 12 months. Longer-term follow up: If appropriate, researchers should consider obtaining consent to allow potential future follow up through efficient means, such as routine data, as part of a separately funded study. 

Rationale

Bile acid diarrhoea is one of several causes of chronic diarrhoea, and chronic diarrhoea is one of the most common reasons for referral to gastroenterology services. A significant proportion of people with chronic functional diarrhoea or diarrhoea-predominant irritable bowel syndrome have evidence of bile acid diarrhoea, however, bile acid diarrhoea can also affect other patient groups, for example people who had cholecystectomy (gall bladder removal), intestinal resection, peptic ulcer surgery, chronic pancreatitis, coeliac disease or diabetes mellitus, among others.

Bile acids are synthesised in the liver and stored in the gallbladder. After a meal, the gall bladder contracts, releasing the bile acids into the small bowel, where they aid in the digestion of lipids. Normally, 95% of bile acids are reabsorbed in the terminal ileum (the end of the small bowel) and are recycled back to the liver. If there is a failure of re-absorption, excess bile acids escape into the colon (the large bowel) where they stimulate electrolyte and water secretion. This causes bile acid malabsorption, leading to bile acid diarrhoea. Bile acid diarrhoea presents as chronic watery, non-bloody, continuous or intermittent diarrhoea, usually with an urgency, often with faecal incontinence, and anxiety.

Although not life threatening, bile acid diarrhoea can have a considerable impact on lifestyle and quality of life because the associated increased frequency of bowel motions may limit the person's ability to travel or leave the house.

The main treatment goal for people with bile acid diarrhoea is control of the diarrhoea. In many cases, symptom improvement may be achieved with low fat diet and oral medication. Loperamide is a common antidiarrhoeal that targets the symptoms, but not the cause of the condition. However, bile acid sequestrants (bile acid binders) target the immediate cause of the bile acid diarrhoea. They act by binding bile acids in the intestine, preventing their effects on water and salt absorption in the colon, thereby reducing the diarrhoea.

There are currently three bile acid sequestrants available: colestyramine, colestipol, and colesevelam. Colestyramine, also known as Questran, is the most frequently used bile acid sequestrant, however, colestyramine and colestipol are powders that require mixing with water or juice, and some people report they dislike their unpleasant taste. Bloating and abdominal pain can be side effects. This can lead to poor treatment tolerance, prompting many users of these drugs to discontinue the treatment.

Colesevelam, in contrast, is available in tablet form. It binds to bile acids with higher affinity than colestyramine or colestipol. Colesevelam is more expensive than colestyramine and colestipol, and less often used than colestyramine. There is also a lack of guidance of its use, as well as paucity of high-quality evidence of its clinical and cost-effectiveness.

Therefore, the HTA programme wishes to fund the study outlined above to inform patient choice, future practice and guideline updates. The programme is particularly interested in the impact on patients' quality of live, as well as the cost-effectiveness and potential place of colesevelam in the patient pathway.

To support the ambitions of NIHR’s Best Research for Best Health: the next chapter, NIHR strongly encourages the inclusion of nurses, midwives and allied health professionals within well-developed research teams responding to this call, to increase the building of nurse, midwife and allied health professional-related research activity, capacity and capability across the professions. Depending on the level of experience, this could be through the role of lead applicant, as joint co-applicant supported by detailed mentoring plans submitted with the application, or as a co-applicant member of the research team. Through this activity, NIHR aims to support nurses, midwives and allied health professionals to become future research leaders and release the potential to lead, use, deliver and participate in research as a part of their job.

Additional commissioning brief background information

A background document is available that provides further information to support applicants for this call. It is intended to summarise what prompted the call and the existing evidence base, including relevant work from the HTA and wider NIHR research portfolio. It was researched and written on the basis of information from a search of relevant sources and databases, and in consultation with a number of experts in the field. If you would like a copy please email htaresearchers@nihr.ac.uk.

Making an application

Your application must be submitted online no later than 1pm on 26t July 2023. Applications will be considered by the HTA Funding Committee at its meeting in September.

HTA Programme Stage 1 guidance notes are available, alongside supporting information for applicants.

Please note, shortlisted Stage 1 applicants will be given 8 weeks to submit a Stage 2 application. The Stage 2 application will be considered at the Funding Committee in January 2024.

Applications received electronically after 1pm on the due date will not be considered.

For commissioned topics, the Programme strongly discourages the practice of the same co-applicant joining more than one competing team. There may be unusual circumstances where the same person could be included on more than on application eg a lead from a named charity or a unique national expert in a condition.

For such exceptions, each application needs to state the case as to why the same person is included. The shared co-applicant should not divulge application details between teams. Both teams should acknowledge in their application that they are aware that one of their co-applicants is part of a competing application and that study details have not been shared.

Should you have any queries please email htacommissioning@nihr.ac.uk.