Colesevelam for Bile Acid Diarrhoea: What the New SINBAD Trial Means for Patients

Table of Contents

• Key Points
• Understanding Bile Acid Diarrhoea
• Why This Study Was Needed
• How the Study Was Conducted
• Who Took Part in the Study
• The Treatment Plan
• Key Findings: Does Colesevelam Work?
• Safety and Side Effects
• What This Means for Patients
• Study Limitations
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• In the SINBAD trial, 64% of C4-confirmed bile acid diarrhoea patients achieved remission on colesevelam versus 16% on placebo.
• Colesevelam raised remission odds about ninefold in C4-diagnosed patients and about elevenfold in SeHCAT-diagnosed patients.
• The SINBAD trial reported no serious adverse events; bloating and abdominal pain were the most common side effects.
• The C4 blood test identified patients who responded as well to colesevelam as the SeHCAT scan, supporting wider use.
• Treatment in the trial lasted 12 days, with remission defined as fewer than 3 total and fewer than 1 watery stool daily.

Understanding Bile Acid Diarrhoea

Bile acid diarrhoea (BAD) is a chronic condition caused by an excess of bile acids reaching the colon (large intestine). Normally, bile acids—produced by the liver to help digest fats—are reabsorbed in the final part of the small intestine. When this process fails or bile acid production exceeds absorption, the excess acids spill into the colon, where they trigger increased fluid secretion and faster bowel transit. The result is chronic, watery diarrhoea that can significantly impair quality of life.

The condition is far from rare. The estimated population prevalence is approximately 1%, meaning roughly one in every hundred people may be affected. Yet it is frequently overlooked or misdiagnosed.

One striking statistic from the study highlights this diagnostic gap: when patients with irritable bowel syndrome (IBS) are formally tested for bile acid diarrhoea, 29–35% turn out to have BAD instead. This means that a substantial proportion of people diagnosed with IBS may actually have a treatable bile acid problem.

Why This Study Was Needed

Diagnosing bile acid diarrhoea is not straightforward. The gold standard test is the SeHCAT test (tauroselcholic [⁷⁵Se] acid), a nuclear medicine scan that measures how much of a radiolabelled bile acid is retained in the body over one week. However, this test is available only in specialised centres in a limited number of countries. An alternative is a blood test measuring plasma 7α-hydroxy-4-cholesten-3-one (C4), a by-product of bile acid production. The C4 test is potentially more widely available, but it has roughly 50% sensitivity compared with the SeHCAT test—meaning it can miss about half of cases.

Even with an accurate diagnosis, there has been a significant evidence gap. The mainstay of treatment has been bile acid sequestrants—medications that bind bile acids in the colon and neutralise their diarrhoea-inducing effects. The oldest of these, colestyramine, has been used for over 50 years. A newer option, colesevelam, binds bile acids more strongly and across a broader spectrum of bile acid types. Clinical data from cholesterol treatment suggest colesevelam also has fewer side effects and better tolerability than the older sequestrants.

However, the evidence supporting these drugs for BAD has been weak. Observational (non-randomised) studies have reported remission rates of 70–90% with sequestrants, but placebo-controlled trials have been scarce and inconclusive. One small trial using enterocoated colestyramine in 14 selected patients with Crohn's disease and small bowel resection showed some benefit. But the few controlled trials in broader populations did not show colestyramine or colesevelam to be superior to placebo regarding bowel habits, although some secondary non-clinical measurements did improve.

This left a critical question unanswered: do these medications genuinely work for bile acid diarrhoea when tested in a rigorous, blinded, placebo-controlled design? The SINBAD trial (Sequestrant colesevelam in bile acid diarrhoea) was designed to answer this.

How the Study Was Conducted

The SINBAD trial was an investigator-initiated, multicentre, double-blind, randomised, placebo-controlled, phase 4 clinical trial. It was conducted at four Danish secondary care centres. The researchers enrolled consecutive patients who were already being referred for routine SeHCAT testing because a doctor suspected bile acid diarrhoea. The study ran between October 25, 2018, and July 1, 2021, with the final patient chart review completed on February 13, 2022.

The trial used a rigorous design to ensure unbiased results. Both patients and study personnel were blinded—meaning neither knew whether the patient was receiving the active drug or a placebo. A pharmacist with no involvement in patient care generated the randomisation list using a web-based tool, with block randomisation (using blocks of 2, 4, or 6 patients) to keep the group sizes balanced across the study sites.

Sealed emergency envelopes were created in case a treatment allocation ever needed to be revealed urgently. Reassuringly, no envelope was ever opened during the study. The randomisation code remained fully masked until after the final 6-month follow-up, and the envelopes were only opened on February 14, 2022—after all data had been collected and locked.

Some additional design details are worth noting for completeness:

• Placebo capsules contained 330 mg lactose monohydrate, 335 mg potato starch, 12 mg gelatin, 3.5 mg magnesium stearate, and 31.5 mg talcum.
• Active capsules contained 625 mg colesevelam hydrochloride.
• Both were over-encapsulated in identical Capsugel DBcaps size AAA shells, with 360 mg microcrystalline cellulose filling surplus space.
• During the study, the C4 reference laboratory was changed from Hôpital Saint-Antoine in Paris to Rigshospitalet in Copenhagen due to a calibrator error in the Paris lab. This change happened before treatment allocation was unmasked, and Copenhagen results were confirmed by a second independent laboratory.

Who Took Part in the Study

The researchers screened a large pool of potential participants. In total, 1,124 patients were prescreened, and 168 patients were ultimately randomly assigned to receive either colesevelam (n=84) or placebo (n=84).

Patients were eligible if they were aged 18 to 79 years, did not have inflammatory bowel disease (IBD), and were attending SeHCAT testing for suspected bile acid diarrhoea. Key exclusions included patients with inflammatory bowel disease, microscopic colitis, suspected or confirmed viral gastroenteritis within the previous 4 weeks, acute non-viral gastroenteritis within the previous 8 weeks, or any debilitating chronic disease as judged by the study investigator.

A crucial practical element of the design was the baseline diarrhoea confirmation. Before randomisation, all patients kept a structured diary for 6 complete days (the week required for SeHCAT testing). Diarrhoea was defined as a daily average of 3.0 or more total bowel movements or 1.0 or more watery bowel movements (Bristol stool scale types 6 and 7—the "fluffy" or entirely liquid forms). Only patients who met this diary-confirmed definition were randomised.

Among the 168 randomised patients, 41 had a C4 concentration greater than 46 ng/mL (22 assigned to colesevelam and 19 assigned to placebo)—this was the primary analysis population. An additional 75 patients had SeHCAT retention of 10% or less (37 in the colesevelam group and 38 in the placebo group), which defined the secondary analysis population. Patients with a normal C4 or SeHCAT result were classified as having "miscellaneous diarrhoea" and were analysed in exploratory analyses.

The Treatment Plan

Treatment lasted 12 days. The starting dose was two capsules of 625 mg twice daily (a total daily dose of 2,500 mg). During the first 5 days—a designated run-in period—blinded study personnel telephoned patients to adjust the dose based on their response. Unless the patient reported constipation, the dose was increased stepwise.

The allowed doses were:

1. One capsule twice daily (1,250 mg/day)
2. Two capsules twice daily (2,500 mg/day)
3. Three capsules twice daily (3,750 mg/day) — the target dose

Dose changes were made in steps of one capsule per dose. Once the final dose was set during the 5-day titration period, it was kept unchanged for the remaining 7 treatment days. No dietary advice was given during the study.

Patients continued their diary recordings throughout treatment. Remission was defined as the absence of both diarrhoea criteria (fewer than 3.0 total bowel movements per day AND fewer than 1.0 watery bowel movement per day) during treatment days 6 through 12. Additional questionnaires measured quality of life and gastrointestinal symptoms, and voluntary stool samples were collected for bile acid analysis.

The primary outcome was the intention-to-treat remission rate in patients whose bile acid diarrhoea was diagnosed by a C4 concentration greater than 46 ng/mL. The key secondary outcome was the remission rate in patients diagnosed by SeHCAT retention of 10% or less. In the intention-to-treat analysis, patients with missing outcome data were counted as treatment failures—a conservative approach. Once the trial ended, patients were followed up for 6 months, with symptom questionnaires repeated and patient charts reviewed for current treatment and its subjective effect.

Key Findings: Does Colesevelam Work?

The results were striking and strongly favour colesevelam.

Primary Outcome: C4-Defined Bile Acid Diarrhoea

Of the 41 patients with C4-confirmed bile acid diarrhoea, 14 of 22 (64%) receiving colesevelam achieved remission, compared with 3 of 19 (16%) receiving placebo. The adjusted odds ratio was 9.1 (95% CI 1.9–62.8; p=0.011). In plain language, this means patients on colesevelam were about 9 times more likely to achieve remission than those on placebo, and the result was statistically significant—meaning there is a less than 1.1% probability this difference occurred by chance. This was the study's primary, pre-specified endpoint, making it a particularly robust finding.

Secondary Outcome: SeHCAT-Defined Bile Acid Diarrhoea

The secondary outcome mirrored the primary result. Among the 75 patients with SeHCAT-defined bile acid diarrhoea, 22 of 37 (59%) in the colesevelam group achieved remission versus 5 of 38 (13%) in the placebo group. The adjusted odds ratio was an even more impressive 11.1 (95% CI 3.4–45.6; p=0.00020). This means patients were about 11 times more likely to achieve remission on colesevelam, and the probability of this being due to chance is less than 0.02%—an exceptionally strong statistical signal.

Comparing the Two Diagnostic Approaches

The consistency between the two diagnostic methods is an important finding. The C4 blood test—which is potentially more widely available than the specialised SeHCAT scan—identified a patient group that responded equally well to treatment. The remission rates were 64% for C4-diagnosed patients and 59% for SeHCAT-diagnosed patients, a very similar magnitude of benefit. This validates the C4 threshold of 46 ng/mL as a clinically meaningful diagnostic cut-off.

Safety and Side Effects

One of the most reassuring aspects of this trial is the safety profile. There were no serious adverse events in either group, and common adverse events were described as transient.

In the primary outcome population (patients with C4-defined bile acid diarrhoea), the side effects reported were:

Colesevelam group (22 patients):

• Abdominal pain: 5 patients
• Bloating: 9 patients
• Nausea: 4 patients

Placebo group (19 patients):

• Abdominal pain: 4 patients
• Bloating: 4 patients
• Nausea: 1 patient

Notably, no participants with bile acid diarrhoea withdrew from the study due to adverse events. Adverse events were recorded from the start of treatment until 72 hours after treatment ended, and patients documented any unusual symptoms and their duration in the study diary.

What This Means for Patients

The clinical significance of this trial is substantial. Before this study, evidence for bile acid sequestrants relied on observational data and a handful of small, inconclusive placebo-controlled trials. The SINBAD trial provides high-quality, phase 4 evidence that colesevelam is genuinely effective at treating bile acid diarrhoea when the diagnosis is confirmed by either C4 or SeHCAT testing.

The fact that two-thirds of patients achieved remission is a significant clinical benefit. Observational data further suggest that once remission is achieved, it is usually sustained over the longer term. This matters enormously for patients with chronic diarrhoea, who often suffer for years with misdiagnoses such as IBS before receiving appropriate treatment.

The trial also has an important diagnostic message. The C4 blood test is simpler and more accessible than the SeHCAT nuclear medicine scan, which is only available in specialised centres in a few countries. The finding that C4-diagnosed patients responded just as well to colesevelam lends strong support to using C4 as a practical diagnostic tool in wider clinical settings. For patients, this could mean faster diagnosis and treatment, without the practical barriers of travelling to specialist nuclear medicine departments.

Based on the 29–35% detection rate of BAD in patients labelled with IBS, diagnosing and treating bile acid diarrhoea properly could have a meaningful impact on a very large group of patients experiencing chronic diarrhoea.

Study Limitations

Like every clinical trial, this study has limitations that should be acknowledged. Understanding these helps patients judge the strength of the evidence.

• Short treatment duration. The treatment and assessment period was only 12 days, with remission assessed during days 6–12. While this is sufficient to establish short-term efficacy, the study cannot directly prove that remission is maintained over months or years. The longer-term benefits are supported by observational data, not this trial.
• Modest primary outcome population. Only 41 patients had C4-defined bile acid diarrhoea (the primary analysis group). Although the results were statistically significant, the confidence intervals were wide—the odds ratio for the primary outcome ranged from 1.9 to 62.8. This reflects the relatively small number of patients and means the precise magnitude of benefit is uncertain.
• No loperamide or other rescue medication. The study did not allow escape or rescue medication, which could have led to withdrawals or the classification of some patients as treatment failures.
• Specific diagnostic thresholds. The study used C4 greater than 46 ng/mL and SeHCAT retention of 10% or less. Different thresholds are used in some centres, and the results may not generalise to all diagnostic criteria.
• All patients had diarrhoea at baseline. The planned mixed-model analysis could not be used because all patients had diarrhoea at baseline, producing a singular fit correlation matrix. The researchers instead used logistic regression with site as a conditional effect.
• No adjustment for multiple testing. Because multiple secondary outcomes were analysed without statistical adjustment, the secondary results should be interpreted as supportive rather than definitive.
• Drug interaction precautions. The study protocol paused other medications known to interact with sequestrants (statins and fibrates) during the treatment window, and patients with significant comorbid disease were excluded. Real-world patients taking multiple medications may need additional considerations.

Recommendations for Patients

Based on this trial and the existing body of evidence, here is practical guidance for patients and clinicians navigating bile acid diarrhoea:

1. If you have chronic diarrhoea and have been told it is IBS, consider asking about bile acid diarrhoea. With a 29–35% prevalence of BAD in the IBS population, testing is strongly recommended in guidelines and could uncover a treatable cause.
2. Ask about the C4 blood test. If SeHCAT scanning is not available in your area, the C4 blood test is a reasonable and potentially widely accessible diagnostic alternative. This trial confirms that a C4 concentration above 46 ng/mL identifies patients who respond well to colesevelam.
3. Understand that bile acid sequestrants are the standard treatment. Colesevelam is not a new or experimental drug—it has been used for hypercholesterolaemia (high cholesterol) for years, with a known and reassuring safety profile. This trial now confirms its effectiveness for bile acid diarrhoea.
4. Be patient with dose adjustment. In this study, the dose was started at two capsules twice daily and titrated over the first 5 days toward a target of three capsules twice daily, based on response and tolerance. If your doctor prescribes colesevelam, some adjustment may be needed to find the dose that works for you.
5. Expect possible mild side effects early in treatment. The most common side effects in this trial were bloating (9 of 22 patients on colesevelam in the primary group), abdominal pain (5 of 22), and nausea (4 of 22). These were transient and no patient with bile acid diarrhoea withdrew due to side effects.
6. Remember that remission is achievable. In this trial, two-thirds of patients (64%) achieved full remission of their diarrhoea symptoms. If you have been living with chronic diarrhoea, effective treatment exists and is worth pursuing.

The researchers also called for future studies to improve biochemical diagnostic options, determine the role of newer treatments such as liraglutide in the treatment algorithm, and assess long-term outcomes including sustained remission, safety, and quality of life. But for now, the SINBAD trial provides solid, practice-changing evidence that colesevelam is an effective and safe option for patients with bile acid diarrhoea.

Frequently Asked Questions

What causes bile acid diarrhoea?

Bile acid diarrhoea happens when excess bile acids reach the colon. Bile acids normally help digest fats and are reabsorbed in the small intestine, but when this fails, they spill into the colon, increasing fluid secretion and speeding bowel transit. This causes chronic watery diarrhoea. It affects about 1% of people and is often misdiagnosed as irritable bowel syndrome.

How is bile acid diarrhoea diagnosed?

The gold-standard test is the SeHCAT nuclear medicine scan, but it is only available in specialised centres. A simpler blood test measures C4, a by-product of bile acid production. In the SINBAD trial, a C4 level above 46 ng/mL identified patients who responded well to treatment, although C4 testing can miss about half of cases.

What was the SINBAD trial?

SINBAD was a double-blind, randomised, placebo-controlled phase 4 trial conducted at four Danish centres. It enrolled 168 patients suspected of having bile acid diarrhoea. Participants received either colesevelam or placebo for 12 days, with dose adjustment in the first 5 days. Researchers measured remission using stool diaries and compared results between the two groups.

How effective was colesevelam in the trial?

Among patients with C4-confirmed bile acid diarrhoea, 64% on colesevelam achieved remission compared with 16% on placebo. In patients diagnosed by SeHCAT, 59% on colesevelam achieved remission versus 13% on placebo. This means colesevelam was about 9 to 11 times more likely to produce remission than placebo.

Who was eligible for the SINBAD trial?

Patients were aged 18 to 79, did not have inflammatory bowel disease, and were already being referred for SeHCAT testing because a doctor suspected bile acid diarrhoea. Before randomisation, everyone kept a 6-day stool diary confirming diarrhoea, defined as an average of 3 or more total bowel movements or at least 1 watery stool per day.

How quickly can colesevelam relieve symptoms?

In the SINBAD trial, treatment lasted 12 days. The dose was adjusted during the first 5 days, and remission was assessed during days 6 through 12. Remission meant having fewer than 3 total bowel movements and fewer than 1 watery bowel movement per day. Two-thirds of C4-confirmed patients achieved remission during this short period.

Source Information

Original Article: "Efficacy and safety of colesevelam for the treatment of bile acid diarrhoea: a double-blind, randomised, placebo-controlled, phase 4 clinical trial"

Authors: Christian Borup, Lars Vinter-Jensen, Søren Peter German Jørgensen, Signe Wildt, Jesper Graff, Tine Gregersen, Anna Zaremba, Trine Borup Andersen, Camilla Nøjgaard, Hans Bording Timm, Dominique Rainteau, Svend Høime Hansen, Jüri Johannes Rumessen, Lars Kristian Munck

Journal: The Lancet Gastroenterology & Hepatology, published online February 6, 2023

DOI: https://doi.org/10.1016/S2468-1253(22)00401-0

Funding: Fabrikant Vilhelm Pedersen og hustrus mindelegat; recommended by the Novo Nordisk Foundation. The funders had no role in study design, data collection, analysis, interpretation, or writing of the report.

Trial Registration: ClinicalTrials.gov, NCT03876717; EudraCT, 2016–001452–22

Copyright: © 2023 Published by Elsevier Ltd. All rights reserved.

This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not constitute medical advice. Always consult your healthcare provider about diagnosis and treatment options.