Colesevelam effective in the treatment of bile acid Diarrhea: Lancet

Colesevelam outperformed placebo in causing remission of bile acid diarrhea with a Plasma 7a-hydroxy-4-cholesten-3-one (C4) concentration greater than 46 ng/mL, says an article published in The Lancet Gastroenterology & Hepatology.

Bile acid diarrhea is a prevalent yet underappreciated cause of prolonged watery diarrhea. The plasma 7-hydroxy-4-cholesten-3-one test can be used instead of the gold standard tauroselcholic [75Se] acid (SeHCAT) test. Sequestrant therapy, including colesevelam, is supported by evidence of low confidence. As a result, Christian Borup and his colleagues undertook this trial to assess the effectiveness and safety of colesevelam in bile acid diarrhea.

Consecutive patients aged 18-79 years were included in this randomized, placebo-controlled, double-blind, investigator-initiated phase 4 study of the sequestrant colesevelam in bile acid diarrhea (SINBAD) at four Danish secondary care facilities. Participants were randomly assigned to either colesevelam (overencapsulated tablets of 625 mg) or placebo for 12 days, with a starting dosage of two capsules twice daily titrated to effect over the first 5 days of therapy. Using block randomization, a pharmacist independent of the trial investigators developed a randomization list on the website randomization.com. During therapy, the C4 and SeHCAT test findings were kept hidden. Diarrhea was treated in all patients, with a daily mean of 30 or more bowel movements or 10 or more watery stool movements. On therapy days 6-12, remission was defined as the absence of both of these criteria. The primary outcome was the incidence of remission in patients with bile acid diarrhea identified by a C4 concentration more than 46 ng/mL. The intention-to-treat remission rate in bile acid diarrhea identified by SeHCAT retention of 10% or less was a secondary outcome.

The key findings of this study were:

1. 168 individuals were randomly randomized to receive colesevelam (n=84) or placebo (n=84) between October 25, 2018, and July 1, 2021.

2. C4 concentrations in 41 individuals exceeded 46 ng/mL.

3. For the C4-defined main outcome, 14 (64%) of 22 people receiving colesevelam achieved remission vs three (16%) of 19 persons receiving placebo.

4. Regarding the SeHCAT-defined secondary endpoint, 75 of the 168 patients had retention of less than 10%; 22 (59%) of 37 colesevelam participants achieved remission vs five (13%) of 38 placebo participants.

5. There were no significant adverse occurrences.

6. The majority of adverse effects were transitory.

7. In the primary outcome population, five individuals had stomach discomfort, nine experienced bloating, and four experienced nausea.

8. Four individuals receiving placebo experienced stomach discomfort, four experienced bloating, and one experienced nausea.

9. Due to adverse effects, no subjects with bile acid diarrhea withdrew.

Reference:

Borup, C., Vinter-Jensen, L., Jørgensen, S. P. G., Wildt, S., Graff, J., Gregersen, T., Zaremba, A., Borup Andersen, T., Nøjgaard, C., Timm, H. B., Rainteau, D., Hansen, S. H., Rumessen, J. J., & Munck, L. K. (2023). Efficacy and safety of colesevelam for the treatment of bile acid diarrhoea: a double-blind, randomised, placebo-controlled, phase 4 clinical trial. In The Lancet Gastroenterology & Hepatology (Vol. 8, Issue 4, pp. 321–331). Elsevier BV. https://doi.org/10.1016/s2468-1253(22)00401-0