Colon to Rectum
Lancet Gastroenterol Hepatol. 2023;8(4):321−31
Efficacy and safety of colesevelam for the treatment of bile acid diarrhea: A double-blind, randomized, place-bo-controlled, phase 4 clinical trial
Background: Bile acid diarrhea is a common but overlooked cause of chronic watery diarrhea. Plasma 7α-hydroxy-4-cholesten-3-one (C4) is an alternative to the gold standard tauroselcholic (75Se) acid (SeHCAT) test. Low-certainty evidence supports sequestrant treatment, including co-lesevelam. The authors aimed to determine the efficacy and safety of colesevelam in bile acid diarrhea.
Methods: In this randomized, double-blind, placebo-controlled, investigator-initiated phase 4 trial of the sequestrant colesevelam in bile acid diarrhea (SINBAD), they enrolled consecutive patients aged 18−79 years without inflammatory bowel disease attending SeHCAT testing for sus-pected bile acid diarrhea at 4 Danish secondary care centers. Participants were randomly allocated 1:1 to receive 12 days of treatment with co-lesevelam (over-encapsulated tablets of 625 mg) or placebo, with the starting dose of 2 capsules twice daily and titrated to effect during the first 5 days of treatment. A pharmacist independent of the clinical investigators generated a randomization list on the web page randomization.com using block randomization (randomization was not stratified). C4 and SeHCAT diagnostic results were blinded during treatment. The authors treated all patients with diarrhea, with a daily mean of 3.0 or more bowel movements or 1.0 or more watery bowel movements (Bristol stool scale type 6 and 7). Remission was defined as the absence of both these criteria during treatment days 6−12. The primary outcome was the in-tention-to-treat remission rate in bile acid diarrhea diagnosed by C4 concentration greater than 46 ng/ml. A secondary outcome was the inten-tion-to-treat remission rate in bile acid diarrhea diagnosed by SeHCAT retention of 10% or less.
Findings: Between October 25, 2018, and July 1, 2021, 168 patients were randomly assigned to receive colesevelam (n = 84) or placebo (n = 84). 41 patients had C4 concentration greater than 46 ng/ml (22 assigned to the colesevelam group and 19 to the placebo group). For the C4-defined primary outcome, 14 of 22 participants (64%) receiving colesevelam versus 3 of 19 participants (16%) receiving placebo achieved remission (ad-justed odds ratio [aOR] = 9.1, 95% confidence interval [CI]: 1.9−62.8; p = 0.011). For the SeHCAT-defined secondary outcome, 75 of the 168 participants had retention of less than 10% (37 assigned to the colesevelam group and 38 assigned to the placebo group); 22 of 37 participants (59%) receiving colesevelam achieved remission versus 5 of 38 participants (13%) receiving placebo (aOR = 11.1, 95% CI: 3.4−45.6; p = 0.00020). There were no serious adverse events. Common adverse events were transient. For patients receiving colesevelam within the primary outcome population, 5 had abdominal pain, 9 had bloating, and 4 had nausea. For patients receiving placebo, 4 had abdominal pain, 4 had bloating, and 1 had nausea. No participants with bile acid diarrhea withdrew due to adverse events.
Interpretation: Colesevelam was superior to placebo at inducing remission of bile acid diarrhea diagnosed with C4 concentration greater than 46 ng/ml. Secondary outcome data suggest similar efficacy treating SeHCAT-defined bile acid diarrhea. Colesevelam was safe during the treatment.