Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study.

Abstract

BACKGROUND:

HIV-associated diarrhea remains a significant concern with limited treatment options.

OBJECTIVE:

To determine the optimal dose, efficacy, and safety of crofelemer for noninfectious diarrhea.

METHODS:

This randomized, double-blind, phase 3 trial used a 2-stage design. Both stages included 2-week screening, 4-week placebo-controlled treatment, and 20-week placebo-free (open-label) extension phases. In stage I, 196 HIV-seropositive patients with chronic diarrhea were randomized to crofelemer 125 mg, 250 mg, or 500 mg or placebo twice daily. Using a prospective analysis, the 125-mg twice-daily dose was selected for stage II. In stage II, 180 new patients were randomized to crofelemer 125 mg twice daily or placebo for 4 weeks. Primary efficacy analysis was the percentage of patients (stages I/II combined) who achieved clinical response (defined as ≤2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response (≤2 watery stools) was assessed weekly.

RESULTS:

Significantly more patients receiving crofelemer 125 mg achieved clinical response versus placebo (17.6% vs 8.0%; one-sided, P = .01). Crofelemer 125 mg resulted in a greater change from baseline in number of daily watery bowel movements (P = .04) and daily stool consistency score (P = .02) versus placebo. During the placebo-free extension phase, percentages of weekly responders ranged from 40% to 56% at weeks 11 to 24. Crofelemer was minimally absorbed, well tolerated, did not negatively impact clinical immune parameters, and had a safety profile comparable to placebo.

CONCLUSIONS:

In HIV-seropositive patients taking stable antiretroviral therapy, crofelemer provided significant improvement in diarrhea with a favorable safety profile.

• Authors: Rodger D Macarthur, Trevor N Hawkins, Stephen J Brown, Anthony Lamarca, Patrick G Clay, Andrew C Barrett, Enoch Bortey, Craig Paterson, Pamela L Golden, William P Forbes
• Journal: HIV clinical trials (HIV Clin Trials) 2013 Nov-Dec Vol. 14 Issue 6 Pg. 261-73 ISSN: 1528-4336 [Print] England
• PMID: 24334179 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Chloride Channels
• Gastrointestinal Agents
• Proanthocyanidins
• crofelemer

Topics

• Adult
• Chloride Channels (antagonists & inhibitors)
• Diarrhea (drug therapy, etiology)
• Double-Blind Method
• Female
• Gastrointestinal Agents (adverse effects, therapeutic use)
• HIV Infections (complications)
• Humans
• Male
• Middle Aged
• Proanthocyanidins (adverse effects, therapeutic use)