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

HIV Clin Trials. Nov-Dec 2013;14(6):261-73. doi: 10.1310/hct1406-261.

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.

Keywords: HIV; antidiarrheals; antiretroviral agents; chloride channels; diarrhea; drug toxicity; proanthocyanidins.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Chloride Channels
  • Gastrointestinal Agents
  • Proanthocyanidins
  • crofelemer