title: 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: Division of Infectious Diseases, Wayne State University, Detroit, Michigan.
authors: Rodger D
authors: RD
authors: Macarthur
authors: Southwest CARE, Santa Fe, New Mexico.
authors: Trevor N
authors: TN
authors: Hawkins
authors: AIDS Research Alliance, Los Angeles, California.
authors: Stephen J
authors: SJ
authors: Brown
authors: Therafirst Medical Center, Fort Lauderdale, Florida.
authors: Anthony
authors: A
authors: Lamarca
authors: University of North Texas System College of Pharmacy, Fort Worth, Texas.
authors: Patrick G
authors: PG
authors: Clay
authors: Salix Pharmaceuticals, Inc, Raleigh, North Carolina.
authors: Andrew C
authors: AC
authors: Barrett
authors: Salix Pharmaceuticals, Inc, Raleigh, North Carolina.
authors: Enoch
authors: E
authors: Bortey
authors: Salix Pharmaceuticals, Inc, Raleigh, North Carolina.
authors: Craig
authors: C
authors: Paterson
authors: Salix Pharmaceuticals, Inc, Raleigh, North Carolina.
authors: Pamela L
authors: PL
authors: Golden
authors: Salix Pharmaceuticals, Inc, Raleigh, North Carolina.
authors: William P
authors: WP
authors: Forbes
mesh_terms: D000328:Adult; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D003967:Diarrhea / Q000188:drug therapy* / Q000209:etiology; D004311:Double-Blind Method; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D008297:Male; D008875:Middle Aged; D044945:Proanthocyanidins / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D018118:Chloride Channels; D005765:Gastrointestinal Agents; D044945:Proanthocyanidins; C546704:crofelemer
keywords: HIV; antidiarrheals; antiretroviral agents; chloride channels; diarrhea; drug toxicity; proanthocyanidins