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

Rodger David MacArthur, Trevor Hawkins, Stephen Brown, Anthony Lamarca, Patrick Clay, Andrew Barrett, Enoch Bortey, Craig Paterson, Pamela Golden, William Forbes

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 â‰2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response (â‰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.

Original languageEnglish (US)
Pages (from-to)261-273
Number of pages13
JournalHIV Clinical Trials
Volume14
Issue number6
DOIs
StatePublished - Jan 1 2013

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Diarrhea
Placebos
HIV
Safety
crofelemer
Therapeutics

Keywords

  • HIV
  • antidiarrheals
  • antiretroviral agents
  • chloride channels
  • diarrhea
  • drug toxicity
  • proanthocyanidins

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT Trial) : A randomized, double-blind, placebo-controlled, two-stage study. / MacArthur, Rodger David; Hawkins, Trevor; Brown, Stephen; Lamarca, Anthony; Clay, Patrick; Barrett, Andrew; Bortey, Enoch; Paterson, Craig; Golden, Pamela; Forbes, William.

In: HIV Clinical Trials, Vol. 14, No. 6, 01.01.2013, p. 261-273.

Research output: Contribution to journalArticle

MacArthur, Rodger David ; Hawkins, Trevor ; Brown, Stephen ; Lamarca, Anthony ; Clay, Patrick ; Barrett, Andrew ; Bortey, Enoch ; Paterson, Craig ; Golden, Pamela ; Forbes, William. / Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT Trial) : A randomized, double-blind, placebo-controlled, two-stage study. In: HIV Clinical Trials. 2013 ; Vol. 14, No. 6. pp. 261-273.
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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 {\^a}‰2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response ({\^a}‰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.",
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AU - Hawkins, Trevor

AU - Brown, Stephen

AU - Lamarca, Anthony

AU - Clay, Patrick

AU - Barrett, Andrew

AU - Bortey, Enoch

AU - Paterson, Craig

AU - Golden, Pamela

AU - Forbes, William

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AB - 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 â‰2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response (â‰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.

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KW - antidiarrheals

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KW - chloride channels

KW - diarrhea

KW - drug toxicity

KW - proanthocyanidins

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