Daniel A Leffler1, Ciaran P Kelly1, Peter H R Green2, Richard N Fedorak3, Anthony DiMarino4, Wendy Perrow5, Henrik Rasmussen5, Chao Wang5, Premysl Bercik6, Natalie M Bachir7, Joseph A Murray8. 1. The Celiac Center at Beth Israel Deaconess Medical Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. 2. Celiac Disease Center at Columbia University, New York, New York. 3. Center of Excellence for Gastrointestinal Immunity and Inflammation Research, University of Alberta, Edmonton, Alberta, Canada. 4. Thomas Jefferson University, Philadelphia, Pennsylvania. 5. Alba Therapeutics Corporation, Baltimore, Maryland. 6. McMaster University, Hamilton, Ontario, Canada. 7. Essentia Health Duluth Clinic, Duluth, Minnesota. 8. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address: Murray.joseph@mayo.edu.
Abstract
BACKGROUND & AIMS: Celiac disease (CeD) is a prevalent autoimmune condition. Recurrent signs and symptoms are common despite treatment with a gluten-free diet (GFD), yet no approved or proven nondietary treatment is available. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study, we assessed larazotide acetate 0.5, 1, or 2 mg 3 times daily to relieve ongoing symptoms in 342 adults with CeD who had been on a GFD for 12 months or longer and maintained their current GFD during the study. The study included a 4-week placebo run-in, 12 weeks of treatment, and a 4-week placebo run-out phase. The primary end point was the difference in average on-treatment Celiac Disease Gastrointestinal Symptom Rating Scale score. RESULTS: The primary end point was met with the 0.5-mg dose of larazotide acetate, with fewer symptoms compared with placebo by modified intention to treat (n = 340) (analysis of covariance, P = .022; mixed model for repeated measures, P = .005). The 0.5-mg dose showed an effect on exploratory end points including a 26% decrease in celiac disease patient-reported outcome symptomatic days (P = .017), a 31% increase in improved symptom days (P = .034), a 50% or more reduction from baseline of the weekly average abdominal pain score for 6 or more of 12 weeks of treatment (P = .022), and a decrease in the nongastrointestinal symptoms of headache and tiredness (P = .010). The 1- and 2-mg doses were no different than placebo for any end point. Safety was comparable with placebo. CONCLUSIONS:Larazotide acetate 0.5 mg reduced signs and symptoms in CeD patients on a GFD better than a GFD alone. Although results were mixed, this study was a successful trial of a novel therapeutic agent targeting tight junction regulation in patients with CeD who are symptomatic despite a GFD. Clinicaltrials.gov: NCT01396213.
RCT Entities:
BACKGROUND & AIMS:Celiac disease (CeD) is a prevalent autoimmune condition. Recurrent signs and symptoms are common despite treatment with a gluten-free diet (GFD), yet no approved or proven nondietary treatment is available. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study, we assessed larazotide acetate 0.5, 1, or 2 mg 3 times daily to relieve ongoing symptoms in 342 adults with CeD who had been on a GFD for 12 months or longer and maintained their current GFD during the study. The study included a 4-week placebo run-in, 12 weeks of treatment, and a 4-week placebo run-out phase. The primary end point was the difference in average on-treatment Celiac DiseaseGastrointestinal Symptom Rating Scale score. RESULTS: The primary end point was met with the 0.5-mg dose of larazotide acetate, with fewer symptoms compared with placebo by modified intention to treat (n = 340) (analysis of covariance, P = .022; mixed model for repeated measures, P = .005). The 0.5-mg dose showed an effect on exploratory end points including a 26% decrease in celiac diseasepatient-reported outcome symptomatic days (P = .017), a 31% increase in improved symptom days (P = .034), a 50% or more reduction from baseline of the weekly average abdominal pain score for 6 or more of 12 weeks of treatment (P = .022), and a decrease in the nongastrointestinal symptoms of headache and tiredness (P = .010). The 1- and 2-mg doses were no different than placebo for any end point. Safety was comparable with placebo. CONCLUSIONS:Larazotide acetate 0.5 mg reduced signs and symptoms in CeDpatients on a GFD better than a GFD alone. Although results were mixed, this study was a successful trial of a novel therapeutic agent targeting tight junction regulation in patients with CeD who are symptomatic despite a GFD. Clinicaltrials.gov: NCT01396213.
Authors: Daniel A Leffler; Melinda Dennis; Brian Hyett; Eoin Kelly; Detlef Schuppan; Ciaran P Kelly Journal: Clin Gastroenterol Hepatol Date: 2007-03-26 Impact factor: 11.382
Authors: Douglas E Brenneman; Catherine Y Spong; Janet M Hauser; Daniel Abebe; Albert Pinhasov; Tania Golian; Illana Gozes Journal: J Pharmacol Exp Ther Date: 2004-03-08 Impact factor: 4.030
Authors: Laura Kivelä; Alberto Caminero; Daniel A Leffler; Maria Ines Pinto-Sanchez; Jason A Tye-Din; Katri Lindfors Journal: Nat Rev Gastroenterol Hepatol Date: 2020-11-20 Impact factor: 46.802