Effect of Bismuth Subsalicylate on Gastrointestinal Tolerability in Healthy Volunteers Receiving Oral Delayed-release Dimethyl Fumarate: PREVENT, a Randomized, Multicenter, Double-blind, Placebo-controlled Study

Abstract

Purpose: Flushing and gastrointestinal (GI) events are commonly associated with the use of delayed-release dimethyl fumarate (DMF) treatment for relapsing multiple sclerosis.

Methods: PREVENT (A Multicenter, Double-Blind, Placebo-Controlled Study of Pepto-Bismol [Bismuth Subsalicylate] on Gastrointestinal Tolerability in Healthy Volunteers Receiving Oral TECFIDERA [Dimethyl Fumarate] Delayed-Release Capsules Twice Daily) is a double-blind, placebo-controlled, 8-week study that evaluated the effect of bismuth subsalicylate on DMF-related GI events. Bismuth subsalicylate 524 mg or placebo were administered 30 min before DMF (weeks 1-4). DMF was dosed twice-daily (BID) at 120 mg (week 1) and 240 mg (weeks 2-8). Using an e-diary device, participants recorded GI and flushing events on the Modified Overall Gastrointestinal Symptom Scale once daily for the preceding 24 h. The primary end point was time to first GI-related event. Secondary end points included frequency and severity of GI-related events.

Findings: A total of 175 participants were enrolled (placebo, n = 87; bismuth subsalicylate, n = 88), and 17 discontinued treatment (placebo, n = 8; bismuth subsalicylate n = 9). A total of 146 participants reported ≥1 GI event: placebo, n = 72 (82.8%); and bismuth subsalicylate, n = 74 (84.1%). There was no statistical difference in risk of a GI event between the groups (P = 0.8292). Mean (SD) time from DMF initiation to first GI event was similar: placebo, 5.4 (8.73) days; and bismuth subsalicylate, 5.6 (10.87) days. Incidence of flatulence (38.6% vs 50.6%) and diarrhea (36.4% vs 48.2%) during weeks 1-4 was numerically lower in the bismuth subsalicylate group compared with the placebo group. Mean worst severity scores for flatulence (1.1 vs 1.8; P = 0.0219) and diarrhea (1.0 vs 1.6; P = 0.0500) were lower with bismuth subsalicylate than with placebo.

Implications: Although coadministration of bismuth subsalicylate did not affect the occurrence of DMF-related GI events overall, it reduced the severity and incidence of flatulence and diarrhea. ClinicalTrials.gov identifier: NCT01915901.

Keywords: adverse drug event; bismuth subsalicylate; dimethyl fumarate; gastrointestinal agents; relapsing-remitting multiple sclerosis.