Clinical Trial: Efficacy and Safety of Velusetrag in Chronic Intestinal Pseudo-Obstruction: A Randomized, Phase 2, Placebo-Controlled, Crossover, Multiple (n = 1), Proof-of-Concept Study.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a rare, severe disorder of gastrointestinal motility. Although 5-hydroxytryptamine type 4 (5-HT4) receptor agonists stimulate gastrointestinal motility, few trials have assessed their therapeutic effects in patients with CIPO. AIM: To assess the efficacy and safety of velusetrag, a highly selective 5-HT4 receptor agonist, in patients with CIPO. METHODS: This was a phase 2, placebo-controlled, crossover, multiple (n = 1), multicenter, double-blind, proof-of-concept trial. Eligible patients were aged 18-80 years, had CIPO (idiopathic or secondary to neurodegenerative disorders) and received ≥ 30% of their daily caloric intake orally. Over four periods, each of four weeks, patients were randomly assigned to once-daily, oral velusetrag 15 mg (two periods) or placebo (two periods), with a 2-week washout between each treatment period. The primary endpoint was the improvement in the weekly global gastrointestinal symptoms average index score (WGGSAIS) from the start to the end of each treatment period, assessed among patients who were responders or naive to previous 5-HT4 receptor agonist treatment. RESULTS: Overall, 17 patients with idiopathic CIPO received treatment and were included in safety analyses; efficacy was assessed in 15 patients. Mean (standard deviation) changes in WGGSAIS during treatment were -0.42 (0.693) for velusetrag and -0.19 (0.688) for placebo (between-treatment difference: -0.24; 95% confidence interval: -0.553, 0.074; p = 0.1279). No deaths or serious or treatment-related treatment-emergent adverse events were reported. CONCLUSION: Velusetrag treatment was associated with improved symptoms versus placebo, although differences were not statistically significant at this sample size. Velusetrag was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05724069; EudraCT number: 2021-000854-24.