Naldemedine for the Prevention of Recurrent Acute Pancreatitis: A Randomised, Double‐Blind, Placebo‐Controlled Trial

BACKGROUND AND AIMS: No medications are currently approved for the prevention of recurrent acute pancreatitis. This trial evaluated whether naldemedine, a peripherally acting μ-opioid receptor antagonist, reduces the risk of acute pancreatitis in patients with recurrent acute pancreatitis. METHODS: This was a multicentre, double-blinded, placebo-controlled randomised trial conducted at four Danish pancreatitis referral centres. Participants aged 18-75 years with recurrent acute pancreatitis, both with and without a diagnosis of chronic pancreatitis, were randomised to receive naldemedine 0.2 mg or a matching placebo daily for up to 12 months. The primary outcome was acute pancreatitis recurrence, defined by the revised Atlanta Criteria. Secondary outcomes included pain flares, gastrointestinal symptoms, and quality of life. At the end of follow-up, the participant's global impression of change, safety and tolerability outcomes, new-onset diabetes and pancreatic exocrine insufficiency were assessed. RESULTS: 74 participants (mean age: 46 years; 41% female) were randomised to naldemedine (n = 36) or placebo (n = 38). During a median follow-up time of 365 days (IQR, 352-370), participants in the naldemedine group had a numerically lower risk of acute pancreatitis compared to placebo (HR 0.54; 95% CI, 0.29-1.01; p = 0.05). No differences were observed between the groups for secondary efficacy, safety, and tolerability outcomes. Participants treated with naldemedine for at least 1 year had a lower risk of acute pancreatitis (HR 0.49; 95% CI, 0.24-0.97; p = 0.04). CONCLUSIONS: Treatment with naldemedine was safe and well-tolerated and may reduce the risk of recurrent acute pancreatitis. A larger confirmatory trial is needed to verify these findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: PAMORA-RAP: NCT04966559.