Abstract
BackgroundModerate to severe acute pancreatitis (AP) is associated with a high rate of complications and increased mortality, yet no targeted pharmacologic treatment currently exists. As pain is a dominant symptom in AP, patients are exposed to excess levels of both endo- and exogenous opioids, which may have harmful effects on the course of AP. This trial investigates the effects of the peripherally acting μ-opioid receptor antagonist (PAMORA) methylnaltrexone on disease severity and clinical outcomes in patients with moderate to severe AP.MethodsPAMORA-AP is a multicentre, investigator-initiated, double-blind, randomised, placebo-controlled, interventional trial, which will be conducted at four referral centres for acute pancreatitis in Denmark. Ninety patients with early-onset AP (pain onset within 48 h) as well as predicted moderate to severe disease (two or more systemic inflammatory response syndrome criteria upon admission) will be prospectively included. Subsequently, participants will be randomised (1:1) to intravenous treatment with either methylnaltrexone or matching placebo (Ringer’s lactate) during 5 days of admission. The primary endpoint will be the group difference in disease severity as defined and measured by the Pancreatitis Activity Scoring System (PASS) score 48 h after randomisation. Secondary endpoints include daily PASS scores; disease severity according to the Atlanta classification; quantification of need for analgesics, nutritional support, intravenous fluid resuscitation and antibiotics; duration of hospital admissions, readmission rates and mortality. Pain intensity and gut function will be self-reported using validated questionnaires. Exploratory endpoints include circulating levels of pro-and anti-inflammatory markers, polyethylene glycol recovery from the urine, circulating levels of blood markers of intestinal permeability, the prevalence of pancreatic complications on computed tomography (CT) scans, and colon transit time assessed using a CT-based radiopaque marker method.DiscussionThis trial aims to evaluate the PAMORA methylnaltrexone as a novel targeted pharmacotherapy in patients with moderate to severe AP with the potential benefit of improved patient outcomes.Trial registrationClinicalTrials.govNCT04743570. Registered on 28 January 2021. EudraCT 2020-002313-18.
Highlights
Background and rationale {6a} Acute pancreatitis (AP) is a frequent gastrointestinal disease [1, 2]
Moderate to severe acute pancreatitis (AP) carries a high rate of complications and mortality as high as 40–50% in patients with persistent organ failure and infected pancreatic necrosis [3, 4]
10% of patients progress towards chronic pancreatitis after just one occurrence of clinical AP, and this rate may increase to 36% in the presence of recurrent AP [48]
Summary
Study setting {9} PAMORA-AP will be conducted at four referral centres for acute pancreatitis in Denmark (Aalborg University Hospital, Odense University Hospital, Copenhagen University Hospital Hvidovre, and Bispebjerg Hospital). From the trial participants’ medical records, the following will be registered: (i) presence of local and systemic complications as well as organ failure (transient or persistent), used to classify the severity of AP according to the revised Atlanta criteria [25]; (ii) need for intensive care unit admission; (iii) need for analgesics; (iv) nutritional support; (v) need for intravenous fluid resuscitation or antibiotics; (vi) invasive treatments; (vii) duration of hospitalisation; (viii) readmissions; and (ix) mortality. Plans to promote participant retention and complete follow-up {18b} IMP administration, blood sample results, vital signs, and concomitant medication will be registered within the trial participants’ medical records as part of their standard treatment, and subsequently transferred to the eCRF. All samples will be destroyed 15 years after the conclusion of the trial at the latest
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