TY - JOUR

T1 - Effects of the peripherally acting μ-opioid receptor antagonist methylnaltrexone on acute pancreatitis severity

T2 - study protocol for a multicentre double-blind randomised placebo-controlled interventional trial, the PAMORA-AP trial

AU - Knoph, Cecilie Siggaard

AU - Cook, Mathias Ellgaard

AU - Fjelsted, Camilla Ann

AU - Novovic, Srdan

AU - Mortensen, Michael Bau

AU - Nielsen, Liv Bjerre Juul

AU - Hansen, Mark Berner

AU - Frøkjær, Jens Brøndum

AU - Olesen, Søren Schou

AU - Drewes, Asbjørn Mohr

N1 - Funding Information: On behalf of the PAMORA trial group, we extend our acknowledgements to our collaborators for their invaluable contribution. Ole Thorlacius-Ussing (Department of Gastrointestinal Surgery, Aalborg University Hospital, Denmark), Lone Schmidt S?rensen (Department of Gastrointestinal Surgery, Aalborg University Hospital, Denmark), Annette Aggerholm Overbye (Department of Gastrointestinal Surgery, Aalborg University Hospital, Denmark), Ann Hauberg (Department of Gastrointestinal Surgery, Aalborg University Hospital, Denmark), Celina Salomon (Department of Surgery, Odense University Hospital, Svendborg, Denmark), Irene Maria H?gsberg (Department of Surgery, Odense University Hospital, Svendborg, Denmark), Mohamad Ali Abdul Ghani (Department of Surgery, Odense University Hospital, Svendborg, Denmark), Sandie J?nch M?ller (Digestive Disease Center K, Bispebjerg University Hospital of Copenhagen, Denmark), Mette Brogaard Barrit (Digestive Disease Center K, Bispebjerg University Hospital of Copenhagen, Denmark), Karen Lisa Hilsted (Gastrounit, Hvidovre University Hospital of Copenhagen, Denmark), Camilla M?ller Vorsholt (Gastrounit, Hvidovre University Hospital of Copenhagen, Denmark), Joy Stinne Timmner (Gastrounit, Hvidovre University Hospital of Copenhagen, Denmark), Morten Laks?foss Lauritsen (Gastrounit, Hvidovre University Hospital of Copenhagen, Denmark), Mariam Lahchich (Gastrounit, Hvidovre University Hospital of Copenhagen, Denmark) and Lamiae El Rhali (Gastrounit, Hvidovre University Hospital of Copenhagen, Denmark). The trial was conceived and initiated by AMD (sponsor) and SSO. CSK drafted the manuscript supported by SSO and AMD. All authors have participated in designing the trial and revising the manuscript. Furthermore, all authors read and approved the final manuscript before submission. No professional writers have been involved in the drafting of this manuscript. Grant of 7.3 MIO DKK by the Novo Nordisk Foundation (#NNF190C0057331). Alternatively, Mech-Sense, Aalborg University Hospital, will cover the expenses. The Novo Nordisk Foundation does not have any specific rights related to the publication of the results. No researchers involved in this trial have an economic interest in the Novo Nordisk Foundation or other financial supporters of this trial. As overall coordinating centre Mech-sense, Aalborg University Hospital, will have full access to the final trial dataset through REDCap. In contrast, each trial centre will have access to the data collected at the respective sites. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Background: Moderate 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. Methods: PAMORA-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. Discussion: This 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 registration: ClinicalTrials.govNCT04743570. Registered on 28 January 2021. EudraCT 2020-002313-18.

AB - Background: Moderate 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. Methods: PAMORA-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. Discussion: This 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 registration: ClinicalTrials.govNCT04743570. Registered on 28 January 2021. EudraCT 2020-002313-18.

KW - Acute pancreatitis

KW - Drug antagonism

KW - Methylnaltrexone

KW - Opioid antagonists

KW - Randomised controlled trial

KW - Treatment

U2 - 10.1186/s13063-021-05885-3

DO - 10.1186/s13063-021-05885-3

M3 - Journal article

C2 - 34924020

AN - SCOPUS:85121440542

VL - 22

JO - Trials

JF - Trials

SN - 1745-6215

IS - 1

M1 - 940

ER -