Effects of Peripherally Acting µ-opioid Receptor Antagonists on Acute Pancreatitis

NCT ID: NCT04743570

Last Updated: 2023-04-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 105 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-05-14
• Study Completion Date: 2023-04-20

Brief Summary

This study will investigate the effect of peripheral acting opioid antagonist (PAMORA) on the disease course of patients with acute inflammation of the pancreas (acute pancreatitis). The study will be conducted by treating hospitalized patients with acute pancreatitis with a PAMORA (methylnaltrexone).

Detailed Description

In this study, the effects of peripheral acting µ-opioid receptor antagonists (PAMORA) on disease development and progression in patients with acute pancreatitis (AP) will be investigated. Patients with AP will be administered Methylnaltrexone (Relistor®) intravenously. This medication is defined as the investigational product. Relistor® is approved and sold on the Danish marked for treatment of opioid-induced constipation. This PAMORA have not previously been investigated in patients with pancreatitis. The dose regimes for this study will be according to label. It has previously been shown, in patients with opioid-induced obstipation and healthy subjects, that opioid antagonism incl. PAMORA treatment increases gut motility, relaxes gastrointestinal sphincters, increases the intestinal water content and improves the immune response, without affecting analgesia. The affinity of PAMORAs to the µ-opioid receptors is much stronger than opioid analgesics. Therefore, they as antagonists have the potential to counteract the harmful effects of opioids on the gut mucosa, bacterial translocation and inflammation despite the high levels of exogenous opioids present in patients with pancreatitis. PAMORAs do not cross the blood-brain barrier and consequently do not interfere with analgesia or other central effects of opioids.

We hypothesize that treatment with the PAMORA methylnaltrexone will antagonize the harmful effects of opioids without reducing analgesia in patients with AP and hence reduce disease severity and improve clinical outcomes. If successful, this sub-study will for the first time document the effects of a targeted pharmacotherapy in AP with the potential benefit of improved patient outcomes.

Conditions

Acute Pancreatitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo treatment

Placebo consisting of Ringer's lactate in matched volume to active drug is added to 1000 mL Ringer's lactate solution and given as a continues infusion over 24 hours using an infusion pump.

Group Type: PLACEBO_COMPARATOR

Placebo treatment

Intervention Type: DRUG

Active drug/placebo is given for the first 5 days of admission.

Methylnaltrexone treatment

0.15 mg/kg methylnaltrexone will be dissolved in 1000 mL Ringer's lactate solution and given as a continues infusion over 24 hours using an infusion pump.

Group Type: ACTIVE_COMPARATOR

Methylnaltrexone treatment

Intervention Type: DRUG

Active drug/placebo is given for the first 5 days of admission.

Interventions

Placebo treatment

Active drug/placebo is given for the first 5 days of admission.

Intervention Type: DRUG

Methylnaltrexone treatment

Active drug/placebo is given for the first 5 days of admission.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Signed informed consent before any study specific procedures
• Able to read and understand Danish
• Male or female age between 18 and 80 years
• The researcher believes that the participant understands what the study entails, is capable of following instructions, can attend when needed, and is expected to complete the study
• The investigator will ensure that fertile female participants have a negative pregnancy test before treatment initiation and use contraception during the study period. The following methods of contraception, if properly used, are generally considered reliable: oral contraceptives, patch contraceptives, injection contraceptives, vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral tubal ligation), vasectomized partner, double barrier (condom and pessary), or sexual abstinence. Methods of contraception will be documented in the source documents
• At least two of the following criteria need to be fulfilled to establish a diagnosis of AP (according to the revised Atlanta criteria (16)): i) abdominal pain consistent with AP (acute onset of a persistent, severe, epigastric pain often radiating to the back); ii) serum amylase activity at least three times greater than the upper limit of normal; and iii) characteristic findings of AP on diagnostic imaging
• Predicted moderate or severe AP based on 2 or more systemic inflammatory response syndrome criteria upon admission

Exclusion Criteria

• Definitive chronic pancreatitis according to the M-ANNHEIM criteria
• Known allergy towards study medication
• Known or suspected major stenosis or perforation of the intestines
• Known or suspected abdominal cancer (incl. intestine, pancreas and the biliary tree)
• Pre-existing renal insufficiency (defined as habitual estimated glomerular filtration rate below 45)
• Severe pre-existing comorbidities (assessed by investigator upon inclusion)
• Severe non-pancreaticobiliary infections or sepsis caused by non-pancreaticobiliary disease
• Child-Pugh class B or C liver cirrhosis
• Females that are currently lactating

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Odense University Hospital

OTHER

Sponsor Role: collaborator

Hvidovre University Hospital

OTHER

Sponsor Role: collaborator

University Hospital Bispebjerg and Frederiksberg

OTHER

Sponsor Role: collaborator

Asbjørn Mohr Drewes

OTHER

Sponsor Role: lead

Responsible Party

Asbjørn Mohr Drewes

Professor, Chief Physician, MD, PhD, DMSc

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Asbjørn M. Drewes, Professor

Role: STUDY_CHAIR

Mech-Sense, Department of Medical Gastroenterology, Aalborg Hospital

Locations

Mech-Sense, Department of Medical Gastroenterology, Aalborg University Hospital

Aalborg, Jutland, Denmark

Digestive Disease Center K, Bispebjerg University Hospital

Bispebjerg, , Denmark

Gastrounit, Hvidovre University Hospital

Hvidovre, , Denmark

Odense Pancreas Center

Svendborg, , Denmark

Countries

Denmark

References

Knoph CS, Cook ME, Novovic S, Hansen MB, Mortensen MB, Nielsen LBJ, Hogsberg IM, Salomon C, Neergaard CEL, Aajwad AJ, Pandanaboyana S, Sorensen LS, Thorlacius-Ussing O, Frokjaer JB, Olesen SS, Drewes AM. No Effect of Methylnaltrexone on Acute Pancreatitis Severity: A Multicenter Randomized Controlled Trial. Am J Gastroenterol. 2024 Nov 1;119(11):2307-2316. doi: 10.14309/ajg.0000000000002904. Epub 2024 Jun 25.

Reference Type: DERIVED

PMID: 38916223 (View on PubMed)

Knoph CS, Cook ME, Fjelsted CA, Novovic S, Mortensen MB, Nielsen LBJ, Hansen MB, Frokjaer JB, Olesen SS, Drewes AM. Effects of the peripherally acting mu-opioid receptor antagonist methylnaltrexone on acute pancreatitis severity: study protocol for a multicentre double-blind randomised placebo-controlled interventional trial, the PAMORA-AP trial. Trials. 2021 Dec 19;22(1):940. doi: 10.1186/s13063-021-05885-3.

Reference Type: DERIVED

PMID: 34924020 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2020-002313-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

N-20200060

Identifier Type: OTHER

Identifier Source: secondary_id

PAMORA_AP, PAMORA-1

Identifier Type: -

Identifier Source: org_study_id