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

Asbjørn Mohr Drewes

Status and phase: Completed; Phase 3; Phase 2

Conditions: Acute Pancreatitis

Treatments: Drug: Placebo treatment; Drug: Methylnaltrexone treatment

Study type: Interventional

Funder types: Other

Identifiers

NCT04743570

2020-002313-18 (EudraCT Number)

N-20200060 (Other Identifier)

PAMORA_AP, PAMORA-1

Details and patient eligibility

About

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).

Full 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.

Enrollment: 105 patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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105 participants in 2 patient groups, including a placebo group

Placebo treatment

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo treatment

Methylnaltrexone treatment

Active Comparator group

Description:

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.

Treatment:

Drug: Methylnaltrexone treatment