Clinical trial NCT04743570: Effects of Peripherally Acting µ-opioid Receptor Antagonists on Acute Pancreatitis
Official title: Effects of Peripherally Acting µ-opioid Receptor Antagonists on Acute Pancreatitis - An Investigator-initiated, Randomized, Placebo-controlled, Double-blind Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Acute Pancreatitis
Lead sponsor: Aalborg University Hospital
Sponsor class: OTHER
Collaborators: name: Odense University Hospital
name: Hvidovre University Hospital
name: University Hospital Bispebjerg and Frederiksberg
First posted: 2021-02-08
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Pancreatitis activity scoring system
timeFrame: 48 hours after randomization
Secondary outcomes:
measure: Pancreatitis activity scoring system
timeFrame: 24 hours after randomization and every 24 hours untill end of study at day 5 (after 120 hours) and again at the day 14 follow-up visit
measure: Difference in assessments of circulating proinflammatory marker
timeFrame: 24 hours after randomization and every 24 hours untill end of study at day 5 (after 120 hours) and again at the day 14 follow-up visit
measure: Difference in assessments of circulating pro- and anti-inflammatory markers
timeFrame: 24 hours after randomization and every 24 hours untill end of study at day 5 (after 120 hours) and again at the day 14 follow-up visit
measure: Intestinal permeability
timeFrame: From 48 to 72 hours after randomization
measure: Intestinal motility
timeFrame: 5 (+/- 1 day) after randomization
measure: Pancreatic complications
timeFrame: Day 5 (+/- 1 day) after randomization
measure: Pain intensity
timeFrame: 24 hours after randomization and every 24 hours untill end of study at day 5 (after 120 hours) and again at the day 14 follow-up visit
measure: Gut function (BSFS)
timeFrame: 24 hours after randomization and every 24 hours untill end of study at day 5 (after 120 hours) and again at the day 14 follow-up visit
measure: Gut function (GSRS)
timeFrame: 24 hours after randomization and every 24 hours untill end of study at day 5 (after 120 hours) and again at the day 14 follow-up visit
measure: Quantification of analgesics
timeFrame: 24 hours after randomization and every 24 hours untill end of study at day 5 (after 120 hours) and again at the day 14 follow-up visit
measure: Use of nutritional support
timeFrame: 24 hours after randomization and every 24 hours untill end of study at day 5 (after 120 hours) and again at the day 14 follow-up visit
measure: Days of hospitalization
timeFrame: Observation period starts from day of randomization and ends after 12 months or on the day of discharge which ever comes first
measure: Use of invasive treatment
timeFrame: Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first
measure: Mortality
timeFrame: Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first
measure: Health resource utilization
timeFrame: Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first
measure: Disease severity
timeFrame: Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Mech-Sense, Department of Medical Gastroenterology, Aalborg University Hospital
state: Jutland
city: Bispebjerg
country: Denmark
facility: Digestive Disease Center K, Bispebjerg University Hospital
city: Hvidovre
country: Denmark
facility: Gastrounit, Hvidovre University Hospital
city: Svendborg
country: Denmark
facility: Odense Pancreas Center
Study officials:
affiliation: Mech-Sense, Department of Medical Gastroenterology, Aalborg Hospital
name: Asbjørn M. Drewes, Professor
role: STUDY_CHAIR
References:
citation: 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.