Clinical trial NCT04966559: Effects of a Peripherally Acting µ-opioid Receptor Antagonist on Recurrent Acute Pancreatitis
Official title: Effects of a Peripherally Acting µ-opioid Receptor Antagonist on Recurrent Acute Pancreatitis An Investigator-initiated, Randomized, Placebo-controlled, Double-blind Clinical Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Pancreatitis, Acute
Lead sponsor: Aalborg University Hospital
Sponsor class: OTHER
Collaborators: name: Odense University Hospital
name: Hvidovre University Hospital
name: University Hospital Bispebjerg and Frederiksberg
name: Karolinska University Hospital
First posted: 2021-07-19
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This study will investigate the effect of a peripheral acting opioid antagonist (PAMORA) on the disease course of patients with recurrent acute inflammation of the pancreas (acute pancreatitis). The study will be conducted by treating outpatients suffering from recurrent acute pancreatitis with a PAMORA (naldemedine) for 12 months.

Detailed description: In this study, the effects of a peripheral acting µ-opioid receptor antagonist (PAMORA) on disease recurrence and progression in patients with recurrent acute pancreatitis (RAP) will be investigated. Patients with RAP will be administered 0,2 mg naldemedine orally daily or matching placebo. This medication is defined as the investigational product. Naldemedine is approved by the European Medical Agency 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.

It is hypothesized that treatment with the PAMORA naldemedine will antagonize the harmful effects of opioids without reducing analgesia in patients with RAP and hence reduce disease severity and improve clinical outcomes. If successful, this study will for the first time document the effects of a targeted pharmacotherapy in RAP 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 or Swedish (depending on site)
* Male or female age between 18 and 74 years
* At least one attack of non-biliary AP (as defined by the revised Atlanta criteria) within the last 12 months and at least two attacks within 5 years
* Clinically stable at time of inclusion
* 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

Exclusion 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 eGFR below 45)
* Female participants that are lactating
* Severe pre-existing comorbidities (assessed by investigator upon inclusion)
* Attack of AP requiring admission within two weeks prior to inclusion
* Gallstone etiology of RAP (MRCP or endoscopic ultrasound excluding biliary etiology of AP must be available prior to enrolment as part of the protocol)
* Treatment with potent CYP3A4-inhibitors (ketoconazol, itraconzol, ritonavir) or P-gp inhibitors (e.g. cyclosporine).

Primary outcomes:
measure: Number of AP attacks verified by the Atlanta Criteria
timeFrame: Observation period starts from day of randomization and ends after a minimum of 6 months and a maximum of 12 months
Secondary outcomes:
measure: Pain intensity
timeFrame: Observation period starts from day of randomization and ends after a minimum of 6 months and a maximum of 12 months
measure: Gut function (BSFS)
timeFrame: Day of randomization and at follow up visit after a minimum of 6 months and a maximum of 12 months
measure: Gut function (GSRS)
timeFrame: Day of randomization and at follow up visit after a minimum of 6 months and a maximum of 12 months
measure: Health resource utilization
timeFrame: Observation period starts from day of randomization and ends after a minimum of 6 months and a maximum of 12 months
measure: Pancreatic volume
timeFrame: Day of randomization and at follow up visit after a minimum of 6 months and a maximum of 12 months
measure: Exocrine pancreatic function
timeFrame: Day of randomization and at follow up visit after a minimum of 6 months and a maximum of 12 months
measure: Endocrine pancreatic function
timeFrame: Day of randomization and at follow up visit after a minimum of 6 months and a maximum of 12 months
measure: Quality of life (EORTC QLQ-C30)
timeFrame: Day of randomization and at follow up visit after a minimum of 6 months and a maximum of 12 months
measure: Impression of change
timeFrame: Day of randomization and at follow up visit after a minimum of 6 months and a maximum of 12 months
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
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
state: Solna (l1:00)
Study officials:
affiliation: Aalborg University Hospital
name: Asbjørn M. Drewes, Professor
role: PRINCIPAL_INVESTIGATOR
References: