Effects of Peripherally Acting µ-opioid Receptor Antagonists on Acute Pancreatitis - An Investigator-initiated, Randomized, Placebo-controlled, Double-blind Clinical Trial
Overview
- Phase
- Phase 2
- Intervention
- Placebo treatment
- Conditions
- Acute Pancreatitis
- Sponsor
- Asbjørn Mohr Drewes
- Enrollment
- 105
- Locations
- 4
- Primary Endpoint
- Pancreatitis activity scoring system
- Status
- Completed
- Last Updated
- 3 years ago
Overview
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.
Investigators
Asbjørn Mohr Drewes
Professor, Chief Physician, MD, PhD, DMSc
Aalborg University Hospital
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
Arms & Interventions
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.
Intervention: Placebo treatment
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.
Intervention: Methylnaltrexone treatment
Outcomes
Primary Outcomes
Pancreatitis activity scoring system
Time Frame: 48 hours after randomization
Difference in Pancreatitis activity scoring system (PASS) score between the methylnaltrexone group and the placebo group. The PASS-score is a weighted score of presence of organ failure, number of criterias of Systemic Inflammatory Response Syndrome fulfilled, abdominal pain (0-10), morphine equivalent dose (mg) and tolerance to solid food. Minimum value is 0 and higher score is equal to higher disease activity. Documentation for the PASS can be found on the following link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519418/
Secondary Outcomes
- Pancreatitis activity scoring system(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)
- Intestinal motility(5 (+/- 1 day) after randomization)
- Pancreatic complications(Day 5 (+/- 1 day) after randomization)
- Quantification of analgesics(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)
- Use of nutritional support(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)
- Days of hospitalization(Observation period starts from day of randomization and ends after 12 months or on the day of discharge which ever comes first)
- Mortality(Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first)
- Disease severity(Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first)
- Intestinal permeability(From 48 to 72 hours after randomization)
- Difference in assessments of circulating proinflammatory marker(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)
- Pain intensity(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)
- Gut function (BSFS)(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)
- Use of invasive treatment(Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first)
- Health resource utilization(Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first)
- Difference in assessments of circulating pro- and anti-inflammatory markers(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)
- Gut function (GSRS)(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)