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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effects of Peripherally Acting µ-opioid Receptor Antagonists on Acute Pancreatitis - An Investigator-initiated, Randomized, Placebo-controlled, Double-blind Clinical Trial

Conditions
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Acute Pancreatitis

Intervention / Treatment
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* Drug: Placebo treatment
* Drug: Methylnaltrexone treatment


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo treatment<br>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. | Drug: Placebo treatment<br>* Active drug/placebo is given for the first 5 days of admission.<br>|
| Active Comparator: Methylnaltrexone treatment<br>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. | Drug: Methylnaltrexone treatment<br>* Active drug/placebo is given for the first 5 days of admission.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pancreatitis activity scoring system | 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/ | 48 hours after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pancreatitis activity scoring system | Difference PASS scores between subgroups | 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 | 
| Difference in assessments of circulating proinflammatory marker | C-Reactive Protein (mg/L) | 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 | 
| Difference in assessments of circulating pro- and anti-inflammatory markers | Interleukin-6, Interleukin-8, Interleukin-18, Tumor necrosis factor alpha, Cluster of Differentiation 163 (serum) (all measured in pg/mL) | 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 permeability | Difference in intestinal permeability between subgroups using the oral polyethylene glycol 400/4000 test | From 48 to 72 hours after randomization | 
| Intestinal motility | Difference in intestinal motility assessed by means of gut/colon transit using a CT-based radiopaque marker method between subgroups | 5 (+/- 1 day) after randomization | 
| Pancreatic complications | Difference in pancreatic complications (e.g. edema, fluid collections and necrosis) assessed and quantified with contrast-enhanced CT | Day 5 (+/- 1 day) after randomization | 
| Pain intensity | Difference between subgroups in pain intensity measured with the questionaire modified Brief Pain Inventory short form on visual analogue scale from 0-10 (0 is no pain and 10 is worst pain). | 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) | Difference between subgroups in gut function assessed by The Bristol Stool Form Scale for assessment of stool frequency as well as stool consistency (scale from 1-7, where 1 is firmeste and 7 is softest) | 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) | Difference between subgroups in gut function assessed by Gastrointestinal Symptom Rating Scale which is a disease-specific instrument of 15 items combined into five symptom clusters depicting reflux, abdominal pain, indigestion, diarrhea and constipation. The GSRS has a seven-point graded Likert-type scale, where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. | 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 | 
| Quantification of analgesics | Difference between subgroups in given dose of analgesics (separated into opioids and non-opioids) based on name, administration route and dose | 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 | Difference between subgroups in the use of nutritional support with registration of the used of either oral nutrition, enteral or parenteral nutrition. | 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 | Difference between subgroups in days of hospitalization and days on intensive ward | Observation period starts from day of randomization and ends after 12 months or on the day of discharge which ever comes first | 
| Use of invasive treatment | Difference between subgroups in use of invasive treatment (e.g. use of drain or surgery) measured in type and frequency of use | Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first | 
| Mortality | Difference between subgroups in mortality rate | Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first | 
| Health resource utilization | Difference in health resource utilization (measured in frequency and type of health services used (e.g. blood sample, MRI etc.) that can be converted into danish currency for economic analyses) between subgroups based on service codes (all services have unique service codes stored digitally). | Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first | 
| Disease severity | Disease severity classified by the revised Atlanta classification system in 3 levels; Mild, Moderate or Severe acute pancreatitis. (Mild acute pancreatitis, with no organ failure, local or systemic complications, Moderately severe acute pancreatitis is with presence of transient organ failure, local complications or exacerbation of co-morbid disease. Severe acute pancreatitis with persistent organ failure (>48 h). | Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first |