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

Primary Purpose

Acute Pancreatitis

Status

Completed

Phase

Phase 2

Locations

Denmark

Study Type

Interventional

Intervention

Placebo treatment

Methylnaltrexone treatment

About this trial

This is an interventional treatment trial for Acute Pancreatitis

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

Mech-Sense, Department of Medical Gastroenterology, Aalborg University Hospital
Digestive Disease Center K, Bispebjerg University Hospital
Gastrounit, Hvidovre University Hospital
Odense Pancreas Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo treatment

Methylnaltrexone treatment

Arm 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.

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.

Outcomes

Primary Outcome Measures

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/

Secondary Outcome Measures

Pancreatitis activity scoring system

Difference PASS scores between subgroups

Difference in assessments of circulating proinflammatory marker

C-Reactive Protein (mg/L)

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)

Intestinal permeability

Difference in intestinal permeability between subgroups using the oral polyethylene glycol 400/4000 test

Intestinal motility

Difference in intestinal motility assessed by means of gut/colon transit using a CT-based radiopaque marker method between subgroups

Pancreatic complications

Difference in pancreatic complications (e.g. edema, fluid collections and necrosis) assessed and quantified with contrast-enhanced CT

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).

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)

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.

Quantification of analgesics

Difference between subgroups in given dose of analgesics (separated into opioids and non-opioids) based on name, administration route and dose

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.

Days of hospitalization

Difference between subgroups in days of hospitalization and days on intensive ward

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

Mortality

Difference between subgroups in mortality rate

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).

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).

Full Information

NCT ID

NCT04743570

First Posted

January 28, 2021

Last Updated

April 20, 2023

Sponsor

Asbjørn Mohr Drewes

Collaborators

Odense University Hospital, Hvidovre University Hospital, University Hospital Bispebjerg and Frederiksberg

1. Study Identification

Unique Protocol Identification Number

NCT04743570

Brief Title

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

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Completed

Study Start Date

May 14, 2021 (Actual)

Primary Completion Date

April 9, 2023 (Actual)

Study Completion Date

April 20, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Asbjørn Mohr Drewes

Collaborators

Odense University Hospital, Hvidovre University Hospital, University Hospital Bispebjerg and Frederiksberg

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Pancreatitis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

105 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo treatment

Arm Type

Placebo Comparator

Arm 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.

Arm Title

Methylnaltrexone treatment

Arm Type

Active Comparator

Arm 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.

Intervention Type

Drug

Intervention Name(s)

Placebo treatment

Intervention Description

Active drug/placebo is given for the first 5 days of admission.

Intervention Type

Drug

Intervention Name(s)

Methylnaltrexone treatment

Intervention Description

Active drug/placebo is given for the first 5 days of admission.

Primary Outcome Measure Information:

Title

Pancreatitis activity scoring system

Description

Time Frame

48 hours after randomization

Secondary Outcome Measure Information:

Title

Pancreatitis activity scoring system

Description

Difference PASS scores between subgroups

Time Frame

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

Title

Difference in assessments of circulating proinflammatory marker

Description

C-Reactive Protein (mg/L)

Time Frame

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

Title

Difference in assessments of circulating pro- and anti-inflammatory markers

Description

Interleukin-6, Interleukin-8, Interleukin-18, Tumor necrosis factor alpha, Cluster of Differentiation 163 (serum) (all measured in pg/mL)

Time Frame

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

Title

Intestinal permeability

Description

Difference in intestinal permeability between subgroups using the oral polyethylene glycol 400/4000 test

Time Frame

From 48 to 72 hours after randomization

Title

Intestinal motility

Description

Difference in intestinal motility assessed by means of gut/colon transit using a CT-based radiopaque marker method between subgroups

Time Frame

5 (+/- 1 day) after randomization

Title

Pancreatic complications

Description

Difference in pancreatic complications (e.g. edema, fluid collections and necrosis) assessed and quantified with contrast-enhanced CT

Time Frame

Day 5 (+/- 1 day) after randomization

Title

Pain intensity

Description

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).

Time Frame

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

Title

Gut function (BSFS)

Description

Time Frame

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

Title

Gut function (GSRS)

Description

Time Frame

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

Title

Quantification of analgesics

Description

Difference between subgroups in given dose of analgesics (separated into opioids and non-opioids) based on name, administration route and dose

Time Frame

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

Title

Use of nutritional support

Description

Difference between subgroups in the use of nutritional support with registration of the used of either oral nutrition, enteral or parenteral nutrition.

Time Frame

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

Title

Days of hospitalization

Description

Difference between subgroups in days of hospitalization and days on intensive ward

Time Frame

Observation period starts from day of randomization and ends after 12 months or on the day of discharge which ever comes first

Title

Use of invasive treatment

Description

Difference between subgroups in use of invasive treatment (e.g. use of drain or surgery) measured in type and frequency of use

Time Frame

Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first

Title

Mortality

Description

Difference between subgroups in mortality rate

Time Frame

Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first

Title

Health resource utilization

Description

Time Frame

Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first

Title

Disease severity

Description

Time Frame

Observation period starts from day of randomization and ends after 12 months or on the day of discharge whichever comes first

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Asbjørn M. Drewes, Professor

Organizational Affiliation

Mech-Sense, Department of Medical Gastroenterology, Aalborg Hospital

Official's Role

Study Chair

Facility Information:

Facility Name

Mech-Sense, Department of Medical Gastroenterology, Aalborg University Hospital

City

Aalborg

State/Province

Jutland

ZIP/Postal Code

9000

Country

Denmark

Facility Name

Digestive Disease Center K, Bispebjerg University Hospital

City

Bispebjerg

Country

Denmark

Facility Name

Gastrounit, Hvidovre University Hospital

City

Hvidovre

Country

Denmark

Facility Name

Odense Pancreas Center

City

Svendborg

Country

Denmark

12. IPD Sharing Statement

Plan to Share IPD

Yes

Citations:

PubMed Identifier

34924020

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.

Results Reference

derived

Learn more about this trial

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

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