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Effects of a Peripherally Acting µ-opioid Receptor Antagonist on Recurrent Acute Pancreatitis

Primary Purpose

Pancreatitis, Acute

Status

Recruiting

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Placebo treatment

Naldemedine 0.2 MG Oral Tablet

About this trial

This is an interventional prevention trial for Pancreatitis, Acute

Eligibility Criteria

18 Years - 74 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 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).

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo treatment

Naldemedine treatment

Arm Description

Film-coated matched placebo-tablets consisting of: Core: Mannitol, USP/Ph. Eur./JP Croscarmellose Sodium, NF/Ph. Eur./JP Magnesium Stearate, NF/Ph. Eur./JP Coating: Opadry Yellow Purified Water, USP/EP

Film-coated matched active-tablets consisting of: Core: Naldemedine Tosylate (0,2 mg) Mannitol, USP/Ph. Eur./JP Croscarmellose Sodium, NF/Ph. Eur./JP Magnesium Stearate, NF/Ph. Eur./JP Coating: Opadry Yellow Purified Water, USP/EP

Outcomes

Primary Outcome Measures

Number of AP attacks verified by the Atlanta Criteria

The primary outcome is defined as difference in number of AP attacks verified by the Atlanta Criteria between the naldemedine group and the placebo group. The Atlanta Criteria is the current gold standard for the diagnosis of AP attack, and it requires a minimum of two out three of the following features: (i) Abdominal pain typical for acute pancreatitis featuring acute onset of a severe and persistent epigastric pain radiating to the back (ii) Serum amylase levels > three times greater than the normal upper limit (iii) Findings of pancreatic inflammation in contrast-enhanced computed tomography, magnetic resonance imaging or transabdominal ultrasonography.

Secondary Outcome Measures

Pain intensity

Individual difference between subgroups in number and severity of pain attacks (without fulfilling AP criteria) assessed by pain diary and modified Brief Pain Inventory short form on visual analogue scale from 0-10 (0 is no pain and 10 is worst pain). For each attack, participants will be asked to fill in the pain attack diary and the modified Brief Pain Inventory short form once.

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.

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).

Pancreatic volume

Difference in pancreatic volume measured in cubic centimeters cm^3 between subgroups, measured by MRI.

Exocrine pancreatic function

Difference between subgroups in exocrine pancreatic function assessed by fecal-elastase (µg/g) test.

Endocrine pancreatic function

Difference between subgroups in endocrine pancreatic function assessed by hemoglobinA1c (HbA1c) (mmol/mol) test.

Quality of life (EORTC QLQ-C30)

Difference between subgroups in quality of life assessed by EORTC QLQ-C30 questionnaire. The questionnaire has been validated for assessment of quality of life in patients with chronic pancreatitis and is composed of single-item measures and multi-item scales with scores ranging from 0 to 100 after linear transformation of the raw score. A high score for a functional scale represents a high level of functioning, as does a high score for the global health status, while a high score for the symptom items represents a high level of symptomatology.

Impression of change

Difference between subgroups in Patient Global Impression of Change. PGIC is a seven-point rating scale for self-report of a patient's experienced efficacy of treatment on their symptoms.

Full Information

NCT ID

NCT04966559

First Posted

July 8, 2021

Last Updated

June 6, 2023

Sponsor

Asbjørn Mohr Drewes

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT04966559

Brief Title

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

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Recruiting

Study Start Date

January 12, 2022 (Actual)

Primary Completion Date

March 30, 2024 (Anticipated)

Study Completion Date

June 1, 2024 (Anticipated)

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, Karolinska University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

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

Pancreatitis, Acute

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Placebo treatment

Arm Type

Placebo Comparator

Arm Description

Arm Title

Naldemedine treatment

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Placebo treatment

Intervention Description

Active drug/placebo is handed out equivalent of 1 tablet of 0,2 mg Naldemedine or placebo daily for 365 days.

Intervention Type

Drug

Intervention Name(s)

Naldemedine 0.2 MG Oral Tablet

Intervention Description

Active drug/placebo is handed out equivalent of 1 tablet of 0,2 mg Naldemedine or placebo daily for 365 days.

Primary Outcome Measure Information:

Title

Number of AP attacks verified by the Atlanta Criteria

Description

Time Frame

Observation period starts from day of randomization and ends after 12 months

Secondary Outcome Measure Information:

Title

Pain intensity

Description

Time Frame

Observation period starts from day of randomization and ends after 12 months

Title

Gut function (BSFS)

Description

Time Frame

Day of randomization and at follow up visit after 12 months

Title

Gut function (GSRS)

Description

Time Frame

Day of randomization and at follow up visit after 12 months

Title

Health resource utilization

Description

Time Frame

Observation period starts from day of randomization and ends after 12 months

Title

Pancreatic volume

Description

Difference in pancreatic volume measured in cubic centimeters cm^3 between subgroups, measured by MRI.

Time Frame

Day of randomization and at follow up visit after 12 months

Title

Exocrine pancreatic function

Description

Difference between subgroups in exocrine pancreatic function assessed by fecal-elastase (µg/g) test.

Time Frame

Day of randomization and at follow up visit after 12 months

Title

Endocrine pancreatic function

Description

Difference between subgroups in endocrine pancreatic function assessed by hemoglobinA1c (HbA1c) (mmol/mol) test.

Time Frame

Day of randomization and at follow up visit after 12 months

Title

Quality of life (EORTC QLQ-C30)

Description

Time Frame

Day of randomization and at follow up visit after 12 months

Title

Impression of change

Description

Difference between subgroups in Patient Global Impression of Change. PGIC is a seven-point rating scale for self-report of a patient's experienced efficacy of treatment on their symptoms.

Time Frame

Day of randomization and at follow up visit after 12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

74 Years

Accepts Healthy Volunteers

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).

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Mathias E. Cook, MSc

Phone

97663520

Ext

+45

m.cook@rn.dk

First Name & Middle Initial & Last Name or Official Title & Degree

Cecilie S. Knoph, MD

Phone

97663520

Ext

+45

c.siggaard@rn.dk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Asbjørn M. Drewes, Professor

Organizational Affiliation

Aalborg University Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

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

City

Aalborg

State/Province

Jutland

ZIP/Postal Code

9000

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Asbjørn Mohr Drewes, MD DMSc PhD

Facility Name

Digestive Disease Center K, Bispebjerg University Hospital

City

Bispebjerg

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Liv Bjerre Juul Nielsen, MD

Facility Name

Gastrounit, Hvidovre University Hospital

City

Hvidovre

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Srdan Novovic, MD, PhD

Facility Name

Odense Pancreas Center

City

Svendborg

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Michael Bau Mortensen, MD DMSc PhD

Facility Name

Karolinska University Hospital

City

Stockholm

State/Province

Solna (l1:00)

ZIP/Postal Code

SE-171 76

Country

Sweden

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Miroslav Vujasinovic, MD, PhD

Phone

8-123 943 20

Ext

+460

mailto:miroslav.vujasinovic@sll.se

12. IPD Sharing Statement

Plan to Share IPD

Yes

Learn more about this trial

Effects of a Peripherally Acting µ-opioid Receptor Antagonist on Recurrent Acute Pancreatitis

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