The Effect of Naldemedine on Opioid-induced Bowel Dysfunction

The Effect of Naldemedine on Opioid-induced Bowel Dysfunction. An Investigator Initiated, Randomized, Double-blinded, Placebo-controlled, Cross-over Clinical Trial

Opioid-induced bowel dysfunction is a frequent condition during opioid therapy for chronic pain. Indeed, up to 90% of people on opioid treated patients experience constipation. Standard laxative treatment is often ineffective in opioid-induced constipation, but peripheral acting mu-receptor antagonists (PAMORAs) have the potential to block the effects of opioids in the gastrointestinal tract while preserving the central analgesic effect. In this study, we will investigated the effects of Naldemedine in preventing the development of opioid-induced bowel dysfunction and constipation during treatment with tramadol

Study Overview

• Status: Recruiting
• Conditions: Constipation; Opioid-Induced Bowel Dysfunction
• Intervention / Treatment: Drug: Naldemedine; Drug: Tramadol; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Asbjørn Mohr Drewes; Phone Number: +45 97 66 35 62; Email: amd@rn.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Recruiting
    • Aalborg University Hospital
    • Contact: Asbjørn Mohr Drewes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy (assessed by a study-affiliated medical doctor)
• Signed informed consent
• Able to read and understand Danish.
• Male (to avoid influence of menstrual cycles).
• Northern European descent (to minimize genetic variance influences on drug metabolism).
• The researcher believes that the participant understands the study details, is compliant and is expected to complete the study.
• Opioid naïve (no history of opioid use/addiction. Opioid use more than a year ago to treat pain post-surgery is accepted. Opioid use in connection with participation in a clinical trial more than a year ago is accepted)
• Between 20 and 40 years of age.
• A STAI (Spielberger State-Trait Anxiety Inventory) score in the range of 20-37 i.e., classified as "no or low anxiety" at inclusion.

Exclusion Criteria:

Known hypersensitivity or allergy towards the used pharmaceutical compounds or pharmaceutical compounds similar to those used in the study.

• Less than three spontaneous bowel movements per week.
• Participation in other studies within 14 days prior to first visit.
• Expected need of medical/surgical treatment during the study.
• Any diagnosed disease, which investigator concludes will affect the trial (including all contraindicated complications: severe chronic obstructive pulmonary disease, pulmonary heart disease, severe bronchial asthma, paralytic ileus, hypercapnia, serious respiratory depression with hypoxia, moderate to severe decreased liver function, gastrointestinal obstruction or perforation, acute surgical abdominal complications such as appendicitis, Mb. Crohn's, ulcerative colitis, and toxic mega colon).

History of substance abuse (alcohol, tetrahydrocannabinol, benzodiazepine, central stimulants and/or opioids, urine drug test will be performed prior to treatment start).

• History of major mental disorders (e.g., major anxiety, major depression or treatment with psychoactive medications etc.)
• Metal implants or pacemaker.
• Daily use of prescription only medicine
• Daily alcohol consumption
• Participation motivated by "wrongful" reasons such as poor economy or psychosocial issues e.g., problems in the family, loneliness, sadness. People with such problems may be more likely to develop substance dependence*.
• Intake of alcohol within 48 hours before start of study period or any alcohol consumption during each study period. If consumption takes place during the study the participant will be excluded.
• Use of any analgesic medication within 48 hours before start as well as for the duration of the study. If consumption takes place during the study the participant will be excluded.
• Nicotine use

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active treatment; Naldemedine + tramadol	Drug: Naldemedine; Naldemedine is administered orally once daily in the morning in a dosage of 0.2 mg.; Drug: Tramadol; In both arms, tramadol is administered orally twice daily in a dosage of 100 mg (daily total of 200mg).
Placebo Comparator: Placebo treatment; Placebo + tramadol	Drug: Tramadol; In both arms, tramadol is administered orally twice daily in a dosage of 100 mg (daily total of 200mg).; Drug: Placebo; Placebo is administered orally once daily in the morning.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total gastrointestinal transit time	Difference in hours from ingestion of a 3D Transit Capsule to expulsion of the capsule during active and placebo treatment	From day 4 to day 8
Colorectal transit time	Difference in hours from the entering in the colon of a 3D Transit Capsule to expulsion of the capsule during active and placebo treatment	From day 4 to day 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Constipation symptoms	Measured on the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire (ranging from 0 (symptom absent) to 4 (very severe).	From day 1 to day 10
Bowel movement frequency	Number of spontaneous bowel movements per day	From day 1 to day 10
Stool consistency	Rated on the Bristol Stool Form Scale (ranging from type 1 (constipation) - type 7 (diarrhea))	From day 1 to day 10
Gastrointestinal symptoms	Measured on the Gastrointestinal Symptom Rating Score (GSRS) questionnaire (ranging from 0 (no discomfort) to 6 (very severe discomfort)	Day 1 and day 10
Opioid-induced constipation	Measured by the Bowel Function Index (BFI) questionnaire (ranging from 0 (not at all) to 100 (very strong).	Day 1 and day 10
Diagnostic evaluation of opioid-induced constipation	Assessed using the Rome IV C6 criteria	Day 10
Opiate withdrawal symptoms	Measured by the Subjective Opiate Withdrawal Scale (ranging from 0 (not at all) to 4 /extremely)	Day 13, 14 or 15
Colon volume	Volumetric quantification of the colon measured using T2-weighted MRI images	Day 10
Colonic water content	Analysis of colonic water content measured using heavily T2-weighted MRI images	Day 10
Defecation assessment	Analysis of rear-front pressure during a simulated defecation using the Fecobionics device	Day 1 and day 10
Colonic motility patterns	Number of motility patterns in the colon measured by the 3D Transit Capsule	From day 4 to day 8

Collaborators and Investigators

• Sponsor: Asbjørn Mohr Drewes
• Investigators: Principal Investigator: Asbjørn Mohr Drewes, Aalborg University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2024
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: March 20, 2024
• First Submitted That Met QC Criteria: March 20, 2024
• First Posted (Actual): March 27, 2024

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Digestive System Diseases; Substance-Related Disorders; Signs and Symptoms, Digestive; Narcotic-Related Disorders; Gastrointestinal Diseases; Constipation; Intestinal Diseases; Opioid-Induced Constipation; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Tramadol
• Other Study ID Numbers: Naldemedine_OIBD; 2023-507744-36-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No