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Colonic Motor Patterns in Healthy Volunteers (NaloxegolHRM)

Primary Purpose

Opioid-Induced Constipation

Status
Completed
Phase
Phase 4
Locations
Belgium
Study Type
Interventional
Intervention
Naloxegol
codeine phosphate
Placebo
Sponsored by
Universitaire Ziekenhuizen KU Leuven
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Opioid-Induced Constipation focused on measuring Naloxegol, Codeine, Colonic manometry, HRM, Motility, Opioid induced constipation, OIC

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria: HV is a man or woman aged 18 to 65 years, inclusive, at prescreening. Normal stool pattern of between 3 defecations per day and 3 per week with a Bristol Stool Form Scale (BSFS) of 1, 2, 6 or 7 in less than 25% of defaecations. HV has not used any opioid medication 14 days prior to randomization. Medications taken for the treatment of allergies, chronic medical conditions, and migraine headaches can be taken during this study (with the exception of opioids for acute treatment of migraines). HV must be on a stable dose of medication for chronic migraines or preventative therapy for at least 1 month at prescreening. HV on stable doses of antidepressants (i.e., for the 3 months prior to prescreening) will be allowed to participate in the study. As needed use of benzodiazepines, if habitual, is permitted. Female subjects must either be: postmenopausal, defined as 52 years or older and amenorrheic for at least 2 years at prescreening, surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), abstinent, or if sexually active, be practicing an effective method of birth control such as hormonal prescription oral contraceptives, progesterone implants or injections, contraceptive patch, intrauterine device, or male partner with a vasectomy. HV must sign an informed consent document before the initiation of any study-related procedures indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study. Exclusion Criteria: HV has a history of inflammatory or immune-mediated GI disorders including inflammatory bowel disease (ie, Crohn's disease, ulcerative colitis), celiac disease and functional bowel disorder. HV has a history of diverticulitis. HV has a history of intestinal obstruction, stricture, toxic megacolon, GI perforation, gastric banding, bariatric surgery, adhesions, ischemic colitis, or impaired intestinal circulation (eg, aortoiliac disease). HV has any of the following surgical history: Any abdominal surgery within the 3 months prior to prescreening; HV has a history of major gastric, hepatic, pancreatic, or intestinal surgery (appendectomy, hemorrhoidectomy, or polypectomy greater than 3 months post-surgery are allowed). HV has current evidence of laxative abuse. HV has a history of a cardiovascular event, including stroke, myocardial infarction, congestive heart failure, or transient ischemic attack within 6 months prior to prescreening. HV has an unstable renal, hepatic, metabolic, or hematologic condition. HV has a history of malignancy within 5 years before prescreening (except squamous and basal cell carcinomas and cervical carcinoma in situ). HV has abnormal thyroid function test as confirmed by thyroid-stimulating hormone <0.3 mcIU/mL or ≥5 mcIU/mL at Prescreening. However, patients who are clinically euthyroid due to thyroid supplement are candidates for the study. HV has current (within 14 days of randomization) or expected use of any narcotic or opioid containing agents, docusate, enemas, GI preparations (including antacids containing aluminum or magnesium, antidiarrheal agents, antinausea agents, antispasmodic agents, bismuth, or prokinetic agents). HV has received an investigational drug or used an investigational medical device within 30 days prior to randomization, or is currently enrolled in an investigational study. HV is pregnant or breastfeeding. HV has any condition that, in the opinion of the investigator, would compromise the well-being of the patient or the study or prevent the HV from meeting or performing study requirements. No smoking on the day of the investigation and the day prior to it. No consumption of grapefruit or grapefruit juice because it can increase Naloxegol plasma levels.

Sites / Locations

  • UZ Leuven

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Other

Other

Arm Label

Naloxegol - Codeine phosphate

Placebo - Codeine phosphate

Naloxegol - Placebo

Arm Description

Participants will receive Naloxegol 25 mg and Codeine syrup in 30 mL and an additional 15 mL at a later stage during the day.

Participants will receive Placebo instaid of Naloxegol 25 mg and Codeine syrup in 30 mL and an additional 15 mL at a later stage during the day.

Participants will receive Naloxegol 25 mg and Sirupus simplex syrup (as a placebo alternative for Codeine syrup) in 30 mL and an additional 15 mL at a later stage during the day.

Outcomes

Primary Outcome Measures

Overall prevalence of anterograde colonic motor patterns in the different treatment categories.
Observational

Secondary Outcome Measures

Evaluation of the overall prevalence of the other colonic motor patterns (retrograde propagating sequences, simultaneous pressure waves, cyclic propagating sequences, high-amplitude propagating sequences)
Observational
Evaluation of the overall prevalence of high-amplitude propagating sequences after Bisacodyl
Observational and interventional
Evaluation of the colonic motility index in the left, right and sigmoid colon.
Observational
Percentage of Participants reporting Adverse Events (AE).
Observational

Full Information

First Posted
August 8, 2018
Last Updated
March 15, 2023
Sponsor
Universitaire Ziekenhuizen KU Leuven
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1. Study Identification

Unique Protocol Identification Number
NCT05770960
Brief Title
Colonic Motor Patterns in Healthy Volunteers
Acronym
NaloxegolHRM
Official Title
Placebo-controlled Crossover Study of the Ability of Naloxegol to Reverse Opioid Effect on Colonic Motor Patterns in Healthy Volunteers
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Completed
Study Start Date
June 27, 2018 (Actual)
Primary Completion Date
May 9, 2019 (Actual)
Study Completion Date
May 9, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Universitaire Ziekenhuizen KU Leuven

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Characterization of motor patterns with opioid agonists (codeine) ingestion, and their reversal by a peripherally acting mu-opioid receptor antagonist (Naloxegol).
Detailed Description
Opioid induced constipation (OIC) is a highly prevalent condition amongst patients treated with opioids, usually for the treatment of chronic pain, both for malignant and non-malignant causes. The prevalence of constipation and other gastrointestinal side effects among chronic opioid users is 40-90%, depending on the underlying pathology, resulting in non-compliance with pain medication or a reduction in quality of life. Opioid receptors in the brain are the target for opioids to induce analgesia. Peripheral opioid receptors, mostly μ receptors, are prevalent in the enteric nervous system, and their activation underlies the occurrence of gastrointestinal side effects of opioids. Opioid-agonist binding to enteric μ receptors results in inhibition of gastric emptying, pyloric muscle tone increase, disturbance of the migrating motor complex, delayed bowel transit, decreased intestinal secretions and an elevation of anal sphincter resting pressure. Peripherally acting μ-opioid receptor antagonists are the treatment of preference for opioid-induced constipation, because they do not cross the blood-brain barrier (BBB) and so do not interfere with central analgesic effects. This peripheral mechanism is the core mechanism of Naloxegol, the most well-known agent for treating opioid overdosing. Through PEGylating, Naloxegol is a P-glycoprotein substrate with very low ability to cross the blood brain barrier (BBB). Studies have shown the ability of Naloxegol improve opioid-induced constipation in patients chronically treated with opioids, not responding to laxatives, significantly. However, the effects of opioids on colonic motor function and their reversal by opioid antagonists are poorly studied. High-resolution manometry (HRM) of the colon is a sophisticated system for studying colonic motility. Over the last few years, using this approach, it has been possible to differentiate multiple motor patterns. Research is ongoing in different functional bowel disorders (FBDs) to establish the contribution of changes in colonic motor patterns to the disease mechanism and/or symptom generation. By measuring pressures with HRM during drug administration, we want to gain insight in bowel function and motor pattern changes during treatment. HRM motor pattern analysis will help to substantiate previous findings in bowel function and OIC symptom improvements in OIC patients treated with Naloxegol.(5) We will study colonic motor patterns in healthy volunteers (HV) in a randomized, double-blind, cross-over designed trial with codeine and Naloxegol, using previously established HRM protocols and drug doses.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Opioid-Induced Constipation
Keywords
Naloxegol, Codeine, Colonic manometry, HRM, Motility, Opioid induced constipation, OIC

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Model Description
Randomized double-blind cross-over design (three-way)
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Naloxegol - Codeine phosphate
Arm Type
Active Comparator
Arm Description
Participants will receive Naloxegol 25 mg and Codeine syrup in 30 mL and an additional 15 mL at a later stage during the day.
Arm Title
Placebo - Codeine phosphate
Arm Type
Other
Arm Description
Participants will receive Placebo instaid of Naloxegol 25 mg and Codeine syrup in 30 mL and an additional 15 mL at a later stage during the day.
Arm Title
Naloxegol - Placebo
Arm Type
Other
Arm Description
Participants will receive Naloxegol 25 mg and Sirupus simplex syrup (as a placebo alternative for Codeine syrup) in 30 mL and an additional 15 mL at a later stage during the day.
Intervention Type
Drug
Intervention Name(s)
Naloxegol
Other Intervention Name(s)
Movantik, Moventig
Intervention Description
Oral administration of Naloxegol after waking up from the Midazolam administration during the colonoscopy.
Intervention Type
Drug
Intervention Name(s)
codeine phosphate
Other Intervention Name(s)
Bronchodine
Intervention Description
Oral administration of Codeine after waking up from the Midazolam administration during the colonoscopy.
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
Siripus simplex syrup
Intervention Description
Oral administration of siripus simplex syrup after waking up from the Midazolam administration during the colonoscopy.
Primary Outcome Measure Information:
Title
Overall prevalence of anterograde colonic motor patterns in the different treatment categories.
Description
Observational
Time Frame
3 times for 6 hours
Secondary Outcome Measure Information:
Title
Evaluation of the overall prevalence of the other colonic motor patterns (retrograde propagating sequences, simultaneous pressure waves, cyclic propagating sequences, high-amplitude propagating sequences)
Description
Observational
Time Frame
3 times for 6 hours
Title
Evaluation of the overall prevalence of high-amplitude propagating sequences after Bisacodyl
Description
Observational and interventional
Time Frame
3 times for 6 hours
Title
Evaluation of the colonic motility index in the left, right and sigmoid colon.
Description
Observational
Time Frame
3 times for 6 hours
Title
Percentage of Participants reporting Adverse Events (AE).
Description
Observational
Time Frame
3 times for 6 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: HV is a man or woman aged 18 to 65 years, inclusive, at prescreening. Normal stool pattern of between 3 defecations per day and 3 per week with a Bristol Stool Form Scale (BSFS) of 1, 2, 6 or 7 in less than 25% of defaecations. HV has not used any opioid medication 14 days prior to randomization. Medications taken for the treatment of allergies, chronic medical conditions, and migraine headaches can be taken during this study (with the exception of opioids for acute treatment of migraines). HV must be on a stable dose of medication for chronic migraines or preventative therapy for at least 1 month at prescreening. HV on stable doses of antidepressants (i.e., for the 3 months prior to prescreening) will be allowed to participate in the study. As needed use of benzodiazepines, if habitual, is permitted. Female subjects must either be: postmenopausal, defined as 52 years or older and amenorrheic for at least 2 years at prescreening, surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), abstinent, or if sexually active, be practicing an effective method of birth control such as hormonal prescription oral contraceptives, progesterone implants or injections, contraceptive patch, intrauterine device, or male partner with a vasectomy. HV must sign an informed consent document before the initiation of any study-related procedures indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study. Exclusion Criteria: HV has a history of inflammatory or immune-mediated GI disorders including inflammatory bowel disease (ie, Crohn's disease, ulcerative colitis), celiac disease and functional bowel disorder. HV has a history of diverticulitis. HV has a history of intestinal obstruction, stricture, toxic megacolon, GI perforation, gastric banding, bariatric surgery, adhesions, ischemic colitis, or impaired intestinal circulation (eg, aortoiliac disease). HV has any of the following surgical history: Any abdominal surgery within the 3 months prior to prescreening; HV has a history of major gastric, hepatic, pancreatic, or intestinal surgery (appendectomy, hemorrhoidectomy, or polypectomy greater than 3 months post-surgery are allowed). HV has current evidence of laxative abuse. HV has a history of a cardiovascular event, including stroke, myocardial infarction, congestive heart failure, or transient ischemic attack within 6 months prior to prescreening. HV has an unstable renal, hepatic, metabolic, or hematologic condition. HV has a history of malignancy within 5 years before prescreening (except squamous and basal cell carcinomas and cervical carcinoma in situ). HV has abnormal thyroid function test as confirmed by thyroid-stimulating hormone <0.3 mcIU/mL or ≥5 mcIU/mL at Prescreening. However, patients who are clinically euthyroid due to thyroid supplement are candidates for the study. HV has current (within 14 days of randomization) or expected use of any narcotic or opioid containing agents, docusate, enemas, GI preparations (including antacids containing aluminum or magnesium, antidiarrheal agents, antinausea agents, antispasmodic agents, bismuth, or prokinetic agents). HV has received an investigational drug or used an investigational medical device within 30 days prior to randomization, or is currently enrolled in an investigational study. HV is pregnant or breastfeeding. HV has any condition that, in the opinion of the investigator, would compromise the well-being of the patient or the study or prevent the HV from meeting or performing study requirements. No smoking on the day of the investigation and the day prior to it. No consumption of grapefruit or grapefruit juice because it can increase Naloxegol plasma levels.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jan Tack, Professor
Organizational Affiliation
UZ Leuven / KU Leuven
Official's Role
Principal Investigator
Facility Information:
Facility Name
UZ Leuven
City
Leuven
State/Province
Vlaams-Brabant
ZIP/Postal Code
3000
Country
Belgium

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Colonic Motor Patterns in Healthy Volunteers

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