Clinical trial NCT05770960: Colonic Motor Patterns in Healthy Volunteers
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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Opioid-Induced Constipation
Keywords: Naloxegol
Codeine
Colonic manometry
HRM
Motility
Opioid induced constipation
OIC
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
First posted: 2023-03-16
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized double-blind cross-over design (three-way)
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. HV is a man or woman aged 18 to 65 years, inclusive, at prescreening.
2. 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.
3. HV has not used any opioid medication 14 days prior to randomization.
4. 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.
5. Female subjects must either be:

   1. postmenopausal, defined as 52 years or older and amenorrheic for at least 2 years at prescreening,
   2. surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy),
   3. abstinent, or
   4. 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.
6. 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:

1. 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.
2. HV has a history of diverticulitis.
3. 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).
4. HV has any of the following surgical history:

   1. Any abdominal surgery within the 3 months prior to prescreening;
   2. HV has a history of major gastric, hepatic, pancreatic, or intestinal surgery (appendectomy, hemorrhoidectomy, or polypectomy greater than 3 months post-surgery are allowed).
5. HV has current evidence of laxative abuse.
6. 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.
7. HV has an unstable renal, hepatic, metabolic, or hematologic condition.
8. HV has a history of malignancy within 5 years before prescreening (except squamous and basal cell carcinomas and cervical carcinoma in situ).
9. 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.
10. 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).
11. 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.
12. HV is pregnant or breastfeeding.
13. 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.
14. No smoking on the day of the investigation and the day prior to it.
15. No consumption of grapefruit or grapefruit juice because it can increase Naloxegol plasma levels.

Primary outcomes:
measure: Overall prevalence of anterograde colonic motor patterns in the different treatment categories.
timeFrame: 3 times for 6 hours
Secondary outcomes:
measure: Evaluation of the overall prevalence of the other colonic motor patterns (retrograde propagating sequences, simultaneous pressure waves, cyclic propagating sequences, high-amplitude propagating sequences)
timeFrame: 3 times for 6 hours
measure: Evaluation of the overall prevalence of high-amplitude propagating sequences after Bisacodyl
timeFrame: 3 times for 6 hours
measure: Evaluation of the colonic motility index in the left, right and sigmoid colon.
timeFrame: 3 times for 6 hours
measure: Percentage of Participants reporting Adverse Events (AE).
timeFrame: 3 times for 6 hours
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: UZ Leuven
state: Vlaams-Brabant
Study officials:
affiliation: UZ Leuven / KU Leuven
name: Jan Tack, Professor
role: PRINCIPAL_INVESTIGATOR
References: