Opioid-Induced ConstipationPhase 4NaloxegolHRMNCT05770960
Colonic Motor Patterns in Healthy Volunteers
A Phase 4 study testing Naloxegol and codeine phosphate in people with Opioid-Induced Constipation, run by Universitaire Ziekenhuizen KU Leuven at 1 site in Belgium.
Trial summary
Characterization of motor patterns with opioid agonists (codeine) ingestion, and their reversal by a peripherally acting mu-opioid receptor antagonist (Naloxegol). Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Opioid-Induced Constipation
- What is being tested?
- Naloxegol and codeine phosphate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 15 participants
- Where
- 1 siteBelgium
- Study dates
- 27 Jun 2018to 9 May 2019
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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,
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- 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.
Who cannot join
- 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).
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Placebo-controlled Crossover Study of the Ability of Naloxegol to Reverse Opioid Effect on Colonic Motor Patterns in Healthy Volunteers
Characterization of motor patterns with opioid agonists (codeine) ingestion, and their reversal by a peripherally acting mu-opioid receptor antagonist (Naloxegol).
Read the 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.
- Conditions
- Opioid-Induced Constipation
- Being tested
- Naloxegol, codeine phosphate, Placebo
- Keywords
- Naloxegol, Codeine, Colonic manometry, HRM, Motility, Opioid induced constipation, OIC
- Medical subject headings
- Opioid-Induced Constipation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NaloxegolDrug
Also called Movantik, Moventig
Oral administration of Naloxegol after waking up from the Midazolam administration during the colonoscopy.
codeine phosphateDrug
Also called Bronchodine
Oral administration of Codeine after waking up from the Midazolam administration during the colonoscopy.
PlaceboOther
Also called Siripus simplex syrup
Oral administration of siripus simplex syrup after waking up from the Midazolam administration during the colonoscopy.
| Study group | Role | What they receive |
|---|---|---|
| Naloxegol - Codeine phosphate | Active comparator | Participants will receive Naloxegol 25 mg and Codeine syrup in 30 mL and an additional 15 mL at a later stage during the day. Receives: Drug: Naloxegol; Drug: codeine phosphate |
| Placebo - Codeine phosphate | Other | 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. Receives: Drug: codeine phosphate; Other: Placebo |
| Naloxegol - Placebo | Other | 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. Receives: Drug: Naloxegol; Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall prevalence of anterograde colonic motor patterns in the different treatment categories.
Observational
Measured: 3 times for 6 hours
Secondary outcomes (4)
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
Measured: 3 times for 6 hours
Evaluation of the overall prevalence of high-amplitude propagating sequences after Bisacodyl
Observational and interventional
Measured: 3 times for 6 hours
Evaluation of the colonic motility index in the left, right and sigmoid colon.
Observational
Measured: 3 times for 6 hours
Percentage of Participants reporting Adverse Events (AE).
Observational
Measured: 3 times for 6 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Mar 2023
- Study start27 Jun 2018
- Primary completion9 May 2019
- Study completion9 May 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Opioid-Induced ConstipationStudies of the same condition, open and under way.
- More trials run by Universitaire Ziekenhuizen KU LeuvenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Randomized double-blind cross-over design (three-way)
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- Universitaire Ziekenhuizen KU Leuven
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jan Tack, Professor, Principal investigator, UZ Leuven / KU Leuven
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05770960
- Sponsor's protocol ID
- S61159
- Acronym
- NaloxegolHRM
- Status last verified
- Mar 2023
- First submitted
- 8 Aug 2018
- Last updated
- 16 Mar 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 16 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Placebo-controlled Crossover Study of the Ability of Naloxegol to Reverse Opioid Effect on Colonic Motor Patterns in Healthy Volunteers
- ClinicalTrials.gov ID
- NCT05770960
- Acronym / sponsor ID
- NaloxegolHRM / S61159
- Conditions
- Opioid-Induced Constipation
- Keywords
- Naloxegol, Codeine, Colonic manometry, HRM, Motility, Opioid induced constipation, OIC
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- Universitaire Ziekenhuizen KU LeuvenUniversity, hospital or other
- Study start
- 27 Jun 2018 (actual)
- Primary completion
- 9 May 2019 (actual)
- Study completion
- 9 May 2019 (actual)
- First posted
- 16 Mar 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- Randomized double-blind cross-over design (three-way)
| Arm | Type | Receives |
|---|---|---|
| Naloxegol - Codeine phosphate | Active comparator | Drug: Naloxegol, Drug: codeine phosphateParticipants will receive Naloxegol 25 mg and Codeine syrup in 30 mL and an additional 15 mL at a later stage during the day. |
| Placebo - Codeine phosphate | Other | Drug: codeine phosphate, Other: PlaceboParticipants 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. |
| Naloxegol - Placebo | Other | Drug: Naloxegol, Other: PlaceboParticipants 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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:
Key exclusion criteria (17 listed)
- 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:
- HV has current evidence of laxative abuse.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NaloxegolAlso: Movantik, MoventigOral administration of Naloxegol after waking up from the Midazolam administration during the colonoscopy. | Drug | Naloxegol - Codeine phosphate, Naloxegol - Placebo |
| codeine phosphateAlso: BronchodineOral administration of Codeine after waking up from the Midazolam administration during the colonoscopy. | Drug | Naloxegol - Codeine phosphate, Placebo - Codeine phosphate |
| PlaceboAlso: Siripus simplex syrupOral administration of siripus simplex syrup after waking up from the Midazolam administration during the colonoscopy. | Other | Naloxegol - Placebo, Placebo - Codeine phosphate |
Primary outcome
Overall prevalence of anterograde colonic motor patterns in the different treatment categories.
Time frame: 3 times for 6 hours
Observational
4 secondary outcomes
Evaluation of the overall prevalence of the other colonic motor patterns (retrograde propagating sequences, simultaneous pressure waves, cyclic propagating sequences, high-amplitude propagating sequences)
Time frame: 3 times for 6 hours
Evaluation of the overall prevalence of high-amplitude propagating sequences after Bisacodyl
Time frame: 3 times for 6 hours
Evaluation of the colonic motility index in the left, right and sigmoid colon.
Time frame: 3 times for 6 hours
Percentage of Participants reporting Adverse Events (AE).
Time frame: 3 times for 6 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Mar 2023.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jan Tack, Professor principal investigator
UZ Leuven / KU Leuven
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Naloxegol and codeine phosphate in people with Opioid-Induced Constipation, run by Universitaire Ziekenhuizen KU Leuven at 1 site in Belgium.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall prevalence of anterograde colonic motor patterns in the different treatment categories. (time frame: 3 times for 6 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Mar 2023.