- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02403830
Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine
April 27, 2017 updated by: University of Florida
Effect of the Peripheral Opioid Receptor Antagonist Methylnaltrexone on the Pharmacokinetic and Pharmacodynamic Profiles of Ticagrelor in Patients Receiving Morphine: a Prospective, Randomized Placebo-controlled Trial
Ticagrelor is associated with more prompt and potent antiplatelet effects compared with clopidogrel, leading to better clinical outcomes, including reduced cardiovascular mortality, across the spectrum of patients with acute coronary syndrome, including those with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).
However, in this latter setting a delay in the onset of its antiplatelet effects has been shown.
Morphine has been identified as a cause of delayed P2Y12 inhibition in patients with STEMI.
Methylnaltrexone is a parenteral peripheral opioid receptor antagonist which has the potential to prevent or reverse opioid-induced peripherally mediated side effects without affecting analgesia.
However, whether the use of intravenous methylnaltrexone may overcome the effects of morphine administration on the pharmacokinetic (PK) and pharmacodynamics (PD) profiles of ticagrelor has not been investigated yet.
The proposed investigation will include patients with coronary artery disease and will have a prospective, randomized, cross-over design.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
Ticagrelor is associated with more prompt and potent antiplatelet effects compared with clopidogrel, leading to better clinical outcomes, including reduced cardiovascular mortality, across the spectrum of patients with acute coronary syndrome, including those with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).
However, in this latter setting a delay in the onset of its antiplatelet effects has been shown.
Morphine has been identified as a cause of delayed P2Y12 inhibition in patients with STEMI.
In fact, opiates are known to inhibit gastric emptying, leading to delayed absorption and potentially decreasing peak plasma levels of orally administered drugs.
Methylnaltrexone is a parenteral peripheral opioid receptor antagonist which has the potential to prevent or reverse opioid-induced peripherally mediated side effects (i.e.
gastric emptying inhibition) without affecting analgesia.
Studies have shown that methylnaltrexone effectively prevented morphine-induced gut motility change.
However, whether the use of intravenous methylnaltrexone may overcome the effects of morphine administration on the pharmacokinetic (PK) and pharmacodynamics (PD) profiles of ticagrelor has not been investigated yet.
The proposed investigation will include patients with coronary artery disease and will have a prospective, randomized, cross-over design.
Patients will be randomized to receive either intravenous methylnaltrexone or placebo.
Immediately after methylnaltrexone administration, patients will receive intravenous morphine and then will receive a 180-mg ticagrelor loading dose 15 minutes after morphine administration.
After a 7 ± 2 days wash-out period, patients will cross-over to the alternate study-treatment arm.
At each visit, blood samples for PK and PD assessments will be collected at several time points.
This study will provide insights on a possible treatment strategy to overcome the impaired P2Y12 inhibition induced by morphine.
Study Type
Interventional
Enrollment (Actual)
30
Phase
- Phase 4
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Florida
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Jacksonville, Florida, United States, 32209
- University of Florida
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 80 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion criteria:
- Patients with angiographically documented CAD.
- On treatment with low-dose aspirin (81 mg) for at least 30 days, as per standard of care.
- Age between 18 and 80 years old.
Exclusion criteria:
- History of prior intracranial bleeding.
- On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor) or with vorapaxar in past 30 days.
- Known allergies to ticagrelor.
- On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, apixaban).
- Treatment with glycoprotein IIb/IIIa inhibitors in past 7 days.
- Known blood dyscrasia or bleeding diathesis.
- Platelet count <80x106/mL.
- Hemoglobin <10 g/dL.
- Active bleeding.
- Hemodynamic instability.
- Creatinine clearance <30 mL/minute (as estimated by Cockcroft-Gault formula).
- Severe hepatic dysfunction.
- Acute or severe bronchial asthma or upper airway obstruction.
- Known or suspected mechanical gastrointestinal obstruction.
- Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker protection.
- Current treatment with any drug interfering with morphine: central nervous system depressants (other narcotic analgesics, general anesthetics, phenothiazines, tricyclic antidepressants, tranquilizers, sedatives, hypnotics, antiemetics, and alcohol), muscle relaxants, mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol), cimetidine, monoamine oxidase inhibitors (MAOIs), anticholinergics.
- Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction with ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromizycin.
- Pregnant females*. *Women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Methylnaltrexone
Patients will be randomly assigned in a 1:1 fashion to receive either i.v methylnaltrexone or placebo (0.9% sodium chloride iv injection).
Methylnaltrexone, at a dose of 0.3 mg/Kg, will be administered diluted with 5 ml of normal saline as a single i.v.
bolus over 1 minute followed by morphine (5-mg intravenous bolus).
Then patients will receive iv morphine and a loading dose of ticagrelor.
|
Methylnaltrexone will be administered diluted with 5 ml of normal saline as a single iv bolus
Other Names:
After methylnaltrexone, patients will receive 5-mg intravenous morphine
Other Names:
After morphine administration, patients will receive a 180-mg ticagrelor loading dose
Other Names:
|
Placebo Comparator: Placebo
Patients will be randomly assigned in a 1:1 fashion to receive either i.v methylnaltrexone or placebo (0.9% sodium chloride iv injection).
Methylnaltrexone, at a dose of 0.3 mg/Kg, will be administered diluted with 5 ml of normal saline as a single i.v.
bolus over 1 minute followed by morphine (5-mg intravenous bolus).
Then patients will receive iv morphine and a loading dose of ticagrelor.
|
After methylnaltrexone, patients will receive 5-mg intravenous morphine
Other Names:
After morphine administration, patients will receive a 180-mg ticagrelor loading dose
Other Names:
Placebo will be administered as a 0.9% sodium chloride iv injection
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Platelet Reactivity Measured by VerifyNow P2Y12
Time Frame: 2 hours
|
Platelet reactivity measured by VerifyNow P2Y12 2 hours after ticagrelor loading dose and reported as P2Y12 reaction units (PRU)
|
2 hours
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Platelet Reactivity Measured by VASP
Time Frame: 2 hours
|
Platelet reactivity measured by VASP 2 hours after ticagrelor loading dose and reported as platelet reactivity index (PRI)
|
2 hours
|
AUC of Ticagrelor Plasma Levels
Time Frame: 6 hours
|
The area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC) was calculated based on ticagrelor plasma levels
|
6 hours
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
August 1, 2015
Primary Completion (Actual)
May 1, 2016
Study Completion (Actual)
May 1, 2016
Study Registration Dates
First Submitted
February 17, 2015
First Submitted That Met QC Criteria
March 25, 2015
First Posted (Estimate)
March 31, 2015
Study Record Updates
Last Update Posted (Actual)
May 30, 2017
Last Update Submitted That Met QC Criteria
April 27, 2017
Last Verified
April 1, 2017
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Myocardial Ischemia
- Heart Diseases
- Cardiovascular Diseases
- Vascular Diseases
- Arteriosclerosis
- Arterial Occlusive Diseases
- Coronary Disease
- Coronary Artery Disease
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Central Nervous System Depressants
- Peripheral Nervous System Agents
- Analgesics
- Sensory System Agents
- Platelet Aggregation Inhibitors
- Purinergic P2Y Receptor Antagonists
- Purinergic P2 Receptor Antagonists
- Purinergic Antagonists
- Purinergic Agents
- Analgesics, Opioid
- Narcotics
- Narcotic Antagonists
- Ticagrelor
- Morphine
- Methylnaltrexone
Other Study ID Numbers
- AZ 10583 IISR
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
NO
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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