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Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine

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ClinicalTrials.gov Identifier: NCT02403830
Recruitment Status : Completed
First Posted : March 31, 2015
Results First Posted : April 27, 2017
Last Update Posted : May 30, 2017
Sponsor:
Information provided by (Responsible Party):
University of Florida

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Coronary Artery Disease Drug: Methylnaltrexone Other: Placebo Drug: Morphine Drug: Ticagrelor Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : August 2015
Actual Primary Completion Date : May 2016
Actual Study Completion Date : May 2016

Resource links provided by the National Library of Medicine


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.
Drug: Methylnaltrexone
Methylnaltrexone will be administered diluted with 5 ml of normal saline as a single iv bolus
Other Name: Relistor

Drug: Morphine
After methylnaltrexone, patients will receive 5-mg intravenous morphine
Other Name: Morphine sulfate

Drug: Ticagrelor
After morphine administration, patients will receive a 180-mg ticagrelor loading dose
Other Name: Brilinta

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.
Other: Placebo
Placebo will be administered as a 0.9% sodium chloride iv injection

Drug: Morphine
After methylnaltrexone, patients will receive 5-mg intravenous morphine
Other Name: Morphine sulfate

Drug: Ticagrelor
After morphine administration, patients will receive a 180-mg ticagrelor loading dose
Other Name: Brilinta




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. 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. 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



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02403830


Locations
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United States, Florida
University of Florida
Jacksonville, Florida, United States, 32209
Sponsors and Collaborators
University of Florida
Investigators
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Principal Investigator: Dominick Angiolillo University of Florida

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT02403830    
Other Study ID Numbers: AZ 10583 IISR
First Posted: March 31, 2015    Key Record Dates
Results First Posted: April 27, 2017
Last Update Posted: May 30, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Coronary Artery Disease
Coronary Disease
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Morphine
Methylnaltrexone
Ticagrelor
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Narcotic Antagonists