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

NCT ID: NCT02403830

Last Updated: 2017-05-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-08-31
• Study Completion Date: 2016-05-31

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.

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.

Conditions

Coronary Artery Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

Methylnaltrexone

Intervention Type: DRUG

Methylnaltrexone will be administered diluted with 5 ml of normal saline as a single iv bolus

Morphine

Intervention Type: DRUG

After methylnaltrexone, patients will receive 5-mg intravenous morphine

Ticagrelor

Intervention Type: DRUG

After morphine administration, patients will receive a 180-mg ticagrelor loading dose

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

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

Morphine

Intervention Type: DRUG

After methylnaltrexone, patients will receive 5-mg intravenous morphine

Ticagrelor

Intervention Type: DRUG

After morphine administration, patients will receive a 180-mg ticagrelor loading dose

Interventions

Methylnaltrexone

Methylnaltrexone will be administered diluted with 5 ml of normal saline as a single iv bolus

Intervention Type: DRUG

Placebo

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

Intervention Type: OTHER

Morphine

After methylnaltrexone, patients will receive 5-mg intravenous morphine

Intervention Type: DRUG

Ticagrelor

After morphine administration, patients will receive a 180-mg ticagrelor loading dose

Intervention Type: DRUG

Other Intervention Names

Relistor; Morphine sulfate; Brilinta

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Dominick Angiolillo

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

University of Florida

Jacksonville, Florida, United States

Countries

United States

References

Franchi F, Rollini F, Park Y, Hu J, Kureti M, Rivas Rios J, Faz G, Yaranov D, Been L, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Bass TA, Angiolillo DJ. Effects of Methylnaltrexone on Ticagrelor-Induced Antiplatelet Effects in Coronary Artery Disease Patients Treated With Morphine. JACC Cardiovasc Interv. 2019 Aug 26;12(16):1538-1549. doi: 10.1016/j.jcin.2019.05.028. Epub 2019 Jul 31.

Reference Type: DERIVED

PMID: 31377269 (View on PubMed)

Other Identifiers

AZ 10583 IISR

Identifier Type: -

Identifier Source: org_study_id