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

NCT02403830 | Completed Phase 4 Results DMC

• 1 other identifier: AZ 10583 IISR
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Coronary Artery Disease

Outcome Measures

Primary Outcomes (1)

• Platelet Reactivity Measured by VerifyNow P2Y12

  Platelet reactivity measured by VerifyNow P2Y12 2 hours after ticagrelor loading dose and reported as P2Y12 reaction units (PRU)

  2 hours

Secondary Outcomes (2)

• Platelet Reactivity Measured by VASP

  2 hours

• AUC of Ticagrelor Plasma Levels

  6 hours

Study Arms (2)

Methylnaltrexone

EXPERIMENTAL

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; Drug: Morphine; Drug: Ticagrelor

Placebo

PLACEBO COMPARATOR

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; Drug: Morphine; Drug: Ticagrelor

Interventions

Methylnaltrexone DRUG

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

Also known as: Relistor

Methylnaltrexone

Placebo OTHER

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

Placebo

Morphine DRUG

After methylnaltrexone, patients will receive 5-mg intravenous morphine

Also known as: Morphine sulfate

Methylnaltrexone; Placebo

Ticagrelor DRUG

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

Also known as: Brilinta

Methylnaltrexone; Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Florida: lead

Study Sites (1)

University of Florida

Jacksonville, Florida, 32209, United States

Location

Related Publications (1)

• 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.

  PMID: 31377269 DERIVED

MeSH Terms

Conditions

Coronary Artery Disease

Interventions

methylnaltrexone; Morphine; Ticagrelor

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Dominick J. Angiolillo, MD, PhD
• Organization: University of Florida College of Medicine-Jacksonville

dominick.angiolillo@jax.ufl.edu

+1-904-244-3933

Study Officials

• Dominick Angiolillo

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 17, 2015
• First Posted: March 31, 2015
• Study Start: August 1, 2015
• Primary Completion: May 1, 2016
• Study Completion: May 1, 2016
• Last Updated: May 30, 2017
• Results First Posted: April 27, 2017

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)