Jacksonville, Florida 32209

  • Coronary Artery Disease

Purpose:

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 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. 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.


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.


Study is Available At:


Original ID:

AZ 10583 IISR


NCT ID:

NCT02403830


Secondary ID:


Study Acronym:


Brief Title:

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


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


Overall Status:

Recruiting


Study Phase:

Phase 4


Genders:

Both


Minimum Age:

18 Years


Maximum Age:

80 Years


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

University of Florida


Oversight Authority:

United States: Food and Drug Administration


Reasons Why Stopped:


Study Type:

Interventional


Study Design:

Allocation: Randomized, Endpoint Classification: P


Number of Arms:

2


Number of Groups:

0


Total Enrollment:

30


Enrollment Type:

Anticipated


Overall Contact Information

Official Name:Dominick Angiolillo
Principal Investigator
University of Florida
Primary Contact:Dominick Angiolillo
dominick.angiolillo@jax.ufl.edu
Backup Contact:Donna Evans
donna.evans@jax.ufl.edu

Study Dates

Start Date:August 2015
Completion Date:June 2016
Completion Type:Anticipated
Primary Completion Date:May 2016
Primary Completion Type:Anticipated
Verification Date:March 2016
Last Changed Date:March 15, 2016
First Received Date:February 17, 2015

Study Outcomes

Outcome Type:Primary Outcome
Measure:Platelet reactivity measured by VerifyNow P2Y12
Time Frame:2 hours
Safety Issues:False
Description:Platelet reactivity will be measured by VerifyNow P2Y12 2 hours after ticagrelor loading dose and will be reported as P2Y12 reaction units (PRU)

Study Interventions

Intervention Type:Drug
Name:Methylnaltrexone
Description:Methylnaltrexone will be administered diluted with 5 ml of normal saline as a single iv bolus
Arm Name:Methylnaltrexone
Other Name:Relistor
Intervention Type:Other
Name:Placebo
Description:Placebo will be administered as a 0.9% sodium chloride iv injection
Arm Name:Placebo
Intervention Type:Drug
Name:Morphine
Description:After methylnaltrexone, patients will receive 5-mg intravenous morphine
Arm Name:Methylnaltrexone
Other Name:Morphine sulfate
Intervention Type:Drug
Name:Ticagrelor
Description:After morphine administration, patients will receive a 180-mg ticagrelor loading dose
Arm Name:Methylnaltrexone
Other Name:Brilinta

Study Arms

Study Arm Type:Placebo Comparator
Arm Name:Placebo
Description: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.
Study Arm Type:Experimental
Arm Name:Methylnaltrexone
Description: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.

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:University of Florida

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: March 26, 2020

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