Influence of METHoxyflurane on ANtiplatelet Effect of Ticagrelor in Patients With Unstable Angina Pectoris (METHANE)

Influence of METHoxyflurane on ANtiplatelet Effect of Ticagrelor in Patients With Unstable Angina Pectoris - METHANE Study

The purpose of this study is to evaluate differences in the pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite in patients who received ticagrelor followed with methoxyflurane versus ticagrelor followed with morphine or ticagrelor alone due to unstable angina pectoris

Study Overview

• Status: Completed
• Conditions: Unstable Angina
• Intervention / Treatment: Drug: Ticagrelor followed with Methoxyflurane; Drug: Ticagrelor followed with Morphine; Drug: Ticagrelor alone

Detailed Description

Results of the IMPRESSION trial published in 2015 proved that morphine use in patients with acute coronary syndromes (ACS) is associated with undesirable impact on pharmacokinetics (PK) and pharmacodynamics (PD) of ticagrelor. Despite that, morphine is still a standard analgesic treatment in ACS patients and it should not be routinely withdrawn. Based on contemporary knowledge, morphine, acting via mi-opioid receptors, was found to inhibit gastrointestinal motility or induce adverse effects such as nausea or vomiting.

We decided to design a clinical study aiming to evaluate the impact of methoxyflurane on PD of ticagrelor in patients diagnosed with unstable angina pectoris (UA). Methoxyflurane is an inhaled anesthetic, registered in Poland in emergency medicine for pain alleviation in trauma patients. The drug was widely used in 1960s to induce general anesthesia, however its clinical utility was reduced with the development of novel anesthetic agents. Taking into account its different mechanism of action, it can be presumed that, contrary to morphine, no respiratory depression should be observed as well as no attenuation or delay of antiaggregatory effect of ticagrelor should occur, as no interaction with mi-receptor in gastrointestinal tract is related to activity of methoxyflurane.

Patients will be randomized in a 1:1:1 ratio into the study arms as follows: 1) 180 mg ticagrelor (2 integral tablets of 90 mg ticagrelor) followed by 3 mg inhaled methoxyflurane, 2) 180 mg ticagrelor followed by 5 mg intravenous morphine, 3) 180 mg ticagrelor alone

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 4

Contacts and Locations

Study Locations

• Poland
  • Kujawsko-Pomorskie
    • Bydgoszcz, Kujawsko-Pomorskie, Poland, 85-094
      • Cardiology Department, Dr. A. Jurasz University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Provision of informed consent prior to any study specific procedures
• Diagnosis of unstable angina
• Male or non-pregnant female, aged 18-80 years
• Provision of informed consent for angiography and PCI
• GRACE score <140 pts

Exclusion Criteria:

• Treatment with ticlopidine, clopidogrel, prasugrel or ticagrelor within 14 days before the study enrollment
• Current treatment with morphine or any opioid "mi" receptor agonist
• Hypersensitivity to ticagrelor
• Current treatment with oral anticoagulant or chronic therapy with low-molecular-weight heparin
• Active bleeding
• History of intracranial hemorrhage
• Recent gastrointestinal bleeding (within 30 days)
• History of coagulation disorders
• Platelet count less than <100 x10^3/mcl
• Hemoglobin concentration less than 10.0 g/dl
• History of moderate or severe hepatic impairment
• History of major surgery or severe trauma (within 3 months)
• Risk of bradycardic events as judged by the investigator
• Second- or third-degree atrioventricular block during screening for eligibility
• History of asthma or severe chronic obstructive pulmonary disease
• Kidney disease requiring dialysis
• Manifest infection or inflammatory state
• Killip class III or IV during screening for eligibility
• Respiratory failure
• History of severe chronic heart failure (NYHA class III or IV)
• Concomitant therapy with strong CYP3A inhibitors (ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir) or strong CYP3A inducers (rifampicin, phenytoin, carbamazepine, dexamethasone, phenobarbital) within 14 days and during study treatment
• Body weight below 50 kg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ticagrelor followed with methoxyflurane; patients who received ticagrelor followed with inhaled methoxyflurane due to unstable angina	Drug: Ticagrelor followed with Methoxyflurane; patients who received ticagrelor followed with inhaled methoxyflurane due to unstable angina; Other Names: Brilique + Penthrox
Active Comparator: Ticagrelor followed with morphine; patients who received ticagrelor followed with intravenous morphine due to unstable angina	Drug: Ticagrelor followed with Morphine; patients who received ticagrelor followed with intravenous morphine due to unstable angina; Other Names: Brilique + Morphine
Active Comparator: Ticagrelor; patients who received ticagrelor without any analgesia due to unstable angina	Drug: Ticagrelor alone; patients who received ticagrelor without any analgesia due to unstable angina; Other Names: Brilique

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean platelet reactivity between the study arms	Mean platelet reactivity between the study arms, assessed using the Multiplate Analyzer	6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The percentage of high platelet reactivity patients (HPR) throughout the study period	the percentage of patients with high platelet reactivity throughout the study period	6 hours
Mean time to achieve platelet reactivity below the threshold for HPR	Mean time required for patients to receive low platelet reactivity in each study arm	6 hours
area under the plasma concentration-time curve for ticagrelor and its active metabolite between the study arms	area under the plasma concentration-time curve for ticagrelor and its active metabolite between the study arms	6 hours

Collaborators and Investigators

• Sponsor: Collegium Medicum w Bydgoszczy
• Investigators: Principal Investigator: Jacek Kubica, Professor, Collegium Medicum w Bydgoszczy

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Actual): January 31, 2024
• Study Completion (Actual): February 29, 2024

Study Registration Dates

• First Submitted: June 19, 2020
• First Submitted That Met QC Criteria: June 19, 2020
• First Posted (Actual): June 23, 2020

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Pain; Neurologic Manifestations; Chest Pain; Angina Pectoris; Angina, Unstable; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, General; Anesthetics; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Analgesics, Opioid; Narcotics; Anesthetics, Inhalation; Ticagrelor; Morphine; Methoxyflurane
• Other Study ID Numbers: METHANE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No