Influence of Morphine on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Patients With Acute Myocardial Infarction

Study Overview
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Brief Summary
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The purpose of the IMPRESSION study is to determine whether intravenous administration of morphine prior to ticagrelor administration in ST-segment elevation myocardial infarction (STEMI) patients and in non-ST-segment elevation myocardial infarction (NSTEMI) patients alters the plasma concentrations of ticagrelor and its active metabolite and whether it is associated with any negative impact on the antiplatelet effect of ticagrelor.

Detailed Description
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The European Society of Cardiology and American Heart Association guidelines recommend use of morphine as a treatment of choice for pain relief in STEMI patients. However, this recommendation, although strong, is only based on expert consensus (class of recommendation I, level of evidence C). Morphine, apart from its analgesic effects, also alleviates the work of breathing and reduces anxiety. On the other hand, despite its favorable analgesic and sedative actions, morphine also exerts adverse effects, which include hypotension, bradycardia, respiratory depression, vomiting and reduction of gastrointestinal motility. Some of the previously listed morphine's side effects could affect the intestinal absorption and thus pharmacokinetics and pharmacodynamics of orally administered drugs which are concomitantly used with morphine. At present, no pharmacokinetic and pharmacodynamic data regarding the concurrent use of morphine and P2Y12 blockers in the STEMI or NSTEMI setting are available. Therefore, evidence-based verification of morphine's influence on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) could provide a valuable insight in the knowledge regarding modern acute myocardial infarction management. Predefined subanalysis: aimed to investigate which one of platelet reactivity assessment methods utilized in the study (VASP assay, MEA, LTA, VerifyNow) best reflects concentration of ticagrelor and its active metabolite (AR-C124910XX). Since there is no reference study examining pharmacokinetics of ticagrelor in STEMI or NSTEMI patients, we decided to perform an internal pilot study of approximately 30 patients (15 patients for each arm) for estimating the final sample size.

Official Title
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A Randomized, Double-blind Study Evaluating the Influence of Morphine on Pharmacokinetics and Pharmacodynamics of Ticagrelor and Its Active Metabolite (AR-C124910XX) in Patients With ST-segment Elevation Myocardial Infarction and Non-ST-segment Elevation Myocardial Infarction.

Conditions
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Non-ST-segment Elevation Myocardial Infarction, ST-segment Elevation Myocardial Infarction, VA Drug Interactions

Intervention / Treatment
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* Drug: Morphine
* Drug: Placebo
* Drug: Ticagrelor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: provision of informed consent prior to any study specific procedures diagnosis of acute ST-segment elevation myocardial infarction or acute non-ST-segment elevation myocardial infarction male or non-pregnant female, aged 18-80 years old provision of informed consent for angiography and PCI Exclusion Criteria: chest pain described by the patient as unbearable or patient's request for analgesics prior morphine administration during the current STEMI or NSTEMI treatment with ticlopidine, clopidogrel, prasugrel or ticagrelor within 14 days before the study enrollment 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) patients considered by the investigator to be at risk of bradycardic events second or third degree atrioventricular block during screening for eligibility history of asthma or severe chronic obstructive pulmonary disease patient required 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Morphine<br>morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor | Drug: Morphine<br>* IV bolus injection<br>* Other names: Morphine sulfate;Drug: Ticagrelor<br>* 180 mg loading dose<br>* Other names: Brilique;|
| Placebo Comparator: Placebo<br>sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor | Drug: Placebo<br>* IV bolus injection<br>* Other names: Sodium chloride 0,9%;Drug: Ticagrelor<br>* 180 mg loading dose<br>* Other names: Brilique;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-12h) | Exposure to ticagrelor during the first 12 hours after ticagrelor loading dose | prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-12h) | Exposure to ticagrelor metabolite during the first 12 hours after ticagrelor loading dose | prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose | 
| Maximum Concentration of Ticagrelor | Maximum concentration (Cmax) of ticagrelor | 12 hours | 
| Maximum Concentration of AR-C124910XX | Maximum concentration (Cmax) of AR-C124910XX | 12 hours | 
| Time to Maximum Concentration for Ticagrelor | Time to maximum concentration (Tmax) for ticagrelor | 12 hours | 
| Time to Maximum Concentration for AR-C124910XX | Time to maximum concentration (Tmax) for AR-C124910XX | 12 hours | 
| Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-6h) | Exposure to ticagrelor during the first 6 hours after ticagrelor loading dose | prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose | 
| Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-6) | Exposure to ticagrelor metabolite during the first 6 hours after ticagrelor loading dose | prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose | 
| Platelet Reactivity Index Assessed by VASP Assay | Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%) | prior to the initial ticagrelor dose | 
| Platelet Reactivity Index Assessed by VASP Assay | Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%) | 30 minutes post ticagrelor dose | 
| Platelet Reactivity Index Assessed by VASP Assay | Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%) | 1 hour post ticagrelor dose | 
| Platelet Reactivity Index Assessed by VASP Assay | Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%) | 2 hours post ticagrelor dose | 
| Platelet Reactivity Index Assessed by VASP Assay | Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%) | 3 hours post ticagrelor dose | 
| Platelet Reactivity Index Assessed by VASP Assay | Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%) | 4 hours post ticagrelor dose | 
| Platelet Reactivity Index Assessed by VASP Assay | Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%) | 6 hours post ticagrelor dose | 
| Platelet Reactivity Index Assessed by VASP Assay | Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%) | 12 hours post ticagrelor dose | 
| Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units) | prior to the initial ticagrelor dose | 
| Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units) | 30 minutes post ticagrelor dose | 
| Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units) | 1 hour post ticagrelor dose | 
| Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units) | 2 hours post ticagrelor dose | 
| Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units) | 3 hours post ticagrelor dose | 
| Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units) | 4 hours post ticagrelor dose | 
| Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units) | 6 hours post ticagrelor dose | 
| Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry | Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units) | 12 hours post ticagrelor dose | 
| P2Y12 Reaction Units Assessed by VerifyNow | P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208) | prior to the initial ticagrelor dose | 
| P2Y12 Reaction Units Assessed by VerifyNow | P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208) | 30 minutes post ticagrelor dose | 
| P2Y12 Reaction Units Assessed by VerifyNow | P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208) | 1 hour post ticagrelor dose | 
| P2Y12 Reaction Units Assessed by VerifyNow | P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208) | 2 hours post ticagrelor dose | 
| P2Y12 Reaction Units Assessed by VerifyNow | P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208) | 3 hours post ticagrelor dose | 
| P2Y12 Reaction Units Assessed by VerifyNow | P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208) | 4 hours post ticagrelor dose | 
| P2Y12 Reaction Units Assessed by VerifyNow | P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208) | 6 hours post ticagrelor dose | 
| P2Y12 Reaction Units Assessed by VerifyNow | P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208) | 12 hours post ticagrelor dose | 
| Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VASP | Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VASP | 2 hours | 
| Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With MEA | Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With MEA | 2 hours | 
| Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VerifyNow | Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VerifyNow | 2 hours | 
| Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VASP | Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VASP | 12 hours | 
| Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With MEA | Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With MEA | 12 hours | 
| Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VerifyNow | Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VerifyNow | 12 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, ticagrelor, morphine, pharmacokinetics, pharmacodynamics, drug interactions, VASP assay, Multiple Electrode Aggregometry, VerifyNow