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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02217878
First Posted: August 15, 2014
Last Update Posted: September 12, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Jacek Kubica, Collegium Medicum w Bydgoszczy
  Purpose
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.

Condition Intervention Phase
ST-segment Elevation Myocardial Infarction Non-ST-segment Elevation Myocardial Infarction VA Drug Interactions Drug: Morphine Drug: Placebo Drug: Ticagrelor Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by Jacek Kubica, Collegium Medicum w Bydgoszczy:

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


Secondary Outcome Measures:
  • Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-12h) [ Time Frame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose ]
    Exposure to ticagrelor metabolite during the first 12 hours after ticagrelor loading dose

  • Maximum Concentration of Ticagrelor [ Time Frame: 12 hours ]
    Maximum concentration (Cmax) of ticagrelor

  • Maximum Concentration of AR-C124910XX [ Time Frame: 12 hours ]
    Maximum concentration (Cmax) of AR-C124910XX

  • Time to Maximum Concentration for Ticagrelor [ Time Frame: 12 hours ]
    Time to maximum concentration (Tmax) for ticagrelor

  • Time to Maximum Concentration for AR-C124910XX [ Time Frame: 12 hours ]
    Time to maximum concentration (Tmax) for AR-C124910XX

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

  • Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-6) [ Time Frame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose ]
    Exposure to ticagrelor metabolite during the first 6 hours after ticagrelor loading dose

  • Platelet Reactivity Index Assessed by VASP Assay [ Time Frame: prior to the initial ticagrelor dose ]
    Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

  • Platelet Reactivity Index Assessed by VASP Assay [ Time Frame: 30 minutes post ticagrelor dose ]
    Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

  • Platelet Reactivity Index Assessed by VASP Assay [ Time Frame: 1 hour post ticagrelor dose ]
    Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

  • Platelet Reactivity Index Assessed by VASP Assay [ Time Frame: 2 hours post ticagrelor dose ]
    Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

  • Platelet Reactivity Index Assessed by VASP Assay [ Time Frame: 3 hours post ticagrelor dose ]
    Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

  • Platelet Reactivity Index Assessed by VASP Assay [ Time Frame: 4 hours post ticagrelor dose ]
    Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

  • Platelet Reactivity Index Assessed by VASP Assay [ Time Frame: 6 hours post ticagrelor dose ]
    Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

  • Platelet Reactivity Index Assessed by VASP Assay [ Time Frame: 12 hours post ticagrelor dose ]
    Platelet Reactivity Index (PRI) evaluated by VASP assay (cut-off value for high platelet reactivity: PRI >50%)

  • Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry [ Time Frame: prior to the initial ticagrelor dose ]
    Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

  • Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry [ Time Frame: 30 minutes post ticagrelor dose ]
    Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

  • Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry [ Time Frame: 1 hour post ticagrelor dose ]
    Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

  • Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry [ Time Frame: 2 hours post ticagrelor dose ]
    Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

  • Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry [ Time Frame: 3 hours post ticagrelor dose ]
    Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

  • Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry [ Time Frame: 4 hours post ticagrelor dose ]
    Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

  • Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry [ Time Frame: 6 hours post ticagrelor dose ]
    Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

  • Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry [ Time Frame: 12 hours post ticagrelor dose ]
    Platelet reactivity assessed by Multiple Electrode Aggregometry (cut-off value for high platelet reactivity: AUC >46 Platelet Arbitrary Aggregation Units)

  • P2Y12 Reaction Units Assessed by VerifyNow [ Time Frame: prior to the initial ticagrelor dose ]
    P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

  • P2Y12 Reaction Units Assessed by VerifyNow [ Time Frame: 30 minutes post ticagrelor dose ]
    P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

  • P2Y12 Reaction Units Assessed by VerifyNow [ Time Frame: 1 hour post ticagrelor dose ]
    P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

  • P2Y12 Reaction Units Assessed by VerifyNow [ Time Frame: 2 hours post ticagrelor dose ]
    P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

  • P2Y12 Reaction Units Assessed by VerifyNow [ Time Frame: 3 hours post ticagrelor dose ]
    P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

  • P2Y12 Reaction Units Assessed by VerifyNow [ Time Frame: 4 hours post ticagrelor dose ]
    P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

  • P2Y12 Reaction Units Assessed by VerifyNow [ Time Frame: 6 hours post ticagrelor dose ]
    P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

  • P2Y12 Reaction Units Assessed by VerifyNow [ Time Frame: 12 hours post ticagrelor dose ]
    P2Y12 Reaction Units (PRU) Assessed by VerifyNow (cut-off value for high platelet reactivity: PRU >208)

  • Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VASP [ Time Frame: 2 hours ]
    Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VASP

  • Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With MEA [ Time Frame: 2 hours ]
    Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With MEA

  • Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VerifyNow [ Time Frame: 2 hours ]
    Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VerifyNow

  • Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VASP [ Time Frame: 12 hours ]
    Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VASP

  • Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With MEA [ Time Frame: 12 hours ]
    Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With MEA

  • Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VerifyNow [ Time Frame: 12 hours ]
    Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VerifyNow


Enrollment: 74
Study Start Date: August 2014
Study Completion Date: June 2015
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Morphine
morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor
Drug: Morphine
IV bolus injection
Other Name: Morphine sulfate
Drug: Ticagrelor
180 mg loading dose
Other Name: Brilique
Placebo Comparator: Placebo
sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor
Drug: Placebo
IV bolus injection
Other Name: Sodium chloride 0,9%
Drug: Ticagrelor
180 mg loading dose
Other Name: Brilique

Detailed Description:

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02217878


Locations
Poland
Cardiology Department, Dr. A. Jurasz University Hospital
Bydgoszcz, Kujawsko-pomorskie, Poland, 85-094
Sponsors and Collaborators
Collegium Medicum w Bydgoszczy
Investigators
Principal Investigator: Prof. Jacek Kubica, MD, PhD Collegium Medicum im. Ludwika Rydygiera w Bydgoszczy, Uniwersytet Mikołaja Kopernika w Toruniu
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Jacek Kubica, Prof. dr hab., Collegium Medicum w Bydgoszczy
ClinicalTrials.gov Identifier: NCT02217878     History of Changes
Other Study ID Numbers: CMUMK202
First Submitted: August 14, 2014
First Posted: August 15, 2014
Results First Submitted: February 4, 2016
Results First Posted: March 3, 2016
Last Update Posted: September 12, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Jacek Kubica, Collegium Medicum w Bydgoszczy:
ST-segment elevation myocardial infarction
non-ST-segment elevation myocardial infarction
ticagrelor
morphine
pharmacokinetics
pharmacodynamics
drug interactions
VASP assay
Multiple Electrode Aggregometry
VerifyNow

Additional relevant MeSH terms:
Infarction
Myocardial Infarction
ST Elevation Myocardial Infarction
Ischemia
Pathologic Processes
Necrosis
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Morphine
Ticagrelor
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action