Clinical trial NCT02217878: Influence of Morphine on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Patients With Acute Myocardial Infarction
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: ST-segment Elevation Myocardial Infarction
Non-ST-segment Elevation Myocardial Infarction
VA Drug Interactions
Keywords: ST-segment elevation myocardial infarction
non-ST-segment elevation myocardial infarction
ticagrelor
morphine
pharmacokinetics
pharmacodynamics
drug interactions
VASP assay
Multiple Electrode Aggregometry
VerifyNow
Lead sponsor: Collegium Medicum w Bydgoszczy
Sponsor class: OTHER
First posted: 2014-08-15
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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 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

Primary outcomes:
measure: Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-12h)
timeFrame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose
Secondary outcomes:
measure: Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-12h)
timeFrame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose
measure: Maximum Concentration of Ticagrelor
timeFrame: 12 hours
measure: Maximum Concentration of AR-C124910XX
timeFrame: 12 hours
measure: Time to Maximum Concentration for Ticagrelor
timeFrame: 12 hours
measure: Time to Maximum Concentration for AR-C124910XX
timeFrame: 12 hours
measure: Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-6h)
timeFrame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose
measure: Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-6)
timeFrame: prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose
measure: Platelet Reactivity Index Assessed by VASP Assay
timeFrame: prior to the initial ticagrelor dose
measure: Platelet Reactivity Index Assessed by VASP Assay
timeFrame: 30 minutes post ticagrelor dose
measure: Platelet Reactivity Index Assessed by VASP Assay
timeFrame: 1 hour post ticagrelor dose
measure: Platelet Reactivity Index Assessed by VASP Assay
timeFrame: 2 hours post ticagrelor dose
measure: Platelet Reactivity Index Assessed by VASP Assay
timeFrame: 3 hours post ticagrelor dose
measure: Platelet Reactivity Index Assessed by VASP Assay
timeFrame: 4 hours post ticagrelor dose
measure: Platelet Reactivity Index Assessed by VASP Assay
timeFrame: 6 hours post ticagrelor dose
measure: Platelet Reactivity Index Assessed by VASP Assay
timeFrame: 12 hours post ticagrelor dose
measure: Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
timeFrame: prior to the initial ticagrelor dose
measure: Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
timeFrame: 30 minutes post ticagrelor dose
measure: Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
timeFrame: 1 hour post ticagrelor dose
measure: Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
timeFrame: 2 hours post ticagrelor dose
measure: Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
timeFrame: 3 hours post ticagrelor dose
measure: Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
timeFrame: 4 hours post ticagrelor dose
measure: Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
timeFrame: 6 hours post ticagrelor dose
measure: Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry
timeFrame: 12 hours post ticagrelor dose
measure: P2Y12 Reaction Units Assessed by VerifyNow
timeFrame: prior to the initial ticagrelor dose
measure: P2Y12 Reaction Units Assessed by VerifyNow
timeFrame: 30 minutes post ticagrelor dose
measure: P2Y12 Reaction Units Assessed by VerifyNow
timeFrame: 1 hour post ticagrelor dose
measure: P2Y12 Reaction Units Assessed by VerifyNow
timeFrame: 2 hours post ticagrelor dose
measure: P2Y12 Reaction Units Assessed by VerifyNow
timeFrame: 3 hours post ticagrelor dose
measure: P2Y12 Reaction Units Assessed by VerifyNow
timeFrame: 4 hours post ticagrelor dose
measure: P2Y12 Reaction Units Assessed by VerifyNow
timeFrame: 6 hours post ticagrelor dose
measure: P2Y12 Reaction Units Assessed by VerifyNow
timeFrame: 12 hours post ticagrelor dose
measure: Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VASP
timeFrame: 2 hours
measure: Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With MEA
timeFrame: 2 hours
measure: Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With VerifyNow
timeFrame: 2 hours
measure: Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VASP
timeFrame: 12 hours
measure: Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With MEA
timeFrame: 12 hours
measure: Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VerifyNow
timeFrame: 12 hours
Other outcomes:
Locations:
city: Bydgoszcz
country: Poland
facility: Cardiology Department, Dr. A. Jurasz University Hospital
state: Kujawsko-pomorskie
Study officials:
affiliation: Collegium Medicum im. Ludwika Rydygiera w Bydgoszczy, Uniwersytet Mikołaja Kopernika w Toruniu
name: Prof. Jacek Kubica, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kubica J, Adamski P, Ostrowska M, Sikora J, Kubica JM, Sroka WD, Stankowska K, Buszko K, Navarese EP, Jilma B, Siller-Matula JM, Marszall MP, Rosc D, Kozinski M. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J. 2016 Jan 14;37(3):245-52. doi: 10.1093/eurheartj/ehv547. Epub 2015 Oct 21.
citation: Kubica J, Adamski P, Ostrowska M, Kozinski M, Obonska K, Laskowska E, Obonska E, Grzesk G, Winiarski P, Paciorek P. Influence of Morphine on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Patients with Acute Myocardial Infarction (IMPRESSION): study protocol for a randomized controlled trial. Trials. 2015 Apr 29;16:198. doi: 10.1186/s13063-015-0724-z.