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

ST-segment Elevation Myocardial Infarction Clinical Trial

— IMPRESSION  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02217878
• Other study ID #: CMUMK202
• Status: Completed
• Phase: Phase 4
• First received: August 14, 2014
• Last updated: February 4, 2016
• Start date: August 2014
• Est. completion date: June 2015

Study information

• Verified date: February 2016
• Source: Collegium Medicum w Bydgoszczy
• Contact: n/a
• Is FDA regulated: No
• Health authority: Poland: Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 74
• Est. completion date: June 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction
• Non-ST-segment Elevation Myocardial Infarction
• ST-segment Elevation Myocardial Infarction
• VA Drug Interactions [VA Drug Interaction]

Intervention

Drug:
• Morphine
IV bolus injection
• Placebo
IV bolus injection
• Ticagrelor
180 mg loading dose

Locations

Country	Name	City	State
Poland	Cardiology Department, Dr. A. Jurasz University Hospital	Bydgoszcz	Kujawsko-pomorskie

Sponsors (1)

Lead Sponsor	Collaborator
Collegium Medicum w Bydgoszczy

Country where clinical trial is conducted

Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-12h)		prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose	No
Secondary	Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-12h)		prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose	No
Secondary	Maximum Concentration (Cmax) of Ticagrelor and AR-C124910XX		12 hours	No
Secondary	Time to Maximum Concentration (Cmax) for Ticagrelor and AR-C124910XX		12 hours	No
Secondary	Platelet Reactivity Index (PRI) Assessed by VASP Assay	It will be assessed in all study participants in all predefined time points.	prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose	No
Secondary	Platelet Arbitrary Aggregation Units/Min Assessed by Multiple Electrode Aggregometry	It will be assessed in all predefined time points in all study participants except those treated with GP IIb/IIIa receptor inhibitors.	prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose	No
Secondary	P2Y12 Reaction Units (PRU) Assessed by VerifyNow	It will be assessed in at least 30% of study participants (with 1:1 ratio between morphine and placebo arms) in all predefined time points. Measurements will not be performed in patients treated with GP IIb/IIIa receptor inhibitors.	prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h, 12h post dose	No
Secondary	Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-6h)		prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose	No
Secondary	Area Under the Plasma Concentration-time Curve for AR-C124910XX (AUC 0-6)		prior to the initial dose and 30min, 1h, 2h, 3h, 4h, 6h post dose	No
Secondary	Percentage of Patients With High Platelet Reactivity (HPR) After the Loading Dose of Ticagrelor Assessed With VASP, MEA and VerifyNow		2 hours	No
Secondary	Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity (HPR) Evaluated With VASP, MEA and VerifyNow		12 hours	No