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.
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 74
- 试验地点
- 1
- 主要终点
- Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-12h)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Morphine
morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor
干预措施: Morphine (Drug)
Morphine
morphine sulfate 5 mg IV followed by 180 mg loading dose of ticagrelor
干预措施: Ticagrelor (Drug)
Placebo
sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor
干预措施: Placebo (Drug)
Placebo
sodium chloride 0,9% 5 mg IV followed by 180 mg loading dose of ticagrelor
干预措施: Ticagrelor (Drug)
结局指标
主要结局
Area Under the Plasma Concentration-time Curve for Ticagrelor (AUC 0-12h)
时间窗: 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
次要结局
- Time to Maximum Concentration for AR-C124910XX(12 hours)
- Percentage of Patients With High Platelet Reactivity After the Loading Dose of Ticagrelor Assessed With MEA(2 hours)
- Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VASP(12 hours)
- Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With MEA(12 hours)
- Maximum Concentration of Ticagrelor(12 hours)
- 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)
- Maximum Concentration of AR-C124910XX(12 hours)
- Time to Maximum Concentration for Ticagrelor(12 hours)
- Platelet Reactivity Index Assessed by VASP Assay(12 hours post ticagrelor dose)
- P2Y12 Reaction Units Assessed by VerifyNow(12 hours post ticagrelor dose)
- 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)
- 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)
- Platelet Arbitrary Aggregation Units Assessed by Multiple Electrode Aggregometry(12 hours post ticagrelor dose)
- Percentage of Patients With High Platelet Reactivity 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 VerifyNow(2 hours)
- Time to Reach Platelet Reactivity Below the Cut-off Value for High Platelet Reactivity Evaluated With VerifyNow(12 hours)
研究者
Jacek Kubica
Prof. dr hab.
Collegium Medicum w Bydgoszczy