Methylnaltrexone as a Method to Improve Ticagrelor Uptake in Morphine Treated STEMI Patients

Study Overview
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Brief Summary
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This study will examine the impact of the peripheral opioid antagonist methylnaltrexone on the onset of effect of ticagrelor in morphine treated patients with ST elevation myocardial infarction (STEMI). Half of the participants will receive methylnaltrexone, while the other half will receive placebo.

Detailed Description
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The rate of drug absorption in the gastro-intestinal tract is often determined by the rate of gastric emptying. Morphine treatment, which is frequently given in order to relieve pain in patients with STEMI, is known to delay gastric emptying, and has indeed emerged as a predictor of delayed/poor antiplatelet response in patients receiving oral prasugrel or ticagrelor. In recent years, morphine has been found to delay the onset of oral P2Y12-inhibitors. To counteract this, the investigators hypothesized that an opioid antagonist may be used. The opioid antagonist naloxone has previously been shown to reduce the morphine induced delay in gastric emptying However, naloxone crosses the blood-brain barrier (BBB) and reduces the pain relieving effects of morphine. In contrast, the morphine antagonist methylnaltrexone has a reduced passage over the BBB and acts primarily as a peripheral morphine antagonist without affecting the morphine-mediated central analgesic effects. The aim of the planned study is to evaluate whether methylnaltrexone bromide may reduce the morphine induced delay in onset of platelet inhibition after a loading dose of 180 mg ticagrelor in morphine treated patients with STEMI undergoing primary percutaneous coronary intervention (PCI), where a rapid and adequate platelet inhibition after the administration of ticagrelor is crucial. As morphine is an inclusion criterion, all patients included in the study will be on morphine treatment. Thus, morphine treatment is not an intervention to be administered as part of the protocol. Stratification according to inferior and anterior/lateral STEMI will be perform to avoid imbalance in the location of myocardial infarction between the groups.

Official Title
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Methylnaltrexone as a Method to imprOVE Platelet Inhibition of Ticagrelor in Morphine-treated Patients With ST-segMENT Elevation Myocardial Infarction: a Prospective, Single Blinded Randomized, Placebo-controlled Trial

Conditions
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STEMI, Morphine, Ticagrelor, Methylnaltrexone

Intervention / Treatment
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* Drug: Methylnaltrexone bromide (Relistor®).
* Drug: Sodium Chloride 9mg/mL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of STEMI Administration of a 180 mg loading dose ticagrelor Analgesic treatment with intravenous morphine pre-PCI Exclusion Criteria: Cardiac arrest Body weight > 114kg Vomiting after intake of ticagrelor loading dose Use of Naloxone before inclusion or during sampling period Inability to understand study outline and instructions Methylnaltrexone bromide contraindication Age <18 years; 8) Women in fertile age Administration of ticagrelor during the week before inclusion Treatment with Cangrexal Ongoing long-term opioid treatment.

Ages Eligible for Study
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Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Methylnaltrexone<br>Methylnaltrexone bromide (Relistor®). Single intravenous injection of 8 mg (0.4 ml solution) for patients weighing 38-61 kg or 12 mg (0.6 ml solution) patients weighing 62-114 kg). | Drug: Methylnaltrexone bromide (Relistor®).<br> <br> |
| Placebo Comparator: Placebo<br>Sodium Chloride, 9mg /mL ingle intravenous injection of 0.4 mL solution for patients weighing 38-61 kg or 0.6 mL solution patients weighing 62-114 kg). | Drug: Sodium Chloride 9mg/mL<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| High on-treatment platelet reactivity (HPR) | HPR defined as platelet reactivity index (PRI) ≥50% using VASP analysis | Two hours after the injection of either active drug or placebo | 
| Number of participants with serious adverse events | Serious AE is any untoward medical occurrence that at any dose: Results in death. Is life-threatening at the time of the event. Requires inpatient hospitalization. Requires prolongation of existing hospitalization. Results in persistent or significant disability/incapacity. Is a congenital anomaly/birth defect. | Within 48 hours after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| High on-treatment platelet reactivity |  | One hour after the injection of either active drug or placebo | 
| Difference in ticagrelor and AR-C124910XX concentrations |  | One and two hours after the injection of either active drug or placebo | 
| Change in patient pain according to visual analog scale |  | One and two hours after the injection of either active drug or placebo | 
| Difference in ticagrelor and AR-C124910XX concentrations between patients with inferior STEMI and patients with anterior/lateral STEMI. |  | One and two hours after the injection of either active drug or placebo | 
| Difference in high on-treatment platelet reactivity (HPR) between patients with inferior STEMI and patients with anterior/lateral STEMI. | HPR defined as platelet reactivity index (PRI) ≥50% using VASP analysis | One and two hours after the injection of either active drug or placebo |