The Effect of Opioids on P2Y12 Receptor Inhibition in Patients With ST-Elevation Myocardial Infarction Who Are Pre-treated With Crushed Ticagrelor (ON-TIME 3)

Fast and accurate platelet inhibition is an important therapeutic goal in the acute treatment of patients with ST-segment elevation myocardial infarction (STEMI). Platelet inhibitory effects induced by normal oral P2Y12 receptor antagonists, for example ticagrelor, are delayed in STEMI patients undergoing primary percutaneous coronary intervention (primary PCI), which may be attributed to impaired absorption affecting drug pharmacokinetics (PK) and pharmacodynamics (PD). Another therapeutic goal in the acute treatment of STEMI is reduction of sympathetic stress and catecholamine release, thereby improving the balance between the demand for and supply of oxygen, by analgesia like fentanyl of morphine. To date, there are no studies that have specifically assessed the pharmacodynamics influences of fentanyl on platelet inhibition in STEMI patients who are pre-treated with crushed ticagrelor tablets. Therefore, In the ON-TIME-3 study, the investigators seek to show the influence of fentanyl on platelet inhibition in STEMI patients who are pre-treated with crushed ticagrelor in the ambulance.

Study Overview

• Status: Completed
• Conditions: STEMI; STEMI - ST Elevation Myocardial Infarction
• Intervention / Treatment: Drug: Paracetamol; Drug: Fentanyl

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Zwolle, Netherlands
    • Isala Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

i. age ≥18 years

ii. referred by ambulance paramedics to Isala (Zwolle) or Zuyderland Hospital (Heerlen)

iii. diagnosed in the ambulance with STEMI defined as:

1. ongoing chest pain >30 minutes and <12 hours duration and
2. ST-segment elevation >0.1 milliVolt in at least 2 contiguous leads

iv. ongoing chest pain with a pain score (NRS) ≥4

v. the patient has been informed of the nature of the study, agrees to its provisions and has provided verbal informed consent in the pre-hospital phase followed by written informed consent in hospital

Exclusion Criteria:

i. presenting with cardiogenic shock; defined as:

1. systolic blood pressure <90 mmHg and
2. heart rate >100/min and
3. peripheral oxygen saturation <90% (without oxygen administration)

ii. patients with a nasogastric tube in situ or requiring a nasogastric tube

iii. patients who already received fentanyl or paracetamol <2 hours prior to randomization

iv. patients on current treatment with P2Y12 inhibitors (ticagrelor, clopidogrel or prasugrel)

v. allergy to morphine or paracetamol

vi. patients with recent major bleeding complications or contraindication to dual antiplatelet therapy:

1. hypersensitivity to aspirin or ticagrelor
2. current use of (new) oral anticoagulation
3. history of bleeding diathesis or known coagulopathy
4. active bleeding
5. refusal of blood transfusions
6. history of intracerebral mass, aneurysm, arteriovenous malformation, or hemorrhagic stroke
7. known severe liver dysfunction

vii. received any organ transplant or is on a waiting list for any organ transplant

viii. patients undergoing dialysis

ix. pregnant or lactating female

x. patients currently participating in another investigational drug or device study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: paracetamol; Patients are randomized to paracetamol 1000 mg iv or fentanyl 1-2 mcg/kg with a maximum of 4 mcg/kg iv.	Drug: Paracetamol; Patients are randomized to paracetamol 1000 mg iv or fentanyl 1-2 mcg/kg with a maximum of 4 mcg/kg iv.
Active Comparator: fentanyl	Drug: Fentanyl; Patients are randomized to paracetamol 1000 mg iv or fentanyl 1-2 mcg/kg with a maximum of 4 mcg/kg iv.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
platelet reactivity	Platelet reactivity units (PRU) directly post-PCI or 1 hour post-angiography	directly post-PCI or 1 hour post-angiography

Collaborators and Investigators

• Sponsor: A.H. Tavenier
• Collaborators: Isala

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2018
• Primary Completion (Actual): October 22, 2019
• Study Completion (Actual): November 22, 2019

Study Registration Dates

• First Submitted: October 30, 2017
• First Submitted That Met QC Criteria: January 12, 2018
• First Posted (Actual): January 17, 2018

Study Record Updates

• Last Update Posted (Actual): February 12, 2020
• Last Update Submitted That Met QC Criteria: February 11, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; ST Elevation Myocardial Infarction; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Antipyretics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Fentanyl; Acetaminophen
• Other Study ID Numbers: ON-TIME 3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No