TIMES: Ticagrelor vs. Placebo/ Clopidogrel With Aspirin in Anterior STEMI Patients Treated With Primary PCI

ST Elevation Myocardial Infarction Clinical Trial

Official title:

A Randomised Mechanistic Study Comparing the Effects of Different Anti-platelet Combinations (Ticagrelor vs. Placebo/ Clopidogrel) With Aspirin in Patients Presenting With Anterior STEMI Treated With Primary PCI

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03145194
• Other study ID #: P01910
• Status: Recruiting
• Phase: Phase 2
• First received: April 13, 2017
• Last updated: May 25, 2017
• Start date: January 30, 2017
• Est. completion date: November 30, 2019

Study information

• Verified date: May 2017
• Source: Papworth Hospital NHS Foundation Trust
• Contact: Stephen Hoole
• Phone: 01480 366172
• Email: s.hoole[@]nhs.net
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a single-centred, double blind randomized controlled trial comparing ticagrelor with placebo in clopidogrel and aspirin loaded patients.

Description:

The very early benefit of ticagrelor in STEMI is co-mediated by adenosine cardioprotection maintaining/ improving myocardial microcirculatory function, as well as via platelet inhibition or possibly other pleiotropic effects.

Ticagrelor increases circulating adenosine by reducing cellular re-uptake. Adenosine is a cardioprotective agent that utilizes cellular survival kinase pathways that may have beneficial effects on the microcirculation and myocardium in patients presenting with STEMI. Adenosine is currently used as a treatment for no-reflow and improves MVO post-STEMI when administered during PPCI. A recent study of healthy volunteers has confirmed that non-invasive coronary flow is augmented by ticagrelor and that this is mediated by adenosine. The Investigators propose that the very early beneficial effects of Ticagrelor in ACS may be adenosine mediated cardioprotection, rather than only due to an antiplatelet effect. This important research is original and a natural progression of the ticagrelor story. It expands the adenosine hypothesis and mode of action of ticagrelor and addresses a novel cardioprotective/ microcirculatory mechanism of action.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 140
• Est. completion date: November 30, 2019
• Est. primary completion date: November 30, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

1. Provision of informed verbal consent prior to any study specific procedures taking place with written consent confirmed prior to in-patient cardiac MRI.

2. Male or female adult patient aged 18 - 90 years old

3. Anterior STEMI (ST elevation = 2mmHg in contiguous chest leads) with chest pain symptom onset < 12 hours

Exclusion Criteria:

1. Cardiogenic shock*

2. Previous anterior myocardial infarction

3. Unfavourable coronary anatomy for PCI: left main / surgical or distal coronary disease

4. Already prescribed Ticagrelor at the time of admission

5. Factors affecting study drug administration/ absorption: vomiting or allergy

6. Concomitant use of potent CYP3A4 inhibitors/ inducers (e.g ketoconazole and rifampicin) or CYP3A4 substrates with a narrow therapeutic window (e.g. cisapride and ergot alkaloids) or simvastatin / lovostatin >40mg oral dose.

7. Severe bleeding diathesis or current active bleeding*

8. History of intracranial haemorrhage

9. Moderate or Severe hepatic impairment

10. Severe asthma or bradycardia/ complete heart block (contraindications to adenosine)*

11. Severe co-morbidity with a life expectancy < 3 months.

12. Women of child bearing potential (as determined by direct questioning of the patient to confirm and this will be documented in the medical notes).

• Patients that are found to have any excluding factor (e.g., unfavourable coronary anatomy for PCI) or develop any excluding factor (e.g., vomiting or cardiogenic shock) before the point of final IMR assessment will be discontinued from the study and followed up at discharge and by telephone at 3 and 12 months for adverse event monitoring purposes only.

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction
• ST Elevation Myocardial Infarction

Intervention

Drug:
• Ticagrelor
2 x 90mg Ticagrelor tablets

Other:
• Placebo
2 x matching placebo tablets

Locations

Country	Name	City	State
United Kingdom	Papworth Hospital NHS Foundation Trust	Papworth Everard	Cambridge

Sponsors (2)

Lead Sponsor	Collaborator
Papworth Hospital NHS Foundation Trust	AstraZeneca

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Creatinine levels (eGRF) at 0, 12 and 24 hours	Safety endpoint.	Baseline to 24 hours.
Other	NYHA Functional Classification and CCS Angina Grading Scale	Clinical grading scales of heart failure and angina.	Discharge to 12 months.
Other	Plasma Ticagrelor levels at the point of final IMR measurement and in-patient Cardiac MRI.	This will explore if the IMR differences observed are related to individual differences in drug levels.	End of PPCI procedure to 24-48 hours.
Other	Plasma Adenosine levels at the point of final IMR measurement and in-patient Cardiac MRI	This will explore if the IMR differences observed are related to individual differences in adenosine levels.	End of PPCI procedure to 24-48 hours.
Other	Multiplatelet® ADP aggregation assessment of platelet reactivity at the point of final IMR measurement and in-patient Cardiac MRI	This will explore if the IMR differences observed are related to individual differences in platelet reactivity levels.	End of PPCI procedure to 24-48 hours.
Primary	Index of Myocardial Resistance (IMR)	To compare final Index of Myocardial Resistance (IMR) at the end of the PPCI procedure between the two arms.	Baseline to end of PPCI procedure.
Secondary	Baseline IMR and change in IMR during PPCI	To compare between the two arms.	Baseline to end of PPCI procedure.
Secondary	ACF and AMR pre/post PPCI	To compare between the two arms.	Baseline to end of PPCI procedure.
Secondary	TIMI flow and TMBG pre/post PPCI	To compare between the two arms.	Baseline to end of PPCI procedure.
Secondary	ST segment resolution	To compare between the two arms.	Baseline to end of PPCI procedure.
Secondary	OCT quantified clot volume pre/post PPCI	To compare between the two arms.	Baseline to end of PPCI procedure.
Secondary	Cardiac troponin - I and CKMB levels at 0, 12 and 24 hours	To compare between the two arms.	Baseline to 24 hours.
Secondary	Cardiac MRI microvascular obstruction between 24-48 hours and infarct size at 3 months	To compare between the two arms.	Baseline to 3 months.