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

Primary Purpose

ST Elevation Myocardial Infarction

Status
Unknown status
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Ticagrelor
Placebo
Sponsored by
Papworth Hospital NHS Foundation Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for ST Elevation Myocardial Infarction

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Papworth Hospital NHS Foundation TrustRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ticagrelor

Placebo

Arm Description

Patients will receive Ticagrelor 180mg (2 x 90mg tablets)

Patients will receive Placebo (2 matching tablets)

Outcomes

Primary Outcome Measures

Index of Myocardial Resistance (IMR)
To compare final Index of Myocardial Resistance (IMR) at the end of the PPCI procedure between the two arms.

Secondary Outcome Measures

Baseline IMR and change in IMR during PPCI
To compare between the two arms.
ACF and AMR pre/post PPCI
To compare between the two arms.
TIMI flow and TMBG pre/post PPCI
To compare between the two arms.
ST segment resolution
To compare between the two arms.
OCT quantified clot volume pre/post PPCI
To compare between the two arms.
Cardiac troponin - I and CKMB levels at 0, 12 and 24 hours
To compare between the two arms.
Cardiac MRI microvascular obstruction between 24-48 hours and infarct size at 3 months
To compare between the two arms.

Full Information

First Posted
April 13, 2017
Last Updated
May 25, 2017
Sponsor
Papworth Hospital NHS Foundation Trust
Collaborators
AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT03145194
Brief Title
TIMES: Ticagrelor vs. Placebo/ Clopidogrel With Aspirin in Anterior STEMI Patients Treated With Primary PCI
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Unknown status
Study Start Date
January 30, 2017 (Actual)
Primary Completion Date
November 30, 2018 (Anticipated)
Study Completion Date
November 30, 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Papworth Hospital NHS Foundation Trust
Collaborators
AstraZeneca

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ST Elevation Myocardial Infarction

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Masking Description
Double blind until the point of primary endpoint.
Allocation
Randomized
Enrollment
140 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Ticagrelor
Arm Type
Experimental
Arm Description
Patients will receive Ticagrelor 180mg (2 x 90mg tablets)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients will receive Placebo (2 matching tablets)
Intervention Type
Drug
Intervention Name(s)
Ticagrelor
Intervention Description
2 x 90mg Ticagrelor tablets
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
2 x matching placebo tablets
Primary Outcome Measure Information:
Title
Index of Myocardial Resistance (IMR)
Description
To compare final Index of Myocardial Resistance (IMR) at the end of the PPCI procedure between the two arms.
Time Frame
Baseline to end of PPCI procedure.
Secondary Outcome Measure Information:
Title
Baseline IMR and change in IMR during PPCI
Description
To compare between the two arms.
Time Frame
Baseline to end of PPCI procedure.
Title
ACF and AMR pre/post PPCI
Description
To compare between the two arms.
Time Frame
Baseline to end of PPCI procedure.
Title
TIMI flow and TMBG pre/post PPCI
Description
To compare between the two arms.
Time Frame
Baseline to end of PPCI procedure.
Title
ST segment resolution
Description
To compare between the two arms.
Time Frame
Baseline to end of PPCI procedure.
Title
OCT quantified clot volume pre/post PPCI
Description
To compare between the two arms.
Time Frame
Baseline to end of PPCI procedure.
Title
Cardiac troponin - I and CKMB levels at 0, 12 and 24 hours
Description
To compare between the two arms.
Time Frame
Baseline to 24 hours.
Title
Cardiac MRI microvascular obstruction between 24-48 hours and infarct size at 3 months
Description
To compare between the two arms.
Time Frame
Baseline to 3 months.
Other Pre-specified Outcome Measures:
Title
Creatinine levels (eGRF) at 0, 12 and 24 hours
Description
Safety endpoint.
Time Frame
Baseline to 24 hours.
Title
NYHA Functional Classification and CCS Angina Grading Scale
Description
Clinical grading scales of heart failure and angina.
Time Frame
Discharge to 12 months.
Title
Plasma Ticagrelor levels at the point of final IMR measurement and in-patient Cardiac MRI.
Description
This will explore if the IMR differences observed are related to individual differences in drug levels.
Time Frame
End of PPCI procedure to 24-48 hours.
Title
Plasma Adenosine levels at the point of final IMR measurement and in-patient Cardiac MRI
Description
This will explore if the IMR differences observed are related to individual differences in adenosine levels.
Time Frame
End of PPCI procedure to 24-48 hours.
Title
Multiplatelet® ADP aggregation assessment of platelet reactivity at the point of final IMR measurement and in-patient Cardiac MRI
Description
This will explore if the IMR differences observed are related to individual differences in platelet reactivity levels.
Time Frame
End of PPCI procedure to 24-48 hours.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Provision of informed verbal consent prior to any study specific procedures taking place with written consent confirmed prior to in-patient cardiac MRI. Male or female adult patient aged 18 - 90 years old Anterior STEMI (ST elevation ≥ 2mmHg in contiguous chest leads) with chest pain symptom onset < 12 hours Exclusion Criteria: Cardiogenic shock* Previous anterior myocardial infarction Unfavourable coronary anatomy for PCI: left main / surgical or distal coronary disease Already prescribed Ticagrelor at the time of admission Factors affecting study drug administration/ absorption: vomiting or allergy 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. Severe bleeding diathesis or current active bleeding* History of intracranial haemorrhage Moderate or Severe hepatic impairment Severe asthma or bradycardia/ complete heart block (contraindications to adenosine)* Severe co-morbidity with a life expectancy < 3 months. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Stephen Hoole
Phone
01480 366172
Ext
6172
Email
s.hoole@nhs.net
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephen Hoole
Organizational Affiliation
Papworth Hospital NHS Foundation Trust
Official's Role
Principal Investigator
Facility Information:
Facility Name
Papworth Hospital NHS Foundation Trust
City
Papworth Everard
State/Province
Cambridge
ZIP/Postal Code
CB23 3RE
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stephen Hoole
Phone
01480 366172
Ext
6172
Email
s.hoole@nhs.net
First Name & Middle Initial & Last Name & Degree
Stephen Hoole

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34187187
Citation
Aetesam-Ur-Rahman M, Brown AJ, Jaworski C, Giblett JP, Zhao TX, Braganza DM, Clarke SC, Agrawal BSK, Bennett MR, West NEJ, Hoole SP. Adenosine-Induced Coronary Steal Is Observed in Patients Presenting With ST-Segment-Elevation Myocardial Infarction. J Am Heart Assoc. 2021 Jul 6;10(13):e019899. doi: 10.1161/JAHA.120.019899. Epub 2021 Jun 30.
Results Reference
derived

Learn more about this trial

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

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