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Platelet Inhibition to Target Reperfusion Injury (PITRI)

Primary Purpose

STEMI

Status

Active

Phase

Phase 2

Locations

Singapore

Study Type

Interventional

Intervention

Cangrelor

About this trial

This is an interventional treatment trial for STEMI focused on measuring STEMI, primary percutaneous coronary intervention (PPCI), cangrelor, reperfusion

Eligibility Criteria

21 Years - 79 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria Subjects must meet all of the inclusion criteria to participate in this study.

Age ≥21 and <80 years of age
STEMI as defined by:
- ≥2 mm ST-segment elevation in 2 or more anterior leads (V1-V4)
- ≥1 mV ST-segment elevation in in 2 or more limb leads (II, III and aVF, I, aVL).
- ST elevation in II, II, aVF less than 1 mm with ST depression in aVL
- Posterior infarction ST depression ≥ 1 mm over either V1, V2, or V3 and ST elevation ≥ 1 mm in either V7, V8 or V9
≤6 hours onset of most severe chest pain to time of admission in the Emergency Medicine Department

Exclusion Criteria All subjects meeting any of the exclusion criteria at baseline will be excluded from participation.

History of previous MI, CVA, TIA or prior CABG surgery
Known contraindications to cardiac MRI (CMR) such as MRI contraindicated implanted devices, significant claustrophobia, severe allergy to gadolinium chelate contrast, severe renal insufficiency (estimated glomerular filtration rate [eGFR] ≤40 mL/min/1.73 m2)
Patients with prior therapy before admission within 7 days of anticoagulant (warfarin, phenindione, dabigatran, apixaban and rivaroxaban), glycoprotein 2B3A inhibitor, P2Y12 inhibitor (ticagrelor, prasugrel, clopidogrel, cangrelor) or thrombolytic therapy
Significant co-morbidities:
- Patients with severe hepatic failure (INR>2)
- Cardiac arrest before randomisation
- Cardiogenic shock
- Poor premorbid status (bed bound / wheelchair bound)
- Collapse / comatose / semi-conscious states
Contraindications to Heparinisation or Anti-Platelet Therapy:
- History of Heparin-Induced Thrombocytopenia (HIT)
- Increased bleeding risk (GI bleeding, traumatic head injury)
Pregnancy
Contrast allergy
Patients on strong CYP3A inhibitors or inducers (such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole, rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital)

Sites / Locations

National University Hospital (NUH)
Tan Tock Seng Hospital (TTSH)
Khoo Teck Puat Hospital
Changi General Hospital
SengKang General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Cangrelor

Placebo

Arm Description

Cangrelor (single intravenous bolus followed by a 120-minute infusion) initiated prior to PPCI.

Matching normal saline placebo (single intravenous bolus followed by a 120-minute infusion) initiated prior to PPCI.

Outcomes

Primary Outcome Measures

Myocardial infarct size by CMR at Day 2 to 7

This will be measured by CMR (mass of late gadolinium enhancement expressed as a percentage of the LV mass).

Secondary Outcome Measures

Microvascular obstruction to calculate myocardial interstitial volume

This will be assessed by CMR performed at 2-7 days post-PPCI

Myocardial salvage index

This will be assessed by cardiac magnetic resonance (CMR) performed at 2-7 days post-PPCI by measuring MI size and the area at risk

Angiographic markers of successful reperfusion

ST-segment resolution 90 min post-PPCI, TIMI flow and frame-count post-PPCI, and TIMI blush grade

Myocardial infarct size by CMR at 6 months

This will be measured by Cardiac MRI 6 months post-PPCI

Post-MI LV remodeling by measuring LV ejection fraction and indexed LV end systolic and diastolic volumes and mass

This will be assessed by CMR by measuring LV ejection fraction and indexed LV end systolic and diastolic volumes and mass.

Platelet function testing

Serial platelet function testing will be performed with VerifyNow in a subset of 70 patients.

MACCE at 30 days, at 6 months, at 12 months, at 24 months, at 5 years and at 10 years

This will include all-cause death, hospitalisation for heart failure (HHF), stent thrombosis, ischemia-induced coronary revascularisation, re-infarction, and stroke. This data will be collected by telephone and reviewing medical notes at 30 days and at the time of the outpatient 6 month cardiac MR scan.

Incidence of definite stent thrombosis at 48 hours

This will be defined according to the criteria of the Academic Research Consortium, which was assessed, with group assignments concealed, at an angiographic core laboratory (Cardiovascular Research Foundation).

Quality of life questionnaire

The EuroQol EQ-5D Health-Related Quality of Life (EUROQOL) questionnaire (www.euroqol.org) will be used to assess patient quality of life post-CABG with or without valve surgery, at baseline (1 day post-PPCI), 30 days (by telephone), and 6 months (at time of outpatient CMR scan).

6-Minute Walk Test (6MWT)

Functional capacity of patients will be measured using the 6-Minute Walk Test

Subjective questionnaire

Subjective questionnaire relating to symptoms post angioplasty and physical activities will be assess at 30±7 days (by telephone), and at 6±1 months (at time of the outpatient CMR scan).

ALDH2 substudy

A saliva sample will be collected from a sub-group of subjects for determination of their ALDH2 genotype.

Full Information

NCT ID

NCT03102723

First Posted

January 5, 2017

Last Updated

April 19, 2022

Sponsor

National Heart Centre Singapore

Collaborators

Tan Tock Seng Hospital, National University Hospital, Singapore, Khoo Teck Puat Hospital, Changi General Hospital, Sengkang General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT03102723

Brief Title

Platelet Inhibition to Target Reperfusion Injury

Acronym

PITRI

Official Title

Platelet Inhibition to Target Reperfusion Injury: The PITRI Trial

Study Type

Interventional

2. Study Status

Record Verification Date

April 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

October 1, 2017 (Actual)

Primary Completion Date

December 2022 (Anticipated)

Study Completion Date

December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Heart Centre Singapore

Collaborators

Tan Tock Seng Hospital, National University Hospital, Singapore, Khoo Teck Puat Hospital, Changi General Hospital, Sengkang General Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

There remains a clinical need to improve health outcomes in patients with ischemic heart disease (IHD) the leading cause of death and disability in Singapore and worldwide. One neglected therapeutic target is 'myocardial reperfusion injury' in ST-segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention (PPCI). This results in microvascular obstruction (MVO) and cardiomyocyte death and contributes upto 50% of the final myocardial infarct (MI) size. Cangrelor, a potent intravenous platelet P2Y12 inhibitor with rapid onset and offset of action, has been demonstrated in experimental animal studies to reduce MI size when administered prior to reperfusion. Whether Cangrelor given together with Ticagrelor would be more effective at reducing MI size in STEMI patients treated by PPCI is not known and is investigated in the Platelet Inhibition to Target Reperfusion Injury (PITRI) trial.

Detailed Description

The PITRI proof-of-concept clinical trial will randomise 210 STEMI patients to receive either Cangrelor (single intravenous bolus followed by a 120-minute infusion) or matching normal/saline placebo, initiated prior to PPCI on top of conventional oral dual antiplatelet therapy (Aspirin + Ticagrelor). The primary endpoint will be acute MI size by cardiac MRI at day 2-7. Secondary endpoints will include incidence and extent of MVO by cardiac MRI; and chronic MI size, left ventricular size and ejection fraction by cardiac MRI at 6 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

STEMI

Keywords

STEMI, primary percutaneous coronary intervention (PPCI), cangrelor, reperfusion

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

228 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cangrelor

Arm Type

Experimental

Arm Description

Cangrelor (single intravenous bolus followed by a 120-minute infusion) initiated prior to PPCI.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Matching normal saline placebo (single intravenous bolus followed by a 120-minute infusion) initiated prior to PPCI.

Intervention Type

Drug

Intervention Name(s)

Cangrelor

Other Intervention Name(s)

Kengreal

Intervention Description

Cangrelor treatment: IV Cangrelor as a single IV bolus (30 μg/kg) followed by an infusion (4 μg/kg/min) of at least 120 minutes duration or until PPCI procedure has ended (whichever is longer) - this will be initiated prior to PPCI. This dosing regimen is identical to that used in the CHAMPION trials. Or Placebo control: IV normal saline as a single IV bolus followed by an infusion of at least 120 minutes duration or until PPCI procedure has ended (whichever is longer) - this will be initiated prior to PPCI.

Primary Outcome Measure Information:

Title

Myocardial infarct size by CMR at Day 2 to 7

Description

This will be measured by CMR (mass of late gadolinium enhancement expressed as a percentage of the LV mass).

Time Frame

2-7 days

Secondary Outcome Measure Information:

Title

Microvascular obstruction to calculate myocardial interstitial volume

Description

This will be assessed by CMR performed at 2-7 days post-PPCI

Time Frame

2-7 days

Title

Myocardial salvage index

Description

This will be assessed by cardiac magnetic resonance (CMR) performed at 2-7 days post-PPCI by measuring MI size and the area at risk

Time Frame

2-7 days

Title

Angiographic markers of successful reperfusion

Description

ST-segment resolution 90 min post-PPCI, TIMI flow and frame-count post-PPCI, and TIMI blush grade

Time Frame

2 to 3 hours

Title

Myocardial infarct size by CMR at 6 months

Description

This will be measured by Cardiac MRI 6 months post-PPCI

Time Frame

6 months

Title

Post-MI LV remodeling by measuring LV ejection fraction and indexed LV end systolic and diastolic volumes and mass

Description

This will be assessed by CMR by measuring LV ejection fraction and indexed LV end systolic and diastolic volumes and mass.

Time Frame

6 months

Title

Platelet function testing

Description

Serial platelet function testing will be performed with VerifyNow in a subset of 70 patients.

Time Frame

2 hours

Title

MACCE at 30 days, at 6 months, at 12 months, at 24 months, at 5 years and at 10 years

Description

Time Frame

6 months

Title

Incidence of definite stent thrombosis at 48 hours

Description

Time Frame

48 hours

Title

Quality of life questionnaire

Description

Time Frame

6 months

Title

6-Minute Walk Test (6MWT)

Description

Functional capacity of patients will be measured using the 6-Minute Walk Test

Time Frame

6 months

Title

Subjective questionnaire

Description

Subjective questionnaire relating to symptoms post angioplasty and physical activities will be assess at 30±7 days (by telephone), and at 6±1 months (at time of the outpatient CMR scan).

Time Frame

6 months

Title

ALDH2 substudy

Description

A saliva sample will be collected from a sub-group of subjects for determination of their ALDH2 genotype.

Time Frame

6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

21 Years

Maximum Age & Unit of Time

79 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria Subjects must meet all of the inclusion criteria to participate in this study. Age ≥21 and <80 years of age STEMI as defined by: ≥2 mm ST-segment elevation in 2 or more anterior leads (V1-V4) ≥1 mV ST-segment elevation in in 2 or more limb leads (II, III and aVF, I, aVL). ST elevation in II, II, aVF less than 1 mm with ST depression in aVL Posterior infarction ST depression ≥ 1 mm over either V1, V2, or V3 and ST elevation ≥ 1 mm in either V7, V8 or V9 ≤6 hours onset of most severe chest pain to time of admission in the Emergency Medicine Department Exclusion Criteria All subjects meeting any of the exclusion criteria at baseline will be excluded from participation. History of previous MI, CVA, TIA or prior CABG surgery Known contraindications to cardiac MRI (CMR) such as MRI contraindicated implanted devices, significant claustrophobia, severe allergy to gadolinium chelate contrast, severe renal insufficiency (estimated glomerular filtration rate [eGFR] ≤40 mL/min/1.73 m2) Patients with prior therapy before admission within 7 days of anticoagulant (warfarin, phenindione, dabigatran, apixaban and rivaroxaban), glycoprotein 2B3A inhibitor, P2Y12 inhibitor (ticagrelor, prasugrel, clopidogrel, cangrelor) or thrombolytic therapy Significant co-morbidities: Patients with severe hepatic failure (INR>2) Cardiac arrest before randomisation Cardiogenic shock Poor premorbid status (bed bound / wheelchair bound) Collapse / comatose / semi-conscious states Contraindications to Heparinisation or Anti-Platelet Therapy: History of Heparin-Induced Thrombocytopenia (HIT) Increased bleeding risk (GI bleeding, traumatic head injury) Pregnancy Contrast allergy Patients on strong CYP3A inhibitors or inducers (such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole, rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Derek John Hausenloy

Organizational Affiliation

National Heart Centre Singapore

Official's Role

Principal Investigator

Facility Information:

Facility Name

National University Hospital (NUH)

City

Singapore

ZIP/Postal Code

119228

Country

Singapore

Facility Name

Tan Tock Seng Hospital (TTSH)

City

Singapore

ZIP/Postal Code

308433

Country

Singapore

Facility Name

Khoo Teck Puat Hospital

City

Singapore

ZIP/Postal Code

768828

Country

Singapore

Facility Name

Changi General Hospital

City

Singapore

ZIP/Postal Code

S529889

Country

Singapore

Facility Name

SengKang General Hospital

City

Singapore

ZIP/Postal Code

S544886

Country

Singapore

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

30421441

Citation

Bulluck H, Chan MHH, Bryant JA, Chai P, Chawla A, Chua TS, Chung YC, Fei G, Ho HH, Ho AFW, Hoe AJ, Imran SS, Lee CH, Lim SH, Liew BW, Yun PLZ, Hock MOE, Paradies V, Roe MT, Teo L, Wong AS, Wong E, Wong PE, Watson T, Chan MY, Tan JW, Hausenloy DJ. Platelet inhibition to target reperfusion injury trial: Rationale and study design. Clin Cardiol. 2019 Jan;42(1):5-12. doi: 10.1002/clc.23110. Epub 2018 Dec 17.

Results Reference

derived

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Platelet Inhibition to Target Reperfusion Injury

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