Platelet Inhibition to Target Reperfusion Injury

STEMI Clinical Trial

— PITRI  

Official title:

Platelet Inhibition to Target Reperfusion Injury: The PITRI Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03102723
• Other study ID #: PITRI-01
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 1, 2017
• Est. completion date: December 2022

Study information

• Verified date: April 2022
• Source: National Heart Centre Singapore
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 228
• Est. completion date: December 2022
• Est. primary completion date: December 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 79 Years

Eligibility

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

1. Age =21 and <80 years of age

2. 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

3. =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.

1. History of previous MI, CVA, TIA or prior CABG surgery

2. 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)

3. 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

4. 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

5. Contraindications to Heparinisation or Anti-Platelet Therapy:

• History of Heparin-Induced Thrombocytopenia (HIT)

• Increased bleeding risk (GI bleeding, traumatic head injury)

6. Pregnancy

7. Contrast allergy

8. 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)

Related Conditions & MeSH terms

• Reperfusion Injury
• STEMI

Intervention

Drug:
• Cangrelor
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.

Locations

Country	Name	City	State
Singapore	Changi General Hospital	Singapore
Singapore	Khoo Teck Puat Hospital	Singapore
Singapore	National University Hospital (NUH)	Singapore
Singapore	SengKang General Hospital	Singapore
Singapore	Tan Tock Seng Hospital (TTSH)	Singapore

Sponsors (6)

Lead Sponsor	Collaborator
National Heart Centre Singapore	Changi General Hospital, Khoo Teck Puat Hospital, National University Hospital, Singapore, Sengkang General Hospital, Tan Tock Seng Hospital

Country where clinical trial is conducted

Singapore, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	2-7 days
Secondary	Microvascular obstruction to calculate myocardial interstitial volume	This will be assessed by CMR performed at 2-7 days post-PPCI	2-7 days
Secondary	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	2-7 days
Secondary	Angiographic markers of successful reperfusion	ST-segment resolution 90 min post-PPCI, TIMI flow and frame-count post-PPCI, and TIMI blush grade	2 to 3 hours
Secondary	Myocardial infarct size by CMR at 6 months	This will be measured by Cardiac MRI 6 months post-PPCI	6 months
Secondary	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.	6 months
Secondary	Platelet function testing	Serial platelet function testing will be performed with VerifyNow in a subset of 70 patients.	2 hours
Secondary	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.	6 months
Secondary	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).	48 hours
Secondary	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 months
Secondary	6-Minute Walk Test (6MWT)	Functional capacity of patients will be measured using the 6-Minute Walk Test	6 months
Secondary	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).	6 months
Secondary	ALDH2 substudy	A saliva sample will be collected from a sub-group of subjects for determination of their ALDH2 genotype.	6 months