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Platelet Inhibition to Target Reperfusion Injury (PITRI)

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ClinicalTrials.gov Identifier: NCT03102723
Recruitment Status : Recruiting
First Posted : April 6, 2017
Last Update Posted : October 18, 2018
Sponsor:
Collaborators:
Tan Tock Seng Hospital
National University Hospital, Singapore
Khoo Teck Puat Hospital
Information provided by (Responsible Party):
National Heart Centre Singapore

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.

Condition or disease Intervention/treatment Phase
STEMI Drug: Cangrelor Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Platelet Inhibition to Target Reperfusion Injury: The PITRI Trial
Actual Study Start Date : October 1, 2017
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Cangrelor

Arm Intervention/treatment
Experimental: Cangrelor
Cangrelor (single intravenous bolus followed by a 120-minute infusion) initiated prior to PPCI.
Drug: Cangrelor
  1. 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

  2. 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.
Other Name: Kengreal

Placebo Comparator: Placebo
Matching normal saline placebo (single intravenous bolus followed by a 120-minute infusion) initiated prior to PPCI.
Drug: Cangrelor
  1. 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

  2. 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.
Other Name: Kengreal




Primary Outcome Measures :
  1. Myocardial infarct size by CMR at Day 2 to 7 [ Time Frame: 2-7 days ]
    This will be measured by CMR (mass of late gadolinium enhancement expressed as a percentage of the LV mass).


Secondary Outcome Measures :
  1. Microvascular obstruction to calculate myocardial interstitial volume [ Time Frame: 2-7 days ]
    This will be assessed by CMR performed at 2-7 days post-PPCI

  2. Myocardial salvage index [ Time Frame: 2-7 days ]
    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

  3. Angiographic markers of successful reperfusion [ Time Frame: 2 to 3 hours ]
    ST-segment resolution 90 min post-PPCI, TIMI flow and frame-count post-PPCI, and TIMI blush grade

  4. Myocardial infarct size by CMR at 6 months [ Time Frame: 6 months ]
    This will be measured by Cardiac MRI 6 months post-PPCI

  5. Post-MI LV remodeling by measuring LV ejection fraction and indexed LV end systolic and diastolic volumes and mass [ Time Frame: 6 months ]
    This will be assessed by CMR by measuring LV ejection fraction and indexed LV end systolic and diastolic volumes and mass.

  6. Platelet function testing [ Time Frame: 2 hours ]
    Serial platelet function testing will be performed with VerifyNow in a subset of 70 patients.

  7. MACCE at 30 days, at 6 months, at 12 months, at 24 months, at 5 years and at 10 years [ Time Frame: 6 months ]
    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.

  8. Incidence of definite stent thrombosis at 48 hours [ Time Frame: 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).

  9. Quality of life questionnaire [ Time Frame: 6 months ]
    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).

  10. 6-Minute Walk Test (6MWT) [ Time Frame: 6 months ]
    Functional capacity of patients will be measured using the 6-Minute Walk Test

  11. Subjective questionnaire [ Time Frame: 6 months ]
    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).

  12. ALDH2 substudy [ Time Frame: 6 months ]
    A saliva sample will be collected from a sub-group of subjects for determination of their ALDH2 genotype.



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03102723


Contacts
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Contact: Derek John Hausenloy 6704 2196 ext 2196 derek.hausenloy@nhcs.com.sg
Contact: Katherina Oh 6704 ext 2290 katherina.oh@nhcs.com.sg

Locations
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Singapore
National University Hospital (NUH) Recruiting
Singapore, Singapore, 119228
Contact: A/Prof Mark Chan    67795555      
Contact: Sock Cheng Poh       sock_cheng_poh@nuhs.edu.sg   
Tan Tock Seng Hospital (TTSH) Recruiting
Singapore, Singapore, 308433
Contact: Dr. Hee Hwa Ho    63577831      
Contact: Tasha Mahadi AB    63578124    tashama@ttsh.com.sg   
Khoo Teck Puat Hospital Not yet recruiting
Singapore, Singapore, 768828
Contact: Lim Boon Khim    66023307      
Principal Investigator: Imran Syed Saqib         
Sponsors and Collaborators
National Heart Centre Singapore
Tan Tock Seng Hospital
National University Hospital, Singapore
Khoo Teck Puat Hospital
Investigators
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Principal Investigator: Derek John Hausenloy National Heart Centre Singapore

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Heart Centre Singapore
ClinicalTrials.gov Identifier: NCT03102723     History of Changes
Other Study ID Numbers: PITRI-01
First Posted: April 6, 2017    Key Record Dates
Last Update Posted: October 18, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by National Heart Centre Singapore:
STEMI
primary percutaneous coronary intervention (PPCI)
cangrelor
reperfusion
Additional relevant MeSH terms:
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Cangrelor
Reperfusion Injury
Vascular Diseases
Cardiovascular Diseases
Postoperative Complications
Pathologic Processes
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs