A Phase 3 Study of Zalunfiban in Subjects With ST-elevation MI

Study Overview
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Brief Summary
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This is a Phase 3 prospective, blinded, randomized, placebo controlled, international multicenter study. Subjects with STEMI will be enrolled in the ambulance if they meet all eligibility criteria. These subjects will be evaluated by (para)medics who transport the subjects to the participating hospitals in Europe and North America. Hospitals and ambulance services with experience in ambulance studies will be selected. Each subject will receive a single subcutaneous injection containing either zalunfiban Dose 1 (0.110 mg/kg) or zalunfiban Dose 2 (0.130 mg/kg) or placebo

Detailed Description
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Subjects will be screened in the ambulance based on the information available; those fulfilling the eligibility criteria who have provided verbal witnessed/short written/Exception from Informed Consent Requirements (EFIC) process informed consent will be randomized and enrolled in the study. Following a single weight-based dose of subcutaneous study drug administered by the ambulance staff, the patient will be transferred to the clinical site PCI center for angiography and intervention. Regular standard of care is performed from the provision of informed consent through the last study mandated subject visit. Concomitant medications will be recorded. Treatment with IV P2Y12 antagonists or other αIIbβ3 receptor before PCI/angiography is prohibited. Demographics, concomitant medications, vital signs, and medical history will be collected in the CRF. Adverse events, bleeding events and injection site reactions will be collected. Angiography and PCI details will be recorded. Full written informed consent will be obtained. Additional blood samples for safety will be collected at 1, 6, 24 and 72 hours (or hospital discharge) post-PCI/angiography. Blood samples for high-sensitive cardiac troponin T (upon arrival and 24 hours post PCI/angiography) and NT-ProBNP (24 hours post PCI/angiography) will be assessed by central laboratory. Follow up phone contacts will occur at 30 days to report AEs, bleeding events, and injection site reactions, and 12-months to record mortality, and hospitalizations for heart failure or atrial fibrillation, and [in the event of stroke], 90 days (±2 weeks) to record the stroke disability. Angiography/PCI data and ECGs will be evaluated at independent Core Laboratories. An independent, blinded Clinical Events Committee will provide central adjudication of all clinical endpoint events. A DSMB will examine the safety data in an ongoing manner and to alert the Steering Committee in case of clinically concerning safety issues that should lead to consideration of altering the trial, and can recommend modification of the study protocol based on pre-specified rules. The duration of participation for each subject will be 12 months (± 1 month), including enrollment, study drug administration, hospitalization, and phone contact follow-up at 30 days (+ 7 days) and 12 months (± 1 month).

Official Title
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A Phase 3 Prospective, Blinded, Randomized, Placebo Controlled, International Multicenter Study to Assess the Safety and Efficacy of a Single SQ Injection of Zalunfiban in Subjects With ST-elevation MI in the Pre-hospital Setting

Conditions
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ST-elevation Myocardial Infarction (STEMI)

Intervention / Treatment
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* Drug: zalunfiban
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males aged ≥18 years or post-menopausal or surgically sterile females ≥50 years or ≥55 years (for Czech Republic study sites only). Weight (by history) between 52 and 130 kg. Subjects with STEMI, presenting with persistent ischemic chest pain (>10 minutes) and new ≥2 mm ST-segment elevation in two adjacent ECG leads, in whom the total duration of symptoms is 4 hours maximum. If time of symptom onset is uncertain, the cardiologist may be contacted to confirm inclusion criteria. Exception from Informed Consent Requirements (EFIC) process, verbal witnessed/ short written informed consent, or written informed consent signed by subject or legally authorized representative/independent witness will be obtained in the acute phase by (para)medics, according to local applicable legal regulations. Subject is willing and able to give informed consent. Written informed consent will be obtained as soon as the subject's clinical condition allows it. Exclusion Criteria: Cardio Pulmonary Resuscitation (CPR) for current Out of Hospital Cardiac Arrest (OHCA). Presenting with systolic blood pressure <90 mmHg (confirmed on repeat assessment) and heart rate >100 beats per minute (bpm). Current known active coronavirus disease 2019 (COVID-19) infection (criteria according to local guidelines). Currently treated with renal dialysis. Current treatment with oral anticoagulation (Vitamin K antagonists [VKA] or direct oral anticoagulants [DOACs]). Major surgery, or trauma or bleeding leading to hospitalization, within the past month. Known history of ischemic or hemorrhagic stroke. Known severe anemia (regular blood transfusion needed). Previously enrolled in this study. Participation in another clinical study with an investigational product or device within the past month. Life expectancy less than one year. -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: zalunfiban Dose 1 (0.110 mg/kg)<br>Subjects will receive a single subcutaneous injection containing zalunfiban Dose 1 (0.110 mg/kg) in the ambulance after diagnosis of STEMI and before hospital arrival | Drug: zalunfiban<br>* zalunfiban is a novel small molecule inhibitor of the platelet αIIbβ3 receptor specifically designed for first medical contact therapy of ST-elevation myocardial infarction (STEMI).<br>* Other names: RUC-4;|
| Experimental: zalunfiban Dose 2 (0.130 mg/kg)<br>Subjects will receive a single subcutaneous injection containing zalunfiban Dose 2 (0.130 mg/kg) in the ambulance after diagnosis of STEMI and before hospital arrival | Drug: zalunfiban<br>* zalunfiban is a novel small molecule inhibitor of the platelet αIIbβ3 receptor specifically designed for first medical contact therapy of ST-elevation myocardial infarction (STEMI).<br>* Other names: RUC-4;|
| Placebo Comparator: Placebo<br>Subjects will receive a single subcutaneous injection containing Placebo in the ambulance after diagnosis of STEMI and before hospital arrival | Drug: Placebo<br>* A placebo will be prepared to those subjects assigned to placebo. Less than 1 mL (depending on subject's weight) will be administered by subcutaneous injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| primary efficacy -clinical outcome | As assessed by a 7-point scale. The 7 outcomes, ranking from worst to best are: Death (all cause) at 30 days follow-up Stroke at 30 days follow-up Recurrent MI (type 1 to 4 MI) at 30 days follow-up Acute stent thrombosis at 24 hours post-PCI/angiography New onset heart failure or rehospitalization for heart failure at 30 days follow-up MI with hs-cTnT levels ≥10x ULN at 24 hours post-PCI/angiography None of the above | at 30 days follow-up after a single subcutaneous injection of zalunfiban versus placebo | 
| primary safety- bleeding events [BARC criteria] | • To assess bleeding events (according to Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO] severe or life threatening criterion for safety assessment and according to the Bleeding Academic Research Consortium [BARC] 3C and 5 criteria for information only) | after a single subcutaneous injection of zalunfiban versus placebo at 30 days post-PCI/angiography | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| secondary efficacy-restoration of the coronary artery blood flow | To assess restoration of the culprit coronary artery blood flow (corrected Thrombolysis in Myocardial Infarction [TIMI] Frame Count) before intended PCI (or post coronary angiography in case no PCI is performed) after a single subcutaneous injection of zalunfiban versus placebo | before PCI (or coronary angiography if no PCI is performed) | 
| efficacy-resolution of ST segment deviation | To assess resolution of ST segment deviation post-PCI/angiography after a single subcutaneous injection of zalunfiban versus placebo | 1 hour post-PCI/angiography | 
| Efficacy-composite of all cause death, recurrent MI, acute stent thrombosis or blinded bail-out use of IV αIIbβ3 antagonists or IV P2Y12 antagonist | To assess a composite of all cause death, recurrent MI, acute stent thrombosis or blinded bail-out use of IV αIIbβ3 antagonists or IV P2Y12 antagonist | at 30 days follow-up after a single subcutaneous injection of zalunfiban versus placebo | 
| Efficacy-acute stent thrombosis | To assess incidence of definite, probable or possible acute stent thrombosis after a single subcutaneous injection of zalunfiban versus placebo | up to 24 hours post-PCI | 
| Safety throughout the study by AE reporting | Recording of AEs and SAEs fibrillation up to 12-months follow-up | AEs up to 30 days follow-up; SAEs up to resolution/stabilization, the SAEs mortality, hospitalization for heart failure and atrial fibrillation up to 12-months follow-up | 
| Safety-platelet count | To assess platelet count after a single subcutaneous injection of zalunfiban versus placebo | before PCI/angiography, at the end of the PCI/angiography, 6 and 24 hours post-PCI/angiography and at hospital discharge/72-hours post-PCI/angiography (whichever occurs first) | 
| Safety-bleeding events (ISTH and TIMI) | To assess bleeding events (according to International Society on Thrombosis and Haemostasis [ISTH] Major and TIMI Major for information only) after a single subcutaneous injection of zalunfiban versus placebo | at 30 days follow-up | 
| Safety-bleeding events (GUSTO mild and moderate, BARC type 2, 3 and 5, ISTH minor and/or major and TIMI minor and major) | To assess incidence of bleeding events according to GUSTO mild and moderate criteria, BARC type 2, 3 and 5 criteria, ISTH minor and or major bleeding, TIMI minor and major criteria | 30 days follow-up | 
| Safety-injection site reactions | To assess the injection site reactions of a single subcutaneous injection of zalunfiban versus placebo | baseline, 1-hour post-PCI/angiography, hospital discharge/72-hours post-PCI/angiography, and at 30 days follow-up |