A Phase 3 prospective, blinded, randomized, placebo controlled, international multicenter study to assess the safety and efficacy of a single subcutaneous injection of zalunfiban in subjects with ST-elevation myocardial infarction in the pre-hospital setting

The use of αIIbβ3 receptor antagonists has been validated as an effective
therapy of MI for patients undergoing percutaneous coronary interventions
(PCI). Treatment with one of the three currently available agents (abciximab,
tirofiban, eptifibatide) has been shown to result in an approximately 20%
reduction in mortality and an approximately 33% reduction in death or
reinfarction at 30 days after treatment. Early treatment of MI with αIIbβ3
receptor antagonists at first medical contact (i.e., by Emergency Medical
System [EMS] personnel or personnel in emergency departments of either *spoke*
hospitals or PCI-capable hospitals) compared to catheterization lab treatment
has been associated with increased pre-procedure blood flow in the target
coronary artery using the Thrombolysis in Myocardial Infarction (TIMI) scale
and indices of myocardial perfusion, smaller infarcts, fewer early and late
complications of MI, and reduced mortality. The improvement in outcome
correlates with the time at which the drugs were administered after the onset
of symptoms.
Despite these data, αIIbβ3 antagonists are not routinely administered at first
medical contact, in part because they require intravenous (IV) administration
of a bolus dose followed by a continuous infusion regulated by an infusion
pump. In addition, all of the agents are associated with thrombocytopenia in a
small percentage of patients (0.5%-2%), with abciximab associated with the
highest frequency.
Zalunfiban is being developed to facilitate pre-hospital and emergency
department therapy at the earliest time point, thus maximizing the chance of
preserving the cardiac muscle. Zalunfiban is differentiated from current αIIbβ3
receptor antagonists because it is based on newer information on the receptor
structure and is specifically designed to facilitate early administration.
Zalunfiban inhibits ligand binding to αIIbβ3 by binding to both the αIIb and β3
subunits and displacing the Mg2+ metal from the ion-dependent adhesion site
(MIDAS) required for ligand binding; this locks the β3 subunit of the
receptor in its inactive conformation. This may decrease the likelihood of
developing thrombocytopenia because data indicate that much of the
thrombocytopenia caused by the current αIIbβ3 receptor antagonists is due to
the presence of antibodies to conformations of the receptor induced by the
binding of the drugs.

This study has been transitioned to CTIS with ID 2023-508485-15-00 check the CTIS register for the current data.

Main study:
Primary:
Efficacy:
- To assess the clinical outcome at 30 days follow-up after administration of a
single subcutaneous injection of zalunfiban versus
placebo in STEMI subjects in the pre-hospital setting.

Safety:
- To assess bleeding events (according to Global Use of Strategies to Open
Occluded Coronary Arteries [GUSTO] severe or life-theratening criterion for
safety assessment and, for information only, according to the Bleeding Academic
Research Consortium [BARC] 3C and 5 criteria) after a single subcutaneous
injection of zalunfiban versus placebo at 30 days follow-up.

Secondary:
To assess after a single s.c. injection of zalunfiban vs placebo:
Efficacy:
- Restoration of the culprit coronary artery blood flow of the Culprit before
intended PCI (or post-CAG in case no PCI performed)
- Resolution of ST-segment deviation post-PCI/CAG
- Blinded bail-out use of IV αIIbβ3 receptor antagonists or IV P2Y12 antagonist
at 24hr post-PCI/CAG
Safety:
- Safety throughout study
-Platelet count pre-PCI/CAG, post-PCI/CAG, 6hr post-PCI/CAG, 24hr post-PCI/CAG
and at discharge/72hr post-PCI/s (whichever occurs first)
- Bleeding events at 30 day FU:
- According to ISTH Major
- According to GUSTO mild and moderate criteria, BARC type 2, 3, and 5
criteria, ISTH minor and/or major bleeding, and TIMI minor and major criteria)
- The injection site reactions of a single s.c. injection of zalunfiban versus
placebo at baseline, 1hr post-PCI/CAG, hospital discharge/72hr post-PCI/CAG,
and at 30 days FU

Sub-study pharmacodynamic effects:
Primary:
To compare the results of the VerifyNow* assay, i.e., platelet reactivity and
degree of platelet inhibition, in subjects with STEMI receiving zalunfiban to
placebo.
Secondary:
- To compare clot strength and other clot kinetics
- To correlate the platelet reactivity with angiographic markers of
reperfusion. These indices include pre-procedural TIMI flow grade, TIMI
myocardial perfusion grade and TIMI thrombus grade.
- To correlate platelet reactivity ECG markers of reperfusion including
ST-segment resolution pre-angiography (presentation/ED ECG - diagnostic ECG),
both qualitative and quantitative.
- To correlate the primary outcome of this sub-study with clinical endpoints
from the main study

This is a Phase 3, blinded, randomized, placebo controlled, international
multicenter study.
Subjects with documented STEMI will be enrolled in the ambulance or hospital.
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.
The duration of participation for each subject will be 12 months (+/- 30 days),
including enrollment, study drug administration, hospitalization, and phone
contact follow-up at 30 days (+7 days), and at 12 months (+/- 30 days). If a
stroke occurs during the first 30 days during this study, possibly an
additional telephone follow-up at 90 days (+/- 2 weeks).

Part A: 30 days from screening to follow-up at day 30 (+ 7 days)
Part B: 11 months from follow-up at day 30 to follow-up at month 12 (± 30 days)

A single subcutaneous injection containing either zalunfiban dose 1 [0.110
mg/kg] or zalunfiban dose 2 [0.130 mg/kg] or placebo.

Burden:
5 x blood sample collection plus 1 single subcutaneous injection.
A compression dressing applied immediately after subcutaneous injection and
removed after PCI/angiography.

Risks and inconveniences:
The following side effects of subcutaneous injection zalunfiban are known:
- may lead to minor injection site reactions at the injection site of the study
drug
- may lead to increased risk of bleeding:
- minor bleeding (e.g. bruising at nearby the injection site of the
study drug)
- major bleeding

The following research tests may involve the following risks/conveniences:
- Blood sampling: Local pain and/or bruising.