The main objective:- To assess the PD properties of a single subcutaneous injection of RUC-4 in STEMI patients presenting to the CCL with the aim to perform primarycoronary angioplasty.- To assess the PK properties of a single subcutaneous injection…
ID
Source
Brief title
Condition
- Myocardial disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Inhibition of TRAP-induced platelet aggregation (%) assessed by VerifyNow at
baseline, and at 15, 45, 60, 90, 120, 180 and 240 minutes after administration
of RUC-4 (the 240 minute time point is only applicable if the RUC-4 dose is
increased in cohort 2 and/or 3)
- RUC-4 concentration (ng/mL) versus time profiles (at baseline and at 15, 45,
90, 120 and 180 minutes after administration of RUC 4) and associated PK
parameters
- Safety and tolerability parameters at baseline and at hospital discharge
Secondary outcome
- Platelet count (µL) at baseline, and at 15, 45, 90, 120 and 180 minutes after
administration of RUC-4 and at hospital discharge
- Bleeding events (according to BARC II, III and V criteria for safety
assessment and according to ISTH Major and TIMI Major for information only) at
baseline, discharge and at 15-day and at 30-day follow-up
- Intraprocedural thrombosis (assessed by PI)
- Injection site reactions at baseline, 1-hour post-PCI, hospital discharge,
and at 15-day and at 30-day follow-up
- Inhibition of ADP-induced platelet aggregation (%) assessed by VerifyNow at
baseline, and at 15, 45, 60, 90, 120, 180 and 240 minutes after administration
of RUC-4 (the 240 minute time point is only applicable if the RUC-4 dose is
increased in cohort 2 and/or 3)
- Differences in PD or PK among the patients (gender, weight, BMI, age)
Background summary
The use of αIIbβ3 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 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.
RUC-4 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. RUC-4 is differentiated from current αIIbβ3 antagonists
because it is based on newer information on the receptor structure and is
specifically designed to facilitate early administration. RUC-4 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 antagonists is due to the presence of antibodies to conformations of the
receptor induced by the binding of the drugs.
Study objective
The main objective:
- To assess the PD properties of a single subcutaneous injection of RUC-4 in
STEMI patients presenting to the CCL with the aim to perform primary
coronary angioplasty.
- To assess the PK properties of a single subcutaneous injection of RUC-4 in
STEMI patients presenting to the CCL with the aim to perform primary
coronary angioplasty.
- To assess safety and tolerability of RUC-4
Secundary objectives:
- To assess platelet count at select time points before and after RUC-4
administration
- To assess bleeding events* of a single SC injection of RUC-4 at select
timepoints after RUC-4 administration, at discharge and at 15-day and at 30-
day follow-up
- To assess intraprocedural thrombosis
- To assess the injection site reactions of a single subcutaneous injection of
RUC-4 at select timepoints after RUC-4 administration and at 15-day and at 30
day follow-up
- To evaluate any differences in PD or PK within each treatment group (gender,
weight, BMI, age)
* According to the BARC (II, III and V), ISTH Major and TIMI Major criteria
Study design
This is an open-label, phase 2 single center study.
The anticipated study duration is 18-20 weeks including 1-month follow-up from
last patient in; with 14-16 weeks enrollment period including up to two interim
analyses for review of data by the SRC (Safety Review Committee) at the
completion of each dose cohort before a dose-escalation. The interim analyses
can be performed without the 30-day follow-up data.
The decision to escalate to a higher (or lower, or maintain the same) dose
level will be based on review of the interim analysis by the SRC.
The duration of participation for each patient will be 1 month (± 7 days)
including enrollment into study, dosing and 30-day post RUC-4 administration
follow-up.
Intervention
A single subcutaneous injection of RUC-4.
3 cohorts:
Initial dose / First Cohort: 0.075 mg/kg.
Second and third Cohort: Decrease dose, increase dose (up to 0.015 mg/kg) or
maintain dose.
Study burden and risks
Burden:
7 or 8 x blood sample collection for which 2 to 4 x intravenous injections.
Risks and inconveniences:
- The following side effects of RUC-4 are known:
- the occurrence of skin irritations at the injection site of RUC-4
- the occurrence of small bleeding events, limited to the injection site of
RUC-4
- The following research tests may involve the following risks/conveniences:
- Blood sampling: Local pain and/or bruising.
Merryfield Row 3210
San Diego CA 92121
US
Merryfield Row 3210
San Diego CA 92121
US
Listed location countries
Age
Inclusion criteria
- Patients with STEMI, presenting with persistent chest pain (>30 min) and
ongoing >= 1 mm ST-segment elevation in two adjacent ECG-leads, with > 6 mm
cumulative ST-segment deviation, in whom the total duration of symptom to first
intracoronary device deployment (excluding a wire) is anticipated to be within
6 hours
- Adult males and females 18 years of age or older
- Females must be non-pregnant, non-lactating, and of non-childbearing
potential (postmenopausal or surgically sterilized)
- Weight (by history) of between 52 and 120 kg
- Written informed consent (following short-form of the informed consent form
at CCL)
Exclusion criteria
- High probability in the opinion of the cardiologist that current STEMI is
caused by stent thrombosis and the previous PCI related to this stent
thrombosis is < 1 month
- High suspicion of COVID-19 infection (known exposure, hypoxia, fever, cough)
- High suspicion of type II MI
- Out of hospital cardiac arrest (OHCA)
- Therapy resistant cardiogenic shock (systolic blood pressure <= 80 mm Hg for >
30 minutes)
- Persistent severe hypertension (systolic blood pressure > 180 mm Hg or
diastolic blood pressure > 110 mm Hg)
- Presentation with atrial fibrillation de novo
- Known severe liver disease
- Known history of severe renal dysfunction (glomerular filtration rate < 30
mL/min or serum creatinine > 200 mmol/L [> 2.5 mg/dL])
- Known left bundle branch block
- Requirement of oral anticoagulation (Vitamin K antagonists {VKA} or direct
oral antagonists {DOACs})
- Chronic use of P2Y12 antagonists
- Current treatment with αIIbβ3 receptor antagonist (other than RUC-4)
- Coagulation abnormality, known bleeding disorder, or history of documented
prior hemorrhagic or thrombotic stroke < 6 months
- History of upper or lower GI bleeding within the past 6 months
- Known clinically important anemia
- Known clinically important thrombocytopenia (platelet count of less than
150,000/µL)
- Known history of allergy to any of the ingredients in the RUC-4 formulation
(i.e., acetate buffer, sucrose)
- Major surgery within the past 6 months
- Life expectancy of less than 6 months
- Any clinically significant abnormality identified prior to enrollment that in
the judgment of the Investigator would preclude safe completion of the study
- Unwillingness or inability to comply with the requirements of this protocol
including the presence of any condition (physical, mental, or social) that is
likely to affect the patient's ability to comply with the
study protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004282-41-NL |
| ClinicalTrials.gov | NCT04284995 |
| CCMO | NL72032.100.19 |