Myocardial Infarction
Conditions
Brief summary
This is a multicenter, randomized, double-blind, active-controlled, dose-titrating phase 2 study to evaluate the safety and efficacy of firibastat administered orally BID (2 daily doses) versus ramipril administered orally BID over 12 weeks after acute anterior MI. Subjects will be followed for 12 weeks (over 4 study visits). A total of 294 male and female subjects with a diagnosis of first acute anterior MI will be randomized. The subjects will need to have a primary percutaneous coronary intervention (PCI) of the index MI related artery within 24 hours after MI.
Detailed description
At Inclusion Visit (Visit 2 \[within 72 hours after acute MI\]), subjects will be randomly assigned to 1 of the following 3 treatment groups in a 1:1:1 ratio: * Group 1: Subjects will receive 50 mg firibastat BID for 2 weeks and then 100 mg BID for 10 weeks * Group 2: Subjects will receive 250 mg firibastat BID for 2 weeks and then 500 mg BID for 10 weeks * Group 3: Subjects will receive 2.5 mg ramipril BID for 2 weeks and then 5 mg BID for 10 weeks Then subjects will undergo study procedures at Titration Visit (Visit 3 \[Day 14\]), Treatment Visit (Visit 4 Day 42\]) and End-of-Treatment Visit (Visit 5 \[Day 84\]).
Interventions
DRUGRamipril
1 or 2 capsules administered orally, twice daily
DRUGFiribastat
1 or 2 capsules administered orally, twice daily
Sponsors
Quantum Genomics SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of first acute anterior MI (ST-elevation myocardial infarction) defined as chest pain \>30 minutes and ST elevation ≥0.2 mV in at least 2 consecutive electrocardiogram (ECG) leads in the anterior area (DI, aVL, V1 V6). * Primary PCI of the index-MI-related artery within 24 hours after the MI.
Exclusion criteria
* Body mass index \>45 kg/m². * Subject is hemodynamically unstable or has cardiogenic shock. * Subjects with clinical signs of HF (Kilipp III and IV). * Systolic blood pressure \<100 mmHg at inclusion visit * Early primary PCI of the index-MI-related artery performed within 3 hours after MI. * Subjects treated with angiotensin-converting-enzyme inhibitor (ACE I), angiotensin receptor blocker (ARB) or sacubitril/valsartan prior to the index magnetic resonance imaging. Note: if treatment was for HTN, ACE I/ARB should be stopped, and, if necessary, another therapeutic class can be prescribed for HTN. If the ACE I/ARB was prescribed for congestive HF, the subject is not considered eligible; if the ACE I/ARB prescribed for another reason cannot be stopped, the subject is not eligible for study inclusion. * Subjects scheduled for implantable cardioverter defibrillator (ICD), cardiac resynchronization therapy, or pacemaker within the next 3 months. If an ICD is indicated for ventricular arrhythmia during the course of the study, a life vest, when possible, should be prescribed and the ICD scheduled after study completion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Left Ventricular Ejection Fraction Assessed by Cardiac Magnetic Resonance Imaging (CMRI) | 84 days | Comparison of the effects of BID oral administration of 2 doses of firibastat to those of BID oral administration of ramipril on the change from Baseline in LVEF on Day 84 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Left-ventricle End-diastolic Volume Assessed by CMRI | 84 days | Comparison of the effects of BID administration of firibastat and ramipril on the change from Baseline to Day 84 in left-ventricle end-diastolic volume |
| Left-ventricle End-systolic Volume Assessed by CMRI | 84 days | Comparison of the effects of BID administration of firibastat and ramipril on the change from Baseline to Day 84 in left-ventricle end-systolic volume |
| Major Cardiac Event (MACE): Combined Clinical Endpoint of Cardiovascular Death, MI, and Cardiac Hospitalization | 84 days | Comparison of the effects of BID administration of firibastat and ramipril on major cardiac event (MACE) over 84 days |
| N-terminal Pro B-type Natriuretic Peptide (NT proBNP) | 84 days | Comparison of the effects of BID administration of firibastat and ramipril on the change from Baseline to Day 84 in N-terminal pro b-type natriuretic peptide (NT proBNP) |
Countries
France, Germany, Hungary, Poland, Slovakia, Spain, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1: Firibastat 100 mg Subjects will receive 50 mg firibastat BID for 2 weeks and then 100 mg BID for 10 weeks.
Firibastat: 1 or 2 capsules administered orally, twice daily | 98 |
| Group 2: Firibastat 500 mg Subjects will receive 250 mg firibastat BID for 2 weeks and then 500 mg BID for 10 weeks.
Firibastat: 1 or 2 capsules administered orally, twice daily | 99 |
| Group 3: Ramipril 5 mg Subjects will receive 2.5 mg ramipril BID for 2 weeks and then 5 mg BID for 10 weeks.
Ramipril: 1 or 2 capsules administered orally, twice daily | 98 |
| Total | 295 |
Baseline characteristics
| Characteristic | Group 3: Ramipril 5 mg | Group 1: Firibastat 100 mg | Total | Group 2: Firibastat 500 mg |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 18 Participants | 15 Participants | 53 Participants | 20 Participants |
| Age, Categorical Between 18 and 65 years | 62 Participants | 57 Participants | 176 Participants | 57 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants | — |
| Region of Enrollment France | 13 participants | 13 participants | 40 participants | 14 participants |
| Region of Enrollment Germany | 4 participants | 4 participants | 11 participants | 3 participants |
| Region of Enrollment Hungary | 22 participants | 25 participants | 67 participants | 20 participants |
| Region of Enrollment Poland | 23 participants | 26 participants | 74 participants | 25 participants |
| Region of Enrollment Slovakia | 23 participants | 21 participants | 70 participants | 26 participants |
| Region of Enrollment Spain | 11 participants | 8 participants | 28 participants | 9 participants |
| Region of Enrollment United Kingdom | 2 participants | 1 participants | 5 participants | 2 participants |
| Sex: Female, Male Female | 20 Participants | 17 Participants | 55 Participants | 18 Participants |
| Sex: Female, Male Male | 60 Participants | 55 Participants | 174 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 98 | 1 / 98 | 1 / 98 |
| other Total, other adverse events | 43 / 98 | 54 / 98 | 54 / 98 |
| serious Total, serious adverse events | 11 / 98 | 18 / 98 | 10 / 98 |
Outcome results
Primary
Left Ventricular Ejection Fraction Assessed by Cardiac Magnetic Resonance Imaging (CMRI)
Comparison of the effects of BID oral administration of 2 doses of firibastat to those of BID oral administration of ramipril on the change from Baseline in LVEF on Day 84
Time frame: 84 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Firibastat 100 mg | Left Ventricular Ejection Fraction Assessed by Cardiac Magnetic Resonance Imaging (CMRI) | 5.6 percentage of left ventricular volumes | Standard Deviation 1.2 |
| Group 2: Firibastat 500 mg | Left Ventricular Ejection Fraction Assessed by Cardiac Magnetic Resonance Imaging (CMRI) | 5.3 percentage of left ventricular volumes | Standard Deviation 1.1 |
| Group 3: Ramipril 5 mg | Left Ventricular Ejection Fraction Assessed by Cardiac Magnetic Resonance Imaging (CMRI) | 5.7 percentage of left ventricular volumes | Standard Deviation 1.1 |
Secondary
Left-ventricle End-diastolic Volume Assessed by CMRI
Comparison of the effects of BID administration of firibastat and ramipril on the change from Baseline to Day 84 in left-ventricle end-diastolic volume
Time frame: 84 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Firibastat 100 mg | Left-ventricle End-diastolic Volume Assessed by CMRI | 14.2 mL | Standard Deviation 4.5 |
| Group 2: Firibastat 500 mg | Left-ventricle End-diastolic Volume Assessed by CMRI | 12.7 mL | Standard Deviation 4.3 |
| Group 3: Ramipril 5 mg | Left-ventricle End-diastolic Volume Assessed by CMRI | 9.4 mL | Standard Deviation 4.4 |
Secondary
Left-ventricle End-systolic Volume Assessed by CMRI
Comparison of the effects of BID administration of firibastat and ramipril on the change from Baseline to Day 84 in left-ventricle end-systolic volume
Time frame: 84 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Firibastat 100 mg | Left-ventricle End-systolic Volume Assessed by CMRI | -0.5 mL | Standard Deviation 3.3 |
| Group 2: Firibastat 500 mg | Left-ventricle End-systolic Volume Assessed by CMRI | -0.4 mL | Standard Deviation 3.2 |
| Group 3: Ramipril 5 mg | Left-ventricle End-systolic Volume Assessed by CMRI | -3.1 mL | Standard Deviation 3.2 |
Secondary
Major Cardiac Event (MACE): Combined Clinical Endpoint of Cardiovascular Death, MI, and Cardiac Hospitalization
Comparison of the effects of BID administration of firibastat and ramipril on major cardiac event (MACE) over 84 days
Time frame: 84 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Firibastat 100 mg | Major Cardiac Event (MACE): Combined Clinical Endpoint of Cardiovascular Death, MI, and Cardiac Hospitalization | 10 Event |
| Group 2: Firibastat 500 mg | Major Cardiac Event (MACE): Combined Clinical Endpoint of Cardiovascular Death, MI, and Cardiac Hospitalization | 8 Event |
| Group 3: Ramipril 5 mg | Major Cardiac Event (MACE): Combined Clinical Endpoint of Cardiovascular Death, MI, and Cardiac Hospitalization | 6 Event |
Secondary
N-terminal Pro B-type Natriuretic Peptide (NT proBNP)
Comparison of the effects of BID administration of firibastat and ramipril on the change from Baseline to Day 84 in N-terminal pro b-type natriuretic peptide (NT proBNP)
Time frame: 84 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Firibastat 100 mg | N-terminal Pro B-type Natriuretic Peptide (NT proBNP) | -1618.7 pg/ml | Standard Deviation 1381.7 |
| Group 2: Firibastat 500 mg | N-terminal Pro B-type Natriuretic Peptide (NT proBNP) | -1596.4 pg/ml | Standard Deviation 2279.6 |
| Group 3: Ramipril 5 mg | N-terminal Pro B-type Natriuretic Peptide (NT proBNP) | -1735.6 pg/ml | Standard Deviation 2326.5 |