E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of left ventricular dysfunction after acute anterior myocardial infarction |
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E.1.1.1 | Medical condition in easily understood language |
Prevention of left ventricular dysfunction after acute anterior myocardial infarction |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10000891 |
E.1.2 | Term | Acute myocardial infarction |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Comparison of the effects of twice daily (bis in die [BID]) oral administration of 2 doses of firibastat to those of BID oral administration of ramipril on the change from Baseline in left ventricular ejection fraction (LVEF) assessed by cardiac magnetic resonance imaging (CMRI) on Day 84 |
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E.2.2 | Secondary objectives of the trial |
To compare the effects of BID administration of firibastat and ramipril on:
- the change from Baseline to Day 84 in left-ventricle end-diastolic and end-systolic volumes assessed by CMRI
- the change from Baseline to Day 84 in average peak of longitudinal and
circumferential strain (assessed by CMRI) in the infarcted segments
- infarct mass (assessed by CMRI) at Day 84
- major cardiac event (MACE): combined clinical endpoint of cardiovascular death, myocardial infarction (MI), and cardiac hospitalization over 84 days
- the change from Baseline to Day 84 in N-terminal pro b-type natriuretic peptide (NT proBNP), procollagen type III aminoterminal peptide (PIIINP), and C reactive protein (CRP)
- the slope of decrease in copeptin blood level change between Baseline and Day 84.
To compare the safety of firibastat and ramipril |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject must provide signed written informed consent. Important Note: Subject must be willing and able to give informed consent for participation in the study.
2. Men and women >= 18 years of age at Screening.
3. 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).
4. Primary PCI of the index-MI-related artery within 24 hours after the MI.
5. Women of childbearing potential and non-surgically sterile male subjects who are sexually active must agree to use an approved highly effective form of contraception from the time of informed consent until 30 days post-dose. Approved forms of contraception include hormonal intrauterine devices, hormonal contraceptives (oral birth control pills, depot, patch, or injectable), together with supplementary double-barrier methods such as condoms or diaphragms with spermicidal gel or foam.
6. Women of childbearing potential must have a negative serum pregnancy test result at the Screening Visit. |
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E.4 | Principal exclusion criteria |
1. Body mass index >45 kg/m².
2. Subject is hemodynamically unstable or has cardiogenic shock.
3. Subjects with clinical signs of HF (Kilipp III and IV corresponding to severe HF).
4. Systolic blood pressure <100 mmHg at Inclusion Visit.
5. Early primary PCI of the index-MI-related artery performed within 3 hours after MI. Important Note: the time of the PCI MUST NOT be delayed because of the protocol; if PCI is performed within 3 hours after MI, the subject is not eligible.
6. Subjects who require treatment with angiotensin-converting-enzyme inhibitor (ACE-I), angiotensin-receptor blocker (ARB), or sacubitril/valsartan after the index magnetic resonance imaging. Note: if treatment was for HTN, ACE-I/ARB should be stopped, right before index magnetic resonance imaging, 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.
7. 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.
8. Subjects with any contraindication related to the CMRI procedure (devices or metal foreign bodies, including pacemaker, defibrillator) including severe claustrophobia according to the lists/safety rules of the local MRI departments.
9. Female who is breast-feeding, pregnant, or planning to become pregnant during the study.
10. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years.
11. Alkaline phosphatase >3 upper limit of normal (ULN), total bilirubin >/= 1.5 ULN, or direct bilirubin >ULN in subjects with Gilbert’s syndrome at the Screening Visit.
12. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, as calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula at the Screening Visit.
13. History of any blood disorder, other than sickle cell trait, causing hemolysis or unstable red blood cells (e.g., malaria, babesiosis, hemolytic anemia, thalassemia, or sickle cell anemia).
14. Clinical evidence of thyroid disease, thyroid hormone therapy that is not stable >=4 weeks prior to Screening, or a thyroid-stimulating hormone (TSH) level <0.75 x lower limit of normal or >1.5 x ULN.
15. History of alcohol or drug abuse within the 3 months prior to the Screening Visit that would interfere with study participation or lead to decreased compliance with study procedures or IP intake in the investigator’s opinion.
16. Participation in another clinical study involving an investigational drug within 30 days prior to Screening, or if a subject plans to participate in another clinical study within 30 days of discontinuation of the IP.
17. Any condition that in the opinion of the investigator would interfere with study participation, may pose a risk to the subject, or would make study participation not in the best interest of the subject.
18. Subjects with a life expectancy of less than 1 year per investigator’s discretion.
19. Any subject who, in the opinion of the investigator, will not be able to follow the protocol.
The contraindications of Ramipril as given in the summary of product characteristics must be checked before any inclusion to ensure that the subject has no contraindication to the administration of Ramipril; otherwise, the subject should be excluded from the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from Baseline to Day 84 in LVEF assessed by CMRI (centralized reading) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Change from Baseline to Day 84 in left-ventricular end-diastolic and end-systolic volumes assessed by CMRI
- Change from Baseline to Day 84 in average peak of longitudinal and circumferential strain in the infarcted segments assessed by CMRI
- Infarct mass at EOT (Day 84) assessed by CMRI
- MACE (i.e., cardiovascular deaths, new MIs, and cardiac hospitalizations) as adjudicated by an independent committee
- Change from Baseline in NT-proBNP, PIIINP, and CRP levels to Day 84
- Slope of decrease in copeptin over time |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Germany |
Hungary |
Poland |
Slovakia |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |