E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Myocardial Infarction |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 18.0 |
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 |
|
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 |
To assess the hepatic and renal safety and tolerability of multiple dose administration of two dose levels of CSL112 (low dose [2 g] or high dose [6 g]) compared with placebo in subjects with acute myocardial infarction. |
|
E.2.2 | Secondary objectives of the trial |
To examine the effect of CSL112 on the time-to-first occurrence of major adverse cardiovascular events (MACE), to characterize the safety and tolerability of CSL112, and to characterize the pharmacokinetics (PK) of CSL112 after multiple dose administration. |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
To characterize the pharmacokinetics and pharmacodynamics of CSL112 after multiple dose administration |
|
E.3 | Principal inclusion criteria |
• Men or women, at least 18 years of age, with evidence of myocardial necrosis in a clinical setting consistent with a type I (spontaneous) acute myocardial infarction (AMI), in the last week. |
|
E.4 | Principal exclusion criteria |
• Ongoing hemodynamic instability
• Evidence of hepatobiliary disease
• Evidence of chronic kidney disease (CKD) (Stage III, IV, or V), defined as moderate or severe renal impairment or if subject is receiving dialysis
• Evidence of unstable renal function
• History of acute kidney injury after previous exposure to an intravenous contrast agent.
• Known history of allergies, hypersensitivity or deficiencies to CSL112 or any of its components
• Other severe comorbid condition, concurrent medication, or other issue that renders the subject unsuitable for participation in the study |
|
E.5 End points |
E.5.1 | Primary end point(s) |
- Clinically important change in drug-induced liver injury defined as a change (from baseline) in alanine aminotransferase (ALT) greater than 3 times the upper limit of normal (ULN) or a change in total bilirubin greater than 2 times ULN, that is confirmed as determined upon repeat measurement.
- Clinically important change in renal status defined as a serum creatinine (Cr) increase to ≥ 1.5 x the baseline value, that is confirmed as determined upon repeat measurement or the need for renal replacement therapy. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline (before 1st infusion) to Day 29. |
|
E.5.2 | Secondary end point(s) |
1. The time-to-first occurrence of a major adverse cardiovascular event (MACE). MACE includes: cardiovascular death, MI, ischemic stroke and hospitalization for unstable angina.
2. Pharmacokinetic profile (baseline-corrected plasma concentrations) of apolipoprotein A-I (apoA-I) and phosphatidylcholine (PC)
3. Plasma apoA-I and PC Cmax
4. Plasma apoA-I and PC Tmax
5. Plasma apoA-I and PC area under the curve (AUC)
6. Plasma apoA-I and PC t1/2
7. Plasma apoA-I and PC Clearance
8. Plasma apoA-I and PC Volume of distribution at steady state
9. The occurrence of adverse reactions or suspected adverse reactions: the overall number and percentage of subjects:
- with adverse events (AEs), including local tolerability events, that
begin during or within 1 hour of an infusion; or
- with AEs considered to be causally related to the test product; or
- with AEs for which the Investigator's causality assessment is missing or indeterminate; or
- who experience an AE for which the incidence rate in an active
treatment arm exceeds the exposure-adjusted incidence rate in the
placebo arm by 30% or more, provided the difference in incidence rates
is 1% or more.
10. Overall AEs: total number of subjects with any AE
11. Bleeding events: number of subjects who experience bleeding events as defined by the Bleeding Academic Research Consortium (BARC) criteria (Mehran et al, 2011)
12. Immunogenic potential of CSL112: number of subjects with serum antibodies to CSL112
13. Change from baseline in serology: assessments (i.e., evidence of
seroconversion or infection) will be conducted for parvovirus B19
14. Change from baseline in nucleic acid testing : assessments (i.e.,
evidence of seroconversion or infection) will be conducted for parvovirus
B19 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From the start of the first infusion up to 112 days after infusion
2.- 8.: Before and after the first and last infusions
9. From the start of the infusion up to approximately Day 112
10. From the start of the infusion up to approximately Day 382.
12.- 14.: Before infusion, and up to approximately Day 112 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 129 |
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 |
Australia |
Austria |
Bulgaria |
Canada |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Poland |
Spain |
United Kingdom |
United States |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |