E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Myocardial Infarction |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 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 |
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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 |
To assess the hepatic and renal safety 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. |
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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. |
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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 |
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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 four days. |
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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 |
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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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline (before 1st infusion) to Day 29. |
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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 occurence 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 administration of the
test product; or -with AEs for which the Investigator's causility assessment is missing or indetermine orwho 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 hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) 1/2, parvovirus B19
14. Change from baseline in nucleic acid testing : assessments (i.e., evidence of seroconversion or infection) will be conducted for HAV, HBV, HCV, HIV 1/2, parvovirus B19 |
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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.- 11.: From the start of the infusion to the subject's end of study visit, up to approximately Day 382.
12.- 14.: Before infusion, and up to approximately Day 112 |
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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 | 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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 110 |
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 |
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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 | 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 |