E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Myocardial Infarction |
Infarto Miocardico Acuto |
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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 | 16.1 |
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. |
Valutare la sicurezza epatica e renale della somministrazione di dosi multiple in due livelli posologici di CSL112 (a basso dosaggio [2 g] o ad alto dosaggio [6 g]) rispetto a placebo nei soggetti con Infarto Miocardico Acuto. |
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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. |
esame dell’effetto di CSL112 sul tempo alla prima manifestazione di eventi avversi cardiovascolari maggiori (major adverse cardiovascular events, MACE), per caratterizzare la sicurezza e la tollerabilità di CSL112 nonché la farmacocinetica (PK) di CSL112 dopo la somministrazione di dosi multiple. |
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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 |
PK/PD substudy to characterize the pharmacokinetics and pharmacodynamics of CSL112 after multiple dose administration |
sottostudio PK/PD per caratterizzare la sicurezza e la tollerabilità di CSL112 nonché la farmacocinetica (PK) di CSL112 dopo la somministrazione di dosi multiple. |
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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.
1. Detection of a rise and/or fall cardiac troponin I or T with at least one
value above the 99th percentile upper reference limit.
AND,
2. Any one or more of the following:
a. Symptoms of ischemia
b. New (or presumably new) significant ST/T wave changes or
left bundle-branch block (LBBB)
c. Development of pathological Q waves on ECG
d. Imaging evidence of new loss of viable myocardium or
regional wall motion abnormality
e. Identification of intracoronary thrombus by angiography |
Uomini o donne di almeno 18 anni di età con evidenza di necrosi miocardica in un contesto clinico coerente con un IMA di tipo I (spontaneo), secondo le seguenti definizioni:
1. Rilevamento di un aumento e/o riduzione della troponina cardiaca I o T con almeno un valore superiore al limite superiore di riferimento del 99o percentile.
E
2. una o più delle seguenti condizioni:
a.Sintomi di ischemia.
b.Nuove (o presumibilmente nuove) modifiche significative dell’onda ST/T o blocco di branca sinistra (BBS).
c.Sviluppo di onde patologiche Q sull’ECG.
d.Evidenza nella diagnostica per immagini di nuova perdita di miocardio vitale o di anomalia del movimento della parete regionale.
e.Identificazione di trombo intracoronarico mediante angiografia.
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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 |
• instabilità emodinamica in corso
• Evidenza di malattia epatobiliare
• Evidenza di malattia renale cronica (CKD) (fase III, IV o V), definita
come moderata o grave insufficienza renale o se il soggetto è in dialisi
• Prove di funzionalità renale instabile
• Storia di danno renale acuto dopo una precedente esposizione ad un
agente di contrasto per via endovenosa.
• Storia nota di allergie, ipersensibilità o carenze a CSL112
o uno dei suoi componenti
• Altra grave condizione di comorbidità, farmaci concomitanti, o altro problema che rende il soggetto non idoneo per la partecipazione allo studio |
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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. |
- Una variazione clinicamente rilevante della lesione epatica indotta dal farmaco definita come variazione (dal basale) dell’alanina amino transferasi (ALT) maggiore di 3 volte il limite superiore della norma (Upper Limit of Normal, ULN), OPPURE una variazione della bilirubina totale maggiore di 2 volte ULN, che si conferma per come determinato alla ripetizione della misurazione.
- Una variazione clinicamente rilevante nello stato renale definita come aumento della creatinina sierica a ≥ 1,5 x il valore basale che si conferma per come determinato alla ripetizione della misurazione o per la necessità di dover ricorrere a terapia sostitutiva renale.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline (before 1st infusion) to Day 29. |
dal basale (prima della prima infusione) al giorno 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 number of subjects with study-drug-related AEs
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 |
1. Il tempo alla prima manifestazione di MACE (major adverse cardiovascular event). MACE include: Decesso cardiovascolare, Infarto miocardico (IM), Ictus ischemico e Ricovero dovuto ad angina instabile
2. Profilo farmacocinetico (concentrazioni plasmatiche corrette al basale) di apolipoproteina A-I (apoA-I) e fosfatidilcolina (PC)
3. apoA-I del plasma e PC Cmax
4. apoA-I del plasma e PC Tmax
5. apoA-I del plasma e PC area sotto la curva (AUC)
6. apoA-I del plasma e and PC t1/2
7. apoA-I del plasma e PC Clearance
8. apoA-I del plasma e PC Volume di distribuzione allo stato stazionario
9. Numero di soggetti con eventi avversi (EA) correlate al farmaco di studio
10. Eventi avversi complessivi : numero totale di pazienti con EA.
11. La manifestazione di eventi emorragici secondo quanto definito dai criteri del Bleeding Academic Research Consortium (BARC) (Mehran et al., 2011).
12. valutazione del potenziale immunogenico di CSL112: numero di soggetti con anticorpi serici di CSL112
13. Valutazione delle variazioni dal basale della sierologia: valutazioni(es. evidenza di sieroconversione o di infezione) per virus dell’epatite A (HAV), virus dell’epatite B (HBV), virus dell’epatite C (HCV), virus dell’immunodeficienza umana (HIV) 1/2, parvovirus B19.
14. Valutazione delle variazioni dal basale delle tecniche di amplificazione degli acidi nucleici: (es. evidenza di sieroconversione o di infezione) per virus dell’epatite A (HAV), virus dell’epatite B (HBV), virus dell’epatite C (HCV), virus dell’immunodeficienza umana (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 |
1. dall’inizio della prima infusione fino al giorno 112 dopo l’infusione.
2.- 8.: prima e dopo la prima e l’ultima infusione
9.- 11.: dall’inizio dell’infusione fino alla visita di fine studio del soggetto, approssimativamente giorno 382.
12.- 14.: prima dell’infusione e fino a circa il giorno 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 | 12 |
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 |
Bulgaria |
Canada |
Denmark |
France |
Italy |
Austria |
Netherlands |
Australia |
Czech Republic |
Germany |
Hungary |
Spain |
Israel |
Poland |
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 | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |