E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060690 |
E.1.2 | Term | Traumatic brain injury |
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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 |
The aim of the study is to determine the safety and tolerability of SLV334 after a single intravenous (i.v.) dose of 1000mg SLV334 and after multiple i.v. doses of 1000mg SLV334 and 2000mg SLV334 (up to 3 days, b.i.d.)compared to placebo in patients with moderate and severe Traumatic Brain Injury (TBI). |
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E.2.2 | Secondary objectives of the trial |
- To determine the pharmacokinetics of SLV334 after a single dose of 1000mg SLV334 and after multiple doses of 1000mg SLV334 and 2000mg SLV334 (up to 3 days, b.i.d.) in subjects with moderate and severe TBI - To assess the effect of SLV334 on clinical assessments such as intracranial pressure (ICP), cerebral perfusion pressure (CPP)and therapy intensity level (TIL) - To assess in a sub-sample of subjects (those with a ventricular catheter or microdialysis), SLV334 levels in the cerebrospinal fluid (CSF) and/or microdialysis compared to systemic levels - To assess in a sub-sample of subjects (as previously), the influence of single and multiple doses of i.v.SLV334 on neurohormone activities/conc.s related to the mode of action (neutral endopeptidase (NEP) and endothelin converting enzyme (ECE) and markers for apoptosis, necrosis and neural damage in the cerebrospinal fluid (CSF)and/or microdialysis compared to placebo and compared to systemic (plasma) levels. |
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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 |
FARMACOCINETICA/FARMACODINAMICA: Versione:Em.2 Data:2008/11/27 Titolo:Compreso nel protocollo principale dello studio Obiettivi:Determinare la farmacocinetica di SLV334 dopo una singola somministrazione di 1000 mg SLV334 e dopo dosaggi multipli di 1000 mg SLV334 e di 2000 mg SLV334 (fino a 3 giorni, b.i.d.) in soggetti con TBI moderata e severa. Determinare leffetto di SLV334 sugli accertamenti clinici quali la pressione intracranica (ICP), la pressione di perfusione cerebrale (CPP) e il livello di intensita` della terapia (therapy intensity level, TIL).
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E.3 | Principal inclusion criteria |
1. Male or female subjects, age between 16 and 70 years, inclusive (the lower age limit will be 18 if required by local regulations); 2. TBI diagnosed by history, clinical examination with Glasgow Coma Scale (GCS) of 12 or less; 3. Evidence of TBI confirmed by abnormalities on Computed Tomography (CT scan); 4. Clinical indication to monitor ICP; 5. Randomization and drug treatment with study drug possible within 8 hours after closed (non-penetrating) head trauma; 6. Informed Consent is given |
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E.4 | Principal exclusion criteria |
1. Life expectancy of less than 24 hours; 2. Any spinal cord injury; 3. Suspected or confirmed pregnancy or lactating women; 4. Penetrating head injury (e.g.missile, gunshot or stab injuries); 5. Bilaterally fixed dilated pupils at the time of randomization; 6. Coma suspected to be primarily due to other causes than head injury (e.g.drug or alcohol overdose); 7. Pure epidural hematoma (lucid interval and absence of structural brain damage on CT scan); 8. Known or CT scan evidence of previous major cerebral damage or known clinical sequelae of prior spinal cord injury; 9. Any severe concomitant condition (e.g.cancer, renal, hepatic, coronary disease or major psychiatric disorder) that can be ascertained at admission and could affect functional outcome; 10. Severe multiple trauma or major organ failure (uncontrolled visceral bleeding, unstable cardio-respiratory or renal function); 11. Severe cardiac or hemodynamic instability after resuscitation (Systolic blood pressure ≤ 100mmHg)consistent with point 1 above; 12. Known treatment with another investigational drug therapy or intervention within 30 days of injury. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety: The primary outcome measure will be the safety of SLV334 including mortality, adverse events (AE),serious adverse events (SAE), vital signs, laboratory variables and ECG Pharmacokinetics: In cohorts 1-3,pharmacokinetics measurements of SLV334 plasma levels will be measured at 6 time-points up to 24 hours after start of the first infusion. In cohort 4, plasma levels of SLV334 will be measured at 12 time-points up to 24 hours after the first dose of Day 3. Pharmacodynamics: - Biomarkers for Endothelin Converting Enzyme (ECE) and Neutral Endopeptidase (NEP): ET-1, Big-ET-1, BNP, ANP and cGMP - Biomarkers for apoptosis and necrosis (alpha II-spectrin breakdown products, UCH-L1 and BA252) |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
A dose crescente in coorti sequenziali |
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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.8.3 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | Information not present in EudraCT |
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 |
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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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End of study is defined as Last Subject Last Visit (follow up visit at 6 months) + 30 days |
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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 | 4 |
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 | 5 |