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    Summary
    EudraCT Number:2008-001409-40
    Sponsor's Protocol Code Number:S334.2.002
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2009-01-20
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2008-001409-40
    A.3Full title of the trial
    A Randomized, Double blind, Placebo-Controlled Dose Escalation Study to Investigate the Safety and Pharmacokinetics after Single and Multiple Doses of SLV334 in Sequential Cohorts of Patients with Moderate and Severe Traumatic Brain Injury.
    Estudio con escalada de dosis, aleatorizado, doble ciego, controlado con placebo que investiga la seguridad y farmacocinetica tras dosis unicas y multiples de SLV334 en cohortes secuenciales de pacientes que sufren traumatismo cerebral moderado y severo.
    A.4.1Sponsor's protocol code numberS334.2.002
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSolvay Pharmaceuticals B.V.
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSLV334
    D.3.2Product code SLV334
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 182821-33-6
    D.3.9.2Current sponsor codeSLV334
    D.3.9.3Other descriptive name{(3S)-3-[({1-[(2R)-2-carboxy-4-(1-naphthyl)butyl] cyclopentyl}carbonyl)amino]-2oxo-2,3,4,5-tetrahydr
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Moderate and severe Traumatic Brain Injury (TBI)
    Traumatismo cerebral moderado y severo.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level PT
    E.1.2Classification code 10060690
    E.1.2Term Traumatic brain injury
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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 1000 mg SLV334 and after multiple i.v. doses of 1000 mg SLV334 and 2000 mg SLV334 (up to 3 days, b.i.d.) compared to placebo in patients with moderate and severe Traumatic Brain Injury (TBI).
    E.2.2Secondary objectives of the trial
    -To determine the pharmacokinetics of SLV334 after a single dose of 1000 mg
    SLV334 and after multiple doses of 1000 mg SLV334 and 2000 mg 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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 ? 100 mmHg) consistent with point #1 above
    12. Known treatment with another investigational drug therapy or intervention within 30 days of injury.
    E.5 End points
    E.5.1Primary end point(s)
    Safety:
    The primary outcome measure will be the safety of SLV334 including mortality, adverse events (AE), serious adverse events (SAE), vitals 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).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Dose escalation in sequential cohorts
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other 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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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
    End of Study is defined as Last Subject Last Visit (Follow up visit at 6 months) + 30 days
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2009-01-20. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects who may be unconscious
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 21
    F.4.2.2In the whole clinical trial 72
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2009-03-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-02-06
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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