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    Summary
    EudraCT Number:2007-003232-35
    Sponsor's Protocol Code Number:197-2004
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2007-07-10
    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 ConcernedAustria - BASG
    A.2EudraCT number2007-003232-35
    A.3Full title of the trial
    Dantrolen as treatment for hyperthermia in patients with subarachnoidal hemorrhage
    A.4.1Sponsor's protocol code number197-2004
    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 SponsorMedizin Universität Wien
    B.1.3.4CountryAustria
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    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 Yes
    D.2.1.1.1Trade name Dantrolen
    D.2.1.1.2Name of the Marketing Authorisation holderProcter und Gamble Pharmaceuticals Germany
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Information not present in EudraCT
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDantrolen
    D.3.2Product code 17.709
    D.3.4Pharmaceutical form Injection*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    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 Yes
    D.3.11.13.1Other medicinal product typepharmaceutical medicinal product
    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 placeboIntravenous 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
    Fever episodes occur in more than 50%of patients with subarachnoidal hemorrhage despite antibiotic and antipyretic therapy.The exact mechanism of hyperthermia-induced brain injury is not known. Hyperthermia might increase the release of excitatory neurotransmitters or trigger an amount of oxygen free radicals. Hyperthermia may also aggravate blood-brain barrier disruption.The deleterious effect of fever has been demonstrated in patients with subarachnoidal hemorrhage.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10020846
    E.1.2Term Hyperthermia therapy
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    We test the hypothesis that dantolen will reduce centrally mediated fever in patients after subarachnoidal hemorrhage. Specifically we will test the hypothesis that dantrolene decreases the magnitude and duration of hyperthermia.
    E.2.2Secondary objectives of the trial
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The study will be restricted to neurosurgical patients after subarachnoidal hemorrhage aged from 18 to 80 years.
    There will be no limitation of enrollment as to patients breathing spontaneously or being ventilator dependant.
    AND
    sustained fever (≥38ºC for more than an hour) without an identifiable infectious cause.
    E.4Principal exclusion criteria
    • Patients who, in the judgment of the attending anesthesiologist, have active infection likely to cause fever. The judgment will be based on the following evidence collected within 24 hours of study enrollment: white blood cell count above 12,000 c/dL, opacities in chest x-rays, sputum containing pus from visual exam, or positive cultures of sputum, blood, or urine.
    • Pregnancy determined by giving a urine pregnancy test immediately before consent is obtained. Female patients less than 50 years of age will undergo a pregnancy test unless there is a history of previous hysterectomy.
    • Patients who have been diagnosed with arrhythmia within 24 hours of study enrollment
    • Patients with a history of muscular dystrophy
    • Patients in whom the dose of mannitol for treatment or placebo groups is contraindicated by having increased serum osmolarity (> 320 mOsmol/L) as measured immediately following signature of informed consent. Hypotension will not be an issue because all neuro intensive care patients are kept at least normotensive using fluid or vasopressors if indicated.
    • Patients who are known to have acute liver disease at the time of study enrollment as shown by the most recent lab tests available within 72 hours of screening. If appropriate tests are not available , they will be performed after informed consent is obtained. The tests are as follows: ALT> 94 u/L, AST > 120 u/L.
    • Patients who have stage 2 cirrhosis
    E.5 End points
    E.5.1Primary end point(s)
    As soon as fever ≥ 38°C is detected, a series of cultures and laboratory samples will be taken per Neuro Intensive Care Unit routine for febrile patients.
    Immediately after drawing the culture samples, fever will be treated according to the ICU protocol: administration of 1000 mg paracetamol per nasogastric tube or orally with a 20-ml flush of free water. If fever does not decline by 0.5°C after 30 minutes patients will be randomly assigned to the dantrolene group or to the placebo group (see below).
    If in the judgment of the anesthesiologist attending the febrile episode is due to an infection, specific antibiotic treatment will be initialized by the anesthesiologist and the study will be stopped, the subject will be considered withdrawn, and the data will not be used. After antibiotic treatment, if another fever episode occurs without any clinical association to infection, the patient will be reevaluated for inclusion/exclusion criteria and if criteria are met the patient will be re-enrolled using a different randomization number.
    Patients who satisfy the inclusion/exclusion criteria of the study and who are enrolled in this study will be randomized with computer-generated grouping to either one of two groups. One group of subjects will be given dantrolene for the first episode of fever The other group will be given placebo. Dantrolene is supplied in 70-ml vials containing 20 mg dantrolene and 3000 mg mannitol, reconstituted with 60 ml of sterile water. Dantrolene will be given in the following dose: 5 mg/kg given intravenously over 30 minutes containing 750 mg/kg mannitol. As placebo mannitol will be used, as 20mg dantrolene contains 3000mg mannitol. The placebo will be given in the following dose: 750 mg/kg (3.75 ml/kg delivered in a 20% solution) intravenously for 30 minutes. Each treatment is a one-time dose.
    The first episode of fever will be treated with the first randomized treatment and the subject will be monitored for 24 hours.
    If the subject’s fever fails to decrease by 0.5°C to the study treatment or continues to increase after 8 hours from the administration of the study treatment, 1000 mg paracetamol per nasogastric tube or orally with a 20-ml flush of free water will be administered again to attempt reduction of the fever. If the subject’s temperature increases to >40°C, physical cooling will be performed by placing Polar Air cover set (10°C) over the subject.
    Dantrolene has a characteristic yellow color. To retain blinding, the infusion bottle and tubing will be covered with an opaque foil by one of the investigators listed on the application who performs the randomization and drug preparation, but is not involved in data collection. Data collection will be performed by medical staff not included into the randomization process.
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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 No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    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.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    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 2007-07-10. 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
    patients intubated and sedated becuse of the subarachnoidal hemorrhage
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state34
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 34
    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 Decision2007-08-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-03-13
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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