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    Summary
    EudraCT Number:2022-002418-18
    Sponsor's Protocol Code Number:2021-10
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-08-15
    Trial 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 ConcernedGermany - BfArM
    A.2EudraCT number2022-002418-18
    A.3Full title of the trial
    AmaNtadine for NeuroenhancEment in acutE patients Study - A prospective pilot proof of concept phase IIb study in intensive and intermediate care unit patients (ANNES)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    AmaNtadine for NeuroenhancEment in acutE patients Study - A prospective pilot proof of concept phase IIb study in intensive and intermediate care unit patients (ANNES)
    A.4.1Sponsor's protocol code number2021-10
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity Hospital Tübingen
    B.1.3.4CountryGermany
    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 supportUniversity Hospital Tuebingen
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Tuebingen
    B.5.2Functional name of contact pointZentrum für klinische Studien
    B.5.3 Address:
    B.5.3.1Street AddressFrondsbergstrasse 23
    B.5.3.2Town/ cityTuebingen
    B.5.3.4CountryGermany
    B.5.4Telephone number004970712985629
    B.5.5Fax number004970712925080
    B.5.6E-mailzks-pm@med.uni-tuebingen.de
    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 Amantadin-ratiopharm®
    D.2.1.1.2Name of the Marketing Authorisation holderratiopharm GmbH
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAmantadin-ratiopharm®
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAMANTADINE HEMISULFATE
    D.3.9.3Other descriptive nameAMANTADINE HEMISULFATE
    D.3.9.4EV Substance CodeSUB78132
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0,4
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients on Intermediate Care and Intensive Care Unit (IMC and ICU) with unresponsive wakefulness syndrome not otherwise explained
    E.1.1.1Medical condition in easily understood language
    Patients on Intermediate Care and Intensive Care Unit (IMC and ICU) with unresponsive wakefulness syndrome not otherwise explained
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To demonstrate that Amantadine is efficacious in increasing the level of vigilance/responsiveness as measured by clinical scores, mainly the Glasgow Coma Scale (GCS).
    E.2.2Secondary objectives of the trial
    • Improvement of vigilance measured via alternative scales (Richmond Agitation-Sedation Scale (RASS), Full Outline of UnResponsiveness (FOUR) Score Coma Scale), Intensive Care Delirium Screening Checklist (ICDSC), National Institute of health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Glasgow Outcome Scale – Extended (GOS-E), Coma Recovery Scale revised (CRS-R) and Montreal Cognitive Assessment (MoCA) after 90 days, EEG results, survival and clinical improvement reported within the therapists’ questionnaire.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Subjects meeting all of the following criteria will be considered for admission to the trial:
    • Must be ≥ 18 years at the time of signing the informed consent.
    • Informed consent:
    o The patient understands the study procedures and voluntarily signs an informed consent document
     or
    o If a subject has per definition reduced consciousness and therefore is not in a position to provide written informed consent, prior to any study related assessments/procedures the patient’s legal representative can give written informed consent. Inclusion of this patient is also possible if two independent physicians agree to include the patient in the study. In this case the Inform Consent of the Patient or his/her legal representative will be sought retroactively as soon as possible .
    • Able to adhere to the study visit schedule and other protocol requirements.
    • Females: pregnancy excluded by measurement of human chorionic gonadotropin (hCG) in serum before start of study medication
    • Subject (male or female) is willing to use highly effective contraceptive methods during treatment and for 4 days (male or female) after the end of treatment (adequate: combined hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasoing system, bilateral tubal occlusion, vasectomized partner1, sexual abstinence2).
    1 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success
    2 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
    • All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.
    • All subjects must agree not to share medication.
    • Reduced consciousness, defined as GCS <8, lasting at least 72 h, ,not otherwise explained
    • Inconspicuous EEG and ECG
    E.4Principal exclusion criteria
    • Subjects presenting with any of the following criteria will not be included in the trial:
    • Women during pregnancy and lactation.
    • History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
    • Participation in other interventional study. (Participation in an observational trial is acceptable.)
    • Reduced consciousness, otherwise sufficiently explained, such as reduced consciousness due to status epilepticus, hyperglycaemia, electrolyte imbalance, hyperkalaemia, akinetic crisis in Parkinson’s disease) Reduced consciousness, otherwise sufficiently explained
    • Delirium (Intensive Care Delirium Screening Checklist (ICDSC) > 4 or >5 in aphasic patients)
    • History of epileptic seizures or status epilepticus
    • Concomitant therapy with memantine
    • Pre-existing cardial conditions Severe uncompensatede.g. heart failure (NYHA IV)
    • cardiomyopathy and, myocarditis
    • Atriventricular block (AV block) second-degree and third-degree
    • known bradykcardia (below 55 beats/minute)
    • Known long QT interval (QTc according to Bazett > 420 ms) or recognizable U-waves or congenital QT syndrome in the Family history
    • a history of serious ventricular arrhythmias, including torsade de pointes
    • hypokalemia or hypomagnesemia
    • concomitant therapy with Budipin or other QT-prolonging drugs
    • impaired renal function, measured by glomerular filtration rate (GFR) < 10 ml/min
    • a history of serious ventricular arrhythmias, including torsade de pointes
    • arrythmia (patients with a QTc time increase of >60ms or interval of >480ms have to be excluded from treatment), simultaneous treatment with other QT time elongating drugs, hypo-magnesaemia or -kalemia)
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is the measure of the level of vigilance by GCS after 120 hrs (± 4hrs. ) from first dosis
    E.5.1.1Timepoint(s) of evaluation of this end point
    120 hrs (± 4hrs.) from first dosis
    E.5.2Secondary end point(s)
    • Improvement of vigilance measured via alternative scales (Richmond Agitation-Sedation Scale (RASS), Full Outline of UnResponsiveness (FOUR) Score Coma Scale), Intensive Care Delirium Screening Checklist (ICDSC), National Institute of health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Glasgow Outcome Scale – Extended (GOS-E), Coma Recovery Scale revised (CRS-R) and Montreal Cognitive Assessment (MoCA) after 90 days
    E.5.2.1Timepoint(s) of evaluation of this end point
    90 days from first treatment
    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 No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned1
    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 No
    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
    LVLS
    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
    E.8.9.2In all countries concerned by the trial years2
    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.1.2.1Number of subjects for this age range: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 No
    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 No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects will receive care within the regular health care system. This might mean staying on the ICU, but also a transfer to a nursing home or a rehabilitation facility depending on the patient’s condition.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects will receive care within the regular health care system. This might mean staying on the ICU, but also a transfer to a nursing home or a rehabilitation facility depending on the patient’s condition.
    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 Decision2022-10-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-11-09
    P. End of Trial
    P.End of Trial StatusOngoing
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