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    Summary
    EudraCT Number:2017-002163-17
    Sponsor's Protocol Code Number:15-138
    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:2019-08-01
    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 number2017-002163-17
    A.3Full title of the trial
    A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTICENTRE STUDY OF THE EFFICACY AND SAFETY OF NICOTINAMIDE IN PATIENTS WITH FRIEDREICHS ATAXIA.
    Eine randomisierte, doppel-verblindete, Placebo-kontrollierte, zweiarmige, multizentrische Studie zur Effizienz und Sicherheit von Nicotinamid in Patienten mit einer Friedreich-Ataxie.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTICENTRE STUDY OF THE EFFICACY AND SAFETY OF NICOTINAMIDE IN PATIENTS WITH FRIEDREICHS ATAXIA.
    Eine randomisierte, doppel-verblindete, Placebo-kontrollierte, zweiarmige, multizentrische Studie zur Effizienz und Sicherheit von Nicotinamid in Patienten mit einer Friedreich-Ataxie.
    A.3.2Name or abbreviated title of the trial where available
    NICOFA
    A.4.1Sponsor's protocol code number15-138
    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 SponsorRWTH Aachen University represented by the Rector himself, represented by the Dean of the Medical Faculty
    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 supportDeutsche Forschungsgemeinschaft
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital RWTH Aachen
    B.5.2Functional name of contact pointCTC-A
    B.5.3 Address:
    B.5.3.1Street AddressPauwelsstr.30
    B.5.3.2Town/ cityAachen
    B.5.3.3Post code52074
    B.5.3.4CountryGermany
    B.5.4Telephone number004924180 80092
    B.5.5Fax number004924180 33 80092
    B.5.6E-mailctc-a@ukaachen.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 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 nameNicotinamide
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNICOTINAMIDE
    D.3.9.1CAS number 98-92-0
    D.3.9.4EV Substance CodeSUB09246MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Friedreich Ataxia
    Friedreich Ataxie
    E.1.1.1Medical condition in easily understood language
    Friedreich Ataxia
    Friedreich Ataxie
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of daily doses of nicotinamide in slowing disease progression as measured by changes in the Scale for the Assessment and Rating of Ataxia (SARA) as compared with placebo in patients with Friedreich´s ataxia.
    E.2.2Secondary objectives of the trial
    To determine the change of secondary endpoints such as quality of life, functional motor and cognitive measures, clinician’s and patient’s global impression-change scales as well as frataxin protein level under treatment of daily doses of nicotinamide as compared with placebo in patients with Friedreich´s ataxia.
    To evaluate cognition, cardiac and spinal cord/brain measures.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients must have a molecular genetic diagnosis of Friedreich ataxia with a GAA-repeat expansion on both alleles of the FXN gene and a SARA Score >7 and <28.
    2. Patients must be ≥18 and <50 years old and have a weight of at least 50kg.
    3. Written informed consent prior to study participation
    4. A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea or of childbearing potential and agrees to use of appropriate contraceptive measures.
    E.4Principal exclusion criteria
    1. Patients with any medical condition or illness that, in the opinion of the investigator would interfere with study compliance and/or impair the patient´s ability to participate or complete the study.
    2. Any uncontrolled medical or neurological/neurodegenerative condition (other than Friedreich ataxia).
    3. Clinically significant psychiatric illness (e.g., uncontrolled major depression, schizophrenia, bipolar affective disorder) within 6 months prior to screening.
    4. Patients with significant clinical dysphagia.
    5. Hypersensitivity to nicotinamide.
    6. Patients known to be positive for human immunodeficiency virus (HIV).
    7. Patients with a significant history of substance abuse (e.g. alcohol or drug abuse) within the previous six months before enrolment.
    8. Patients with a history of severe allergies to medications.
    9. Indication of impaired liver function as shown by an abnormal liver function profile at screening (e.g., repeated values of aspartate aminotransferase [AST], alanine aminotransferase [ALT] and bilirubin ≥3 × the upper limit of normal).
    10. History of malignancy or carcinoma. The following exceptions may be made after discussion with the Sponsor:
    • Subjects with cancers in remission more than 5 years prior to screening.
    • Subjects with a history of excised or treated basal cell or squamous carcinoma.
    • Subjects with prostate cancer in situ.
    11. History or evidence of an autoimmune disorder considered clinically significant by the Investigator or requiring chronic use of systemic corticosteroids or other immunosuppressants.
    12. History of clinically significant cardiac disease (ejection fraction < 40% (normal range 50-70%), cardiac insufficiency defined as New York Heart Association (NYHA) Class >2; clinically significant congenital or acquired valvular disease; symptomatic coronary disease such as prior myocardial infarction or angina, B-type natriuretic peptide (BNP) level increase more than 2 x of the normal age- and gender dependent range; history of unstable arrhythmias, history of atrial fibrillation).
    13. The subject received an investigational drug within 30 days prior to inclusion into this study.
    14. Patients taking sodium valproate or any other known histone deacetylase inhibitor.
    15. Use of vitamin B1 (thiamine), withdrawal should be at least 3 months prior Screening.
    16. Use of vitamin B3 (nicotinamide), withdrawal should be at least 3 months prior Screening.
    17. If patients are taking idebenone or coenzyme Q10 (CoQ), this should be stable over the last three months and not changed during the study.
    18. The subject is unwilling or unable to provide written informed consent and to follow the procedures outlined in the protocol.
    19. For subjects who will undergo an MRI: Any contraindications to MRI such as, but not limited to cardiac pacemaker, implanted cardiac defibrillator, aneurysm clips, carotid artery vascular clamp, neurostimulator, implanted drug infusion devices, metal fragments or foreign objects in the eyes, skin or body, bone growth/fusion stimulator, cochlear, otologic implant, severe claustrophobia or any condition that would counterindicate an MRI scan.
    20. Patients participating in another interventional clinical trial, excluding natural history/observational studies, at start of the study or within the last 30 days before study start.
    21. The subject is mentally or legally incapacitated.
    22. Pregnant females as determined by positive [serum or urine] hCG test at Screening or prior to dosing. Participants of child-bearing age should use adequate contraception as defined in the study protocol.
    23. Lactating females.
    E.5 End points
    E.5.1Primary end point(s)
    Change in the Scale for the Assessment and Rating of Ataxia (SARA)
    E.5.1.1Timepoint(s) of evaluation of this end point
    At screening, baseline, +4 month, +8 month, +12 month, +18 month and +24 month
    E.5.2Secondary end point(s)
    1) Progression of quality of life measures such as the `Activity of Daily Living´ (ADL) scores, `modified Friedreich ataxia rating scale´ (mFARS) and the EuroQol five dimensions questionnaire (EQ-5D)
    2) Progression of `Spinocerebellar Ataxia Functional Index´ (SCAFI) (Schmitz-Hubsch et al., 2008)
    3) Progression of `Composite Cerebellar Functional Severity´ (CCFS), which has been validated in children and adults with Friedreich ataxia (Filipovic Pierucci et al., 2015)
    4) Progression of `Inventory of Non-Ataxia Signs´ (INAS) (Jacobi et al., 2013)
    5) Up-regulation of frataxin protein level
    6) Clinician’s Global Impression-Change Scale (CGI-C)
    7) Patient’s Global Impression-Change Scale (PGI-C)
    8) Safety
    9) Progression of the `Montreal Cognitive Assessment´ (MoCA)
    10) Active modification of the FXN locus, as measured by chromatin immunoprecipitation and chromosome confirmation capture sequencing
    11) Percentual change in left ventricular mass index as measured by echocardiogram
    12) Structural and functional changes of the brain and spinal cord, measured by magnetic resonance imaging (MRI)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1), 2), 3), 4), 6), 7), 9) at baseline, +4 month, +8 month, +12 month, +18 month and +24 month
    5) at baseline, +12 month and +24 month
    8) at baseline, +1 month, +4 month, +8 month, +12 month, +18 month and +24 month
    10) at baseline, +12 month and +24 month
    11) at baseline, +12 month and +24 month
    12) at baseline and +24 month
    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 Yes
    E.6.6Pharmacokinetic Yes
    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) 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 Yes
    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.8.2.4Number of treatment arms in the trial2
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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: 225
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state65
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 160
    F.4.2.2In the whole clinical trial 225
    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)
    None
    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 Decision2019-09-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-08-09
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-03-07
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