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    Summary
    EudraCT Number:2017-002163-17
    Sponsor's Protocol Code Number:15-138
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-10-31
    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 ConcernedUK - MHRA
    A.2EudraCT number2017-002163-17
    A.3Full title of the trial
    A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTICENTRE STUDY OF THE EFFICACY AND SAFETY OF NICOTINAMIDE IN PATIENTS WITH FRIEDREICH´S ATAXIA (NICOFA)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Use of Nicotinamide for the Treatment of Patients with Friedreich's Ataxia.
    A.3.2Name or abbreviated title of the trial where available
    NICOFA
    A.4.1Sponsor's protocol code number15-138
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03761511
    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, Center for Translational & Clinical Research Aachen (CTC-A)
    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 supportEfficacy and Mechanism Evaluation Programme
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationImperial College London
    B.5.2Functional name of contact pointRichard Festenstein
    B.5.3 Address:
    B.5.3.1Street AddressHammersmith Hospital, Du Cane Road
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW12 0NN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+442033138310
    B.5.6E-mailr.festenstein@imperial.ac.uk
    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.2.1.1.1Trade name Nicotinamide
    D.2.1.1.2Name of the Marketing Authorisation holderEuro OTC Pharma GmbH
    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.3.9.3Other descriptive nameSUB09246MIG
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    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's ataxia.

    Friedreich ataxia is the most frequent early-onset autosomal recessive hereditary ataxia. It is caused by a pathological expansion of a GAA repeat in the first intron of the frataxin gene (FXN) and results in decreased levels of FXN protein. FXN deficiency results in a relentlessly progressive neurodegenerative condition which frequently presents around puberty. Patients gradually lose coordination, become dysarthric and are frequently wheelchair-bound as adolescents.
    E.1.1.1Medical condition in easily understood language
    Friedreich’s ataxia, an incurable disease, that starts in childhood and results in a progressive loss of coordination, slurred speech, difficulty swallowing and breathlessness due to heart failure.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10017374
    E.1.2Term Friedreich's ataxia
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to determine whether daily doses of nicotinamide are slowing disease progression in patients with Friedreich´s ataxia compared to placebo. Disease progression will be measured using the Scale for the Assessment and Rating of Ataxia (SARA). For this purpose patients will be given a score following assessment (physical examination) by a doctor on their impairment level.
    E.2.2Secondary objectives of the trial
    The secondary objective is 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.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects, fulfilling the following inclusion criteria are suitable for participation in the study:

    1. Patients must have a molecular genetic diagnosis of Friedreich’s 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 50 kg.
    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 highly effective birth control methods (Pearl Index < 1).
    E.4Principal exclusion criteria
    Subjects, fulfilling one or more of the following exclusion criteria will not be included in the study:

    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’s 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 2x 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, tranylcypromine, or any other known histone deacetylase inhibitor.
    15. Use of vitamin B1 (thiamine), withdrawal should be at least 3 months prior to screening or 5 half-lives, whichever is longer.
    16. Use of vitamin B3 (nicotinamide), withdrawal should be at least 3 months prior to 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 pharmacological and non-pharmacological 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)
    The primary objective of the study is 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 ataxia.

    The primary endpoint is therefore SARA, validated for Friedreich ataxia and shown to be the most suitable measure of disease progression in Friedreich ataxia.

    Compared to placebo patients we estimate a reduction of disease progression (rated with SARA) by 50% i.e. 0.59/year in the treatment group, giving a mean difference after 2 years of 1.19.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The endpoint (SARA scale) will be measured at screening, baseline, 1, 4, 8, 12, 18 and 24 months.
    E.5.2Secondary end point(s)
    Secondary end points will include:

    Quality of life (EQ5D, ADL), functional (SCAFI, CCFS), modified Friedreich’s Ataxia Ratings Scale (mFARS) and cognitive measures (MoCA), clinician’s and patient’s global impression-change scale (CGI-C, PGI-C), frataxin protein level, safety reasons, and survival/death

    E.5.2.1Timepoint(s) of evaluation of this end point
    The above endpoints will be measured at baseline, 1, 4, 8, 12, 18 and 24 months.
    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 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 concerned2
    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 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
    The end of trial will be the date of the last scheduled visit of the last participant.
    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 months3
    E.8.9.1In the Member State concerned days28
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    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 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 90
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state90
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 225
    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)
    A clinician will discuss follow-up treatment options and the return of the patient to routine care pathways during their last visit (24 months). Available safety and efficacy data available to the clinician as well as the patient's wishes will be considered when deciding on an appropriate follow-up plan. Nicotinamide supply will not be offered to the participants after the study ends.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-01-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-05
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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