Friedreich AtaxiaPhase 2NICOFANCT03761511
Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia
A Phase 2 study testing Nicotinamide in people with Friedreich Ataxia, run by RWTH Aachen University at 7 sites in 6 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Friedreich Ataxia
- What is being tested?
- Nicotinamide
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 7 sitesin 6 countries
- Study dates
- Apr 2023to Dec 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 and age <50 years.
- Patients must be ≥18 years old and have a weight of at least 50kg.
- Written informed consent prior to study participation
- 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
Who cannot join
- 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.
- Any uncontrolled medical or neurological/neurodegenerative condition (other than Friedreich ataxia).
- Clinically significant psychiatric illness (e.g., uncontrolled major depression, schizophrenia, bipolar affective disorder) within 6 months prior to screening.
- Patients with significant clinical dysphagia.
- Hypersensitivity to nicotinamide.
- Patients known to be positive for human immunodeficiency virus (HIV).
Show all 27Show fewer
- Patients with a significant history of substance abuse (e.g. alcohol or drug abuse) within the previous six months before enrolment.
- Patients with a history of severe allergies to medications.
- 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).
- 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.
- History or evidence of an autoimmune disorder considered clinically significant by the Investigator or requiring chronic use of systemic corticosteroids or other immunosuppressants.
- The subject has a history of any other illness, which, in the opinion of the Investigator, might pose an unacceptable risk by administering study medication.
- 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).
- The subject received an investigational drug within 30 days prior to inclusion into this study.
- Patients taking sodium valproate, tranylcypromine or any other known histone deacetylase inhibitor.
- Use of vitamin B1 (thiamine), withdrawal should be at least 3 months prior screening or 5 half-lives, whichever is longer.
- Use of vitamin B3 (nicotinamide), withdrawal should be at least 3 months prior screening.
- If patients are taking idebenone or coenzyme Q10 (CoQ), this should be stable over the last three months and not changed during the study.
- The subject is unwilling or unable to provide written informed consent and to follow the procedures outlined in the protocol.
- 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.
- Patients participating at start or have been within 30 days before start of study in another pharmacological and non-pharmacological clinical trial, excluding natural history / observational studies.
- The subject is mentally or legally incapacitated.
- 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.
- Lactating females.
Trial locations and contacts
7 sites in 6 countries.
7 sites in 6 countries
United Kingdom2 sites
Imperial College London
London, W12 0HS
University College London
London, WC1N 3BG
France1 site
Service de génétique médicale - Hôpital La Pitié Salpetrière
Paris, 75646
About this study
Official title: A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicentre Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich 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 wheel-chair bound as adolescents. There is no disease modifying therapy and many patients die prematurely of cardiomyopathy. It was subsequently found that the FXN gene is silenced at the chromatin level by the formation of heterochromatin and that this heterochromatin formation can be antagonized by histone deacetylase inhibitors (HDACi) (Chan et al., 2013). A recent proof-of-concept clinical study on ten patients with Friedreich ataxia demonstrated that FXN levels can be restored to those seen in asymptomatic carriers using the class III HDACi nicotinamide at a dose that is well tolerated by patients (Libri et al., 2014). Since carriers are asymptomatic, this degree of restoration of FXN expression might be expected to halt disease progression. Nicotinamide readily crosses the blood brain barrier and has previously been given at high doses for long periods to normal individuals without serious adverse effects (Gale et al., 2004; Knip et al., 2000). This study will be the first to provide clinical evidence for the efficacy and safety of nicotinamide in patients with Friedreich´s ataxia.
- Conditions
- Friedreich Ataxia
- Being tested
- Nicotinamide, Placebo
- Keywords
- Friedreich Ataxia, Nicotinamide, Rare disease, ZSEA, SARA
- Medical subject headings
- Friedreich Ataxia, Rare Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NicotinamideDrug
Nicotinamide 4 g (capsules) or highest tolerated dose with a minimum of 2 g/d per os once daily
PlaceboDrug
Matching Placebo (capsules) once daily
| Study group | Role | What they receive |
|---|---|---|
| Treatment arm | Active comparator | Nicotinamide 4 g (capsules) or highest tolerated dose with a minimum of 2 g/d per os once daily Receives: Drug: Nicotinamide |
| Placebo arm | Placebo comparator | Matching Placebo (capsules) once daily Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Scale for the Assessment and Rating of Ataxia (SARA)
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 SARA is a tool for assessing ataxia. It has eight categories with accumulative score ranging from 0 (no ataxia) to 40 (most severe ataxia). When completing the outcome measure each category is assessed and scored accordingly. Scores for the eight items range as follows:
Gait (0-8 points), Stance (0-6 points), Sitting (0-4 points) Speech disturbance (0-6 points) Finger chase (0-4 points) Nose-finger test (0-4 points) Fast alternating hand movement (0-4 points) Heel-shin slide (0-4 points) Once each of the 8 categories have been assessed, the total is calculated to determine the severity of ataxia.
Measured: 1 year
Secondary outcomes (5)
Progression of quality of life measures via questionnaire EuroQol five dimensions questionnaire (EQ-5D)
This is a generic instrument, developed and validated by the EuroQoL Group (1990), in which the patient self-rates in particular his/her health status on a visual analogue scale (VAS); the best score is 100.
Measured: 1 year
Modified Friedreich Ataxia Rating Scale (mFARS)
Modified FARS scores are defined as the sum of scores for bulbar function, upper limb coordination, lower limb coordination, and upright stability. The mFARS consists of three subscales, comprising a general score for ataxia, a score for activities of daily living and a neurological examination. The scores can be added to make a total score ranging from 0 to 159. A higher score indicates a greater level of disability.
Measured: 1 year
Progression of cerebellar severity measured by 'Composite Cerebellar Functional Severity´ (CCFS) score
CCFS includes two tests performed with the dominant hand,named the click test and the 9 holes pegboard test (9HPT). An electronic device was created to perform CCFS and to calculate the Z score by subtracting the expected time
Measured: 1 year
Clinician's Global Impression-Change Scale (CGI-C) including comparison of change to the last visit
The Clinical Global Impression - Improvement scale (CGI-I) is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. and rated as: 1. Very much improved; 2. Much improved; 3. Minimally improved; 4. No change; 5. Minimally worse; 6. Much worse; 7. Very much worse
Measured: 1 year
Safety issues measured by appearance of AEs/SAEs
AEs may be volunteered spontaneously by the patient, or discovered as a result of general non-directed questioning by the study personnel or by physical examination.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Dec 2018
- Study startApr 2023 (estimated)
- Primary completionJun 2025 (estimated)
- Study completionDec 2025 (estimated)
Why it stopped: Due to a temporary halt the recruitment start was delayed. A re-evaluation of the sponsor revealed, that the study is no longer feasible due to increased administrative and financial requirements.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Friedreich AtaxiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- RWTH Aachen University
- Sponsor type
- University, hospital or other
- Collaborators
- Assistance Publique - Hôpitaux de Paris
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03761511
- Sponsor's protocol ID
- 15-138
- Acronym
- NICOFA
- Status last verified
- Jan 2024
- First submitted
- 27 Nov 2018
- Last updated
- 24 Jan 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: The study results will be published in appropriate international scientific journals, and publishing details will be given in the clinical study agreement. The study will be registered and study results will be disclosed by the principal investigator in one or more public clinical study registry(ies), according to national/international use.
Publications
Reetz K, Hilgers RD, Isfort S, Dohmen M, Didszun C, Fedosov K, Kistermann J, Mariotti C, Durr A, Boesch S, Klopstock T, Rodriguez de Rivera Garrido FJ, Schols L, Klockgether T, Pandolfo M, Korinthenberg R, Lavin P, Molenberghs G, Libri V, Giunti P, Festenstein R, Schulz JB; EFACTS or NICOFA study group. Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA). Neurol Res Pract. 2019 Oct 15;1:33. doi: 10.1186/s42466-019-0038-9. eCollection 2019.
PubMed 33324899
Study at a glance
From the registry record, last updated by the sponsor on 24 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicentre Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia
- ClinicalTrials.gov ID
- NCT03761511
- Acronym / sponsor ID
- NICOFA / 15-138
- Conditions
- Friedreich Ataxia
- Keywords
- Friedreich Ataxia, Nicotinamide, Rare disease, ZSEA, SARA
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Due to a temporary halt the recruitment start was delayed. A re-evaluation of the sponsor revealed, that the study is no longer feasible due to increased administrative and financial requirements.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- RWTH Aachen UniversityUniversity, hospital or other
- Collaborators
- Assistance Publique - Hôpitaux de Paris
- Study start
- Apr 2023 (estimated)
- Primary completion
- Jun 2025 (estimated)
- Study completion
- Dec 2025 (estimated)
- First posted
- 3 Dec 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 wheel-chair bound as adolescents. There is no disease modifying therapy and many patients die prematurely of cardiomyopathy. It was subsequently found that the FXN gene is silenced at the chromatin level by the formation of heterochromatin and that this heterochromatin formation can be antagonized by histone deacetylase inhibitors (HDACi) (Chan et al., 2013). A recent proof-of-concept clinical study on ten patients with Friedreich ataxia demonstrated that FXN levels can be restored to those seen in asymptomatic carriers using the class III HDACi nicotinamide at a dose that is well tolerated by patients (Libri et al., 2014). Since carriers are asymptomatic, this degree of restoration of FXN expression might be expected to halt disease progression. Nicotinamide readily crosses the blood brain barrier and has previously been given at high doses for long periods to normal individuals without serious adverse effects (Gale et al., 2004; Knip et al., 2000). This study will be the first to provide clinical evidence for the efficacy and safety of nicotinamide in patients with Friedreich´s ataxia.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment arm | Active comparator | Drug: NicotinamideNicotinamide 4 g (capsules) or highest tolerated dose with a minimum of 2 g/d per os once daily |
| Placebo arm | Placebo comparator | Drug: PlaceboMatching Placebo (capsules) once daily |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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 and age <50 years.
- Patients must be ≥18 years old and have a weight of at least 50kg.
- Written informed consent prior to study participation
- 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
Key exclusion criteria (27 listed)
- 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.
- Any uncontrolled medical or neurological/neurodegenerative condition (other than Friedreich ataxia).
- Clinically significant psychiatric illness (e.g., uncontrolled major depression, schizophrenia, bipolar affective disorder) within 6 months prior to screening.
- Patients with significant clinical dysphagia.
- Hypersensitivity to nicotinamide.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NicotinamideNicotinamide 4 g (capsules) or highest tolerated dose with a minimum of 2 g/d per os once daily | Drug | Treatment arm |
| PlaceboMatching Placebo (capsules) once daily | Drug | Placebo arm |
Primary outcome
Scale for the Assessment and Rating of Ataxia (SARA)
Time frame: 1 year
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 SARA is a tool for assessing ataxia. It has eight categories with accumulative score ranging from 0 (no ataxia) to 40 (most severe ataxia). When completing the outcome measure each category is assessed and scored accordingly. Scores for the eight items range as follows: Gait (0-8 points), Stance (0-6 points), Sitting (0-4 points) Speech disturbance (0-6 points) Finger chase (0-4 points) Nose-finger test (0-4 points) Fast alternating hand movement (0-4 points) Heel-shin slide (0-4 points) Once each of the 8 categories have been assessed, the total is calculated to determine the severity of ataxia.
5 secondary outcomes
Progression of quality of life measures via questionnaire EuroQol five dimensions questionnaire (EQ-5D)
Time frame: 1 year
Modified Friedreich Ataxia Rating Scale (mFARS)
Time frame: 1 year
Progression of cerebellar severity measured by 'Composite Cerebellar Functional Severity´ (CCFS) score
Time frame: 1 year
Clinician's Global Impression-Change Scale (CGI-C) including comparison of change to the last visit
Time frame: 1 year
Safety issues measured by appearance of AEs/SAEs
Time frame: 1 year
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jan 2024.
- Derived from this study: PubMed 33324899Reetz K, Hilgers RD, Isfort S, Dohmen M, Didszun C, Fedosov K, Kistermann J, Mariotti C, Durr A, Boesch S, Klopstock T, Rodriguez de Rivera Garrido FJ, Schols L, Klockgether T, Pandolfo M, Korinthenberg R, Lavin P, Molenberghs G, Libri V, Giunti P, Festenstein R, Schulz JB; EFACTS or NICOFA study group. Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA). Neurol Res Pract. 2019 Oct 15;1:33. doi: 10.1186/s42466-019-0038-9. eCollection 2019.
- Individual participant dataSharing planned: Undecided. The study results will be published in appropriate international scientific journals, and publishing details will be given in the clinical study agreement. The study will be registered and study results will be disclosed by the principal investigator in one or more public clinical study registry(ies), according to national/international use.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
7 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nicotinamide in people with Friedreich Ataxia, run by RWTH Aachen University at 7 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 24 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in United Kingdom, Austria, France, Germany, Italy and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Scale for the Assessment and Rating of Ataxia (SARA) (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03761511, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jan 2024.