Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicentre Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia

Conditions
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Friedreich Ataxia

Intervention / Treatment
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* Drug: Nicotinamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment arm<br>Nicotinamide 4 g (capsules) or highest tolerated dose with a minimum of 2 g/d per os once daily | Drug: Nicotinamide<br>* Nicotinamide 4 g (capsules) or highest tolerated dose with a minimum of 2 g/d per os once daily<br>|
| Placebo Comparator: Placebo arm<br>Matching Placebo (capsules) once daily | Drug: Placebo<br>* Matching Placebo (capsules) once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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 | 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 | 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. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Friedreich Ataxia, Nicotinamide, Rare disease, ZSEA, SARA