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

NCT03761511 | Withdrawn Phase 2 DMC

• 1 other identifier: 15-138
• Study Type: interventional
• Target: N/A
• Locations: 6 countries
• Sites: 7

Brief 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. 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

Keywords

Friedreich Ataxia; Nicotinamide; Rare disease; ZSEA; SARA

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Progression of quality of life measures via questionnaire EuroQol five dimensions questionnaire (EQ-5D)

  1 year

• Modified Friedreich Ataxia Rating Scale (mFARS)

  1 year

• Progression of cerebellar severity measured by 'Composite Cerebellar Functional Severity´ (CCFS) score

  1 year

• Clinician's Global Impression-Change Scale (CGI-C) including comparison of change to the last visit

  1 year

• Safety issues measured by appearance of AEs/SAEs

  1 year

Study Arms (2)

Treatment arm

ACTIVE COMPARATOR

Nicotinamide 4 g (capsules) or highest tolerated dose with a minimum of 2 g/d per os once daily

Drug: Nicotinamide

Placebo arm

PLACEBO COMPARATOR

Matching Placebo (capsules) once daily

Drug: Placebo

Interventions

Nicotinamide DRUG

Nicotinamide 4 g (capsules) or highest tolerated dose with a minimum of 2 g/d per os once daily

Treatment arm

Placebo DRUG

Matching Placebo (capsules) once daily

Placebo arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• RWTH Aachen University: lead
• Assistance Publique - Hôpitaux de Paris: collaborator

Study Sites (7)

Medical University Innsbruck

Innsbruck, 6020, Austria

Location

Service de génétique médicale - Hôpital La Pitié Salpetrière

Paris, 75646, France

Location

University Hospital RWTH Aachen

Aachen, 52074, Germany

Location

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, 20133, Italy

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Imperial College London

London, W12 0HS, United Kingdom

Location

University College London

London, WC1N 3BG, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 33324899 DERIVED

MeSH Terms

Conditions

Friedreich Ataxia; Rare Diseases

Interventions

Niacinamide

Condition Hierarchy (Ancestors)

Spinocerebellar Degenerations; Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Mitochondrial Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 27, 2018
• First Posted: December 3, 2018
• Study Start: April 1, 2023
• Primary Completion: June 1, 2025
• Study Completion: December 1, 2025
• Last Updated: January 24, 2024

Record last verified: 2024-01

Locations

FR (1); GB (2); ES (1); IT (1); DE (1); AU (1)