Effect of Nicotinamide in Friedreich's Ataxia

NCT01589809 | Unknown Phase 2

• 1 other identifier: CR01849
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of the interventional study is to determine whether Nicotinamide is effective at upregulating the Frataxin (FXN) gene in patients with Friedreich's ataxia (FRDA) where this gene is abnormally 'switched off'. The purpose of the non-interventional study is to investigate the use of novel, highly-sensitive technology to capture clinical deficit and measure subtle changes in the activities of daily living and to correlate functional changes to levels of expression of Frataxin protein and the epigenetic structure of the Frataxin gene over a 9-12 month period without nicotinamide. Healthy volunteers will be included as comparators in this part of the study.

Conditions

Neurodegenerative Disorders

Keywords

Congenital, familial and genetic disorders; Nervous System Diseases

Outcome Measures

Primary Outcomes (1)

• Significant upregulation of Frataxin (FXN) in patients with Friedrich ataxia using an antibody dipstick assay (interventional part)

  Low levels of Frataxin (FXN) (\<30% of normal) cause Friedrich ataxia. The trial will determine the effect of oral nicotinamide in upregulating FXN. Therefore the primary outcome is upregulation of Frataxin levels above baseline. This will be measured using an antibody dipstick assay (Mitosciences) and chromatin immunoprecipitation studies.

  Daily administration up to 9 weeks

Secondary Outcomes (6)

• Assessment of impact on clinical phenotype using the SARA scale to measure degree of ataxia (interventional part of the study)

  Daily administration up to 9 weeks

• Use of novel highly-sensitive technology to capture clinical deficit (non-interventional part)

  6-9 months

• Correlate functional changes to levels of expression of Frataxin protein and the epigenetic structure of the Frataxin gene over a 6-9 month period without nicotinamide (non-interventional part).

  6-9 months

• Assessment of additional FRDA biomarkers using gene expression profiling (interventional study).

  Daily administration up to 9 weeks

• Chromatin immunoprecipitation (interventional study)

  Daily administration up to 9 weeks

Study Arms (1)

Nicotinamide

EXPERIMENTAL

Comparison is made within-subjects to different doses and no treatment

Drug: nicotinamide

Interventions

nicotinamide DRUG

dose-escalation, 2-8 grams, oral

Also known as: Vitamin B3

Nicotinamide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have a molecular genetic diagnosis of FRDA, consisting of a GAA-repeat expansion on both alleles of the FXN gene.
• Participants must be over the age of 18 years living in the UK and registered with a GP.
• Participants must provide informed consent. If written consent is not possible due to physical incapacity, written consent on behalf of the participant will be sought from the participant's relatives or carer.
• A female participant 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 \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \<40 pg/ml (\<140 pmol/L) is confirmatory\].
• Child-bearing potential and agrees to use one of the following contraception methods:
• True abstinence: When this is in line with the preferred and usual lifestyle of the participant. \[Periodic abstinence (e.g.,calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception\].
• Contraceptive Methods with a Failure Rate of \< 1%:
• Oral contraceptive, either combined or progestogen alone;
• Injectable progestogen;
• Implants of levonorgestrel;
• Estrogenic vaginal ring;
• Percutaneous contraceptive patches; -
• Intrauterine device (IUD) or intrauterine system (IUS) that meets the \<1% failure rate as stated in the product label;
• Male partner(s) sterilisation (vasectomy with documentation of azoospermia) prior to the female participants entry into the study;

You may not qualify if:

• Participants with significant clinical dysphagia.
• Participants taking Sodium Valproate or any other known histone deacetylase inhibitor.
• Participants taking part in another interventional clinical trial or who have done so within 30 days before screening.
• Participants known to be positive for human immunodeficiency virus (HIV).
• Participants with any additional medical condition or illness that, in the opinion of the CI would interfere with study compliance and/or impair the participants ability to participate or complete the study. Concurrent diseases or conditions that may interfere with study participation or safety include liver disease, bleeding disorders, arrhythmias, organ transplant, organ failure, current neoplasm, poorly controlled diabetes mellitus, poorly controlled hypertension, clinically significant haematological or biochemical abnormality.
• Patients with a history of substance abuse (e.g. alcohol or drug abuse) within the previous 6 months before enrolment.
• Participants with a history of severe allergies.
• Female participants who are lactating or pregnant (positive pre-randomisation serum pregnancy test) or plan to become pregnant during the study.
• Hypersensitivity to Nicobion (nicotinamide) or any of the excipients in this preparation
• Liver function tests outside the normal range: aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin which in the opinion of the CI would put the participants safety at risk.
• Up to 20 participants must have a molecular genetic diagnosis of FRDA, consisting of a GAA-repeat expansion on both alleles of the FXN gene.
• Up to 20 participants must be HV.
• Participants are over the age of 18 years, living in the UK and registered with a GP.
• Participants must provide informed consent. If written consent is not possible due to physical incapacity, written consent on behalf of the participant will be sought from the participant's relatives or carer.
• Women of child-bearing potential must have a negative urine pregnancy test.

Sponsors & Collaborators

• Imperial College London: lead

Study Sites (2)

NIHR/Wellcome Trust Imperial CRF

London, Hammersmith, W12 0HS, United Kingdom

Location

National Hospital for Neurology and Neurosurgery

London, WC1N 3BG, United Kingdom

Location

Related Publications (1)

• Libri V, Yandim C, Athanasopoulos S, Loyse N, Natisvili T, Law PP, Chan PK, Mohammad T, Mauri M, Tam KT, Leiper J, Piper S, Ramesh A, Parkinson MH, Huson L, Giunti P, Festenstein R. Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study. Lancet. 2014 Aug 9;384(9942):504-13. doi: 10.1016/S0140-6736(14)60382-2. Epub 2014 Apr 30.

  PMID: 24794816 DERIVED

MeSH Terms

Conditions

Neurodegenerative Diseases; Genetic Diseases, Inborn; Nervous System Diseases

Interventions

Niacinamide

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

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

Study Officials

• Vincenzo Libri, Dr

  Imperial College London

  PRINCIPAL INVESTIGATOR

• Paola Giunti, Dr

  NHNN, 02034483153

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 20, 2012
• First Posted: May 2, 2012
• Study Start: June 1, 2012
• Primary Completion: June 1, 2015
• Study Completion: December 1, 2017
• Last Updated: July 2, 2017

Record last verified: 2017-01

Locations

GB (2)