Effect of Nicotinamide (Vitamin B3) in Friedreich's Ataxia
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Purpose
The purpose of this 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'.
| Condition | Intervention | Phase |
|---|---|---|
|
Neurodegenerative Disorders |
Drug: nicotinamide |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Pharmacodynamics Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Pharmacodynamic Studies of a Histone Deacetylase Inhibitor in Friedreich's Ataxia |
- significant upregulation of Frataxin (FXN) in patients with Freidrich ataxia using an antibody dipstick assay (Mitosciences) [ Time Frame: up to 9 weeks ] [ Designated as safety issue: Yes ]Low levels of Frataxin (FXN) (<30% of normal) cause Freidrich ataxia. The trial will determine the effect of oral niocotinamide 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. The safety and tolerability of nicotinamide in FRDA patients will also be determined.
- Assessment of impact on clinical phenotype using the SARA scale to measure degree of ataxia [ Time Frame: 9 weeks ] [ Designated as safety issue: No ]Assessment of impact on clinical phenotype using the SARA scale to measure degree of ataxia
| Estimated Enrollment: | 20 |
| Study Start Date: | June 2012 |
| Estimated Study Completion Date: | December 2013 |
| Estimated Primary Completion Date: | September 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Nicotinamide
Comparison is made within-subjects to different doses and no treatment
|
Drug: nicotinamide
dose-escalation, 2-8 grams, oral
Other Name: Vitamin B3
|
Detailed Description:
Friedreich's ataxia (FRDA) is caused by a GAA repeat expansion in the Frataxin gene causing its repression which resembles the archetypal epigenetic phenomenon of Position Effect Variegation and hence can be modulated by chromatin modifiers The investigators have now confirmed that a similar form of silencing occurs in cells from FRDA patients. Based on these findings histone deacteylase (HDAC) inhibitors which can overcome such silencing have been identified. The investigators have extended this result by showing that the classical Class III HDAC inhibitor, nicotinamide, can relieve silencing in cells from patients. Nicotinamide is a vitamin and a registered drug and has been previously administered to humans with no significant ill effects. The investigators will perform pharmacodynamic studies on nicotinamide in humans with FRDA to investigate whether the investigators can upregulate Frataxin and if so, to determine an optimum dosing regimen. Nicotinamide will be administered orally following a standard drug escalation regimen and blood samples taken to measure Frataxin level and chromatin structure of the Frataxin gene. The end-point of the study is to achieve significant upregulation of Frataxin in patients providing a potential therapy for this currently untreatable condition.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients must have a molecular genetic diagnosis of FRDA, consisting of a GAA-repeat expansion on both alleles of the FXN gene.
- FRDA patients over the age of 18 years.
- Patients must be well enough and willing to provide written informed consent.
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 [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:
- Abstinence
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) sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study;
- Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus vaginal spermicidal
Exclusion Criteria:
- Patients with significant clinical dysphagia,
- Patients taking Sodium Valproate or any other known histone deacetylase inhibitor.
- Patient's participating in another clinical trial or who have done so within 30 days before screening.
- Patients known to be positive for human immunodeficiency virus (HIV).
- Patients with any additional 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. 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.
- Patients with a history of severe allergies.
- Inability to provide informed consent.
- Female patients who are lactating or pregnant (positive pre-randomisation serum pregnancy test) or plan to become pregnant during the study. 10. Unable or unwilling to provide written informed consent
Contacts and Locations| Contact: Richard Festensetin, Prof | 02083838310 | r.festenstein@imperial.ac.uk |
| Contact: Naomi Loyse, Dr | 020 838 36199 | n.loyse@imperial.ac.uk |
| United Kingdom | |
| NIHR/Wellcome Trust Imperial CRF | Recruiting |
| London, Hammersmith, United Kingdom, W12 0HS | |
| Contact: richard festenstein r.festenstein@imperial.ac.uk | |
| Contact: naomi loyse n.loyse@imperial.ac.uk | |
| Principal Investigator: Richard Festenstein | |
| Principal Investigator: Vincenzo Libri | |
| National Hospital for Neurology and Neurosurgery | Recruiting |
| London, United Kingdom, WC1N 3BG | |
| Contact: Paola Giunti 02034483153 p.giunti@ucl.ac.uk | |
| Contact: Sarah Green 07801968488 Sarah.Green3@candi.nhs.uk | |
| Principal Investigator: Paola Giunti | |
| Principal Investigator: | Vincenzo Libri, Dr | Imperial College London |
| Principal Investigator: | Paola Giunti, Dr | NHNN, 02034483153 |
More Information
No publications provided
| Responsible Party: | Imperial College London |
| ClinicalTrials.gov Identifier: | NCT01589809 History of Changes |
| Other Study ID Numbers: | CR01849 |
| Study First Received: | February 20, 2012 |
| Last Updated: | April 4, 2013 |
| Health Authority: | United Kingdom: National Institute for Health Research United Kingdom: Research Ethics Committee United Kingdom: Medicines and Healthcare Products Regulatory Agency |
Keywords provided by Imperial College London:
|
Congenital, familial and genetic disorders Nervous System Diseases |
Additional relevant MeSH terms:
|
Neurodegenerative Diseases Friedreich Ataxia Spinocerebellar Degenerations Cerebellar Diseases Brain Diseases Central Nervous System Diseases Nervous System Diseases Spinal Cord Diseases Heredodegenerative Disorders, Nervous System Genetic Diseases, Inborn Mitochondrial Diseases Metabolic Diseases Niacinamide Niacin Nicotinic Acids |
Vitamin B Complex Vitamins Histone Deacetylase Inhibitors Micronutrients Growth Substances Physiological Effects of Drugs Pharmacologic Actions Vasodilator Agents Cardiovascular Agents Therapeutic Uses Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents Enzyme Inhibitors |
ClinicalTrials.gov processed this record on May 19, 2013