Trial record 4 of 19 for:    Open Studies | "Cerebellar Diseases"

Effect of Nicotinamide (Vitamin B3) in Friedreich's Ataxia

This study is currently recruiting participants.
Verified April 2013 by Imperial College London
Sponsor:
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT01589809
First received: February 20, 2012
Last updated: April 4, 2013
Last verified: April 2013
  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

Resource links provided by NLM:


Further study details as provided by Imperial College London:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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
Criteria

Inclusion Criteria:

  1. Patients must have a molecular genetic diagnosis of FRDA, consisting of a GAA-repeat expansion on both alleles of the FXN gene.
  2. FRDA patients over the age of 18 years.
  3. Patients must be well enough and willing to provide written informed consent.
  4. 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:

  1. Patients with significant clinical dysphagia,
  2. Patients taking Sodium Valproate or any other known histone deacetylase inhibitor.
  3. Patient's participating in another clinical trial or who have done so within 30 days before screening.
  4. Patients known to be positive for human immunodeficiency virus (HIV).
  5. 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.
  6. Patients with a history of substance abuse (e.g. alcohol or drug abuse) within the previous 6 months before enrolment.
  7. Patients with a history of severe allergies.
  8. Inability to provide informed consent.
  9. 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01589809

Contacts
Contact: Richard Festensetin, Prof 02083838310 r.festenstein@imperial.ac.uk
Contact: Naomi Loyse, Dr 020 838 36199 n.loyse@imperial.ac.uk

Locations
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            
Sponsors and Collaborators
Imperial College London
Investigators
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:
Cerebellar Diseases
Friedreich Ataxia
Neurodegenerative Diseases
Spinocerebellar Degenerations
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