Effect of Nicotinamide in Friedreich's Ataxia

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Imperial College London
Sponsor:
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT01589809
First received: February 20, 2012
Last updated: June 18, 2014
Last verified: March 2014
  Purpose

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.


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 Friedrich ataxia using an antibody dipstick assay (interventional part) [ Time Frame: Daily administration up to 9 weeks ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Assessment of impact on clinical phenotype using the SARA scale to measure degree of ataxia (interventional part of the study) [ Time Frame: Daily administration up to 9 weeks ] [ Designated as safety issue: No ]
    Assessment of impact on clinical phenotype using the SARA scale to measure degree of ataxia

  • Use of novel highly-sensitive technology to capture clinical deficit (non-interventional part) [ Time Frame: 6-9 months ] [ Designated as safety issue: No ]
    Investigate the use of novel, highly-sensitive technology to capture clinical deficit and measure subtle changes in the activities of daily living over a 6-9 month period without nicotinamide.

  • 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). [ Time Frame: 6-9 months ] [ Designated as safety issue: No ]
    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).

  • Assessment of additional FRDA biomarkers using gene expression profiling (interventional study). [ Time Frame: Daily administration up to 9 weeks ] [ Designated as safety issue: No ]
    Assessment of additional FRDA biomarkers using gene expression profiling (interventional study).

  • Chromatin immunoprecipitation (interventional study) [ Time Frame: Daily administration up to 9 weeks ] [ Designated as safety issue: No ]
    Further assessment of efficacy by means of chromatin immunoprecipitation to look for epigenetic changes at the Frataxin locus compatible with transcriptional upregulation. Such information might also be useful in identifying patients more likely to respond to this therapy by upregulating FXN (interventional study).

  • Determine the safety and tolerability of nicotinamide in FRDA patients (interventional study). [ Time Frame: Daily administration up to 9 weeks. ] [ Designated as safety issue: Yes ]
    Determine the safety and tolerability of nicotinamide in FRDA patients (interventional study).


Estimated Enrollment: 40
Study Start Date: June 2012
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: June 2014 (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 deacetylase (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.

In the interventional study, 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.

In the non-interventional study, we will investigate the use of novel, highly-sensitive technology to capture clinical deficit and measure subtle changes in the activities of daily living and 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 as comparators will be included in this part of the study. HVs will undergo the same assessments as participants with Friedreich ataxia once.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria for the interventional study

  1. Participants must have a molecular genetic diagnosis of FRDA, consisting of a GAA-repeat expansion on both alleles of the FXN gene.
  2. Participants must be over the age of 18 years living in the UK and registered with a GP.
  3. 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.
  4. 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 participant's entry into the study;
  • Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus vaginal spermicidal agent (foam/gel/film/cream/suppository).

Exclusion Criteria for the interventional study

  1. Participants with significant clinical dysphagia.
  2. Participants taking Sodium Valproate or any other known histone deacetylase inhibitor.
  3. Participants taking part in another interventional clinical trial or who have done so within 30 days before screening.
  4. Participants known to be positive for human immunodeficiency virus (HIV).
  5. Participants with any additional medical condition or illness that, in the opinion of the CI would interfere with study compliance and/or impair the participant'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. Participants with a history of severe allergies.
  8. Female participants who are lactating or pregnant (positive pre-randomisation serum pregnancy test) or plan to become pregnant during the study.
  9. Hypersensitivity to Nicobion (nicotinamide) or any of the excipients in this preparation
  10. Liver function tests outside the normal range: aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin which in the opinion of the CI would put the participant's safety at risk.

Inclusion Criteria for the non-interventional study

  1. 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 age and sex matched to the above participants.

  2. Participants are over the age of 18 years, living in the UK and registered with a GP.
  3. 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.
  4. Women of child-bearing potential must have a negative urine pregnancy test.

Exclusion Criteria for the non-interventional study

1. Contraindications to MRI including, but not limited to: intracranial aneurism clips (except Sugita), history of metal lathe work or possibility of intra-orbital metal fragments, pacemakers and non-MR compatible heart valves or other non-MR compatible implants, history of claustrophobia or participant feels unable to lie still on their back for a period of 60-90mins in the fMRI scanner.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01589809

Contacts
Contact: Richard Festensetin, Prof 02083838310 r.festenstein@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   
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 by Imperial College London

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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: June 18, 2014
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
Brain Diseases
Central Nervous System Diseases
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Metabolic Diseases
Mitochondrial Diseases
Nervous System Diseases
Spinal Cord Diseases
Spinocerebellar Degenerations
Histone Deacetylase Inhibitors
Niacin
Niacinamide
Nicotinic Acids
Antimetabolites
Cardiovascular Agents
Enzyme Inhibitors
Growth Substances
Hypolipidemic Agents
Lipid Regulating Agents
Micronutrients
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Vasodilator Agents
Vitamin B Complex
Vitamins

ClinicalTrials.gov processed this record on October 23, 2014