Neurodegenerative DisordersPhase 2NCT01589809
Effect of Nicotinamide in Friedreich's Ataxia
A Phase 2 study testing nicotinamide in people with Neurodegenerative Disorders, run by Imperial College London at 2 sites in United Kingdom.
Trial 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'. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Neurodegenerative Disorders
- What is being tested?
- nicotinamide
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 2 sitesUnited Kingdom
- Study dates
- Jun 2012to Dec 2017
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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:
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- 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;
- Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus vaginal spermicidal agent (foam/gel/film/cream/suppository).
- 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.
Who cannot join
- 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.
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- 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.
- 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.
Trial locations and contacts
2 sites in 1 country.
United Kingdom2 sites
NIHR/Wellcome Trust Imperial CRF
London, Hammersmith, W12 0HS
National Hospital for Neurology and Neurosurgery
London, WC1N 3BG
About this study
Official title: Pharmacodynamic Studies of a Histone Deacetylase Inhibitor in Friedreich's Ataxia
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.
Read the 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.
- Conditions
- Neurodegenerative Disorders
- Being tested
- nicotinamide
- Keywords
- Congenital, familial and genetic disorders, Nervous System Diseases
- Medical subject headings
- Neurodegenerative Diseases, Genetic Diseases, Inborn, Nervous System Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
nicotinamideDrug
Also called Vitamin B3
dose-escalation, 2-8 grams, oral
| Study group | Role | What they receive |
|---|---|---|
| Nicotinamide | Experimental | Comparison is made within-subjects to different doses and no treatment Receives: Drug: nicotinamide |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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)
Assessment of impact on clinical phenotype using the SARA scale to measure degree of ataxia
Measured: Daily administration up to 9 weeks
Use of novel highly-sensitive technology to capture clinical deficit (non-interventional part)
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.
Measured: 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).
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).
Measured: 6-9 months
Assessment of additional FRDA biomarkers using gene expression profiling (interventional study).
Assessment of additional FRDA biomarkers using gene expression profiling (interventional study).
Measured: Daily administration up to 9 weeks
Chromatin immunoprecipitation (interventional study)
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).
Measured: Daily administration up to 9 weeks
Determine the safety and tolerability of nicotinamide in FRDA patients (interventional study).
Determine the safety and tolerability of nicotinamide in FRDA patients (interventional study).
Measured: Daily administration up to 9 weeks.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 May 2012 (estimated)
- Study startJun 2012
- Primary completionJun 2015
- Study completionDec 2017 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Neurodegenerative DisordersStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Vincenzo Libri, Dr, Principal investigator, Imperial College LondonPaola Giunti, Dr, Principal investigator, NHNN, 02034483153
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01589809
- Sponsor's protocol ID
- CR01849
- Status last verified
- Jan 2017
- First submitted
- 20 Feb 2012
- Last updated
- 2 Jul 2017
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 24794816
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacodynamic Studies of a Histone Deacetylase Inhibitor in Friedreich's Ataxia
- ClinicalTrials.gov ID
- NCT01589809
- Acronym / sponsor ID
- CR01849
- Conditions
- Neurodegenerative Disorders
- Keywords
- Congenital, familial and genetic disorders, Nervous System Diseases
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Study start
- Jun 2012
- Primary completion
- Jun 2015 (actual)
- Study completion
- Dec 2017 (estimated)
- First posted
- 2 May 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Nicotinamide | Experimental | Drug: nicotinamideComparison is made within-subjects to different doses and no treatment |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- 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].
Key exclusion criteria (11 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| nicotinamideAlso: Vitamin B3dose-escalation, 2-8 grams, oral | Drug | Nicotinamide |
Primary outcome
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
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.
6 secondary outcomes
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
Use of novel highly-sensitive technology to capture clinical deficit (non-interventional part)
Time frame: 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).
Time frame: 6-9 months
Assessment of additional FRDA biomarkers using gene expression profiling (interventional study).
Time frame: Daily administration up to 9 weeks
Chromatin immunoprecipitation (interventional study)
Time frame: Daily administration up to 9 weeks
Determine the safety and tolerability of nicotinamide in FRDA patients (interventional study).
Time frame: Daily administration up to 9 weeks.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Derived from this study: PubMed 24794816Libri 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Vincenzo Libri, Dr principal investigator
Imperial College London
Paola Giunti, Dr principal investigator
NHNN, 02034483153
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing nicotinamide in people with Neurodegenerative Disorders, run by Imperial College London at 2 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01589809, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.