E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Inherited mainly neurodegenerative disease resulting in severe disco-ordination, and heart disase with an increased incidence of blindness, deafness and diabetes. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10017374 |
E.1.2 | Term | Friedreich's ataxia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary aim 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'. |
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E.2.2 | Secondary objectives of the trial |
The secondary aims are to determine a well-tolerated dose of nicotinamide required to achieve upregulation of Frataxin in FRDA and to gain insight into the way the gene is abnormally regulated and the mechanism whereby nicotinamide might overcome this. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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: o Abstinence o 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 agent (foam/gel/film/cream/suppository). |
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E.4 | Principal 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
This is a proof-of-concept dose escalation study. For the single dose study, Frataxin levels will be measured during each of a maximum of 5 visits; separated by a minimum washout of 1 week. For the multiple dose study, having identified either a maximum tolerated dose or a dose that upregulates Frataxin to normal levels, this dose will be given daily for 5 days and daily Frataxin levels measured. |
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E.5.2 | Secondary end point(s) |
To measure the effect on histone acetylation and methylation at the aberrantly silenced Frataxin gene, chromatin (extracted from blood) will be assessed by immunoprecipitation with antibodies against acetylated histones following nicotinamide administration. In this way we will gain insight into the molecular mechanism whereby nicotinmaide might upregulate Frataxin. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
This evaluation will take place following the single-dose escalation after an effective or MTD dose has been identified (visit 5) and again following the multiple dose study after 5 days of oral dosing with nicotinamide at this dose. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
This is a dose-escalation study |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Comparison is made within-subjects to different doses and no treatment |
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E.8.2.4 | Number of treatment arms in the trial | 0 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 1 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The last visit of the last subject undergoing the trial. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 30 |