E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10017374 |
E.1.2 | Term | Friedreich's ataxia |
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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 objective of this study is to demonstrate the safety and tolerability of deferiprone in subjects with Friedreich’s ataxia (FRDA). |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to evaluate the efficacy of deferiprone for the treatment of FRDA, as assessed by a 9-Hole Peg Test (9HPT), Timed 25-Food Walk (T25FW), Low-Contrast Letter Acuity test (LCLA), International Cooperative Ataxia Rating Scale (ICARS), and Friedreich’s Ataxia Rating Scale (FARS).
The tertiary objects are to evaluate the effect of deferiprone on: 1) cardiac funciont as measured by changes in Left Ventricular Shortening Fraction (LVSF), Left Ventricular Ejection Fraction (LVEF) and Left Ventricular (LV) mass using echocardiogram (ECHO), 2) quality of life using quality-of-life surveys, and 3) functional status using Activities of Daily Living (ADL).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Diagnosis of FRDA, with confirmed mutation (excludes point mutation) in the frataxin (FXN) gene and GAA repeats ≥ 400 on the shorter allele. 2. Males or females aged 7 to 35 years 3. No exposure to idebenone, coenzyme Q10, vitamin C, vitamin E or other antioxidants as a supplement or as a drug therapy for a period of at least one month prior to start of treatment and during the study. 4. Neurological testing: A FARS score >20 and <85 at Screening and Baseline. 5. Female subjects of childbearing potential must have a negative pregnancy test at Baseline. In addition, a female subject must confirm that during the study and within 30 days following the completion of the study or early termination she: • will use an effective method of contraception, OR • has had a tubal ligation (supporting evidence required), OR • has had a hysterectomy (supporting evidence required), OR • participates in a non-heterosexual lifestyle, OR • indicates her only male sexual partner has been sterilized (supporting evidence required). Effective methods of contraception include oral contraceptives, intrauterine devices (IUDs) (in place for at least 3 months prior to first dose), diaphragm or condom, providing they are used with contraceptive foam or cream, or abstinence from sexual intercourse. Supporting evidence for sterilization consists of a surgical report or letter from the family physician. 6. If the subject is a heterosexual, sexually-active male, he confirms that he and/or his female partner will use an effective method of contraception for the length of the trial and for 30 days following completion of the study or early termination. Effective methods of contraception for males include condoms or sterilization or abstinence from sexual intercourse. 7. Signed and witnessed written informed consent/assent obtained prior to the first study intervention, as well as the ability to adhere to study restrictions, appointments and evaluation schedule. |
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E.4 | Principal exclusion criteria |
1. Iron deficiency defined as ferritin levels below the reference range for age- and sex-matched controls 2. Unable to complete T25FW AND with score > 5 minutes in the 9HPT. (Subjects who can complete T25FW or with a score ≤ 5 minutes in the 9HPT will be allowed to enrol if the score has not doubled compared to screening). 3. Abnormal ALT, greater than 2.0 times the upper limit of normal on two consecutive assessments. 4. Serum creatinine outside the normal reference range. 5. History or evidence of neutropenia/agranulocytosis defined by an absolute neutrophil count (ANC) < 1.5 x 109/L or thrombocytopenia defined by a platelet count <150 x 109/L. 6. Refusal to participate in screening procedures or unable to participate in screening procedures or unable to comply with the requirements of the protocol. 7. Receiving any investigational drug products or having received any investigational product within 30 days prior to enrolment into this study. 8. Subjects who have previously taken deferiprone. 9. Subjects who, in the opinion of the Investigator, represent poor medical, psychological or psychiatric risks, and for whom participation in an investigational trial would be unwise. 10. Pregnant, breastfeeding or planning to become pregnant during the study period. 11. History of malignancy. 12. History of alcohol or drug abuse. 13. Investigators, site personnel directly affiliated with this study and their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted. 14. Hypersensitivity to the active substance (deferiprone) or any of the excipients in the oral solution. |
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E.5 End points |
E.5.1 | Primary end point(s) |
9-Hole Peg Test: The 9HPT is a quantitative test of the functionality of the upper extremities (see Appendix 4). The test will be administered by a trained examiner (not necessarily the Investigator) in accordance with the Schedule of Events. The subject is instructed to place pegs into set holes as quickly as possible and then remove all the pegs. The test is performed two consecutive times with the dominant hand, followed by two consecutive times with the non-dominant hand. The maximum time allotted for each test (dominant or non-dominant hand) will be 5 minutes. The total time in seconds it takes the subject to complete the task is recorded. The average time for the four tests will be evaluated as a measure of treatment efficacy. Timed 25-Foot Walk: The T25FW is a quantitative mobility and leg function performance test (see Appendix 5). The test will be administered by a trained examiner (not necessarily the Investigator) in accordance with the Schedule of Events. The subject is instructed to walk 25 feet along a pre-defined straight course as quickly as possible. The task will be immediately repeated by having the subject walk back to the starting point. Subjects will be allowed to use assistive devices when completing this task. The total time in seconds it takes the subject to walk 25 feet will be recorded for each test. The average time for the two tests will be evaluated as a measure of treatment efficacy. Low Contrast Letter Acuity: LCLA is a quantitative clinical measure to determine the level of visual dysfunction. Low-Contrast Sloan Letter Charts (LCSLC, Precision Vision, LaSalle, IL), which provide a quantitative and standardized method of visual function assessment, will be used for this study. These charts have gray letters of progressively smaller size on a white background. Two charts for low contrast (2.5% and 1.25%) as well as one chart for high contrast (100%; to determine visual acuity) will be used in this study. Subjects are requested to identify single letters on each chart at 3.2 meters distance for the 100% contrast and at 2 meters distance for the 2.5 and 1.25% contrast and scored based on number of letters correctly identified on each chart. The combined letter score from four charts will be recorded as a summary measure and will be evaluated as a measure of treatment efficacy. Subjects will be allowed to use their habitual distance correction glasses or contact lenses. The test will be administered by a trained individual. International Cooperative Ataxia Rating Scale: ICARS is a semi-quantitative scale based upon 19 test parameters that assess sensory and motor skills (see Appendix 6). ICARS allows measurement of postural and gait ataxia (seven tasks, 0-34 points), limb ataxia (six tasks on both sides, and one writing task, 0-52 points), dysarthria of speech (two items, 0-8 points), and oculomotor signs (three items, 0-6 points). The overall score ranges from 0 to 100, with a score of 0 representing normal sensory and motor skills and 100 the worst. Subjects who are unable to perform a task receive the worst score, whatever the cause may be. ICARS testing will be performed by the same examiner (where possible) at various scheduled time points in the study as outlined in the Schedule of Events. Friedreich’s Ataxia Rating Scale: FARS is a neurological exam with 25 maneuvers and three quantitative performance measures (see Appendix 7), encompassing bulbar function, coordination of upper and lower limbs, peripheral nervous system function, deep tendon reflexes, stability and gait. FARS will be conducted by a trained examiner (not necessarily the Investigator) in accordance with the Schedule of Events. Whenever possible, FARS testing will be performed by the same examiner at each of the scheduled time points outlined in the Schedule of Events. Since there is some overlap between ICARS and FARS, the exams will be merged into one complete exam consisting of a total of 34 maneuvers. Quality of Life: The SF-10 and SF-36 are questionnaires that assess a range of health concepts. The SF-10 will be completed by the parent(s) or guardian(s) of subjects (aged 7 to <18 years), and the SF-36 will be completed by the adult subjects (aged 18 to 35 years), in accordance with the Schedule of Events. Echocardiogram: ECHO to assess LVSF, LVEF and LV mass will be performed at visits outlined in the Schedule of Events. Activities of Daily Living: Activities of Daily Living (ADL) is a quantitative method to assess the functional status of the subject. Subjects are given a score between 0 and 36, with a score of 0 representing normal functional status, and 36 the worst. Whenever possible, the ADL will be performed by the same examiner at each of the scheduled time points outlined in the Schedule of Events. |
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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 | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
New indication of deferiprone for the treatment of Friedreich's ataxia. |
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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 | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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Specified in the protocol. |
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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 | |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 10 |