A Study of Efficacy, Safety and Tolerability of Idebenone in the Treatment of Friedreich's Ataxia (FRDA) Patients

Study Overview
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Brief Summary
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The purpose of this trial is to study the efficacy, safety and tolerability of idebenone in 12 months of treatment in children and adults with Friedreich's Ataxia. This is a randomised placebo-controlled double-blind trial conducted in Europe. Efficacy outcomes include measures of neurological impairment and function, and measures of the heart.

Detailed Description
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Idebenone, a short-chain analogue of Co-enzyme Q10 (CoQ10), has the potential to moderate underlying causes of Friedreich's Ataxia through its antioxidant activity and its role as an electron carrier in the respiratory chain promoting mitochondrial ATP production. The current 12-month placebo-controlled treatment study in 232 patients aims to confirm the positive effect of idebenone on neurological function, as for instance observed in the recent 48-patient, 6-month NICOSIA study in children, using the International Cooperative Ataxia Rating Scale (ICARS) and the newly developed Friedreich's Ataxia Rating Scale (FARS). In addition, the study aims to confirm the positive effect on cardiomyopathy associated with FRDA observed in several small studies. Cardiac anatomy and function will be assessed using echocardiography, tissue Doppler imaging and cardiac MRI methods in patients with FRDA cardiomyopathy. In addition exercise capacity, measured as peak workload, will be assessed in patients able to comply with a modified exercise protocol.

Official Title
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A Phase III Double-blind, Randomised, Placebo-controlled Study of the Efficacy, Safety and Tolerability of Idebenone in the Treatment of Friedreich's Ataxia Patients

Conditions
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Friedreich's Ataxia

Intervention / Treatment
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* Drug: idebenone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of FRDA with confirmed FRDA mutations Patients 8 years of age or older at baseline Patients with body weight ≥ 25kg Patients who in the opinion of the investigator are able to comply with the requirements of the study, including swallowing the medication Negative urine pregnancy test at screening and at baseline (women of childbearing potential) Exclusion Criteria: Treatment with idebenone or Coenzyme Q10 within the past 1 month Pregnancy and/or breast-feeding Clinically significant abnormalities of clinical haematology or biochemistry including, but not limited to, elevations greater than 1.5 times the upper limit of normal of SGOT, SGPT, or creatinine Past or present history of abuse of drugs or alcohol

Ages Eligible for Study
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Minimum Age: 8 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Idebenone<br>Patients under/equal 45 kg: idebenone 180 mg/day Patients over 45 kg: idebenone 360 mg/day | Drug: idebenone<br>* 12 months of 1 of 3 treatments arms of oral idebenone or placebo.Treatment taken 3 times daily with meals.<br>|
| Experimental: Group B: Idebenone<br>Patients under/equal 45 kg: idebenone 450 mg/day Patients over 45 kg: idebenone 900 mg/day | Drug: idebenone<br>* 12 months of 1 of 3 treatments arms of oral idebenone or placebo.Treatment taken 3 times daily with meals.<br>|
| Experimental: C: Idebenone<br>Patients under/equal 45 kg: idebenone 1350 mg/day Patients over 45 kg: idebenone 2250 mg/day | Drug: idebenone<br>* 12 months of 1 of 3 treatments arms of oral idebenone or placebo.Treatment taken 3 times daily with meals.<br>|
| Placebo Comparator: D: Placebo<br>placebo | Drug: Placebo<br>* 12 months of 1 of 3 treatments arms of oral idebenone or placebo.Treatment taken 3 times daily with meals.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in International Cooperative Ataxia Rating Scale (ICARS) Scores From Baseline Assessment to Week 52 | The International Cooperative Ataxia Rating Scale (ICARS) is a commonly used evaluation and is composed of four clinical sub-scores involving the following: posture and gait, limb coordination, speech and oculomotor function.The ICARS score is the total sum of the sub scores and ranges from 0 to 100, with 100 indicative of the most severely affected outcome. | Baseline and week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Friedreich's Ataxia Rating Scale (FARS) Scores From Baseline Assessment to Week 52 | The Friedreich Ataxia Rating Scale (FARS) is made up of a measure of ataxia, and activities of daily living subscale and a neurological subscale. The scores from the three subscales are added to generate a total score ranging from 0 to 159, with a higher score indicating a greater level of disability. | Baseline and week 52 | 
| Proportion of Patients Improving (Responding) on ICARS by a Clinically Relevant Margin | The International Cooperative Ataxia Rating Scale (ICARS) is a commonly used evaluation and is composed of four clinical sub-scores involving the following: posture and gait, limb coordination, speech and oculomotor function.The ICARS score is the total sum of the sub scores and ranges from 0 to 100, with 100 indicative of the most severely affected outcome. ICARS Responder Analysis at Week 52: Percentage of subjects Improving by 2.5 Points or More. | week 52 | 
| Proportion of Patients Improving on Left Ventricular Peak Systolic Strain Rate or Showing a Reduction in Left Ventricular Mass Index (LVMI) With no Worsening in Strain Rate | (In the statistical analysis sub-population presenting with cardiac involvement as defined by the FRDA cardiomyopathy criteria) | 1 year | 
| Change in Peak Systolic Strain Rate From Baseline to Week 52 | Mean Change of Peak systolic longitudinal strain rate (PSLSR) from Baseline to Week 52 in subjects with cardiac involvement (FRDA-CM criteria), where positive value in PSLSR is a deterioration and negative value an improvement. | 1 year | 
| Change in Peak Workload From Baseline to Week 52 | Assessed by a modified exercise test, in a subset of patients able to undertake this. Wpeak has been calculated from the following formula: Workload last fully completed stage + (seconds completed in last stage / 60 * (4 [if arm ergonometry] or 10 [if leg ergonometry])). | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FRDA, idebenone, FRDA disease