Friedreich's Ataxia
Conditions
Keywords
FRDA, idebenone, FRDA disease
Brief summary
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
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.
Interventions
DRUGidebenone
12 months of 1 of 3 treatments arms of oral idebenone or placebo.Treatment taken 3 times daily with meals.
DRUGPlacebo
12 months of 1 of 3 treatments arms of oral idebenone or placebo.Treatment taken 3 times daily with meals.
Sponsors
Santhera Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in International Cooperative Ataxia Rating Scale (ICARS) Scores From Baseline Assessment to Week 52 | Baseline and 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Friedreich's Ataxia Rating Scale (FARS) Scores From Baseline Assessment to Week 52 | Baseline and 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. |
| Proportion of Patients Improving (Responding) on ICARS by a Clinically Relevant Margin | 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. ICARS Responder Analysis at Week 52: Percentage of subjects Improving by 2.5 Points or More. |
| 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 | 1 year | (In the statistical analysis sub-population presenting with cardiac involvement as defined by the FRDA cardiomyopathy criteria) |
| Change in Peak Systolic Strain Rate From Baseline to Week 52 | 1 year | 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. |
| Change in Peak Workload From Baseline to Week 52 | 1 year | 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 \[if leg ergonometry\])). |
Countries
Austria, Belgium, France, Germany, Netherlands, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A: Idebenone Patients under/equal 45 kg: idebenone 180 mg/day Patients over 45 kg: idebenone 360 mg/day
idebenone: 12 months of 1 of 3 treatments arms of oral idebenone or placebo.Treatment taken 3 times daily with meals. | 57 |
| Group B: Idebenone Patients under/equal 45 kg: idebenone 450 mg/day Patients over 45 kg: idebenone 900 mg/day
idebenone: 12 months of 1 of 3 treatments arms of oral idebenone or placebo.Treatment taken 3 times daily with meals. | 57 |
| C: Idebenone Patients under/equal 45 kg: idebenone 1350 mg/day Patients over 45 kg: idebenone 2250 mg/day
idebenone: 12 months of 1 of 3 treatments arms of oral idebenone or placebo.Treatment taken 3 times daily with meals. | 59 |
| D: Placebo placebo
Placebo: 12 months of 1 of 3 treatments arms of oral idebenone or placebo.Treatment taken 3 times daily with meals. | 59 |
| Total | 232 |
Baseline characteristics
| Characteristic | Total | D: Placebo | Group A: Idebenone | C: Idebenone | Group B: Idebenone |
|---|---|---|---|---|---|
| Age, Continuous | 30.9 years STANDARD_DEVIATION 13.3 | 30.4 years STANDARD_DEVIATION 13.3 | 30.9 years STANDARD_DEVIATION 13.7 | 30.9 years STANDARD_DEVIATION 13.6 | 31.6 years STANDARD_DEVIATION 13.1 |
| Region of Enrollment Austria | 13 participants | 5 participants | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Belgium | 13 participants | 4 participants | 3 participants | 5 participants | 1 participants |
| Region of Enrollment France | 17 participants | 6 participants | 5 participants | 4 participants | 2 participants |
| Region of Enrollment Germany | 156 participants | 36 participants | 40 participants | 39 participants | 41 participants |
| Region of Enrollment Netherlands | 12 participants | 3 participants | 3 participants | 3 participants | 3 participants |
| Region of Enrollment United Kingdom | 21 participants | 5 participants | 4 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 107 Participants | 32 Participants | 23 Participants | 27 Participants | 25 Participants |
| Sex: Female, Male Male | 125 Participants | 27 Participants | 34 Participants | 32 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 55 / 57 | 52 / 57 | 52 / 59 | 55 / 59 |
| serious Total, serious adverse events | 7 / 57 | 4 / 57 | 8 / 59 | 7 / 59 |
Outcome results
Primary
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.
Time frame: Baseline and week 52
Population: The Intent-To-Treat (ITT) population included all randomized subjects who received at least one dose of the study medication and had a confirmed diagnosis of FRDA, did not take idebenone within one month pre-Screening or between Screening and Visit 1, and were not under idebenone treatment at Baseline according to available PK results at Visit 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Idebenone | Absolute Change in International Cooperative Ataxia Rating Scale (ICARS) Scores From Baseline Assessment to Week 52 | 1.6 units on a scale | Standard Deviation 5.85 |
| Group B: Idebenone | Absolute Change in International Cooperative Ataxia Rating Scale (ICARS) Scores From Baseline Assessment to Week 52 | 1.7 units on a scale | Standard Deviation 6.64 |
| C: Idebenone | Absolute Change in International Cooperative Ataxia Rating Scale (ICARS) Scores From Baseline Assessment to Week 52 | 1.2 units on a scale | Standard Deviation 5.22 |
| D: Placebo | Absolute Change in International Cooperative Ataxia Rating Scale (ICARS) Scores From Baseline Assessment to Week 52 | 1.1 units on a scale | Standard Deviation 6.76 |
Secondary
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.
Time frame: Baseline and week 52
Population: The comparison was carried out in the ITT population, on data imputed using the last observation carried forward (LOCF) method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Idebenone | Absolute Change in Friedreich's Ataxia Rating Scale (FARS) Scores From Baseline Assessment to Week 52 | 0.9 units on a scale | Standard Deviation 7.19 |
| Group B: Idebenone | Absolute Change in Friedreich's Ataxia Rating Scale (FARS) Scores From Baseline Assessment to Week 52 | 1.2 units on a scale | Standard Deviation 5.24 |
| C: Idebenone | Absolute Change in Friedreich's Ataxia Rating Scale (FARS) Scores From Baseline Assessment to Week 52 | 1.4 units on a scale | Standard Deviation 5.6 |
| D: Placebo | Absolute Change in Friedreich's Ataxia Rating Scale (FARS) Scores From Baseline Assessment to Week 52 | 0.9 units on a scale | Standard Deviation 6.77 |
Secondary
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.
Time frame: 1 year
Population: Subgroup of subjects with cardiac involvement as defined by Friedreich's ataxia cardiomyopathy (FRDA-CM)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Idebenone | Change in Peak Systolic Strain Rate From Baseline to Week 52 | 0.007 1/s | Standard Deviation 0.22 |
| Group B: Idebenone | Change in Peak Systolic Strain Rate From Baseline to Week 52 | -0.004 1/s | Standard Deviation 0.265 |
| C: Idebenone | Change in Peak Systolic Strain Rate From Baseline to Week 52 | 0.085 1/s | Standard Deviation 0.227 |
| D: Placebo | Change in Peak Systolic Strain Rate From Baseline to Week 52 | 0.024 1/s | Standard Deviation 0.192 |
Secondary
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 \[if leg ergonometry\])).
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Idebenone | Change in Peak Workload From Baseline to Week 52 | 1.15 Watts | Standard Deviation 16.362 |
| Group B: Idebenone | Change in Peak Workload From Baseline to Week 52 | -7.41 Watts | Standard Deviation 34.499 |
| C: Idebenone | Change in Peak Workload From Baseline to Week 52 | -6.91 Watts | Standard Deviation 20.179 |
| D: Placebo | Change in Peak Workload From Baseline to Week 52 | -1.54 Watts | Standard Deviation 16.509 |
Secondary
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)
Time frame: 1 year
Population: Subgroup of subjects with cardiac involvement as defined by Friedreich's ataxia cardiomyopathy (FRDA-CM)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A: Idebenone | 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 | 50 percentage of patients |
| Group B: Idebenone | 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 | 51.4 percentage of patients |
| C: Idebenone | 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 | 30.3 percentage of patients |
| D: Placebo | 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 | 44.1 percentage of patients |
Secondary
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.
Time frame: week 52
Population: The Intent-To-Treat (ITT) population included all randomized subjects who received at least one dose of the study medication and had a confirmed diagnosis of FRDA, did not take idebenone within one month pre-Screening or between Screening and Visit 1, and were not under idebenone treatment at Baseline according to available PK results at Visit 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A: Idebenone | Proportion of Patients Improving (Responding) on ICARS by a Clinically Relevant Margin | 18.2 percentage of patients |
| Group B: Idebenone | Proportion of Patients Improving (Responding) on ICARS by a Clinically Relevant Margin | 23.6 percentage of patients |
| C: Idebenone | Proportion of Patients Improving (Responding) on ICARS by a Clinically Relevant Margin | 23.7 percentage of patients |
| D: Placebo | Proportion of Patients Improving (Responding) on ICARS by a Clinically Relevant Margin | 31 percentage of patients |