Ambulatory Care, Muscular Dystrophy, Duchenne
Conditions
Keywords
Idebenone, Duchenne Muscular Dystrophy (DMD), Respiratory function, Ambulatory and non-ambulatory patients, Subjects not using glucocorticoids
Brief summary
The aim of this Phase III study was to assess the efficacy of idebenone on pulmonary function, motor function, muscle strength and quality of life in patients with DMD. Furthermore, the safety and tolerability of idebenone was assessed.
Detailed description
This study was a Phase III, multicenter, randomized, double-blind, placebo-controlled efficacy and safety study. DMD patients (ambulatory and non-ambulatory) at age 10-18 years were enrolled at sites in Europe and North America. Study subjects were randomized in a 1:1 ratio to receive either idebenone (900 mg/day) or placebo 3 times a day with meals for 52 weeks. The primary endpoint was the difference between Catena®/Raxone® and placebo in the change from Baseline to week 52 in Peak Expiratory Flow (PEF as percent predicted, PEF%p, a measure of respiratory muscle strength) as measured by hospital-based spirometry. PEF was also measured by the patient at home using the hand-held ASMA-1 device (secondary endpoint). Other respiratory endpoints included Forced Expiratory Volume in 1 second (as percent predicted, FEV1%p, an additional measure of respiratory muscle strength) and Forced Vital Capacity (as percent predicted, FVC%p, a measure of restrictive lung disease predictive of morbidity and mortality in DMD).
Interventions
DRUGPlacebo
Placebo (900 mg/day) 2 tabl (150 mg each) x 3 times orally with meals
DRUGIdebenone
Idebenone (900 mg/day) 2 tabl (150 mg each) x 3 times orally 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
MALE
Age
10 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
1. Patients 10 - 18 years of age at Baseline. 2. Signed and dated informed consent. 3. Documented diagnosis of DMD or severe dystrophinopathy and clinical features consistent of typical DMD at diagnosis (i.e. documented delayed motor skills and muscle weakness by age 5 years). DMD should be confirmed by mutation analysis in the dystrophin gene or by substantially reduced levels of dystrophin protein (i.e. absent or \<5% of normal) on Western blot or immunostain. 4. Ability to provide reliable and reproducible repeat PEF within 15% of the first assessment (i.e. Baseline vs. Screening). 5. Patients assessed by the investigator as willing and able to comply with the requirements of the study, possess the required cognitive abilities and are able to swallow study medication.
Exclusion criteria
1. Patients dependent on assisted ventilation at Screening and/or Baseline (defined as non-invasive nocturnal ventilation, daytime non-invasive ventilation or continuous invasive ventilation). 2. Patients with documented DMD-related hypoventilation for which assisted ventilation is needed according to current standard of care guidelines (e.g. FVC\< 30%) or is required in the opinion of the Investigator. 3. Patients with a percent predicted PEF \> 80% at Baseline. 4. Patients unable to form a mouth seal to allow precise respiratory flow measurements and mouth pressures. 5. Symptomatic heart failure (high probability of death within one year of Baseline) and/or symptomatic ventricular arrhythmias. 6. Participation in the previous Phase II or Phase II Extension study (SNT-II-001 or SNT-II-001-E) for idebenone. 7. Participation in any other therapeutic trial and/or intake of any investigational drug within 90 days prior to Baseline. 8. Use of carnitine, creatine, glutamine, oxatomide, or any herbal medicines within 30 days prior to Baseline. 9. Use of coenzyme Q10 or vitamin E (if taken at a dose of 5 times above the daily physiological requirement) within 30 days prior to Baseline. 10. Any previous use of idebenone. 11. Any concomitant medication with a depressive or stimulating effect on respiration or the respiratory tract. 12. Planned or expected spinal fixation surgery during the study period (as judged by the investigator). 13. Asthma, bronchitis/COPD, bronchiectasis, emphysema, pneumonia or the presence of any other non-DMD respiratory illness that affects PEF. 14. Chronic use of beta-2 agonists or any use of other bronchodilating medication (e.g. inhaled steroids, sympathomimetics, anticholinergics). Please note: Chronic use if defined as a daily intake for more than 14 days. 15. Moderate or severe hepatic impairment or severe renal impairment. 16. Prior or ongoing medical condition or laboratory abnormality that in the Investigator's opinion could adversely affect the safety of the subject. Please note: Patients who suffer from a severe, unstable condition including (but not limited to) cancer, auto-immune diseases, haematological diseases, metabolic disorders or immunodeficiencies, and who are at risk of an aggravation unrelated to the study condition, can only be included in the study if accepted in writing by the Sponsor's Medical Monitor. 17. Relevant history of or current drug or alcohol abuse or use of any tobacco/marijuana products/smoking 18. Known individual hypersensitivity to idebenone or to any of the ingredients/excipients of the study medication 19. Systemic glucocorticoid therapy 1. Chronic use of systemic glucocorticoid therapy for DMD related conditions within 12 months of Baseline (the 12 month non-use period) 2. More than 2 rounds of acute systemic glucocorticoid burst therapy (of ≤2 week duration) for non-DMD related conditions within the 12 month non-use period 3. Use of any round of systemic glucocorticoid burst therapy of longer than 2 weeks duration within the 12 month non-use period 4. Use of systemic glucocorticoid burst therapy less than 8 weeks prior to baseline
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Percent Predicted Peak Expiratory Flow (PEF) at Week 52 | Baseline and Week 52 | Change from Baseline in Percent Predicted Peak Expiratory Flow (PEF) at Week 52 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 52 | Baseline and Week 52 | Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 52 |
| Change From Baseline to Week 52 in Muscle Strength | Baseline and Week 52 | The change from Baseline to Week 52 in muscle strength as measured by Hand-Held Myometry (HHM) was performed following standardized procedures. As almost all patients were non-ambulatory, only analyses of upper limb muscle strength were performed. Results for elbow flexors and for elbow extensors are reported below.The highest value of 3 consecutive measurements with an interval of at least 10 seconds were recorded. The HHM was measured using MicroFET2, a digital hand held muscle tester. The selected unit of measure was Newtons (N). |
| Change From Baseline to Week 52 in Quality of Life Assessed by PedsQL™ Paediatric Quality of Life Inventory | Baseline and Week 52 | PedsQL Quality of Life Inventory contains paediatric HRQOL measurements: Physical, Emotional,Social and School Functioning. Item Scaling: 5-point Likert scale from 0 (Never) to 4 (Almost always). 3-point scale: 0 (Not at all), 2 (Sometimes) and 4 (A lot) for the Young Child (ages 5-7). Scores are transformed on a scale from 0 to 100 ( 0=100, 1=75, 2=50, 3=25, 4=0) Total Score: Sum of all the items over the number of items answered on all the Scales. The values reported below are overall scores on Paediatric Quality of Life Inventory in Child/Teen Report. These scores were obtained by averaging scores for all the described subscales. The overall scores range between 0-100 with 0 = worst outcome and 100= best outcome |
| Percentage of Patients Reporting Adverse Events | 52 Weeks | — |
Countries
Austria, Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, Switzerland, United States
Participant flow
Recruitment details
Recruiting centres were in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA. Patients were enrolled between July 27, 2009 (study start date), and Dec 14, 2012; the study end date (last patient completed the study) was Jan 14, 2014.
Pre-assignment details
65 patients were randomly assigned and two patients were allocated to the same treatment as their randomly assigned siblings. One patient never took study medication, resulting in 66 patients who were treated and included in the safety population (34 in the placebo group and 32 in the idebenone group).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Two matching placebo tablets were taken three times a day with meals | 34 |
| Idebenone Two150 mg tablets were taken three times a day with meals (total dose 900 mg daily). | 32 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliance | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Spinal fixation surgery | 0 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Idebenone | Total |
|---|---|---|---|
| Age, Continuous | 15 years STANDARD_DEVIATION 2.5 | 13.5 years STANDARD_DEVIATION 2.7 | 14.3 years STANDARD_DEVIATION 2.7 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 34 Participants | 32 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 34 | 30 / 32 |
| serious Total, serious adverse events | 5 / 34 | 2 / 32 |
Outcome results
Primary
Change From Baseline in Percent Predicted Peak Expiratory Flow (PEF) at Week 52
Change from Baseline in Percent Predicted Peak Expiratory Flow (PEF) at Week 52
Time frame: Baseline and Week 52
Population: This analysis was performed on the ITT population(n=64). This population included all randomized patients who received at least one dose of the study medication and provided at least one post-Baseline assessment. It excluded siblings who had been allocated to the same study treatment as a randomized sibling.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Percent Predicted Peak Expiratory Flow (PEF) at Week 52 | -8.84 percentage |
| Idebenone | Change From Baseline in Percent Predicted Peak Expiratory Flow (PEF) at Week 52 | -2.57 percentage |
Secondary
Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 52
Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 52
Time frame: Baseline and Week 52
Population: This analysis was performed on the ITT population(n=64). This population included all randomized patients who received at least one dose of the study medication and provided at least one post-Baseline assessment. It excluded siblings who had been allocated to the same study treatment as a randomized sibling.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 52 | -8.95 percentage of Predicted FVC |
| Idebenone | Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 52 | -5.67 percentage of Predicted FVC |
Secondary
Change From Baseline to Week 52 in Muscle Strength
The change from Baseline to Week 52 in muscle strength as measured by Hand-Held Myometry (HHM) was performed following standardized procedures. As almost all patients were non-ambulatory, only analyses of upper limb muscle strength were performed. Results for elbow flexors and for elbow extensors are reported below.The highest value of 3 consecutive measurements with an interval of at least 10 seconds were recorded. The HHM was measured using MicroFET2, a digital hand held muscle tester. The selected unit of measure was Newtons (N).
Time frame: Baseline and Week 52
Population: The number of patients (N) in each treatment group is the number of patients with baseline assessments
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline to Week 52 in Muscle Strength | Elbow Flexors | 0.13 Newtons |
| Placebo | Change From Baseline to Week 52 in Muscle Strength | Elbow Extensors | 1.32 Newtons |
| Idebenone | Change From Baseline to Week 52 in Muscle Strength | Elbow Flexors | -2.32 Newtons |
| Idebenone | Change From Baseline to Week 52 in Muscle Strength | Elbow Extensors | 0.26 Newtons |
Secondary
Change From Baseline to Week 52 in Quality of Life Assessed by PedsQL™ Paediatric Quality of Life Inventory
PedsQL Quality of Life Inventory contains paediatric HRQOL measurements: Physical, Emotional,Social and School Functioning. Item Scaling: 5-point Likert scale from 0 (Never) to 4 (Almost always). 3-point scale: 0 (Not at all), 2 (Sometimes) and 4 (A lot) for the Young Child (ages 5-7). Scores are transformed on a scale from 0 to 100 ( 0=100, 1=75, 2=50, 3=25, 4=0) Total Score: Sum of all the items over the number of items answered on all the Scales. The values reported below are overall scores on Paediatric Quality of Life Inventory in Child/Teen Report. These scores were obtained by averaging scores for all the described subscales. The overall scores range between 0-100 with 0 = worst outcome and 100= best outcome
Time frame: Baseline and Week 52
Population: The number of patients (N) in each treatment group is the number of patients with Baseline assessments.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change From Baseline to Week 52 in Quality of Life Assessed by PedsQL™ Paediatric Quality of Life Inventory | 2.46 units on a scale |
| Idebenone | Change From Baseline to Week 52 in Quality of Life Assessed by PedsQL™ Paediatric Quality of Life Inventory | -1.34 units on a scale |
Secondary
Percentage of Patients Reporting Adverse Events
Time frame: 52 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients Reporting Adverse Events | 94.1 percentage of patients reporting AEs |
| Idebenone | Percentage of Patients Reporting Adverse Events | 93.8 percentage of patients reporting AEs |