phase iii study of idebenone in duchenne muscular dystrophy (dmd)

Conditions: Muscular Dystrophy, Duchenne; Ambulatory Care

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.

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).

Eligibility criteria:
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

Keywords: idebenone duchenne muscular dystrophy (dmd) respiratory function ambulatory and non-ambulatory patients subjects not using glucocorticoids