title: Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial.
abstract: BACKGROUND
  Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids.
  
  
  METHODS
  In a multicentre phase 3 trial in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA, patients (age 10-18 years old) with Duchenne muscular dystrophy were randomly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive idebenone (300 mg three times a day) or matching placebo orally for 52 weeks. Study personnel and patients were masked to treatment assignment. The primary endpoint was change in peak expiratory flow (PEF) as percentage predicted (PEF%p) from baseline to week 52, measured with spirometry. Analysis was by intention to treat (ITT) and a modified ITT (mITT), which was prospectively defined to exclude patients with at least 20% difference in the yearly change in PEF%p, measured with hospital-based and weekly home-based spirometry. This study is registered with ClinicalTrials.gov, number NCT01027884.
  
  
  RESULTS
  31 patients in the idebenone group and 33 in the placebo group comprised the ITT population, and 30 and 27 comprised the mITT population. Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (-3·05%p [95% CI -7·08 to 0·97], p=0·134, vs placebo -9·01%p [-13·18 to -4·84], p=0·0001; difference 5·96%p [0·16 to 11·76], p=0·044) and ITT populations (-2·57%p [-6·68 to 1·54], p=0·215, vs -8·84%p [-12·73 to -4·95], p<0·0001; difference 6·27%p [0·61 to 11·93], p=0·031). Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC, and FEV1. The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (idebenone, eight [25%] and six [19%] of 32 patients; placebo, nine [26%] and seven [21%] of 34 patients). Transient and mild diarrhoea was more common in the idebenone group than in the placebo group (eight [25%] vs four [12%] patients).
  
  
  CONCLUSIONS
  Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy.
  
  
  BACKGROUND
  Santhera Pharmaceuticals.
authors.affiliation: University Hospitals Leuven, Leuven, Belgium. Electronic address: gunnar.buyse@uzleuven.be.
authors.forename: Gunnar M
authors.initials: GM
authors.lastname: Buyse
authors.affiliation: Institut de Myologie, Université Pierre et Marie Curie INSERM UMR 974, CNRS FRE 3617, Groupe Hospitalier de la Pitié Salpetrière, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.affiliation: Universitätsklinikum, Essen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schara
authors.affiliation: Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Chiara S M
authors.initials: CSM
authors.lastname: Straathof
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Eugenio Medea, Lecco, Italy.
authors.forename: M Grazia
authors.initials: MG
authors.lastname: D'Angelo
authors.affiliation: Gottfried von Preyer'sches Kinderspital, Vienna, Austria.
authors.forename: Günther
authors.initials: G
authors.lastname: Bernert
authors.affiliation: Centre Hospitalier Régional Universitaire de Lille, Lille, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Cuisset
authors.affiliation: Nemours Children's Hospital, Orlando, FL, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finkel
authors.affiliation: University Hospitals Leuven, Leuven, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Goemans
authors.affiliation: University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Craig M
authors.initials: CM
authors.lastname: McDonald
authors.affiliation: 4Pharma, Liestal, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Rummey
authors.affiliation: Santhera Pharmaceuticals, Liestal, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meier
mesh_terms: D000293:Adolescent; D000975:Antioxidants / Q000627:therapeutic use*; D002648:Child; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D010366:Peak Expiratory Flow Rate; D012120:Respiration Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D012129:Respiratory Function Tests; D012132:Respiratory Muscles / Q000503:physiopathology; D016896:Treatment Outcome; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D014451:Ubiquinone; C036619:idebenone