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Lancet. 2015 May 2;385(9979):1748-1757. doi: 10.1016/S0140-6736(15)60025-3. Epub 2015 Apr 20.

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.

Author information

1
University Hospitals Leuven, Leuven, Belgium. Electronic address: gunnar.buyse@uzleuven.be.
2
Institut de Myologie, Université Pierre et Marie Curie INSERM UMR 974, CNRS FRE 3617, Groupe Hospitalier de la Pitié Salpetrière, Paris, France.
3
Universitätsklinikum, Essen, Germany.
4
Leiden University Medical Center, Leiden, Netherlands.
5
Istituto di Ricovero e Cura a Carattere Scientifico Eugenio Medea, Lecco, Italy.
6
Gottfried von Preyer'sches Kinderspital, Vienna, Austria.
7
Centre Hospitalier Régional Universitaire de Lille, Lille, France.
8
Nemours Children's Hospital, Orlando, FL, USA.
9
University Hospitals Leuven, Leuven, Belgium.
10
University of California Davis Medical Center, Sacramento, CA, USA.
11
4Pharma, Liestal, Switzerland.
12
Santhera Pharmaceuticals, Liestal, Switzerland.

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.

FINDINGS:

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).

INTERPRETATION:

Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy.

FUNDING:

Santhera Pharmaceuticals.

PMID:
25907158
DOI:
10.1016/S0140-6736(15)60025-3
[Indexed for MEDLINE]

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