Clinical trial NCT01027884: Phase III Study of Idebenone in Duchenne Muscular Dystrophy (DMD)
Official title: A Phase III Double-Blind, Randomised, Placebo-Controlled Study of the Efficacy, Safety and Tolerability of Idebenone in 10-18 Year Old Patients With Duchenne Muscular Dystrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Muscular Dystrophy, Duchenne
Ambulatory Care
Keywords: Idebenone
Duchenne Muscular Dystrophy (DMD)
Respiratory function
Ambulatory and non-ambulatory patients
Subjects not using glucocorticoids
Lead sponsor: Santhera Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2009-12-09
Enrollment: 65
Sex: MALE
Minimum age (years): 10
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Change From Baseline in Percent Predicted Peak Expiratory Flow (PEF) at Week 52
timeFrame: Baseline and Week 52
Secondary outcomes:
measure: Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 52
timeFrame: Baseline and Week 52
measure: Change From Baseline to Week 52 in Muscle Strength
timeFrame: Baseline and Week 52
measure: Change From Baseline to Week 52 in Quality of Life Assessed by PedsQL™ Paediatric Quality of Life Inventory
timeFrame: Baseline and Week 52
measure: Percentage of Patients Reporting Adverse Events
timeFrame: 52 Weeks
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Charlotte
country: United States
facility: Carolinas Medical Center, Neurosciences and Spine Institute
state: North Carolina
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Nashville
country: United States
facility: Monroe Carell, Jr. Children's Hospital at Vanderbilt
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Methodist Neurological Institute
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Wien
country: Austria
facility: Dr. Günther Bernert, Prim. Univ. Doz.
city: Leuven
country: Belgium
facility: University Hospitals Leuven- Children Hospital
city: Lille
country: France
facility: Hôpital Roger Salengro, CHRU Lille
city: Paris Cedex 13
country: France
facility: Prof. Thomas Voit , MD, PhD
city: Essen
country: Germany
facility: Universitätsklinikum Essen, Zentrum für Kinderheikunde
city: Freiburg
country: Germany
facility: Universitätsklinik Freiburg Zentrum für Kinderheilkunde und Jugendmedizin
city: Bosisio Parini, Lecco
country: Italy
facility: Fondazione IRCCS "Eugenio Medea"
city: Milan
country: Italy
facility: Azienda Ospedaliera Niguarda Ca' Granda Centro Clinico Nemo
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria della Seconda Università degli Studi di Napoli
city: Leiden
country: Netherlands
facility: Ass. Prof. Jan Verschuuren , MD, PhD
state: P.O. Box 9600
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
city: Stockholm
country: Sweden
facility: Prof. Thomas Sejersen, MD, PhD
city: Lausanne
country: Switzerland
facility: CHUV Lausanne Neuropediatrie
Study officials:
affiliation: University Hospitals Leuven, B-3000, Belgium
name: Prof. Gunnar Buyse, MD, PhD.
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsklinikum Essen, D-45122 Essen, Germany
name: Dr. Ulrike Schara, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center (LUMC), 2300 RC Leiden, the Netherlands
name: Ass. Prof. Jan Verschuuren, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Unité de Neuropédiatrie, CHUV - BH11, 1011 Lausanne-CH, Switzerland
name: Dr. Pierre-Yves Jeannet, Médecin Associé, MER
role: PRINCIPAL_INVESTIGATOR
affiliation: Université Pierre et Marie curie VI - Institut de Myologie - groupe hospitalier Pitié Salpétrière - 47/83 boulevard de l'hôpital, 75651 Paris Cedex 13, France
name: Prof. Thomas Voit, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Astrid Lindgrens Barnsjukhus- Karolinska Universitetssjukhuset, SE-17176 Stockholm, Sweden
name: Prof. Thomas Sejersen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vorstand der Abteilung für Kinder- und Jugendheilkunde, Gottfried v. Preyer'sches Kinderspital, 1100 Wien, Austria
name: Dr. Günther Bernert, Prim. Univ. Doz.
role: PRINCIPAL_INVESTIGATOR
affiliation: Division of Neurology - The Children's Hospital of Philadelphia - 34th Street and Civic Center Blvd, Philadelphia, PA 19104-1771, USA
name: Gihan Tennekoon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Roger Salengro, CHRU, Service de neurologie infantile, Lille, France
name: Jean-Marie Cuisset, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas Southwestern Medical Center, TX, USA
name: Susan Iannaccone, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Charlotte-Mecklenburg Hospital Authority, Charlotte, NC, USA
name: Susan Sparks, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsklinik Freiburg Zentrum für Kinderheilkunde und Jugendmedizin
name: Janbernd Kirschner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fondazione IRCCS "Eugenio Medea"
name: Maria Grazia Nadia D'Angelo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Azienda Ospedaliera Niguarda Ca'Granda Centro Clinico Nemo
name: Ksenija Gorni, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Monroe Carell Jr. Children's Hospital at Vanderbilt
name: Bryan W. Burnette, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida
name: Barry Byrne, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Colorado
name: Michele Yang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Seattle Children's Hospital
name: Susan Apkon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Methodist Neurological Institute, Houston
name: Ericka Simpson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: Craig McDonald, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Azienda Ospedaliera Universitaria della Seconda Università degli Studi di Napoli
name: Luisa Politano, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario 12 de Octubre
name: Ana Camacho Salas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitari y Politècnic La Fe de Valencia
name: Juan Jesus Vilchez, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Buyse GM, Voit T, Schara U, Straathof CSM, D'Angelo MG, Bernert G, Cuisset JM, Finkel RS, Goemans N, McDonald CM, Rummey C, Meier T; DELOS Study Group. 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. Lancet. 2015 May 2;385(9979):1748-1757. doi: 10.1016/S0140-6736(15)60025-3. Epub 2015 Apr 20.
citation: Meier T, Rummey C, Leinonen M, Spagnolo P, Mayer OH, Buyse GM; DELOS Study Group. Characterization of pulmonary function in 10-18 year old patients with Duchenne muscular dystrophy. Neuromuscul Disord. 2017 Apr;27(4):307-314. doi: 10.1016/j.nmd.2016.12.014. Epub 2017 Jan 6.