Phase III Study of Idebenone in Duchenne Muscular Dystrophy (DMD) (DELOS)

• ClinicalTrials.gov Identifier: NCT01027884
• Recruitment Status: Completed
• First Posted: December 9, 2009
• Results First Posted: October 19, 2015
• Last Update Posted: October 19, 2015
• Sponsor: Santhera Pharmaceuticals
• Information provided by (Responsible Party): Santhera Pharmaceuticals

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Muscular Dystrophy, Duchenne; Ambulatory Care	Drug: Placebo; Drug: Idebenone	Phase 3

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: July 2009
• Actual Primary Completion Date: January 2014
• Actual Study Completion Date: April 2014

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Placebo 900 mg/day	Drug: Placebo; Placebo (900 mg/day) 2 tabl (150 mg each) x 3 times orally with meals
Experimental: Idebenone; Idebenone 900 mg/day	Drug: Idebenone; Idebenone (900 mg/day) 2 tabl (150 mg each) x 3 times orally with meals; Other Names: CATENA®; RAXONE®

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Percent Predicted Peak Expiratory Flow (PEF) at Week 52 [ Time Frame: Baseline and Week 52 ]
   Change from Baseline in Percent Predicted Peak Expiratory Flow (PEF) at Week 52

Secondary Outcome Measures :

1. Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 52 [ Time Frame: Baseline and Week 52 ]
   Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 52
2. Change From Baseline to Week 52 in Muscle Strength [ Time Frame: 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).

3. Change From Baseline to Week 52 in Quality of Life Assessed by PedsQL™ Paediatric Quality of Life Inventory [ Time Frame: 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

4. Percentage of Patients Reporting Adverse Events [ Time Frame: 52 Weeks ]

Eligibility Criteria

• Ages Eligible for Study: 10 Years to 18 Years (Child, Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

University of California Davis Medical Center

Sacramento, California, United States, 95817

United States, Colorado

Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Florida

University of Florida

Gainesville, Florida, United States, 32610

United States, North Carolina

Carolinas Medical Center, Neurosciences and Spine Institute

Charlotte, North Carolina, United States, 28207

United States, Pennsylvania

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104-1771

United States, Tennessee

Monroe Carell, Jr. Children's Hospital at Vanderbilt

Nashville, Tennessee, United States, 37232

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390-9105

Methodist Neurological Institute

Houston, Texas, United States, 77030

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98105

Austria

Dr. Günther Bernert, Prim. Univ. Doz.

Wien, Austria, 1100

Belgium

University Hospitals Leuven- Children Hospital

Leuven, Belgium, B - 3000

France

Hôpital Roger Salengro, CHRU Lille

Lille, France, 59037

Prof. Thomas Voit , MD, PhD

Paris Cedex 13, France, 75651

Germany

Universitätsklinikum Essen, Zentrum für Kinderheikunde

Essen, Germany, D-45122

Universitätsklinik Freiburg Zentrum für Kinderheilkunde und Jugendmedizin

Freiburg, Germany, 79106

Italy

Fondazione IRCCS "Eugenio Medea"

Bosisio Parini, Lecco, Italy, 23842

Azienda Ospedaliera Niguarda Ca' Granda Centro Clinico Nemo

Milan, Italy, 20162,

Azienda Ospedaliera Universitaria della Seconda Università degli Studi di Napoli

Napoli, Italy, 80138

Netherlands

Ass. Prof. Jan Verschuuren , MD, PhD

Leiden, P.O. Box 9600, Netherlands, 2300 RC

Spain

Hospital Universitario 12 de Octubre

Madrid, Spain, 28041

Hospital Universitario y Politécnico La Fe

Valencia, Spain, 46009

Sweden

Prof. Thomas Sejersen, MD, PhD

Stockholm, Sweden, 17176

Switzerland

CHUV Lausanne Neuropediatrie

Lausanne, Switzerland, 1011

Sponsors and Collaborators

Santhera Pharmaceuticals

Investigators

• Principal Investigator: Prof. Gunnar Buyse, MD, PhD.; University Hospitals Leuven, B-3000, Belgium
• Principal Investigator: Dr. Ulrike Schara, MD, PhD; Universitätsklinikum Essen, D-45122 Essen, Germany
• Principal Investigator: Ass. Prof. Jan Verschuuren, MD, PhD; Leiden University Medical Center (LUMC), 2300 RC Leiden, the Netherlands
• Principal Investigator: Dr. Pierre-Yves Jeannet, Médecin Associé, MER; Unité de Neuropédiatrie, CHUV - BH11, 1011 Lausanne-CH, Switzerland
• Principal Investigator: Prof. Thomas Voit, MD, PhD; Université Pierre et Marie curie VI - Institut de Myologie - groupe hospitalier Pitié Salpétrière - 47/83 boulevard de l'hôpital, 75651 Paris Cedex 13, France
• Principal Investigator: Prof. Thomas Sejersen, MD, PhD; Astrid Lindgrens Barnsjukhus- Karolinska Universitetssjukhuset, SE-17176 Stockholm, Sweden
• Principal Investigator: Dr. Günther Bernert, Prim. Univ. Doz.; Vorstand der Abteilung für Kinder- und Jugendheilkunde, Gottfried v. Preyer'sches Kinderspital, 1100 Wien, Austria
• Principal Investigator: Gihan Tennekoon, MD; Division of Neurology - The Children's Hospital of Philadelphia - 34th Street and Civic Center Blvd, Philadelphia, PA 19104-1771, USA
• Principal Investigator: Jean-Marie Cuisset, MD; Hôpital Roger Salengro, CHRU, Service de neurologie infantile, Lille, France
• Principal Investigator: Susan Iannaccone, MD; University of Texas Southwestern Medical Center, TX, USA
• Principal Investigator: Susan Sparks, MD; The Charlotte-Mecklenburg Hospital Authority, Charlotte, NC, USA
• Principal Investigator: Janbernd Kirschner, MD; Universitätsklinik Freiburg Zentrum für Kinderheilkunde und Jugendmedizin
• Principal Investigator: Maria Grazia Nadia D'Angelo, MD; Fondazione IRCCS "Eugenio Medea"
• Principal Investigator: Ksenija Gorni, MD; Azienda Ospedaliera Niguarda Ca'Granda Centro Clinico Nemo
• Principal Investigator: Bryan W. Burnette, MD; Monroe Carell Jr. Children's Hospital at Vanderbilt
• Principal Investigator: Barry Byrne, MD; University of Florida
• Principal Investigator: Michele Yang, MD; Children's Hospital Colorado
• Principal Investigator: Susan Apkon, MD; Seattle Children's Hospital
• Principal Investigator: Ericka Simpson, MD; Methodist Neurological Institute, Houston
• Principal Investigator: Craig McDonald, MD; University of California, Davis
• Principal Investigator: Luisa Politano, MD; Azienda Ospedaliera Universitaria della Seconda Università degli Studi di Napoli
• Principal Investigator: Ana Camacho Salas, MD; Hospital Universitario 12 de Octubre
• Principal Investigator: Juan Jesus Vilchez, MD; Hospital Universitari y Politècnic La Fe de Valencia

More Information

Additional Information:

Related Info 

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Santhera Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01027884
• Other Study ID Numbers: SNT-III-003
• First Posted: December 9, 2009
• Results First Posted: October 19, 2015
• Last Update Posted: October 19, 2015
• Last Verified: September 2015

Keywords provided by Santhera Pharmaceuticals:

Idebenone; Duchenne Muscular Dystrophy (DMD); Respiratory function; Ambulatory and non-ambulatory patients; Subjects not using glucocorticoids

Additional relevant MeSH terms:

Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Idebenone; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs