A Phase III Double-blind Study With Idebenone in Patients With Duchenne Muscular Dystrophy (DMD) Taking Glucocorticoid Steroids (SIDEROS)

• ClinicalTrials.gov Identifier: NCT02814019
• Recruitment Status: Terminated
• First Posted: June 27, 2016
• Last Update Posted: December 3, 2021
• Sponsor: Santhera Pharmaceuticals
• Information provided by (Responsible Party): Santhera Pharmaceuticals

Study Description

Brief Summary:

The purpose of the study is to assess the efficacy of idebenone in delaying the loss of respiratory function in patients with DMD receiving concomitant glucocorticoid steroids

Condition or disease	Intervention/treatment	Phase
Duchenne Muscular Dystrophy (DMD)	Drug: Idebenone 150 mg film-coated tablets; Drug: placebo	Phase 3

Detailed Description:

The SIDEROS trial is a randomized, placebo controlled, parallel group study of the efficacy of idebenone in delaying the loss of respiratory function, whilst also monitoring safety and tolerability of idebenone in at least 266 DMD patients taking stable dose of concomitant glucocorticoid steroids.

The study treatment period will be 18 months/ 78 weeks and the idebenone dose will be 900 mg/day. Participants can use deflazacort or prednisolone and be on any dose regimen.

Since glucocorticoid steroids are widely used in ambulant boys from an early age until late into teenage and even adult years, this study will not take age and ambulatory status into account and will only exclude patients that need daytime ventilator assistance.

The schedule of assessments will include a Screening Visit and up to 9 protocol visits, including a Follow-up Visit.

A Screening Visit will take place a maximum of 4 weeks prior to the Baseline Visit (Visit 1, study day -1). Beginning at Baseline, the patient will receive study medication to be taken at home, and will undergo regular assessments in the clinic throughout the study period until Visit 8 at Week 78 at which time the study will be completed and medication discontinued.

All patients completing Visit 8/Week 78, and considered eligible by the Investigator will be able to participate in an open-label extension study (SIDEROS-E) and will continue to receive idebenone until idebenone is commercially available for patients included in the study or SIDEROS-E is terminated by the Sponsor, whichever occurs first. The duration of the SIDEROS-E study will be defined in a separate protocol.

For all patients not participating in the extension study (SIDEROS-E), a Follow-up Visit (Visit 9/Follow-up Visit) will take place 4 weeks after end of Treatment at Visit 8/Week 78 or after premature discontinuation of study medication.

Each hospital visit will include efficacy assessments (respiratory function assessed by hospital-based spirometry, oxygen saturation, end-tidal CO2) and safety assessments (adverse events, concomitant medication, physical examination, vital signs, safety laboratory evaluations). In addition, respiratory function will be assessed weekly at home with a hand-held device in order to closely monitor respiratory function between hospital visits.

The study medication, all medical procedures and laboratory testing, and the visits to the study centre are free of charge. In addition the patients will receive a travel allowance to cover reasonable expenses to and from the study centre. Participants will not otherwise be compensated for this study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 255 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, Randomized, Placebo-Controlled Study Assessing the Efficacy, Safety and Tolerability of Idebenone in Patients With Duchenne Muscular Dystrophy Receiving Glucocorticoid Steroids
• Study Start Date: September 2016
• Actual Primary Completion Date: December 1, 2020
• Actual Study Completion Date: December 1, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: idebenone 150 mg film-coated tablets; 900 mg idebenone/day (2 tablets to be taken 3 times a day with meals)	Drug: Idebenone 150 mg film-coated tablets
Placebo Comparator: placebo; matching placebo tablets	Drug: placebo

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Forced Vital Capacity percent predicted (FVC %p) at Week 78 [ Time Frame: 78 weeks ]
   Delaying the loss of respiratory function in patients with DMD receiving glucocorticoid steroids as measured by changes in FVC %p from Baseline to Week 78 using hospital based spirometry.

Secondary Outcome Measures :

1. Change From Baseline in Percent Predicted Peak Expiratory Flow (PEF %p) at Week 78 [ Time Frame: 78 weeks ]

   Delaying the loss of respiratory function in patients with DMD receiving glucocorticoid steroids as measured by:

   •The change from Baseline to Week 78 in PEF %p assessed by hospital-based spirometry measurements

2. Change From Baseline in Forced Vital Capacity (FVC) at Week 78 [ Time Frame: 78 weeks ]

   Delaying the loss of respiratory function in patients with DMD receiving glucocorticoid steroids as measured by:

   •The time to first 10% decline in FVC (L) during the 78-week treatment period, assessed by hospital-based spirometry measurements

3. Change from Baseline in Inspiratory Flow Reserve (IFR) at Week 78 [ Time Frame: 78 weeks ]

   Delaying the loss of respiratory function in patients with DMD receiving glucocorticoid steroids as measured by:

   •The change from Baseline to Week 78 in IFR assessed by hospital-based spirometry measurements

Eligibility Criteria

• Ages Eligible for Study: 10 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male patients with a 35% ≤ FVC ≤ 80% of predicted value at Screening and at Baseline and who, in the opinion of the investigator are in the respiratory function decline phase.
2. Minimum 10 years old at Screening.
3. Signed and dated Informed Consent Form.
4. Documented diagnosis of DMD (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 immunostaining.
5. Chronic use of systemic glucocorticoid steroids for DMD related conditions continuously for at least 12 months prior to Baseline without any dose adjustments on a mg/kg basis in the last 6 months (only dose adjustments determined by weight changes are allowed).
6. Ability to provide reliable FVC values at Screening and Baseline, and reproducible within 15% (relative change) at Baseline compared to Screening.
7. 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.
8. Patients who prior to Screening have been immunized with 23-valent pneumococcal polysaccharide vaccine or any other pneumococcal polysaccharide vaccine as per national recommendations, as well as annually immunized with inactivated influenza vaccine.

Exclusion Criteria:

1. Symptomatic heart failure (defined as patients with structural heart disease, dyspnea, fatigue and impaired tolerance to exercise; Stage C by the ACCF/AHA guideline or NYHA Classes III-IV) and/or symptomatic ventricular arrhythmias.
2. Ongoing participation in any other therapeutic trial and/or intake of any investigational drug within 90 days prior to Baseline (only exception allowed is use of Deflazacort in the US as part of the Expanded Access Program, or any approved corticosteroid product in trial for regimen optimization, for which the patient met the inclusion criterion 5).
3. Ongoing exon-skipping therapy or read-through gene therapy for DMD; previous exon-skipping or read-through gene therapy is allowed if the stop date was more than 6 months prior to Screening.
4. Planned or expected spinal fusion surgery during the study period (as judged by the Investigator; i.e. due to rapidly progressing scoliosis), previous spinal fusion surgery is allowed if it took place more than 6 months prior to Screening.
5. Asthma, bronchitis/COPD, bronchiectasis, emphysema, pneumonia or presence of any other non-DMD respiratory illness that affects respiratory function.
6. Chronic use of beta2-agonists or any use of other bronchodilating/bronchoconstricting medication (inhaled steroids, sympathomimetics, anticholinergics, antihistamines); chronic use is defined as a daily intake for more than 14 days.
7. Any bronchopulmonary illness that required treatment with antibiotics within 3 months prior to Screening.
8. Moderate or severe hepatic impairment (use as guidance Child-Pugh class B [7 to 9 points] or Child-Pugh class C [10 to 15 points] - see Appendix B) or severe renal impairment (eGFR <30 mL/min/1.73 m2).
9. Prior or ongoing medical condition or laboratory abnormality that in the Investigator's opinion may put the patient at significant risk may confound the study results or may interfere significantly with the patient's participation in the study.
10. Relevant history of or current drug or alcohol abuse, or use of any tobacco or marijuana products/smoking.
11. Known individual hypersensitivity to idebenone or to any of the ingredients or excipients of the study medication.
12. Daytime ventilator assistance (defined as use of any assisted ventilation while awake).

Note: Patients who suffer from a severe, unstable condition including (but not limited to) cancer, auto-immune diseases, hematological 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 Senior Clinical Research Physician.

Contacts and Locations

Locations

United States, Alabama

University of Alabama

Birmingham, Alabama, United States, 35233

United States, Arizona

Phoenix Children's Hospital

Phoenix, Arizona, United States, 85016

Banner University of Arizona Medical Center

Tucson, Arizona, United States, 85724

United States, California

Childrens Hospital of Los Angeles

Los Angeles, California, United States, 90027

David Geffen School of Medicine at UCLA

Los Angeles, California, United States, 90095

UC Davis Department of Physical Medicine and Rehabilitation

Sacramento, California, United States, 95817

Loma Linda University Healthcare

San Bernardino, California, United States, 92354

United States, Florida

Shriners Hospitals for Children-Tampa

Tampa, Florida, United States, 33612

United States, Georgia

Rare Disease Research

Atlanta, Georgia, United States, 30318

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Kansas

University of Kansas

Fairway, Kansas, United States, 66103

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Children's Hospital Boston

Boston, Massachusetts, United States, 02115

United States, Minnesota

Gillette Children's Specialty Healthcare

Saint Paul, Minnesota, United States, 55101

United States, New York

University of Rochester Medical Center

Rochester, New York, United States, 14642

United States, North Carolina

Neurosciences Institute, Neurology - Charlotte Carolinas Healthcare System

Charlotte, North Carolina, United States, 28207

United States, Ohio

Cincinnati Children's Hospital

Cincinnati, Ohio, United States, 45229-3039

MetroHealth Medical Center

Cleveland, Ohio, United States, 44109-1988

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104-1771

United States, Texas

Cook Children's Medical Center

Fort Worth, Texas, United States, 76087

Austria

Gottfried von Preyer'sches Kinderspital

Wien, Austria, 1100

Belgium

University Hospital Leuven

Leuven, Belgium, 3000

Centre de Référence Neuromusculaire, CHR Citadelle

Liège, Belgium, 4000

Bulgaria

Sofia Medical University

Sofia, Bulgaria, 1431

France

Service de neuropédiatrie Pôle Pédiatrie CHRU de Lille - Hôpital Jeanne de Flandre

Lille, France, 59037

CHRU de Montpellier - Hôpital Gui de Chauliac

Montpellier, France, 34295

Hôpital Hôtel Dieu

Nantes, France, 44093

I-Motion - Plateforme d'essais cliniques pédiatriques Hôpital Armand Trousseau bâtiment Lemariey porte 20

Paris, France

Hôpital des enfants

Toulouse, France, 31059

Germany

Universitätsmedizin Berlin Campus Virchow-Klinikum

Berlin, Germany, 13353

Universitätsklinikum Essen

Essen, Germany, 45147

Universitätsklinik Freiburg Zentrum für Kinderheilkunde und Jugendmedizin

Freiburg, Germany

Universitätsklinikum Hamburg-Eppendorf, Klinik für Kinder- und Jugendmedizin

Hamburg, Germany, 20246

Universitätsklinikum Heidelberg Zentrum für Kinder- und Jugendmedizin

Heidelberg, Germany

Uniklinik Köln

Köln, Germany, 50937

Zentrum für neuromuskuläre Erkrankungen

München, Germany

Hungary

Semmelweis University 2nd Department of Paediatrics

Budapest, Hungary

Ireland

Children's University Hospital

Dublin, Ireland, 1

Israel

Institute of Neurology at Schneider Children's Medical Center of Israel

Petah Tiqva, Israel, 4920235

Italy

Fondazione IRCCS Eugenio Medea

Bosisio Parini, Italy, 23842

Istituto Giannina Gaslini

Genova, Italy, 16147

Scientific Coordinator Nemo Sud Clinical Center

Messina, Italy, 98125

Centro Clinico NEMO (NEuroMuscular Omnicentre), Niguarda Hospital

Milano, Italy

Servizio di Cardiomiologia e Genetica Medica, AOU Università degli Studi della Campania "Luigi Vanvitelli"

Napoli, Italy, 80131

Reparto Di Neurologia dell'Osperdale Di Padova

Padova, Italy, 35122

Dipartimento di Clinica Neurologica e Psichiatrica dell'Età Evolutiva della Fondazione IRCCS "C. Mondino" di Pavia

Pavia, Italy, 27100

U.O.C. Neuropsichiatria Infantile

Roma, Italy, 00168

Netherlands

LUMC

Leiden, Netherlands

Radboud university medical centre

Nijmegen, Netherlands, 6500

Spain

Hospital Sant Joan de Déu Neuropediatra

Barcelona, Spain, 08950

Hospital Universitari Vall D' Hebron

Barcelona, Spain, 8950

Hospital Universitario La Paz

Madrid, Spain, 28046

Hospital Universitario Virgen del Rocio

Sevilla, Spain, 41013

Hospital La Fe de Valencia

Valencia, Spain, 106 46026

Sweden

Sahlgrenska University Hospital

Gothenburg, Sweden

Switzerland

Center for neuromuscular disorders, Universitäts-Kinderspital beider Basel (UKBB)

Basel, Switzerland, 4301

United Kingdom

Leeds Teaching Hospital NHS Trust

Leeds, United Kingdom, LS1 3EX

UCL, National Hospital for Neurology and Neurosurgery

London, United Kingdom, WC1 3BG

Great Ormond Street Hospital for Children

London, United Kingdom, WC1N 3JH

John Walton Muscular Dystrophy Research Centre

Newcastle, United Kingdom

Robert Jones and Agnes Hunt Orthopaedic Hospital

Oswestry, United Kingdom, SY10 7AG

Oxford University hospitals NHS Foundation Trust

Oxford, United Kingdom, OX39DU

Royal Hallamshire Hospital

Sheffield, United Kingdom, S10 2JF

Sponsors and Collaborators

Santhera Pharmaceuticals

More Information

Publications:

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.

McDonald CM, Meier T, Voit T, Schara U, Straathof CS, D'Angelo MG, Bernert G, Cuisset JM, Finkel RS, Goemans N, Rummey C, Leinonen M, Spagnolo P, Buyse GM; DELOS Study Group. Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy. Neuromuscul Disord. 2016 Aug;26(8):473-80. doi: 10.1016/j.nmd.2016.05.008. Epub 2016 May 12.

Buyse GM, Voit T, Schara U, Straathof CS, D'Angelo MG, Bernert G, Cuisset JM, Finkel RS, Goemans N, Rummey C, Leinonen M, Mayer OH, Spagnolo P, Meier T, McDonald CM; DELOS Study Group. Treatment effect of idebenone on inspiratory function in patients with Duchenne muscular dystrophy. Pediatr Pulmonol. 2017 Apr;52(4):508-515. doi: 10.1002/ppul.23547. Epub 2016 Aug 29.

• Responsible Party: Santhera Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02814019
• Other Study ID Numbers: SNT-III-012
• First Posted: June 27, 2016
• Last Update Posted: December 3, 2021
• Last Verified: November 2021

Keywords provided by Santhera Pharmaceuticals:

respiratory function in DMD

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