Clinical trial NCT02814019: A Phase III Double-blind Study With Idebenone in Patients With Duchenne Muscular Dystrophy (DMD) Taking Glucocorticoid Steroids
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Duchenne Muscular Dystrophy (DMD)
Keywords: respiratory function in DMD
Lead sponsor: Santhera Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2016-06-27
Enrollment: 255
Sex: MALE
Minimum age (years): 10
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility 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.

Primary outcomes:
measure: Change From Baseline in Forced Vital Capacity percent predicted (FVC %p) at Week 78
timeFrame: 78 weeks
Secondary outcomes:
measure: Change From Baseline in Percent Predicted Peak Expiratory Flow (PEF %p) at Week 78
timeFrame: 78 weeks
measure: Change From Baseline in Forced Vital Capacity (FVC) at Week 78
timeFrame: 78 weeks
measure: Change from Baseline in Inspiratory Flow Reserve (IFR) at Week 78
timeFrame: 78 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Tucson
country: United States
facility: Banner University of Arizona Medical Center
state: Arizona
city: Los Angeles
country: United States
facility: Childrens Hospital of Los Angeles
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA
state: California
city: Sacramento
country: United States
facility: UC Davis Department of Physical Medicine and Rehabilitation
state: California
city: San Bernardino
country: United States
facility: Loma Linda University Healthcare
state: California
city: Tampa
country: United States
facility: Shriners Hospitals for Children-Tampa
state: Florida
city: Atlanta
country: United States
facility: Rare Disease Research
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Fairway
country: United States
facility: University of Kansas
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Saint Paul
country: United States
facility: Gillette Children's Specialty Healthcare
state: Minnesota
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Charlotte
country: United States
facility: Neurosciences Institute, Neurology - Charlotte Carolinas Healthcare System
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Wien
country: Austria
facility: Gottfried von Preyer'sches Kinderspital
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Liège
country: Belgium
facility: Centre de Référence Neuromusculaire, CHR Citadelle
city: Sofia
country: Bulgaria
facility: Sofia Medical University
city: Lille
country: France
facility: Service de neuropédiatrie Pôle Pédiatrie CHRU de Lille - Hôpital Jeanne de Flandre
city: Montpellier
country: France
facility: CHRU de Montpellier - Hôpital Gui de Chauliac
city: Nantes
country: France
facility: Hôpital Hôtel Dieu
city: Paris
country: France
facility: I-Motion - Plateforme d'essais cliniques pédiatriques Hôpital Armand Trousseau bâtiment Lemariey porte 20
city: Toulouse
country: France
facility: Hôpital des enfants
city: Berlin
country: Germany
facility: Universitätsmedizin Berlin Campus Virchow-Klinikum
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Freiburg
country: Germany
facility: Universitätsklinik Freiburg Zentrum für Kinderheilkunde und Jugendmedizin
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf, Klinik für Kinder- und Jugendmedizin
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg Zentrum für Kinder- und Jugendmedizin
city: Köln
country: Germany
facility: Uniklinik Köln
city: München
country: Germany
facility: Zentrum für neuromuskuläre Erkrankungen
city: Budapest
country: Hungary
facility: Semmelweis University 2nd Department of Paediatrics
city: Dublin
country: Ireland
facility: Children's University Hospital
city: Petah Tiqva
country: Israel
facility: Institute of Neurology at Schneider Children's Medical Center of Israel
city: Bosisio Parini
country: Italy
facility: Fondazione IRCCS Eugenio Medea
city: Genova
country: Italy
facility: Istituto Giannina Gaslini
city: Messina
country: Italy
facility: Scientific Coordinator Nemo Sud Clinical Center
city: Milano
country: Italy
facility: Centro Clinico NEMO (NEuroMuscular Omnicentre), Niguarda Hospital
city: Napoli
country: Italy
facility: Servizio di Cardiomiologia e Genetica Medica, AOU Università degli Studi della Campania "Luigi Vanvitelli"
city: Padova
country: Italy
facility: Reparto Di Neurologia dell'Osperdale Di Padova
city: Pavia
country: Italy
facility: Dipartimento di Clinica Neurologica e Psichiatrica dell'Età Evolutiva della Fondazione IRCCS "C. Mondino" di Pavia
city: Roma
country: Italy
facility: U.O.C. Neuropsichiatria Infantile
city: Leiden
country: Netherlands
facility: LUMC
city: Nijmegen
country: Netherlands
facility: Radboud university medical centre
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Déu Neuropediatra
city: Barcelona
country: Spain
facility: Hospital Universitari Vall D' Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital La Fe de Valencia
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Basel
country: Switzerland
facility: Center for neuromuscular disorders, Universitäts-Kinderspital beider Basel (UKBB)
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospital NHS Trust
city: London
country: United Kingdom
facility: UCL, National Hospital for Neurology and Neurosurgery
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
city: Newcastle
country: United Kingdom
facility: John Walton Muscular Dystrophy Research Centre
city: Oswestry
country: United Kingdom
facility: Robert Jones and Agnes Hunt Orthopaedic Hospital
city: Oxford
country: United Kingdom
facility: Oxford University hospitals NHS Foundation Trust
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
Study officials:
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: 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.
citation: 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.