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

Duchenne Muscular Dystrophy (DMD) Clinical Trial

— SIDEROS  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02814019
• Other study ID #: SNT-III-012
• Status: Terminated
• Phase: Phase 3
• Start date: September 2016
• Est. completion date: December 1, 2020

Study information

• Verified date: November 2021
• Source: Santhera Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 255
• Est. completion date: December 1, 2020
• Est. primary completion date: December 1, 2020
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 10 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Duchenne Muscular Dystrophy (DMD)
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

Drug:
• Idebenone 150 mg film-coated tablets

• placebo

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Santhera Pharmaceuticals

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Bulgaria,  France,  Germany,  Hungary,  Ireland,  Israel,  Italy,  Netherlands,  Spain,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Forced Vital Capacity percent predicted (FVC %p) at Week 78	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.	78 weeks
Secondary	Change From Baseline in Percent Predicted Peak Expiratory Flow (PEF %p) at Week 78	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	78 weeks
Secondary	Change From Baseline in Forced Vital Capacity (FVC) at Week 78	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	78 weeks
Secondary	Change from Baseline in Inspiratory Flow Reserve (IFR) at Week 78	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	78 weeks

External Links

•   https://www.siderosdmd.com/