Clinical Trials Register

Summary
EudraCT Number:	2016-000602-10
Sponsor's Protocol Code Number:	SNT-III-012
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-02-06
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-000602-10

A.3

Full title of the trial

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

Studio di fase III, randomizzato, in doppio cieco, controllato con placebo per valutare l'efficacia, la sicurezza e la tollerabilità di idebenone in pazienti affetti da distrofia muscolare di Duchenne (DMD) che assumono glucocorticosteroidi

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A clinical study to assess how effective and safe is idebenone treatment in
patients with Duchenne Muscular Dystrophy (DMD) who are currently
receiving Glucocorticoid steroids

A.3.2

Name or abbreviated title of the trial where available

SIDEROS

A.4.1

Sponsor's protocol code number

SNT-III-012

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02814019

A.5.4

Other Identifiers

Name:

US IND

Number:

103801

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	SANTHERA PHARMACEUTICALS
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Santhera Pharmaceuticals (Switzerland) Limited
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Santhera Pharmaceuticals (Switzerland) Limited
B.5.2	Functional name of contact point	Irina Coserea
B.5.3	Address:
B.5.3.1	Street Address	Hammerstrasse 49
B.5.3.2	Town/ city	Liestal
B.5.3.3	Post code	CH-4410
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41 61 906 8938
B.5.5	Fax number	+41 61 9068951
B.5.6	E-mail	Irina.Coserea@santhera.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	RAXONE - 150 MG- COMPRESSE RIVESTITE CON FILM- USO ORALE- FLACONE (HDPE)- 180 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	SANTHERA PHARMACEUTICALS (DEUTSCHLAND) GMBH
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/07/437
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IDEBENONE
D.3.9.1	CAS number	58186-27-9
D.3.9.2	Current sponsor code	IDEBENONE
D.3.9.3	Other descriptive name	IDEBENONE
D.3.9.4	EV Substance Code	SUB08114MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Duchenne Muscular Dystrophy (DMD)

Distrofia muscolare di Duchenne

E.1.1.1

Medical condition in easily understood language

DMD is a genetic disease characterised by rapidly progressive muscle
weakness and wasting which leads to severe disability

Distrofia muscolare di Duchenne

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10013801
E.1.2	Term	Duchenne muscular dystrophy
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of idebenone compared to placebo, in delaying
the loss of respiratory function in patients with DMD receiving
glucocorticoid steroids as measured by changes in Forced Vital Capacity
percent predicted (FVC %p) using hospital-based spirometry

• Valutare l'efficacia di idebenone rispetto al placebo nel rallentamento della perdita di funzionalità respiratoria in pazienti con DMD che assumono glucocorticosteroidi, misurata in base alle variazioni del valore percentuale atteso della capacità vitale forzata (FVC %p) mediante spirometria ambulatoriale.

E.2.2

Secondary objectives of the trial

 To assess the efficacy of idebenone compared to placebo in delaying
the loss of respiratory function in patients with DMD receiving
glucocorticoid steroids as measured by:
 Changes in Peak Expiratory Flow percent predicted (PEF %p) using
hospital-based spirometry
 Time to loss of 10% of Baseline Forced Vital Capacity (FVC) using
hospital-based spirometry
 To assess the efficacy of idebenone compared to placebo in delaying
the loss of inspiratory muscle function as measured by changes in
Inspiratory Flow Reserve (IFR) using hospital-based spirometry

• Valutare l'efficacia di idebenone rispetto al placebo nel rallentare la perdita di funzionalità respiratoria in pazienti con DMD che assumono glucocorticosteroidi, misurata in base a:

• Variazione della percentuale prevista del picco di flusso espiratorio (PEF %p) valutata mediante spirometria ambulatoriale

• Tempo trascorso fino alla perdita del 10% della capacità vitale forzata (FVC) alla Baseline, misurato mediante spirometria ambulatoriale

• Valutare l’efficacia di idebenone rispetto al placebo nel rallentare la perdita di funzione dei muscoli inspiratori, misurata in base alle variazioni della riserva di flusso inspiratorio (IFR) mediante spirometria ambulatoriale.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

SIDEROS PK SUB STUDY, V0.1, 20Jul2016, To establish the pharmacokinetic profile of idebenone and its metabolites when taken at a dose of 300mg t.i.d in paediatric and adult patients with Duchenne Muscular Dystrophy (DMD) taking glucocorticoid steroids as concomitant therapy

SIDEROS PK SOTTOSTUDIO, V0.1, 20Jul2016, Per stabilire il profilo farmacocinetico dell'idebenone e dei suoi metaboliti assunto alla dose di 300 mg t.i.d in pazienti pediatrici e adulti affetti da distrofia muscolare di Duchenne (DMD) in terapia concomitante con steroidi glucocorticoidi

E.3

Principal inclusion criteria

1. Male patients with a 30% ≤ FVC ≤ 80% of predicted value at
Screening and at Baseline.
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 adjustment determined by weight
changes are allowed).
6. Ability to provide reliable and reproducible repeat FVC within
15% of the screening assessment at Baseline.
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 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.

1. Pazienti maschi con 30% ≤ FVC ≤ 80% di valore predetto allo Screening e alla Baseline.
2. minimo 10 anni di età allo screening

3. Modulo di Consento informato datato e firmato.

4. Diagnosi documentata di DMD (distrofinopatia grave) e segni clinici coerenti con DMD tipica alla diagnosi (vale a dire, ritardo motorio e debolezza muscolare documentati a insorgenza entro il quinto anno di età). La DMD deve essere confermata mediante analisi mutazionale del gene della distrofina o da livelli significativamente ridotti di proteina distrofina (vale a dire, assente o <5% rispetto alla norma) su Western blot o immunocolorazione.

5. Uso cronico di glucocorticosteroidi per via sistemica per il trattamento continuativo di condizioni associate a DMD per almeno 12 mesi prima della Baseline senza aggiustamenti posologici su base mg/kg negli ultimi 6 mesi (sono ammessi solo aggiustamenti posologici giustificati da variazioni ponderali).

6. Capacità di dimostrare ripetutamente una FVC affidabile e riproducibile entro il 15% della valutazione di screening alla Baseline.

7. Pazienti che a giudizio dello Sperimentatore siano interessati a partecipare allo studio e in grado di soddisfarne i requisiti, in possesso delle abilità cognitive richieste e in grado di ingerire il farmaco dello studio.

8. Pazienti che siano stati immunizzati con vaccino pneumococcico polisaccaridico 23 valente o qualsiasi altro vaccino pneumococcico polisaccaridico secondo le raccomandazioni nazionali e immunizzati annualmente con vaccino antinfluenzale inattivato (se il paziente ha almeno 6 mesi di età).

E.4

Principal exclusion criteria

1. Symptomatic heart failure (defined as Stage C by ACCF/AHA
guideline or NYHA 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 US
as part of the Expanded Access Program).
3. Prior or ongoing exon-skipping or read-through gene therapy
for DMD.
4. Planned or expected spinal fixation surgery during the study
period (as judged by the Investigator, i.e. due to rapidly
progressing scoliosis), prior spinal fixation 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, anti-cholinergics, 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 (Child-Pugh class B [7
to 9 points] or Child-Pugh class C [10 to 15 points]) or severe
renal impairment (eGFR <30 mL/min/1.73 m2).
9. Prior or ongoing medical condition or laboratory abnormality
which 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
study1.
10. History of or current drug or alcohol abuse or use of any
tobacco/marijuana products/smoking.
11. Known individual hypersensitivity to idebenone or to any of the
ingredients/excipients of the study medication.
12. Daytime ventilator assistance (defined as use of any assisted
ventilation while awake).

1. Insufficienza cardiaca sintomatica (inquadrabile nello Stadio C secondo la classificazione dell’ACCF/AHA o nello stadio III-IV secondo quella della NYHA) e/o aritmie ventricolari sintomatiche.

2. Partecipazione in corso ad altri trial terapeutici e/o assunzione di farmaci sperimentali di qualsiasi tipo nei 90 giorni precedenti alla Baseline (con la sola eccezione di Deflazacort negli USA nell’ambito del Programma di accesso allargato).

3. Terapia genica - precedente o in corso - basata su exon-skipping o read-through per il trattamento della DMD.

4. Intervento di fissazione vertebrale, programmato o atteso, durante il periodo dello studio (secondo la valutazione dello Sperimentatore, es., in presenza di scoliosi a rapida progressione); sono ammessi interventi di fissazione vertebrale purché effettuati almeno 6 mesi prima dello Screening.

5. Asma, bronchite/broncopneumopatia cronica ostruttiva, bronchiettasia, enfisema, polmonite o presenza di altre patologie respiratorie diverse dalla DMD che interessano la funzione respiratoria.

6. Uso cronico di beta2-agonisti o qualsiasi uso di altri farmaci broncodilatatori/broncocostrittori (steroidi per via inalatoria, simpaticomimetici, anticolinergici, antistaminici); l’uso cronico è definito come assunzione giornaliera per un periodo superiore a 14 giorni.

7. Patologie broncopolmonari che abbiano richiesto il trattamento con antibiotici nei 3 mesi precedenti allo Screening.

8. Insufficienza epatica da moderata a severa (rispettivamente in classe B [da 7 a 9 punti] o in classe C [da 10 a 15 punti] secondo la classificazione di Child-Pugh) o grave insufficienza renale (eGFR <30 mL/min/1,73 m2).

9. Condizione medica o valori di laboratorio anomali - precedenti o attuali - che, giudizio dello Sperimentatore, possano rappresentare un rischio significativo per il paziente, confondere i risultati dello studio o interferire in maniera sostanziale con la partecipazione del paziente allo studio1.
10. Storia di abuso o abuso attuale di sostanze stupefacenti o di alcolici o di qualsiasi prodotto a base di tabacco o marijuana o simili.

11. Ipersensibilità individuale nota a idebenone o a qualsiasi ingrediente/eccipiente del farmaco dello studio.

12. Assistenza ventilatoria durante il giorno (definita come ricorso a qualsiasi tipo di

E.5 End points

E.5.1

Primary end point(s)

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

• Variazione della FVC %p fra la Baseline e la Settimana 78, valutata mediante spirometria ambulatoriale

E.5.1.1

Timepoint(s) of evaluation of this end point

78 weeks

E.5.2

Secondary end point(s)

The secondary endpoints will be evaluated in the following order in a
hierarchical manner:
• The change from Baseline to Week 78 in PEF %p assessed by
hospital-based spirometry measurements
• The time to first 10% decline in FVC (L) during the 78-week
treatment period, assessed by hospital-based spirometry
measurements
• The change from Baseline to Week 78 in IFR assessed by
hospital-based spirometry measurements

Gli endpoint secondari saranno valutati gerarchicamente nell’ordine seguente:
• Variazione del PEF %p fra la Baseline e la Settimana 78, valutata mediante spirometria ambulatoriale

• Tempo trascorso fino al primo declino del 10% della FVC (L) durante il periodo di trattamento di 78 settimane, valutato mediante spirometria ambulatoriale

• Variazione dell’IFR fra la Baseline e la Settimana 78, valutata mediante spirometria ambulatoriale

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoint 1: 78 weeks
Secondary endpoint 2: 13, 26, 39, 52, 65 and 78 weeks
Secondary endpoint 3: 78 weeks

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

Belgium

France

Germany

Italy

Netherlands

Spain

Sweden

Switzerland

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

200

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

DMD is mainly diagnosed in the first decade of life and therefore
patients below the age of consent are expected to be enrolled into the
trial

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

130

F.4.2.2

In the whole clinical trial

266

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

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 the SIDEROSE
is terminated or Marketing Authorization is obtained for idebenone in
DMD, whichever occurs first.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-10-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-20

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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