Clinical Trials Register

Summary
EudraCT Number:	2016-000602-10
Sponsor's Protocol Code Number:	SNT-III-012
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-11-18
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

Spain - AEMPS

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

Estudio de fase III, doble ciego, aleatorizado y controlado con placebo para
evaluar la eficacia, la seguridad y la tolerabilidad de idebenona en pacientes
con distrofia muscular de Duchenne que reciben glucocorticoesteroides

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.5.4

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 (Switzerland) Limited
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	+4161906 8938
B.5.5	Fax number	+41619068951
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
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	European Union
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.3.1	Product name	Idebenone
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	Oral use
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.3.9.3	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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

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 muscular de Duchenne (DMD)

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

La DMD es una enfermedad genética caracterizada por debilidad muscular y pérdida de peso rápidamente progresiva que conduce a una discapacidad severa

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	19.0
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

Evaluar la eficacia de idebenona en comparación con placebo, en la
ralentización de la pérdida de la función respiratoria en pacientes con
DMD que reciben glucocorticoesteroides medida por los cambios en
el porcentaje previsto de la capacidad vital forzada (FVC %p) con
espirometría realizada en el hospital.

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

Evaluar la eficacia de idebenona en comparación con placebo en
la ralentización de la pérdida de la función respiratoria en pacientes
con DMD que reciben glucocorticoesteroides medida por:
 Los cambios en el porcentaje previsto en el flujo espiratorio
máximo (PEF %p) con una espirometría realizada en el hospital.
 El tiempo transcurrido hasta la pérdida del 10 % del valor inicial
de la capacidad vital forzada (FVC).
 Evaluar la eficacia de idebenona en comparación con placebo en
la ralentización de la pérdida de la función del músculo
inspiratorio medida por los cambios en la reserva de flujo
inspiratorio (IFR) con una espirometría realizada en el hospital.

E.2.3

Trial contains a sub-study

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. Pacientes varones con un 30 % ≤ FVC ≤ 80 % del valor previsto en
la vista de selección y en la visita inicial.
2. Mínimo 10 años de edad en el momento de la selección
3. Formulario de consentimiento informado firmado y fechado.
4. Diagnóstico documentado de DMD (distrofinopatía grave) y
características clínicas coherentes con el diagnóstico típico de la
DMD, es decir, habilidades motrices ralentizadas y debilidad
muscular a la edad de 5 años. Confirmación de la MDM mediante el
análisis de mutaciones en el gen de la distrofina o mediante niveles
sustancialmente reducidos de la proteína distrofina (es decir,
ausente o < 5 % de lo normal) obtenidos con análisis de Western
blot o por inmunotinción.
5. Uso crónico de glucocorticoesteroides sistémicos para las
afecciones relacionadas con la DMD durante al menos 12 meses
antes de la visita inicial sin ajustes de la dosis basados en mg/kg en
los últimos 6 meses (solo se permite el ajuste de la dosis
determinado por los cambios en el peso).
6. Habilidad para proporcionar una FVC de forma repetida, fiable y
reproducible dentro del 15 % obtenido en la evaluación de
selección en la visita inicial.
7. Pacientes evaluados por el investigador y que se consideren
con voluntad y capacidad para cumplir con los requisitos del
estudio, que tengan las habilidades cognitivas necesarias y que
puedan tragar la medicación del estudio.
8. Pacientes que hayan recibido la vacuna antineumocócica
polisacárida 23-valente o cualquier otra antineumococia
polisacarida equivalente según recomendaciones nacionales y
que además reciban la vacuna anual inactivada contra la gripe.

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 study .
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. Insuficiencia cardíaca sintomática (según la clasificación de la
ACC/AHA estadio C o de grado III-IV según la NYHA) o arritmias
ventriculares sintomáticas.
2. Estar participando en otro ensayo terapéutico o estar tomando
otro fármaco en fase de investigación durante los 90 días previos
a la visita inicial (la única excepción es el uso de deflazacort en
los EE. UU. como parte del programa de acceso ampliado).
3. Omisión de exón o terapia de lectura génica previa o en curso
para la DMD.
4. Cirugía de fijación de la columna vertebral prevista o planificada
durante el periodo del estudio (según el criterio del investigador, es
decir, debido a una escoliosis de progresión rápida), pero se permite
la cirugía previa de fijación de la columna vertebral si se ha
realizado más de 6 meses antes de la selección.
5. Asma, bronquitis/EPOC, bronquiectasia, enfisema, neumonía
o presencia de otras enfermedades respiratorias no
relacionadas con la DMD que afecten a la función
respiratoria.
6. Uso crónico de agonistas beta 2 o el uso de otra medicación
broncodilatadora/broncoconstrictora (esteroides inhalados,
simpaticomiméticos, anticolinérgicos, antihistaminas). El uso crónico
se define como la toma diaria durante más de 14 días.
7. Enfermedades broncopulmonares que requieran tratamiento
con antibióticos durante los 3 meses previos a la selección.
8. Insuficiencia hepática moderada o grave (Child-Pugh clase B [de 7 a
9 puntos] o Child-Pugh clase C [de 10 a 15 puntos]) o insuficiencia
renal grave (eGFR <30 ml/min/1,73 m2).
9. Afección médica previa o en curso o anomalía de laboratorio que,
según la opinión del investigador, pueda poner en grave riesgo al
paciente, confundir los resultados del estudio o interferir de modo
significativo en la participación del paciente en el estudio1.
10. Antecedentes o adicción actual a las drogas, al alcohol, al
tabaco o al consumo de marihuana.
11. Hipersensibilidad individual conocida a idebenona o a alguno de los
componentes/excipientes de la medicación del estudio.
12. Asistencia ventilatoria diurna (definida como cualquier tipo de
ventilación

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

El cambio desde la visita inicial hasta la semana 78 en el FVC %p
evaluado con las mediciones de la espirometría realizada en el
hospital.

E.5.1.1

Timepoint(s) of evaluation of this end point

78 weeks

78 semanas

E.5.2

Secondary end point(s)

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

Los criterios de valoración secundarios se evaluarán en el siguiente orden
jerárquico:
 El cambio desde la visita inicial hasta la semana 78 en el PEF %p
evaluado con las mediciones de la espirometría realizada en el
hospital.
 El tiempo transcurrido hasta el primer deterioro del 10 % en la
FVC (l) durante el periodo de tratamiento de 78 semanas,
evaluado con las mediciones de la espirometría realizada en el
hospital.
 El cambio desde la visita inicial hasta la semana 78 en la IFR
evaluado con las mediciones de la espirometría realizada en el
hospital.

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

Criterio de valoración secundario 1: 78 semanas
Criterio de valoración secundario 2: 13, 26, 39, 52, 65 y 78 semanas
Criterio de valoración secundario 3: 78 semanas

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

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

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 months

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:

266

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)

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 SIDEROS-E 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

2016-12-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-12-02

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-10-05

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