Clinical Trials Register

Summary
EudraCT Number:	2015-004405-16
Sponsor's Protocol Code Number:	SNT-IV-005
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-03-18
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

2015-004405-16

A.3

Full title of the trial

External Natural History Controlled, open-Label Intervention Study to Assess the Efficacy and Safety of Long-Term Treatment with Raxone® in Leber?s Hereditary Optic Neuropathy (LHON)

Estudio de intervención abierto controlado por grupo de evolución natural externo para evaluar la eficacia y la seguridad del tratamiento prolongado con Raxone® en la neuropatía óptica hereditaria de Leber (NOHL)

A.3.1

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

Clinical study to assess the effectiveness and safety of Raxone during long time treatment in patients with LHON

Estudio clinico para evaluar la efectividad y la seguridad con Raxone durante el tratamiento prolongado en pacientes con NOHL.

A.3.2

Name or abbreviated title of the trial where available

(LEROS) Open- Label Study to assess the Efficacy and Safety of Raxone in LHON Patients

(LEROS) Estudio abierto para evaluar la eficacia y seguridad de Raxone en NOHL

A.4.1

Sponsor's protocol code number

SNT-IV-005

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
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) Ltd
B.5.2	Functional name of contact point	Medical Affairs Director
B.5.3	Address:
B.5.3.1	Street Address	Via I. Rosellini 12
B.5.3.2	Town/ city	Milan
B.5.3.3	Post code	20124
B.5.3.4	Country	Italy
B.5.4	Telephone number	34686 935 930
B.5.6	E-mail	Xavier.Lloria@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/3/07/434
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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Leber?s Hereditary Optic Neuropathy / LHON is a maternally inherited loss of vision due to atrophy of the optic nerve. It typically presents in young adults, mostly men, as painless acute or subacute visual failure of both eyes in quick succession. The estimated prevalence is approximately 2.2 per 100,000 (Mascialino et al., 2012) and LHON is thus an Orphan Disease according to EU and US criteria.

La NOHL consiste en una pérdida de visión heredada por vía materna que se debe a una atrofia del nervio óptico. Normalmente se presenta en adultos jóvenes, principalmente varones, como pérdida visual aguda o subaguda indolora de ambos ojos en rápida sucesión. La prevalencia estimada es de aproximadamente el 2,2 por 100 000 (Mascialino et al., 2012), por lo que la NOHL es una enfermedad rara según los criterios de la UE y los EE. UU.

E.1.1.1

Medical condition in easily understood language

Raxone is a medicine used to treat Leber?s hereditary optic neuropathy (LHON), a rare hereditary disease that can lead to blindness.

Raxone es un medicamento utilizado para tratar la neuropatía óptica hereditaria de Leber (NOHL), una enfermedad hereditaria rara que puede conducir a la ceguera.

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10062951
E.1.2	Term	Leber's hereditary optic atrophy neuropathy
E.1.2	System Organ Class	100000004850

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 efficacy of Raxone® in the promotion of recovery or stabilization of visual acuity in patients treated with Raxone® ?1 year after the onset of symptoms, compared to an external natural history control group of idebenone naïve patients

Evaluar la eficacia de Raxone® en la estimulación de la recuperación o estabilización de la agudeza visual en pacientes tratados con Raxone® ? 1 año después de la aparición de los síntomas, en comparación con un grupo de control de evolución natural externo de pacientes no tratados anteriormente con idebenona.

E.2.2

Secondary objectives of the trial

? To assess efficacy of Raxone® in the promotion of recovery or stabilization of vision in LHON patients treated with Raxone® >1 year after the onset of symptoms, compared to an external natural history control group of idebenone naïve patients
? To compare the promotion of recovery or stabilization of visual acuity in LHON patients treated with Raxone® ?1 and >1 year after the onset of symptoms
? To assess the influence of mutation on the promotion of recovery or stabilization of visual acuity in LHON patients treated with Raxone®
? To assess the influence of time since onset of symptoms prior to the initiation of treatment with Raxone® on the promotion of recovery or stabilization of visual acuity in LHON patients
? To assess the influence of duration of treatment with Raxone® on changes in visual acuity in LHON patients
? To assess safety of long-term treatment of LHON patients with Raxone®

? Evaluar la eficacia de Raxone® en la estimulación de la recuperación o estabilización de la visión en pacientes con NOHL tratados con Raxone® > 1 año después de la aparición de los síntomas, en comparación con un grupo de control de evolución natural externo de pacientes que no han recibido tratamiento anteriormente con idebenona. /Comparar la estimulación de la recuperación o estabilización de la agudeza visual en pacientes con NOHL tratados con Raxone® ? 1 y > 1 año después de la aparición de los síntomas. /Evaluar la influencia de la mutación en la estimulación de la recuperación o estabilización de la agudeza visual en pacientes con NOHL tratados con Raxone®. /Evaluar la influencia del tiempo desde la aparición de los síntomas antes del inicio del tratamiento con Raxone® sobre la estimulación de la recuperación o estabilización de la agudeza visual en pacientes con NOHL. /Por favor ver la sección ¨Criterios de valoración secundarios¨de la synopsis para ver los puntos no incluidos

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

The following criteria should be assessed during Baseline Visit before randomization. If any does not apply, the patient must not be included in the study:
1. Impaired visual acuity in affected eyes due to LHON
2. No explanation for visual loss besides LHON
3. Age?12 years
4. Onset of symptoms ?5 years prior to Baseline
5. Confirmation of either G11778A, G3460A or T14484C LHON mtDNA (for the ITT population, not required for enrolment)
6. Written informed consent obtained from the patient
7. Ability and willingness to comply with study procedures and visits
8. Women of Childbearing Potential (WCBP) who have a negative urine or serum pregnancy test at Baseline visit and who are willing to use a highly effective contraceptive measure and maintain it until treatment discontinuation

Se deben evaluar los siguientes criterios durante la visita inicial antes de la aleatorización. Si no se cumple alguno de ellos, no se deberá incluir al paciente en el estudio:
1. Deterioro de la agudeza visual en los ojos afectados por la NOHL
2. Pérdida de visión que no se explica por otra causa aparte de la NOHL
3. Edad +o=12 años
4. Inicio de los síntomas ? 5 años antes del inicio del estudio
5. Confirmación de la mutación en el ADNmt de NOHL G11778A, G3460A o T14484C
(para la población ITT, no es necesario para la inscripción)
6. Consentimiento informado por escrito obtenido del paciente
7. Capacidad y disposición a cumplir los procedimientos y las visitas del estudio
8. Mujeres en edad fértil (MEF) que tengan una prueba de embarazo en orina o en suero negativa en la visita inicial y que estén dispuestas a utilizar un método anticonceptivo altamente eficaz y mantenerlo hasta la interrupción del tratamiento

E.4

Principal exclusion criteria

The following criteria should be checked during Baseline Visit before randomization. If any applies, the patient must not be included in the study:
1. Patient has provided natural history data to the Case Record Survey (SNT-CRS-002)
2. Any previous use of idebenone
3. Any other cause of visual impairment (e.g. glaucoma, diabetic retinopathy, AIDS related visual impairment, cataract, macular degeneration, etc.) or any active ocular disorder (uveitis, infections, inflammatory retinal disease, thyroid eye disease, etc.)
4. Known history of clinically significant elevations (greater than 3 times the upper limit of normal) of AST, ALT or creatinine
5. Patient has a condition or is in a situation which, in an investigator?s opinion may put the patient at significant risk, may confound study results or may interfere significantly with the patient?s participation in the study
6. Participation in another clinical trial of any investigational drug within 3 months prior to Baseline
7. Hypersensitivity to the active substance or to any of the following excipients (as listed in section 6.1 of Raxone SmPC): Lactose monohydrate, Microcrystalline cellulose, Croscarmellose sodium, Povidone K25, Magnesium stearate, Colloidal silica, Macrogol 3350, Poly(vinyl alcohol), Talc, Titanium dioxide, Sunset yellow FCF (E110).
8. Women who are pregnant or have a positive pregnancy test at Baseline visit
9. Women who are breastfeeding

Se deben comprobar los siguientes criterios durante la visita inicial antes de la aleatorización. Si alguno se cumple, no se deberá incluir al paciente en el estudio:
1. El paciente ha proporcionado datos de evolución natural para el estudio de registro de casos (SNT-CRS-002).
2. Cualquier uso previo de idebenona.
3. Cualquier otra causa de deficiencia visual (p. ej., glaucoma, retinopatía diabética, deficiencia visual relacionada con el SIDA, cataratas, degeneración macular, etc.) o cualquier trastorno ocular activo (uveítis, infecciones, enfermedad inflamatoria de la retina, enfermedad de Graves, etc.).
4. Antecedentes conocidos de elevaciones clínicamente significativas (superiores a tres veces el límite superior de la normalidad) de AST, ALT o creatinina.
5. El paciente tiene una afección o está en una situación que, en opinión del investigador, puede ponerle en riesgo importante, puede confundir los resultados del estudio o puede interferir de forma significativa con la participación del paciente en el estudio.
6. Participación en otro ensayo clínico de cualquier fármaco en investigación en los tres meses previos al inicio del estudio.
7. Hipersensibilidad al principio activo o a alguno de los excipientes siguientes (que se enumeran en la sección 6.1 del RCP de Raxone): lactosa monohidrato, celulosa microcristalina, croscarmelosa sódica, povidona K25, estearato de magnesio, sílice coloidal, macrogol 3350, alcohol poli(vinílico), talco, dióxido de titanio, amarillo anaranjado FCF (E110).
8. Mujeres embarazadas o que tienen una prueba de embarazo positiva en la visita inicial
9. Mujeres en periodo de lactancia

E.5 End points

E.5.1

Primary end point(s)

Proportion of eyes with clinically relevant recovery of VA from Baseline or in which Baseline VA better than 1.0 logMAR was maintained at Month 12 in patients treated with Raxone® ?1 year after the onset of symptoms, compared to matching external natural history control group
Clinically Relevant Recovery (CRR) is defined as a change from ?off-chart? visual acuity (VA) to at least 1.6 logMAR value or an improvement of at least 0.2 logMAR value within ?on-chart?.

Proporción de ojos con recuperación clínicamente relevante de la AV con respecto al valor inicial o en los que la AV inicial mejor de 1,0 logMAR se mantenía en el mes 12 en los pacientes tratados con Raxone® ? 1 año después de la aparición de los síntomas, en comparación con el grupo de control de evolución natural externo correspondiente.
La recuperación clínicamente relevante (RCR) se define como un cambio en la agudeza visual (AV) ?sin optotipo? hasta al menos un valor de 1,6 logMAR o una mejora de al menos un valor de 0,2 logMAR ?con optotipo?.

E.5.1.1

Timepoint(s) of evaluation of this end point

see E.5.1 text

Ver el texto E.5.1

E.5.2

Secondary end point(s)

? Components of the primary endpoint:
- Proportion of eyes with CRR of VA from Baseline at Month 12 compared to matching external natural history control group
- Proportion of eyes in which Baseline VA better than 1.0 logMAR was maintained at Month 12 compared to matching external natural history control group
? Proportion of eyes in patients treated with Raxone® >1 year after the onset of symptoms with CRR of VA from Baseline or in which Baseline VA better than 1.0 logMAR was maintained at Month 12 compared to external natural history control group, in all patients and classified by mutation
? Proportion of eyes and patients treated with Raxone® ?1 year after the onset of symptoms with CRR of VA from Baseline or in which Baseline visual acuity better than 1.0 logMAR was maintained following 6, 18 and 24 months of treatment with Raxone® compared to matching external natural history control group, in all patients and classified by mutation
? Proportion of eyes/patients treated with Raxone® ?1 year or >1 year after the onset of symptoms with ?Off-chart? VA at Baseline in whom VA improves to better than 1.60 logMAR by Month 6, 12, 18 and 24
? Proportion of eyes/patients treated with Raxone® ?1 year or >1 year after the onset of symptoms with VA in the categories of better than 1.0 logMAR, 1.0 to 1.68 logMAR and above 1.68 logMAR at each assessment time point up to Month 24
? Safety as assessed by AE count and laboratory analyses during the study

? Componentes del criterio de valoración principal:
- Proporción de ojos con RCR de la AV respecto al valor inicial en el mes 12 en comparación con el grupo de control de evolución natural externo correspondiente.
- Proporción de ojos en los que la AV inicial mejor de 1,0 logMAR se mantenía en el mes 12 en comparación con el grupo de control de evolución natural externo correspondiente.
? Proporción de ojos en pacientes tratados con Raxone® > 1 año después de la aparición de los síntomas con RCR de la AV respecto al valor inicial o en los que la AV inicial mejor de 1,0 logMAR se mantenía en el mes 12 en comparación con el grupo de control de evolución natural externo, en todos los pacientes y clasificados por mutación.
? Proporción de ojos y pacientes tratados con Raxone® ?1 año después de la aparición de los síntomas con RCR de la AV respecto al valor inicial o en los que la agudeza visual inicial mejor de 1,0 logMAR se mantenía después de 6, 18 y 24 meses de tratamiento con Raxone® en comparación con el grupo de control de evolución natural externo, en todos los pacientes y clasificados por mutación.
? Proporción de ojos/pacientes tratados con Raxone® ? 1 o > 1 año después de la aparición de los síntomas con AV ?sin optotipo? al inicio del estudio en los que la AV mejora hasta un valor mejor de 1,60 logMAR en los meses 6, 12, 18 y 24.
? Proporción de ojos/pacientes tratados con Raxone® ? 1 o > 1 año después de la aparición de los síntomas con AV en las categorías de mejor de 1,0 logMAR, de 1,0 a 1,68 logMAR y por encima de 1,68 logMAR en cada punto temporal de evaluación hasta el mes 24.
? Seguridad evaluada mediante el recuento de AA y pruebas analíticas durante el estudio.

E.5.2.1

Timepoint(s) of evaluation of this end point

see E.5.2 text

Ver el texto E.5.1

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

E.8.2.3

Other

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

last visit of the last subject undergoing the trial

ultima visita del último paciente en el estudio

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

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)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

188

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

Yes

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

Yes

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

Paediatric population

Población Pediatrica

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

250

F.4.2.2

In the whole clinical trial

250

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)

At the end of the study, in countries where the drug will not be at that time available on the market, every effort will be made to assure continued access to Raxone® to the patients who derived and are still deriving a benefit from treatment administration. Where required and according to the local specific regulation, special access programmes (e.g. Named Patient Programs (NPP)) may be put in place.

Al final del estudio, en países en los que el fármaco no estará disponible en el mercado en ese momento, se hará todo lo posible por garantizar el acceso continuado a Raxone® a los pacientes que hayan obtenido y sigan obteniendo un beneficio de la administración del tratamiento. Cuando sea necesario, y según la normativa local específica, se pueden poner en práctica programas de acceso especiales (p. ej., programas para pacientes concretos, [Named Patient Programs, NPP]).

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

2016-05-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-03-29

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