Clinical Trials Register

Summary
EudraCT Number:	2017-004378-32
Sponsor's Protocol Code Number:	WN39434
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:	2018-05-28
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

2017-004378-32

A.3

Full title of the trial

A phase III, randomized, double-blind, placebo-controlled, efficacy, and safety study of Balovaptan in adults with Autism Spectrum Disorder with a 2 year open-label extension.

ESTUDIO DE FASE III, ALEATORIZADO, DOBLE CIEGO Y CONTROLADO CON PLACEBO PARA EVALUAR LA EFICACIA Y LA SEGURIDAD DE BALOVAPTÁN EN ADULTOS CON TRASTORNO DEL ESPECTRO AUTISTA CON UNA EXTENSIÓN ABIERTA DE DOS AÑOS

A.3.1

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

A Study to Evaluate Efficacy, and Safety of Balovaptan in Adults with Autism Spectrum Disorder with a 2 Year Open-Label Extension

Estudio para evaluar la eficacia y la seguridad de Balovaptan en adultos con trastorno del espectro autista con una extensión abierta de 2 años.

A.4.1

Sponsor's protocol code number

WN39434

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	Roche Farma S.A(Soc. Unipersonal) que realiza el ensayo en España y actúa como representante de F. Hoffmann-La Roche LTD
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	F. Hoffmann-La Roche Ltd
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	F. Hoffmann-La Roche Ltd
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+34913257300
B.5.6	E-mail	spain.start_up_unit@roche.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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Balovaptan
D.3.2	Product code	RO5285119
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	Balovaptan
D.3.9.2	Current sponsor code	RO5285119
D.3.9.3	Other descriptive name	v1a(2)
D.3.9.4	EV Substance Code	SUB32013
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	10
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

Autism Spectrum Disorder

Trastorno del Espectro Autista

E.1.1.1

Medical condition in easily understood language

ASD is a neurodevelopmental disorder that impairs the ability to communicate and interact

TEA es un trastorno del neurodesarrollo que afecta a la habilidad de comunicar e interactuar

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10063844
E.1.2	Term	Autism spectrum disorder
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10003805
E.1.2	Term	Autism
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10034739
E.1.2	Term	Pervasive developmental disorder NOS
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of 10 mg of balovaptan compared with placebo based on the Vineland TM-II two-domain composite (2DC) score

Evaluar la eficacia de 10 mg de balovaptán en comparación con placebo basado en la puntuación Vineland™-II 2DC

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of 10 mg of balovaptan compared with placebo based on the Vineland-II 2DC score, Pediatric Quality of Life Inventory TM Generic Core Scales(PedsQLTM), Version 4.0, summary and total scores, Vineland-II composite standard score, Vineland-II Socialization, Communication, Daily Living Skills domain standard scores, Clinical Global Impressions(CGI) –Severity(S) and Improvement(I), Hamilton Anxiety Rating Scale (HAM-A) total and domain scores

Evaluar la eficacia de 10 mg de balovaptán en comparación con placebo basado en la puntuación Vineland™-II 2DC, puntuaciones PedsQL™, versión 4.0, resumen y puntuaciones totales, puntuación normalizada combinada Vineland-II, puntuación de la escala de socialización, comunicación, habilidades para la vida cotidiana, escala CGI-S, escala CGI-I, y puntuación total y de dominios de la escala HAM-A para evaluar el efecto sobre la ansiedad de la escala Vineland-II

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Males or females, age 18 years or older
- Subject meets the Diagnostic and Statistical Manual of Mental Disorders, Version 5 (DSM-5) criteria for ASD for an autism diagnosis and is confirmed using Autism Diagnostic Observation Schedule (ADOS)-2 criteria
- Social Responsiveness Scale (SRS)-2, proxy version, total t score >=66 at screening
- A full scale IQ score >=70 on the Wechsler Abbreviated Scale of Intelligence®-II
- Ability and willingness to fully comply with study visit schedule and regular assessments and fluency in the language of the site
- Subject’s participation in the study or discontinuation of prohibited medication will not pose undue risks to the subject, in the investigator’s opinion
- Subject has an appropriate study partner, in the opinion of the investigator
- For women of childbearing potential: agreement to remain abstinent or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 30 days after the last dose of study drug
- Treatment with permitted medications and behavioral therapy regimens, with the intent that such treatments remain stable throughout the study and with no expected changes before the Week 24 visit

-Varón o mujer de 18 años de edad, como mínimo
-Cumplimiento de los criterios de TEA del Manual Diagnóstico y Estadístico de los Trastornos Mentales, versión 5 (DSM-5) para un diagnóstico de autismo y confirmación mediante los criterios ADOS™-2 (Calendario de Observaciones Diagnósticas del Autismo™)
-Puntuación t total en la escala SRS™-2 (Escala de Sensibilidad Social™), versión para representantes, ≥ 66 en el período de selección.
-Puntuación de cociente de inteligencia (CI) en escala completa ≥ 70 en la escala WASI®-II
-Capacidad y disposición para cumplir plenamente el calendario de visitas del estudio y las evaluaciones regulares y habla con soltura en el idioma del centro.
-La participación del sujeto en el estudio o la suspensión de medicamentos prohibidos no supondrán riesgos innecesarios para el sujeto, en opinión del investigador.
-El sujeto cuenta con un acompañante para el estudio adecuado, en opinión del investigador.
-Mujeres en edad fértil: Compromiso de practicar abstinencia sexual o de utilizar un método anticonceptivo con un índice de fallos < 1% anual durante el período de tratamiento y hasta 30 días después de la última dosis del fármaco del estudio.
-Tratamiento con medicamentos permitidos y regímenes de terapia conductista, con la intención de mantener estables dichos tratamientos durante todo el estudio y sin cambios previstos antes de la visita de la semana 24.

E.4

Principal exclusion criteria

General Exclusion Criteria
- Pregnancy or breastfeeding, or intention to become pregnant during the study
Neurologic and Psychiatric Exclusion Criteria
-Previous initiation of new or major change in psychosocial intervention within 6 weeks prior to screening
- Unstable or uncontrolled clinically significant affective or psychotic disorders and/or neurologic disorder that may interfere with the assessment of safety or efficacy endpoints
- Alcohol or substance abuse or dependence disorder during the last 12 months, as defined using the DSM-5 criteria
- Significant risk for suicidal behavior, in the opinion of the investigator
- Epilepsy or seizure disorder considered not well controlled within the past 6 months or changes in anticonvulsive therapy within the last 6 months
- Clinical diagnosis of peripheral neuropathy
Exclusions Related to Cardiovascular Disorders
- Within the last 2 years, unstable or clinically significant cardiovascular disease
- Uncontrolled hypertension
Exclusions Related to Other Organ Systems
- Positive serology results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) 1 or 2
- History of coagulopathies, bleeding disorders, blood dyscrasias, hematological malignancies, myelosuppression, or current major bleeding event
- Concomitant disease or condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or what would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study
- Confirmed clinically significant abnormality in parameters of hematology, clinical chemistry, coagulation, or urinalysis
- Medical history of malignancy, if not considered cured
Additional Exclusion Criteria
- Allowed medications have not been stable for 12 weeks prior to screening
- Previous treatment with prohibited medications or herbal remedies within 2 weeks prior to randomization or 5 half-lives
- Blood donation or loss of blood > 500 mL within 3 months prior to randomization
- Previous participation in an investigational drug or device study within 60 days prior to randomization or previous enrollment in investigational trials of balovaptan

Criterios de exclusión generales
-Embarazo o lactancia, o intención de quedarse embarazada durante el estudio.
Criterios de exclusión neurológicos y psiquiátricos
-Comienzo o modificación importante de una intervención psicosocial en las 6 semanas previas a la selección.
-Trastornos afectivos o psicóticos clínicamente importantes inestables o no controlados y/o trastornos neurológicos que puedan interferir en la evaluación de los criterios de valoración de la seguridad o la eficacia.
-Trastorno por abuso o dependencia de alcohol o sustancias durante los 12 últimos meses, según se define en los criterios del DSM-5.
-Riesgo importante de comportamiento suicida, en opinión del investigador.
-Epilepsia o trastorno convulsivo mal controlado en los 6 últimos meses o modificaciones del tratamiento anticonvulsivo en los 6 últimos meses.
-Diagnóstico clínico de neuropatía periférica.
Exclusiones relacionadas con trastornos cardiovasculares
-En los 2 últimos años, enfermedad cardiovascular inestable o clínicamente importante
-Hipertensión arterial no controlada
-Exclusiones relacionadas con otros sistemas orgánicos
-Resultados serológicos positivos para antígeno de superficie del virus de la hepatitis B, anticuerpos contra el virus de la hepatitis C o virus de la inmunodeficiencia humana de tipo 1 o 2.
-Antecedentes de coagulopatías, trastornos hemorrágicos, discrasias sanguíneas, neoplasias malignas hematológicas, mielosupresión o episodios hemorrágicos importantes activos.
-Cualquier enfermedad o trastorno concomitante, o su tratamiento, que pueda interferir en el desarrollo del estudio, o que, en opinión del investigador, podría suponer un riesgo inaceptable para el sujeto en este estudio.
-Anomalía clínicamente significativa confirmada en los parámetros de hematología, bioquímica clínica, coagulación o análisis de orina.
-Antecedentes de neoplasia maligna, si no se considera curada.
Otros criterios de exclusión
-Los medicamentos permitidos no se han mantenido estables durante las 12 semanas previas a la selección.
-Tratamiento previo con medicamentos o productos de herbolario prohibidos en las 2 semanas previas a la aleatorización o el equivalente a 5 semividas
-Donación o pérdida de sangre > 500 ml en los 3 meses previos a la aleatorización
-Participación en un estudio de un fármaco o dispositivo en investigación en los 60 días previos a la aleatorización o participación previa en ensayos de investigación de balovaptán.

E.5 End points

E.5.1

Primary end point(s)

1. Change from baseline at Week 24 on the Vineland TM -II 2DC score

1. Cambio desde basal a la semana 24 en la puntuación Vineland™-II 2DC

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Baseline (Day 1) and Week 24

1. Basal (dia 1) y semana 24

E.5.2

Secondary end point(s)

1. Change from baseline at Week 12 on the Vineland-II 2DC score
2. Change from baseline at Weeks 12 and 24 in the PedsQLTM Core module, Version 4.0, on summary and total scores
3. Change from baseline at Weeks 12 and 24 in the Vineland-II a composite standard score
4. Change from baseline at Weeks 12 and 24 in Vineland-II Socialization domain standard score
5. Change from baseline at Weeks 12 and 24 in Vineland-II Communication domain standard score
6. Change from baseline at Weeks 12 and 24 in Vineland-II Daily Living Skills domain standard score
7. Change from baseline in severity of clinical impressions as measured by CGI-S after 12 weeks and 24 weeks of treatment
8. Improvements in clinical impressions, as measured by CGI-I after 12 weeks and 24 weeks of treatment
9. Change from baseline in the HAM-A total and domain scores at Weeks 12 and 24
10. Proportion of subjects with a >=6-point improvement in Vineland-II 2DC score at Weeks 12 and 24

1. Cambio desde basal a la semana 12 en la puntuación Vineland™-II 2DC
2. Cambio desde basal a la semana 12 y 24 en la puntuacion PedsQL™, versión 4.0, resumen y puntuación total.
3.Cambio desde basal a la semana 12 y 24 en la puntuación normalizada combinada Vineland-II
4. Cambio desde basal a la semana 12 y 24 en la puntuación de la escala de socialización Vineland-II
5. Cambio desde basal a la semana 12 y 24 en la puntuación de la escala de comunicación Vineland-II
6. Cambio desde basal a la semana 12 y 24 en la puntuación de la escala de habilidades para la vida cotidiana Vineland II
7. Cambio desde basal en la severidad de las impresiones clinicas medida por CGI-S después de la semana 12 y 24 de tratamiento
8. Mejora de las impresiones clinicas medidas por CGI después de la semana 12 y 24 de tratamiento.
9. Cambio desde basal en la puntuación total y de dominios de la escala HAM-A en las semanas 12 y 24.
10. Proporción de sujetos con una mejoría ≥ 4 puntos de la puntuación Vineland-II 2DC en las semanas 12 y 24

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Baseline and Week 12
2-6. Baseline, Week 12 and Week 24
7-8. Week 12 and Week 24
9-10. Baseline, Week 12 and Week 24

1. Basal y semana 12
2-6. Basal, semanas 12 y 24
7-8. Semanas 12 y 24
9-10. Basal, semanas 12 y 24

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

Yes

E.8.1.7.1

Other trial design description

2 años de extension en abierto

2 year open label extension

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

Canada

France

Germany

Italy

Spain

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

The date when the last subject, last visit occurs in the open-label extension period or the follow-up period.
It is anticipated that it may take from 18 to 28 months to recruit all subjects for the study. Hence, the total length of the study is estimated to be approximately 4-5 years.

El final del estudio se define como la fecha de la última visita del último sujeto en el período de extensión abierto o el período de seguimiento.
Se prevé tardar entre 18 y 28 meses en reclutar a todos los sujetos para el estudio. En consecuencia, se calcula que la duración total del estudio será de 4–5 años.

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

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

349

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

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Patients aged 65 or above are not expected to be recruited but will not be excluded if eligible

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

F.4.2.2

In the whole clinical trial

350

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)

There are no plans to provide the Roche IMP (balovaptan) or any other study treatments or interventions to subjects who have completed the study.
The Sponsor may evaluate whether to continue providing balovaptan in accordance with the Roche Global Policy on Continued Access to IMPs, available at: http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
Subjects are eligible to receive balovaptan as part of the OLE, provided they have completed 24 weeks of treatment

El promotor no tiene planes de proporcionar el IMP de Roche o cualquier otro tratamiento o intervencion del estudio a pacientes que han completado el ensayo. El promotor evaluará si continua proporcionando balovaptan de acuerdo con la política global de Roche de acceso continuado a IMPs disponible en: http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
Los pacientes son elegibles para balovaptan como parte del OLE siempre que hayan completado 24 semanas de tratamiento

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

2018-09-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-07-06

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