Clinical Trials Register

Summary
EudraCT Number:	2021-002076-39
Sponsor's Protocol Code Number:	WC42759
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:	2022-01-03
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

2021-002076-39

A.3

Full title of the trial

A PHASE II, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY TO EVALUATE THE SAFETY AND EFFICACY OF BALOVAPTAN IN PATIENTS WITH ACUTE ISCHEMIC STROKE AT HIGH RISK OF DEVELOPING MALIGNANT CEREBRAL EDEMA

ESTUDIO DE FASE II, ALEATORIZADO, DOBLE CIEGO, CONTROLADO CON PLACEBO Y MULTICÉNTRICO PARA EVALUAR LA SEGURIDAD Y LA EFICACIA DE BALOVAPTÁN EN PACIENTES CON ICTUS ISQUÉMICO AGUDO Y ALTO RIESGO DE PRESENTAR EDEMA CEREBRAL MALIGNO

A.3.1

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

A Study to Evaluate the Safety and Ability of Balovaptan to Reduce the Risk of Severe Brain Swelling in Patients with Acute Ischemic Stroke

Estudio para evaluar la seguridad y la capacidad del balovaptán para reducir el riesgo de inflamación cerebral grave en pacientes con accidente cerebrovascular isquémico agudo

A.4.1

Sponsor's protocol code number

WC42759

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. U. que realiza el ensayo en España y que actúa como representante 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	+349132557300
B.5.5	Fax number	+34913248196
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/F48-01
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Balovaptan
D.3.9.1	CAS number	1228088-30-9
D.3.9.2	Current sponsor code	RO5285119
D.3.9.4	EV Substance Code	SUB213812
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
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	Concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute Ischemic Stroke (AIS)

ictus isquémico agudo (IIA)

E.1.1.1

Medical condition in easily understood language

AIS is defined by the sudden loss of blood flow to an area of the brain with the resulting loss of neurologic function and can result in permanent damage to the affected area of the brain.

IIA es la pérdida repentina de flujo sanguíneo a un área del cerebro con la pérdida resultante de la función neurológica y puede resultar en daño permanente en el área afectada del cerebro.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

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	10008107
E.1.2	Term	Cerebral edema
E.1.2	System Organ Class	100000004852

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 balovaptan compared with placebo based on the amount of midline shift (MLS)

Evaluar la eficacia de balovaptán en comparación con un placebo

E.2.2

Secondary objectives of the trial

● To evaluate the efficacy of balovaptan compared with placebo based on global disability, amount of MLS, proportion of patients with surgical decompressive hemicraniectomy (DHC), proportion of patients who received hyperosmolar therapy, impairment of consciousness, neurological impairment, mortality, functional independence, stroke disability and health-related quality of life, hospital length of stay and ICU length of stay
● To evaluate the safety of balovaptan compared with placebo
● To characterize the balovaptan, M2, and M3 pharmacokinetic (PK) profile

●Evaluar la eficacia de balovaptán en comparación con un placebo basado en la Discapacidad global,Magnitud de la DLM,Proporción de pacientes con HCD quirúrgica realizada,Proporción de pacientes que reciben tratamiento hiperosmolar,Alteración de la conciencia,Deterioro neurológico,Mortalidad,Independencia funcional,Discapacidad por ictus y calidad de vida,Duración de la estancia hospitalaria y en la UCI.
●Evaluar la eficacia de balovaptán en comparación con un placebo.
●Concentraciones plasmáticas de balovaptán y sus metabolitos principales (M2 y M3) en los momentos especificado

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

● Participants who are between the ages >=18 and <=80 years at the time of signing Informed Consent Form
● Diagnosis of large vessel occlusion (LVO) in the anterior circulation such that study drug administration can be initiated within 12 hours of last known well (LKW) and at risk of malignant cerebral edema (MCE) development, as defined as follows: Documented occlusion of terminus ICA and/or MCA on CTA or magnetic resonance angiogram AND ASPECTS score <= 5 AND National Institutes of Health Stroke Scale (NIHSS) > 15 for the non-dominant hemisphere and > 20 for the dominant hemisphere
● Participants who present with a wake-up stroke (WUS) who are <=8 hours from awakening
● Participants with a history of seizures on anti-epileptic medications may be included if they have been on stable doses of those medications for at least 12 weeks prior to LKW, they have not experienced seizures during that time frame, and their anti-epileptic medicines are continued during the study
● For women of childbearing potential agreement to remain abstinent or use contraception and agree to refrain from donating eggs, during the treatment period and for at least 28 days after the final dose of balovaptan
● No specific contraception methods for males are required

1. Pacientes con edades comprendidas entre >= 18 y <= 80 años en el momento de firmar el documento de consentimiento informado.
2. Diagnóstico de OGV en la circulación anterior de tal modo que la administración del fármaco del estudio pueda iniciarse en las 12 horas siguientes al ISI y riesgo de desarrollo de ECM, definido por lo siguiente: Oclusión documentada de la ACI terminal o la ACM en la TCA o la angiorresonancia magnética y Puntuación ASPECTS ≤ 5 y NIHSS > 15 para el hemisferio no dominante y > 20 para el hemisferio dominante.
3. Participantes con ID que estén <= 8 horas desde el despertar, siempre que cumplan los criterios anteriores.
4. Pacientes con antecedentes de crisis convulsivas tratadas con antiepilépticos que hayan recibido dosis estables de estos medicamentos durante al menos 12 semanas antes del ISI, no hayan experimentado crisis epilépticas durante ese período y continúen con sus antiepilépticos durante el estudio
5. Para las mujeres en edad fértil, acuerden permanecer en la abstinencia o utilizar métodos anticonceptivos y abstenerse de donar óvulos durante el período de tratamiento y durante al menos 28 días después de la dosis final de balovaptán.
6. No se requieren métodos anticonceptivos específicos para hombres

E.4

Principal exclusion criteria

● Participants who are >12 hours from LKW at the start of treatment with study drug or >8 hours from awakening with WUS
● Any MLS on brain imaging
● Evidence of parenchymatous hematoma ([PH]1 or PH2) on baseline imaging (per Heidelberg classification)
● Evidence of additional anterior cerebral artery (ACA) infarction
● Diagnosis of brain death
● Planned surgical decompression prior to randomization
● Participants with a known history of a hereditary bleeding disorder which increases bleeding risk
● Chronic kidney disease stage III or higher
● Hepatic injury
● Diagnosis of diabetes insipidus
● Participants who have received any prophylactic hyperosmolar therapy
● Participants who have received treatment with any other V1a and/or V2 receptor-blocking agent or glyburide
● A preexisting medical condition for which the participant is unlikely to survive the next 6 months
● Planned limitation or withdrawal of life-sustaining treatment during hospital admission
● Participants who are pregnant or breastfeeding, or intending to become pregnant

1. Cuando hayan transcurrido > 12 horas desde el ISI al inicio del tratamiento con el fármaco del estudio o > 8 horas desde el despertar con ID.
2. Cualquier DLM medida al nivel del septum pellucidum en la TCSC de la selección por el radiólogo del centro
3. Signos de hematoma parenquimatoso ([HP]1 o HP2) en los estudios de imagen basales (según la clasificación de Heidelberg
4. Signos de infarto adicional de la arteria cerebral anterior (ACA).
5. Diagnóstico de muerte cerebral
6. Descompresión quirúrgica prevista antes de la aleatorización
7. Pacientes con antecedentes conocidos de un trastorno hemorrágico hereditario que aumente el riesgo de hemorragia
8. Nefropatía crónica en estadio III o superior
9. Lesión hepática
10. Diagnóstico de diabetes insípida.
11. Pacientes que hayan recibido cualquier tratamiento profiláctico hiperosmolar
12. Una condición médica preexistente para la cual es poco probable que el participante sobreviva los próximos 6 meses.
13. Limitación o retirada planificada del tratamiento de soporte vital durante la admisión al hospital
14. Pacientes que están embarazadas o en período de lactancia, o que tienen la intención de quedar embarazadas.

E.5 End points

E.5.1

Primary end point(s)

1. Amount of MLS, as measured in millimeters at the level of the septum pellucidum on NCCT at 72 hours from LKW

1.,Magnitud de la DLM , medida en milímetros, al nivel del septum pellucidum en la TCSC obtenidas a las 48 horas y las 96-120 horas del inicio de los síntomas de ictus

E.5.1.1

Timepoint(s) of evaluation of this end point

1. At 72 hours from LKW

1.A las 72 horas del ISI

E.5.2

Secondary end point(s)

1. Global disability, defined as the proportion of participants with modified Rankin Scale-Structured Interview (mRS-SI) score <=4 versus >4 measured at Day 90
2. Amount of MLS, as measured in millimeters at the level of the septum pellucidum on non-contrast computed tomography (NCCT) at 48 hours and 96-120 hours from LKW
3. Proportion of patients with surgical DHC performed
4. Proportion of patients who received hyperosmolar therapy following initiation of study treatment
5. Impairment of consciousness, as measured by the Glasgow Coma Scale (GCS) score up to Day 4
6. Neurological impairment, as measured by the NIHSS on hospital Day 4 and Day 90
7. Mortality at Day 30
8. Global disability, as measured by the mRS-SI at Day 30
9. Functional independence, as measured by the FIM at discharge or Day 10 and Day 90
10. Stroke disability and health-related quality of life, as measured by the Stroke Impact Scale (SIS)-16 at Day 30 and Day 90
11. Hospital length of stay
12. ICU length of stay
13. Incidence and severity of adverse events, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0)
14. Any safety signals seen on brain imaging
15. Change from baseline in targeted vital signs and ECG
16. Change from baseline in targeted clinical laboratory test results
17. Plasma concentration of balovaptan and its major metabolites (M2 and M3) at specified timepoints
18. Area under the concentration-time curve from Time 0 to 24 hours after a given dose (AUC24hr) of balovaptan and its major metabolites (M2 and M3) as calculated by non-compartmental analysis (NCA)
19. Maximum observed concentration (Cmax) of balovaptan and its major metabolites (M2 and M3) as calculated by NCA or taken directly from measured concentration
20. Plasma drug concentration 24 hours after the administration of a given dose (C24hr) of balovaptan and its major metabolites (M2 and M3) as calculated by NCA or taken directly from measured concentration

1. Discapacidad global, definida como la proporción de participantes con mRS <= 4 frente a >4 medida 90 días después de la aleatorización.

2. Magnitud de la DLM anteroseptal, medida en milímetros, al nivel del septum pellucidum en la TCSC obtenidas a las 48 horas y las 96-120 horas del inicio de los síntomas de ictus
3. Proporción de pacientes con HCD quirúrgica realizada
4. Proporción de pacientes que reciben tratamiento hiperosmolar después del inicio del tratamiento del estudio
5. Alteración de la conciencia, determinada mediante la GCS hasta el día 4
6. NIHSS los días 4 y 90 en el hospital
7. Mortalidad a los 30 días
8. Discapacidad global, determinada mediante la mRS-SI el día 30.
9. Independencia funcional, determinada mediante la FIM en el momento del alta hospitalaria o el día 10 (si el pacientes no ha sido dado de alta antes) y a los 90 días
10. Discapacidad por ictus y calidad de vida relacionada con la salud, determinadas mediante la SIS-16 a los 30 y 90 días
11. Duración de la estancia hospitalaria
12 Duración en la UCI
13. Incidencia e intensidad de los acontecimientos adversos, con determinación de la intensidad conforme a los criterios CTCAE del NCI v5.0
14. Cualquier señal de seguridad observada en las imágenes cerebrales.
15. Variación con respecto al momento basal de las constantes vitales y el ECG específicos.
16. Variación de los resultados analíticos de interés con respecto al momento basal
17. Concentraciones plasmáticas de balovaptán y sus metabolitos principales (M2 y M3) en los momentos especificados
18 y 19. Parámetros FC, como AUC24 h, Cmáx y C24h, calculados mediante ANC o basados directamente en las concentraciones medidas.
20. Concentración plasmática del fármaco 24 horas después de la administración de una dosis determinada (C24 h) de balovaptán y sus principales metabolitos (M2 y M3) calculados por NCA o tomados directamente de la concentración medida

E.5.2.1

Timepoint(s) of evaluation of this end point

1. At Day 90
2. At 48 hours and 96-120 hours from LKW
3. Up to Day 90
4. Up to Day 90
5. Up to Day 4
6. At Day 4 and Day 90
7. At Day 30
8. At Day 30
9. At discharge or Day 10 and at Day 90
10. At Day 30 and Day 90
11-12. Up to Day 90
13-Screening to Day 90
14-16. Baseline to Day 90
17-20. At 1 hour prior to drug administration; at 5 minutes, 2.5, 5, 12 hours after completion of each drug administration and at 24, 48 and 120 hours after completion of the last drug administration

1. En el día 90
2. A las 48 horas y entre 96 y 120 horas desde el ISI
3. Hasta el día 90
4. Hasta el día 90
5. Hasta el día 4
6. El día 4 y el día 90
7. El día 30
8. El día 30
9. Al alta o el día 10 y el día 90
10. El día 30 y el día 90
11-12. Hasta el día 90
13-Proyección hasta el día 90
14-16. Visita basal hasta el día 90
17-20. 1 hora antes de la administración del fármaco; a los 5 minutos, 2.5, 5, 12 horas después de completar la administración de cada fármaco y a las 24, 48 y 120 horas después de completar la última administración del fármaco

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Canada

Spain

United Kingdom

United States

France

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

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:

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

A legally authorized representative will be used for the consent process if the patient is deemed by the treating physician and/or site investigator to not have decision making capacity due to the nature of their stroke symptoms.

Se utilizará un representante legalmente autorizado para el proceso de consentimiento si el médico tratante y/o el ip del centro considera que el paciente no tiene capacidad para tomar decisiones por la naturaleza de los síntomas

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

F.4.2.2

In the whole clinical trial

108

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)

Currently, the Sponsor does not have any plans to provide balovaptan or any other study treatments to participants 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 Investigational Medicinal Product, available at the following
website: http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

Actualmente, el Promotor no tiene planes de proporcionar balovaptán ni ningún otro tratamiento del estudio a los participantes que hayan completado el estudio. El Promotor puede evaluar si continúa proporcionando balovaptán de acuerdo con la Política Global de Roche sobre Acceso Continuo a Medicamentos en Investigación, disponible en la siguiente página
sitio web: http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

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

2022-02-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-02-10

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

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IMP with orphan designation in the indication
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