Clinical Trials Register

Summary
EudraCT Number:	2010-020603-79
Sponsor's Protocol Code Number:	AB08004
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:	2012-10-22
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

2010-020603-79

A.3

Full title of the trial

A prospective, multicentre, randomized, double-blind, placebo-controlled, 2-parallel groups, phase 2 study to evaluate efficacy and safety of 12 weeks treatment with masitinib versus placebo in patients with acute ischemic stroke receiving stroke unit care with or without rt-PA therapy

Estudio fase II, prospectivo, multicéntrico, randomizado, doble ciego, controlado con placebo, de 2 grupos paralelos para evaluar la eficacia y seguridad del tratamiento de 12 semanas con masitinib versus placebo en pacientes con ictus isquémico agudo en la unidad de cuidados de ictus con o sin tratamiento rt-PA

A.3.1

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

Evaluation of masitinib in acute ischemic stroke

Evaluación de masitinib en pacientes con ictus isquémico agudo

A.3.2

Name or abbreviated title of the trial where available

not applicable

A.4.1

Sponsor's protocol code number

AB08004

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	AB Science
B.1.3.4	Country	France
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	ABScience
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ABScience
B.5.2	Functional name of contact point	Alain Moussy
B.5.3	Address:
B.5.3.1	Street Address	3 avanue George V
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75008
B.5.3.4	Country	France
B.5.4	Telephone number	0033 1 47 20 30 08
B.5.5	Fax number	0033 1 47 20 24 11
B.5.6	E-mail	alain.moussy@ab-science.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	masitinib
D.3.2	Product code	AB1010 tablets
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	Masitinib mesylate
D.3.9.1	CAS number	790-299-79-5
D.3.9.2	Current sponsor code	AB1010
D.3.9.3	Other descriptive name	NA
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	100
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Masitinib mesylate
D.3.9.1	CAS number	790-299-79-5
D.3.9.2	Current sponsor code	AB1010
D.3.9.3	Other descriptive name	NA
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	200
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

patients suffering from Acute Ischemic Stroke

Pacientes con ictus isquémico agudo

E.1.1.1

Medical condition in easily understood language

Stroke

Ictus

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10023027
E.1.2	Term	Ischaemic stroke NOS
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

The objective of this study is to compare efficacy and safety of masitinib versus placebo in patients with acute ischemic stroke receiving stroke unit care with or without rt-PA therapy

El objetivo del presente estudio es comparar la eficacia y seguridad de masitinib versus placebo, en pacientes con ictus isquémico agudo que reciben atención en unidades especializadas de ictus con o sin rt-PA.

E.2.2

Secondary objectives of the trial

Secondary endpoints
· Neurological deficit measured by National Institute of Health Stroke Scale (NIHSS) score at Hour 2, Hour 24, Week 2, Week 4, Week 8 and Week 12
· Modified Rankin Scale score at Week 2 defining success as score value 0-1
· Barthel Index measure of activity of daily living at Week 2 and 12
· Volume of cerebral infarction measured by MRI at baseline, Week 2 and Week 12
· Hemorrhage rate secondary to rt-PA treatment measured by MRI at H24
· Recanalization rate on patients with documented arterial occlusion during W0-W12 period
· Survival Rate at Week 12
· Stroke Specific Quality of Life Scale (SS-QOL) score at Week 1, Week 2, Week 4, Week 8 and Week 12
Safety endpoints
Adverse events (AEs), laboratory assessments (biochemistry, haematology and urinalysis), physical examination,
vital signs and ECGs

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male of female patient, age ? 18 years
2. Patient with a clinical diagnosis of acute stroke consistent with acute hemispheric cerebral infarction including hemiparesis and/ or hemiplegia involving the arm, leg, or both
3. Patient with symptom onset of ? 12 hours before the start of treatment and symptoms present for ? 1 hour
4. Patient with NIHSS score ? 8 with at least 2 points from section 5 and 6 (motor)
5. Patient with pre stroke Modified Rankin Scale < 1.
6. Patient fully conscious
7. Patient functionally independent before the stroke (Barthel Index score = 100)
8. Patient whose weight ? 49,9 kg and BMI > 18 at the time of informed consent signature
9. Patient with adequate organ functions defined as:
? Absolute neutrophil count (ANC) ? 2.0 x 109/L,
? Hemoglobin ? 10g/dL
? Platelets (PTL) ? 100 x 109/L
? AST/ALT ? 2.5x ULN
? Bilirubin ? 1.5x ULN
? Creatinin clearance > 60 mL/min (Cockcroft and Gault formula)
? Albumin > 1x LLN
? Urea ? 1.5 x ULN
? Dipstick proteinuria < 30 mg/dL. In case of dipstick proteinuria ? 30 mg/dL, 24 hours proteinuria < 1.5g/24 hours.
10. Man and woman of childbearing potential (entering the study after a menstrual period and who have a negative pregnancy test), must agree to use two methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake
11. Patient able and willing to comply with study procedures as per protocol
12. Patient or her/his representative able to understand, sign, and date the written informed consent form at baseline visit prior to any protocol-specific procedures
13. Patient affiliated to a social security system
14. Patient /representative able to understand the patient card and to follow the patient card procedures in caseof sign or syptoms of severe neutropenia or severe cutaneous toxicity , during the first two months of treatment

1. Sexo masculino o femenino, edad ? 18 años.
2. Paciente con diagnóstico clínico de ictus agudo compatible con un infarto cerebral hemisférico, con hemiparesia y/o hemiplejia que afecten al brazo, la pierna o a ambos.
3. Paciente/representante capaz de comprender la tarjeta del paciente y seguir las instrucciones en caso de signos o síntomas de neutropenia o toxicidad cutánea severa, durante los dos primeros meses de tratamiento.
4. Paciente con aparición de los síntomas ? 12 horas antes del inicio del tratamiento y presencia de los síntomas ? 1 hora.
5. Paciente con puntuación de la NIHSS ? 8 y como mínimo 2 puntos de los apartados 5 y 6 (afectación motriz).
6. Paciente con puntuación de la Escala de Rankin modificada < 1 antes del ictus.
7. Paciente con la conciencia conservada.
8. Paciente con autonomía funcional antes del ictus (puntuación del Índice de Barthel = 100).
9. Paciente con peso ? 49,9 kg e índice de masa corporal (IMC) >18 en el momento de firmar el consentimiento informado.
10. Paciente con función orgánica correcta, definida por los parámetros siguientes:
? Recuento absoluto de neutrófilos (RAN) ? 2,0 × 109/l
? Hemoglobina ? 10 g/dl
? Plaquetas (PTL) ? 100 × 109/l
? AST/ALT ? 2,5 × LSN
? Bilirrubina ? 1,5 × LSN
? Aclaramiento de creatinina > 60 ml/min (fórmula de Cockcroft-Gault)
? Albuminemia ? 1 × LIN
? Urea ? 1,5 × LSN
? Proteinuria en tira reactiva < 30 mg/dl. En caso de proteinuria ? 30 mg/dl según la tira, proteinuria de 24 horas ? 1,5 g/24 horas.
11. En el caso de varones y mujeres en edad fértil (que en el momento de su inclusión hayan pasado una menstruación y hayan dado negativo a la prueba del embarazo), compromiso de utilizar dos métodos anticonceptivos (el paciente, uno; y la pareja, otro) válidos desde el punto de vista científico durante todo el estudio y hasta que hayan transcurrido 3 meses de la última dosis del tratamiento.
12. Capacidad y voluntad del paciente de cumplir con los procedimientos del protocolo.
13. Paciente/representante capaz de comprender, firmar y fechar el consentimiento informado en la visita basal, antes de que se realice ningún procedimiento específico del estudio.
14. Afiliación a un régimen de la seguridad social.

E.4

Principal exclusion criteria

1. Patient with a clinical diagnosis of acute stroke consistent with intracerebral hemorrhage
2. Patient inability to swallow study treatment tablets (tablets cannot be crushed, chewed or divided).
3. Patient with neurological sequellae from previous illness
4. Patient having cardiac disorders defined by at least one of the following conditions:
· Patient with recent cardiac history (within 6 months) of:
- Acute coronary syndrome
- Acute heart failure (class III or IV of the NYHA classification)
- Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular
fibrillation, resuscitated sudden death)
· Patient with cardiac failure class III or IV of the NYHA classification
· Patient with severe conduction disorders which are not prevented by permanent pacing (atrioventricular
block 2 and 3, sino-atrial block)
· Syncope without known aetiology within 3 months
· Uncontrolled severe hypertension, according to the judgment of the investigator, or symptomatic
hypertension
5. Patient with severe concurrent illness and/or with life expectancy < 6 months
6. Patient with history of primary malignancy < 5 years, except treated basal cell skin cancer or cervical carcinoma in situ
7. Patient with a known diagnosis of human immunodeficiency virus (HIV) infection
8. Pregant or nursing female
9. Patient with history of poor compliance or history of drug/alcohol abuse, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent.

1. Paciente con diagnóstico clínico de ictus agudo compatible con una hemorragia intracerebral.
2. Paciente con incapacidad de deglutir los comprimidos del fármaco en estudio (no se permite triturarlos, masticarlos ni partirlos).
3. Paciente con secuelas neurológicas de una enfermedad anterior.
4. Paciente con cardiopatías definidas por al menos una de los trastornos siguientes:
? Antecedentes recientes de cardiopatías (en los últimos 6 meses) de:
- Síndrome coronario agudo,
- Insuficiencia cardíaca aguda (clase III ó IV de la clasificación de la NYHA),
- Arritmias ventriculares significativas (taquicardia ventricular persistente, fibrilación ventricular, muerte súbita resucitada).
? Insuficiencia cardíaca de clase III ó IV según la clasificación de la NYHA.
? Trastornos graves de la conducción que no se hayan corregido con marcapasos permanente (bloqueo auriculoventricular de 2.º y 3.er grados, bloqueo sinoauricular).
? Síncope de etiología desconocida en los últimos 3 meses.
? Hipertensión grave no controlada, según el criterio del investigador, o hipertensión sintomática.
5. Paciente con enfermedad concurrente grave y/o esperanza de vida inferior a los 6 meses.
6. Paciente con antecedentes de neoplasias malignas primarias en los últimos 5 años, a excepción del carcinoma basocelular y el carcinoma de cuello uterino in situ si se han tratado.
7. Paciente con infección documentada por el virus de la inmunodeficiencia humana (VIH).
8. Embarazo o lactancia materna en el caso de las mujeres.
9. Antecedentes de incumplimiento terapéutico o abuso de alcohol/drogas, ó presencia o antecedentes de enfermedades psiquiátricas que interfieran en la capacidad del paciente de cumplir con el protocolo del estudio o de otorgar su consentimiento informado.

E.5 End points

E.5.1

Primary end point(s)

?Modified Rankin Scale score at week 12 defining success as score value 0-1.

Escala de Rankin modificada en la semana 12, entendiendo por evolución satisfactaria un valor 0-1

E.5.1.1

Timepoint(s) of evaluation of this end point

week 12

semana 12

E.5.2

Secondary end point(s)

Criterios secundarios de valoración
? Déficit neurológico, determinado según National Institutes of Health Stroke Scale (NIHSS), a las 2 horas, 24 horas, 2 semanas, 4 semanas, 8 semanas y 12 semanas.
? Escala de Rankin modificada en la semana 2, entendiendo por evolución satisfactoria un valor 0-1.
? Autonomía en las actividades cotidianas, determinada según el Índice de Barthel en las semanas 2 y 12.
? Volumen del infarto cerebral, determinado mediante TAC en visita basal, semana 2 y semana 12.
? Incidencia de hemorragias secundarias al tratamiento con rt-PA, determinadas mediante TAC, a las 24 horas.
? Tasa de recanalizaciones entre los pacientes con oclusión arterial documentada, en el período comprendido entre la semana 0 y la semana 12.
? Tasa de supervivencia en la semana 12.
? Puntuación de la Escala de Calidad de Vida Específica para el Ictus (SS-QOL) en la semana 1, semana 2, semana 4, semana 8 y semana 12.
Criterios de valoración de la seguridad
Acontecimientos adversos (AA), determinaciones de laboratorio (bioquímica, hematología y orina), exploraciones físicas, constantes vitales y ECGs.

E.5.2.1

Timepoint(s) of evaluation of this end point

Hour 2, Hour 24, Week 2, Week 4, Week 8 and Week 12

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

Yes

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)

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

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

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero