Clinical Trials Register

Summary
EudraCT Number:	2019-001724-35
Sponsor's Protocol Code Number:	AMASCIS-02
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-07-11
Trial 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

2019-001724-35

A.3

Full title of the trial

AMASCIS-02. ALOGENIC ADIPOSE TISSUE-DERIVED MESENCHYMAL STEM CELLS IN ISCHEMIC STROKE. A PHASE IIB MULTICENTER DOUBLE BLIND PLACEBO CONTROLLED CLINICAL TRIAL.

AMASCIS-02. ADMINISTRACIÓN INTRAVENOSA DE CÉLULAS TRONCALES MESENQUIMALES ALOGÉNICAS DE TEJIDO ADIPOSO EN EL INFARTO CEREBRAL AGUDO. ENSAYO CLÍNICO FASE IIB MULTICÉNTRICO Y DOBLE CIEGO CONTROLADO CON PLACEBO.

A.3.1

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

ALOGENIC ADIPOSE TISSUE-DERIVED MESENCHYMAL STEM CELLS IN ISCHEMIC STROKE.

TRATAMIENTO CON CÉLULAS TRONCALES MESENQUIMALES ALOGÉNICAS DERIVADAS DE TEJIDO ADIPOSO EN EL INFARTO CEREBRAL.

A.4.1

Sponsor's protocol code number

AMASCIS-02

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	Fundación para la Investigación Biomédica del Hospital Universitario de La Paz (FIBHULP)
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Fundación de Investigación del Hospital Universitario La Paz (FIBHULP)
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fundación para la Investigación Biomédica del Hospital Universitario de La Paz (FIBHULP)
B.5.2	Functional name of contact point	UCICEC
B.5.3	Address:
B.5.3.1	Street Address	Paseo de la Castellana 261
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28046
B.5.3.4	Country	Spain
B.5.4	Telephone number	+3491727 70 004248
B.5.5	Fax number	+3491727 70 004248
B.5.6	E-mail	victoria.hernandez.ucicec@gmail.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	Allogeneic Adipose - derived stem cells
D.3.4	Pharmaceutical form	Solution for injection/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	Mesenchymal Stem Cells
D.3.9.3	Other descriptive name	MESENCHYMAL STEM CELLS (MSCS)
D.3.9.4	EV Substance Code	SUB176600
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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	Solution for injection/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

Moderate-severe ischemic stroke

Infarto cerebral moderado-grave

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	22.1
E.1.2	Level	LLT
E.1.2	Classification code	10055221
E.1.2	Term	Ischemic stroke
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 assess the safety of the intravenous administration of allogeneic stem cells from adipose tissue within the first 4 days from stroke onset in acute ischemic stroke patients.

Evaluar la seguridad del tratamiento con células madre alogénicas procedentes de tejido adiposo administradas por vía intravenosa en los primeros cuatro días desde la ocurrencia de un infarto cerebral.

E.2.2

Secondary objectives of the trial

To assess the potential efficacy of allogeneic stem cells from adipose tissue when administered within the first 4 days from stroke onset in acute ischemic stroke patients.

Evaluar la potencial eficacia del tratamiento con células madre alogénicas procedentes de tejido adiposo administradas por vía intravenosa en los primeros 4 días desde la ocurrencia de un infarto cerebral.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male and female acute ischemic patients aged more than 18 years

2. Patients should be treated within 4 days (+/-1 days) from the onset of stroke symptoms. If the time of symptom onset is unknown, this shall refer to the last time the patient was observed as asymptomatic.

3. A computed tomography (CT) or magnetic resonance imaging (MRI) scan compatible with the clinical diagnosis of acute non-lacunar IS in the region of the middle cerebral artery (with cortical or subcortical involvement).

4 .A score on the National Institute of Health Stroke Scale (NIHSS) of 8-20, with at least two of these points in sections 5 and 6 (motor deficit) at the time of inclusion and in which a measurable focal neurologic deficit persists to the time of treatment.

5. A prestroke score on the Modified Rankin Scale (mRS) ≤1 (no significant disability).

6. Female subjects non-child bearing potential. Female subjects who are of non-childbearing potential are defined as meeting at least 1 of the following criteria:
a)Have undergone a documented hysterectomy and/or bilateral oophorectomy;
b)Have medically confirmed ovarian failure; or
c)Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause.

7. Female subjects of child-bearing potential need a negative pregnancy test and must agree to use adequate contraception for the duration of the study (from screening through the final of the study). The following types of contraception are considered adequate provided they are locally authorized for use: oral, transdermal, or injectable (depot) estrogen and/or progestogen, selective estrogen receptor modulator therapy, intrauterine contraceptive device, double barrier method (e.g., condom and diaphragm or spermicidal gel) or vasectomy.

8. Signed informed consent

1. Mayores de 18 años

2. Pacientes que puedan ser tratados dentro de los primeros cuatro días (+/- 1día) desde el inicio de los síntomas del infarto cerebral. Si la hora de inicio es desconocida, se considerará el último momento en el cual el paciente estuvo asintomático.

3. Diagnostico de infarto cerebral no lacunar en territorio de arteria cerebral media confirmado mediante tomografía computarizada (TC) craneal o resonancia magnética (RM) cerebral.

4. Puntuación de entre 8-20 en la escala National Institute of Health Stroke Scale (NIHSS) en el momento de inclusión en el estudio. Por lo menos dos de estos puntos deben ser de las secciones 5 y 6 (déficit motor). El déficit neurológico objetivable debe permanecer en el momento de la administración del tratamiento.

5. Presentar una puntuación en la escala Modified Rankin Scale (mRS) ≤ 1 (no incapacidad significativa) previo al infarto cerebral.

6. Mujeres sin potencial posibilidad actual de embarazo; cumpliendo al menos una de las siguientes características:
a)Realización previa de histerectomía y/o doble anexectomía, adecuadamente documentadas.
b)Fallo ovárico medicamente confirmado
c)Haber alcanzado la menopausia, definida de la siguiente manera: cese de menstruación regular durante al menos doce meses consecutivos sin ninguna causa patológica o fisiológica alternativa.

7. Mujeres con potencial posibilidad actual de embarazo que presenten un test de embarazo negativo y que acepten la utilización de medidas de anticoncepción adecuadas durante la realización del estudio (desde el momento de evaluación inicial hasta la finalización del estudio).

8.Firmar el Consentimiento Informado.

E.4

Principal exclusion criteria

1. Comatose patients; patients with a score of 2 or more on item 1a of the NIHSS related to the degree of awareness.

2. Evidence on neuroimaging of a brain tumor, cerebral edema with midline shift and a clinically significant compression of ventricles, cerebellar or brainstem infarction, and intraventricular, intracerebral, or subarachnoid hemorrhage. Petechial small haemorrhages are not exclusion criteria.

3. Current drug or alcohol use or dependence.

4. Active infectious disease, including human immunodeficiency virus, hepatitis B, and hepatitis C. A controlled infection is not an exclusion criterion.

5. Pre-existing dementia.

6. A health status, any clinical condition (eg, short life expectancy, and coexisting disease or a surgical or endovascular planned procedure) or other characteristic that precludes appropriate diagnosis, treatment, or follow-up in the trial.

7. Patients who are participating in another clinical trial.

8. Inability or unwillingness of the individual or their legal guardian/representative to provide written informed consent.

1. Pacientes en estado comatoso; con una puntuación de ≥2 en el ítem 1a de la escala NIHSS (relativo al nivel de conciencia)

2. Evidencia de tumor, edema cerebral con desplazamiento de la línea media y compresión significativa de los ventrículos cerebrales, cerebelo o tronco cerebral y hemorragia intraparenquimatosa, intraventricular o subaracnoidea en pruebas de neuroimagen. Hemorragias petequiales de pequeño tamaño no se consideran un criterio de exclusión.

3. Abuso o dependencia actual de alcohol o de drogas .

4. Enfermedades infecciosas activas, incluyendo el virus de la inmunodeficiencia humana, hepatitis B y hepatitis C. Una infección controlada no sería criterio de exclusión.

5. Demencia previa al infarto cerebral.

6. Un estado de salud o cualquier condición clínica (por ejemplo, corta esperanza de vida, enfermedades graves o procedimientos quirúrgicos o endovasculares) que puedan impedir un diagnóstico, tratamiento o seguimiento adecuado en el estudio.

7. Pacientes que estén participando en otro ensayo clínico

8. Incapacidad o falta de voluntad por parte del representante legal del paciente de dar su Consentimiento Informado por escrito, en los casos en los que el paciente no pueda firmar el Consentimiento Informado por sí mismo.

E.5 End points

E.5.1

Primary end point(s)

The safety of mesenchymal stem cells from adipose tissue will be assessed using the following parameters:

- Adverse events (AES) reported spontaneously or in response to questions not addressed. Serious adverse events. These will be recorded in each visit during all the study period.

- Neurological and systemic complications: deteriorating stroke, stroke recurrences, brain oedema, seizures, hemorrhagic transformation, respiratory infections, urinary tract infections, deep venous thrombosis, and pulmonary embolism. These will be recorded in each visit during all the study period.

-Efectos adversos reportados de manera espontánea o en respuesta a preguntas que no aborden el tema. Éstos serán anotados y se emitirá el informe correspondiente en cada una de las visitas del estudio.

-Complicaciones neurológicas o sistémicas: infarto cerebral con empeoramiento progresivo, recurrencias, edema cerebral, crisis epilépticas, transformación hemorrágica, infecciones respiratorias o del tracto urinario, trombosis venosas profundas o tromboembolismo pulmonar. Éstos serán anotados y se emitirá el informe correspondiente en cada una de las visitas del estudio

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety evaluations will be performed at every scheduled visit during the study duration: V1 (screening), V2 (baseline), V3 (2h), V4 (24h), V5 (7 days or hospital discharge), V6 (3m), V7 (6m), V8 (12m), V9 (18m), V10 (24m).

Las evaluaciones de seguridad se realizarán en cada una de las visitas programadas durante la duración completa del estudio: V1 (cribado), V2 (basal), V3 (2h), V4 (24h), V5 (7 días o alta hospitalaria), V6 (3m), V7 (6m), V8 (12m), V9 (18m), V10 (24m).

E.5.2

Secondary end point(s)

1. Modified Rankin Scale (mRS): success is considered positive when the patient obtains a score of 0-3, and failure scores of 4 to 6 at months 3, 6, 12 and 24. Additional exploratory efficacy analysis: mRS shift at months 3, 6, 12 and 24.

2.NIH Stroke Scale: It will be measured at all the scheduled visits. Success is considered positive when the patient obtains an improvement of 75% or more from baseline. Additional exploratory efficacy analysis: differences in the distribution of median (IQR) and in the frequency of NIHSS ≤1 between groups.

3. Biomarkers. Granulocyte-macrophage colony-stimulating factor (GM-CSF), Platelet-derived growth factor BB (PDGF-BB), Brain-derived neurotrophic factor (BDNF), Vascular endothelial growth factor (VEGF), Transforming growth factor 1 (TGF-1), Endostatin, Glial fibrillary acid protein (GFAP), Myelin basic protein (MBP), Matrix Metalloproteinase 3 (MMP-3) and extracelular vesicles.

1. Escala Modified Rankin Scale (mRS): se considera éxito cuando el paciente puntúa 0-3, y fracaso si puntúa de 4-6. Las escala se valorará en los meses 3, 6, 12 y 24 desde la inclusión en el ensayo. Se analizará también el cambio en el mRS en los meses 3, 6, 12 y 24.

2. Escala NIHSS: se valorará en cada una de las visitas. Se considera éxito cuando el paciente presenta una mejoría del 75% o más desde el estado basal. Se realizará un análisis exploratorio de eficacia adicional para medir las diferencias en la distribución de la mediana y en la frecuencia de puntuación de NIHSS ≤ 1 entre los grupos de tratamiento.

3. Marcadores bioquímicos de reparación cerebral GM-CSF, PDGF-BB, BDNF, VEGF, TGF-1, GFAP, MBP, MMP-3 y vesículas extracelulares.

E.5.2.1

Timepoint(s) of evaluation of this end point

Modified Rankin Scale (mRS) and mRS shift: screening and months 3, 6, 12 and 24.
NIH Stroke Scale: all scheduled visits
Biomarkers: They will be measured at baseline, day 7 and month 3.

Escala de Rankin modificada (ERm) y cambio en ERm: cribado, meses 3, 6, 12 y 24
Escala NIHSS: en todas las visitas programadas
Biomarcadores de reparación cerebral: Se medirán en la visita de administración del tratamiento, al séptimo día y a los 3 meses.

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

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

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

Última visita del último sujeto incluido 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

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

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

It is possible that, due to aphasia o hemiplegia caused by ischemic stroke, some of the patients may not be able to give their consent personally. Otherwise, they are expected to able to give their consent.

Es posible que algún paciente, al presentar afasia o hemiplejia debido al ictus, no pueda dar su consentimiento personalmente. En las demás situaciones se espera que los pacientes sean capaces de dar su consentimiento personal para participar.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

None

Ninguno

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

2020-06-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-06-11

P. End of Trial
P.	End of Trial Status	Ongoing

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