Clinical Trials Register

Summary
EudraCT Number:	2019-002302-46
Sponsor's Protocol Code Number:	IMIB-TCIM/ELAII-2019-01
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:	2019-08-09
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

2019-002302-46

A.3

Full title of the trial

Phase II clinical trial of intramuscular infusion of autologous bone marrow stem cells in patients with amyotrophic lateral sclerosis

Ensayo clínico en fase II de infusión intramuscular de células madre de médula ósea autólogas en pacientes con Esclerosis lateral amiotrófica

A.3.1

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

Phase II clinical trial of intramuscular infusion of autologous bone marrow stem cells in patients with amyotrophic lateral sclerosis

Ensayo clínico en fase II de infusión intramuscular de células madre de médula ósea autólogas en pacientes con Esclerosis lateral amiotrófica

A.4.1

Sponsor's protocol code number

IMIB-TCIM/ELAII-2019-01

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 Formación e Investigación Sanitarias de la Región de Murcia
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 para la Formación e Investigación Sanitarias de la Región de Murcia
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 Formación e Investigación Sanitarias de la Región de Murcia
B.5.2	Functional name of contact point	Lola Serna Guirao
B.5.3	Address:
B.5.3.1	Street Address	C/ Luis Fontes Pagan, 9
B.5.3.2	Town/ city	Murcia
B.5.3.3	Post code	30003
B.5.3.4	Country	Spain
B.5.4	Telephone number	34968359763
B.5.5	Fax number	34968359777
B.5.6	E-mail	lola.serna@carm.es

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	autologous adult bone marrow mononuclear cells (BM-MNC) unexpanded
D.3.4	Pharmaceutical form	Solution for injection/infusion in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	autologous adult bone marrow mononuclear cells unexpanded
D.3.9.1	CAS number	no available
D.3.9.2	Current sponsor code	IMIB-TCIM/ELAII-2019-01
D.3.9.3	Other descriptive name	autologous adult bone marrow mononuclear cells unexpanded
D.3.10	Strength
D.3.10.1	Concentration unit	ml millilitre(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.5
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
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	Solution for infusion
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Amyotrophic Lateral Sclerosis

Esclerosis lateral amiotrófica

E.1.1.1

Medical condition in easily understood language

ALS

ELA

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. To determine if the infusion of autologous intramuscular MON CMN in the tibialis anterior and 1st dorsal inteosseus muscles of patients with ALS can stop or slow down the progressive loss of functional motor units in these muscles.
2. To study, in a sufficient sample of patients with ALS, whether the different degree of involvement and the different evolution of the pathological process in different muscles, characteristic very typical of this disease, translates into an efficacy different from the intramuscular injection of CMN of MO. Clinical heterogeneity and the presence of muscles with different degrees of involvement will be completed with genetic studies
3. Determine the safety of the procedure.

1. Determinar si la infusión de CMN de MO autólogas intramusuculares en los músculos tibial anterior y 1º inteóseo dorsal de los pacientes con ELA puede detener o enlentecer la pérdida progresiva de unidades motoras funcionales en dichos músculos.
2. Estudiar, en una muestra suficiente de pacientes con ELA, si el diferente grado de afectación y la diferente evolución del proceso patológico en músculos diferentes, característica muy típica de esta enfermedad, se traduce en una eficacia distinta de la inyección intramuscular de CMN de MO. La heterogeneidad clínica y la presencia de músculos con distinto grado de afectación se completará con estudios genéticos
3. Determinar la seguridad del procedimiento.

E.2.2

Secondary objectives of the trial

1. To make a detailed study and a prolonged follow-up of the functional (electrophysiological) properties of the motor units of two upper and lower extemity muscles in ALS patients. Determine which electrophysiological parameters (fundamentally those related to the estimation of the number of functional motor units) correlate better with the evolution of the disease.

2. To determine the utility of muscle ultrasound for the monitoring of muscle morphology in the evolution of patients with ALS.

3. Carry out a genetic study of the patients included in the trial in order to correlate clinical aspects of the disease and the effect of the procedure with the presence of genetic alterations recently described and related to sporadic ALS (e.g. C9orf72).

1. Hacer un estudio detallado y un seguimiento prolongado de las propiedades funcionales (electrofisiológicas) de las unidades motoras de dos músculos de la extemidad superior e inferior en pacientes de ELA. Determinar qué parámetros electrofisiológicos (fundamentalemente los relacionados con la estimación del número de unidades motoras funcionales) se correlacionan mejor con la evolución de la enfermedad.

2. Determinar la utilidad de la ecografía muscular para el seguimiento de la morfología muscular en la evolución de pacientes con ELA.

3. Hacer un estudio genético de los pacientes incluidos en el ensayo con objeto de correlacionar aspectos clínicos de la enfermedad y el efecto del procedimiento con la presencia de alteraciones genéticas recientemente descritas y relacionadas con la ELA esporádica (e.g. C9orf72).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Diagnosis of ALS defined or probable according to the criteria established by the World Federation of Neurology
- Age between 18 and 70 years.
- Patient that offers sufficient guarantees of adherence to the protocol.
- Neurophysiological data that confirm lower motor neuron involvement at lumbar and cervical level.
- Assessment of the motor deficit in the dorsiflexion of both feet (between 3 and 5 points on the MRC scale).

- Diagnóstico de ELA definida o probable de acuerdo con los criterios establecidos por la World Federation of Neurology
- Edad comprendida entre los 18 y los 70 años.
- Paciente que ofrezca garantías suficientes de adhesión al protocolo.
- Datos neurofisiológicos que confirmen afectación de motoneurona inferior a nivel lumbar y cervical.
- Valoración del déficit motor en la flexión dorsal de ambos pies (entre 3 y 5 puntos en la escala MRC).

E.4

Principal exclusion criteria

Mellitus diabetes.
- Other diseases that may occur with polyneuropathies.
- Previous history of cerebral stroke.
- Previous pathology of the peripheral nervous system that affects one or both lower or upper limbs, with or without clinically evident neurological sequelae.
- Pregnant or breast-feeding patients
- Patients who are physiologically capable of becoming pregnant, unless they are using a reliable method of contraception (Annex III)
- Patients with cardiac, renal, hepatic, systemic, immune disease that may influence the patient's survival during the trial.
- Positive serology for hepatitis B, hepatitis C or HIV.
- Clinical and anesthesiological criteria that contraindicate either sedation or the extraction of MO itself (alteration of the coagulation system or anticoagulated patient with inability to withdraw anticoagulation, hemodynamic instability, skin alteration in the puncture site, etc.)
- Inclusion in other clinical trials in the last 6 months.
- Inability to understand informed consent.

- Diabetes Mellitus.
- Otras enfermedades que puedan cursar con polineuropatías.
- Historia previa de ictus cerebral.
- Patología previa del sistema nervioso periférico que afectara a uno o ambos miembros inferiores o superiores, con o sin secuelas neurológicas clínicamente evidentes.
- Pacientes embarazadas o en período de lactancia activa
- Pacientes fisiológicamente capaces de quedarse embarazadas, excepto que estén utilizando un método anticonceptivo fiable (Anexo III)
- Pacientes con enfermedad cardiaca, renal, hepática, sistémica, inmune que pueda influir en la supervivencia del paciente durante el ensayo.
- Serología positiva para hepatitis B, hepatitis C o VIH.
- Criterios clínicos y anestesiológicos que contraindiquen bien la sedación o bien la propia extracción de MO (Alteración del sistema de la coagulación o paciente anticoagulado con imposibilidad para retirar la anticoagulación, inestabilidad hemodinámica, alteración cutánea en la zona de punción, etc.)
- Inclusión en otros ensayos clínicos en los últimos 6 meses.
- Incapacidad de comprender el consentimiento informado.

E.5 End points

E.5.1

Primary end point(s)

D50 index obtained from the stimulus intensity curves - size of the PAMC (D50, number without dimensions)

Absence of AAG with possible, probable or defined relationship with the procedure.

Rate of non-serious adverse events with possible, probable or defined relationship with the procedure.

Índice D50 obtenido a partir de las curvas intensidad de estímulo – tamaño del PAMC (D50; número sin dimensiones)

Ausencia de AAG con relación posible, probable o definida con el procedimiento.

Tasa de acontecimientos adversos no graves con relación posible, probable o definida con el procedimiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

• D50 index obtained from stimulus intensity curves - size of the PAMC (D50, number without dimensions)
• Absence of AAG with possible, probable or defined relationship with the procedure.
• Rate of non-serious adverse events with possible, probable or defined relationship with the procedure

• Índice D50 obtenido a partir de las curvas intensidad de estímulo – tamaño del PAMC (D50; número sin dimensiones)
• Ausencia de AAG con relación posible, probable o definida con el procedimiento.
• Tasa de acontecimientos adversos no graves con relación posible, probable o definida con el procedimiento

E.5.2

Secondary end point(s)

• Neurophysiological:

-Techniques for estimating the number of functional motor units (MUNE) by:

1. Quantification of the PAMC curve using the D50 index (no.).
2. "Motor unit number index (MUNIX and MUSIX) (number and microV respectively).

- Density of fibers (DF): No.

Quantifies the average number of muscle fibers per motor unit. It is obtained from records made with concentric needle electrodes. The average number of motor unit potentials is calculated at 20 different positions in the muscle.

- Compound muscle action potential (PAMC)

o Amplitude of the PAMC: mV
o Area of the PAMC: mV / ms

PAMC is recorded after stimulation with supramaximal intensity (pulses of 0.1-0.2 ms at 1 Hz) of the common peroneal nerve, at the level of the head of the fibula. The electrical stimulus is placed in a fixed position during the entire registration process. In the TA PAMC it will be registered simultaneously in 5 positions oriented longitudinally along the TA muscle. To determine these 5 positions, bone references that are reproducible between members and between different patients will be used. From among the records obtained in these 5 positions, the one in which the amplitude and / or area of the PAMC is maximum will be selected and all the parameters obtained from the records in this position (MUNE and DF) will be used for the statistical analysis. This registration position will also be used as a reference for the infusion in the TA muscle of the autologous MON CMNs (experimental) or placebo (control). In the PID, the optimal point of registration will be determined, which will also be the reference for intramuscular injection.

• Neurofisiológicas:

-Técnicas de estimación del número de unidades motoras funcionales (MUNE) mediante:

1. Cuantificación de la curva de PAMC scan mediante el índice D50 (nº).
2. “Motor unit number index (MUNIX y MUSIX) (nº y microV respectivamente).

- Densidad de fibras (DF): Nº

Cuantifica el número medio de fibras musculares por unidad motora. Se obtiene a partir de registros realizados con electrodos de aguja concéntricos. El número medio de potenciales de unidad motora es calculado en 20 posiciones diferentes en el músculo.

- Potencial de acción muscular compuesto (PAMC)

o Amplitud del PAMC: mV
o Área del PAMC: mV/ms

El PAMC es registrado después de la estimulación con intensidad supramáxima (pulsos de 0,1-0,2 ms a 1 Hz) del nervio peroneo común, a nivel de la cabeza del peroné. El estímulo eléctrico es colocado en una posición fija durante todo el proceso de registro. En el TA PAMC será registrado simultáneamente en 5 posiciones orientadas longitudinalmente a lo largo del músculo TA. Para determinar estas 5 posiciones se utilizarán referencias óseas que son reproducibles entre miembros y entre diferentes pacientes. De entre los registros obtenidos en estas 5 posiciones se seleccionará aquel en el que la amplitud y / o área del PAMC sea máxima y todos los parámetros obtenidos a partir de los registros en esta posición (MUNE y DF) se utilizarán para el análisis estadístico. Esta posición de registro también se utilizará como referencia para la infusión en el músculo TA de las CMN de MO autólogas (experimental) o placebo (control). En el PID se determinará el punto óptimo de registro, que también será la referencia para la inyección intramuscular.

E.5.2.1

Timepoint(s) of evaluation of this end point

24 months

24 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

E.6.4

Safety

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

24 months after the last patient infused

24 meses después de la infusión realizada al último paciente incluído

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

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

F.4 Planned number of subjects to be included

F.4.1

In the member state

100

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

Niguno

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

2019-10-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-30

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

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