Clinical Trials Register

Summary
EudraCT Number:	2019-002446-21
Sponsor's Protocol Code Number:	ARTROCELL
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:	2020-01-10
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

2019-002446-21

A.3

Full title of the trial

Phase III, multicentre, randomized, open clinical trial comparing treatment with allogenic mesenchymal cells against autologous mesenchymal cells and against active control with hyaluronic acid in patients with knee osteoarthritis.

Ensayo clínico fase III, multicéntrico, aleatorizado, abierto, de comparación del tratamiento con células mesenquimales alogénicas frente a células mesenquimales autólogas y frente a control activo con ácido hialurónico en pacientes con artrosis de rodilla.

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

ARTROCELL

A.4.1

Sponsor's protocol code number

ARTROCELL

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	IBSAL (Instituto de Investigación Biomédica de Salamanca)
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	Instituto de Salud Carlos III
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	SCReN - UICEC CAUSA/IBSAL
B.5.2	Functional name of contact point	Clinical project manager
B.5.3	Address:
B.5.3.1	Street Address	Paseo de San Vicente, 58-182
B.5.3.2	Town/ city	Salamanca
B.5.3.3	Post code	37007
B.5.3.4	Country	Spain
B.5.4	Telephone number	349232911005577
B.5.6	E-mail	esperanza.lopez@scren.es

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
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	Durolane
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarticular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Hyaluronc acid
D.3.9.1	CAS number	9004-61-9
D.3.9.3	Other descriptive name	HYALURONIC ACID
D.3.9.4	EV Substance Code	SUB14126MIG
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	60
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.IMP: 2
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 mesenquimal cells
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarticular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AUTOLOGOUS ADULT HUMAN MESENCHYMAL STEM CELLS EX-VIVO EXPANDED
D.3.9.3	Other descriptive name	BONE MARROW-DERIVED MESENCHYMAL STEM CELLS
D.3.9.4	EV Substance Code	SUB194470
D.3.10	Strength
D.3.10.1	Concentration unit	million IU million international units
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
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	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.IMP: 3
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	Allogenic mesenchymal stem cells
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarticular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ALLOGENEIC ADULT HUMAN MESENCHYMAL STEM CELLS EX-VIVO EXPANDED
D.3.9.3	Other descriptive name	ALLOGENEIC ADULT HUMAN MESENCHYMAL STEM CELLS EX-VIVO EXPANDED
D.3.9.4	EV Substance Code	SUB196571
D.3.10	Strength
D.3.10.1	Concentration unit	million IU million international units
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Knee osteoarthritis

Osteoartritis de rodilla

E.1.1.1

Medical condition in easily understood language

Knee osteoarthritis

Osteoartritis de rodilla

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

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	10023476
E.1.2	Term	Knee osteoarthritis
E.1.2	System Organ Class	100000004859

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate comparatively the efficacy of allogeneic MSCs and autologous MSCs against an active control with hyaluronic acid in terms of clinical-functional and radiological response.

Evaluar comparativamente la eficacia de las MSC alogénicas y de las MSC autólogas frente a un control activo con ácido hialurónico en términos de respuesta clínico-funcional y radiológica.

E.2.2

Secondary objectives of the trial

• Analyze comparatively changes in the quality of life of patients in the three experimental groups
• Confirm the feasibility of the cell treatment of both cell types in a multi-center strategy with various Cell Production Units, analyzing the rate of products that do not comply with the release criteria and the characteristics of the product released and infused.
• Collect the rate of adverse effects and other pharmacovigilance parameters in the three treatment branches.

• Analizar comparativamente los cambios en la calidad de vida de los pacientes en los tres grupos experimentales
• Confirmar la factibilidad del tratamiento celular de ambos tipos celulares en una estrategia multicéntrica con diversas Unidades de Producción Celular, analizando la tasa de productos no conformes con los criterios de liberación y las características del producto liberado e infundido.
• Recoger la tasa de efectos adversos y otros parámetros de farmacovigilancia en las tres ramas de tratamiento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Kellgren and Lawrence grade 2, 3 or 4 gonarthrosis.
2. Chronic painful knee of mechanical characteristics.
3. Absence of local or systemic septic process.
4. Hematological and biochemical analysis without significant alterations that contraindicate the treatment.
5. Informed written consent of the patient.
6. The patient is able to understand the nature of the study.
7. NEGATIVE Serologies: RPR, HIV, HBV, HCV and HCV PCR, in the 30 days prior to bone marrow extraction.
8. Body Mass Index 20-35 Kg / m2.

1. Gonartrosis grado 2, 3 o 4 de Kellgren y Lawrence.
2. Rodilla dolorosa crónica de características mecánicas.
3. Ausencia de proceso séptico local o sistémico.
4. Análisis hematológicas y bioquímicas sin alteraciones significativas que contraindiquen el tratamiento.
5. Consentimiento informado por escrito del paciente.
6. El paciente es capaz de entender la naturaleza de estudio.
7. Serologías NEGATIVAS: RPR, VIH, VHB, VHC y PCR VHC, en los 30 días anteriores a la extracción de la médula ósea..
8. Índice de Masa Corporal 20-35 Kg/m2.

E.4

Principal exclusion criteria

1. Patient <18 years, or legally dependent.
2. Patient> 75 years.
3. Present infection (to be included in the study, no infectious signs should be evidenced).
4. Congenital or evolutionary diseases that translate malformation and / or significant deformations of the knee (varus <10º; valgus <20º) and condition difficulties of application and evaluation of the results.
5. Weight overload expressed in body mass index (BMI) greater than 30.5 (grade II obesity). Being BMI = mass (Kg): (height (m)) 2.
6. Women who are pregnant or pretend to be pregnant or breastfeeding.
7. Neoplastic disease.
8. Primary or secondary immunosuppression.
9. Intra-articular infiltration of any drug in the 3 months prior to inclusion in the study.
10. Simultaneous participation in another clinical trial or treatment with another product under investigation in the 30 days prior to inclusion in the study.
11. Other pathologies or circumstances that compromise participation in the study according to medical criteria.

1. Paciente < 18 años, o legalmente dependiente.
2. Paciente > 75 años.
3. Infección presente (para incluirse en el estudio no debe evidenciarse ningún signo infeccioso).
4. Enfermedades congénitas o evolutivas que traduzcan malformación y/o deformaciones significativas de la rodilla (varo<10º; valgo<20º) y condicionen dificultades de aplicación y de evaluación de los resultados.
5. Sobrecarga ponderal expresada en índice de masa corporal (IMC) superior a 30,5 (obesidad grado II). Siendo IMC= masa (Kg): (altura (m))2.
6. Mujeres embarazadas o que pretenden estarlo, o en periodo de lactancia.
7. Enfermedad neoplásica.
8. Inmunodepresión primaria o secundaria.
9. Infiltración intraarticular de cualquier fármaco en los 3 meses previos a la inclusión en el estudio.
10. Participación simultánea en otro ensayo clínico o tratamiento con otro producto en fase de investigación en los 30 días previos a la inclusión en el estudio.
11. Otras patologías o circunstancias que comprometan la participación en el estudio según criterio médico.

E.5 End points

E.5.1

Primary end point(s)

Assessment of the clinical-functional and radiological response response based on the following parameters:
- Measurement of pain intensity according to the EVA pain scale at 12 months.
- Assessment of functional capacity and pain according to the LENESQUE scale at 12 months
- Measurement of symptomatology and perceived physical disability according to the WOMAC scale at 12 months.
- Estimation of the improvement or stabilization of the lesions in the MR images in T2-mapping at 12 months.

Valoración de la respuesta respuesta clínico-funcional y radiológica en función de los siguientes parámetros:
- Medida de la intensidad del dolor según la escala de dolor EVA a los 12 meses .
- Valoración de la capacidad funcional y el dolor según la escala de LENESQUE a los 12 meses
- Medida de la sintomatología y la discapacidad física percibida según la escala WOMAC a los 12 meses.
- Estimación de la mejoría o estabilización de las lesiones en las imágenes de RM en T2-mapping a los 12 meses.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months.
Intermediate values will be collected in order to estimate patient evolution at 7 days and 3 and 6 months.

12 Meses.
Se recogerán valores intermedios para evaluar la evolución del paciente a los 7 días y a los 3 y 6 meses.

E.5.2

Secondary end point(s)

- Assessment of perceived quality of life on the SF-12 scale at 6 and 12 months.
- Rate of products that do not comply with the validation criteria in each branch of experimental treatment.
- Rate of adverse effects in each of the treatment branches.

- Valoración de la calidad de vida percibida en la escala SF-12 a los 6 y 12 meses.
- Tasa de productos no conformes con los criterios de validación en cada rama de tratamiento experimental.
- Tasa de efectos adversos en cada una de las ramas de tratamiento.

E.5.2.1

Timepoint(s) of evaluation of this end point

- Día +1
- Día +7
- 3 Meses
- 6 Meses
- 12 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)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

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

Last patient last visit

Última visita del último paciente

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)

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

120

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)

Usual treatment/common practice National Health System

Práctica habitual en el Sistema Nacional de Salud.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Red Nacional de Terapia Celular

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-04-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-08

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

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