Clinical Trials Register

Summary
EudraCT Number:	2022-003465-38
Sponsor's Protocol Code Number:	MS-tolDC_Phase2-RESTORE
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:	2023-01-31
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

2022-003465-38

A.3

Full title of the trial

A controlled phase II clinical trial evaluating the safety and efficacy of myelin peptide-loaded tolDC as treatment for multiple sclerosis

A.3.1

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

Clinical trial to evaluate the safety and efficacy of a treatment from patient's own dendritic cells in multiple sclerosis.

Ensayo clínico para evaluar la seguridad y la eficacia, en pacientes con esclerosis múltiple, de un tratamiento con células dendríticas del propio paciente.

A.4.1

Sponsor's protocol code number

MS-tolDC_Phase2-RESTORE

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	Antwerp University Hospital
B.1.3.4	Country	Belgium
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	Horizon 2020
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Antwerp
B.5.2	Functional name of contact point	Nathalie Cools
B.5.3	Address:
B.5.3.1	Street Address	Drie Eikenstraat 655
B.5.3.2	Town/ city	Edegem
B.5.3.3	Post code	2650
B.5.3.4	Country	Belgium
B.5.6	E-mail	nathalie.cools@uantwerpen.be
B.Sponsor: 2
B.1.1	Name of Sponsor	Hospital Universitari Germans Trias i Pujol
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	Horizon 2020
B.4.2	Country	European Union
B.4.1	Name of organisation providing support	Instituto de Salud Carlos III- Red SCReN
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	ICS-Hospital Germans Trias i Pujol
B.5.2	Functional name of contact point	Crisitina Ramo Tello
B.5.3	Address:
B.5.3.1	Street Address	Carretera de Canyet s/n
B.5.3.2	Town/ city	Badalona
B.5.3.3	Post code	08916
B.5.3.4	Country	Spain
B.5.4	Telephone number	34934978571
B.5.6	E-mail	cramot.germanstrias@gencat.cat

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	cryopreserved myelin-derived peptide-loaded tolerogenic dendritic cells
D.3.2	Product code	tolDC - intranodal
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intralymphatic use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Autologous myelin-derived peptide-pulsed tolerogenic dendritic cells
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	tolDC
D.3.9.3	Other descriptive name	cell suspension containing dendritic cells
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Diagnosis of multiple sclerosis, according to the most recent diagnostic criteria

Esclerosis Múltiple, según los criterios diagnósticos más recientes

E.1.1.1

Medical condition in easily understood language

Diagnosis of multiple sclerosis, according to the most recent diagnostic criteria

Esclerosis Múltiple, siguiendo los criterios diagnósticos más recientes

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10028245
E.1.2	Term	Multiple sclerosis
E.1.2	System Organ Class	10029205 - Nervous system disorders

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	10046859
E.1.2	Term	Vaccination
E.1.2	System Organ Class	100000004865

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 primary objective of the phase II study is to determine whether intradermal (in Belgium) or intranodal (in Spain) injection of tolDC is effective and safe. Adverse events, clinical relapse rates, neurological disability (assessed using various scales) and magnetic resonance imaging (MRI) endpoints will be measured over 18 months. Patients, receiving the tolDC intervention, will be compared to a standard-of-care control group
- primairy endpoints: safety (reporting of adverse events) and efficacy (the number of new and/or enlarging T2 lesions on MRI scans)
- secondary endpoints: (i) clinical: relapse rate, EDSS, 9HPT, T25FW and SDMT, and (ii) non-clinical: all other MRI outcomes
- Tertiary and exploratory endpoints: immunological responses and patient-reported quality of life (MS-QoL54)

El objetivo principal del ensayo de Fase II es determinar si la inyección de tolDC vía intradérmica (en Bélgica) o intranodal (en España) es efectiva y segura. Se recogerán y medirán durante 18 meses variables de acontecimientos adversos, tasas de recaídas clínicas, la discapacidad neurológica (evaluada mediante diferentes escalas) e imágenes de Resonancia Magnética (MRI). Los pacientes que reciban la intervención con tolDC, se compararán con un grupo control de estándar de tratamiento.
- Criterios de valoración primarios: seguridad (notificación de acontecimientos adversos) y eficacia (número de nuevas lesiones en T2 y/o aumento de volumen de las lesiones en T2 en las resonancias magnéticas)
-Criterios de valoración secundarios:
(i): clínicos: tasa de recaídas, EDSS, 9HPT, T25FW y SDMT, y (ii) no clínicos: todos los demás resultados de MRI
- Criterios de valoración terciarios y exploratorios: respuestas inmunológicas y calidad de vida informada por el paciente (MS-QoL54)

E.2.2

Secondary objectives of the trial

not applicable

no aplica

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age 18-60 years;
• Expanded disability status scale (EDSS) of 0.0 - 6.0 inclusive;
• Active MS (relapsing remitting and progressive): 1 relapse in the past year and/or at least 1 enhancing lesion on brain MRI in the past year and/or at least 1 new or enlarging T2 lesion in comparison with a reference scan from maximum 1 year before;
• MS patients already on first-line treatment or who will start first-line treatment (control arm) or untreated patients (no wish to be treated with currently available disease-modifying treatments or presence of treatment-related side effects; intervention arms);
• No evidence of relapse in the month prior to start of screening and throughout the screening phase;
• Normal total lymphocyte count;
• Normal peripheral B cell count;
• Able to sign informed consent;
• Ability to comply with the protocol assessments;
• Appropriate venous access;
• Appropriate cervical node mapping (only applicable for intranodal injection, in Spain)
• Use of adequate contraceptive measures in female and male patients of reproductive potential, for the duration of the trial.

• Edad 18-60 años;
• Escala ampliada del estado de discapacidad (EDSS) de 0.0 - 6.0 inclusive;
• Esclerosis Múltiple activa (remitente recurrente y progresiva): 1 recaída en el último año y/o al menos 1 lesión que realce en la resonancia magnética cerebral en el último año y/o al menos 1 lesión nueva o con aumento de volumen en T2 en comparación con un escáner de referencia desde máximo 1 año antes;
• Pacientes con EM que ya están en tratamiento de primera línea o que comenzarán la primera línea de tratamiento (brazo control) o pacientes no tratados (no desean ser tratados con tratamientos modificadores de la enfermedad actualmente disponibles o presencia de efectos secundarios relacionados con el tratamiento; brazos de intervención);
• Sin evidencia de recaída en el mes anterior al inicio de la selección y durante toda la fase de selección;
• Recuento total normal de linfocitos;
• Recuento normal de células B periféricas;
• Capaz de firmar el consentimiento informado;
• Capacidad para cumplir con las evaluaciones del protocolo;
• Accesos venosos apropiados;
• Mapeo apropiado de ganglios cervicales (solo aplicable para la inyección intraganglionar, en España)
• Uso de medidas anticonceptivas adecuadas en pacientes de ambos sexos con potencial reproductivo, durante la duración del ensayo.

E.4

Principal exclusion criteria

For the tolDC intervention groups only:
• Previous use of immunosuppressive or cytostatic treatment, including cyclophosphamide, mitoxantrone, bone marrow transplantation or (hematopoietic or mesenchymal) stem cell transplantation (at any time) prior to enrolment;
• Previous use of cladribine with last course within last 2 years or alemtuzumab with last course within last 4 years;
• Use of interferon beta and glatiramer acetate in the 4 previous weeks;
• Treatment with fingolimod, natalizumab, immunoglobulins or plasmapheresis in the past 3 months; teriflunomide in the previous 15 weeks; anti-CD20 monoclonal antibody (including ofatumumab, rituximab and ocrelizumab) within the past 6 months prior to the first administration and until confirmation of B cell count normalization;

For all participants:
• Relapse / use of corticosteroids for any reason in the previous month;
• Pregnancy or planning pregnancy in the next 12 months and breast feeding;
• Fertile patients, both men and women, who are not using an adequate method of contraception. If the patient is menopausal or sterile, this has to be documented in the medical history.
• Drug or alcohol abuse;
• Inability to undergo MRI assessments;
• History of or actual signs of immunodeficiency or malignancies;
• History of oncological diseases unless local basal cell carcinoma
• Concurrent clinically relevant cardiac, immunological, pulmonary, neurological, renal or other major disease;
• Hepatitis B or C, HIV serology, syphilis or tuberculosis;
• Splenectomy;
• Dementia or severe psychiatric, cognitive or behavioral problems or other comorbidity that could interfere with the compliance to the protocol;
• Participating in another interventional clinical trial, or having participated in one, in the last 3 months;
• Previous treatment with tolDC.

Sólo para los grupos de intervención con tolDC:
• Uso previo de tratamiento inmunosupresor o citostático, incluyendo ciclofosfamida, mitoxantrona, trasplante de médula ósea o trasplante de células madre (hematopoyético o mesenquimal) (en cualquier momento) antes de la inclusión;
• Uso previo de cladribina con el último ciclo dentro de los 2 años previos o alemtuzumab con el último ciclo en los últimos 4años;
• Uso de interferón beta y acetato de glatirámero en los 4 semanas anteriores;
• Tratamiento con fingolimod, natalizumab, inmunoglobulinas o plasmaféresis en los últimos 3 meses; teriflunomida en las 15 semanas previas; anticuerpos monoclonales anti-CD20 (incluyendo ofatumumab, rituximab y ocrelizumab) en los últimos 6 meses anteriores a la primera administración, y hasta la confirmación de la normalización del recuento de células B;

Para todos los participantes:
• Recaída / uso de corticosteroides por cualquier motivo en el mes anterior;
• Embarazo o planificación del embarazo en los próximos 12 meses y lactancia materna;
• Pacientes fértiles, tanto hombres como mujeres, que no estén utilizando un método anticonceptivo. Si una paciente es menopáusica o estéril, debe estar documentado en la historia clínica;
• Abuso de drogas o alcohol;
• Incapacidad para someterse a evaluaciones de resonancia magnética;
• Antecedentes o signos actuales de inmunodeficiencia o neoplasias malignas;
• Antecedentes de enfermedades oncológicas salvo carcinoma basocelular local;
• Enfermedad concurrente clínicamente relevante cardíaca, inmunológica, pulmonar, neurológica, renal u otra enfermedad importante;
• Hepatitis B o C, serología del VIH, sífilis o tuberculosis;
• Esplenectomía;
• Demencia o problemas psiquiátricos, cognitivos o conductuales graves u otra comorbilidad que podría interferir con el cumplimiento del protocolo;
• Estar participando en otro ensayo clínico de intervención, o haber participado en uno en los últimos 3 meses;
• Tratamiento previo con tolDC.

E.5 End points

E.5.1

Primary end point(s)

- Efficacy (the number of new and/or enlarging T2 lesions on MRI scans)
- Safety (reporting of adverse events)

• Eficacia (el número de lesiones nuevas en T2 y/o con aumento de volumen de las lesiones en T2 en las resonancias magnéticas)
• Seguridad (notificación de acontecimientos adversos)

E.5.1.1

Timepoint(s) of evaluation of this end point

- trial entry, defined as the day that the patient signs the informed consent form
- at each vaccination visit (V1 to V6)
- at follow up visits (F1, F3, F6 and F12)

• A la inclusión en el ensayo, definida como el día en que el paciente firma el formulario de consentimiento informado
• En cada visita de administración del producto celular (V1 a V6)
• En las visitas de seguimiento (F1, F3, F6 y F12)

E.5.2

Secondary end point(s)

- clinical: relapse rate, EDSS, 9HPT, T25FW and SDMT
- non-clinical: T2 lesion volume, atrophy rate, total brain volume and fractional anisotropy (FA) on MRI scans

• Clínicas: tasa de recaídas, EDSS, (Expanded Disability Status Scale), 9HPT ( Nine-Hole Peg Tes), T25FW (Timed 25 foot walk) y SDMT (Symbol Digit Modalities test)
• No clínicas: volumen de lesiones en T2, tasa de atrofia, volumen cerebral total y anisotropía fraccional (FA) en resonancias magnéticas

E.5.2.1

Timepoint(s) of evaluation of this end point

CLINICAL:
- trial entry, defined as the day that the patient signs the informed consent form
- at each vaccination visit (V1 to V6)
- at follow up visits (F1, F3, F6 and F12)

NON-CLINICAL:
- at screening, V1, V4, V6, F1, F6 and F12

• De las variables CLÍNICAS:
- A la inclusión en el ensayo definida como el día en que el paciente firma el formulario de consentimiento informado
- En cada visita de administración del producto celular (V1 a V6)
- En las visitas de seguimiento (F1, F3, F6 y F12)

• De las variables NO CLÍNICAS:
- En la selección, V1, V4, V6, F1, F6 y F12

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Standard-of-care

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

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

The final end date of this trial is defined as the date when 24 evaluable patients per arm have completed the study

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)

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

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

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. Normal treatment and follow-up.

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	Spanish Clinical Research Network- SCREN
G.4.3.4	Network Country	Spain

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2023-06-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-04-24

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

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