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Tolerogenic Dendritic Cells as a Therapeutic Strategy for the Treatment of Multiple Sclerosis Patients (TOLERVIT-MS) (TOLERVIT-MS)

Primary Purpose

Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis, Chronic Progressive

Status

Recruiting

Phase

Phase 1

Locations

Spain

Study Type

Interventional

Intervention

Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)

Interferon-beta

About this trial

This is an interventional treatment trial for Multiple Sclerosis, Relapsing-Remitting focused on measuring Multiple Sclerosis, Dendritic Cells, Immune Tolerance, Myelin Proteins, Tolerogenic dendritic cells

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

EDSS of 0.0 - 6.5.
Multiple Sclerosis according to 2010 revised Mc Donald criteria, and less than 15 years of evolution of disease.
Patients with:
- Active relapsing remitting multiple sclerosis (RRMS) (more than 1 relapse in last year and/or occurrence of ≥3 new T2 lesions or Gd positive) who not wish to be treated with current therapies.
- Low activity RRMS (1 relapse in last year or occurrence of 1 or 2 T2 lesions or Gd positive) without treatment.
- Progressive forms of MS with activity (at least 1 relapse in last year or occurrence 1 or 2 T2 lesions or Gd positive).
- RRMS treated with interferon beta (Additional group)
T cell proliferation to the pool of myelin peptides against which is to induce immune tolerance: Myelin basic protein (MBP)13-32, MBP83-99, MBP111-129, MBP146-170, proteolipid protein (PLP) 139-154, Myelin oligodendrocyte glycoprotein (MOG)1-20, MOG35 -55).
Adequate peripheral venous access.
Signed informed consent.

Exclusion Criteria:

Use of corticosteroids during the prior 4 weeks.
Use of interferon beta -in patients who is retired by inefficiency or other causes- and glatiramer acetate in the 4 weeks prior.
Use of fingolimod, dimethylfumarate, natalizumab, immunoglobulins or plasmapheresis at 12 weeks; and teriflunomide in the 15 weeks prior.
Use of azathioprine, mitoxantrone, rituximab, methotrexate, cyclophosphamide, cyclosporine, alemtuzumab or other immunosuppressive drug, except corticosteroids, at any time.
Bone marrow or stem cell transplant at any time.
Relapse during the month prior of starting treatment. If it appears and the patient meets the eligibility criteria, must wait long enough until the end of the 30 days free of relapse. If corticosteroids are administered, the MRI performed during this period should not be considered, and a new MRI will be performed at 4 weeks after administration of corticosteroids.
Pregnancy or planning pregnancy within the next 12 months and breastfeeding.
Fertile patients who are not using an appropriate method of contraception. If the patient is menopausal or sterile it must be documented in the medical record.
Abusing drugs or alcohol.
Inability to undergo MRI evaluations.
Seropositivity for HIV, hepatitis B or C and/or syphilis.
History of oncological disease.
Clinically relevant concomitant disease: cardiac, pulmonary, neurological, renal or other major illness.
Splenectomy.
Dementia, psychiatric problems or other comorbidities that might interfere protocol compliance.
To be participating in another clinical study or to have participated in one in the last 3 months.

Sites / Locations

Hospital Universitari Germans Trias i PujolRecruiting
Clínica Universidad de Navarra

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

5 * 10 ^6 tolDC-VitD3

10 * 10 ^6 tolDC-VitD3

15 * 10 ^6 tolDC-VitD3

Interferon-beta

Arm Description

5 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)

10 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3).

15 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3).

Additional group (patients treated with beta-interferon) will receive the selected dose of those 3 previously cohorts studied

Outcomes

Primary Outcome Measures

Safety as assessed by the occurrence and severity of adverse events

Occurence and severity of adverse events will be recorded

Neurologic changes

New relapse. Disability progression on Expanded Disability Status Scale (EDSS)

Radiologic changes

Number of new or enlarging T2 lesions on brain MRI. Number of Gadolinium (Gd)-enhancing T1 lesions on brain MRI

Secondary Outcome Measures

Annual relapse rate (ARR)

Expanded Disability Status Scale (EDSS)

9-Hole Peg Test (9HPT)

25-Foot Walking Test (T25FW)

Symbol Digit Modalities Test (SDMT)

Radiologic preliminary efficacy

Number of new or enlarging T2 lesions on brain MRI. Number of Gadolinium (Gd)-enhancing T1 lesions on brain MRI

Lymphocyte proliferation to myelin peptides

Blood Immunomonitoring studies

Feasibility

Generation of Good Manufacturing Practices (GMP)-grade cell product released according to Quality Control. Feasibility of cellular product injection.

Full Information

NCT ID

NCT02903537

First Posted

July 21, 2016

Last Updated

July 6, 2023

Sponsor

Fundació Institut Germans Trias i Pujol

Collaborators

Clinica Universidad de Navarra, Universidad de Navarra

1. Study Identification

Unique Protocol Identification Number

NCT02903537

Brief Title

Tolerogenic Dendritic Cells as a Therapeutic Strategy for the Treatment of Multiple Sclerosis Patients (TOLERVIT-MS)

Acronym

TOLERVIT-MS

Official Title

Tolerance-Induction With Dendritic Cells Treated With Vitamin-D3 and Loaded With Myelin Peptides, in Multiple Sclerosis Patients (TOLERVIT-MS)

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Recruiting

Study Start Date

July 6, 2017 (Actual)

Primary Completion Date

December 2023 (Anticipated)

Study Completion Date

December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Fundació Institut Germans Trias i Pujol

Collaborators

Clinica Universidad de Navarra, Universidad de Navarra

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to determine the safety and tolerability of the intranodal administration of autologous monocyte-derived dendritic cells tolerised with Vitamin-D3 and pulsed with myelin peptides (tolDC-VitD3) in multiple sclerosis patients . To select the most appropriate regime for the development of future therapeutic trials. To evaluate the preliminary proof of concept by clinical and/or radiological activity and immunological markers.

Detailed Description

Phase I dose ascending ("best of five") clinical trial. First group will start by intranodal injection in cervical lymph nodes of 5*10^6 tolDC-VitD3. Up titration depending on security outcomes to 10*10^6 tolDC-VitD3, same route in second cohort dose and next uptitration to 15*10^6 tolDC-VitD3. Six cycles per patient with the following schema: for the first four cycles the administration will be each 2 weeks, for the remaining 2 cycles administration each 4 weeks. A last cohort with the dose identified in the previous groups, administered in patients treated with beta interferon, same route, same dose schema.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis, Chronic Progressive

Keywords

Multiple Sclerosis, Dendritic Cells, Immune Tolerance, Myelin Proteins, Tolerogenic dendritic cells

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

16 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

5 * 10 ^6 tolDC-VitD3

Arm Type

Experimental

Arm Description

5 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)

Arm Title

10 * 10 ^6 tolDC-VitD3

Arm Type

Experimental

Arm Description

10 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3).

Arm Title

15 * 10 ^6 tolDC-VitD3

Arm Type

Experimental

Arm Description

15 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3).

Arm Title

Interferon-beta

Arm Type

Experimental

Arm Description

Additional group (patients treated with beta-interferon) will receive the selected dose of those 3 previously cohorts studied

Intervention Type

Drug

Intervention Name(s)

Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)

Other Intervention Name(s)

tolDC-VitD3

Intervention Description

Intranodal administration

Intervention Type

Drug

Intervention Name(s)

Interferon-beta

Other Intervention Name(s)

beta-interferon

Intervention Description

Subcutaneous administration interferon-beta

Primary Outcome Measure Information:

Title

Safety as assessed by the occurrence and severity of adverse events

Description

Occurence and severity of adverse events will be recorded

Time Frame

24 months

Title

Neurologic changes

Description

New relapse. Disability progression on Expanded Disability Status Scale (EDSS)

Time Frame

24 months

Title

Radiologic changes

Description

Number of new or enlarging T2 lesions on brain MRI. Number of Gadolinium (Gd)-enhancing T1 lesions on brain MRI

Time Frame

24 months

Secondary Outcome Measure Information:

Title

Annual relapse rate (ARR)

Time Frame

24 months

Title

Expanded Disability Status Scale (EDSS)

Time Frame

24 months

Title

9-Hole Peg Test (9HPT)

Time Frame

24 months

Title

25-Foot Walking Test (T25FW)

Time Frame

24 months

Title

Symbol Digit Modalities Test (SDMT)

Time Frame

24 months

Title

Radiologic preliminary efficacy

Description

Number of new or enlarging T2 lesions on brain MRI. Number of Gadolinium (Gd)-enhancing T1 lesions on brain MRI

Time Frame

24 months

Title

Lymphocyte proliferation to myelin peptides

Time Frame

24 months

Title

Blood Immunomonitoring studies

Time Frame

24 months

Title

Feasibility

Description

Generation of Good Manufacturing Practices (GMP)-grade cell product released according to Quality Control. Feasibility of cellular product injection.

Time Frame

6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: EDSS of 0.0 - 6.5. Multiple Sclerosis according to 2010 revised Mc Donald criteria, and less than 15 years of evolution of disease. Patients with: Active relapsing remitting multiple sclerosis (RRMS) (more than 1 relapse in last year and/or occurrence of ≥3 new T2 lesions or Gd positive) who not wish to be treated with current therapies. Low activity RRMS (1 relapse in last year or occurrence of 1 or 2 T2 lesions or Gd positive) without treatment. Progressive forms of MS with activity (at least 1 relapse in last year or occurrence 1 or 2 T2 lesions or Gd positive). RRMS treated with interferon beta (Additional group) T cell proliferation to the pool of myelin peptides against which is to induce immune tolerance: Myelin basic protein (MBP)13-32, MBP83-99, MBP111-129, MBP146-170, proteolipid protein (PLP) 139-154, Myelin oligodendrocyte glycoprotein (MOG)1-20, MOG35 -55). Adequate peripheral venous access. Signed informed consent. Exclusion Criteria: Use of corticosteroids during the prior 4 weeks. Use of interferon beta -in patients who is retired by inefficiency or other causes- and glatiramer acetate in the 4 weeks prior. Use of fingolimod, dimethylfumarate, natalizumab, immunoglobulins or plasmapheresis at 12 weeks; and teriflunomide in the 15 weeks prior. Use of azathioprine, mitoxantrone, rituximab, methotrexate, cyclophosphamide, cyclosporine, alemtuzumab or other immunosuppressive drug, except corticosteroids, at any time. Bone marrow or stem cell transplant at any time. Relapse during the month prior of starting treatment. If it appears and the patient meets the eligibility criteria, must wait long enough until the end of the 30 days free of relapse. If corticosteroids are administered, the MRI performed during this period should not be considered, and a new MRI will be performed at 4 weeks after administration of corticosteroids. Pregnancy or planning pregnancy within the next 12 months and breastfeeding. Fertile patients who are not using an appropriate method of contraception. If the patient is menopausal or sterile it must be documented in the medical record. Abusing drugs or alcohol. Inability to undergo MRI evaluations. Seropositivity for HIV, hepatitis B or C and/or syphilis. History of oncological disease. Clinically relevant concomitant disease: cardiac, pulmonary, neurological, renal or other major illness. Splenectomy. Dementia, psychiatric problems or other comorbidities that might interfere protocol compliance. To be participating in another clinical study or to have participated in one in the last 3 months.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Cristina Ramo, MD.PhD. Neurologist

Phone

+34934978433

cramot.germanstrias@gencat.cat

First Name & Middle Initial & Last Name or Official Title & Degree

Ana M Barriocanal, MD.PhD.Clinical Pharmacologist

Phone

+34934978488

ambarrioocanal@igtp.cat

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Cristina Ramo, MD.PhD.Neurologist

Organizational Affiliation

Badalona Hospital Germans Trias i Pujol. Neurology service. Multiple Sclerosis department

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Eva Martínez-Cáceres, MD.PhD.Immunology

Organizational Affiliation

Badalona Hospital Germans Trias i Pujol. Immunology

Official's Role

Study Director

Facility Information:

Facility Name

Hospital Universitari Germans Trias i Pujol

City

Badalona

State/Province

Barcelona

ZIP/Postal Code

08916

Country

Spain

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Cristina Ramo, MD.PhD

Phone

+34934978433

cramot.germanstrias@gencat.cat

First Name & Middle Initial & Last Name & Degree

Ana M Barriocanal, MD.PhD

Phone

+34934978488

ambarriocanal@igtp.cat

First Name & Middle Initial & Last Name & Degree

Eva Martínez-Cáceres, MD.PhD.Immunology

First Name & Middle Initial & Last Name & Degree

Silvia Presas, MD.Neurology

First Name & Middle Initial & Last Name & Degree

Magí Farré, MD.PhD.Clinical Pharmacology

First Name & Middle Initial & Last Name & Degree

Ana M Barriocanal, MD.PhD.Clinical Pharmacology

First Name & Middle Initial & Last Name & Degree

María J Mansilla, MD.Immunology

First Name & Middle Initial & Last Name & Degree

Bibiana Quirant, MD.Immunology

First Name & Middle Initial & Last Name & Degree

Aina Teniente, MD.Immunology

First Name & Middle Initial & Last Name & Degree

Juan Navarro, MD.Immunology

First Name & Middle Initial & Last Name & Degree

Josep Munuera, MD.Radiology

First Name & Middle Initial & Last Name & Degree

Anna Massuet, MD.Radiology

First Name & Middle Initial & Last Name & Degree

Jordi Reverter, MD.Endocrine Intervention

First Name & Middle Initial & Last Name & Degree

Anna Suñol, RN

Facility Name

Clínica Universidad de Navarra

City

Pamplona

State/Province

Navarra

ZIP/Postal Code

31008

Country

Spain

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jaime Gállego, MD.PhD

Phone

+34948255400

Ext

3594

jgallego@unav.es

First Name & Middle Initial & Last Name & Degree

Amaya Izal

Phone

+34948255400

Ext

2724

aizal@unav.es

First Name & Middle Initial & Last Name & Degree

Jaime Gallego, MD.PhD. Neurology

First Name & Middle Initial & Last Name & Degree

Purificación De Castro, MD.Neurology

First Name & Middle Initial & Last Name & Degree

Felipe Prosper, MD.Haematology

First Name & Middle Initial & Last Name & Degree

Susana Inogés, MD.Immunology

First Name & Middle Initial & Last Name & Degree

Ascensión López, MD.Immunology

First Name & Middle Initial & Last Name & Degree

Enrique Andreu, MD.Cell therapy

First Name & Middle Initial & Last Name & Degree

Javier Larrache, MD.Radiology

First Name & Middle Initial & Last Name & Degree

Carmen Azcona, RN

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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23740901

Citation

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Links:

URL

http://www.afactt.eu

Description

European Cooperation in Science and Technology (COST), Action BM1305 "Action to focus and accelerate cell-based tolerogenic therapies"

Learn more about this trial

Tolerogenic Dendritic Cells as a Therapeutic Strategy for the Treatment of Multiple Sclerosis Patients (TOLERVIT-MS)

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