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

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ClinicalTrials.gov Identifier: NCT02903537
Recruitment Status : Recruiting
First Posted : September 16, 2016
Last Update Posted : May 1, 2018
Sponsor:
Collaborator:
Clinica Universidad de Navarra, Universidad de Navarra
Information provided by (Responsible Party):
Fundació Institut Germans Trias i Pujol

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.


Condition or disease Intervention/treatment Phase
Multiple Sclerosis, Relapsing-Remitting Multiple Sclerosis, Chronic Progressive Drug: Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3) Drug: Interferon-beta Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Tolerance-Induction With Dendritic Cells Treated With Vitamin-D3 and Loaded With Myelin Peptides, in Multiple Sclerosis Patients (TOLERVIT-MS)
Actual Study Start Date : July 6, 2017
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : September 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 5 * 10 ^6 tolDC-VitD3
5 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)
Drug: Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)
Intranodal administration
Other Name: tolDC-VitD3

Experimental: 10 * 10 ^6 tolDC-VitD3
10 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3).
Drug: Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)
Intranodal administration
Other Name: tolDC-VitD3

Experimental: 15 * 10 ^6 tolDC-VitD3
15 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3).
Drug: Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)
Intranodal administration
Other Name: tolDC-VitD3

Experimental: Interferon-beta
Additional group (patients treated with beta-interferon) will receive the selected dose of those 3 previously cohorts studied
Drug: Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)
Intranodal administration
Other Name: tolDC-VitD3

Drug: Interferon-beta
Subcutaneous administration interferon-beta
Other Name: beta-interferon




Primary Outcome Measures :
  1. Safety as assessed by the occurrence and severity of adverse events [ Time Frame: 24 months ]
    Occurence and severity of adverse events will be recorded

  2. Neurologic changes [ Time Frame: 24 months ]
    New relapse. Disability progression on Expanded Disability Status Scale (EDSS)

  3. Radiologic changes [ Time Frame: 24 months ]
    Number of new or enlarging T2 lesions on brain MRI. Number of Gadolinium (Gd)-enhancing T1 lesions on brain MRI


Secondary Outcome Measures :
  1. Annual relapse rate (ARR) [ Time Frame: 24 months ]
  2. Expanded Disability Status Scale (EDSS) [ Time Frame: 24 months ]
  3. 9-Hole Peg Test (9HPT) [ Time Frame: 24 months ]
  4. 25-Foot Walking Test (T25FW) [ Time Frame: 24 months ]
  5. Symbol Digit Modalities Test (SDMT) [ Time Frame: 24 months ]
  6. Radiologic preliminary efficacy [ Time Frame: 24 months ]
    Number of new or enlarging T2 lesions on brain MRI. Number of Gadolinium (Gd)-enhancing T1 lesions on brain MRI

  7. Lymphocyte proliferation to myelin peptides [ Time Frame: 24 months ]
  8. Blood Immunomonitoring studies [ Time Frame: 24 months ]
  9. Feasibility [ Time Frame: 6 months ]
    Generation of Good Manufacturing Practices (GMP)-grade cell product released according to Quality Control. Feasibility of cellular product injection.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. EDSS of 0.0 - 6.5.
  2. Multiple Sclerosis according to 2010 revised Mc Donald criteria, and less than 15 years of evolution of disease.
  3. 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)
  4. 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).
  5. Adequate peripheral venous access.
  6. Signed informed consent.

Exclusion Criteria:

  1. Use of corticosteroids during the prior 4 weeks.
  2. Use of interferon beta -in patients who is retired by inefficiency or other causes- and glatiramer acetate in the 4 weeks prior.
  3. Use of fingolimod, dimethylfumarate, natalizumab, immunoglobulins or plasmapheresis at 12 weeks; and teriflunomide in the 15 weeks prior.
  4. Use of azathioprine, mitoxantrone, rituximab, methotrexate, cyclophosphamide, cyclosporine, alemtuzumab or other immunosuppressive drug, except corticosteroids, at any time.
  5. Bone marrow or stem cell transplant at any time.
  6. 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.
  7. Pregnancy or planning pregnancy within the next 12 months and breastfeeding.
  8. 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.
  9. Abusing drugs or alcohol.
  10. Inability to undergo MRI evaluations.
  11. Seropositivity for HIV, hepatitis B or C and/or syphilis.
  12. History of oncological disease.
  13. Clinically relevant concomitant disease: cardiac, pulmonary, neurological, renal or other major illness.
  14. Splenectomy.
  15. Dementia, psychiatric problems or other comorbidities that might interfere protocol compliance.
  16. To be participating in another clinical study or to have participated in one in the last 3 months.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02903537


Contacts
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Contact: Cristina Ramo, MD.PhD. Neurologist +34934978433 cramot.germanstrias@gencat.cat
Contact: Ana M Barriocanal, MD.PhD.Clinical Pharmacologist +34934978488 ambarrioocanal@igtp.cat

Locations
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Spain
Hospital Universitari Germans Trias i Pujol Recruiting
Badalona, Barcelona, Spain, 08916
Contact: Cristina Ramo, MD.PhD    +34934978433    cramot.germanstrias@gencat.cat   
Contact: Ana M Barriocanal, MD.PhD    +34934978488    ambarriocanal@igtp.cat   
Sub-Investigator: Eva Martínez-Cáceres, MD.PhD.Immunology         
Sub-Investigator: Silvia Presas, MD.Neurology         
Sub-Investigator: Magí Farré, MD.PhD.Clinical Pharmacology         
Sub-Investigator: Ana M Barriocanal, MD.PhD.Clinical Pharmacology         
Sub-Investigator: María J Mansilla, MD.Immunology         
Sub-Investigator: Bibiana Quirant, MD.Immunology         
Sub-Investigator: Aina Teniente, MD.Immunology         
Sub-Investigator: Juan Navarro, MD.Immunology         
Sub-Investigator: Josep Munuera, MD.Radiology         
Sub-Investigator: Anna Massuet, MD.Radiology         
Sub-Investigator: Jordi Reverter, MD.Endocrine Intervention         
Sub-Investigator: Anna Suñol, RN         
Clínica Universidad de Navarra Not yet recruiting
Pamplona, Navarra, Spain, 31008
Contact: Jaime Gállego, MD.PhD    +34948255400 ext 3594    jgallego@unav.es   
Contact: Amaya Izal    +34948255400 ext 2724    aizal@unav.es   
Principal Investigator: Jaime Gallego, MD.PhD. Neurology         
Sub-Investigator: Purificación De Castro, MD.Neurology         
Sub-Investigator: Felipe Prosper, MD.Haematology         
Sub-Investigator: Susana Inogés, MD.Immunology         
Sub-Investigator: Ascensión López, MD.Immunology         
Sub-Investigator: Enrique Andreu, MD.Cell therapy         
Sub-Investigator: Javier Larrache, MD.Radiology         
Sub-Investigator: Carmen Azcona, RN         
Sponsors and Collaborators
Fundació Institut Germans Trias i Pujol
Clinica Universidad de Navarra, Universidad de Navarra
Investigators
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Principal Investigator: Cristina Ramo, MD.PhD.Neurologist Badalona Hospital Germans Trias i Pujol. Neurology service. Multiple Sclerosis department
Study Director: Eva Martínez-Cáceres, MD.PhD.Immunology Badalona Hospital Germans Trias i Pujol. Immunology

Additional Information:
Publications:

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Responsible Party: Fundació Institut Germans Trias i Pujol
ClinicalTrials.gov Identifier: NCT02903537     History of Changes
Other Study ID Numbers: TOLERVIT-MS
2015-003541-26 ( EudraCT Number )
First Posted: September 16, 2016    Key Record Dates
Last Update Posted: May 1, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Fundació Institut Germans Trias i Pujol:
Multiple Sclerosis
Dendritic Cells
Immune Tolerance
Myelin Proteins
Tolerogenic dendritic cells

Additional relevant MeSH terms:
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Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Multiple Sclerosis, Chronic Progressive
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Interferons
Interferon-beta
Cholecalciferol
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs
Calcium-Regulating Hormones and Agents
Vitamins
Micronutrients
Nutrients
Growth Substances
Bone Density Conservation Agents