Clinical trial NCT02903537: Tolerogenic Dendritic Cells as a Therapeutic Strategy for the Treatment of Multiple Sclerosis Patients (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
Overall status: RECRUITING
Phase: PHASE1
Conditions: Multiple Sclerosis, Relapsing-Remitting
Multiple Sclerosis, Chronic Progressive
Keywords: Multiple Sclerosis
Dendritic Cells
Immune Tolerance
Myelin Proteins
Tolerogenic dendritic cells
Lead sponsor: Fundació Institut Germans Trias i Pujol
Sponsor class: OTHER
Collaborators: name: Clinica Universidad de Navarra, Universidad de Navarra
First posted: 2016-09-16
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Safety as assessed by the occurrence and severity of adverse events
timeFrame: 24 months
measure: Neurologic changes
timeFrame: 24 months
measure: Radiologic changes
timeFrame: 24 months
Secondary outcomes:
measure: Annual relapse rate (ARR)
timeFrame: 24 months
measure: Expanded Disability Status Scale (EDSS)
timeFrame: 24 months
measure: 9-Hole Peg Test (9HPT)
timeFrame: 24 months
measure: 25-Foot Walking Test (T25FW)
timeFrame: 24 months
measure: Symbol Digit Modalities Test (SDMT)
timeFrame: 24 months
measure: Radiologic preliminary efficacy
timeFrame: 24 months
measure: Lymphocyte proliferation to myelin peptides
timeFrame: 24 months
measure: Blood Immunomonitoring studies
timeFrame: 24 months
measure: Feasibility
timeFrame: 6 months
Other outcomes:
Locations:
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
state: Navarra
Study officials:
affiliation: Badalona Hospital Germans Trias i Pujol. Neurology service. Multiple Sclerosis department
name: Cristina Ramo, MD.PhD.Neurologist
role: PRINCIPAL_INVESTIGATOR
affiliation: Badalona Hospital Germans Trias i Pujol. Immunology
name: Eva Martínez-Cáceres, MD.PhD.Immunology
role: STUDY_DIRECTOR
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