MEsenchymal StEm Cells for Multiple Sclerosis

MEsenchymal StEm Cells for Multiple Sclerosis (MESEMS) Phase I-II Clinical Trial With Autologous Mesenchymal Stem Cells (MSCs) for the Therapy of Multiple Sclerosis

A double-blind, randomized, cross-over phase I/II study to evaluate the safety and the efficacy of the intravenous administration of autologous Mesenchymal Stem Cells (MSC) to patients with active multiple sclerosis (MS) resistant to currently available therapies.

The mechanism of action of MSC relies on their ability to modulate pathogenic immune responses and provide neuroprotection through the release of anti-apoptotic, anti-oxidant and trophic factors as demonstrated by in vitro and in vivo preclinical studies.

Patients will be randomized to receive immediate vs. delayed treatment with either a dose equal to 1-2 millions/kg of body weight of autologous MSC, or equivalent volume of suspension media at baseline. At 6 months treatments will be reversed.

The primary outcome of this study is to evaluate

• treatment's safety within one year from MSC administration by measuring the the number, time-frame and severity of adverse event and
• treatment's activity in terms of reduction in the total number of contrast-gadolinium enhancing lesions (GEL) by magnetic resonance imaging (MRI) scans.

Secondary outcomes are to gain preliminary information on the efficacy of the experimental treatment in terms of combined MRI activity and clinical efficacy (incidence of relapses and disability progression).

Inclusion Criteria:

- 1. Diagnosis of MS

a. Relapsing remitting MS (RRMS) not responding to at least a year of attempted therapy with one or more of the approved therapies (beta-interferon, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) as evidenced by one or more of the following: i. ≥1 clinically documented relapse in past 12 months

ii. ≥2 clinically documented relapses in last 24 months

iii. ≥1 GEL at MRI performed within the last 12 months

b. Secondary progressive MS (SPMS) not responding to at least a year of attempted therapy with one or more of the approved therapies (beta-interferon, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) as evidenced by both:

i. an increase of ≥1 point of the expanded disability status scale (EDSS) (if at randomization EDSS ≤ 5.0) or 0.5 EDSS point (if at randomization EDSS ≥ 5.5) in the last 12 months

ii. ≥1 clinically documented relapse or ≥ 1 GEL at MRI within the last twelve months.

c. Primary progressive MS (PPMS) patients with all the following features:

i. an increase of ≥1 EDSS point (if at randomization EDSS ≤ 5.0) or 0.5 EDSS point (if at randomization EDSS ≥5.5), in the last twelve months

ii. ≥ 1 GEL at MRI performed within the last 12 months

iii. positive cerebrospinal fluid (CSF) (oligoclonal banding

• 2. Age 18 to 50 years
• 3. Disease duration 2 to 10 years (included)
• 4. EDSS 3.0 to 6.5

Exclusion Criteria:

• 1. RRMS not fulfilling inclusion criteria
• 2. SPMS not fulfilling inclusion criteria
• 3. PPMS not fulfilling inclusion criteria
• 4. Any active or chronic infection including infection with HIV1-2 or chronic Hepatitis B or Hepatitis C
• 5. Treatment with any immunosuppressive therapy, including natalizumab and fingolimod, within the 3 months prior to randomization
• 6. Treatment with interferon-beta or glatiramer acetate within the 30 days prior to randomization
• 7. Treatment with corticosteroids within the 30 days prior to randomization
• 8. Relapse occurred during the 60 days prior to randomization
• 9. Previous history of a malignancy other than basal cell carcinoma of the skin or carcinoma in situ that has been in remission for more than one year
• 10. Severely limited life expectancy by another co-morbid illness
• 11. History of previous diagnosis of myelodysplasia or previous hematologic disease or current clinically relevant abnormalities of white blood cell counts
• 12. Pregnancy or risk or pregnancy (this includes patients that are unwilling to practice active contraception during the duration of the study)
• 13. eGFR < 60 mL/min/1.73m2 or known renal failure or inability to undergo MRI examination.
• 14. Inability to give written informed consent in accordance with research ethics board guidelines