Safety and Efficacy of Intravenous Autologous Mesenchymal Stem Cells for MS: a Phase 2 Proof of Concept Study

The mechanism of action of Mesenchymal Stem Cells (MSCs) 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) Males and females with a diagnosis of MS

• Relapsing remitting MS (RRMS) not responding to at least 1 year of attempted therapy with one or more of the approved therapies (beta-interferon, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, dimethyl fumarate, teriflunomide, alemtuzumab) as evidenced by at least one of the following:

• i) ≥1 clinically documented relapse in past 12 months
• ii) ≥2 clinically documented relapses in past 24 months
• iii) ≥1 gadolinium-enhancing lesion (GEL) at MRI performed within the past 12 months
• 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, dimethylfumarate, teriflunomide, alemtuzumab) as evidenced by both:

• 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 past 12 months
• ii) ≥1 clinically documented relapse or ≥ 1 gadolinium-enhancing lesion (GEL) at MRI within the past 12 months
• 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 past 12 months
• ii) ≥ 1 gadolinium-enhancing lesion (GEL) at MRI performed within the past 12 months
• iii) positive cerebrospinal fluid (CSF) (oligoclonal banding)
• 2) Age 18 to 50 years old, inclusive at time of informed consent
• 3) Disease duration 2 to 15 years (inclusive)
• 4) EDSS 2.5 to 6.5
• 5) Able and willing to sign informed consent prior to any study-related activities

Exclusion criteria

• 1) RRMS not fulfilling inclusion criteria
• 2) SPMS not fulfilling inclusion criteria
• 3) PPMS not fulfilling inclusion criteria
• 4) A history of active or chronic infection including infection with HIV1-2, chronic Hepatitis B or Hepatitis C
• 5) Treatment with any immunosuppressive therapy, including natalizumab and fingolimod, within the 3 months prior to randomization
• 6) Previous treatment with cladribine or alemtuzumab
• 7) Treatment with interferon-beta, glatiramer acetate, teriflunomide or dimethyl fumarate within the 30 days prior to randomization (all teriflunomide patients will be required to have followed a wash-out with either cholestyramine or activated charcoal as indicated in the product monograph)
• 8) Treatment with corticosteroids within the 30 days prior to randomization
• 9) Relapse occurred during the 60 days prior to randomization
• 10) Previous history of a malignancy (patient reported) other than basal cell carcinoma of the skin or carcinoma in situ that has been in remission for more than one year
• 11) Severely limited life expectancy by any other co-morbid illness
• 12) History of previous diagnosis of myelodysplasia or previous hematologic disease (patient reported) or current clinically relevant abnormalities of white blood cell counts
• 13) Pregnancy or risk of pregnancy (this includes participants that are not willing to practice active contraception for the duration of the study)
• 14) eGFR < 60 mL/min/1.73m2 or known renal failure or inability to undergo MRI examination
• 15) Known allergy to gentamicin or related aminoglycosides
• 16) Inability to give written informed consent in accordance with research ethics board guidelines
• 17) Concomitant participation in another clinical trial
• 18) Inability to adhere to protocol according to the investigator's medical judgement