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

Phase 2

Completed

• Conditions: Multiple Sclerosis
• Interventions: Biological: Mesenchymal Stem Cells

• Registration Number: NCT02239393
• Lead Sponsor: Ottawa Hospital Research Institute

Brief Summary

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 week 24 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 number, time-frame and severity of adverse events and

* Treatment's activity in terms of reduction in total number of 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).

Detailed Description

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).

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2014-09-10
• Study First Submitted QC: 2014-09-10
• Study First Posted: 2014-09-12
• Study Start: 2015-06
• Primary Completion: 2019-12
• Study Completion: 2019-12
• Status Verified: 2020-03
• Last Update Submitted: 2020-03-03
• Last Update Posted: 2020-03-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 31

Inclusion Criteria

• 1. Males and females with a diagnosis of MS

  1. 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

  2. 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

  3. 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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Autologous Mesenchymal Stem Cells	Mesenchymal Stem Cells	At week 0 a single infusion of either ex-vivo expanded autologous MSC or suspension media will be administered intravenously at a dose of 1 to 2 x 1000000 MSC/Kg body weight. At week 24, another infusion will be performed for cross-over re-treatment: at week 24 treatments will be reversed compared to week 0.
Suspension media	Mesenchymal Stem Cells	At week 0 a single infusion of either ex-vivo expanded autologous MSC or suspension media will be administered intravenously at a dose of 1 to 2 x 1000000 MSC/Kg body weight. At week 24, another infusion will be performed for cross-over re-treatment: at week 24 treatments will be reversed compared to week 0.

Primary Outcome Measures

Name	Time	Method
Efficacy	24 weeks from first infusion	Total number of gadolinium-enhancing lesions (GEL) on MRI scan
Safety	24 weeks from first infusion	Incidence and severity of adverse events in MSC treatment group compared to placebo group

Secondary Outcome Measures

Name	Time	Method
Efficacy	48 weeks from first infusion	Time to sustained progression of disability and proportion of progression-free patients compared between treatment groups during the first 24 weeks and after cross-over.

Trial Locations

Locations (2)

Health Sciences Centre; 🇨🇦 Winnipeg, Manitoba, Canada

Ottawa Hospital - General Campus; 🇨🇦 Ottawa, Ontario, Canada