Stem Cells in Rapidly Evolving Active Multiple Sclerosis

Study Overview
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Brief Summary
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This is a randomised, double-blind crossover study to study the effect of intravenous treatment with autologous (derived from the individuals themselves) mesenchymal stem cells (MSCs) in patients with multiple sclerosis (MS).

Detailed Description
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Current treatments for MS target the immune system and are not curative. There is much interest in MSCs as they have the potential to not only affect the immune system but may also promote repair. This study will use MSCs that are harvested from the bone marrow and grown for up to 52 days before being given back to the person from whom they were harvested. This avoids any chemotherapy so is therefore safer than other types of stem cells. In this crossover study, everyone will receive their own stem cells back but in half of the patients it will be delayed by 24 weeks. The primary outcomes are to check that the procedure is safe and to measure any changes on the MRI at 24 weeks. Other more exploratory measures will try to assess effects on repair in the central nervous system (CNS).

Official Title
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Stem Cells in Rapidly Evolving Active Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Mesenchymal stem cells
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with clinically and radiologically active multiple sclerosis as defined by: Diagnosis of MS: Relapsing remitting MS (RRMS): ≥ 1 moderate-severe relapse and ≥1 GEL in past 18 months or ≥ 1 moderate-severe relapse and ≥1 new T2 lesion in past 18 months. Secondary progressive MS (SPMS) with an increase of ≥ 1 EDSS point (if baseline EDSS ≤ 5) or 0.5 EDSS point (if baseline EDSS ≥ 5.5), in the previous 18 months and ≥ 1 GEL in past 18 months or ≥ 1 moderate-severe relapse and ≥1 new T2 lesion in past 18 months. Primary progressive MS (PPMS) patients with positive oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) and an increase of ≥ 1 EDSS point (if baseline EDSS is ≤ 5.0) or 0.5 EDSS point (if baseline EDSS is ≥ 5.5), or quantifiable, objective evidence of equivalent progression in the previous 18 months and ≥ 1 GEL in past 18 months or ≥ 1 new T2 lesion in past 18 months. Age 18 to 50 years. Disease duration 2 to 10 years from diagnosis (inclusive). Expanded Disability Status Scale (EDSS) 2.0 to 6.5 at screening evaluation. ≥ 1 GEL on MRI within 6 months prior to harvesting. Adequate culture of a subject's MSCs and their release for clinical use. Exclusion Criteria: RRMS without at least one severe relapse in the previous 18 months or without at least one GEL or one new T2 in the previous 18 months. SPMS without relapses and without new lesions (GEL or T2 positive) at MRI in the last 18 months. PPMS without positive CSF OCBs or without a GEL or new T2 lesion in the previous 18 months. No gadolinium enhancing lesion(s) in the 3 months prior to bone marrow harvesting. A previously ineligible patient who failed to meet the MRI requirements of the inclusion criteria will not be reviewed again even if further imaging, revealing ≥ 1 GEL, becomes available. Failure of bone marrow (BM) sample to generate MSCs suitable for clinical use within a specified time frame (4 weeks). Treatment with any immunosuppressive therapy, including natalizumab and fingolimod, within the last 3 months. Treatment with interferon-beta or glatiramer acetate within the last 1 month. Treatment with alemtuzumab (campath-1H) within the last 2 years. Prior treatment with total lymphoid irradiation and autologous or allogeneic hematopoietic stem cell transplantation. Participation in clinical trials of any experimental drugs in the 6 months before study entry. Corticosteroid treatment in the last 30 days. Presence of any active or chronic infection. Previous history of a malignancy other than basal cell carcinoma of the skin and carcinoma in situ that has been in remission for more than one year. Severely limited life expectancy by any other co-morbid illness. Abnormal blood counts, a history of myelodysplasia or other cytopenia. Known pregnancy, positive urine pregnancy test at screening or risk or pregnancy (this includes patients who are unwilling to practice active contraception during the duration of the study). Contraindication to MRI including but not limited to intracranial aneurysm clips (except Sugita), history of intra-orbital metal fragments that have not been removed by an MD (as confirmed by orbital X-Ray), pacemaker and non-MRI compatible devices (e.g. heart valves, inner ear implants), history of claustrophobia or the inability of the subject to lie still on their back for a period of 1.5 hours in the MRI scanner. An estimated glomerular filtration rate (eGFR)< 60 mL/min/1.73m2 or history or presence of renal impairment (e.g. serum creatinine clearance less than 30ml/min). Inability to give written informed consent/comply with study procedures. Any significant organ dysfunction or co-morbidity that the Investigators consider would put the subject at unacceptable risk by participating in the study or that would interfere with the functional assessments.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mesenchymal stem cells<br>1-2 x106 MSCs/kg administered at Week 0 | Drug: Mesenchymal stem cells<br>* 1.0-2.0 million cells/kg body weight<br>* Other names: Mesenchymal stromal cells;|
| Sham Comparator: Placebo<br>Suspension media administered at Week 0 | Drug: Placebo<br>* Placebo<br>* Other names: Sham;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency, Timing and Severity of Adverse events in MSC and placebo groups as Assessed by CTCAE v4.0 | The number,time-frame and severity of adverse events in the stem cell treatment group will be compared to the placebo group. | Up to 1 year from baseline | 
| Total number of GELs at weeks 4, 12 and 24 after MSC therapy | To evaluate the efficacy of autologous mesenchymal stem cells in MS patients, quantified by the reduction in the number of new contrast-enhancing lesions on MRI scans over 24 weeks and the total number of GEL counted over months 1, 3 and 6 will be compared between treatment groups. | Up to 1 year from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| contrast enhancing lesions identified over months 1, 3 and 6 will be compared between treatment groups. | Number of contrast enhancing lesions identified over months 1, 3 and 6 will be compared between treatment groups. | Months 1, 3 and 6 | 
| Comparison of contrast enhancing lesions between treatment periods | The number of contrast enhancing lesions counted over months 7, 9 and 12 (cross-over re-treatment) compared between treatment periods (placebo vs. active treatment) for each patient. | Months 1-12 | 
| Combined unique MRI activity | The number of new or enlarging T2, or enhancing or re-enhancing lesions. | Months 1-12 | 
| Relapses | number of relapses in MSC treatment group vs. placebo group in the first 6 months and after cross-over re-treatment in the two groups | 20 months | 
| Progression of disability | time to sustained progression of disability and proportion of progression-free patients. | 36 months | 
| Disease free patients | The proportion of disease-free patients (i.e. patients without relapses) and progression of MRI activity in the two groups. | 36 months | 
| MSFC score | the changes in the Multiple Sclerosis Functional Composite (MSFC) score in MSC treatment group compared to the placebo group. | 36 months | 
| peripheral immune responses | changes in immune cell frequencies and serum cytokines after MSCs | 48 weeks | 
| Type 4 hypersensitivity reaction | The effect of mesenchymal stem cells on delayed type hypersensitivity (Type 4 hypersensitivity reaction) as measured by the Mantoux test | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple sclerosis, mesenchymal stem cells, bone marrow, rapidly evolving