Study of Mesenchymal Autologous Stem Cells as Regenerative Treatment for Multiple Sclerosis

Study Overview
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Brief Summary
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The primary objective of the study is to investigate neuroregenerative efficacy (proof of concept) of intrathecal treatment with autologous MSCs as measured by neurophysiological parameters in patients with progressive MS. Secondary objectives are to assess neuroregenerative efficacy as measured by other neurophysiological parameters as well as clinical, opthalmological and MRI modalities, and to assess safety of the treatment procedure.

Detailed Description
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Prospective, interventional, randomized, placebo-controlled, cross-over study. Patients are randomized to either treatment arm A or B. Patients in both treatment arms receive intrathecal autologous MSCs, arm A at baseline and arm B at six months. All patients undergo bone marrow (BM) aspiration prior to baseline. Patients in treatment arm A receive intrathecal autologous MSCs whereas patients in treatment arm B receive placebo. The treatment is blinded for the patients. The BM aspirate from patients in treatment arm B is processed, cryopreserved and stored in a biobank. At six months, all patients undergo a second BM aspiration. Patients in treatment arm A now receive placebo. The BM aspirate from patients in treatment arm A is processed, cryopreserved and stored in a biobank. Patients in treatment arm B receive intrathecal autologous MSCs. The treatment is blinded for the patients. Primary outcome is assessed at six months and secondary outcomes are assessed at six, twelve and eighteen months post baseline. Investigator assessing outcomes are blinded to patient treatment allocation.

Official Title
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Study of Mesenchymal Autologous Stem Cells as Regenerative Treatment for Multiple Sclerosis

Conditions
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Multiple Sclerosis, Progressive Multiple Sclerosis

Intervention / Treatment
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* Other: MSCs
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 to ≤55, both genders Diagnosis of secondary progressive or primary progressive MS using revised McDonald criteria of clinically definite MS An EDSS score of 4 to 7 Disease duration 2 - 15 years Signed, written informed consent Exclusion Criteria: Any illness or prior/ongoing treatment that in the opinion of the investigators would jeopardize the ability of the patient to tolerate autologous stem cell treatment Any ongoing infection, including Tbc, CMV, EBV, HSV, VZV, hepatitis virus, toxoplasmosis, HIV or syphilis infections, as well as heaptitis B surface antigen positivity and/or hepatitis C PCR positivity Current immunomodulatory/immunosuppressive treatment Immunomodulatory/immunosuppressive treatment within 6 months prior to inclusion. This includes, but is not restricted to treatment with natalizumab, fingolimod, dimetylfumurat, glatiramer acetate, interferon beta medications, teriflunomide, and siponimod. Treatment with kladribin, ocrelizumab, rituximab, and alemtuzumab within 12 months prior to inclusion Treatment with hematopoietic stem cell therapy within 12 months prior to inclusion Treatment with glucocorticoids or ACTH within three months prior to start of inclusion Having experienced an MS relapse within 2 years prior to study inclusion Current treatment with fampridin History of malignancy other than basal cell carcinoma of the skin or carcinoma in situ that has been in remission for more than one year Severely limited life expectancy by another co-morbid illness History of previous diagnosis of myelodysplasia or previous hematologic disease (including lymphoproliferative disease, bone marrow insufficiency or previous lymphoid irradiation) or current clinically relevant abnormalities of white blood cell counts Immunocompromised patients Estimated glomerular filtration rate <60 ml/min/1.73 m2 or known renal failure Bleeding or clotting diathesis or the use of antithrombotic or anticoagulative treatment Platelet (thrombocyte) count <100 x 10*9/L Participation in another experimental clinical study within the preceding 12 months Contraindications to MRI Prior or current major depression Prior or current psychiatric illness, mental deficiency or cognitive dysfunction influencing the patient ability to make an informed consent or comply with the treatment and follow-up phases of this protocol. Pregnancy or risk of pregnancy (this includes patients that are unwilling to practice active contraception during the duration of the study), breastfeeding or lactation History of autologous/allogenic bone marrow transplantation or peripheral blood cell transplant Known hypersensitivity against paracetamol, codein or xylocain Diagnosis or strong suspicion of polyneuropathy Prior or current alcohol or drug dependencies Inability to give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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
Interventional Model Description: Prospective, randomized, placebo-controlled, cross-over study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - Crossover with MSCs at baseline and placebo at 6 months<br>Receives mesenchymal stem cells at baseline and placebo at 6 months | Other: MSCs<br>* Autologous bone-marrow derived mesenchymal stem cells<br>* Other names: Mesenchymal stem cells;Drug: Saline<br>* Isotonic saline<br>|
| Experimental: Arm B - Crossover with placebo at baseline and MSCs at 6 months<br>Receives placebo at baseline and mesenchymal stem cells at 6 months | Other: MSCs<br>* Autologous bone-marrow derived mesenchymal stem cells<br>* Other names: Mesenchymal stem cells;Drug: Saline<br>* Isotonic saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurophysiological parameters - Combined evoked potentials | Somatosensoric evoked potentials (SEP) + visual evoked potentials (VEP) + motor evoked potentials (MEP), latency (ms) and amplitude (mV) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurophysiological parameters - Somatosensoric evoked potantials | SEP, latency (ms) and amplitude (mV) | 6 and 12 months | 
| Neurophysiological parameters - Motor evoked potentials | MEP, latency (ms) and amplitude (mV) | 6 and 12 months | 
| Neurophysiological parameters - Visual evoked potentials | VEP, latency (ms) and amplitude (mV) | 6 and 12 months | 
| MRI-Lesion volumes | T1- and T2-weighted hyperintense lesion volume | 6 and 12 months | 
| MR- Brain volumes | Brain volumes | 6 and 12 months | 
| Expanded disability status scale | EDSS | 6, 12 and 18 months | 
| Patient reported outcomes (PROs) | Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), European Quality of Life 5 dimensions (EQ-5D-5L), Multiple Sclerosis Impact Scale (MSIS) and Fatigue severity scale (FSS) | 6, 12 and 18 months | 
| Nine-Hole-Peg Test (9-HPT) | Nine-Hole-Peg Test (9-HPT) | 6, 12 and 18 months | 
| Timed 25 Foot Walk (T25FW) | Timed 25 Foot Walk (T25FW) | 6, 12 and 18 months | 
| Visual function | Visual acuity, visual field, color vision and contrast sensitivity | 6, 12 and 18 months | 
| Optical coherence tomography (OCT) | Retinal thickness | 6, 12 and 18 months | 
| Rate and nature of adverse- and serious adverse events | Adverse events | 6, 12 and 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mesenchymal stem cells, Multiple sclerosis