Safety and Efficacy of Repeated Administration of NurOwn (MSC-NTF Cells) in Participants With Progressive MS

Study Overview
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Brief Summary
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A multidose open-label study with autologous Mesenchymal Stromal Stem Cells Secreting Neurotrophic Factors (MSC-NTF cells) involving 20 participants with progressive MS at multiple investigational study sites.

Detailed Description
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An open-label study with a single treatment arm involving 20 participants with progressive MS at multiple investigational study sites. After providing informed consent, participants meeting the inclusion and exclusion criteria will be randomized and approximately 4 weeks later will undergo a bone-marrow aspiration (BMA). Each participants will receive three Intrathecal cell transplantations within 16 weeks and will be followed for 12 weeks for safety and efficacy.

Official Title
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A Phase 2 Open-label Multicenter Study to Evaluate the Safety and Efficacy of Repeated Administration of NurOwn® [Autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors (NTF), MSC-NTF] Cells in Participants With Progressive MS

Conditions
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Multiple Sclerosis, Chronic Progressive

Intervention / Treatment
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* Biological: NurOwn (MSC-NTF cells)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females ages 18 to 65 years old, inclusive, at the Screening Visit. Clinical diagnosis of Progressive MS (Primary and Secondary) based on the 2017 revised MacDonald Criteria and confirmation by the Investigator that the disease has entered the progressive stage for at least 6 months prior to enrollment. No evidence of clinical MS relapse or high dose pulse corticosteroid treatment within 6 months prior to screening Disability status at screening with an Expanded Disability Status Scale (EDSS) 3.0-6.5, inclusive. Able to walk 25 feet in 60 seconds or less. Stable dose of non-excluded MS Disease Modifying Therapy for at least 6 months prior to Screening Visit (Visit 1). Women of childbearing potential shall either be surgically sterile, or must agree not to become pregnant for the duration of the study. Women must be willing to undergo a serum pregnancy test at screening, and at the conclusion of the study. Participants of childbearing potential must agree to use a medically approved form of birth control (abstinence, intrauterine device (IUD), oral contraception, barrier and spermicide or hormonal implant) throughout the duration of the study and for at least 3 months following the last transplantation. For those women who are sexually active and using oral contraceptives, a second form of barrier contraception is required. Men must be willing to consistently use two forms of contraceptive if their partners are of childbearing age. Capable of providing informed consent and willing and able to follow study procedures, including willingness to undergo multiple/repeated lumbar puncture. Exclusion Criteria: Prior stem cell therapy of any kind. Active participation in any other MS interventional study or use of unapproved MS investigational therapy within 90 days prior to the Screening Visit (Visit 1). Inability to lie flat for the duration of intrathecal cell transplantation and/or bone marrow biopsy, or inability to tolerate study procedures for any other reason. History of clinically significant autoimmune disease (excluding thyroid disease) that may confound study results, in the opinion of the Investigator and the medical monitor, myelodysplastic or myeloproliferative disorder, leukemia or lymphoma, whole body irradiation, hip fracture, or severe scoliosis. Any unstable clinically significant medical condition other than multiple sclerosis (e.g., within six months of Screening Visit (Visit 1), had myocardial infarction, angina pectoris, and/or congestive heart failure), treatment with anticoagulants that, in the opinion of the investigator, would compromise the safety of participants. Any history of malignancy within the previous 5 years, except for non-melanoma localized skin cancers (with no evidence of metastasis, significant invasion, or reoccurrence within three years of Screening Visit (Visit 1)). Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value >3.0 times the upper normal limit. Serum creatinine value >2.0 times the upper normal limit. Positive test for Hepatitis B (HBV; surface antigen (HBsAg) and antibodies to core antigen (IgG and IgM anti-HBc)), Hepatitis C (HCV), or human immunodeficiency virus (HIV) 1 and 2. Current use of immunosuppressant medication or use of such medication within 6 months of study enrollment (aside from Rituximab or other approved B-cell immunotherapy). Alemtuzumab (Lemtrada), Cladribine (NDA submitted), Natalizumab (Tysabri), S1P modulators (Gilenya) are excluded for safety reasons due to the known risk of systemic autoimmune disease, malignancy, opportunistic infections, and cardiovascular toxicity associated with these therapies, as well as theoretical effects on MSC-NTF cell homing and migration, that may be associated with Natalizumab and/or S1P modulators (Gilenya). Any history of acquired or inherited immune deficiency syndrome. Any history of either substance abuse within the past year, or unstable psychiatric disease according to the Investigator's judgment. Pregnant women or women currently breastfeeding. Subjects for whom MRI is contraindicated (i.e., have a pacemaker or other metallic implanted device, or are unable to remain in the machine for period of time needed to acquire a scan.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Interventional Model Description: Open label
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NurOwn (MSC-NTF cells)<br>Autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors | Biological: NurOwn (MSC-NTF cells)<br>* Autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events | Combined safety of all 3 intrathecal doses of NurOwn® (MSC-NTF cells) Number of participants who experienced Treatment-emergent Adverse Events during the study. Treatment-emergent Adverse Event is an adverse event that occurs for the first time after initiation of first treatment or if it had occurred prior to initiation first treatment, it worsens in severity after initiation of first treatment. | Up to 28 weeks post-first treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With 25% or Greater Improvement From Baseline in Time 25 Foot Walk (T25FW) Speed or Nine-Hole Peg Test (9-HPT) | 25% or greater improvement at 28 weeks from Baseline in Time 25 Foot Walk (T25FW) speed or 9 Hole Peg Test (9-HPT). The T25FW is a quantitative mobility and leg function performance test based on a timed 25-feet walk. The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. T25FW is the average of the two successive trials. Higher values represent better outcomes. The 9HPT is used to measure upper extremity function in patients with various neurological diagnoses. The participant is asked to pick up the nine pegs, puts them in the nine holes, and, once completed, removes them again as quickly as possible, replacing them into the container. The total time to complete the task is recorded. Higher values represent worse outcomes. | From Baseline (pre-first treatment) to 28 weeks post-first treatment | 
| Number of Participants With 25% or Greater Improvement From Baseline to Week 28 in Timed 25 Foot Walk (T25FW) Speed | ≥25% improvement in T25FW speed over 28 weeks The T25FW is a quantitative mobility and leg function performance test based on a timed 25-feet walk. The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The task is immediately administered again by having the patient walk back the same distance Baseline T25FW is the average of the two successive trials. Higher values represent better outcomes | From Baseline (pre-first treatment) to 28 weeks post-first treatment | 
| Number of Participants With 25% or Greater Improvement From Baseline to Week 28 in 9-HPT | The Nine-Hole Peg Test (9HPT) is used to measure upper extremity function in patients with various neurological diagnoses. The participant is seated at a table with a small, shallow container holding nine pegs and a wood or plastic block containing nine empty holes. On a start command when a stopwatch is started, the participant picks up the nine pegs one at a time as quickly as possible, puts them in the nine holes, and, once they are in the holes, removes them again as quickly as possible one at a time, replacing them into the shallow container. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. Baseline 9HPT is the average of 2 trials of dominant hand and nondominant hand. The higher values represent a worse outcome. | From Baseline (pre-first treatment) to 28 weeks post-first treatment | 
| Number of Participants Who Had >5.5 in Expanded Disability Status Scale (EDSS) at Baseline, With ≥0.5 Points Improvement From Baseline to Week 28 | Expanded Disability Status Scale (EDSS) provides a total score on a scale that ranges from 0 (no disability) through 1 to 10 (death due to MS), in 0.5-point steps. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the sequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The higher score represents the worse outcome. | From Baseline (pre-first treatment) to 28 weeks post-first treatment | 
| Number of Participants With ≥10 Points Improvement From Baseline to Week 28 in Multiple Sclerosis Walking Scale (MSWS-12) | The Multiple Sclerosis Walking Scale (MSWS)-12 is a patient-reported outcome measure of the walking limitations due to MS during the past 2 weeks. It contains 12 questions that assess the impact of MS on different aspects of walking function and quality. Total administration time should be approximately 5 minutes. Activities are rated by participant from min. 1 (not at all) to max. 5 (extremely) and summed to calculate a total score using a scale from 0 to 60 (ranging from low to high impact on walking). This score is then divided by 60 and multiplied by 100 to get a score between 0 and 100 A higher score represents a worse outcome. | From Baseline (pre-first treatment) to 28 weeks post-first treatment | 
| Number of Participants With ≥8 Letter Improvement From Baseline to Week 28 in LCLA Binocular 2.5% Contrast Level | The Low contrast letter acuity (LCLA) is a leading outcome measure to assess visual disability in multiple sclerosis (MS) research Total administration time, for a typical MS patient, is approximately 10-15 minutes to complete, when testing each eye individually and binocular vision for two different contrast levels. The score for each chart is quantified as the number of letters identified correctly with a minimum scrore of 0 letter and a maximum score of 70 letters. The higher score represents the better outcome. | From Baseline (pre-first treatment) to 28 weeks post-first treatment | 
| Number of Participants With ≥ 3 Points Improvement From Baseline to Week 28 in Symbol Digit Modalities Test (SDMT) Score | Symbol Digit Modalities test (SDMT) is a commonly used test to assess psychomotor speed, which measures processing speed as well as motor speed. It is a paper-pencil measure which requires an individual to substitute digits for abstract symbols using a reference key Scoring involves summing the number of correct substitutions within the 90 second interval (max = 110) Minimum score is 0 and maximum score 110. The higher score represents the better outcome. | From Baseline (pre-first treatment) to 28 weeks post-first treatment | 
| Change in Concentration of Vascular Endothelial Growth Factor (VEGF) Neuroprotective Biomarker From Baseline in the Cerebrospinal Fluid (CSF) 16 Weeks Following First NurOwn® Treatment | Change from baseline (pre-first treatment) in the concentration of Vascular endothelial growth factor (VEGF) neuroprotective biomarker in the Cerebrospinal fluid (CSF) at 16 weeks following first NurOwn® treatment The concentration of the biomarker is measured as Picogram per milliliter (pg/ml). A higher concentration of neuroprotective biomarkers suggests a better outcome | From Baseline (pre-first treatment) to 16 weeks post first treatment | 
| Change in Concentration of Hepatocyte Growth Factor (HGF) Neuroprotective Biomarker From Baseline in the Cerebrospinal Fluid (CSF) 16 Weeks Following NurOwn® Treatment | Change from baseline in the concentration of Hepatocyte growth factor (HGF) neuroprotective biomarker in the Cerebrospinal Fluid (CSF) at 16 weeks following the first NurOwn® treatment The concentration of the biomarker is measured as Picogram per milliliter (pg/ml). A higher concentration of neuroprotective biomarkers suggests a better outcome | From Baseline (pre-first treatment) to 16 weeks post first treatment |