Feasibility Study of Tolerogenic Fibroblasts in Patients With Refractory Multiple Sclerosis

Study Overview
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Brief Summary
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Fibroblasts have demonstrated potent immune modulatory and therapeutic activity in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, as well as in other models of autoimmune and inflammatory diseases. This study will assess primary safety and secondary efficacy endpoints of intravenous administration of 100 million tolerogenic fibroblasts to 5 patients with relapsing remitting MS resistant to interferon. While the safety of fibroblasts administered clinically is established, it is unknown whether these cells are effective in the treatment of multiple sclerosis (MS). Our hypothesis is that the tolerogenic fibroblasts will be well-tolerated and meet our primary objective. In addition, The investigators are optimistic that they will see signs of efficacy based on the following: Neurological assessment of the MS functional composite assessment which comprises of EDSS, the expanded EDSS (Rating Neurologic Impairment in Multiple Sclerosis, the Scripps neurological rating scale (NRS), paced auditory serial addition test (PASAT), the nine-hole peg test, and 25-foot walking time, short-form 36 (SF-36) quality of life questionnaire and gadolinium-enhanced MRI scans of the brain and cervical spinal cord.

Detailed Description
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Fibroblasts have demonstrated potent immune modulatory and therapeutic activity in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, as well as in other models of autoimmune and inflammatory diseases. Mechanistically, tolerogenic fibroblasts produce anti-inflammatory and immune modulatory factors, which appear to be therapeutic in the context of autoimmunity, including IL-10 and TGF-beta. Additionally, tolerogenic fibroblasts produce neurotrophic mediators that enhance myelin production and/or prevent neuronal apoptosis. This study will assess primary safety and secondary efficacy endpoints of intravenous administration of 100 million tolerogenic fibroblasts to 5 patients with relapsing remitting MS resistant to interferon. While the safety of fibroblasts administered clinically is established, it is unknown whether these cells are effective in the treatment of multiple sclerosis (MS). Research Hypothesis: Intravenous administration of 100 million tolerogenic fibroblasts will be well tolerated and induce a therapeutic effect in relapse remitting MS patients. Rationale: The family of Mesenchymal Stem Cells (MSCs) is immune-modulatory, and bone marrow MSCs (BM-MSCs) have induced therapeutic responses in patients with MS [1]. Tolerogenic fibroblasts possess superior immune modulatory activity compared to BM-MSCs and adipose MSCs. The investigators, therefore, seek to perform a five-patient trial to assess the safety and signs of efficacy of this cell population in MS patients resistant to interferon. The trial's primary objective is freedom from treatment-associated adverse events at 1, 2, 4, 8, and 16 weeks post-treatment. The study's secondary objective will be efficacy as assessed at baseline, weeks 2, 4, 8, and 16. The results will be quantified based on the following: Neurological assessment of the MS functional composite assessment, which comprises of EDSS, the expanded EDSS (Rating Neurologic Impairment in Multiple Sclerosis, the Scripps neurological rating scale (NRS), paced auditory serial addition test (PASAT), the nine-hole peg test, and 25-foot walking time, short-form 36 (SF-36) quality of life questionnaire and gadolinium-enhanced MRI scans of the brain and cervical spinal cord.

Official Title
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Feasibility Study of Tolerogenic Fibroblasts in Patients With Refractory Multiple Sclerosis

Conditions
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Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis

Intervention / Treatment
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* Biological: Tolerogenic Fibroblasts


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients willing to sign an informed consent and capable of understanding the features of this clinical trial. Willing to keep a weekly diary and undergo observation for four months Non-pregnant patients 18-55 years of age with MS according to the revised McDonald criteria and meeting the Possner criteria for clinically defined MS. EDSS scores of 2·0 to 5·5 points assessed at least three months after the last acute attack of MS. Exclusion Criteria: Patients with evidence of active proliferative retinopathy. Patients with poorly controlled diabetes mellitus (HbA1C > 8.5%). Patients with renal insufficiency (Creatinine > 2.5) or failure. Infection as evidenced by WBC count of >15,000 k/cumm and/or temperature >38C. History of organ transplant. History of previous or active malignancy, except for localized cutaneous basal or squamous cell carcinoma or carcinoma in situ of the cervix History of sickle cell anemia Cardiovascular conditions: Exercise limiting angina ( Canadian Cardiovascular Society Class greater or equal to 3 Congestive heart failure (New York Heart Association class greater or equal to 3 Unstable angina Acute ST elevation myocardial infarction (MI) within one month Transient ischemic attack or stroke within one month Severe valvular disease

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
Intervention Model: Single Group Assignment
Interventional Model Description: The proposed study will assess primary safety and secondary efficacy endpoints of allogeneic tolerogenic fibroblasts administered through Intravenous infusion at a single dose of 100 million cells to 5 patients with relapsing remitting MS resistant to interferon.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tolerogenic fibroblasts administered via intravenous infusion<br>A single dose of 100 million tolerogenic fibroblasts administered via intravenous infusion. | Biological: Tolerogenic Fibroblasts<br>* administrating single dose of 100 million tolerogenic fibroblasts via intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Adverse even monitoring of subjects for 4 hours after infusion | Monitor subjects for possible treatment-related acute immune symptoms or vascular occlusion symptoms during the administration of the allogeneic tolerogenic fibroblasts via intravenous infusion. | Monitoring during the Intravenous infusion of allogeneic tolerogenic fibroblasts, and continued for 4 hours after infusion | 
| Safety: Complete Blood Count to monitor inflammation markers | Complete Blood Count used to monitor inflammation markers included white blood cell (WBC), neutrophil (N), lymphocyte (L), neutrophil-lymphocyte ratio (NLR), mean platelet volume (MPV), and platelet-lymphocyte ratio. This safety test is to monitor subjects for inflammation during the course of the study, relating to the course of the disease, or allogeneic tolerogenic fibroblasts administered through Intravenous infusion | Day before infusion to establish a baseline, week 8, and week 16 after infusion | 
| Safety: Serum chemistry to monitor impact on serum chemistry | This test will measure the amount of certain substances in serum samples, including electrolytes (such as sodium, potassium, and chloride), fats, proteins, glucose (sugar), and enzymes. Blood chemistry tests give essential information about how well a person's kidneys, liver, and other organs are working. An abnormal amount of a substance in the blood can be a sign of disease or a side effect of treatment. Blood chemistry tests help diagnose and monitor many conditions before, during, and after treatment. Also called blood chemistry study. | Day before infusion to establish a baseline, week 8, and week 16 after infusion | 
| Safety: 12-lead Electrocardiogram (ECG) to monitor cardiovascular health | A 12-lead electrocardiogram will be used to monitor the baseline cardiovascular health of the participants and continue to monitor their cardiovascular health during the course of the study measuring heart rate, blood pressure, ventricular rate, PR interval, RP interval, QRS interval, and GT interval. This safety test is to monitor the subjects for cardiac events related to the course of the disease, or allogeneic tolerogenic fibroblasts administered through Intravenous infusion | Day before infusion to establish a baseline, week 8, and week 16 after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Expanded Disability Status Scale (EDSS) to quantify disability scale and monitors changes | The Expanded Disability Status Scale (EDSS) quantifies disability in multiple sclerosis and monitors changes in the level of disability over time. The test is based on neurological examination and impact on Functional Systems representing network of neurons in the brain. It is widely used in clinical trials and the assessment of people with MS. The scale was developed by a neurologist called John Kurtzke in 1983 as an advance from his previous 10 step Disability Status Scale (DSS). The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist. | Day before infusion to establish a baseline, week 8, and week 16 after infusion | 
| Efficacy: Paced Auditory Serial Addition Test (PASAT) to measure cognitive function and processing speed | PASAT is a measure of cognitive function that assesses auditory information processing speed, flexibility, and calculation ability. The test was developed by Gronwell in 1977 and later adapted by Rao and colleagues in 1989 for use in MS. The PASAT is presented using audio cassette tape or compact disk to ensure standardization in the rate of stimulus presentation. In the test, single digits are presented every 3 seconds, and the patient must add each new digit to the one immediately prior to it. Shorter inter-stimulus intervals, e.g., 2 seconds or less, have also been used with the PASAT but tend to increase the difficulty of the task. | Day before infusion to establish a baseline, week 8, and week 16 after infusion | 
| Efficacy: Nine-Hole Peg Test to measure and quantify upper extermity function | The 9-HPT is a brief, standardized, quantitative test of upper extremity function. Both the dominant and non-dominant hands are tested twice. The patient 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 patient 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. | Day before infusion to establish a baseline, week 8, and week 16 after infusion | 
| Efficacy: Timed 25-Foot Walk Test to quantify mobility and leg function | The T25-FW is a quantitative mobility and leg function performance test based on a timed 25-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 time is calculated from the initiation of the instruction to start and ends when the patient has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. Patients may use assistive devices when doing this task. | Day before infusion to establish a baseline, week 8, and week 16 after infusion | 
| Efficacy: Gadolinium Enhanced MRI to detect demyelinated areas of the nerves | Gadolinium Enhanced MRI is used to detect demyelinated areas of the nerves in the brain and cervical spinal cord. These Damaged areas can be observed by MRI presented as plaques, and the intensity of the plaques can determine the age of multiple sclerosis caused lesions. | Day before infusion to establish a baseline, and week 16 after infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stem cells, regenerative medicine, tissue regeneration, Immune modulation, MS, Cell Therapy, Fibroblasts, Fibrobiologics