Feasibility Study of Tolerogenic Fibroblasts in Patients With Refractory Multiple Sclerosis
Trial Snapshot
- Phase
- Early Phase 1
- Status
- Completed
- Sponsor
- Enrollment
- 5
- Locations
- 2
- Primary Endpoint
- Safety: Adverse even monitoring of subjects for 4 hours after infusion
Study Overview
Brief Summary
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
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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 55 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Outcomes
Primary Outcomes
Safety: Adverse even monitoring of subjects for 4 hours after infusion
Time Frame: Monitoring during the Intravenous infusion of allogeneic tolerogenic fibroblasts, and continued 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.
Safety: Complete Blood Count to monitor inflammation markers
Time Frame: Day before infusion to establish a baseline, week 8, and week 16 after infusion
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
Safety: Serum chemistry to monitor impact on serum chemistry
Time Frame: Day before infusion to establish a baseline, week 8, and week 16 after infusion
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.
Safety: 12-lead Electrocardiogram (ECG) to monitor cardiovascular health
Time Frame: Day before infusion to establish a baseline, week 8, and week 16 after infusion
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
Secondary Outcomes
- Efficacy: Paced Auditory Serial Addition Test (PASAT) to measure cognitive function and processing speed(Day before infusion to establish a baseline, week 8, and week 16 after infusion)
- Efficacy: Expanded Disability Status Scale (EDSS) to quantify disability scale and monitors changes(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(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(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(Day before infusion to establish a baseline, and week 16 after infusion)