Clinical Application of Stem Cell Educator Therapy in Type 1 Diabetes

Study Overview
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Brief Summary
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Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that causes a deficit of pancreatic islet beta cells. Millions of individuals worldwide have T1D, and incidence increases annually. Several recent clinical trials point to the need for an approach that produces comprehensive immune modulation at both the local pancreatic and systemic levels. Stem Cell Educator (SCE) therapy offers comprehensive immune modulation at both the local and systemic levels in T1D by using a patient's own immune cells (including platelets) that are educated by cord blood stem cells. Tested clinically in more than 200 patients, SCE therapy has shown lasting reversal in autoimmunity in T1D patients, including improved C-peptide levels, reduced median glycated hemoglobin A1C (HbA1C) values, and decreased median daily usage of insulin. SCE therapy circulates a patient's blood through a blood cell separator, briefly cocultures the patient's immune cells with adherent Cord Blood Stem Cells (CB-SCs) in vitro, and returns the educated autologous immune cells to the patient's circulation.

Detailed Description
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The SCE device is made of a hydrophobic material from FDA-approved (USP Class VI) dishes that tightly binds stem cells CB-SCs without interfering with their immune modulating capability. We originally designed a chamber for co-culture of lymphocytes and CB-SCs that included nine discs of the material with a flow pathway and adherent CB-SCs sandwiched between a top cover plate and a bottom collecting plate. In this trial, we are going to use the 12-layer SCE device. The SCE therapy carried a lower risk of infection than a typical blood transfusion, and did not introduce stem cells or reagents into the patients. In addition, CB-SCs have very low immunogenicity, and the CB-SCs cultured in the device are a highly restricted population and contain no CD3+ T cells or other lymphocyte subsets, eliminating the need for human leukocyte antigen (HLA) matching prior to treatment. This innovative approach has the potential to provide CB-SC-mediated immune modulation therapy for multiple autoimmune diseases while mitigating the safety and ethical concerns associated with other approaches such as T1D, type 2 diabetes (T2D), and alopecia areata (AA) in clinics. The relative simplicity of the approach may also provide cost and time savings relative to other approaches.

Official Title
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Clinical Application of Stem Cell Educator Therapy in Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Combination Product: Stem Cell Educator therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients ( 14 years) Must have a diagnosis of type 1 diabetes mellitus based on the 2015 American Diabetes Association criteria for the Clarification and Diagnosis of diabetes. Must have a blood test confirming the presence of at least one autoantibody to pancreatic islet Cells (IAA, IA2, GAD 65, ZnT8). Fasting C-peptide level > 0.3 ng/ml HbA1C < 10% at enrollment Recent diagnosis (within two years of enrollment) Adequate venous access for apheresis Must be equipped with a continuous glucose monitoring system (CGMS) Ability to provide informed consent For female patients only, willingness to use FDA-recommended birth control (http://www.fda.gov/downloads/ForConsumers/ByAudience/ForWomen/FreePublications/UCM356451.pdf) until 6 months post treatment. Must agree to comply with all study requirements and be willing to complete all study visits Exclusion Criteria: AST or ALT 2 > x upper limit of normal. Abnormal bilirubin (total bilirubin > 1.2 mg/dL, direct bilirubin > 0.4 mg/dL) Creatinine > 2.0 mg/dl. Known coronary artery disease or EKG suggestive of coronary artery disease unless cardiac clearance for apheresis is obtained from a cardiologist. Known active infection such as Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) Pregnancy assessed by a positive serum pregnancy test or breastfeeding mothers Use of immunosuppressive medication within one month of enrollment including but not limited to prednisone, cyclosporine, tacrolimus, sirolimus, and chemotherapy. Presence of any other autoimmune diseases (lupus, rheumatoid arthritis, scleroderma, etc.) Anticoagulation other than ASA. Hemoglobin < 10 g/dl or platelets < 100 k/ml Is unable or unwilling to provide informed consent Presence of any other physical or psychological medical condition that, in the opinion of the investigator, would preclude participation

Ages Eligible for Study
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Minimum Age: 14 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: Parallel Assignment
Interventional Model Description: Treatment group receive Stem Cell Educator therapy, control group receive conventional insulin therapy.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment of T1D with Stem Cell Educator therapy<br>Recruited T1D subjects will receive one treatment with SCE therapy. | Combination Product: Stem Cell Educator therapy<br>* Patients with T1D will be evaluated by the study principal investigator or co-investigators. Informed consent will be obtained at the initial screening visit. The initial screening visit will occur within 30 days of initiation of SCE therapy. The second screening visit will occur within 7 days of therapy. Subjects who meet all criteria will be scheduled for treatment. All enrolled subjects will receive treatment with the SCE system consisting of a single session of mononuclear cells (MNC) collection by apheresis where 10 L of blood will be processed on day -1. The MNC product will then be exposed over to the SCE and on day 0 the product will be infused intravenously back to the patient.<br>|
| Experimental: Conventional insulin therapy<br>Control group will receive conventional insulin therapy. | Combination Product: Stem Cell Educator therapy<br>* Patients with T1D will be evaluated by the study principal investigator or co-investigators. Informed consent will be obtained at the initial screening visit. The initial screening visit will occur within 30 days of initiation of SCE therapy. The second screening visit will occur within 7 days of therapy. Subjects who meet all criteria will be scheduled for treatment. All enrolled subjects will receive treatment with the SCE system consisting of a single session of mononuclear cells (MNC) collection by apheresis where 10 L of blood will be processed on day -1. The MNC product will then be exposed over to the SCE and on day 0 the product will be infused intravenously back to the patient.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment Adverse Events in T1D Subjects | The occurrence of treatment-related adverse events will be evaluated post the treatment with SCE therapy. | 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminary efficacy of SCE therapy to improve beta cell function | Preliminary efficacy as measured by Area under the C-peptide curve (AUC) over the first 2 hours of a 3-hour mixed meal tolerance test (MMTT) | 12 months | 
| Preliminary efficacy of SCE therapy to improve glucose control | Change in HbA1C levels over time | 12 months | 
| Preliminary efficacy of SCE therapy to reduce insulin dose | Change in daily insulin requirements | 12 months | 
| Efficacy of SCE therapy in immune modulation | Measurements of immune markers at baseline, 1, 3, 6, 9, and 12 months. Peripheral blood mononuclear cells (PBMC) will be collected and tested by flow cytometry. | 12 month |