Allogeneic Mesenchymal Human Stem Cells Infusion Therapy for Endothelial DySfunctiOn in Diabetic Subjects

Study Overview
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Brief Summary
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This is a 16 subject trial to demonstrate the safety of allogeneic hMSCs administered via infusion therapy for diabetic subjects with endothelial dysfunction.

Official Title
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A Phase I/II, Randomized, Double Blind, Pilot Trial to Evaluate the Safety and Efficacy of Allogeneic Mesenchymal Human Stem Cells Infusion Therapy for Endothelial DySfunctiOn in Diabetic Subjects

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: 20 million Allogeneic Mesenchymal Human Stem Cells
* Drug: 100 million Allogeneic Mesenchymal Human Stem Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be ≥ 21 and < 90 (inclusive) years of age. Provide written informed consent. Have endothelial dysfunction defined by impaired flow-mediated vasodilation (FMD <7%). Have an ejection fraction > 45% by gated blood pool scan, two- dimensional echocardiogram, cardiac MRI, cardiac CT or left ventriculogram within the prior 3 months. Have Diabetes mellitus type 2 documented by hemoglobin adult type 1 component (A1C) > 7% or on medical therapy for diabetes. Females of childbearing potential must use two forms of birth control for the duration of the study. Female subjects must undergo a blood or urine pregnancy test at screening and within 36 hours prior to infusion. Exclusion Criteria: In order to participate in this study, a subject Must Not: Be younger than 21 years or older than 90 years of age. Have a baseline glomerular filtration rate <35 ml/min 1.73m^2 estimated using the Modification of Diet in renal disease (MDRD) formula. Have an ejection fraction <45% by gated blood pool scan, two-dimensional echocardiogram, cardiac MRI, cardiac CT or left ventriculogram within the past year, as documented by medical history. Have poorly controlled blood glucose levels with hemoglobin A1C > 8.5%. Have a history of proliferative retinopathy or severe neuropathy requiring medical treatment. Have a hematologic abnormality as evidenced by hematocrit < 25%, white blood cell < 2,500/ul or platelet values < 100,000/ul without another explanation. Have liver dysfunction, as evidenced by enzymes (AST and ALT) greater than three times the upper limit of normal. Have a bleeding diathesis or coagulopathy (INR > 1.3), cannot be withdrawn from anticoagulation therapy, or will refuse blood transfusions. Have Lymphadenectomy or Lymph node dissection in the right arm. Be an organ transplant recipient or have a history of organ or cell transplant rejection. Have a clinical history of malignancy within the past 5 years (i.e., subjects with prior malignancy must be disease free for 5 years), except curatively- treated basal cell or squamous cell carcinoma, or cervical carcinoma. Have a condition that limits lifespan to < 1 year. Have a history of drug or alcohol abuse within the past 24 months. Be on chronic therapy with immunosuppressant medication, such as corticosteroids or Tumor Necrosis Factor - alpha (TNFα) antagonists. Be serum positive for HIV, Syphilis - VDRL (Confirmation with FTA-ABS if needed (Syphilis)), hepatitis B surface antigen or viremic hepatitis C. Be currently participating (or participated within the previous 30 days) in an investigational therapeutic or device trial. Be pregnant, nursing, or of childbearing potential while not practicing effective contraceptive methods. Any other condition that in the judgment of the Investigator would be a contraindication to enrollment or follow-up.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 90 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pilot Phase 20 million allogeneic hMSCs<br>Participants in this group will receive one peripheral intravenous infusion of 20 million allogeneic Mesenchymal Human Stem Cells (hMSCs) | Drug: 20 million Allogeneic Mesenchymal Human Stem Cells<br>* 1 single intravenous infusion<br>* Other names: stem cells;|
| Experimental: Pilot Phase 100 million hMSCs<br>Participants in this group will receive one peripheral intravenous infusion of 100 million allogeneic Mesenchymal Human Stem Cells (hMSCs) | Drug: 100 million Allogeneic Mesenchymal Human Stem Cells<br>* 1 single intravenous infusion<br>* Other names: stem cells;|
| Experimental: Randomized Phase 20 million allogeneic hMSCs<br>Participants in this group will receive one peripheral intravenous infusion of 20 million allogeneic Mesenchymal Human Stem Cells (hMSCs) | Drug: 20 million Allogeneic Mesenchymal Human Stem Cells<br>* 1 single intravenous infusion<br>* Other names: stem cells;|
| Experimental: Randomized Phase 100 million allogeneic hMSCs<br>Participants in this group will receive one peripheral intravenous infusion of 100 million allogeneic Mesenchymal Human Stem Cells (hMSCs) | Drug: 100 million Allogeneic Mesenchymal Human Stem Cells<br>* 1 single intravenous infusion<br>* Other names: stem cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment Emergent Serious Adverse Events (TE-SAEs) | TE-SAEs as evaluated by the investigator which may include but not limited to: death, non-fatal pulmonary embolism, stroke, hospitalization for worsening dyspnea and clinically significant laboratory test abnormalities. | Up to one month (post infusion) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EPC-CFU Levels | Endothelial Progenitor Cell Colony Forming Units (EPC-CFU) will be assessed from blood samples | At Baseline, Day 3, Day 7, Day 14, Day 28, Day 90, Day 180, Day 365 | 
| CRP Marker Levels | C-Reactive Protein (CRP) levels will be assessed from blood samples and reported in mg/L | At Baseline, Day 3, Day 7, Day 14, Day 28, Day 90, Day 180, Day 365 | 
| Circulating Angiogenic Factor Levels | Circulating Angiogenic Factor levels including Vascular Endothelial Growth Factor (VEGF), Stem Cell Factor (SCF) and Stromal Cell-Derived Factor 1 (SDF-1) will be assessed from blood samples and reported in ng/mL | At Baseline, Day 3, Day 7, Day 14, Day 28, Day 90, Day 180, Day 365 | 
| Flow Mediated Diameter Percentage (FMD%) | FMD will be assessed using brachial artery ultrasound | At Baseline, Day 3, Day 7, Day 14, Day 28, Day 90, Day 180, Day 365 | 
| Circulating Inflammatory Marker Levels | Circulating inflammatory marker levels including Interleukin (IL) -1 and IL-6 will be assessed from blood samples and reported in pg/mL | At Baseline, Day 3, Day 7, Day 14, Day 28, Day 90, Day 180, Day 365 | 
| Tumor Necrosis Factor (TNF) Alpha Levels | Measured from blood samples (pg/mL) | At Baseline, Day 3, Day 7, Day 14, Day 28, Day 90, Day 180, Day 365 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Endothelial dysfunction, Stem cells