Allogeneic Mesenchymal Human Stem Cell Infusion Therapy for Endothelial DySfunctiOn in Diabetic Subjects With Symptomatic Ischemic Heart Disease. (ACESO-IHD)

Study Overview
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Brief Summary
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The purpose of this study is to test the hypothesis that allogeneic Mesenchymal Stem Cells (MSCs) promote systemic and coronary endothelial repair through rescue of bone marrow progenitors in type 2 diabetic patients with symptomatic IHD compared to placebo.

Official Title
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Allogeneic Mesenchymal Human Stem Cell Infusion Therapy for Endothelial DySfunctiOn in Diabetic Subjects With Symptomatic Ischemic Heart Disease.

Conditions
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Diabetes Mellitus, Ischemic Heart Disease

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be ≥ 18 years of age (males and females). Provide written informed consent. Have a diagnosis of symptomatic ischemic heart disease (IHD) and an indication for standard-of-care coronary angiography. Have Diabetes Mellitus (DM) type 2 documented by glycated hemoglobin (HbA1C) > 7%, or on medical therapy for diabetes. Exclusion Criteria: Be younger than 18 years of age. Have history of prior myocardial Infarction and revascularization. Have a baseline glomerular filtration rate (GFR) <30 ml/min 1.73m2 estimated using the Modification of Diet for Renal Disease (MDRD) formula. Have poorly controlled blood glucose levels with hemoglobin A1C > 8.5% in the previous 3 months. Have a history of proliferative retinopathy or severe neuropathy requiring medical treatment. Have an indication for standard-of-care surgical (including valve surgery, placement of left-ventricular assist device) or percutaneous intervention for the treatment of valvular heart disease (including valvuloplasty). Have known hypersensitivity or contraindication to aspirin; both heparin and bivalirudin; all available P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor); or any zotarolimus, cobalt, chromium, nickel, tungsten, acrylic, or fluoropolymers; or hypersensitivity to contrast media that cannot be adequately premedicated. Have a hematologic abnormality as evidenced by hematocrit < 25%, white blood cell < 2,500/microliter (uL) or platelet values < 100,000/uL without another explanation (per investigator discretion). 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. 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 serum positive for HIV, hepatitis B surface antigen (sAg), 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 and not on contraceptive medications. (May participate if on 2 forms of contraceptives). Any other condition that in the judgment of the Investigator would be a contraindication to enrollment or follow-up. Coronary lesions with restenosis or heavy calcification.

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Allogeneic Mesenchymal Stem Cells (MSCs) Group<br>Participants in this group will be receive a single administration of intravenous allogeneic human Mesenchymal Stem Cells (hMSCs) (100 million). | Drug: 100 million Allogeneic Mesenchymal Human Stem Cells<br>* 1 single intravenous infusion<br>* Other names: stem cells;|
| Experimental: Group 2: Placebo Group<br>Participants in this group will receive a single dose of placebo (Cell-free PlasmaLyte-A medium supplemented with 1% HSA) infusion. | Other: Placebo<br>* Placebo delivered via peripheral intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-Percutaneous Coronary Intervention (PCI) coronary artery endothelial function as assessed via CFR | Coronary Flow Reserve (CFR) as measured via cardiac catheterization angiography | 6 months (post-infusion) | 
| Post-PCI coronary artery endothelial function as assessed via FFR | Fractional Flow Reserve (FFR) as measured via cardiac catheterization angiography | 6 months (post infusion) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Target lesion lumen loss | Target lesion lumen loss as assessed by quantitative coronary angiography (QCA). | 6 months (post-infusion) | 
| Flow Mediated Diameter Percentage (FMD%) | FMD% is measured via brachial artery ultrasound | 6 months post-infusion | 
| EPC-CFUs levels | Endothelial progenitor cells (EPC)-colony forming units (CFUs) will be assessed from blood samples. | 6 months post-infusion | 
| Circulating angiogenic factors marker levels | Circulating angiogenic marker levels including Protein Kinase B, Stromal Cell Derived Factor 1 (SDF-1), Notch, Vascular Endothelial Growth Factor (VEGF) and Colony Forming Units (CFU) will be assessed from blood samples. | 6 months post-infusion | 
| Circulating inflammatory markers | Circulating inflammatory markers including Cluster of Differentiation (CD) 3 CD 25 or CD 3 CD 69 will be assessed from blood samples. | 6 months post-infusion | 
| Seattle Angina Questionnaire (SAQ) Angina Frequency | SAQ is a 7 item questionnaire with a total score ranging from 0-100 with the higher scores indicating less physical limitations, less angina, symptom frequency and better quality of life. | 6 months post-infusion | 
| EuroQol(EQ)-5 Dimension (5D) Quality of Life Questionnaire | EQ-5D Quality of Life Questionnaire has a total score ranging from 0-10 with higher scores indicating better quality of life. | 6 months post-infusion | 
| EQ-5D Quality of life Questionnaire Overall Health Status Question | EQ-5D Quality of Life Questionnaire Overall Health Status question has a total score ranging from 0-100 with higher scores indicating better quality of life. | 6 months post-infusion | 
| Short Form (SF) 36 Questionnaire Quality of Life Questionnaire | SF 36 Quality of Life Questionnaire consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale. Lower scores indicate the more disability, and higher scores indicate less disability. | 6 months post-infusion | 
| International Index of Erectile Function (IIEF) Questionnaire | IIEF is a 15 item questionnaire to be completed by males only, with scores ranging from 0-75. Higher scores indicate better male sexual function/quality of life. | 6 months post-infusion | 
| Sexual Quality of Life - Females (SQOL-F) Questionnaire | SQOL-F Questionnaire is an 18 item questionnaire in which female participants are asked to record responses on a 6-point Likert scale (completely agree to completely disagree). Total score can range from 18 to 108. Higher scores indicate better female sexual quality of life. | 6 months post-infusion | 
| Incidence of Treatment-Emergent Serious Adverse Events (TE-SAE) | TE-SAEs will be defined as the composite of: death, non-fatal myocardial infarction (MI), stroke, hospitalization for heart failure, sustained ventricular arrhythmias or atrial fibrillation. TE-SAEs will be assessed by treating physician. | 1 month post infusion | 
| Incidence of Major Adverse Cardiac Events (MACE) | Defined as the composite incidence of (1) death, (2) hospitalization for cardiovascular events or (3) non-fatal MI. MACE will be assessed by treating physician. | 12 months | 
| Rates of Adverse Events | Rates of treatment emergent adverse event (AE) and serious adverse event (SAE) as assessed by treating physician will be reported. | 12 months | 
| Number of participants with abnormal lab values | Number of participants with clinically significant abnormal serum hematology and clinical chemistry values will be reported. Clinical significance will be assessed by treating physician. | 12 months | 
| Number of participants with Target Vessel Failure | Number of participants with target vessel failure will be reported. Target vessel failure is defined as any participant that encounters revascularization, death, or MI attributed to the target vessel post-PCI | 12 months | 

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