Safety and Efficacy of Allogeneic MSCs in Promoting T-regulatory Cells in Patients With Small Abdominal Aortic Aneurysms

Study Overview
=================
Brief Summary
-----------------
This project is to determine the safety and explore the effectiveness of allogeneic (not cells of the participant but those of another human) mesenchymal stromal cells (MSCs) in decreasing inflammation and possible enlargement of the participants' abdominal aortic aneurysm. Participants will be selected as a possible subject because of an abdominal aortic aneurysm discovered on the ultrasound or computed tomographic (CT) scan requested by the participants' doctor. The purpose of this study is to collect information that will be used to determine if MSCs can be used to decrease inflammation and possibly slow down enlargement of the participants' aneurysm. The investigators will also be collecting blood samples to study special inflammatory cells that cause aneurysms as well as asking participants to have a PET (positron emission tomography) scan that can measure inflammation directly in the participants' aneurysm.

Detailed Description
-----------------
This is a phase I, double blinded trial that will enroll 50 patients with Abdominal Aortic Aneurysms (AAA) measuring 3-5 cm in maximal transverse diameter (MTD). This study will assess the safety of MSCs in doses of 1 million MSCs/kg. or 3 million MSCs/kg. delivered intra-venously. This trial test the hypothesis that MSCs, in a dose dependent fashion, promote the frequency and immune suppressor function of CD4+CD25+ FoxP3+ T-regulatory cells and decrease AAA inflammation as measured by 18-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT). The primary safety endpoints will be incidence of treatment related adverse events accrued over 24 months. Efficacy measures are changes in frequency and immune suppressor function of Tregs, number and cytotoxic activity of CD4+/CD8+ CD28- T-cells, activated monocytes, and changes in aortic inflammation as measured by uptake of 18-FDG PET/CT compared to baseline. Incidence of surgical intervention, aneurysm related death, quality of life, and major adverse cardiac events will be recorded.

Official Title
-----------------
Mesenchymal Stem Cells Induce Regulatory T Cells in Patients With Aortic Aneurysm

Conditions
-----------------
Abdominal Aortic Aneurysm

Intervention / Treatment
-----------------
* Biological: MSCs
* Biological: MSCs
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Be 40 and 85 years of age. Have diagnosis of noninflammatory degenerative infrarenal abdominal aortic aneurysms measuring 3-5 cm. in diameter by Computed Tomography (CT) scan. Females of childbearing potential must be willing to use one form of birth control for the duration of the study. Female participants must undergo a blood or urine pregnancy test at screening. Exclusion Criteria: Inflammatory AAA defined by a thickened aortic wall and retroperitoneal fibrosis and adhesions of peritoneal organs, and elevated erythrocyte sedimentation rate or in the opinion of investigator. Mycotic AAA defined as saccular morphology, a positive blood culture, fever, or in the opinion of the investigator. Symptomatic, Saccular, or any AAA associated with thoracic aorta dilatation >5.0 cm. Infra-renal AAA associated with Marfan's or Ehlers-Danlos Syndrome or other connective tissue disorders. Common or external iliac artery aneurysm > 30 cm. in maximal transverse diameter. AAA due to dissection. Allergy to iodine contrast. History of cancer within the last 5 years, except basal cell skin carcinoma with clean border pathology report. eGFR< 30mL/min. Any condition requiring immunosuppressant medications (e.g., for treatment of organ transplants, psoriasis, Crohn's disease, alopecia areata, rheumatoid arthritis, scleroderma, lupus). Acute coronary syndrome in the last 30 days prior to enrollment.* CHF hospitalization within the last 30 days prior to enrollment.* HIV or HCV positive. Contraindication to Computed Tomography or known allergy to contrast media. Any bleeding diathesis defined as an INR 2.0 (off anticoagulation therapy) or history of platelet count less than 70,000 or hemophilia. Pregnant or breast feeding women. Significant hepatic dysfunction (ALT or AST greater than 2 times normal). Life expectancy less than two years. Inability to provide written informed consent due to cognitive or language barriers (interpreter permitted). Presence of any clinical condition that in the opinion of the PI or the sponsor makes the patient not suitable to participate in the trial. As defined by the standard definitions of CHF and ACS by the American Heart Association.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intravenous infusion of 1 million allogenic MSC's/Kg<br>In a randomized fashion, the MSCs, in the appropriate dose, will be shipped to the performance site where the MSCs will be thawed, diluted and administered. The thawed MSCs with be administered within 4 hours to subjects in a monitored setting with telemetry and pulse oximetry. Patients will be premedicated with hydrocortisone and diphenhydramine. All subjects will be monitored throughout the infusion procedure with vital signs and pulse oximetry at 15 minutes prior to infusion and ending 2 hours post procedure. They will also be evaluated for clinical signs of pulmonary distress. All patients will be admitted overnight for continued observation. The patient will be examined the following day and discharged home. | Biological: MSCs<br>* Intravenous infusion of 1 million allogeneic MSCs/kg.<br>Biological: MSCs<br>* Intravenous infusion of 3 million allogeneic MSCs/kg<br>Drug: Placebo<br>* Intravenous infusion of Plasmalyte A (placebo)<br>* Other names: Plasmalyte A;|
| Active Comparator: Intravenous infusion of 3 million allogeneic MSCs/kg<br>In a randomized fashion, the MSCs, in the appropriate dose, will be shipped to the performance site where the MSCs will be thawed, diluted and administered.The thawed MSCs with be administered within 4 hours to subjects in a monitored setting with telemetry and pulse oximetry. Patients will be premedicated with hydrocortisone and diphenhydramine. All subjects will be monitored throughout the infusion procedure with vital signs and pulse oximetry at 15 minutes prior to infusion and ending 2 hours post procedure. They will also be evaluated for clinical signs of pulmonary distress. All patients will be admitted overnight for continued observation. The patient will be examined the following day and discharged home. | Biological: MSCs<br>* Intravenous infusion of 1 million allogeneic MSCs/kg.<br>Biological: MSCs<br>* Intravenous infusion of 3 million allogeneic MSCs/kg<br>Drug: Placebo<br>* Intravenous infusion of Plasmalyte A (placebo)<br>* Other names: Plasmalyte A;|
| Placebo Comparator: Intravenous infusion of Plasmalyte A (placebo)<br>In a randomized fashion, the Plasmalyte A will be shipped to the performance site where it will be thawed and administered. The Plasmalyte A will be administered within 4 hours to subjects in a monitored setting with telemetry and pulse oximetry as will be performed on active groups in order to protect the blinding of this study. Patients will be pre-medicated with hydrocortisone and diphenhydramine. All subjects will be monitored throughout the infusion procedure with vital signs and pulse oximetry at 15 minutes prior to infusion and ending 2 hours post procedure. They will also be evaluated for clinical signs of pulmonary distress. All patients will be admitted overnight for continued observation. The patient will be examined the following day and discharged home. | Biological: MSCs<br>* Intravenous infusion of 1 million allogeneic MSCs/kg.<br>Biological: MSCs<br>* Intravenous infusion of 3 million allogeneic MSCs/kg<br>Drug: Placebo<br>* Intravenous infusion of Plasmalyte A (placebo)<br>* Other names: Plasmalyte A;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment related adverse events at 12 months post MSC administration as evidenced by the Investigator | The safety of systemic administration of allogeneic MSCs will be measured by treatment-related adverse events. The categories of systems are cardiovascular, respiratory, or infectious. Two categories of severity will be serious adverse (SAE) and major adverse cardiac events (MACE). Within each of these categories adverse events will be listed in descending order of frequency for the treatment-group. In addition for each category, the sum and difference between the two routes of delivery of the proportions will be reported as percent incidence. Confidence Intervals at the 95% confidence level and P-values for these four groups will be calculated. Since four previous trials have not reported adverse events with MSC treatment, confidence intervals will be generated by the method of the Wilson Score Interval. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in circulating inflammatory cell phenotypes as measured by 18-FDG PET/CT | This trial will also test the hypothesis that MSCs, in a dose dependent fashion (1 x106 MSC/kg. vs. 3.0 x 106 MSC/kg. ), promote the frequency and immune suppressor function of Treg cells as measured by 18-fluorodeoxyglucose positron emission tomography/computed tomography compared to baseline. | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
aneurysms, aortic aneurysm, Abdominal aortic aneurysm