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

Mesenchymal Stem Cells Induce Regulatory T Cells in Patients With Aortic Aneurysm

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.

Study Overview

• Status: Terminated
• Conditions: Abdominal Aortic Aneurysm
• Intervention / Treatment: Biological: MSCs; Biological: MSCs; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202-2884
      • Richard L. Roudebush VA Medical Center, Indianapolis, IN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Intravenous infusion of 1 million allogenic MSC's/Kg; 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; Intravenous infusion of 1 million allogeneic MSCs/kg.; Biological: MSCs; Intravenous infusion of 3 million allogeneic MSCs/kg; Drug: Placebo; Intravenous infusion of Plasmalyte A (placebo); Other Names: Plasmalyte A
ACTIVE_COMPARATOR: Intravenous infusion of 3 million allogeneic MSCs/kg; 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; Intravenous infusion of 1 million allogeneic MSCs/kg.; Biological: MSCs; Intravenous infusion of 3 million allogeneic MSCs/kg; Drug: Placebo; Intravenous infusion of Plasmalyte A (placebo); Other Names: Plasmalyte A
PLACEBO_COMPARATOR: Intravenous infusion of Plasmalyte A (placebo); 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; Intravenous infusion of 1 million allogeneic MSCs/kg.; Biological: MSCs; Intravenous infusion of 3 million allogeneic MSCs/kg; Drug: Placebo; Intravenous infusion of Plasmalyte A (placebo); 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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in aortic inflammation 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 decrease of AAA inflammation as measured by 18-fluorodeoxyglucose positron emission tomography/computed tomography compared to baseline.	12 months

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Michael P Murphy, MD BS, Richard L. Roudebush VA Medical Center, Indianapolis, IN

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 5, 2016
• Primary Completion (ACTUAL): September 30, 2021
• Study Completion (ACTUAL): September 30, 2021

Study Registration Dates

• First Submitted: July 25, 2016
• First Submitted That Met QC Criteria: July 25, 2016
• First Posted (ESTIMATE): July 27, 2016

Study Record Updates

• Last Update Posted (ACTUAL): August 9, 2022
• Last Update Submitted That Met QC Criteria: August 4, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: aortic aneurysm; Abdominal aortic aneurysm; aneurysms
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Aortic Diseases; Aneurysm; Aortic Aneurysm; Aortic Aneurysm, Abdominal; Pharmaceutical Solutions; Ophthalmic Solutions; Plasma-lyte 148
• Other Study ID Numbers: CLNB-06-15F; 1510579216 (OTHER: IU IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No