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

Primary Purpose

Abdominal Aortic Aneurysm

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
MSCs
MSCs
Placebo
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Abdominal Aortic Aneurysm focused on measuring aneurysms, aortic aneurysm, Abdominal aortic aneurysm

Eligibility Criteria

40 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Richard L. Roudebush VA Medical Center, Indianapolis, IN

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Intravenous infusion of 1 million allogenic MSC's/Kg

Intravenous infusion of 3 million allogeneic MSCs/kg

Intravenous infusion of Plasmalyte A (placebo)

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

First Posted
July 25, 2016
Last Updated
August 4, 2022
Sponsor
VA Office of Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT02846883
Brief Title
Safety and Efficacy of Allogeneic MSCs in Promoting T-regulatory Cells in Patients With Small Abdominal Aortic Aneurysms
Acronym
VIVAAA
Official Title
Mesenchymal Stem Cells Induce Regulatory T Cells in Patients With Aortic Aneurysm
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Terminated
Why Stopped
Early Termination as required by VA DSMB due to slow enrollment
Study Start Date
December 5, 2016 (Actual)
Primary Completion Date
September 30, 2021 (Actual)
Study Completion Date
September 30, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Abdominal Aortic Aneurysm
Keywords
aneurysms, aortic aneurysm, Abdominal aortic aneurysm

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderOutcomes Assessor
Allocation
Randomized
Enrollment
28 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intravenous infusion of 1 million allogenic MSC's/Kg
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Intravenous infusion of 3 million allogeneic MSCs/kg
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Intravenous infusion of Plasmalyte A (placebo)
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
MSCs
Intervention Description
Intravenous infusion of 1 million allogeneic MSCs/kg.
Intervention Type
Biological
Intervention Name(s)
MSCs
Intervention Description
Intravenous infusion of 3 million allogeneic MSCs/kg
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Plasmalyte A
Intervention Description
Intravenous infusion of Plasmalyte A (placebo)
Primary Outcome Measure Information:
Title
Incidence of treatment related adverse events at 12 months post MSC administration as evidenced by the Investigator
Description
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.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Changes in circulating inflammatory cell phenotypes as measured by 18-FDG PET/CT
Description
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.
Time Frame
12 months
Other Pre-specified Outcome Measures:
Title
Changes in aortic inflammation as measured by 18-FDG PET/CT
Description
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.
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael P Murphy, MD BS
Organizational Affiliation
Richard L. Roudebush VA Medical Center, Indianapolis, IN
Official's Role
Principal Investigator
Facility Information:
Facility Name
Richard L. Roudebush VA Medical Center, Indianapolis, IN
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202-2884
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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