Abdominal Aortic Aneurysm
Conditions
Keywords
aneurysms, aortic aneurysm, Abdominal aortic aneurysm
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.
Interventions
BIOLOGICAL1 million MSCs/kg
Intravenous infusion of 1 million allogeneic MSCs/kg.
BIOLOGICAL3 million MSCs/kg
Intravenous infusion of 3 million allogeneic MSCs/kg
DRUGPlacebo
Intravenous infusion of Plasmalyte A (placebo)
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
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. * Estimated glomerular filtration rate (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 (ACS) in the last 30 days prior to enrollment.\* * Congestive heart failure (CHF) hospitalization within the last 30 days prior to enrollment.\* * HIV or Hepatitis C (HCV) positive. * Contraindication to Computed Tomography or known allergy to contrast media. * Any bleeding diathesis defined as an International Normalized Ratio (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 (alanine transaminase (ALT) or aspartate aminotransferase (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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Circulating Inflammatory Cell Phenotypes as Measured by Mass Cytometry | 12 months | This trial will test the hypothesis that MSCs, in a dose dependent fashion (1 x 10\^6 MSC/kg vs 3 x 10\^6 MSC/kg) promote the frequency and immune suppressor function of Treg cells as measured by mass cytometry compared to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment Related Adverse Events at 12 Months Post MSC Administration as Evidenced by the Investigator | 12 months | The safety of systemic administration of allogeneic MSCs will be measured by treatment-related adverse events over a period of 12 months. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
MSCs: Intravenous infusion of 1 million allogeneic MSCs/kg.
MSCs: Intravenous infusion of 3 million allogeneic MSCs/kg
Placebo: Intravenous infusion of Plasmalyte A (placebo) | 6 |
| 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.
MSCs: Intravenous infusion of 1 million allogeneic MSCs/kg.
MSCs: Intravenous infusion of 3 million allogeneic MSCs/kg
Placebo: Intravenous infusion of Plasmalyte A (placebo) | 10 |
| 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.
MSCs: Intravenous infusion of 1 million allogeneic MSCs/kg.
MSCs: Intravenous infusion of 3 million allogeneic MSCs/kg
Placebo: Intravenous infusion of Plasmalyte A (placebo) | 12 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Primary endpoint - endovascular aortic repair | 0 | 0 | 1 |
| Overall Study | Study terminated by VA DSMB due to low enrollment | 5 | 9 | 9 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Intravenous Infusion of 1 Million Allogenic MSC's/Kg | Intravenous Infusion of 3 Million Allogeneic MSCs/kg | Intravenous Infusion of Plasmalyte A (Placebo) |
|---|---|---|---|---|
| AAA size 3.0 - 3.9 cm (max. transverse diameter) | 14 Participants | 2 Participants | 7 Participants | 5 Participants |
| AAA size 4.0 - 5.0 cm (max. transverse diameter) | 14 Participants | 4 Participants | 3 Participants | 7 Participants |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 19 Participants | 2 Participants | 8 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 4 Participants | 2 Participants | 3 Participants |
| Age, Continuous | 67.43 years | 64.17 years | 69 years | 67.75 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 6 Participants | 10 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 6 Participants | 10 Participants | 11 Participants |
| Region of Enrollment United States | 28 Participants | 6 Participants | 10 Participants | 12 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 28 Participants | 6 Participants | 10 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 1 / 10 | 1 / 12 |
| other Total, other adverse events | 3 / 6 | 2 / 10 | 3 / 12 |
| serious Total, serious adverse events | 0 / 6 | 2 / 10 | 1 / 12 |
Outcome results
Primary
Changes in Circulating Inflammatory Cell Phenotypes as Measured by Mass Cytometry
This trial will test the hypothesis that MSCs, in a dose dependent fashion (1 x 10\^6 MSC/kg vs 3 x 10\^6 MSC/kg) promote the frequency and immune suppressor function of Treg cells as measured by mass cytometry compared to baseline.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravenous Infusion of 1 Million Allogenic MSCs/kg | Changes in Circulating Inflammatory Cell Phenotypes as Measured by Mass Cytometry | 21.2 cells | Standard Deviation 3.2 |
| Intravenous Infusion of 3 Million Allogeneic MSCs/kg | Changes in Circulating Inflammatory Cell Phenotypes as Measured by Mass Cytometry | 73.2 cells | Standard Deviation 6.9 |
| Intravenous Infusion of Plasmalyte A (Placebo) | Changes in Circulating Inflammatory Cell Phenotypes as Measured by Mass Cytometry | 0.1 cells | Standard Deviation 0.2 |
Comparison: The primary statistical evaluation for Aim 1 will focus on the chronologically increasing counts of T-regulatory cells over time following MSC administration in both delivery groups. Using the pattern of increased counts with time and the standard deviation reported by Ito and colleagues in healthy subjects, 36 subjects provides 81.0% power to detect such a change.A p value of \<0.05 will be considered significant.p-value: <0.05Regression, Cox
Secondary
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 over a period of 12 months.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravenous Infusion of 1 Million Allogenic MSCs/kg | Incidence of Treatment Related Adverse Events at 12 Months Post MSC Administration as Evidenced by the Investigator | 0 Participants |
| Intravenous Infusion of 3 Million Allogeneic MSCs/kg | Incidence of Treatment Related Adverse Events at 12 Months Post MSC Administration as Evidenced by the Investigator | 0 Participants |
| Intravenous Infusion of Plasmalyte A (Placebo) | Incidence of Treatment Related Adverse Events at 12 Months Post MSC Administration as Evidenced by the Investigator | 0 Participants |