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

Peripheral Artery Disease Clinical Trial

— VIVAAA  

Official title:

A Phase I Study to Examine the Safety and Efficacy of Allogeneic MSCs in Promoting T-regulatory Cell Immune Suppressor Function in Patients With Small Abdominal Aortic Aneurysms (AAA)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02843854
• Other study ID #: 1510579216
• Status: Not yet recruiting
• Phase: Phase 1
• First received: March 1, 2016
• Last updated: July 21, 2016
• Start date: October 2016
• Est. completion date: April 2020

Study information

• Verified date: July 2016
• Source: Indiana University
• Contact: Kristen E Wanczyk, RN,CCRC
• Phone: 317-988-9548
• Email: keevans[@]iu.edu
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

This study will assess the safety and efficacy of systemic (IV) administration of escalating doses of allogeneic MSCs in modulating immune cell phenotypes and suppressing aortic inflammation in patients with small AAA. Subjects will be randomized in a 1:1:1 fashion to receive mesenchymal stromal cells (1 million or 3 million MSC/kg) intra-venously or placebo (Plasmalyte A).

Description:

This is a phase I, double blinded trial that will enroll 36 patients with AAA measuring 35-45 mm 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 36
• Est. completion date: April 2020
• Est. primary completion date: August 2019
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Be = 40 and =80 years of age.

2. Have diagnosis of non-inflammatory degenerative infrarenal abdominal aortic aneurysms measuring 35-45 mm. in diameter by Computed Tomography (CT) scan.

3. 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:

1. 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.

2. Mycotic AAA defined as saccular morphology, a positive blood culture, fever, or in the opinion of the investigator.

3. Symptomatic, Saccular, or any AAA associated with thoracic aorta dilatation > 5.0 cm.

4. Infra-renal AAA associated with Marfan's or Ehlers-Danlos Syndrome or other connective tissue disorders

5. Common or external iliac artery aneurysm > 30 mm. in maximal transverse diameter.

6. AAA due to dissection.

7. Allergy to iodine contrast.

8. History of cancer within the last 5 years, except basal cell skin carcinoma with clean border pathology report.

9. eGFR< 30mL/min.

10. Any condition requiring immunosuppressant medications (e.g., for treatment of organ transplants, psoriasis, Crohn's disease, alopecia areata, rheumatoid arthritis, scleroderma, lupus).

11. Acute coronary syndrome in the last 30 days prior to enrollment.*

12. CHF hospitalization within the last 30 days prior to enrollment.*

13. HIV or HCV positive, or active HBV.

14. Contraindication to Computed Tomography or known allergy to contrast media.

15. Any bleeding diathesis defined as an INR = 2.0 (off anticoagulation therapy) or history of platelet count less than 70,000 or hemophilia.

16. Pregnant or breast feeding women.

17. Significant hepatic dysfunction (ALT or AST greater than 2 times normal).

18. Life expectancy less than two years.

19. Inability to provide written informed consent due to cognitive or language barriers (interpreter permitted).

20. 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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• AAA
• Abdominal Aortic Aneurysm
• Aneurysm
• Aortic Aneurysm
• Aortic Aneurysm, Abdominal
• Peripheral Arterial Disease
• Peripheral Artery Disease
• Vascular Disease
• Vascular Diseases

Intervention

Biological:
• 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.
• Intravenous infusion of 1 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 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.
• 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 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.

Locations

Country	Name	City	State
United States	Richard L. Roudebush VA Medical Center	Indianapolis	Indiana

Sponsors (1)

Lead Sponsor	Collaborator
Michael Murphy

Country where clinical trial is conducted

United States, 

References & Publications (12)

Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002 May 15;99(10):3838-43. — View Citation

Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, Tracy M, Ghersin E, Johnston PV, Brinker JA, Breton E, Davis-Sproul J, Schulman IH, Byrnes J, Mendizabal AM, Lowery MH, Rouy D, Altman P, Wong Po Foo C, Ruiz P, Amador A, Da Silva J, McNiece IK, Heldman AW, George R, Lardo A. Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA. 2012 Dec 12;308(22):2369-79. Erratum in: JAMA. 2013 Aug 21;310(7):750. George, Richard [added]; Lardo, Albert [added]. — View Citation

Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, Hermiller JB Jr, Reisman MA, Schaer GL, Sherman W. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009 Dec 8;54(24):2277-86. doi: 10.1016/j.jacc.2009.06.055. — View Citation

Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum likelihood. Biometrics. 1997 Sep;53(3):983-97. — View Citation

Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringdén O; Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008 May 10;371(9624):1579-86. doi: 10.1016/S0140-6736(08)60690-X. — View Citation

Meijer CA, Stijnen T, Wasser MN, Hamming JF, van Bockel JH, Lindeman JH; Pharmaceutical Aneurysm Stabilisation Trial Study Group. Doxycycline for stabilization of abdominal aortic aneurysms: a randomized trial. Ann Intern Med. 2013 Dec 17;159(12):815-23. — View Citation

Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007 Nov 15;110(10):3499-506. Epub 2007 Jul 30. Review. — View Citation

Nordon IM, Hinchliffe RJ, Loftus IM, Thompson MM. Pathophysiology and epidemiology of abdominal aortic aneurysms. Nat Rev Cardiol. 2011 Feb;8(2):92-102. doi: 10.1038/nrcardio.2010.180. Epub 2010 Nov 16. Review. — View Citation

Sharma AK, Lu G, Jester A, Johnston WF, Zhao Y, Hajzus VA, Saadatzadeh MR, Su G, Bhamidipati CM, Mehta GS, Kron IL, Laubach VE, Murphy MP, Ailawadi G, Upchurch GR Jr. Experimental abdominal aortic aneurysm formation is mediated by IL-17 and attenuated by mesenchymal stem cell treatment. Circulation. 2012 Sep 11;126(11 Suppl 1):S38-45. Erratum in: Circulation. 2012 Oct 23;126(17):e278. — View Citation

Stroupe KT, Lederle FA, Matsumura JS, Kyriakides TC, Jonk YC, Ge L, Freischlag JA; Open Versus Endovascular Repair (OVER) Veterans Affairs Cooperative Study Group. Cost-effectiveness of open versus endovascular repair of abdominal aortic aneurysm in the OVER trial. J Vasc Surg. 2012 Oct;56(4):901-9.e2. doi: 10.1016/j.jvs.2012.01.086. Epub 2012 May 27. — View Citation

Tan J, Wu W, Xu X, Liao L, Zheng F, Messinger S, Sun X, Chen J, Yang S, Cai J, Gao X, Pileggi A, Ricordi C. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA. 2012 Mar 21;307(11):1169-77. doi: 10.1001/jama.2012.316. — View Citation

Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP. A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest. 2013 Jun;143(6):1590-8. doi: 10.1378/chest.12-2094. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of treatment related adverse events at 12 months post MSC administration as evidenced by the Investigator using the MedDRA scale.	The safety of systemic administration of allogeneic MSCs will be measured by treatment-related adverse events. Treatment-related adverse events will be categorized by overlapping systems and severities. The three categories of systems are cardiovascular, respiratory, or infectious. Two categories of severity will be serious adverse (SAE) and major adverse cardiac events (MACE). For completeness, instances of adverse events may appear in more than one category. 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	Yes
Secondary	Changes in circulating inflammatory cell phenotypes and aortic inflammation as measured by 18-FDG PET/CT	This trial will also test the hypothesis that MSCs, in a dose dependent fashion (1 million MSC/kg. vs. 3.0 million MSC/kg. ), promote the frequency and immune suppressor function of Treg cells and decrease AAA inflammation as measured by 18-fluorodeoxyglucose positron emission tomography/computed tomography compared to baseline.	12 months	No