Purpose

The purpose of this study is: - To see if polyTregs can reduce inflammation in a transplanted kidney. - To find out what effects, good or bad, polyTregs will have in the kidney recipient. - To find out what effects, good or bad, taking everolimus after polyTregs will have in the kidney recipient.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

Individuals who meet all of the following criteria are eligible for enrollment as study participants:

1. Subject must be able to understand and provide informed consent;

2. Age ≥18 years of age at the time of study entry

3. Recipients of non- Human Leukocyte Antigen (HLA) identical living or deceased renal transplants;

4. Protocol renal allograft biopsy at 5 months (± 8 weeks) after transplantation with Banff i1 and/or ti1 with concomitant t scores t0, t1,t2 or t3; Banff i2 and/or ti2 with concomitant t scores t0 or t1; and without v > 0, [ptc + g] ≥2, C4d >1 (by immunofluorescence, IF), or C4d > 0 (by immunohistochemistry, IHC); confirmed by central pathologist. Subjects must not be treated for pathologic criteria (e.g. steroids).

5. Estimated glomerular filtration rate (eGFR) ≥35 ml/min at the time of study entry;

6. Maintenance immunosuppression consisting of tacrolimus, MMF/MPA (≥1000 mg/720 mg daily) ± prednisone (≤10 mg/day);

7. Positive Epstein-Barr Virus (EBV) serology at the time of study entry;

8. Current immunizations including TdAP, hepatitis B, pneumococcal and seasonal influenza vaccines at the time of study entry, completed prior to enrollment and no less than 14 days prior to planned manufacturing collection.

9. Documented Hepatitis B (HB) serologies must be:

1. Positive HB surface antibody, negative HB core antibody and negative HB surface antigen for recipients immune to hepatitis B

2. Negative HB surface antibody, negative HB core antibody and negative HB surface antigen for non-immune/ HBV naïve recipients provided donor had negative HB core antibody and negative HB surface antigen at the time of donation.

10. Negative TB test (PPD, interferon-gamma release assay, ELISPOT testing) within 1 year prior to enrollment. Subjects with a history of TB (positive TB test without active infection) must have completed one of the latent TB infection treatment regimens endorsed by the CDC (Division of TB Elimination, 2016). Alternative regimens for latent TB infection eradication will be adjudicated by the site's infectious disease specialist.

11. Women subjects of childbearing potential must have reviewed the Mycophenolate Mycophenolate Risk Evaluation and Mitigation Strategy (REMS) and have a negative pregnancy test upon study entry (Reference:https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPati entsandProviders/ucm318880.htm);

12. Female subjects with child-bearing potential, must agree to use FDA approved methods of birth control for the duration of the study; subjects must consult with their physician and determine the most suitable method(s) that are greater than 80% effective (http://www.fda.gov/birthcontrol).

Treg Infusion Inclusion Criteria:

1. Individuals randomized to the polyTreg and darTreg groups who continue to meet all of the enrollment criteria.

mTOR Conversion Inclusion Criteria:

Individuals who meet all of these criteria are eligible for mTOR conversion:

1. Received either polyTreg or darTregs infusion;

2. Inflammatory load on 2 week post-infusion biopsy has decreased by ≥50% relative to the baseline biopsy, confirmed by central pathologist.

Exclusion Criteria

Individuals who meet any of these criteria are not eligible for enrollment as study participants:

1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol;

2. History of malignancy; except adequately treated basal cell carcinoma;

3. History of graft loss from acute rejection within 1 year after any previous transplant;

4. History of transplant renal artery stenosis;

5. History of cellular rejection prior to enrollment that did not respond to steroids and/or subsequent creatinine after treatment for rejection greater than 15% above baseline;

6. Known hypersensitivity to mTOR inhibitors or contraindication to everolimus (including history of wound healing complications);

7. Any chronic illness requiring uninterrupted anti-coagulation after kidney transplantation;

8. Post-transplant DSA >5000 MFI or post-transplant treatment with IVIg for DSA. Enrolled subjects with post-transplant DSA >2000 MFI will not be eligible for mTOR conversion.

9. Positive HIV 1 or HIV 2 serology prior to transplantation;

10. Positive Hepatitis C virus (HCV) Ab serology or positive HBSAg prior to transplantation;

11. Proteinuria with urine pr/cr > 0.5 g/g;

12. Any condition requiring chronic use of corticosteroids >10mg/day at the time of study entry;

13. Subjects requiring treatment for pathologic findings on study eligibility biopsy (see inclusion 5).

14. Active infection at the time of study entry;

15. History of active TB or latent TB without adequate treatment (see inclusion 11).

16. Serum BK virus >1,000 copies/ml by Polymerase Chain Reaction (PCR) at the time of study entry;

17. Hematocrit <27%; White Blood Cell (WBC) count < 3,000/μL; Absolute Neutrophil Count (ANC) < 1,500/μL; lymphocyte count <800/μL; platelet count <100,000/μL at the time of study entry;

18. Participation in any other studies with investigational drugs or regimens in the preceding year;

19. Any condition or prior treatment which, in the opinion of the investigator, precludes study participation.

20. Unable to provide adequate biopsy specimen (paraffin embedded formalin fixed) from eligibility biopsy (3-7 months post -transplant) for quantitative analysis.

Treg Infusion Exclusion Criteria:

Individuals randomized to polyTreg and darTreg groups who meet any of these criteria are not eligible for Treg infusion:

1. Received any vaccination within 14 days prior to blood collection for Treg manufacture;

2. Unacceptable Treg product;

3. Positive pregnancy test for women of child bearing potential.

mTOR Conversion Exclusion Criteria:

1. Post-transplant Donor-Specific Antibodies (DSA) >2000 mean florescence intensity (MFI).

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Active Comparator
Maintenance CNI based immunosuppression therapy group
Standard of care (N=15 participants in this group)
  • Drug: Tacrolimus
    Other names:
    • FK-506
    • FR-900506
    • Prograf
  • Drug: Mycophenolate mofetil
    All enrolled participants will be on MMF (or MPA below) at the time of study entry at a minimum dose of 1000mg per day.
    Other names:
    • Cellcept
    • MMF
  • Drug: Mycophenolic acid
    All enrolled participants will be on MPA (or MMF above) at the time of study entry at a minimum dose of 720mg per day.
    Other names:
    • Myfortic
    • MPA
  • Procedure: Biopsy, Kidney
    Other names:
    • Kidney Biopsy
  • Procedure: Blood Draw
    Other names:
    • Phlebotomy
    • Venipuncture
Experimental
Polyclonal Regulatory T Cells group
Subjects to receive polyTregs (550 ± 450 x 10^6). After receiving at least 300X10^6 polyTregs infusion, eligible subjects will start mammalian Target of Rapamycin (mTOR) inhibitor. Target tacrolimus trough levels prior to conversion to everolimus are 4-11 μg/dl, which falls within standard of care. For eligible participants in polyTregs and darTregs groups, the tacrolimus dose will be reduced by 50% when everolimus is initiated. Tacrolimus will be discontinued 4 weeks after initiation of everolimus therapy. Everolimus, a mTOR inhibitor immunosuppressant, will be initiated at a dose of 1.5 mg orally twice daily and titrated, as needed. Participants will begin everolimus with target trough levels of 3-8μg/L for 4 weeks while still taking tacrolimus. Everolimus target trough levels will be 6-10 μg/L when tacrolimus is discontinued. (N=15 participants in this group)
  • Biological: Polyclonal Regulatory T Cells
    Participants randomized to polyTregs group will receive a single infusion of 550 ± 450 x 10^6 polyTregs.
    Other names:
    • Polyclonal Tregs
    • polyTregs
  • Drug: Everolimus
    Other names:
    • Zortress
  • Drug: Tacrolimus
    Other names:
    • FK-506
    • FR-900506
    • Prograf
  • Drug: Mycophenolate mofetil
    All enrolled participants will be on MMF (or MPA below) at the time of study entry at a minimum dose of 1000mg per day.
    Other names:
    • Cellcept
    • MMF
  • Drug: Mycophenolic acid
    All enrolled participants will be on MPA (or MMF above) at the time of study entry at a minimum dose of 720mg per day.
    Other names:
    • Myfortic
    • MPA
  • Drug: Acetaminophen
    650 mg acetaminophen, administered 30-60 minutes prior to infusion as pre-medication.
    Other names:
    • Tylenol
  • Drug: Diphenhydramine
    25-50 mg diphenhydramine intravenously or by mouth, administered 30-60 minutes prior to infusion as pre-medication.
    Other names:
    • Benadryl
  • Procedure: Biopsy, Kidney
    Other names:
    • Kidney Biopsy
  • Procedure: Blood Draw
    Other names:
    • Phlebotomy
    • Venipuncture
  • Procedure: Leukapheresis
    Other names:
    • leukocytapheresis
  • Procedure: IS regimen conversion
    Conversion from Tacrolimus, a calcineurin inhibitors (CNI), to Everolimus, an mTOR inhibitor.
    Other names:
    • Everolimus Conversion

Recruiting Locations

University of Alabama, Birmingham
Birmingham, Alabama 35294
Contact:
Jill Andringa
205-934-0035
jillrn@uab.edu

More Details

NCT ID
NCT02711826
Status
Recruiting
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

Study Contact

Detailed Description

Inflammation occurs when the body's defense system recognizes a foreign object (such as a transplanted kidney), and responds by sending white blood cells to attack the foreign object. These cells and the substances they produce can damage the transplanted kidney. There is currently no standard treatment for inflammation in the kidney; some transplant centers do not treat inflammation at all. Rejection is a more severe form of inflammation and injury. Both inflammation and rejection are diagnosed by looking at a piece of kidney (a kidney biopsy) under a microscope. Kidneys that have inflammation and/or rejection do not work as well or last as long as kidneys without injury.

People who have a transplant take immunosuppressive drugs (IS) to prevent inflammation and rejection. Although kidney transplant recipients usually do well in the first five years after transplant, transplant researchers are interested in finding ways to prevent inflammation and rejection without IS, or with lower doses of IS in order to avoid side effects.

While some white blood cells cause inflammation, other types of white blood cells, called T regulatory cells (Tregs), can control inflammation. Tregs may have an important role in controlling or preventing inflammation and rejection. A person's Tregs can be grown in the laboratory to increase their number (polyTreg). These Tregs can be given back through a needle placed in a vein (IV). PolyTregs, when given to the recipient, might reduce inflammation in the transplanted kidney. However, this effect has not yet been shown.

One of the IS drugs used in kidney transplant is Everolimus. Everolimus has been shown to help Tregs survive better than other types of IS drugs.

This is a randomized open‐label trial to determine the safety and efficacy of a single dose of autologous polyTregs in renal transplant recipients with subclinical inflammation (SCI) in the 3 to 7 months post‐transplant allograft protocol biopsy compared to control patients treated with CNI‐based immunosuppression. The efficacy of the Treg therapy will be assessed by the reduction of graft inflammation on biopsies performed at 7 months after study group allocation compared to the eligibility biopsy.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.