Treg Therapy in Subclinical Inflammation in Kidney Transplantation
NCT ID: NCT02711826
Last Updated: 2025-04-09
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1/PHASE2
32 participants
INTERVENTIONAL
2016-09-20
2023-08-04
Brief Summary
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* 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.
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Maintenance CNI based immunosuppression therapy group
Standard of care
(N=7 participants in this group)
Tacrolimus
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.
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.
Biopsy, Kidney
Blood Draw
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=7 participants in this group)
Polyclonal Regulatory T Cells
Participants randomized to polyTregs group will receive a single infusion of 550 ± 450 x 10\^6 polyTregs.
Everolimus
Tacrolimus
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.
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.
Acetaminophen
650 mg acetaminophen, administered 30-60 minutes prior to infusion as pre-medication.
Diphenhydramine
25-50 mg diphenhydramine intravenously or by mouth, administered 30-60 minutes prior to infusion as pre-medication.
Biopsy, Kidney
Blood Draw
Leukapheresis
IS regimen conversion
Conversion from Tacrolimus, a calcineurin inhibitors (CNI), to Everolimus, an mTOR inhibitor.
Interventions
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Polyclonal Regulatory T Cells
Participants randomized to polyTregs group will receive a single infusion of 550 ± 450 x 10\^6 polyTregs.
Everolimus
Tacrolimus
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.
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.
Acetaminophen
650 mg acetaminophen, administered 30-60 minutes prior to infusion as pre-medication.
Diphenhydramine
25-50 mg diphenhydramine intravenously or by mouth, administered 30-60 minutes prior to infusion as pre-medication.
Biopsy, Kidney
Blood Draw
Leukapheresis
IS regimen conversion
Conversion from Tacrolimus, a calcineurin inhibitors (CNI), to Everolimus, an mTOR inhibitor.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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) ≥30 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. Current immunizations including TdAP, hepatitis B, pneumococcal and seasonal influenza vaccines prior to study treatment, completed prior to randomization and no less than 14 days prior to planned manufacturing collection;
8. 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.
9. 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.
10. Female 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/PostmarketDrugSafetyInformationforPatientsandProviders/ucm318880.htm); and
11. 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).
1. Individuals randomized to the polyTreg and darTreg groups who continue to meet all of the enrollment criteria; and
2. Negative SARS-COV2 by RTP-PCR testing within 1 week of Treg infusion.
Individuals who meet all of these criteria are eligible for mTOR conversion:
1. Received at least 300 x 10\^6 polyTreg infusion;
2. Resolution of inflammation on the 2 week post-infusion biopsy as compared to the baseline biopsy, confirmed by central pathologist.
Exclusion Criteria
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.
* Note: 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 HBSAg or HBcAb serology;
11. Proteinuria with urine protein-to-creatinine ratio \> 1.0 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;
16. Serum BK virus \>1,000 copies/ml by Polymerase Chain Reaction (PCR) at the time of study entry;
17. Hematocrit \<27%; Absolute Neutrophil Count (ANC) \< 1,000/μL; and/or lymphocyte count \<500/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.
21. Epstein-Barr virus (EBV) naïve recipient of a kidney from an EBV positive donor; and/or historically EBV naïve recipient with primary EBV infection at the time of screening (e.g., anti-VCA IgM positive and EBNA negative), a positive EBV PCR.
22. Hepatitis C Virus AB positive subjects with negative HCV PCR are eligible if they have spontaneously cleared infection or are in sustained virologic remission for at least 12 weeks after treatment.
23. Positive SARS-CoV2 testing by RT-PCR
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.
1. Post-transplant Donor-Specific Antibodies (DSA) \>2000 mean florescence intensity (MFI).
2. Any condition or clinical variable, which in the opinion of the site investigator, precludes conversion to mTOR
18 Years
ALL
No
Sponsors
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Clinical Trials in Organ Transplantation
NETWORK
National Institute of Allergy and Infectious Diseases (NIAID)
NIH
Responsible Party
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Principal Investigators
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Flavio Vincenti, MD
Role: PRINCIPAL_INVESTIGATOR
University of California at San Francisco
Sindhu Chandran, MD
Role: STUDY_CHAIR
University of California at San Francisco
Locations
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University of Alabama, Birmingham
Birmingham, Alabama, United States
University of California at San Francisco
San Francisco, California, United States
University of Colorado Health Transplant Center - Anschutz
Aurora, Colorado, United States
Northwestern University Comprehensive Transplant Center
Chicago, Illinois, United States
University of Michigan
Ann Arbor, Michigan, United States
Cleveland Clinic
Cleveland, Ohio, United States
Countries
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Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Document Type: Informed Consent Form: Donor ICF
Document Type: Informed Consent Form: Recipient ICF
Related Links
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National Institute of Allergy and Infectious Diseases (NIAID)
Division of Allergy, Immunology, and Transplantation (DAIT)
Clinical Trials in Organ Transplantation (CTOT)
Other Identifiers
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DAIT CTOT-21
Identifier Type: -
Identifier Source: org_study_id
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