Treg Therapy in Subclinical Inflammation in Kidney Transplantation
TASK
Treg Adoptive Therapy in Subclinical Inflammation in Kidney Transplantation (CTOT-21)
1 other identifier
interventional
32
1 country
6
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_1
Started Sep 2016
Longer than P75 for phase_1
6 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
March 11, 2016
CompletedFirst Posted
Study publicly available on registry
March 17, 2016
CompletedStudy Start
First participant enrolled
September 20, 2016
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 4, 2023
CompletedStudy Completion
Last participant's last visit for all outcomes
August 4, 2023
CompletedResults Posted
Study results publicly available
October 8, 2024
CompletedApril 9, 2025
March 1, 2025
6.9 years
March 11, 2016
June 6, 2024
March 24, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (6)
Incidence of Banff 2A or Higher Acute Cell-mediated Rejection and/or Acute Antibody Mediated Rejection
Acute cell-mediated rejection was defined using the Banff 2007 criteria. Participants with a Banff grade of greater than or equal to 2A were determined to have met the endpoint. Severity is graded as 1A, 1B, 2A, 2B, or 3, with 1A being the mildest form of cellular rejection and 3 being the most severe form of cellular rejection. Antibody mediated rejection was defined as diffusely positive staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury.
405 days post-group allocation
Timing of Banff 2A or Higher Acute Cell-mediated Rejection and/or Acute Antibody Mediated Rejection
Acute cell-mediated rejection was defined using the Banff 2007 criteria. Participants with a Banff grade of greater than or equal to 2A were determined to have met the endpoint. Severity is graded as 1A, 1B, 2IA, 2IB, or 3, with 1A being the mildest form of cellular rejection and 3 being the most severe form of cellular rejection. Antibody mediated rejection was defined as diffusely positive staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury.
405 days post-group allocation
Incidence of Study Defined Grade 3 or Higher Infection
This outcome measure includes infections reported as adverse events. Severe infection was defined in the study as a Grade 3 or higher infection. Severity is graded as 1 through 5, with 1 being least severe to 5 being most severe. Grade 3 is any infection associated with hemodynamic compromise requiring pressors; any infection necessitating ICU level of care; any infection necessitating operative intervention; any infection involving the central nervous system; any infection with a positive fungal blood culture; any proven or probable aspergillus infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection. Grade 4 is any life-threatening infection. Grade 5 is any infection resulting in death.
405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups
Timing of Study Defined Grade 3 or Higher Infection
This outcome measure includes infections reported as adverse events. Severe infection was defined in the study as a Grade 3 or higher infection. Severity is graded as 1 through 5, with 1 being least severe to 5 being most severe. Grade 3 is any infection associated with hemodynamic compromise requiring pressors; any infection necessitating ICU level of care; any infection necessitating operative intervention; any infection involving the central nervous system; any infection with a positive fungal blood culture; any proven or probable aspergillus infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection. Grade 4 is any life-threatening infection. Grade 5 is any infection resulting in death.
405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups.
Percent Change in Inflammation
The change in inflammation was measured by the percentage area of the renal cortex occupied by inflammatory cells on biopsy 7 months after group allocation. This change was expressed as the percent change relative to the baseline biopsy. The measurements were obtained using computer-assisted quantitative image analysis.
At baseline biopsy and at 7 months post-group allocation
Immunologic Profiles of Kidney Transplant Recipients
CRM (Common Response Module) score is a geometric mean of CRM gene expression. This score is used to identify evidence of rejection or inflammation in participants at the time of biopsy.
At 2 weeks post-polyTregs infusion (for polyTregs infusion group) and at 7 months post-group allocation (both groups)
Secondary Outcomes (20)
Incidence of polyTregs Infusion Reactions
365 days after Treg infusion for the participants in the polyTregs group
Severity of polyTregs Infusion Reactions
365 days after Treg infusion for the participants in the polyTregs group
Timing of polyTregs Infusion Reactions
365 days after Treg infusion for the participants in the polyTregs group
Incidence of Culture-proven and Clinically Diagnosed Infection.
405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups
Severity of Culture-proven and Clinically Diagnosed Infection
405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups
- +15 more secondary outcomes
Study Arms (2)
Maintenance CNI based immunosuppression therapy group
ACTIVE COMPARATORStandard of care (N=7 participants in this group)
Polyclonal Regulatory T Cells group
EXPERIMENTALSubjects 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)
Interventions
Participants randomized to polyTregs group will receive a single infusion of 550 ± 450 x 10\^6 polyTregs.
All enrolled participants will be on MMF (or MPA below) at the time of study entry at a minimum dose of 1000mg per day.
All enrolled participants will be on MPA (or MMF above) at the time of study entry at a minimum dose of 720mg per day.
650 mg acetaminophen, administered 30-60 minutes prior to infusion as pre-medication.
25-50 mg diphenhydramine intravenously or by mouth, administered 30-60 minutes prior to infusion as pre-medication.
Conversion from Tacrolimus, a calcineurin inhibitors (CNI), to Everolimus, an mTOR inhibitor.
Eligibility Criteria
You may qualify if:
- Individuals who meet all of the following criteria are eligible for enrollment as study participants:
- Subject must be able to understand and provide informed consent;
- Age ≥18 years of age at the time of study entry;
- Recipients of non- Human Leukocyte Antigen (HLA) identical living or deceased renal transplants;
- 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).
- Estimated glomerular filtration rate (eGFR) ≥30 ml/min at the time of study entry;
- Maintenance immunosuppression consisting of tacrolimus, MMF/MPA (≥1000 mg/720 mg daily) ± prednisone (≤10 mg/day);
- 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;
- Documented Hepatitis B (HB) serologies must be:
- Positive HB surface antibody, negative HB core antibody and negative HB surface antigen for recipients immune to hepatitis B
- 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.
- 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.
- 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
- 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).
- Individuals randomized to the polyTreg and darTreg groups who continue to meet all of the enrollment criteria; and
- +4 more criteria
You may not qualify if:
- Individuals who meet any of these criteria are not eligible for enrollment as study participants:
- Inability or unwillingness of a participant to give written informed consent or comply with study protocol;
- History of malignancy; except adequately treated basal cell carcinoma;
- History of graft loss from acute rejection within 1 year after any previous transplant;
- History of transplant renal artery stenosis;
- 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;
- Known hypersensitivity to mTOR inhibitors or contraindication to everolimus (including history of wound healing complications);
- Any chronic illness requiring uninterrupted anti-coagulation after kidney transplantation;
- 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.
- Positive HIV 1 or HIV 2 serology prior to transplantation;
- Positive HBSAg or HBcAb serology;
- Proteinuria with urine protein-to-creatinine ratio \> 1.0 g/g;
- Any condition requiring chronic use of corticosteroids \>10mg/day at the time of study entry;
- Active infection at the time of study entry;
- +15 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (6)
University of Alabama, Birmingham
Birmingham, Alabama, 35294, United States
University of California at San Francisco
San Francisco, California, 94118, United States
University of Colorado Health Transplant Center - Anschutz
Aurora, Colorado, 80045, United States
Northwestern University Comprehensive Transplant Center
Chicago, Illinois, 60611, United States
University of Michigan
Ann Arbor, Michigan, 48109, United States
Cleveland Clinic
Cleveland, Ohio, 44195, United States
Related Links
MeSH Terms
Interventions
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Director, Clinical Research Operations Program
- Organization
- DAIT/NIAID
Study Officials
- PRINCIPAL INVESTIGATOR
Flavio Vincenti, MD
University of California at San Francisco
- STUDY CHAIR
Sindhu Chandran, MD
University of California at San Francisco
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
March 11, 2016
First Posted
March 17, 2016
Study Start
September 20, 2016
Primary Completion
August 4, 2023
Study Completion
August 4, 2023
Last Updated
April 9, 2025
Results First Posted
October 8, 2024
Record last verified: 2025-03
Data Sharing
- IPD Sharing
- Will share
The plan is to share data in ImmPort \[https://immport.niaid.nih.gov/ \], a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts, upon completion of the study.