Kidney TransplantPhase 1/2TASKNCT02711826
Treg Therapy in Subclinical Inflammation in Kidney Transplantation
A Phase 1/2 study testing Polyclonal Regulatory T Cells, Everolimus and Tacrolimus in people with Kidney Transplant and Adult Living Donor Kidney Transplant Recipients, run by National Institute of Allergy and Infectious Diseases (NIAID) at 6 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Kidney Transplant, Adult Living Donor Kidney Transplant Recipients, Renal Transplant
- What is being tested?
- Polyclonal Regulatory T Cells, Everolimus and Tacrolimus
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 32 participants
- Where
- 6 sitesUnited States
- Study dates
- 20 Sep 2016to 4 Aug 2023
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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;
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- 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).
- Treg Infusion Inclusion Criteria:
- Individuals randomized to the polyTreg and darTreg groups who continue to meet all of the enrollment criteria; and
- Negative SARS-COV2 by RTP-PCR testing within 1 week of Treg infusion.
- mTOR Conversion Inclusion Criteria:
- Individuals who meet all of these criteria are eligible for mTOR conversion:
- Received at least 300 x 10^6 polyTreg infusion;
- Resolution of inflammation on the 2 week post-infusion biopsy as compared to the baseline biopsy, confirmed by central pathologist.
Who cannot join
- 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;
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- 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;
- Subjects requiring treatment for pathologic findings on study eligibility biopsy (see inclusion 5).
- Active infection at the time of study entry;
- History of active TB or latent TB without adequate treatment;
- Serum BK virus >1,000 copies/ml by Polymerase Chain Reaction (PCR) at the time of study entry;
- Hematocrit <27%; Absolute Neutrophil Count (ANC) < 1,000/μL; and/or lymphocyte count <500/μL at the time of study entry;
- Participation in any other studies with investigational drugs or regimens in the preceding year;
- Any condition or prior treatment which, in the opinion of the investigator, precludes study participation.
- Unable to provide adequate biopsy specimen (paraffin embedded formalin fixed) from eligibility biopsy (3-7 months post -transplant) for quantitative analysis.
- 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.
- 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.
- Positive SARS-CoV2 testing by RT-PCR
- Treg Infusion Exclusion Criteria:
- Individuals randomized to polyTreg and darTreg groups who meet any of these criteria are not eligible for Treg infusion:
- Received any vaccination within 14 days prior to blood collection for Treg manufacture;
- Unacceptable Treg product;
- Positive pregnancy test for women of child bearing potential.
- mTOR Conversion Exclusion Criteria:
- Post-transplant Donor-Specific Antibodies (DSA) >2000 mean florescence intensity (MFI).
- Any condition or clinical variable, which in the opinion of the site investigator, precludes conversion to mTOR
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
United States6 sites
University of Michigan
Ann Arbor, Michigan, 48109
University of Colorado Health Transplant Center - Anschutz
Aurora, Colorado, 80045
University of Alabama, Birmingham
Birmingham, Alabama, 35294
Northwestern University Comprehensive Transplant Center
Chicago, Illinois, 60611
Cleveland Clinic
Cleveland, Ohio, 44195
University of California at San Francisco
San Francisco, California, 94118
About this study
Official title: Treg Adoptive Therapy in Subclinical Inflammation in Kidney Transplantation (CTOT-21)
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.
Read the 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.
- Conditions
- Kidney Transplant, Adult Living Donor Kidney Transplant Recipients, Renal Transplant, Living Kidney Donor
- Being tested
- Polyclonal Regulatory T Cells, Everolimus, Tacrolimus, Mycophenolate mofetil, Mycophenolic acid
- Keywords
- graft inflammation, Treg, polyclonally expanded Tregs (polyTregs), calcineurin inhibitors (CNIs), mTOR inhibitors
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Polyclonal Regulatory T CellsBiological
Also called Polyclonal Tregs, polyTregs
Participants randomized to polyTregs group will receive a single infusion of 550 ± 450 x 10^6 polyTregs.
EverolimusDrug
Also called Zortress
TacrolimusDrug
Also called FK-506, FR-900506, Prograf
Also called Cellcept, MMF
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 acidDrug
Also called Myfortic, MPA
All enrolled participants will be on MPA (or MMF above) at the time of study entry at a minimum dose of 720mg per day.
AcetaminophenDrug
Also called Tylenol
650 mg acetaminophen, administered 30-60 minutes prior to infusion as pre-medication.
DiphenhydramineDrug
Also called Benadryl
25-50 mg diphenhydramine intravenously or by mouth, administered 30-60 minutes prior to infusion as pre-medication.
Biopsy, KidneyProcedure or surgery
Also called Kidney Biopsy
Blood DrawProcedure or surgery
Also called Phlebotomy, Venipuncture
LeukapheresisProcedure or surgery
Also called leukocytapheresis
IS regimen conversionProcedure or surgery
Also called Everolimus Conversion
Conversion from Tacrolimus, a calcineurin inhibitors (CNI), to Everolimus, an mTOR inhibitor.
| Study group | Role | What they receive |
|---|---|---|
| Maintenance CNI based immunosuppression therapy group | Active comparator | Standard of care
(N=7 participants in this group) Receives: Drug: Tacrolimus; Drug: Mycophenolate mofetil; Drug: Mycophenolic acid; Procedure: Biopsy, Kidney; Procedure: Blood Draw |
| Polyclonal Regulatory T Cells group | Experimental | 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) Receives: Biological: Polyclonal Regulatory T Cells; Drug: Everolimus; Drug: Tacrolimus; Drug: Mycophenolate mofetil; Drug: Mycophenolic acid; Drug: Acetaminophen; Drug: Diphenhydramine; Procedure: Biopsy, Kidney; Procedure: Blood Draw; Procedure: Leukapheresis; Procedure: IS regimen conversion |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
An infusion reaction is characterized by an adverse reaction to the infusion of pharmacological substance, as defined using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 set forth by the National Cancer Institute.
Measured: 365 days after Treg infusion for the participants in the polyTregs group
Severity of polyTregs Infusion Reactions
Severity of infusion reactions were defined using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 set forth by the National Cancer Institute. Severity of adverse events is graded as 1 through 5, with 1 being least severe to 5 being most severe.
Measured: 365 days after Treg infusion for the participants in the polyTregs group
Timing of polyTregs Infusion Reactions
An infusion reaction is characterized by an adverse reaction to the infusion of pharmacological substance, as defined using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 set forth by the National Cancer Institute.
Measured: 365 days after Treg infusion for the participants in the polyTregs group
Incidence of Culture-proven and Clinically Diagnosed Infection.
A culture-proven and clinically diagnosed infection in this study was defined as any locally reported infection due to bacterial organism, due to fungal organism, due to CMV, or which met adverse event criteria, except for COVID-19.
Measured: 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
A culture-proven and clinically diagnosed infection was defined as any locally reported infection due to bacterial organism, fungal organism, CMV, or which met adverse event criteria, except for COVID-19. 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. If a culture proven and clinically diagnosed infection did not qualify for AE reporting, then it did not have a severity grade.
Measured: 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 Culture-proven and Clinically Diagnosed Infection
A culture-proven and clinically diagnosed infection in this study was defined as any locally reported infection due to bacterial organism, fungal organism, CMV, or which met adverse event criteria, except for COVID-19.
Measured: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups
Incidence of Acute Rejection Using Banff Grading
Acute cell-mediated rejection was defined using the Banff 2007 criteria. Participants with a Banff grade of greater than or equal to 1A 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.
Measured: 405 days post-group allocation
Severity of Acute Rejection Using Banff Grading
Acute cell-mediated rejection was defined using the Banff 2007 criteria. Participants with a Banff grade of greater than or equal to 1A 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.
Measured: 405 days post-group allocation
Timing of Acute Rejection Using Banff Grading
Acute cell-mediated rejection was defined using the Banff 2007 criteria. Participants with a Banff grade of greater than or equal to 1A 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.
Measured: 405 days post-group allocation
Incidence of BK Viremia
BK viremia was determined using locally reported serum PCR results. PCR results reported as positive and >0 copies/mL were considered as meeting the endpoint. Only positive results following Treg infusion were considered for participants in the polyTregs and darTregs groups.
Measured: 405 days post-group allocation
Timing of BK Viremia
BK viremia was determined using locally reported serum PCR results. PCR results reported as positive and >0 copies/mL were considered as meeting the endpoint. Only positive results following Treg infusion were considered for participants in the polyTregs and darTregs groups.
Measured: 405 days post-group allocation
Incidence of Cytomegalovirus (CMV) Reactivation
CMV reactivation was defined as CMV viremia and determined using locally reported serum, plasma, or whole blood PCR results. PCR results reported as >0 IU/mL were considered as meeting the endpoint. Only positive results following Treg infusion were considered for participants in the polyTregs and darTregs groups.
Measured: 405 days post-group allocation
Timing of CMV Reactivation
CMV reactivation was defined as CMV viremia and determined using locally reported serum, plasma, or whole blood PCR results. PCR results reported as >0 IU/mL were considered as meeting the endpoint. Only positive results following Treg infusion were considered for participants in the polyTregs and darTregs groups.
Measured: 405 days post-group allocation
Incidence of > 10% Decrease in Estimated Glomerular Filtration Rate (eGFR) Compared to Baseline
Glomerular filtration rate (GFR) is a measure of kidney function and helps determine the stage of kidney disease. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 2021 equation. A value of 90+ means kidney function is normal. A value between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease. Values between 30 and 59 indicate moderately reduced kidney function. Values between 15 and 29 indicate severely reduced kidney function. Values below 15 indicate very severe or end stage kidney failure. The percent change in eGFR was calculated at each post-baseline timepoint as [(post-baseline eGFR minus baseline (i.e., screening) eGFR) divided by baseline eGFR] multiplied by 100 and rounded to the nearest hundredth for each participant. A participant was considered to have met the endpoint if at least one instance of a greater than 10% decrease from baseline was observed.
Measured: 405 days post-group allocation
Timing of > 10% Decrease in eGFR Compared to Baseline
Glomerular filtration rate (GFR) is a measure of kidney function and helps determine the stage of kidney disease. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 2021 equation. A value of 90+ means kidney function is normal. A value between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease. Values between 30 and 59 indicate moderately reduced kidney function. Values between 15 and 29 indicate severely reduced kidney function. Values below 15 indicate very severe or end stage kidney failure. The percent change in eGFR was calculated at each post-baseline timepoint as [(post-baseline eGFR minus baseline (i.e., screening) eGFR) divided by baseline eGFR] multiplied by 100 and rounded to the nearest hundredth for each participant. A participant was considered to have met the endpoint if at least one instance of a greater than 10% decrease from baseline was observed.
Measured: 405 days post-group allocation
Incidence of Acute Rejection After Converting to mTOR Therapy Following polyTregs Infusion
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.
Measured: 69 days post-group allocation to 405 days post-group allocation
Timing of Acute Rejection After Converting to mTOR Therapy Following polyTregs Infusion
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.
Measured: 69 days post-group allocation to 405 days post-group allocation
Proportion of Participants Exhibiting >=25% Relative Decrease of Inflammation Between Baseline Kidney Biopsy and the Week 2 Kidney Biopsy
The change in inflammation was measured by the percentage area of the renal cortex occupied by inflammatory cells on biopsy 2 weeks after polyTregs infusion. This change was expressed as the percent change relative to the baseline biopsy. The measurements were obtained using computer-assisted quantitative image analysis.
Measured: Baseline biopsy to week 2 kidney biopsy
Proportion of Participants Exhibiting >=50% Relative Decrease of Inflammation Between Baseline Kidney Biopsy and the Week 2 Kidney Biopsy
The change in inflammation was measured by the percentage area of the renal cortex occupied by inflammatory cells on biopsy 2 weeks after polyTregs infusion. This change was expressed as the percent change relative to the baseline biopsy. The measurements were obtained using computer-assisted quantitative image analysis.
Measured: Baseline biopsy to week 2 kidney biopsy
Proportion of Participants Exhibiting >=25% Relative Decrease of Inflammation Between Baseline Kidney Biopsy and the 6 Month Kidney Biopsy
The change in inflammation was measured by the percentage area of the renal cortex occupied by inflammatory cells on biopsy 7 months after study 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.
Measured: Baseline biopsy to 7 months post-group allocation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2016 (estimated)
- Study start20 Sep 2016
- Primary completion4 Aug 2023
- Study completion4 Aug 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Kidney TransplantStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 32 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Collaborators
- Clinical Trials in Organ Transplantation
- Responsible party
- Sponsor
- Investigators
- Flavio Vincenti, MD, Principal investigator, University of California at San FranciscoSindhu Chandran, MD, Study chair, University of California at San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02711826
- Sponsor's protocol ID
- DAIT CTOT-21
- Acronym
- TASK
- Status last verified
- Mar 2025
- First submitted
- 11 Mar 2016
- Last updated
- 24 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: 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.
Study at a glance
From the registry record, last updated by the sponsor on 24 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treg Adoptive Therapy in Subclinical Inflammation in Kidney Transplantation (CTOT-21)
- ClinicalTrials.gov ID
- NCT02711826
- Acronym / sponsor ID
- TASK / DAIT CTOT-21
- Conditions
- Kidney Transplant, Adult Living Donor Kidney Transplant Recipients, Renal Transplant, Living Kidney Donor
- Keywords
- graft inflammation, Treg, polyclonally expanded Tregs (polyTregs), calcineurin inhibitors (CNIs), mTOR inhibitors
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 32 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Collaborators
- Clinical Trials in Organ Transplantation
- Study start
- 20 Sep 2016 (actual)
- Primary completion
- 4 Aug 2023 (actual)
- Study completion
- 4 Aug 2023 (actual)
- First posted
- 17 Mar 2016 (estimated)
- Results
- Posted 8 Oct 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Maintenance CNI based immunosuppression therapy group | Active comparator | Drug: Tacrolimus, Drug: Mycophenolate mofetil, Drug: Mycophenolic acid, Procedure: Biopsy, Kidney, Procedure: Blood DrawStandard of care (N=7 participants in this group) |
| Polyclonal Regulatory T Cells group | Experimental | Biological: Polyclonal Regulatory T Cells, Drug: Everolimus, Drug: Tacrolimus, Drug: Mycophenolate mofetil, Drug: Mycophenolic acid, Drug: Acetaminophen, Drug: Diphenhydramine, Procedure: Biopsy, Kidney, Procedure: Blood Draw, Procedure: Leukapheresis, Procedure: IS regimen conversionSubjects 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) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- 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).
Key exclusion criteria (33 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Polyclonal Regulatory T CellsAlso: Polyclonal Tregs, polyTregsParticipants randomized to polyTregs group will receive a single infusion of 550 ± 450 x 10^6 polyTregs. | Biological | Polyclonal Regulatory T Cells group |
| EverolimusAlso: Zortress | Drug | Polyclonal Regulatory T Cells group |
| TacrolimusAlso: FK-506, FR-900506, Prograf | Drug | Maintenance CNI based immunosuppression therapy group, Polyclonal Regulatory T Cells group |
| Mycophenolate mofetilAlso: Cellcept, MMFAll enrolled participants will be on MMF (or MPA below) at the time of study entry at a minimum dose of 1000mg per day. | Drug | Maintenance CNI based immunosuppression therapy group, Polyclonal Regulatory T Cells group |
| Mycophenolic acidAlso: Myfortic, MPAAll enrolled participants will be on MPA (or MMF above) at the time of study entry at a minimum dose of 720mg per day. | Drug | Maintenance CNI based immunosuppression therapy group, Polyclonal Regulatory T Cells group |
| AcetaminophenAlso: Tylenol650 mg acetaminophen, administered 30-60 minutes prior to infusion as pre-medication. | Drug | Polyclonal Regulatory T Cells group |
| DiphenhydramineAlso: Benadryl25-50 mg diphenhydramine intravenously or by mouth, administered 30-60 minutes prior to infusion as pre-medication. | Drug | Polyclonal Regulatory T Cells group |
| Biopsy, KidneyAlso: Kidney Biopsy | Procedure or surgery | Maintenance CNI based immunosuppression therapy group, Polyclonal Regulatory T Cells group |
| Blood DrawAlso: Phlebotomy, Venipuncture | Procedure or surgery | Maintenance CNI based immunosuppression therapy group, Polyclonal Regulatory T Cells group |
| LeukapheresisAlso: leukocytapheresis | Procedure or surgery | Polyclonal Regulatory T Cells group |
| IS regimen conversionAlso: Everolimus ConversionConversion from Tacrolimus, a calcineurin inhibitors (CNI), to Everolimus, an mTOR inhibitor. | Procedure or surgery | Polyclonal Regulatory T Cells group |
Primary outcome
Incidence of Banff 2A or Higher Acute Cell-mediated Rejection and/or Acute Antibody Mediated Rejection
Time frame: 405 days post-group allocation
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.
Timing of Banff 2A or Higher Acute Cell-mediated Rejection and/or Acute Antibody Mediated Rejection
Time frame: 405 days post-group allocation
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.
Incidence of Study Defined Grade 3 or Higher Infection
Time frame: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups
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.
Timing of Study Defined Grade 3 or Higher Infection
Time frame: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups.
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.
Percent Change in Inflammation
Time frame: At baseline biopsy and at 7 months post-group allocation
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.
Immunologic Profiles of Kidney Transplant Recipients
Time frame: At 2 weeks post-polyTregs infusion (for polyTregs infusion group) and at 7 months post-group allocation (both groups)
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.
20 secondary outcomes
Incidence of polyTregs Infusion Reactions
Time frame: 365 days after Treg infusion for the participants in the polyTregs group
Severity of polyTregs Infusion Reactions
Time frame: 365 days after Treg infusion for the participants in the polyTregs group
Timing of polyTregs Infusion Reactions
Time frame: 365 days after Treg infusion for the participants in the polyTregs group
Incidence of Culture-proven and Clinically Diagnosed Infection.
Time frame: 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
Time frame: 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 Culture-proven and Clinically Diagnosed Infection
Time frame: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups
Incidence of Acute Rejection Using Banff Grading
Time frame: 405 days post-group allocation
Severity of Acute Rejection Using Banff Grading
Time frame: 405 days post-group allocation
Timing of Acute Rejection Using Banff Grading
Time frame: 405 days post-group allocation
Incidence of BK Viremia
Time frame: 405 days post-group allocation
Timing of BK Viremia
Time frame: 405 days post-group allocation
Incidence of Cytomegalovirus (CMV) Reactivation
Time frame: 405 days post-group allocation
Timing of CMV Reactivation
Time frame: 405 days post-group allocation
Incidence of > 10% Decrease in Estimated Glomerular Filtration Rate (eGFR) Compared to Baseline
Time frame: 405 days post-group allocation
Timing of > 10% Decrease in eGFR Compared to Baseline
Time frame: 405 days post-group allocation
Incidence of Acute Rejection After Converting to mTOR Therapy Following polyTregs Infusion
Time frame: 69 days post-group allocation to 405 days post-group allocation
Timing of Acute Rejection After Converting to mTOR Therapy Following polyTregs Infusion
Time frame: 69 days post-group allocation to 405 days post-group allocation
Proportion of Participants Exhibiting >=25% Relative Decrease of Inflammation Between Baseline Kidney Biopsy and the Week 2 Kidney Biopsy
Time frame: Baseline biopsy to week 2 kidney biopsy
Proportion of Participants Exhibiting >=50% Relative Decrease of Inflammation Between Baseline Kidney Biopsy and the Week 2 Kidney Biopsy
Time frame: Baseline biopsy to week 2 kidney biopsy
Proportion of Participants Exhibiting >=25% Relative Decrease of Inflammation Between Baseline Kidney Biopsy and the 6 Month Kidney Biopsy
Time frame: Baseline biopsy to 7 months post-group allocation
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Sep 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- National Institute of Allergy and Infectious Diseases (NIAID)Link provided by the sponsor.
- Division of Allergy, Immunology, and Transplantation (DAIT)Link provided by the sponsor.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Flavio Vincenti, MD principal investigator
University of California at San Francisco
Sindhu Chandran, MD study chair
University of California at San Francisco
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Polyclonal Regulatory T Cells, Everolimus and Tacrolimus in people with Kidney Transplant and Adult Living Donor Kidney Transplant Recipients, run by National Institute of Allergy and Infectious Diseases (NIAID) at 6 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of Banff 2A or Higher Acute Cell-mediated Rejection and/or Acute Antibody Mediated Rejection (time frame: 405 days post-group allocation). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Sep 2026.