Clinical trial NCT02711826: Treg Therapy in Subclinical Inflammation in Kidney Transplantation
Official title: Treg Adoptive Therapy in Subclinical Inflammation in Kidney Transplantation (CTOT-21)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Clinical Trials in Organ Transplantation
First posted: 2016-03-17
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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) ≥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).

Treg Infusion Inclusion Criteria:

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.

mTOR Conversion Inclusion Criteria:

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:

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.

   * 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

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).
2. Any condition or clinical variable, which in the opinion of the site investigator, precludes conversion to mTOR

Primary outcomes:
measure: Incidence of Banff 2A or Higher Acute Cell-mediated Rejection and/or Acute Antibody Mediated Rejection
timeFrame: 405 days post-group allocation
measure: Timing of Banff 2A or Higher Acute Cell-mediated Rejection and/or Acute Antibody Mediated Rejection
timeFrame: 405 days post-group allocation
measure: Incidence of Study Defined Grade 3 or Higher Infection
timeFrame: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups
measure: Timing of Study Defined Grade 3 or Higher Infection
timeFrame: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups.
measure: Percent Change in Inflammation
timeFrame: At baseline biopsy and at 7 months post-group allocation
measure: Immunologic Profiles of Kidney Transplant Recipients
timeFrame: At 2 weeks post-polyTregs infusion (for polyTregs infusion group) and at 7 months post-group allocation (both groups)
Secondary outcomes:
measure: Incidence of polyTregs Infusion Reactions
timeFrame: 365 days after Treg infusion for the participants in the polyTregs group
measure: Severity of polyTregs Infusion Reactions
timeFrame: 365 days after Treg infusion for the participants in the polyTregs group
measure: Timing of polyTregs Infusion Reactions
timeFrame: 365 days after Treg infusion for the participants in the polyTregs group
measure: Incidence of Culture-proven and Clinically Diagnosed Infection.
timeFrame: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups
measure: Severity of Culture-proven and Clinically Diagnosed Infection
timeFrame: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups
measure: Timing of Culture-proven and Clinically Diagnosed Infection
timeFrame: 405 days after randomization for participants in the maintenance group; 365 days after Treg infusion for the participants in the polyTregs or darTregs groups
measure: Incidence of Acute Rejection Using Banff Grading
timeFrame: 405 days post-group allocation
measure: Severity of Acute Rejection Using Banff Grading
timeFrame: 405 days post-group allocation
measure: Timing of Acute Rejection Using Banff Grading
timeFrame: 405 days post-group allocation
measure: Incidence of BK Viremia
timeFrame: 405 days post-group allocation
measure: Timing of BK Viremia
timeFrame: 405 days post-group allocation
measure: Incidence of Cytomegalovirus (CMV) Reactivation
timeFrame: 405 days post-group allocation
measure: Timing of CMV Reactivation
timeFrame: 405 days post-group allocation
measure: Incidence of > 10% Decrease in Estimated Glomerular Filtration Rate (eGFR) Compared to Baseline
timeFrame: 405 days post-group allocation
measure: Timing of > 10% Decrease in eGFR Compared to Baseline
timeFrame: 405 days post-group allocation
measure: Incidence of Acute Rejection After Converting to mTOR Therapy Following polyTregs Infusion
timeFrame: 69 days post-group allocation to 405 days post-group allocation
measure: Timing of Acute Rejection After Converting to mTOR Therapy Following polyTregs Infusion
timeFrame: 69 days post-group allocation to 405 days post-group allocation
measure: Proportion of Participants Exhibiting >=25% Relative Decrease of Inflammation Between Baseline Kidney Biopsy and the Week 2 Kidney Biopsy
timeFrame: Baseline biopsy to week 2 kidney biopsy
measure: Proportion of Participants Exhibiting >=50% Relative Decrease of Inflammation Between Baseline Kidney Biopsy and the Week 2 Kidney Biopsy
timeFrame: Baseline biopsy to week 2 kidney biopsy
measure: Proportion of Participants Exhibiting >=25% Relative Decrease of Inflammation Between Baseline Kidney Biopsy and the 6 Month Kidney Biopsy
timeFrame: Baseline biopsy to 7 months post-group allocation
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama, Birmingham
state: Alabama
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado Health Transplant Center - Anschutz
state: Colorado
city: Chicago
country: United States
facility: Northwestern University Comprehensive Transplant Center
state: Illinois
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
Study officials:
affiliation: University of California at San Francisco
name: Flavio Vincenti, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California at San Francisco
name: Sindhu Chandran, MD
role: STUDY_CHAIR
References: