Assessment of Biomarker-Guided CNI Substitution In Kidney Transplantation

About

Brief Summary

800 adult first time kidney transplant recipients will be enrolled in the Observational Study and followed to evaluate their Human Leukocyte Antigen (HLA)-DR/DQ molecular mismatch (mMM) score as a risk-stratifying prognostic biomarker. Six months after transplant the study will identify those who meet the eligibility criteria for the Nested Randomized Control Trial (RCT). 300 eligible subjects will be randomized 2:1 to abatacept or Standard of care (SOC) in the randomization and followed for 18 months monitoring for safety and improvement in renal function, neurocognitive function, and a life participation patient reported outcome measure (PROM).

The primary objective of the Observational Study is to test the validity of the HLA-DR/DQ mMM score as a prognostic biomarker for stratification of post-transplant alloimmune risk. Whereas the objective of the Nested RCT is to test whether a superior outcome in kidney function (primary endpoint), as well as secondary endpoints (neurocognitive function, and life participation PROM), will be achieved in patients who are transitioned from Tacrolimus (TAC) to abatacept, while maintaining efficacy (freedom from biopsy proven acute rejection).

Primary Purpose

Treatment

Study Type

Interventional

Phase

Phase 2

Eligibility

Gender

All

Healthy Volunteers

No

Minimum Age

18 Years

Maximum Age

70 Years

Inclusion Criteria:

Observational Study:

Subject must be able to understand and provide informed consent
Received (within 14 days) or candidate for an ABO-compatible kidney transplant, including A2 to B
Panel Reactive Antibody <=60% as determined by local site
Virtual cross-match negative as determined by local site or Donor Specific Antibody (DSA) negative by central lab within 14 days post-transplant
Female subjects of childbearing potential must have a negative pregnancy test upon study entry
All subjects with reproductive potential must agree to use highly effective contraception for the duration of the study (http://www.fda.gov/birthcontrol)
Hepatitis C Virus Ab positive subjects with negative Hepatitis C Virus polymerase chain reaction (HCV PCR) are eligible if they have spontaneously cleared infection or are in sustained virologic remission
Vaccines up to date as per Division of Allergy, Immunology, and Transplantation (DAIT) guidance for patients in transplant trials (Refer to Manual of Procedures).
Triple Immunosuppression - Calcineurin Inhibitor/Mycophenolic Acid/Steroid (CNI/MPA/steroid)
- CNI (Tacrolimus (TAC), target trough [C0] level: 0-3 mo, 8-12 ng/mL; 4-6 mo, 6-10 ng/mL; >6 mo, 5-8 ng/mL])
- MPA [target dose: mycophenolate mofetil >=500 mg bid or mycophenolate sodium >=360 mg bid]); and
- Glucocorticoid, with a minimum dose equivalent to 5mg of prednisone per day Nested Randomized Control Trial (RCT):
Subject must be able to understand and provide informed consent
A 6-month protocol biopsy free of Biopsy Proven Acute Rejection (BPAR)(by Central Pathology Core)
Negative 6-month serum test for DSA (by Central HLA Core)
eGFRCKD-EPI 30-90 ml/min/1.73m^2 at 6 months
Has a verified negative purified protein derivative (PPD) or negative testing for tuberculosis using an approved IGRA blood test, such as QuantiFERON Gold TB or T-SPOT-TB assay OR has completed treatment for latent tuberculosis and has a negative chest x-ray. PPD or IGRA testing must occur within 52 weeks prior to randomization. These requirements apply as well to prior recipients of Bacille Calmette-Gurin (BCG) vaccination
Minimum Mycophenolate mofetil (MPA) dose (MPA 500 mg po bid, or Mycophenolate sodium 360 mg po bid)
Minimum Prednisone dose of 5mg per day
Hepatitis C Virus Ab positive subjects with negative HCV PCR are eligible if they have spontaneously cleared infection or are in sustained virologic remission
Hepatitis C Virus negative recipients of a Hepatitis C Virus positive organ are eligible if they have undergone treatment and are in sustained virologic remission
Female subjects of childbearing potential must have a negative pregnancy test upon study entry
All subjects with reproductive potential, must agree to use highly effective contraception the duration of the study-specific methods may be listed, if applicable

Exclusion Criteria:

Observational Study:

Inability or unwillingness of a participant to give written informed consent or comply with study protocol including a mandated 6-mo kidney transplant biopsy
Non-Kidney Transplant (KTx) (pre-existing or concurrent)
Current use of immunomodulatory agents (including but not limited to: Rituximab, anti-Tumor necrosis factor(TNF) Monoclonal antibodies (mAb), or Belatacept, abatacept, Janus kinase inhibitors)
Transplant in which the kidney donor is the recipient's Identical twin
Epstein-Barr virus (EBV) sero-negative KTx recipient
Chronic obstructive pulmonary disease (COPD)
Untreated Latent Tuberculosis (TB)
Human immunodeficiency virus (HIV) infection
Active Hepatitis B infection (HBsAg+ or anti-HBcore +)
Enrollment in another investigational trial
Current, diagnosed, mental illness or current, diagnosed or self-reported drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements
Recent recipient of any licensed or investigational live attenuated vaccine(s) within 4 weeks of enrollment
Use of investigational drugs within 8 weeks of participation
Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study
Use of Campath(R) Nested Randomized Control Trial (RCT):
Inability or unwillingness of a participant to give written informed consent or comply with study protocol
Biopsy Proven Acute Rejection (BPAR) or treated clinically-diagnosed rejection in the 6 months following enrollment in the Observational Study
Positive for a Donor Specific Antibody (DSA) 0-6 months post-kidney transplant
Acute Banff interstitial (i) score >0 on a 6-month protocol biopsy as determined by core pathology read
Presence of recurrent on de novo glomerulonephropathy 0-6 months post-kidney transplant
Presence of active infection including BK virus (BKV), Cytomegalovirus (CMV) or EBV viremia by Polymerase chain reaction (PCR) analysis
Unable or unwilling to undergo protocol biopsies
Not on Tacrolimus/Mycophenolic Acid (MPA)/Pred
Unable to administer therapy s.c.
Thrombocytopenia (<50,000/mm^3)
Pregnant, or unwilling to practice highly effective birth control
Use of immunomodulatory agents (including but not limited to Rituximab, anti-TNF mAb, or Belatacept, abatacept, Janus kinase inhibitors) * since enrollment, other than cytolytic agents (i.e., Thymoglobulin(R)or Campath(R) or Basiliximab(R) used for induction therapy at the time of transplant
Use of investigational drugs since transplant
Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study