To Compare the Effects of Immediate-release Tacrolimus and Astagraf XL on Donor-Specific Antibody (DSA) Formation and the Development of Immune Activation (IA) in de Novo Kidney Transplant Recipients

This study compared the incidence of a two-part composite endpoint consisting of de novo donor specific antibody (DSA) formation or a designation of immune activation (IA) on peripheral blood molecular profiling in participants maintained on twice daily, immediate-release tacrolimus versus those maintained on Astagraf XL in the first year post-transplant.

This was an exploratory, two year (shortened to 1 year due to a stopping rule necessitated by the adaptive design), prospective, randomized, multi-center, open-label trial examining long-term kidney transplant outcomes through the use of an adaptive design and a two-part, composite surrogate endpoint. Specifically, it was designed to compare the effects of twice daily, immediate-release tacrolimus and once daily Astagraf XL on DSA formation and the development of a peripheral blood molecular profile indicating the presence of IA in de novo kidney transplant recipients during the first year following transplantation. For the purposes of this study, IA was defined as a positive molecular signature using a molecular assay in all participants.

Participants were screened prior to surgery and randomized 1:1 to receive immediate-release tacrolimus, administered twice daily, or Astagraf XL, as a component of a standard immunosuppression maintenance regimen also consisting of corticosteroids (if given per institutional protocol) and mycophenolate mofetil (MMF) (or Myfortic® equivalent). Investigators were encouraged to start participants on the randomized study treatment (immediate release tacrolimus or Astagraf XL) within 48 hours of transplantation (pre-transplant administration of study treatment was not allowed). However, if medically indicated per the treating physician's discretion, initiation of study treatment was delayed for up to seven days post-transplant.

Eligibility Criteria:
Inclusion Criteria:

* Recipient of a de novo kidney from a living or deceased donor. Note: Recipient of an en bloc deceased donor kidney transplant from a pediatric donor ≥5 years of age AND weighing greater than 20 kg is allowed.
* If deceased donor, a Kidney Donor Profile Index (KDPI) ≤ 85 (Donation after Circulatory Death \[DCD\] and what was previously known as extended criteria donor \[ECD\] organ recipients are eligible for enrollment provided KDPI ≤85).
* At least one antigen mismatch at major Major Histocompatibility Complex (MHC) (class I or class II).
* Willingness to comply with study protocol.
* Subject agrees not to participate in another investigational drug study while on treatment.
* Female subject must be either:

  a. Of non-child-bearing potential i. Post-menopausal (defined as at least 1 year without any menses) prior to screening, or ii. Documented surgically sterile or status post-hysterectomy b. Or, if of childbearing potential, i. Agree not to try to become pregnant during the study and for 90 days after the final study drug administration ii. And have a negative serum or urine pregnancy test within 7 days prior to transplant procedure iii. And, if heterosexually active, agree to consistently use two forms of highly effective birth control (at least one of which must be a barrier method) which includes consistent and correct usage of established oral contraception, established intrauterine device or intrauterine system, or barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository or vasectomy in the male partner, starting at screening and throughout the study period and for 90 days after the final study drug administration.
* Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at screening and continuing throughout the study period and for 90 days after the final study drug administration.
* Male subject must not donate sperm starting at screening throughout the study period and for 90 days after the final study drug administration.
* Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 90 days after the final study drug administration.
* Female subject must not donate ova starting at screening and throughout the study period, and for 90 days after the final study drug administration.
* Will be receiving induction immunotherapy (either T-cell depleting agent, anti-CD52 monoclonal antibody, or Interleukin-2 (IL-2) co-stimulation blocker), with dose and frequency of the chosen induction agent determined by local standard of care. Steroid-only induction therapy does not satisfy this criterion.

Exclusion Criteria:

* Patient is known to have a positive test for latent Tuberculosis (TB) and has not previously received adequate anti-microbial therapy or would require TB prophylaxis after transplant.
* Uncontrolled concomitant infection or any unstable medical condition that could interfere with study objectives.
* Significant liver disease, defined as having, during the past 28 days, consistently elevated Aspartate Aminotransferase, GOT (AST) Serum Glutamic Oxaloacetic Transaminase (SGOT) and/or Alanine Aminotransferase, GPT (ALT) Serum Glutamic Pyruvic Transaminase (SPGT) levels greater than 3 times the upper value of the normal range of the investigational site.
* Patient currently taking or maintained on another form of extended-release tacrolimus following his/her transplant procedure.
* Patient who will be maintained on a non-tacrolimus-based maintenance immunosuppressive regimen following his/her transplant procedure.
* Patient currently taking, having taken within 30 days, or who will be maintained on an Mammalian target of rapamycin (mTOR) inhibitor following his/her transplant procedure.
* Use of an investigational study drug in the 30 days prior to the transplant procedure.
* Contraindication or hypersensitivity to drugs or any of their components that constitute the immunosuppression regimen.
* 6 Antigen (Ag) match or zero mismatch at major Major Histocompatibility Complex (MHC) (class I or class II).
* Receipt of an Blood Group System (A, B, AB, and O) (ABO)-incompatible organ. Note: A2 donor to O recipient or A2 donor to B recipient is considered ABO-compatible and not excluded by this criterion.
* Presence of current or historic pre-formed anti-Human Leukocyte Antigen (HLA) DSA against the current donor (evidence of pre-formed, non-donor HLA is not exclusionary) as defined by a subject meeting any of the following criteria\*: a) positive virtual crossmatch, b) positive T- or B-cell crossmatch by National Institutes of Health (NIH) antiglobulin lymphocytotoxicity method\*\* , c) .Positive T- or B-cell flow cytometry crossmatch defined by the Multiparameter flow cytometry (MFC) criteria used by the center's HLA lab for their local proficiency testing.,\*\* d) An Mean Fluorescence Intensity (MFI) greater than or approaching 1000 using flow cytometry/Luminex-based, specific anti-HLA antibody testing.

  * \* Patients are eligible to enroll with a negative virtual crossmatch if used in lieu of a physical crossmatch, if, use of such is required to obviate the accrual of excessive ischemia time. However, continued participation is predicated on the performance of the physical crossmatch within 48 hours of transplant. If the physical crossmatch is positive, the subject will be discontinued.
  * \*\* If b or c above are positive secondary to a suspected positive auto-crossmatch, that is not exclusionary as long as a and b above are not met.
* Receipt of desensitization, antibody-removal, anti-B-cell, or anti-plasma cell therapy in the 90 days preceding the transplant procedure.
* Planned initiation (prior to transplant) of desensitization, antibody-removal, anti-B-cell, or anti-plasma cell therapy within 7 days of the transplant procedure.
* Donor or recipient with known hepatitis C infection (Hepatitis C Virus (HCV) antibody positive), Human Immunodeficiency Virus (HIV) infection (HIV antibody positive), acute hepatitis B infection (Hepatitis B Surface Antigen (HBsAg) positive, anti-Hepatitis B Virus Core (HBc) positive, Immunoglobulin M (IgM) anti-HBc positive, anti-HBs negative) chronic hepatitis B infection (HBsAg positive, anti-HBc positive, IgM anti-HBc negative, anti-HBs negative), or equivocal hepatitis B status (HBsAg negative, anti-HBc positive, anti-HBs negative). Patients (donor or recipient) who have normal liver function tests (LFT) and who are either hepatitis C positive with a negative viral load or have natural or vaccine-acquired immunity from hepatitis B are not excluded by this criterion.
* Primary focal segmental glomerulosclerosis.
* Subject has a current malignancy or history of malignancy (within the past 5 years), except non-metastatic basal or squamous cell carcinoma of the skin or carcinoma-in-situ of the cervix that has been successfully treated.
* Recipient of multi-organ or dual kidney transplants (inclusive of current transplant and any prior non-renal transplants). Note: Patients with prior kidney transplants are eligible.
* Recipient of an en bloc, pediatric deceased donor kidney from a donor less than 5 years of age OR weighing less than 20 kg.
* Prior graft loss secondary to Cytomegalovirus (CMV) or BK nephropathy.
* Prior history of invasive organ disease in the presence of CMV or BKV or clinically significant CMV viremia.
* History of clinically significant BK viruria.
* Any condition which makes the subject unsuitable for study participation.
* Planned complete steroid avoidance (Steroid initiation and subsequent taper / withdrawal will be allowed and will be under the purview of the treating physician).
* Planned receipt of post-transplant prophylactic HCV treatment.