Clinical trial NCT02723591: 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
Official title: Astagraf XL® to Understand the Impact of Immunosuppression on De Novo DSA Development and Chronic Immune Activation in Kidney Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Kidney Transplantation
Keywords: FK506
Kidney Transplantation
Tacrolimus
Astagraf XL
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2016-03-30
Enrollment: 599
Sex: ALL
Minimum age (years): 16
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Primary outcomes:
measure: Percentage of Participants Who Were Positive for de Novo DSA (dnDSA) or Immune Activation (IA) Occurrence
timeFrame: From date of transplant until 1 year
Secondary outcomes:
measure: Percentage of Participants Who Were Positive, Negative or Indeterminate for dnDSA Occurrence
timeFrame: From date of transplant until 1 year
measure: Peak Mean Fluorescence Intensity (MFI) of DSA Positive Participants
timeFrame: From date of transplant until 1 year
measure: Percentage of DSA Positive Participants With Weak, Moderate and Strong Antibody Strentgh
timeFrame: From date of transplant until 1 year
measure: Percentage of DSA Positive Participants With DSA Persistence
timeFrame: From date of transplant until 1 year
measure: Percentage of Participants Who Were Positive or Negative for Complement Component 1, Q Subcomponent (C1q)-Binding DSA
timeFrame: From date of transplant until 1 year
measure: Percentage of Participants Who Were Positive or Negative for DSA Immunoglobulin G (IgG3) Isotype
timeFrame: From date of transplant until 1 year
measure: Percentage of DSA Positive Participants With Human Leukocyte Antigen, Class II, DQ Locus (HLA-DQ)
timeFrame: From date of transplant until 1 year
measure: Percentage of Participants Who Were Positive for IA Occurrence From Day 1 to Day 365 Visit
timeFrame: From day 1 to day 365 visit
measure: Percentage of Participants Who Were Positive for IA Occurrence From Day 30 to Day 365 Visit
timeFrame: From day 30 to day 365 visit
measure: Percentage of Participants With IA Persistence
timeFrame: From date of transplant until 1 year
measure: Percentage of Participants With Presence of Transplant Glomerulopathy (TG) on Biopsy
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Presence of Microcirculatory Inflammation (MI) on Biopsy
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Presence of Interstitial Fibrosis and Tubular Atrophy (IFTA) and Inflammation on Biopsy
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Estimated Glomerular Filtration Rate (eGFR) Threshold of <30 Millimetre Per Minute Per 1.73 Meter Square (mL/Min/1.73m^2)
timeFrame: At 1 year post transplant
measure: Percentage of Participants With eGFR Threshold of <40 mL/Min/1.73m^2
timeFrame: At 1 year post transplant
measure: Percentage of Participants With eGFR Threshold of <50 mL/Min/1.73m^2
timeFrame: At 1 year post transplant
measure: Percentage of Participants With a Five-point Decline in eGFR
timeFrame: From 30 days post transplant until 1 year
measure: eGFR at Day 30, Day 90, Day 180, Day 270 and Day 365
timeFrame: Day 30, day 90, day 180, day 270 and day 365
measure: Percentage of Participants With Graft Loss
timeFrame: From date of transplant until 1 year
measure: Percentage of Participants Who Died
timeFrame: From date of transplant until 1 year
measure: Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR)
timeFrame: From date of transplant until 1 year
measure: Percentage of Participants Who Were Lost to Follow-up
timeFrame: From date of transplant until 1 year
measure: Percentage of Participants With Either Graft Loss, Death, BPAR or Lost to Follow-up
timeFrame: From date of transplant until 1 year
measure: Percentage of Participants With Any Antibody-Mediated Rejection (ABMR)
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Normal Biopsy Findings
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With C4d Deposition Without Active Rejection
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Acute ABMR
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Grade I, II and III Acute ABMR
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Chronic ABMR
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Borderline Changes
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Acute T-cell Mediated Rejection (TCMR)
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Chronic TCMR
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Grade I, II and III IFTA
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Any Additional Findings
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Glomerulitis (g) Biopsy Score Assessed Using Banff Lesion Scores
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Tubulitis (t) Biopsy Score Assessed Using Banff Lesion Scores
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Intimal Arteritis (v) Biopsy Score Assessed Using Banff Lesion Scores
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Mononuclear Cell Interstitial Inflammation (i) Biopsy Score Assessed Using Banff Lesion Scores
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Glomerular Basement Membrane Double Contours (cg) Biopsy Score Assessed Using Banff Lesion Scores
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Tubular Atrophy (ct) Biopsy Score Assessed Using Banff Lesion Scores
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Interstitial Fibrosis (ci) Biopsy Score Assessed Using Banff Lesion Scores
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Vascular Fibrous Intimal Thickening (cv) Biopsy Score Assessed Using Banff Lesion Scores
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Arteriolar Hyalinosis (ah) Biopsy Score Assessed Using Banff Lesion Scores
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Peritubular Capillaritis (Ptc) Biopsy Score Assessed Using Banff Lesion Scores
timeFrame: From date of transplant until month 14
measure: Percentage of Participants With Mesangial Matrix Expansion (mm) Biopsy Score Assessed Using Banff Lesion Scores
timeFrame: From date of transplant until month 14
measure: Time to First Occurrence of DSA
timeFrame: From date of transplant until 1 year
measure: Time to First Occurrence of HLA-DQ DSA
timeFrame: From date of transplant until 1 year
measure: Time to First Occurrence of C1q-binding DSA
timeFrame: From date of transplant until 1 year
measure: Time to First Occurrence of DSA IgG3 Isotype
timeFrame: From date of transplant until 1 year
measure: Time to First Occurrence of IA
timeFrame: From date of transplant until 1 year
measure: Time to First Occurrence of TG on Biopsy
timeFrame: From date of transplant until 1 year
measure: Time to Occurrence of Death
timeFrame: From date of transplant until 1 year
measure: Time to First Occurrence of Local BPAR
timeFrame: From date of transplant until 1 year
measure: Time to First Occurrence of Acute Forms of ABMR
timeFrame: From date of transplant until 1 year
measure: Time to First Occurrence of Chronic Forms of ABMR
timeFrame: From date of transplant until 1 year
measure: Time to First Occurrence of Acute TCMR
timeFrame: From date of transplant until 1 year
measure: Time to First Occurrence of Chronic TCMR
timeFrame: From date of transplant until 1 year
measure: Time to First Occurrence of Borderline Changes
timeFrame: From date of transplant until 1 year
measure: Time to First Occurrence of IFTA
timeFrame: From date of transplant until 1 year
measure: Percentage of Participants With Treatment-emergent Adverse Event(TEAEs), Related TEAEs, Treatment-emergent Serious Adverse Event (TESAEs), Related TESAEs, TEAEs Leading to Discontinuation of Study Treatment and TEAEs Leading to Death
timeFrame: From first dose of study drug up to 7 days after last dose of study drug (up to 2 years)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Site US10006
state: Alabama
city: Scottsdale
country: United States
facility: Site US10025
state: Arizona
city: Los Angeles
country: United States
facility: Site US10031
state: California
city: Sacramento
country: United States
facility: Site US10005
state: California
city: San Francisco
country: United States
facility: Site US10016
state: California
city: Aurora
country: United States
facility: Site US10024
state: Colorado
city: New Haven
country: United States
facility: Site US10003
state: Connecticut
city: Washington
country: United States
facility: Site US10014
state: District of Columbia
city: Jacksonville
country: United States
facility: Site US10030
state: Florida
city: Chicago
country: United States
facility: Site US10020
state: Illinois
city: Chicago
country: United States
facility: Site US10010
state: Illinois
city: Baltimore
country: United States
facility: Site US10001
state: Maryland
city: Boston
country: United States
facility: Site US10007
state: Massachusetts
city: Ann Arbor
country: United States
facility: Site US10013
state: Michigan
city: Detroit
country: United States
facility: Site US10032
state: Michigan
city: Minneapolis
country: United States
facility: Site US10029
state: Minnesota
city: Rochester
country: United States
facility: Site US10027
state: Minnesota
city: Livingston
country: United States
facility: Site US10019
state: New Jersey
city: Buffalo
country: United States
facility: Site US10004
state: New York
city: New York
country: United States
facility: Site US10037
state: New York
city: New York
country: United States
facility: Site US10022
state: New York
city: New York
country: United States
facility: Site US10028
state: New York
city: Syracuse
country: United States
facility: Site US10021
state: New York
city: Portland
country: United States
facility: Site US10026
state: Oregon
city: Charleston
country: United States
facility: Site US10002
state: South Carolina
city: Houston
country: United States
facility: Site US10036
state: Texas
city: Salt Lake City
country: United States
facility: Site US10018
state: Utah
city: Charlottesville
country: United States
facility: Site US10012
state: Virginia
city: Falls Church
country: United States
facility: Site US10008
state: Virginia
city: Madison
country: United States
facility: Site US10023
state: Wisconsin
Study officials:
affiliation: Astellas Medical Affairs, Americas
name: Medical Monitor
role: STUDY_DIRECTOR
References: