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 (ASTOUND)

Astagraf XL® to Understand the Impact of Immunosuppression on De Novo DSA Development and Chronic Immune Activation in Kidney Transplantation

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.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: Tacrolimus; Drug: Tacrolimus immediate release

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.

• Study Type: Interventional
• Enrollment (Actual): 599
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Site US10006
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Site US10025
  • California
    • Los Angeles, California, United States, 90033
      • Site US10031
    • Sacramento, California, United States, 95817
      • Site US10005
    • San Francisco, California, United States, 94115
      • Site US10016
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Site US10024
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Site US10003
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Site US10014
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Site US10030
  • Illinois
    • Chicago, Illinois, United States, 60605
      • Site US10020
    • Chicago, Illinois, United States, 60611
      • Site US10010
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Site US10001
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Site US10007
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Site US10013
    • Detroit, Michigan, United States, 48202
      • Site US10032
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Site US10029
    • Rochester, Minnesota, United States, 55905
      • Site US10027
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Site US10019
  • New York
    • Buffalo, New York, United States, 14215
      • Site US10004
    • New York, New York, United States, 10032
      • Site US10037
    • New York, New York, United States, 10065
      • Site US10022
    • New York, New York, United States, 10467
      • Site US10028
    • Syracuse, New York, United States, 13210
      • Site US10021
  • Oregon
    • Portland, Oregon, United States, 97210
      • Site US10026
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Site US10002
  • Texas
    • Houston, Texas, United States, 77030
      • Site US10036
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Site US10018
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Site US10012
    • Falls Church, Virginia, United States, 22042
      • Site US10008
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Site US10023

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tacrolimus, Extended Release (Astagraf XL®) Once Daily; Participants received tacrolimus extended release (Astagraf XL) at a starting dose of 0.15 milligram per kilogram (mg/kg), once daily, orally within 48 hours of transplantation (per the treating physician's discretion) for up to 1 year. Dose adjustments were allowed such that participants receiving tacrolimus maintained a minimal trough concentration of 6 nanogram per milliliter (ng/mL) at all times during the study.	Drug: Tacrolimus; Oral Capsule; Other Names: Advagraf; FK506E; Astagraf XL
Active Comparator: Tacrolimus, Immediate Release Twice Daily (BID); Participants received tacrolimus immediate release as per the institutionally-derived protocol, BID, orally within 48 hours of transplantation (per the treating physician's discretion) for up to 1 year. Dose adjustments were allowed such that participants receiving tacrolimus maintained a minimal trough concentration of 6 ng/mL at all times during the study.	Drug: Tacrolimus immediate release; Oral Capsule; Other Names: Prograf; FK506; generic immediate release tacrolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Were Positive for de Novo DSA (dnDSA) or Immune Activation (IA) Occurrence	DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching mean fluorescence intensity (MFI)=1000 at any time during the study. IA was considered either present or absent using the Trugraf™ v2.0 molecular assay. A negative designation (Trugraf TX Normal) was referred to as Immune Quiescence (IQ). Due to operating characteristics of the assay, a positive designation was considered evidence of IA in all participants.	From date of transplant until 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Were Positive, Negative or Indeterminate for dnDSA Occurrence	DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching MFI=1000 at any time during the study. Indeterminate was defined as MFI signal was >1000 and DSA was suspected, but could not be confirmed due to inadequate donor typing. Participants whose samples for the test were not available were reported as unknown.	From date of transplant until 1 year
Peak Mean Fluorescence Intensity (MFI) of DSA Positive Participants	Peak MFI of DSA positive participants was reported.	From date of transplant until 1 year
Percentage of DSA Positive Participants With Weak, Moderate and Strong Antibody Strentgh	DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching MFI=1000 at any time during the study.	From date of transplant until 1 year
Percentage of DSA Positive Participants With DSA Persistence	DSA was regarded as persistent under the following conditions: (i) DSA was detected and remained above the threshold for positivity (MFI = 1000) for two consecutive or nonconsecutive measurements, or (ii) the new appearance of a DSA at the threshold for positivity when preceded by a DSA of a different specificity that had subsequently become non-detectable.	From date of transplant until 1 year
Percentage of Participants Who Were Positive or Negative for Complement Component 1, Q Subcomponent (C1q)-Binding DSA	Percentage of participants who were positive or negative for C1q-binding DSA were reported.	From date of transplant until 1 year
Percentage of Participants Who Were Positive or Negative for DSA Immunoglobulin G (IgG3) Isotype	Percentage of participants who were positive or negative for IgG3 isotype were reported.	From date of transplant until 1 year
Percentage of DSA Positive Participants With Human Leukocyte Antigen, Class II, DQ Locus (HLA-DQ)	Percentage of DSA positive participants with HLA-DQ Class-II were reported.	From date of transplant until 1 year
Percentage of Participants Who Were Positive for IA Occurrence From Day 1 to Day 365 Visit	IA was considered either present or absent using the Trugraf™ v2.0 molecular assay. A negative designation (Trugraf TX Normal) was referred to as Immune Quiescence (IQ). Due to operating characteristics of the assay, a positive designation was considered evidence of IA in all participants.	From day 1 to day 365 visit
Percentage of Participants Who Were Positive for IA Occurrence From Day 30 to Day 365 Visit	IA was considered either present or absent using the Trugraf™ v2.0 molecular assay. A negative designation (Trugraf TX Normal) was referred to as Immune Quiescence (IQ). Due to operating characteristics of the assay, a positive designation was considered evidence of IA in all participants.	From day 30 to day 365 visit
Percentage of Participants With IA Persistence	IA was regarded as persistent under the following conditions: (i) IA was detected and remained above the threshold for positivity for two consecutive or non-consecutive measurements, or (ii) the new appearance of an IA at the threshold for positivity when preceded by an IA of a different specificity that had subsequently become non-detectable.	From date of transplant until 1 year
Percentage of Participants With Presence of Transplant Glomerulopathy (TG) on Biopsy	TG was defined as chronic glomerulopathy (cg) >0 on centrally-interpreted institutional protocol biopsy or biopsy obtained for cause during the first year post-transplant with +2 months visit window.	From date of transplant until month 14
Percentage of Participants With Presence of Microcirculatory Inflammation (MI) on Biopsy	MI was defined as glomerulitis (g) + peritubular capillaritis (ptc)>=2 on centrally-interpreted institutional protocol biopsy or biopsy obtained for cause during the first year post-transplant, with +2 months visit window.	From date of transplant until month 14
Percentage of Participants With Presence of Interstitial Fibrosis and Tubular Atrophy (IFTA) and Inflammation on Biopsy	IFTA and inflammation was defined as IFTA positive and inflammation positive (i >0) on centrally-interpreted institutional protocol biopsy or biopsy obtained for cause during the first year posttransplant, with +2 months visit window.	From date of transplant until month 14
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)	The eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) formula.	At 1 year post transplant
Percentage of Participants With eGFR Threshold of <40 mL/Min/1.73m^2	The eGFR was calculated using the MDRD formula.	At 1 year post transplant
Percentage of Participants With eGFR Threshold of <50 mL/Min/1.73m^2	The eGFR was calculated using the MDRD formula.	At 1 year post transplant
Percentage of Participants With a Five-point Decline in eGFR	The eGFR was calculated using the MDRD formula.	From 30 days post transplant until 1 year
eGFR at Day 30, Day 90, Day 180, Day 270 and Day 365	The eGFR was calculated using the MDRD formula.	Day 30, day 90, day 180, day 270 and day 365
Percentage of Participants With Graft Loss	Graft loss was defined as re-transplantation, transplant nephrectomy, or a return to dialysis for at least a six week duration, or participants' death.	From date of transplant until 1 year
Percentage of Participants Who Died	Percentage of participants who died were reported.	From date of transplant until 1 year
Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR)	Positivity was determined by local biopsy, central pathology, or reported adverse events.	From date of transplant until 1 year
Percentage of Participants Who Were Lost to Follow-up	Percentage of participants who were lost to follow-up were reported.	From date of transplant until 1 year
Percentage of Participants With Either Graft Loss, Death, BPAR or Lost to Follow-up	Percentage of participants with either graft loss, death, BPAR or lost to follow-up were reported.	From date of transplant until 1 year
Percentage of Participants With Any Antibody-Mediated Rejection (ABMR)	Percentage of participants with ABMR were reported. Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. A positive assessment is defined as antibody mediated changes that are diagnosed as either acute ABMR or chronic active ABMR.	From date of transplant until month 14
Percentage of Participants With Normal Biopsy Findings	Percentage of participants with normal biopsy findings were reported.	From date of transplant until month 14
Percentage of Participants With C4d Deposition Without Active Rejection	Percentage of participants with C4d deposition without active rejection were reported.	From date of transplant until month 14
Percentage of Participants With Acute ABMR	Percentage of participants with acute ABMR were reported.	From date of transplant until month 14
Percentage of Participants With Grade I, II and III Acute ABMR	Percentage of participants with grade I, II and III acute ABMR were reported. Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Acute ABMR was graded as Grade I: acute tubular necrosis-like -like minimal inflammation, Grade II: Capillary and or glomerular inflammation (ptc/g >0) and/or thromboses, and Grade III: arterial - v3.	From date of transplant until month 14
Percentage of Participants With Chronic ABMR	Percentage of participants with chronic ABMR were reported.	From date of transplant until month 14
Percentage of Participants With Borderline Changes	Percentage of participants with borderline changes were reported.	From date of transplant until month 14
Percentage of Participants With Acute T-cell Mediated Rejection (TCMR)	Percentage of participants with acute TCMR were reported.	From date of transplant until month 14
Percentage of Participants With Chronic TCMR	Percentage of participants with chronic TCMR were reported.	From date of transplant until month 14
Percentage of Participants With Grade I, II and III IFTA	Percentage of participants with Grade I, II and III IFTA were reported. Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. IFTA was graded as Grade I: mild interstitial fibrosis and tubular atrophy (<25% of cortical area), Grade II: moderate interstitial fibrosis and tubular atrophy (26-50% of cortical area), and Grade III: severe interstitial fibrosis and tubular atrophy/ loss (>50% of cortical area).	From date of transplant until month 14
Percentage of Participants With Any Additional Findings	Percentage of participants with any additional findings (other than Normal biopsy, borderline changes, acute and chronic ABMR, Grade I, II, and III ABMR, C4D deposition, acute and chronic TCMR, Grade I, II, and III TCMR, Grade I, II and III IFTA, acute tubular necrosis, interstitial nephritis, pyelonephritis, bk virus, calcineurin inhibitor toxicity, hemolytic uremic syndrome and recurrent disease) were reported.	From date of transplant until month 14
Percentage of Participants With Glomerulitis (g) Biopsy Score Assessed Using Banff Lesion Scores	Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No glomerulitis, Score 1= <25% glomerulitis, Score 2= 25 to 75% glomerulitis and Score 3= >75% glomerulitis.	From date of transplant until month 14
Percentage of Participants With Tubulitis (t) Biopsy Score Assessed Using Banff Lesion Scores	Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No mononuclear cells in tubules or single focus of tubulitis only, Score 1= Foci with 1 to 4 mononuclear cells/tubular cross section (or 10 tubular cells), Score 2= Foci with 5 to 10 mononuclear cells/tubular cross section (or 10 tubular cells) and Score 3= Foci with >10 mononuclear cells/tubular cross section or the presence of ≥2 areas of tubular basement membrane destruction accompanied by i2/i3 inflammation and t2 elsewhere.	From date of transplant until month 14
Percentage of Participants With Intimal Arteritis (v) Biopsy Score Assessed Using Banff Lesion Scores	Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No arteritis, Score 1= Mild to moderate intimal arteritis in at least 1 arterial cross section, Score 2= Severe intimal arteritis with at least 25% luminal area lost in at least 1 arterial cross section and Score 3= Transmural arteritis and/or arterial fibrinoid change and medial smooth muscle necrosis with lymphocytic infiltrate in vessel.	From date of transplant until month 14
Percentage of Participants With Mononuclear Cell Interstitial Inflammation (i) Biopsy Score Assessed Using Banff Lesion Scores	Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No inflammation or in less than 10% of unscarred cortical parenchyma, Score 1= Inflammation in 10 to 25% of unscarred cortical parenchyma, Score 2= Inflammation in 26 to 50% of unscarred cortical parenchyma and Score 3= Inflammation in more than 50% of unscarred cortical parenchyma.	From date of transplant until month 14
Percentage of Participants With Glomerular Basement Membrane Double Contours (cg) Biopsy Score Assessed Using Banff Lesion Scores	Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No GBM double contours by light microscopy (LM) or electron microscopy (EM), Score 1= No GBM double contours by LM but GBM double contours (incomplete or circumferential) in at least 3 glomerular capillaries by EM or Double contours of the GBM in 1-25% of capillary loops in the most affected nonsclerotic glomerulus by LM , Score 2= Double contours affecting 26 to 50% of peripheral capillary loops in the most affected-glomerulus and Score 3= Double contours affecting more than 50% of peripheral capillary loops in the most affected-glomerulus.	From date of transplant until month 14
Percentage of Participants With Tubular Atrophy (ct) Biopsy Score Assessed Using Banff Lesion Scores	Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No tubular atrophy, Score 1= Tubular atrophy involving up to 25% of the area of cortical tubules, Score 2= Tubular atrophy involving 26 to 50% of the area of cortical tubules and Score 3= Tubular atrophy involving in >50% of the area of cortical tubules.	From date of transplant until month 14
Percentage of Participants With Interstitial Fibrosis (ci) Biopsy Score Assessed Using Banff Lesion Scores	Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= Interstitial fibrosis in up to 5% of cortical area, Score 1= Interstitial fibrosis in 6 to 25%of cortical area (mild interstitial fibrosis), Score 2= Interstitial fibrosis in 26 to 50% of cortical area (moderate interstitial fibrosis) and Score 3= Interstitial fibrosis in >50% of cortical area (severe interstitial fibrosis).	From date of transplant until month 14
Percentage of Participants With Vascular Fibrous Intimal Thickening (cv) Biopsy Score Assessed Using Banff Lesion Scores	Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No chronic vascular changes, Score 1= Vascular narrowing of up to 25% luminal area by fibrointimal thickening, Score 2= Vascular narrowing of 26 to 50% luminal area by fibrointimal thickening and Score 3= Vascular narrowing of more than 50% luminal area by fibrointimal thickening.	From date of transplant until month 14
Percentage of Participants With Arteriolar Hyalinosis (ah) Biopsy Score Assessed Using Banff Lesion Scores	Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No periodic acid-Schiff (PAS)-positive hyaline arteriolar thickening, Score 1= Mild to moderate PAS-positive hyaline thickening in at least 1 arteriole, Score 2= Moderate to severe PAS-positive hyaline thickening in more than 1 arteriole and Score 3= Severe PAS-positive hyaline thickening in many arterioles.	From date of transplant until month 14
Percentage of Participants With Peritubular Capillaritis (Ptc) Biopsy Score Assessed Using Banff Lesion Scores	Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= Maximum number of leukocytes <3, Score 1= At least 1 leukocyte cell in ≥10% of cortical PTCs with 3-4 leukocytes in most severely involved PTC, Score 2= At least 1 leukocyte in ≥10% of cortical PTC with 5-10 leukocytes in most severely involved PTC and Score 3= At least 1 leukocyte in ≥10% of cortical PTC with >10 leukocytes in most severely involved PTC.	From date of transplant until month 14
Percentage of Participants With Mesangial Matrix Expansion (mm) Biopsy Score Assessed Using Banff Lesion Scores	Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No more than mild mesangial matrix increase in any glomerulus, Score 1= At least moderate mesangial matrix increase in up to 25% of nonsclerotic glomeruli, Score 2= At least moderate mesangial matrix increase in 26% to 50% of nonsclerotic glomeruli and Score 3= At least moderate mesangial matrix increase in >50% of nonsclerotic glomeruli.	From date of transplant until month 14
Time to First Occurrence of DSA	DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching MFI=1000 at any time during the study.	From date of transplant until 1 year
Time to First Occurrence of HLA-DQ DSA	Time to first occurrence of HLA-DQ DSA was reported.	From date of transplant until 1 year
Time to First Occurrence of C1q-binding DSA	Time to first occurrence of C1q-binding DSA was reported.	From date of transplant until 1 year
Time to First Occurrence of DSA IgG3 Isotype	Time to first occurrence of DSA IgG3 isotype was reported.	From date of transplant until 1 year
Time to First Occurrence of IA	Time to first occurrence of IA was reported.	From date of transplant until 1 year
Time to First Occurrence of TG on Biopsy	Time to first occurrence of TG on biopsy was reported.	From date of transplant until 1 year
Time to Occurrence of Death	Time to occurrence of death was reported.	From date of transplant until 1 year
Time to First Occurrence of Local BPAR	Time to first occurrence of local BPAR was reported.	From date of transplant until 1 year
Time to First Occurrence of Acute Forms of ABMR	Time to first occurrence of acute forms of ABMR was reported.	From date of transplant until 1 year
Time to First Occurrence of Chronic Forms of ABMR	Time to first occurrence of chronic forms of ABMR was reported.	From date of transplant until 1 year
Time to First Occurrence of Acute TCMR	Time to first occurrence of acute TCMR was reported.	From date of transplant until 1 year
Time to First Occurrence of Chronic TCMR	Time to first occurrence of chronic TCMR was reported.	From date of transplant until 1 year
Time to First Occurrence of Borderline Changes	Time to first occurrence of borderline changes was reported.	From date of transplant until 1 year
Time to First Occurrence of IFTA	Time to first occurrence of IFTA was reported.	From date of transplant until 1 year
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	A TEAE was defined as an Adverse Event (AE) observed on or after the day of starting the administration of the test drug/comparative drug.	From first dose of study drug up to 7 days after last dose of study drug (up to 2 years)

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Investigators: Study Director: Medical Monitor, Astellas Medical Affairs, Americas

Publications and helpful links

Helpful Links

• Link to results on the Astellas Clinical Study Results website.

Study record dates

Study Major Dates

• Study Start (Actual): September 9, 2016
• Primary Completion (Actual): June 14, 2019
• Study Completion (Actual): June 14, 2019

Study Registration Dates

• First Submitted: March 3, 2016
• First Submitted That Met QC Criteria: March 24, 2016
• First Posted (Estimate): March 30, 2016

Study Record Updates

• Last Update Posted (Actual): August 4, 2020
• Last Update Submitted That Met QC Criteria: July 19, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Tacrolimus; Kidney Transplantation; FK506; Astagraf XL
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: IDTX-MA-3004; 2018-003867-79 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No