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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)

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ClinicalTrials.gov Identifier: NCT02723591
Recruitment Status : Completed
First Posted : March 30, 2016
Results First Posted : June 29, 2020
Last Update Posted : August 4, 2020
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Tracking Information
First Submitted Date  ICMJE March 3, 2016
First Posted Date  ICMJE March 30, 2016
Results First Submitted Date  ICMJE June 11, 2020
Results First Posted Date  ICMJE June 29, 2020
Last Update Posted Date August 4, 2020
Actual Study Start Date  ICMJE September 9, 2016
Actual Primary Completion Date June 14, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 11, 2020)
Percentage of Participants Who Were Positive for de Novo DSA (dnDSA) or Immune Activation (IA) Occurrence [ Time Frame: From date of transplant until 1 year ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 24, 2016)
Combined incidence of DSA or IA [ Time Frame: At 1 year post transplant or EOS (up to 2 years post transplant) ]
DSA considered as a binary variable (positive or negative), with positivity based on a threshold criteria of Mean Fluorescence Intensity approaching 1000. Immune Activation (IA): considered as a binary variable (present or absent) based on validated molecular signatures. End of study (EOS)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2020)
  • Percentage of Participants Who Were Positive, Negative or Indeterminate for dnDSA Occurrence [ Time Frame: From date of transplant until 1 year ]
    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.
  • Peak Mean Fluorescence Intensity (MFI) of DSA Positive Participants [ Time Frame: From date of transplant until 1 year ]
    Peak MFI of DSA positive participants was reported.
  • Percentage of DSA Positive Participants With Weak, Moderate and Strong Antibody Strentgh [ Time Frame: From date of transplant until 1 year ]
    DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching MFI=1000 at any time during the study.
  • Percentage of DSA Positive Participants With DSA Persistence [ Time Frame: From date of transplant until 1 year ]
    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.
  • Percentage of Participants Who Were Positive or Negative for Complement Component 1, Q Subcomponent (C1q)-Binding DSA [ Time Frame: From date of transplant until 1 year ]
    Percentage of participants who were positive or negative for C1q-binding DSA were reported.
  • Percentage of Participants Who Were Positive or Negative for DSA Immunoglobulin G (IgG3) Isotype [ Time Frame: From date of transplant until 1 year ]
    Percentage of participants who were positive or negative for IgG3 isotype were reported.
  • Percentage of DSA Positive Participants With Human Leukocyte Antigen, Class II, DQ Locus (HLA-DQ) [ Time Frame: From date of transplant until 1 year ]
    Percentage of DSA positive participants with HLA-DQ Class-II were reported.
  • Percentage of Participants Who Were Positive for IA Occurrence From Day 1 to Day 365 Visit [ Time Frame: 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.
  • Percentage of Participants Who Were Positive for IA Occurrence From Day 30 to Day 365 Visit [ Time Frame: 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.
  • Percentage of Participants With IA Persistence [ Time Frame: From date of transplant until 1 year ]
    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.
  • Percentage of Participants With Presence of Transplant Glomerulopathy (TG) on Biopsy [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Presence of Microcirculatory Inflammation (MI) on Biopsy [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Presence of Interstitial Fibrosis and Tubular Atrophy (IFTA) and Inflammation on Biopsy [ Time Frame: From date of transplant until month 14 ]
    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.
  • 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) [ Time Frame: At 1 year post transplant ]
    The eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) formula.
  • Percentage of Participants With eGFR Threshold of <40 mL/Min/1.73m^2 [ Time Frame: At 1 year post transplant ]
    The eGFR was calculated using the MDRD formula.
  • Percentage of Participants With eGFR Threshold of <50 mL/Min/1.73m^2 [ Time Frame: At 1 year post transplant ]
    The eGFR was calculated using the MDRD formula.
  • Percentage of Participants With a Five-point Decline in eGFR [ Time Frame: From 30 days post transplant until 1 year ]
    The eGFR was calculated using the MDRD formula.
  • eGFR at Day 30, Day 90, Day 180, Day 270 and Day 365 [ Time Frame: Day 30, day 90, day 180, day 270 and day 365 ]
    The eGFR was calculated using the MDRD formula.
  • Percentage of Participants With Graft Loss [ Time Frame: From date of transplant until 1 year ]
    Graft loss was defined as re-transplantation, transplant nephrectomy, or a return to dialysis for at least a six week duration, or participants' death.
  • Percentage of Participants Who Died [ Time Frame: From date of transplant until 1 year ]
    Percentage of participants who died were reported.
  • Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR) [ Time Frame: From date of transplant until 1 year ]
    Positivity was determined by local biopsy, central pathology, or reported adverse events.
  • Percentage of Participants Who Were Lost to Follow-up [ Time Frame: From date of transplant until 1 year ]
    Percentage of participants who were lost to follow-up were reported.
  • Percentage of Participants With Either Graft Loss, Death, BPAR or Lost to Follow-up [ Time Frame: From date of transplant until 1 year ]
    Percentage of participants with either graft loss, death, BPAR or lost to follow-up were reported.
  • Percentage of Participants With Any Antibody-Mediated Rejection (ABMR) [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Normal Biopsy Findings [ Time Frame: From date of transplant until month 14 ]
    Percentage of participants with normal biopsy findings were reported.
  • Percentage of Participants With C4d Deposition Without Active Rejection [ Time Frame: From date of transplant until month 14 ]
    Percentage of participants with C4d deposition without active rejection were reported.
  • Percentage of Participants With Acute ABMR [ Time Frame: From date of transplant until month 14 ]
    Percentage of participants with acute ABMR were reported.
  • Percentage of Participants With Grade I, II and III Acute ABMR [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Chronic ABMR [ Time Frame: From date of transplant until month 14 ]
    Percentage of participants with chronic ABMR were reported.
  • Percentage of Participants With Borderline Changes [ Time Frame: From date of transplant until month 14 ]
    Percentage of participants with borderline changes were reported.
  • Percentage of Participants With Acute T-cell Mediated Rejection (TCMR) [ Time Frame: From date of transplant until month 14 ]
    Percentage of participants with acute TCMR were reported.
  • Percentage of Participants With Chronic TCMR [ Time Frame: From date of transplant until month 14 ]
    Percentage of participants with chronic TCMR were reported.
  • Percentage of Participants With Grade I, II and III IFTA [ Time Frame: From date of transplant until month 14 ]
    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).
  • Percentage of Participants With Any Additional Findings [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Glomerulitis (g) Biopsy Score Assessed Using Banff Lesion Scores [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Tubulitis (t) Biopsy Score Assessed Using Banff Lesion Scores [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Intimal Arteritis (v) Biopsy Score Assessed Using Banff Lesion Scores [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Mononuclear Cell Interstitial Inflammation (i) Biopsy Score Assessed Using Banff Lesion Scores [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Glomerular Basement Membrane Double Contours (cg) Biopsy Score Assessed Using Banff Lesion Scores [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Tubular Atrophy (ct) Biopsy Score Assessed Using Banff Lesion Scores [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Interstitial Fibrosis (ci) Biopsy Score Assessed Using Banff Lesion Scores [ Time Frame: From date of transplant until month 14 ]
    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).
  • Percentage of Participants With Vascular Fibrous Intimal Thickening (cv) Biopsy Score Assessed Using Banff Lesion Scores [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Arteriolar Hyalinosis (ah) Biopsy Score Assessed Using Banff Lesion Scores [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Peritubular Capillaritis (Ptc) Biopsy Score Assessed Using Banff Lesion Scores [ Time Frame: From date of transplant until month 14 ]
    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.
  • Percentage of Participants With Mesangial Matrix Expansion (mm) Biopsy Score Assessed Using Banff Lesion Scores [ Time Frame: From date of transplant until month 14 ]
    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.
  • Time to First Occurrence of DSA [ Time Frame: From date of transplant until 1 year ]
    DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching MFI=1000 at any time during the study.
  • Time to First Occurrence of HLA-DQ DSA [ Time Frame: From date of transplant until 1 year ]
    Time to first occurrence of HLA-DQ DSA was reported.
  • Time to First Occurrence of C1q-binding DSA [ Time Frame: From date of transplant until 1 year ]
    Time to first occurrence of C1q-binding DSA was reported.
  • Time to First Occurrence of DSA IgG3 Isotype [ Time Frame: From date of transplant until 1 year ]
    Time to first occurrence of DSA IgG3 isotype was reported.
  • Time to First Occurrence of IA [ Time Frame: From date of transplant until 1 year ]
    Time to first occurrence of IA was reported.
  • Time to First Occurrence of TG on Biopsy [ Time Frame: From date of transplant until 1 year ]
    Time to first occurrence of TG on biopsy was reported.
  • Time to Occurrence of Death [ Time Frame: From date of transplant until 1 year ]
    Time to occurrence of death was reported.
  • Time to First Occurrence of Local BPAR [ Time Frame: From date of transplant until 1 year ]
    Time to first occurrence of local BPAR was reported.
  • Time to First Occurrence of Acute Forms of ABMR [ Time Frame: From date of transplant until 1 year ]
    Time to first occurrence of acute forms of ABMR was reported.
  • Time to First Occurrence of Chronic Forms of ABMR [ Time Frame: From date of transplant until 1 year ]
    Time to first occurrence of chronic forms of ABMR was reported.
  • Time to First Occurrence of Acute TCMR [ Time Frame: From date of transplant until 1 year ]
    Time to first occurrence of acute TCMR was reported.
  • Time to First Occurrence of Chronic TCMR [ Time Frame: From date of transplant until 1 year ]
    Time to first occurrence of chronic TCMR was reported.
  • Time to First Occurrence of Borderline Changes [ Time Frame: From date of transplant until 1 year ]
    Time to first occurrence of borderline changes was reported.
  • Time to First Occurrence of IFTA [ Time Frame: From date of transplant until 1 year ]
    Time to first occurrence of IFTA was reported.
  • 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 [ Time Frame: From first dose of study drug up to 7 days after last dose of study drug (up to 2 years) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 24, 2016)
  • Composite endpoint of incidence of acquiring DSA or incidence of positive evidence of TG on centrally interpreted biopsy [ Time Frame: Up to 1 year post transplant or EOS (up to 2 years post transplant) ]
    For validation of peripheral blood molecular profiling. Transplant Glomerulopathy (TG)
  • Incidence of DSA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    DSA considered as a binary variable (positive or negative), with positivity based on a threshold criteria of Mean Fluorescence Intensity approaching 1000
  • Incidence of IA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    IA considered as a binary variable (present or absent) based on validated molecular signatures
  • Incidence of TG on biopsy [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
  • Incidence of chronic active ABMR on biopsy [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Antibody-mediated rejection (ABMR)
  • Incidence of C1q-binding DSA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    Complement Component 1, Q Subcomponent-binding DSA (C1q-binding DSA). Assessed in subjects who are DSA positive. Considered as a binary variable (positive or negative)
  • Incidence of HLA-DQ DSA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    Human Leukocyte Antigen, Class II, DQ locus DSA (HLA-DQ DSA). Assessed in subjects who are DSA positive
  • Incidence of subAR [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    Subclinical Acute Rejection (subAR), a validated molecular signature phenotype
  • Incidence of TX [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    Transplant eXcellent (TX), a validated molecular signature phenotype
  • Incidence of cAR [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    Clinical Acute Rejection (cAR), a validated molecular signature phenotype
  • Incidence of ADNR [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    Acute Dysfunction / No Rejection (ADNR), a validated molecular signature phenotype
  • Incidence of CR [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    Chronic Rejection (CR), a validated molecular signature phenotype
  • Incidence of DSA IgG3 isotype [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    DSA Immunoglobulin G3 (DSA IgG3). Assessed in subjects who are DSA positive
  • Incidence of required antibody reduction [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Assessed in subjects who are DSA positive
  • Incidence of eGFR threshold of less than 30 mL/min/1.73m2 [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Estimated Glomerular Filtration Rate (eGFR)
  • Incidence of eGFR threshold of 40 mL/min/1.73m2 [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
  • Incidence of eGFR threshold of 50 mL/min/1.73m2 [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
  • Incidence of graft loss [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Graft loss is defined as subject death, retransplantation, transplant nephrectomy, or a return to dialysis for at least a 6 week duration
  • Incidence of death [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
  • Incidence of local BPAR [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Biopsy-proven acute rejection (BPAR)
  • Incidence of loss to follow up [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
  • Time to various eGFR thresholds [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Thresholds of less than 30, 40, and 50 mL/min/1.73 m2)
  • Time to first occurrence of graft loss [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Graft loss is defined as subject death, retransplantation, transplant nephrectomy, or a return to dialysis for at least a 6 week duration
  • Time to first occurrence of mortality [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
  • Time to first occurrence of local BPAR [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
  • Incidence of particular categories of DSA strength (weak, moderate, strong) in participants with incident DSA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
  • Assessment of the frequency of the type of antibody reduction employed [ Time Frame: : From date of transplant until EOS (up to 2 years post transplant) ]
  • Patient MFI scores in participants who are DSA positive [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    Mean Fluorescence Intensity (MFI). Through assessment of MFI between treatment groups
  • Incidence of ci scores greater than one [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Interstitial fibrosis scores (ci scores). Per Banff criteria
  • Incidence of ct scores greater than one [ Time Frame: From date of transplant until EOS (up to 2 years post transplant ]
    Tubular atrophy scores (ct scores). Per Banff criteria
  • Incidence of ptc scores greater than one [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Peritubular capillaritis scores (ptc scores). Per Banff criteria
  • Biopsy scores for g [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Early allograft glomerulitis scores (g scores). Per Banff criteria
  • Biopsy scores for t [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Tubulitis scores (t scores). Per Banff criteria
  • Biopsy scores for v [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Intimal arteritis scores (v scores). Per Banff criteria
  • Biopsy scores for i [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Early monocellular interstitial inflammation scores (i scores). Per Banff criteria
  • Biopsy scores for cg [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Allograft glomerulopathy scores (cg scores). Per Banff criteria
  • Biopsy scores for ct [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Tubular atrophy scores (ct scores). Per Banff criteria
  • Biopsy scores for ci [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Interstitial fibrosis scores (ci scores). Per Banff criteria
  • Biopsy scores for cv [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Vascular fibrous intimal thickening scores (cv scores). Per Banff criteria
  • Biopsy scores for ah [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Arteriolar hyaline thickening scores (ah scores). Per Banff criteria
  • Biopsy scores for ptc [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Peritubular capillaritis scores (ptc scores). Per Banff criteria
  • Biopsy scores for mm [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Mesangial matrix increase scores (mm scores). Per Banff criteria
  • Safety assessed by each type of Adverse Events [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Based on system organ class and preferred term from the most recent version of MedDRA. Medical Dictionary for Regulatory Activities (MedDRA)
  • The number of individuals remaining with DSA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    For patients who develop IA on molecular profiling, with specific focus on subAR
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE Astagraf XL® to Understand the Impact of Immunosuppression on De Novo DSA Development and Chronic Immune Activation in Kidney Transplantation
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Kidney Transplantation
Intervention  ICMJE
  • Drug: Tacrolimus
    Oral Capsule
    Other Names:
    • Advagraf
    • FK506E
    • Astagraf XL
  • Drug: Tacrolimus immediate release
    Oral Capsule
    Other Names:
    • FK506
    • Prograf
    • generic immediate release tacrolimus
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Tacrolimus
  • 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.
    Intervention: Drug: Tacrolimus immediate release
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 20, 2018)
599
Original Estimated Enrollment  ICMJE
 (submitted: March 24, 2016)
550
Actual Study Completion Date  ICMJE June 14, 2019
Actual Primary Completion Date June 14, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years to 70 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02723591
Other Study ID Numbers  ICMJE IDTX-MA-3004
2018-003867-79 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
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.
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.
URL: https://www.clinicalstudydatarequest.com/
Responsible Party Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )
Study Sponsor  ICMJE Astellas Pharma Global Development, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Monitor Astellas Medical Affairs, Americas
PRS Account Astellas Pharma Inc
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP