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.
Brief Title
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
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.
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.
Completion Date
Completion Date Type
Actual
Conditions
Kidney Transplantation
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.
* 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.
Inclusion 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.
* 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.
Gender
All
Gender Based
false
Keywords
FK506
Kidney Transplantation
Tacrolimus
Astagraf XL
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
70 Years
Minimum Age
16 Years
NCT Id
NCT02723591
Org Class
Industry
Org Full Name
Astellas Pharma Inc
Org Study Id
IDTX-MA-3004
Overall Status
Completed
Phases
Phase 4
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Astagraf XL® to Understand the Impact of Immunosuppression on De Novo DSA Development and Chronic Immune Activation in Kidney Transplantation
Primary Outcomes
Outcome Description
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.
Outcome Measure
Percentage of Participants Who Were Positive for de Novo DSA (dnDSA) or Immune Activation (IA) Occurrence
Outcome Time Frame
From date of transplant until 1 year
Secondary Ids
Secondary Id
2018-003867-79
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Percentage of Participants Who Were Positive, Negative or Indeterminate for dnDSA Occurrence
Outcome Description
Peak MFI of DSA positive participants was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Peak Mean Fluorescence Intensity (MFI) of DSA Positive Participants
Outcome Description
DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching MFI=1000 at any time during the study.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Percentage of DSA Positive Participants With Weak, Moderate and Strong Antibody Strentgh
Outcome Description
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.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Percentage of DSA Positive Participants With DSA Persistence
Outcome Description
Percentage of participants who were positive or negative for C1q-binding DSA were reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Percentage of Participants Who Were Positive or Negative for Complement Component 1, Q Subcomponent (C1q)-Binding DSA
Outcome Description
Percentage of participants who were positive or negative for IgG3 isotype were reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Percentage of Participants Who Were Positive or Negative for DSA Immunoglobulin G (IgG3) Isotype
Outcome Description
Percentage of DSA positive participants with HLA-DQ Class-II were reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Percentage of DSA Positive Participants With Human Leukocyte Antigen, Class II, DQ Locus (HLA-DQ)
Outcome Description
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.
Outcome Time Frame
From day 1 to day 365 visit
Outcome Measure
Percentage of Participants Who Were Positive for IA Occurrence From Day 1 to Day 365 Visit
Outcome Description
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.
Outcome Time Frame
From day 30 to day 365 visit
Outcome Measure
Percentage of Participants Who Were Positive for IA Occurrence From Day 30 to Day 365 Visit
Outcome Description
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.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Percentage of Participants With IA Persistence
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Presence of Transplant Glomerulopathy (TG) on Biopsy
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Presence of Microcirculatory Inflammation (MI) on Biopsy
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Presence of Interstitial Fibrosis and Tubular Atrophy (IFTA) and Inflammation on Biopsy
Outcome Description
The eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) formula.
Outcome Time Frame
At 1 year post transplant
Outcome 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)
Outcome Description
The eGFR was calculated using the MDRD formula.
Outcome Time Frame
At 1 year post transplant
Outcome Measure
Percentage of Participants With eGFR Threshold of <40 mL/Min/1.73m^2
Outcome Description
The eGFR was calculated using the MDRD formula.
Outcome Time Frame
At 1 year post transplant
Outcome Measure
Percentage of Participants With eGFR Threshold of <50 mL/Min/1.73m^2
Outcome Description
The eGFR was calculated using the MDRD formula.
Outcome Time Frame
From 30 days post transplant until 1 year
Outcome Measure
Percentage of Participants With a Five-point Decline in eGFR
Outcome Description
The eGFR was calculated using the MDRD formula.
Outcome Time Frame
Day 30, day 90, day 180, day 270 and day 365
Outcome Measure
eGFR at Day 30, Day 90, Day 180, Day 270 and Day 365
Outcome Description
Graft loss was defined as re-transplantation, transplant nephrectomy, or a return to dialysis for at least a six week duration, or participants' death.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Percentage of Participants With Graft Loss
Outcome Description
Percentage of participants who died were reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Percentage of Participants Who Died
Outcome Description
Positivity was determined by local biopsy, central pathology, or reported adverse events.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR)
Outcome Description
Percentage of participants who were lost to follow-up were reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Percentage of Participants Who Were Lost to Follow-up
Outcome Description
Percentage of participants with either graft loss, death, BPAR or lost to follow-up were reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Percentage of Participants With Either Graft Loss, Death, BPAR or Lost to Follow-up
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Any Antibody-Mediated Rejection (ABMR)
Outcome Description
Percentage of participants with normal biopsy findings were reported.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Normal Biopsy Findings
Outcome Description
Percentage of participants with C4d deposition without active rejection were reported.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With C4d Deposition Without Active Rejection
Outcome Description
Percentage of participants with acute ABMR were reported.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Acute ABMR
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Grade I, II and III Acute ABMR
Outcome Description
Percentage of participants with chronic ABMR were reported.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Chronic ABMR
Outcome Description
Percentage of participants with borderline changes were reported.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Borderline Changes
Outcome Description
Percentage of participants with acute TCMR were reported.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Acute T-cell Mediated Rejection (TCMR)
Outcome Description
Percentage of participants with chronic TCMR were reported.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Chronic TCMR
Outcome Description
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).
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Grade I, II and III IFTA
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Any Additional Findings
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Glomerulitis (g) Biopsy Score Assessed Using Banff Lesion Scores
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Tubulitis (t) Biopsy Score Assessed Using Banff Lesion Scores
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Intimal Arteritis (v) Biopsy Score Assessed Using Banff Lesion Scores
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Mononuclear Cell Interstitial Inflammation (i) Biopsy Score Assessed Using Banff Lesion Scores
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Glomerular Basement Membrane Double Contours (cg) Biopsy Score Assessed Using Banff Lesion Scores
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Tubular Atrophy (ct) Biopsy Score Assessed Using Banff Lesion Scores
Outcome Description
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).
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Interstitial Fibrosis (ci) Biopsy Score Assessed Using Banff Lesion Scores
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Vascular Fibrous Intimal Thickening (cv) Biopsy Score Assessed Using Banff Lesion Scores
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Arteriolar Hyalinosis (ah) Biopsy Score Assessed Using Banff Lesion Scores
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Peritubular Capillaritis (Ptc) Biopsy Score Assessed Using Banff Lesion Scores
Outcome Description
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.
Outcome Time Frame
From date of transplant until month 14
Outcome Measure
Percentage of Participants With Mesangial Matrix Expansion (mm) Biopsy Score Assessed Using Banff Lesion Scores
Outcome Description
DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching MFI=1000 at any time during the study.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of DSA
Outcome Description
Time to first occurrence of HLA-DQ DSA was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of HLA-DQ DSA
Outcome Description
Time to first occurrence of C1q-binding DSA was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of C1q-binding DSA
Outcome Description
Time to first occurrence of DSA IgG3 isotype was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of DSA IgG3 Isotype
Outcome Description
Time to first occurrence of IA was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of IA
Outcome Description
Time to first occurrence of TG on biopsy was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of TG on Biopsy
Outcome Description
Time to occurrence of death was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to Occurrence of Death
Outcome Description
Time to first occurrence of local BPAR was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of Local BPAR
Outcome Description
Time to first occurrence of acute forms of ABMR was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of Acute Forms of ABMR
Outcome Description
Time to first occurrence of chronic forms of ABMR was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of Chronic Forms of ABMR
Outcome Description
Time to first occurrence of acute TCMR was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of Acute TCMR
Outcome Description
Time to first occurrence of chronic TCMR was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of Chronic TCMR
Outcome Description
Time to first occurrence of borderline changes was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of Borderline Changes
Outcome Description
Time to first occurrence of IFTA was reported.
Outcome Time Frame
From date of transplant until 1 year
Outcome Measure
Time to First Occurrence of IFTA
Outcome Description
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.
Outcome Time Frame
From first dose of study drug up to 7 days after last dose of study drug (up to 2 years)
Outcome 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
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
70
Minimum Age Number (converted to Years and rounded down)
16
Investigators
Investigator Type
Principal Investigator
Investigator Name
Enver Akalin
Investigator Email
eakalin@montefiore.org
Investigator Phone
718-920-4815