Kidney TransplantationPhase 4ASTOUNDNCT02723591
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
A Phase 4 study testing Tacrolimus and Tacrolimus immediate release in people with Kidney Transplantation, run by Astellas Pharma Global Development, Inc. at 30 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 16 to 70 years
- Conditions the study is for
- Kidney Transplantation
- What is being tested?
- Tacrolimus and Tacrolimus immediate release
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 599 participants
- Where
- 30 sitesUnited States
- Study dates
- 9 Sep 2016to 14 Jun 2019
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 to 70 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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:
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
30 sites in 1 country.
30 sites in 1 country
United States30 sites
Site US10013
Ann Arbor, Michigan, 48109
Site US10024
Aurora, Colorado, 80045
Site US10001
Baltimore, Maryland, 21201
Site US10006
Birmingham, Alabama, 35294
Site US10007
Boston, Massachusetts, 02114
Site US10004
Buffalo, New York, 14215
Site US10002
Charleston, South Carolina, 29425
Site US10012
Charlottesville, Virginia, 22903
Site US10020
Chicago, Illinois, 60605
Site US10010
Chicago, Illinois, 60611
Site US10032
Detroit, Michigan, 48202
Site US10008
Falls Church, Virginia, 22042
Site US10036
Houston, Texas, 77030
Site US10030
Jacksonville, Florida, 32224
Site US10019
Livingston, New Jersey, 07039
Site US10031
Los Angeles, California, 90033
Site US10023
Madison, Wisconsin, 53792
Site US10029
Minneapolis, Minnesota, 55455
Site US10003
New Haven, Connecticut, 06510
Site US10037
New York, New York, 10032
Site US10022
New York, New York, 10065
Site US10028
New York, New York, 10467
Site US10026
Portland, Oregon, 97210
Site US10027
Rochester, Minnesota, 55905
Site US10005
Sacramento, California, 95817
Site US10018
Salt Lake City, Utah, 84112
Site US10016
San Francisco, California, 94115
Site US10025
Scottsdale, Arizona, 85259
Site US10021
Syracuse, New York, 13210
Site US10014
Washington D.C., District of Columbia, 20007
About this study
Official title: Astagraf XL® to Understand the Impact of Immunosuppression on De Novo DSA Development and Chronic Immune Activation in Kidney Transplantation
This study compared the incidence of a two-part composite endpoint consisting of de novo donor specific antibody (DSA) formation or a designation of immune activation (IA) on peripheral blood molecular profiling in participants maintained on twice daily, immediate-release tacrolimus versus those maintained on Astagraf XL in the first year post-transplant.
Read the 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.
- Conditions
- Kidney Transplantation
- Being tested
- Tacrolimus, Tacrolimus immediate release
- Keywords
- FK506, Kidney Transplantation, Tacrolimus, Astagraf XL
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TacrolimusDrug
Also called Advagraf, FK506E, Astagraf XL
Oral Capsule
Tacrolimus immediate releaseDrug
Also called FK506, Prograf, generic immediate release tacrolimus
Oral Capsule
| Study group | Role | What they receive |
|---|---|---|
| Tacrolimus, Extended Release (Astagraf XL®) Once Daily | Active comparator | 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. Receives: Drug: Tacrolimus |
| Tacrolimus, Immediate Release Twice Daily (BID) | Active comparator | 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. Receives: Drug: Tacrolimus immediate release |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants Who Were Positive for de Novo DSA (dnDSA) or Immune Activation (IA) Occurrence
DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching mean fluorescence intensity (MFI)=1000 at any time during the study. IA was considered either present or absent using the Trugraf™ v2.0 molecular assay. A negative designation (Trugraf TX Normal) was referred to as Immune Quiescence (IQ). Due to operating characteristics of the assay, a positive designation was considered evidence of IA in all participants.
Measured: From date of transplant until 1 year
Secondary outcomes (60)
Percentage of Participants Who Were Positive, Negative or Indeterminate for dnDSA Occurrence
DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching MFI=1000 at any time during the study. Indeterminate was defined as MFI signal was >1000 and DSA was suspected, but could not be confirmed due to inadequate donor typing. Participants whose samples for the test were not available were reported as unknown.
Measured: From date of transplant until 1 year
Peak Mean Fluorescence Intensity (MFI) of DSA Positive Participants
Peak MFI of DSA positive participants was reported.
Measured: From date of transplant until 1 year
Percentage of DSA Positive Participants With Weak, Moderate and Strong Antibody Strentgh
DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching MFI=1000 at any time during the study.
Measured: From date of transplant until 1 year
Percentage of DSA Positive Participants With DSA Persistence
DSA was regarded as persistent under the following conditions: (i) DSA was detected and remained above the threshold for positivity (MFI = 1000) for two consecutive or nonconsecutive measurements, or (ii) the new appearance of a DSA at the threshold for positivity when preceded by a DSA of a different specificity that had subsequently become non-detectable.
Measured: From date of transplant until 1 year
Percentage of Participants Who Were Positive or Negative for Complement Component 1, Q Subcomponent (C1q)-Binding DSA
Percentage of participants who were positive or negative for C1q-binding DSA were reported.
Measured: From date of transplant until 1 year
Percentage of Participants Who Were Positive or Negative for DSA Immunoglobulin G (IgG3) Isotype
Percentage of participants who were positive or negative for IgG3 isotype were reported.
Measured: From date of transplant until 1 year
Percentage of DSA Positive Participants With Human Leukocyte Antigen, Class II, DQ Locus (HLA-DQ)
Percentage of DSA positive participants with HLA-DQ Class-II were reported.
Measured: From date of transplant until 1 year
Percentage of Participants Who Were Positive for IA Occurrence From Day 1 to Day 365 Visit
IA was considered either present or absent using the Trugraf™ v2.0 molecular assay. A negative designation (Trugraf TX Normal) was referred to as Immune Quiescence (IQ). Due to operating characteristics of the assay, a positive designation was considered evidence of IA in all participants.
Measured: From day 1 to day 365 visit
Percentage of Participants Who Were Positive for IA Occurrence From Day 30 to Day 365 Visit
IA was considered either present or absent using the Trugraf™ v2.0 molecular assay. A negative designation (Trugraf TX Normal) was referred to as Immune Quiescence (IQ). Due to operating characteristics of the assay, a positive designation was considered evidence of IA in all participants.
Measured: From day 30 to day 365 visit
Percentage of Participants With IA Persistence
IA was regarded as persistent under the following conditions: (i) IA was detected and remained above the threshold for positivity for two consecutive or non-consecutive measurements, or (ii) the new appearance of an IA at the threshold for positivity when preceded by an IA of a different specificity that had subsequently become non-detectable.
Measured: From date of transplant until 1 year
Percentage of Participants With Presence of Transplant Glomerulopathy (TG) on Biopsy
TG was defined as chronic glomerulopathy (cg) >0 on centrally-interpreted institutional protocol biopsy or biopsy obtained for cause during the first year post-transplant with +2 months visit window.
Measured: From date of transplant until month 14
Percentage of Participants With Presence of Microcirculatory Inflammation (MI) on Biopsy
MI was defined as glomerulitis (g) + peritubular capillaritis (ptc)>=2 on centrally-interpreted institutional protocol biopsy or biopsy obtained for cause during the first year post-transplant, with +2 months visit window.
Measured: From date of transplant until month 14
Percentage of Participants With Presence of Interstitial Fibrosis and Tubular Atrophy (IFTA) and Inflammation on Biopsy
IFTA and inflammation was defined as IFTA positive and inflammation positive (i >0) on centrally-interpreted institutional protocol biopsy or biopsy obtained for cause during the first year posttransplant, with +2 months visit window.
Measured: From date of transplant until month 14
Percentage of Participants With Estimated Glomerular Filtration Rate (eGFR) Threshold of <30 Millimetre Per Minute Per 1.73 Meter Square (mL/Min/1.73m^2)
The eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) formula.
Measured: At 1 year post transplant
Percentage of Participants With eGFR Threshold of <40 mL/Min/1.73m^2
The eGFR was calculated using the MDRD formula.
Measured: At 1 year post transplant
Percentage of Participants With eGFR Threshold of <50 mL/Min/1.73m^2
The eGFR was calculated using the MDRD formula.
Measured: At 1 year post transplant
Percentage of Participants With a Five-point Decline in eGFR
The eGFR was calculated using the MDRD formula.
Measured: From 30 days post transplant until 1 year
eGFR at Day 30, Day 90, Day 180, Day 270 and Day 365
The eGFR was calculated using the MDRD formula.
Measured: Day 30, day 90, day 180, day 270 and day 365
Percentage of Participants With Graft Loss
Graft loss was defined as re-transplantation, transplant nephrectomy, or a return to dialysis for at least a six week duration, or participants' death.
Measured: From date of transplant until 1 year
Percentage of Participants Who Died
Percentage of participants who died were reported.
Measured: From date of transplant until 1 year
Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR)
Positivity was determined by local biopsy, central pathology, or reported adverse events.
Measured: From date of transplant until 1 year
Percentage of Participants Who Were Lost to Follow-up
Percentage of participants who were lost to follow-up were reported.
Measured: From date of transplant until 1 year
Percentage of Participants With Either Graft Loss, Death, BPAR or Lost to Follow-up
Percentage of participants with either graft loss, death, BPAR or lost to follow-up were reported.
Measured: From date of transplant until 1 year
Percentage of Participants With Any Antibody-Mediated Rejection (ABMR)
Percentage of participants with ABMR were reported. Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. A positive assessment is defined as antibody mediated changes that are diagnosed as either acute ABMR or chronic active ABMR.
Measured: From date of transplant until month 14
Percentage of Participants With Normal Biopsy Findings
Percentage of participants with normal biopsy findings were reported.
Measured: From date of transplant until month 14
Percentage of Participants With C4d Deposition Without Active Rejection
Percentage of participants with C4d deposition without active rejection were reported.
Measured: From date of transplant until month 14
Percentage of Participants With Acute ABMR
Percentage of participants with acute ABMR were reported.
Measured: From date of transplant until month 14
Percentage of Participants With Grade I, II and III Acute ABMR
Percentage of participants with grade I, II and III acute ABMR were reported. Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Acute ABMR was graded as Grade I: acute tubular necrosis-like -like minimal inflammation, Grade II: Capillary and or glomerular inflammation (ptc/g >0) and/or thromboses, and Grade III: arterial - v3.
Measured: From date of transplant until month 14
Percentage of Participants With Chronic ABMR
Percentage of participants with chronic ABMR were reported.
Measured: From date of transplant until month 14
Percentage of Participants With Borderline Changes
Percentage of participants with borderline changes were reported.
Measured: From date of transplant until month 14
Percentage of Participants With Acute T-cell Mediated Rejection (TCMR)
Percentage of participants with acute TCMR were reported.
Measured: From date of transplant until month 14
Percentage of Participants With Chronic TCMR
Percentage of participants with chronic TCMR were reported.
Measured: From date of transplant until month 14
Percentage of Participants With Grade I, II and III IFTA
Percentage of participants with Grade I, II and III IFTA were reported. Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. IFTA was graded as Grade I: mild interstitial fibrosis and tubular atrophy (<25% of cortical area), Grade II: moderate interstitial fibrosis and tubular atrophy (26-50% of cortical area), and Grade III: severe interstitial fibrosis and tubular atrophy/ loss (>50% of cortical area).
Measured: From date of transplant until month 14
Percentage of Participants With Any Additional Findings
Percentage of participants with any additional findings (other than Normal biopsy, borderline changes, acute and chronic ABMR, Grade I, II, and III ABMR, C4D deposition, acute and chronic TCMR, Grade I, II, and III TCMR, Grade I, II and III IFTA, acute tubular necrosis, interstitial nephritis, pyelonephritis, bk virus, calcineurin inhibitor toxicity, hemolytic uremic syndrome and recurrent disease) were reported.
Measured: From date of transplant until month 14
Percentage of Participants With Glomerulitis (g) Biopsy Score Assessed Using Banff Lesion Scores
Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No glomerulitis, Score 1= <25% glomerulitis, Score 2= 25 to 75% glomerulitis and Score 3= >75% glomerulitis.
Measured: From date of transplant until month 14
Percentage of Participants With Tubulitis (t) Biopsy Score Assessed Using Banff Lesion Scores
Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No mononuclear cells in tubules or single focus of tubulitis only, Score 1= Foci with 1 to 4 mononuclear cells/tubular cross section (or 10 tubular cells), Score 2= Foci with 5 to 10 mononuclear cells/tubular cross section (or 10 tubular cells) and Score 3= Foci with >10 mononuclear cells/tubular cross section or the presence of ≥2 areas of tubular basement membrane destruction accompanied by i2/i3 inflammation and t2 elsewhere.
Measured: From date of transplant until month 14
Percentage of Participants With Intimal Arteritis (v) Biopsy Score Assessed Using Banff Lesion Scores
Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No arteritis, Score 1= Mild to moderate intimal arteritis in at least 1 arterial cross section, Score 2= Severe intimal arteritis with at least 25% luminal area lost in at least 1 arterial cross section and Score 3= Transmural arteritis and/or arterial fibrinoid change and medial smooth muscle necrosis with lymphocytic infiltrate in vessel.
Measured: From date of transplant until month 14
Percentage of Participants With Mononuclear Cell Interstitial Inflammation (i) Biopsy Score Assessed Using Banff Lesion Scores
Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No inflammation or in less than 10% of unscarred cortical parenchyma, Score 1= Inflammation in 10 to 25% of unscarred cortical parenchyma, Score 2= Inflammation in 26 to 50% of unscarred cortical parenchyma and Score 3= Inflammation in more than 50% of unscarred cortical parenchyma.
Measured: From date of transplant until month 14
Percentage of Participants With Glomerular Basement Membrane Double Contours (cg) Biopsy Score Assessed Using Banff Lesion Scores
Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No GBM double contours by light microscopy (LM) or electron microscopy (EM), Score 1= No GBM double contours by LM but GBM double contours (incomplete or circumferential) in at least 3 glomerular capillaries by EM or Double contours of the GBM in 1-25% of capillary loops in the most affected nonsclerotic glomerulus by LM , Score 2= Double contours affecting 26 to 50% of peripheral capillary loops in the most affected-glomerulus and Score 3= Double contours affecting more than 50% of peripheral capillary loops in the most affected-glomerulus.
Measured: From date of transplant until month 14
Percentage of Participants With Tubular Atrophy (ct) Biopsy Score Assessed Using Banff Lesion Scores
Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No tubular atrophy, Score 1= Tubular atrophy involving up to 25% of the area of cortical tubules, Score 2= Tubular atrophy involving 26 to 50% of the area of cortical tubules and Score 3= Tubular atrophy involving in >50% of the area of cortical tubules.
Measured: From date of transplant until month 14
Percentage of Participants With Interstitial Fibrosis (ci) Biopsy Score Assessed Using Banff Lesion Scores
Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= Interstitial fibrosis in up to 5% of cortical area, Score 1= Interstitial fibrosis in 6 to 25%of cortical area (mild interstitial fibrosis), Score 2= Interstitial fibrosis in 26 to 50% of cortical area (moderate interstitial fibrosis) and Score 3= Interstitial fibrosis in >50% of cortical area (severe interstitial fibrosis).
Measured: From date of transplant until month 14
Percentage of Participants With Vascular Fibrous Intimal Thickening (cv) Biopsy Score Assessed Using Banff Lesion Scores
Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No chronic vascular changes, Score 1= Vascular narrowing of up to 25% luminal area by fibrointimal thickening, Score 2= Vascular narrowing of 26 to 50% luminal area by fibrointimal thickening and Score 3= Vascular narrowing of more than 50% luminal area by fibrointimal thickening.
Measured: From date of transplant until month 14
Percentage of Participants With Arteriolar Hyalinosis (ah) Biopsy Score Assessed Using Banff Lesion Scores
Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No periodic acid-Schiff (PAS)-positive hyaline arteriolar thickening, Score 1= Mild to moderate PAS-positive hyaline thickening in at least 1 arteriole, Score 2= Moderate to severe PAS-positive hyaline thickening in more than 1 arteriole and Score 3= Severe PAS-positive hyaline thickening in many arterioles.
Measured: From date of transplant until month 14
Percentage of Participants With Peritubular Capillaritis (Ptc) Biopsy Score Assessed Using Banff Lesion Scores
Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= Maximum number of leukocytes <3, Score 1= At least 1 leukocyte cell in ≥10% of cortical PTCs with 3-4 leukocytes in most severely involved PTC, Score 2= At least 1 leukocyte in ≥10% of cortical PTC with 5-10 leukocytes in most severely involved PTC and Score 3= At least 1 leukocyte in ≥10% of cortical PTC with >10 leukocytes in most severely involved PTC.
Measured: From date of transplant until month 14
Percentage of Participants With Mesangial Matrix Expansion (mm) Biopsy Score Assessed Using Banff Lesion Scores
Central pathology reading was performed as per the 2007 Update to the Banff '97 classification. Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. [Roufosse C et. al 2018]. Here, Score 0= No more than mild mesangial matrix increase in any glomerulus, Score 1= At least moderate mesangial matrix increase in up to 25% of nonsclerotic glomeruli, Score 2= At least moderate mesangial matrix increase in 26% to 50% of nonsclerotic glomeruli and Score 3= At least moderate mesangial matrix increase in >50% of nonsclerotic glomeruli.
Measured: From date of transplant until month 14
Time to First Occurrence of DSA
DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching MFI=1000 at any time during the study.
Measured: From date of transplant until 1 year
Time to First Occurrence of HLA-DQ DSA
Time to first occurrence of HLA-DQ DSA was reported.
Measured: From date of transplant until 1 year
Time to First Occurrence of C1q-binding DSA
Time to first occurrence of C1q-binding DSA was reported.
Measured: From date of transplant until 1 year
Time to First Occurrence of DSA IgG3 Isotype
Time to first occurrence of DSA IgG3 isotype was reported.
Measured: From date of transplant until 1 year
Time to First Occurrence of IA
Time to first occurrence of IA was reported.
Measured: From date of transplant until 1 year
Time to First Occurrence of TG on Biopsy
Time to first occurrence of TG on biopsy was reported.
Measured: From date of transplant until 1 year
Time to Occurrence of Death
Time to occurrence of death was reported.
Measured: From date of transplant until 1 year
Time to First Occurrence of Local BPAR
Time to first occurrence of local BPAR was reported.
Measured: From date of transplant until 1 year
Time to First Occurrence of Acute Forms of ABMR
Time to first occurrence of acute forms of ABMR was reported.
Measured: From date of transplant until 1 year
Time to First Occurrence of Chronic Forms of ABMR
Time to first occurrence of chronic forms of ABMR was reported.
Measured: From date of transplant until 1 year
Time to First Occurrence of Acute TCMR
Time to first occurrence of acute TCMR was reported.
Measured: From date of transplant until 1 year
Time to First Occurrence of Chronic TCMR
Time to first occurrence of chronic TCMR was reported.
Measured: From date of transplant until 1 year
Time to First Occurrence of Borderline Changes
Time to first occurrence of borderline changes was reported.
Measured: From date of transplant until 1 year
Time to First Occurrence of IFTA
Time to first occurrence of IFTA was reported.
Measured: From date of transplant until 1 year
Percentage of Participants With Treatment-emergent Adverse Event(TEAEs), Related TEAEs, Treatment-emergent Serious Adverse Event (TESAEs), Related TESAEs, TEAEs Leading to Discontinuation of Study Treatment and TEAEs Leading to Death
A TEAE was defined as an Adverse Event (AE) observed on or after the day of starting the administration of the test drug/comparative drug.
Measured: From first dose of study drug up to 7 days after last dose of study drug (up to 2 years)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Mar 2016 (estimated)
- Study start9 Sep 2016
- Primary completion14 Jun 2019
- Study completion14 Jun 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Kidney TransplantationStudies of the same condition, open and under way.
- More trials run by Astellas Pharma Global Development, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 599 participants (actual)
Sponsor and investigators
- Lead sponsor
- Astellas Pharma Global Development, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Monitor, Study director, Astellas Medical Affairs, Americas
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02723591
- Sponsor's protocol ID
- IDTX-MA-3004
- Other IDs
- 2018-003867-79, 2018
- Acronym
- ASTOUND
- Status last verified
- Nov 2024
- First submitted
- 3 Mar 2016
- Last updated
- 18 Dec 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- Yes: 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 products 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. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
Study at a glance
From the registry record, last updated by the sponsor on 18 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Astagraf XL® to Understand the Impact of Immunosuppression on De Novo DSA Development and Chronic Immune Activation in Kidney Transplantation
- ClinicalTrials.gov ID
- NCT02723591
- Acronym / sponsor ID
- ASTOUND / IDTX-MA-3004
- Conditions
- Kidney Transplantation
- Keywords
- FK506, Kidney Transplantation, Tacrolimus, Astagraf XL
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 599 participants (actual)
- Lead sponsor
- Astellas Pharma Global Development, Inc.Industry (pharma, biotech, devices)
- Study start
- 9 Sep 2016 (actual)
- Primary completion
- 14 Jun 2019 (actual)
- Study completion
- 14 Jun 2019 (actual)
- First posted
- 30 Mar 2016 (estimated)
- Results
- Posted 29 Jun 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tacrolimus, Extended Release (Astagraf XL®) Once Daily | Active comparator | Drug: TacrolimusParticipants 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. |
| Tacrolimus, Immediate Release Twice Daily (BID) | Active comparator | Drug: Tacrolimus immediate releaseParticipants 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. |
Who may qualify
- Ages
- 16 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (12 listed)
- 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.
Key exclusion criteria (26 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TacrolimusAlso: Advagraf, FK506E, Astagraf XLOral Capsule | Drug | Tacrolimus, Extended Release (Astagraf XL®) Once Daily |
| Tacrolimus immediate releaseAlso: FK506, Prograf, generic immediate release tacrolimusOral Capsule | Drug | Tacrolimus, Immediate Release Twice Daily (BID) |
Primary outcome
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.
60 secondary outcomes
Percentage of Participants Who Were Positive, Negative or Indeterminate for dnDSA Occurrence
Time frame: From date of transplant until 1 year
Peak Mean Fluorescence Intensity (MFI) of DSA Positive Participants
Time frame: From date of transplant until 1 year
Percentage of DSA Positive Participants With Weak, Moderate and Strong Antibody Strentgh
Time frame: From date of transplant until 1 year
Percentage of DSA Positive Participants With DSA Persistence
Time frame: From date of transplant until 1 year
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 DSA Immunoglobulin G (IgG3) Isotype
Time frame: From date of transplant until 1 year
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 Participants Who Were Positive for IA Occurrence From Day 1 to Day 365 Visit
Time frame: From day 1 to day 365 visit
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
Percentage of Participants With IA Persistence
Time frame: From date of transplant until 1 year
Percentage of Participants With Presence of Transplant Glomerulopathy (TG) on Biopsy
Time frame: From date of transplant until month 14
Percentage of Participants With Presence of Microcirculatory Inflammation (MI) on Biopsy
Time frame: From date of transplant until month 14
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
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
Percentage of Participants With eGFR Threshold of <40 mL/Min/1.73m^2
Time frame: At 1 year post transplant
Percentage of Participants With eGFR Threshold of <50 mL/Min/1.73m^2
Time frame: At 1 year post transplant
Percentage of Participants With a Five-point Decline in eGFR
Time frame: From 30 days post transplant until 1 year
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
Percentage of Participants With Graft Loss
Time frame: From date of transplant until 1 year
Percentage of Participants Who Died
Time frame: From date of transplant until 1 year
Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR)
Time frame: From date of transplant until 1 year
Percentage of Participants Who Were 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
Time frame: From date of transplant until 1 year
Percentage of Participants With Any Antibody-Mediated Rejection (ABMR)
Time frame: From date of transplant until month 14
Percentage of Participants With Normal Biopsy Findings
Time frame: From date of transplant until month 14
Percentage of Participants With C4d Deposition Without Active Rejection
Time frame: From date of transplant until month 14
Percentage of Participants With Acute ABMR
Time frame: From date of transplant until month 14
Percentage of Participants With Grade I, II and III Acute ABMR
Time frame: From date of transplant until month 14
Percentage of Participants With Chronic ABMR
Time frame: From date of transplant until month 14
Percentage of Participants With Borderline Changes
Time frame: From date of transplant until month 14
Percentage of Participants With Acute T-cell Mediated Rejection (TCMR)
Time frame: From date of transplant until month 14
Percentage of Participants With Chronic TCMR
Time frame: From date of transplant until month 14
Percentage of Participants With Grade I, II and III IFTA
Time frame: From date of transplant until month 14
Percentage of Participants With Any Additional Findings
Time frame: From date of transplant until month 14
Percentage of Participants With Glomerulitis (g) Biopsy Score Assessed Using Banff Lesion Scores
Time frame: From date of transplant until month 14
Percentage of Participants With Tubulitis (t) Biopsy Score Assessed Using Banff Lesion Scores
Time frame: From date of transplant until month 14
Percentage of Participants With Intimal Arteritis (v) Biopsy Score Assessed Using Banff Lesion Scores
Time frame: From date of transplant until month 14
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
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
Percentage of Participants With Tubular Atrophy (ct) Biopsy Score Assessed Using Banff Lesion Scores
Time frame: From date of transplant until month 14
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Dec 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes. 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 products 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. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Monitor study director
Astellas Medical Affairs, Americas
30 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Tacrolimus and Tacrolimus immediate release in people with Kidney Transplantation, run by Astellas Pharma Global Development, Inc. at 30 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 30 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Jun 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Dec 2024.