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To Compare the Effects of Immediate-release Tacrolimus and Astagraf XL on Donor-Specific Antibody (DSA) Formation and the Development of Immune Activation (IA) in de Novo Kidney Transplant Recipients (ASTOUND)

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ClinicalTrials.gov Identifier: NCT02723591
Recruitment Status : Recruiting
First Posted : March 30, 2016
Last Update Posted : September 25, 2018
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Brief Summary:
This study will compare 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 patients maintained on twice daily, immediate-release tacrolimus versus those maintained on Astagraf XL in the first two years post-transplant.

Condition or disease Intervention/treatment Phase
Kidney Transplantation Drug: Tacrolimus Drug: Tacrolimus immediate release Phase 4

Detailed Description:

This is an exploratory, two year, 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 is 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 immune activation (IA) in de novo kidney transplant recipients during the first two years following transplantation. For the purposes of this study, IA will be defined as a molecular signature indicating either clinical acute rejection (cAR) or subacute rejection (subAR).

Patients will be 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 are encouraged to start subjects on the randomized study treatment (immediate release tacrolimus or Astagraf XL) within 48 hours of transplantation (pre-transplant administration of study treatment is not allowed). However, if medically indicated per the treating physician's discretion, initiation of study treatment may be delayed for up to seven days post-transplant.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 550 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Astagraf XL® to Understand the Impact of Immunosuppression on De Novo DSA Development and Chronic Immune Activation in Kidney Transplantation
Actual Study Start Date : September 9, 2016
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Tacrolimus

Arm Intervention/treatment
Active Comparator: Tacrolimus, extended release (Astagraf XL®)
Astagraf XL (once daily)
Drug: Tacrolimus
Oral
Other Names:
  • Advagraf
  • FK506E
  • Astagraf XL

Active Comparator: Tacrolimus, immediate release
Prograf (twice daily), generic immediate release tacrolimus (twice daily)
Drug: Tacrolimus immediate release
Oral
Other Names:
  • FK506
  • Prograf
  • generic immediate release tacrolimus




Primary Outcome Measures :
  1. Combined incidence of DSA or IA on peripheral blood molecular profiling [ Time Frame: At 1 year post transplant or EOS (up to 2 years post transplant) ]
    DSA considered as a binary variable (positive or negative), with positivity based on a threshold criteria of Mean Fluorescence Intensity approaching 1000. Immune Activation (IA): considered as a binary variable (present or absent) based on validated molecular signatures. End of study (EOS)


Secondary Outcome Measures :
  1. Incidence of DSA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    DSA considered as a binary variable (positive or negative), with positivity based on a threshold criteria of Mean Fluorescence Intensity approaching 1000

  2. Incidence of IA (inclusive of cAR and subAR) [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    IA considered as a binary variable (present or absent) based on validated molecular signatures

  3. Incidence of TG on biopsy [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    TG: Transplant Glomerulopathy

  4. Incidence of acute and chronic forms of ABMR on biopsy [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Antibody-mediated rejection (ABMR)

  5. Incidence of C1q-binding DSA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    Complement Component 1, Q Subcomponent-binding DSA (C1q-binding DSA). Assessed in subjects who are DSA positive. Considered as a binary variable (positive or negative)

  6. Incidence of HLA-DQ DSA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    Human Leukocyte Antigen, Class II, DQ locus DSA (HLA-DQ DSA). Assessed in subjects who are DSA positive

  7. Incidence of DSA IgG3 isotype [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    DSA Immunoglobulin G3 (DSA IgG3). Assessed in subjects who are DSA positive

  8. Incidence of required antibody reduction [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    The requirement for and type of antibody reduction required

  9. Incidence of eGFR threshold of less than 30 mL/min/1.73m2 [ Time Frame: From 30 days post transplant until EOS (up to 2 years post transplant) ]
    Estimated Glomerular Filtration Rate (eGFR)

  10. Incidence of eGFR threshold of less than 40 mL/min/1.73m2 [ Time Frame: From 30 days post transplant until EOS (up to 2 years post transplant) ]
    Estimated Glomerular Filtration Rate (eGFR)

  11. Incidence of eGFR threshold of less than 50 mL/min/1.73m2 [ Time Frame: From 30 days post transplant until EOS (up to 2 years post transplant) ]
    Estimated Glomerular Filtration Rate (eGFR)

  12. Incidence of graft loss [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Graft loss is defined as subject death, retransplantation, transplant nephrectomy, or a return to dialysis for at least a 6 week duration

  13. Incidence of death [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Subject death

  14. Incidence of local BPAR (inclusive of ABMR and TCMR) [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Biopsy-proven acute rejection (BPAR). Antibody Mediated Rejection (ABMR). T-cell Mediated Rejection (TCMR)

  15. Incidence of loss to follow up [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Lost to follow up is defined as a subject failing to complete their final study visit no more than 30 days prior to the scheduled visit, and without prior incidence of local BPAR, graft loss, or death

  16. Time to first occurrence of DSA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Donor Specific Antibody (DSA)

  17. Time to first occurrence of HLA-DQ DSA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Human Leukocyte Antigen, Class II, DQ locus Donor Specific Antibody (HLA-DQ DSA)

  18. Time to first occurrence of C1q-binding DSA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Complement component C1q-binding Donor Specific Antibody

  19. Time to first occurrence of DSA IgG3 isotype [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Immunoglobulin G3 Donor Specific Antibody (IgG3 DSA)

  20. Time to first occurrence of IA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Immune Activation (IA)

  21. Time to first occurrence of TG on biopsy [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Transplant Glomerulopathy (TG)

  22. Time to first occurrence of mortality [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Subject death

  23. Time to first occurrence of local BPAR [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Biopsy-proven acute rejection

  24. Assessment of the frequency of the type of antibody reduction employed [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    The ordinal strength of antibody reduction therapy will be summarized using frequencies

  25. Assessment of participant MFI values [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Mean Fluorescence Intensity (MFI). Through assessment of MFI between treatment groups

  26. Assessment of participant eGFR values [ Time Frame: From 30 days post transplant until EOS (up to 2 years post transplant) ]
    Through assessment of eGFR between treatment groups

  27. Incidence of ci scores greater than one [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Interstitial fibrosis scores (ci scores). Per Banff criteria

  28. Incidence of ct scores greater than one [ Time Frame: From date of transplant until EOS (up to 2 years post transplant] ]
    Tubular atrophy scores (ct scores). Per Banff criteria

  29. Incidence of ptc scores greater than one [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Peritubular capillaritis scores (ptc scores). Per Banff criteria

  30. Biopsy scores for g [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Early allograft glomerulitis scores (g scores). Per Banff criteria

  31. Biopsy scores for t [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Tubulitis scores (t scores). Per Banff criteria

  32. Biopsy scores for v [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Intimal arteritis scores (v scores). Per Banff criteria

  33. Biopsy scores for i [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Early monocellular interstitial inflammation scores (i scores). Per Banff criteria

  34. Biopsy scores for cg [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Allograft glomerulopathy scores (cg scores). Per Banff criteria

  35. Biopsy scores for ct [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Tubular atrophy scores (ct scores). Per Banff criteria

  36. Biopsy scores for ci [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Interstitial fibrosis scores (ci scores). Per Banff criteria

  37. Biopsy scores for cv [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Vascular fibrous intimal thickening scores (cv scores). Per Banff criteriaVascular fibrous intimal thickening scores (cv scores). Per Banff criteria

  38. Biopsy scores for ah [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Arteriolar hyaline thickening scores (ah scores). Per Banff criteria

  39. Biopsy scores for ptc [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Peritubular capillaritis scores (ptc scores). Per Banff criteria

  40. Biopsy scores for mm [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Mesangial matrix increase scores (mm scores). Per Banff criteria

  41. Safety assessed by each type of Adverse Events [ Time Frame: From date of transplant until EOS (up to 2 years post transplant) ]
    Based on system organ class and preferred term from the most recent version of MedDRA. Medical Dictionary for Regulatory Activities (MedDRA)

  42. The number of individuals remaining with DSA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    For patients who develop DSA

  43. The number of individuals remaining with IA [ Time Frame: From date of transplant until EOS (up to 2 years post transplant), assessed at days 30, 90, 180, 270, 365 and 730 ]
    For patients who develop IA

  44. Incidence of whether a five-point decline in eGFR occurs [ Time Frame: From 30 days post transplant until EOS (up to 2 years post transplant) ]
    Estimated Glomerular Filtration Rate (eGFR)

  45. Time to first occurrence of select BANFF histology grades: acute forms of ABMR [ Time Frame: From 30 days post transplant until EOS (up to 2 years post transplant) ]
    Acute Antibody-mediated rejection (ABMR)

  46. Time to first occurrence of select BANFF histology grades: chronic forms of ABMR [ Time Frame: From 30 days post transplant until EOS (up to 2 years post transplant) ]
    Chronic Antibody-mediated rejection (ABMR)

  47. Time to first occurrence of select BANFF histology grades: acute TCMR [ Time Frame: From 30 days post transplant until EOS (up to 2 years post transplant) ]
    Acute T-cell mediated rejection (TCMR)

  48. Time to first occurrence of select BANFF histology grades: chronic TCMR [ Time Frame: From 30 days post transplant until EOS (up to 2 years post transplant) ]
    Chronic T-cell mediated rejection (TCMR)

  49. Time to first occurrence of select BANFF histology grades: borderline changes [ Time Frame: From 30 days post transplant until EOS (up to 2 years post transplant) ]
    Borderline changes

  50. Time to first occurrence of select BANFF histology grades: interstitial fibrosis [ Time Frame: From 30 days post transplant until EOS (up to 2 years post transplant) ]
    Interstitial fibrosis tubular atrophy



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  • 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 AND 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02723591


Contacts
Contact: Astellas Medical Affairs, Americas 800-888-7704 ext 5473 astellas.registration@astellas.com

  Show 31 Study Locations
Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Investigators
Study Director: Medical Monitor Astellas Medical Affairs, Americas

Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT02723591     History of Changes
Other Study ID Numbers: IDTX-MA-3004
First Posted: March 30, 2016    Key Record Dates
Last Update Posted: September 25, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
FK506
Kidney Transplantation
Tacrolimus
Astagraf XL

Additional relevant MeSH terms:
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action