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

NCT02723591 | Completed Phase 4 Results

• 2 other identifiers: IDTX-MA-30042018-003867-79
• Study Type: interventional
• Target: 599
• Locations: 1 country
• Sites: 30

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.

Conditions

Kidney Transplantation

Keywords

FK506; Kidney Transplantation; Tacrolimus; Astagraf XL

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Who Were Positive for de Novo DSA (dnDSA) or Immune Activation (IA) Occurrence

  DSA was considered as a categorical (binary) variable with positivity determined at a threshold criteria approaching mean fluorescence intensity (MFI)=1000 at any time during the study. IA was considered either present or absent using the Trugraf™ v2.0 molecular assay. A negative designation (Trugraf TX Normal) was referred to as Immune Quiescence (IQ). Due to operating characteristics of the assay, a positive designation was considered evidence of IA in all participants.

  From date of transplant until 1 year

Secondary Outcomes (60)

• Percentage of Participants Who Were Positive, Negative or Indeterminate for dnDSA Occurrence

  From date of transplant until 1 year

• Peak Mean Fluorescence Intensity (MFI) of DSA Positive Participants

  From date of transplant until 1 year

• Percentage of DSA Positive Participants With Weak, Moderate and Strong Antibody Strentgh

  From date of transplant until 1 year

• Percentage of DSA Positive Participants With DSA Persistence

  From date of transplant until 1 year

• Percentage of Participants Who Were Positive or Negative for Complement Component 1, Q Subcomponent (C1q)-Binding DSA

  From date of transplant until 1 year

Study Arms (2)

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.

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.

Drug: Tacrolimus immediate release

Interventions

Tacrolimus DRUG

Oral Capsule

Also known as: Advagraf, FK506E, Astagraf XL

Tacrolimus, Extended Release (Astagraf XL®) Once Daily

Tacrolimus immediate release DRUG

Oral Capsule

Also known as: FK506, Prograf, generic immediate release tacrolimus

Tacrolimus, Immediate Release Twice Daily (BID)

Eligibility Criteria

• Age: 16 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.
• \* 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.
• 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.

Sponsors & Collaborators

• Astellas Pharma Global Development, Inc.: lead

Study Sites (30)

Site US10006

Birmingham, Alabama, 35294, United States

Location

Site US10025

Scottsdale, Arizona, 85259, United States

Location

Site US10031

Los Angeles, California, 90033, United States

Location

Site US10005

Sacramento, California, 95817, United States

Location

Site US10016

San Francisco, California, 94115, United States

Location

Site US10024

Aurora, Colorado, 80045, United States

Location

Site US10003

New Haven, Connecticut, 06510, United States

Location

Site US10014

Washington D.C., District of Columbia, 20007, United States

Location

Site US10030

Jacksonville, Florida, 32224, United States

Location

Site US10020

Chicago, Illinois, 60605, United States

Location

Site US10010

Chicago, Illinois, 60611, United States

Location

Site US10001

Baltimore, Maryland, 21201, United States

Location

Site US10007

Boston, Massachusetts, 02114, United States

Location

Site US10013

Ann Arbor, Michigan, 48109, United States

Location

Site US10032

Detroit, Michigan, 48202, United States

Location

Site US10029

Minneapolis, Minnesota, 55455, United States

Location

Site US10027

Rochester, Minnesota, 55905, United States

Location

Site US10019

Livingston, New Jersey, 07039, United States

Location

Site US10004

Buffalo, New York, 14215, United States

Location

Site US10037

New York, New York, 10032, United States

Location

Site US10022

New York, New York, 10065, United States

Location

Site US10028

New York, New York, 10467, United States

Location

Site US10021

Syracuse, New York, 13210, United States

Location

Site US10026

Portland, Oregon, 97210, United States

Location

Site US10002

Charleston, South Carolina, 29425, United States

Location

Site US10036

Houston, Texas, 77030, United States

Location

Site US10018

Salt Lake City, Utah, 84112, United States

Location

Site US10012

Charlottesville, Virginia, 22903, United States

Location

Site US10008

Falls Church, Virginia, 22042, United States

Location

Site US10023

Madison, Wisconsin, 53792, United States

Location

Related Links

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

MeSH Terms

Interventions

Tacrolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Clinical Trial Disclosure
• Organization: Astellas Pharma Global Development, Inc. (APGD)

astellas.resultsdisclosure@astellas.com

800-888-7704

Study Officials

• Medical Monitor

  Astellas Medical Affairs, Americas

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 3, 2016
• First Posted: March 30, 2016
• Study Start: September 9, 2016
• Primary Completion: June 14, 2019
• Study Completion: June 14, 2019
• Last Updated: December 18, 2024
• Results First Posted: June 29, 2020

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.

Locations

US (30)