Subcutaneous Abatacept in Renal Transplant Recipients

This is a Phase I, open-label, prospective, single-arm single-center study to evaluate the feasibility, effectiveness, and safety of a regimen substituting subcutaneous abatacept early post-transplant in place of intravenous belatacept as an immunosuppressant in first-time renal transplant recipients.

There is a single arm in this study; the Investigational (abatacept) group. Participants will be assigned to a treatment regimen between 2 and 5 months after transplantation. The study drug will be administered until month 12 post-transplant; at that point, all participants will be transitioned to a physician-directed immunosuppressive regimen post-study.

• Abatacept 125Mg/Ml Syringe (Drug), also known as Orencia: Participants on a qualifying belatacept regimen (with low-dose tacrolimus, mycophenylate mofetil (MMF), and prednisone) will have their maintenance regimen changed from i.v. Belatacept to s.c. abatacept, which will continue through week 52 (month 12) post-transplant: Costimulation blockade: \- Abatacept 125 mg subcutaneous weekly

Primary outcomes

• Number of Participants Who Are Compliant With Self-administration [Up to 12 months post-transplantation, an average of 8 months]: Compliance and self-administration will be measured using the abatacept administration logs and autoinjector accountability.
• Number of Participants Who Remain Free of Biopsy-proven Acute T-cell Mediated Rejection (aTCMR) or Antibody-mediated Rejection (ABMR) as Defined by Banff Criteria at or Before 12 Months After Transplantation. [Up to 12 months post-transplantation, an average of 8 months]: For-cause biopsies may be performed as dictated by the clinical team. A for-cause biopsy (i.e., graft dysfunction) may be performed in cases of increased serum creatinine, proteinuria, or other clinical symptoms at the discretion of the site Investigator.
• Number of Participants Presenting Serious Adverse Events [Up to 12 months post-transplantation, an average of 8 months]: Assessments of serious adverse events will be completed at each study visit from the time abatacept starts through 12 months post-transplant.
• Number of Participants With Serious Infections [Up to 12 months post-transplantation, an average of 8 months]: Any serious infection requiring hospitalization or prolonged therapy, including but not limited to treatment ≥ 20 days, will be documented.
• Number of Patients With Cytomegalovirus (CMV) Viremia Stratified by the Magnitude [Up to 12 months post-transplantation, an average of 8 months]: All subjects will be monitored for CMV infection by quantitative polymerase chain reaction (PCR) in the blood per the Emory Transplant Center standard of care protocol, CMV viremia stratified by count ≥35 but <10,000 or ≥ 10,000.
• Number of Patients With BK Viremia Stratified by the Magnitude [Up to 12 months post-transplantation, an average of 8 months]: Undetected, >0 but < 1,000, ≥ 1,000 but <10,000, or ≥ 10,000 - 100,000, ≥100,000 or stratified by log, which is reported as a result.
• Number of Participants Who Develop Any Malignancy [Up to 12 months post-transplantation, an average of 8 months]: Incidence of any malignancy, including Post-Transplant Lymphoproliferative Disorder (PTLD)

Secondary outcomes

• Number of Participants Experiencing the Composite Outcome of Death or Allograft Failure [Up to 12 months post-transplantation, an average of 8 months]: Death and/or allograft failure at or before 12 months after transplantation
• Number of Participants With Biopsy-proven Acute T-cell Mediated Cellular Rejection (BP-aTCMR) [Up to 12 months post-transplantation, an average of 8 months]: Incidence of biopsy-proven acute T-cell mediated cellular rejection (BP-aTCMR)
• Number of Participants Treated for Rejection [Up to 12 months post-transplantation, an average of 8 months]: The number of participants treated for rejection with any of the following: i) corticosteroids within 12 months, ii) T-cell depleting therapy within 12 months, iii) any other treatment for rejection within 12 months of transplantation
• Number of Participants Treated for Acute Rejection Due to Clinical Suspicion Rather Than BP-aTCMR or BP-aABMR Within 12 Months of Transplantation. [Up to 12 months post-transplantation, an average of 8 months]: For-cause biopsies may be performed as dictated by the clinical team. A for-cause biopsy (i.e., graft dysfunction) may be performed in cases of increased serum creatinine, proteinuria, or other clinical symptoms at the discretion of the site Investigator.
• Number of Participants With Biopsy-proven Active Antibody-mediated Rejection (BP-aABMR) [Up to 12 months post-transplantation, an average of 8 months]: For-cause biopsies may be performed as dictated by the clinical team. A for-cause biopsy (i.e., graft dysfunction) may be performed in cases of increased serum creatinine, proteinuria, or other clinical symptoms at the discretion of the site Investigator.
• Number of Participants With Changes in Allograft Biopsies for the 5 Categories of aTCMR Specified in the Banff Schema [Up to 12 months post-transplantation, an average of 8 months]: For-cause biopsies may be performed as dictated by the clinical team. A for-cause biopsy (i.e., graft dysfunction) may be performed in cases of increased serum creatinine, proteinuria, or other clinical symptoms at the discretion of the site Investigator.
• Time to Changes in Allograft Biopsies for the 5 Categories of aTCMR Specified in the Banff Schema [Up to 12 months post-transplantation, an average of 8 months]: Calculations will be made from the start of abatacept through to 12 months post-transplant. A for-cause biopsy (i.e., graft dysfunction) may be performed in cases of increased serum creatinine, proteinuria, or other clinical symptoms at the discretion of the site Investigator.
• Number of Participants Who Develop De-novo Donor Specific Antibody (DSA) [Up to 12 months post-transplantation, an average of 8 months]: Number of participants who develop de-novo DSA
• Estimated Glomerular Filtration Rate (eGFR) [Baseline and 12 months post-transplantation]: The eGFR will be calculated at the time abatacept is started and 12 months post-transplant
• Number of Days to Events [TCMR, ABMR, De-novo Specific Antibodies (DSA) Formation, Graft Loss]. [Up to 12 months post-transplantation, an average of 8 months]: All events will be documented, and calculations will be made from the start of abatacept through 12 months post-transplant.

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* Must be able to understand and provide informed consent.
* Male or Female, 18-70 years of age at the time of enrollment (all races and ethnicities)
* Negative crossmatch (virtual or physical) at the time of transplant
* No less than 8 weeks, no more than 20 weeks post-transplant at enrollment
* A first-time renal transplant who has been treated with belatacept from the time of transplant, receiving tacrolimus (target trough 3-5 ng/ml), mycophenolate mofetil (or mycophenolic acid or azathioprine), prednisone (also see exclusion criteria).
* eGFR ≥ 40ml/min/m2 \[using 2021 the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation\].
* Prior documented evidence of Epstein-Barr virus (EBV) seropositivity must be available.
* Female study participants of childbearing potential must have a negative pregnancy test before enrollment.
* Agreement to use contraception that is more than 80% effective.
* Vaccines are current as per the Division of Allergy, Immunology, and Transplantation (DAIT) guidance for patients in transplant trials.
* Study participants must have a negative purified protein derivative (PPD) or negative testing for tuberculosis using an approved Interferon Gamma Release Assay (IGRA) blood test, such as QuantiFERON®-Gold tuberculosis (TB) or T-SPOT®-TB assay. PPD or IGRA testing must be documented to have been performed within the 52 weeks before enrollment. Patients with latent TB may become eligible after completion of treatment.

Exclusion Criteria:

* Inability or unwillingness of a study participant to give written informed consent or comply with the study protocol.
* Recipient of previous organ transplant of any type.
* Multi-organ transplant.
* Calculated Panel Reactive Antibody (cPRA) >80 at the time of enrollment.
* History of any episode of biopsy-proven Banff rejection (including borderline rejection or any grade of acute TCMR) before enrollment.
* History of any malignancy including lymphoma within 5 years of enrollment. Study participants with curatively treated non-melanomatous skin cancer or curatively treated cervical carcinoma in situ may be enrolled.
* Any past or current issue which in the opinion of the investigator may pose additional risks to the participant in the study, may interfere with the study participant's ability to comply with the study requirements, or may impact the quality or interpretation of the data obtained from the study.
* Human immunodeficiency virus (HIV): individuals known to be HIV positive.
* Hepatitis C virus (HCV): any study participant who receives a kidney from a seropositive or HCV RNA PCR-positive donor is ineligible. Any study participant who was HCV RNA PCR positive at transplant is ineligible. Any study participant with a history of HCV seropositivity or HCV infection who has not met the criteria for sustained spontaneous clearance or sustained viral response to therapy is ineligible.
* Hepatitis B virus (HBV): Individuals with any of the following are NOT eligible:

  * Recipient or donor positive for hepatitis B surface antigen (HBsAg)
  * Recipient or donor positive for antibodies to hepatitis B core antigen (anti-HBc)
  * Recipient or donor is known to have had a positive HBV DNA PCR
* Evidence of CMV viremia or clinical CMV infection at any time after transplant.
* Kidney recipients who were CMV seronegative who received an organ from a CMV seropositive donor.
* BK viremia of greater than 4.3 DNA log copies/ml (greater than 20,000 copies/ml) at any time post-transplant.
* Active uncontrolled infection within 1 month of enrollment.
* Clinically significant proteinuria (urinary protein/Cr ratio >1.0).
* Receiving belatacept at a dose other than 5 mg/kg body weight.
* Receiving mycophenolate mofetil at a dose of less than 1000 mg daily (or mycophenolic acid or azathioprine equivalent).
* Receiving prednisone at a dose greater than 5 mg daily.
* Presence of donor-specific antibody by Luminex single antigen bead assay.

Participant flow

Outcome results

• Number of Participants Who Are Compliant With Self-administration (Primary), Count of participants, Participants: Abatacept 8
• Number of Participants Who Remain Free of Biopsy-proven Acute T-cell Mediated Rejection (aTCMR) or Antibody-mediated Rejection (ABMR) as Defined by Banff Criteria at or Before 12 Months After Transplantation. (Primary), Count of participants, Participants: Abatacept 13
• Number of Participants Presenting Serious Adverse Events (Primary), Count of participants, Participants: Abatacept 1
• Number of Participants With Serious Infections (Primary), Count of participants, Participants: Abatacept 0
• Number of Patients With Cytomegalovirus (CMV) Viremia Stratified by the Magnitude (Primary), Count of participants, Participants: Abatacept 1
• Number of Patients With BK Viremia Stratified by the Magnitude (Primary), Count of participants, Participants: Abatacept 13
• Number of Participants Who Develop Any Malignancy (Primary), Count of participants, Participants: Abatacept 0
• Number of Participants Experiencing the Composite Outcome of Death or Allograft Failure (Secondary), Count of participants, Participants: Abatacept 0
• Number of Participants With Biopsy-proven Acute T-cell Mediated Cellular Rejection (BP-aTCMR) (Secondary), Count of participants, Participants: Abatacept 1
• Number of Participants Treated for Rejection (Secondary), Count of participants, Participants: Abatacept 1
• Number of Participants Treated for Acute Rejection Due to Clinical Suspicion Rather Than BP-aTCMR or BP-aABMR Within 12 Months of Transplantation. (Secondary), Count of participants, Participants: Abatacept 1
• Number of Participants With Biopsy-proven Active Antibody-mediated Rejection (BP-aABMR) (Secondary), Count of participants, Participants: Abatacept 1
• Number of Participants With Changes in Allograft Biopsies for the 5 Categories of aTCMR Specified in the Banff Schema (Secondary), Count of participants, Participants: Abatacept 1
• Time to Changes in Allograft Biopsies for the 5 Categories of aTCMR Specified in the Banff Schema (Secondary), Number, days: Abatacept 28
• Number of Participants Who Develop De-novo Donor Specific Antibody (DSA) (Secondary), Count of participants, Participants: Abatacept 0
• Estimated Glomerular Filtration Rate (eGFR) (Secondary), Mean, mL/min/1.73 m^2: Abatacept 67.5 +/- 18.8
• Number of Days to Events [TCMR, ABMR, De-novo Specific Antibodies (DSA) Formation, Graft Loss]. (Secondary), Number, days to acute rejection: Abatacept 28

Adverse events

Time frame: Information on adverse events was collected from all participants throughout the study intervention and up to 12 months post-transplant, with an average of 8 months.

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2023-11-06)
• Informed Consent Form (PDF, 2024-07-11)

• Idelberto R Badell, MD, Principal investigator, Emory University

NIH grants: U01AI138909