Belatacept in Heart Transplantation

Registration Number
NCT06478017
Lead Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Brief Summary

This is a phase 2, prospective, multi-center, open-label clinical trial. Sixty-six (66) primary heart transplant recipients will be randomized (1:2) to receive either standard-of-care, tacrolimus-based immunosuppression, or a belatacept-based regimen with gradual tacrolimus withdrawal over 9-months post-transplant. Both study arms will receive CellCept® (myc...

Detailed Description

Not available

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
66
Inclusion Criteria

Study entry

  1. Subject must be able to understand the purpose of the study and be willing to participate and provide written consent
  2. Recipient of a primary heart transplant (heart transplant only)
  3. Epstein-Barr Virus (EBV) seropositive
  4. Agreement to use contraception; according to the Food and Drug Administration (FDA) Office of Women's Health (http://www.fda.gov/birthcontrol), there are a number of birth control methods that are more than 80% effective. Female participants of child-bearing potential must consult with their physician and determine the most suitable method(s) from this list to be used for the duration of the study
  5. In the absence of a contraindication, vaccinations must be up to date per the Division of Allergy, Immunology, and Transplantation (DAIT) Vaccination Guidance for Patients in Transplant Trials (Refer to the Manual of Procedures)
  6. Mechanical support or investigational drug trials where the intervention ends at the time of transplantation are permitted.

Randomization

  1. Recipient of a primary heart transplant
  2. No desensitization therapy prior to transplant
  3. Negative crossmatch actual or virtual, on the most recent sera as determined by the participating study center
  4. Female subjects of childbearing potential must have a negative pregnancy test (serum or urine) prior to randomization
  5. Agreement to use contraception; according to the FDA Office of Women's Health (http://www.fda.gov/birthcontrol), there are a number of birth control methods that are more than 80% effective. Female participants of child-bearing potential must consult with their physician and determine the most suitable method(s) from this list to be used for the duration of the study. Those who choose oral contraception must agree to use a second form of contraception after administration of study drug for a period of 1 year after the last dose of study drug
  6. Estimated Glomerular Filtration Rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration equation (CKD-epi)) >30ml/min/1.73m^2 and <100ml/min/1.73m^2
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Exclusion Criteria

Study entry

  1. Candidate for multiple solid organ or tissue transplants

  2. Prior history of any organ, tissue, or cellular transplant

  3. Currently breast-feeding a child or plans to become pregnant during the timeframe of the study follow up period

  4. History of severe allergic and/or anaphylactic reactions to humanized or murine monoclonal antibodies

  5. Known hypersensitivity to NULOIX (belatacept) or ORENCIA (Abatacept)

  6. Previous treatment with NULOIX (belatacept) or ORENCIA (Abatacept)

  7. Epstein Barr Virus (EBV) seronegative or indeterminant

  8. Human Immunodeficiency Virus (HIV) positive

  9. Hepatitis B surface antigen positive

  10. Hepatitis B core antibody positive

  11. Hepatitis C virus antibody (HCV Ab+) and hepatitis C virus (HCV) Polymerase Chain Reaction (PCR) positive patients

  12. Patients with a previous history of active Tuberculosis (TB)

  13. Subjects must be tested for latent TB infection (LTBI) within a year prior to transplant. Testing should be conducted using either a PPD or Interferon-gamma release assay (i.e., QuantiFERON-TB, T-SPOT.TB). Patients with a positive test for latent TB infection (LTBI) must have completed appropriate therapy for LTBI (https://www.cdc.gov/tb/topic/treatment/ltbi.htm). A subject is considered eligible only if they have a negative test for LTBI within one year prior to transplant OR if they have completed appropriate LTBI therapy within one year prior to transplant

  14. Positive serology for T. cruzi or known/suspected history of Chagas disease

  15. Findings on pre-transplant or pre-randomization chest x-ray suggestive of fungal infection.

    Participants with a normal chest x-ray but positive serologies for coccidiomycosis, histoplasmosis, or blastomycosis, who have previously been fully treated, will be permitted to participate but require prophylaxis as further outlined in Section 7

  16. Known active current viral, fungal, mycobacterial or other infections (including, but not limited to atypical mycobacterial disease and herpes zoster), not including drive line infections

  17. White blood cell (WBC) count <3.0 or an absolute neutrophil count (ANC) of less than 1500 cells/mm3 on >=2 occasions at any time prior to enrollment

  18. History of central nervous system (CNS) infection

  19. History of active inflammatory bowel disease, chronic diarrhea, or malabsorption

  20. History of malignancy, per discretion of oncology consult and study oversight team, will be permitted to participate

  21. History of AL amyloidosis

  22. Patients who are administered or intended to be administered induction therapy (cytolytic agents such as anti-thymocyte globulin or anti-IL2R therapies such as basiliximab) in the immediate peri- transplant period

  23. Patients who i) have undergone desensitization, ii) are undergoing or are planned to undergo desensitization, or iii) are intended to receive therapeutic interventions that are used for the purpose of desensitization prior to transplant

  24. Pretransplant Calculated Panel Reactive Antibody (cPRA) calculated by Single Antigen Bead (SAB) testing > 25%

  25. The use of immunosuppressive biologics within 3 months prior to transplant is not permitted. Non- immunosuppressive biologics such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors must be stopped at the time of transplant

  26. Patients for whom there is an intent to administer biologics other than those indicated by protocol during the study period

  27. The intended use of high dose (>= 2g/kg) intravenous immunoglobulin before or at the time of transplant or before study drug administration

  28. A personal history of severe hypogammaglobulinemia (<300mg/dL)

  29. Intent to give the patient a live vaccine within 30 days prior to randomization

  30. Use or intended use of other investigational drugs after transplant

  31. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the potential participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study

Randomization

  1. Recipient of multiple solid organ or tissue transplants

  2. Prior history of any organ, tissue, or cellular transplant

  3. Currently breast-feeding a child or plans to become pregnant during the timeframe of the study follow up period

  4. History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies

  5. Known hypersensitivity to Belatacept (NULOJIX) or Abatacept (ORENCIA)

  6. Previous treatment with Belatacept (NULOJIX) or Abatacept (ORENCIA)

  7. Epstein Barr Virus (EBV) seronegative or indeterminant

  8. HIV positive patient

  9. Hepatitis B surface antigen positive patient

  10. Hepatitis B core antibody positive patient

  11. Hepatitis B negative transplant recipient that received a transplant from a Hepatitis B core antibody positive donor

  12. Hepatitis C virus antibody (HCV Ab+) and HCV PCR positive patients

  13. Recipient of allograft from a hepatitis C virus nucleic acid test (NAT) positive donor

  14. Patients with a previous history of active Tuberculosis (TB)

  15. Subjects must be tested for latent TB infection (LTBI) within a year prior to transplant. Testing should be conducted using either a PPD or Interferon-gamma release assay (i.e., QuantiFERON-TB, T-SPOT.TB). Patients with a positive test for latent TB infection (LTBI) must complete appropriate therapy for LTBI (https://www.cdc.gov/tb/topic/treatment/ltbi.htm). A subject is considered eligible only if they have a negative test for LTBI within one year prior to transplant OR if they have completed appropriate LTBI therapy within one year prior to transplant

  16. Positive serology for T. cruzi or known/suspected history of Chagas disease

  17. Findings on pre-transplant or pre-randomization chest x-ray suggestive of fungal infection.

    Participants with a normal chest x-ray but positive serologies for coccidiomycosis, histoplasmosis, or blastomycosis, who have previously been fully treated, will be permitted to participate but require prophylaxis as further outlined in Section 7

  18. Known active current viral, fungal, mycobacterial or other infections (including, but not limited to atypical mycobacterial disease and herpes zoster), not including drive line infections

  19. White blood cell (WBC) count <3.0 or an absolute neutrophil count (ANC) of less than 1500 cells/mm3 on >=2 occasions at any time prior to randomization

  20. CMV high risk mismatch (D+/R-)

  21. History of central nervous system (CNS) infection

  22. History of active inflammatory bowel disease, chronic diarrhea, or malabsorption

  23. History of malignancy, per discretion of oncology consult and study oversight team, will be permitted to participate

  24. History of AL amyloidosis

  25. Patients who are administered or intended to be administered induction therapy (cytolytic agents such as anti-thymocyte globulin or anti-IL2R therapies such as basiliximab) in the immediate peri- transplant period

  26. Patients who have undergone desensitization or received therapeutic interventions that are used for the purpose of desensitization prior to transplant

  27. cPRA calculated by Single Antigen Bead (SAB) testing > 25% at the time of transplant or any donor specific antibodies before or at the time of transplant (local lab)

  28. Patients who have been treated with immunosuppressive biologics within 3 months prior to transplant (non-immunosuppressive biologics must have been stopped at the time of transplant)

  29. Patients for whom there is an intent to administer biologics other than those indicated by protocol during the study period

  30. Patients who are administered or intended to be administered high dose (>=2g/kg) intravenous immunoglobulin in the immediate post-transplant period

  31. A personal history of severe hypogammaglobulinemia (<300mg/dL)

  32. Receipt of a live vaccine within 30 days prior to randomization

  33. Intent to use any other investigational drugs after transplantation

  34. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements, or that may impact the quality or interpretation of the data obtained from the study

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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Belatacept + Tacrolimus withdrawalTacrolimus1. Maintenance Immunosuppression: NULOJIX (belatacept) 2. Maintenance Immunosuppression: CellCept (mycophenolate mofetil- MMF), or Myfortic (mycophenolate sodium) 3. Calcineurin Inhibitors (CNI) Taper: Prograf® (tacrolimus), or tacrolimus generic 4. Corticosteroid: Prednisone (no less than 5mg per day continued throughout the study period)
Belatacept + Tacrolimus withdrawalMycophenolate Mofetil/Sodium1. Maintenance Immunosuppression: NULOJIX (belatacept) 2. Maintenance Immunosuppression: CellCept (mycophenolate mofetil- MMF), or Myfortic (mycophenolate sodium) 3. Calcineurin Inhibitors (CNI) Taper: Prograf® (tacrolimus), or tacrolimus generic 4. Corticosteroid: Prednisone (no less than 5mg per day continued throughout the study period)
Standard-of-CareMycophenolate Mofetil/Sodium1. Maintenance Immunosuppression: Prograf (tacrolimus), or tacrolimus generic; 2. Maintenance Immunosuppression: CellCept (mycophenolate mofetil- MMF), or Myfortic (mycophenolate sodium); 3. Corticosteroid +/- taper: Prednisone
Standard-of-CarePrednisone1. Maintenance Immunosuppression: Prograf (tacrolimus), or tacrolimus generic; 2. Maintenance Immunosuppression: CellCept (mycophenolate mofetil- MMF), or Myfortic (mycophenolate sodium); 3. Corticosteroid +/- taper: Prednisone
Belatacept + Tacrolimus withdrawalBelatacept1. Maintenance Immunosuppression: NULOJIX (belatacept) 2. Maintenance Immunosuppression: CellCept (mycophenolate mofetil- MMF), or Myfortic (mycophenolate sodium) 3. Calcineurin Inhibitors (CNI) Taper: Prograf® (tacrolimus), or tacrolimus generic 4. Corticosteroid: Prednisone (no less than 5mg per day continued throughout the study period)
Standard-of-CareTacrolimus1. Maintenance Immunosuppression: Prograf (tacrolimus), or tacrolimus generic; 2. Maintenance Immunosuppression: CellCept (mycophenolate mofetil- MMF), or Myfortic (mycophenolate sodium); 3. Corticosteroid +/- taper: Prednisone
Belatacept + Tacrolimus withdrawalPrednisone1. Maintenance Immunosuppression: NULOJIX (belatacept) 2. Maintenance Immunosuppression: CellCept (mycophenolate mofetil- MMF), or Myfortic (mycophenolate sodium) 3. Calcineurin Inhibitors (CNI) Taper: Prograf® (tacrolimus), or tacrolimus generic 4. Corticosteroid: Prednisone (no less than 5mg per day continued throughout the study period)
Primary Outcome Measures
NameTimeMethod
Proportion of subjects who experience acute cellular rejection (ACR) >ISHLT 2R (local or core read), hemodynamic compromise (HDC) rejection in the absence of a biopsy or histological rejection, re-transplantation, or death as a composite endpoint.From randomization to 18 months post-transplantation
Secondary Outcome Measures
NameTimeMethod
Slope of estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) equationFrom baseline to 18 months post-transplantation, assessed at Baseline, Month 1, 6 and 18
Number of de novo donor specific antibodies per patientFrom randomization to 18 months post-transplantation
Proportion of subjects who are free from mixed rejection (ACR > ISHLT 2R ACR and AMR > ISHLT AMR 1)From randomization to 18 months post-transplantation
Proportion of subjects who are free from ACR greater than or equal to 2RFrom randomization to 18 months post-transplantation
Proportion of subjects who are free from ACR 3RFrom randomization to 18 months post-transplantation
Proportion of subjects who are free from hemodynamic compromise rejection in the absence of a biopsy or histological rejectionFrom randomization to 18 months post-transplantation
Cumulative incidence of serious infections, including CMV viremia and disease, requiring inpatient/intravenous therapyFrom randomization to 18 months post-transplantation
Incidence of deathFrom randomization to 18 months post-transplantation
Incidence of re-listing or re-transplantationFrom randomization to 18 months post-transplantation
Proportion of subjects with eGFR <60mL/min/1.73m2 measured by CKD-EPIFrom randomization to 18 months post-transplantation
Proportion of subjects with eGFR<45mL/min/1.73m2 measured by CKD-EPIFrom randomization to 18 months post-transplantation
Mean change in albumin/creatinine ratio in urineFrom baseline to 18 months post-transplantation
Change in Chronic Kidney Disease (CKD) stage measured using the mean difference on a continuous measurement scaleFrom Baseline to 18 months post-transplantation, assessed at Baseline, Month 1, 12 and 18

Chronic Kidney Disease scale:

Stage 1: Glomerular Filtration Rate (GFR) \>90mL/min Stage 2: GFR = 60-89mL/min Stage 3A: GFR=45-59mL/min Stage 3B: GFR=30-44mL/min Stage 4: GFR=15-29mL/min Stage 5: GFR\<15mL/min

Proportion of subjects with CKD stage 4 or 5From randomization to 18 months, assessed at Month 12 and 18
Mean difference in eGFR between the two arms12 months and 18 months
Proportion of subjects who are free from any detection of de novo donor-specific antibodies (dnDSA)From randomization to 18 months post-transplantation
Proportion of subjects who are free from any treated rejectionFrom randomization to 18 months post-transplantation
Incidence of acute cellular rejection (ACR) >= International Society of Heart and Lung Transplantation (ISHLT) 2RFrom randomization to 18 months post-transplantation
Incidence of malignanciesFrom randomization to 18 months post-transplantation
Incidence of post-transplant lymphoproliferative disorder (PTLD)From randomization to 18 months post-transplantation
Proportion of subjects who are free from antibody mediated rejection (AMR) (AMR > ISHLT AMR 1)From randomization to 18 months post-transplantation
Incidence of acute cellular rejection (ACR) >= International Society of Heart and Lung Transplantation (ISHLT) 3RFrom randomization to 18 months post-transplantation
Incidence of interruption/discontinuation of study drugFrom randomization to 18 months post-transplantation

Trial Locations

Locations (4)

Cedars Sinai Heart Institute/ Cedars Sinai Medical (Site # 71146)

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Los Angeles, California, United States

Tampa General Hospital (Site # 71150)

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Tampa, Florida, United States

NYU Langone Health (Site # 71177)

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New York, New York, United States

University of Utah Medical Center (Site # 71126)

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Salt Lake City, Utah, United States

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