Belatacept in Heart Transplantation

National Institute of Allergy and Infectious Diseases (NIAID)

Status and phase: Enrolling; Phase 2

Conditions: Heart Transplant

Treatments: Drug: Tacrolimus; Drug: Prednisone; Drug: Belatacept; Drug: Mycophenolate Mofetil/Sodium

Study type: Interventional

Funder types: NIH

Identifiers

NCT06478017

DAIT RTB-013

Details and patient eligibility

About

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® (mycophenolate mofetil- MMF) or Myfortic® (mycophenolate sodium). Corticosteroids will be continued throughout the study in the belatacept arm.

The primary objective is to evaluate whether NULOJIX® (belatacept), when implemented with gradual tacrolimus withdrawal over 9 months, is safe with respect to preventing the composite endpoint of acute cellular rejection (ACR) >= International Society of Heart and Lung Transplantation (ISHLT) 2R, hemodynamic compromise rejection in the absence of a biopsy or histological rejection, re-transplantation, and death at 18 months post-transplant.

Enrollment: 66 estimated patients

Sex: All

Ages: 18 to 71 years old

Volunteers: No Healthy Volunteers

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 <120ml/min/1.73m^2

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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66 participants in 2 patient groups

Belatacept + Tacrolimus withdrawal

Experimental group

Description:

1. 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)

Treatment:

Drug: Mycophenolate Mofetil/Sodium

Drug: Belatacept

Drug: Prednisone

Drug: Tacrolimus

Standard-of-Care

Active Comparator group

Description:

1. Maintenance Immunosuppression: Prograf (tacrolimus), or tacrolimus generic; 2. Maintenance Immunosuppression: CellCept (mycophenolate mofetil- MMF), or Myfortic (mycophenolate sodium); 3. Corticosteroid +/- taper: Prednisone

Treatment:

Drug: Mycophenolate Mofetil/Sodium

Drug: Prednisone

Drug: Tacrolimus