Clinical trial NCT06478017: Belatacept in Heart Transplantation
Official title: Belatacept With Delayed Tacrolimus Withdrawal Versus Standard-of-Care Tacrolimus in Heart Transplant Recipients (RTB-013)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Heart Transplant
Keywords: Heart transplant
Transplantation
Standard of care
Belatacept
Tacrolimus
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2024-06-27
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Maximum age (years): 71
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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® (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.


Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: From randomization to 18 months post-transplantation
Secondary outcomes:
measure: Slope of estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) equation
timeFrame: From baseline to 18 months post-transplantation, assessed at Baseline, Randomization, Month 1, 6 and 18
measure: Proportion of subjects with eGFR <60mL/min/1.73m^2 measured by CKD-EPI
timeFrame: From randomization to 18 months post-transplantation
measure: Proportion of subjects with eGFR<45mL/min/1.73m^2 measured by CKD-EPI
timeFrame: From randomization to 18 months post-transplantation
measure: Mean change in albumin/creatinine ratio in urine
timeFrame: From baseline to 18 months post-transplantation
measure: Change in Chronic Kidney Disease (CKD) stage measured using the mean difference on a continuous measurement scale
timeFrame: From Baseline to 18 months post-transplantation, assessed at Baseline, Month 1, 12 and 18
measure: Proportion of subjects with CKD stage 4 or 5
timeFrame: From randomization to 18 months, assessed at Month 12 and 18
measure: Mean difference in eGFR between the two arms
timeFrame: 12 months and 18 months
measure: Proportion of subjects who are free from any detection of de novo donor-specific antibodies (dnDSA)
timeFrame: From randomization to 18 months post-transplantation
measure: Number of de novo donor specific antibodies per patient
timeFrame: From randomization to 18 months post-transplantation
measure: Proportion of subjects who are free from ACR greater than or equal to 2R
timeFrame: From randomization to 18 months post-transplantation
measure: Proportion of subjects who are free from ACR 3R
timeFrame: From randomization to 18 months post-transplantation
measure: Proportion of subjects who are free from any treated rejection
timeFrame: From randomization to 18 months post-transplantation
measure: Proportion of subjects who are free from antibody mediated rejection (AMR) (AMR > ISHLT AMR 1)
timeFrame: From randomization to 18 months post-transplantation
measure: Proportion of subjects who are free from hemodynamic compromise rejection in the absence of a biopsy or histological rejection
timeFrame: From randomization to 18 months post-transplantation
measure: Proportion of subjects who are free from mixed rejection (ACR > ISHLT 2R ACR and AMR > ISHLT AMR 1)
timeFrame: From randomization to 18 months post-transplantation
measure: Incidence of acute cellular rejection (ACR) >= International Society of Heart and Lung Transplantation (ISHLT) 2R
timeFrame: From randomization to 18 months post-transplantation
measure: Incidence of acute cellular rejection (ACR) >= International Society of Heart and Lung Transplantation (ISHLT) 3R
timeFrame: From randomization to 18 months post-transplantation
measure: Cumulative incidence of serious infections, including CMV viremia and disease, requiring inpatient/intravenous therapy
timeFrame: From randomization to 18 months post-transplantation
measure: Incidence of post-transplant lymphoproliferative disorder (PTLD)
timeFrame: From randomization to 18 months post-transplantation
measure: Incidence of death
timeFrame: From randomization to 18 months post-transplantation
measure: Incidence of re-listing or re-transplantation
timeFrame: From randomization to 18 months post-transplantation
measure: Incidence of malignancies
timeFrame: From randomization to 18 months post-transplantation
measure: Incidence of interruption/discontinuation of study drug
timeFrame: From randomization to 18 months post-transplantation
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars Sinai Heart Institute/ Cedars Sinai Medical (Site # 71146)
state: California
city: Tampa
country: United States
facility: Tampa General Hospital (Site # 71150)
state: Florida
city: New York
country: United States
facility: NYU Langone Health (Site # 71177)
state: New York
city: Salt Lake City
country: United States
facility: University of Utah Medical Center (Site # 71126)
state: Utah
Study officials:
affiliation: Massachusetts General Hospital
name: Joren C Madsen, MD, DPhil
role: STUDY_CHAIR
affiliation: Cedars-Sinai Medical Center
name: Jon A. Kobashigawa, MD
role: STUDY_CHAIR
affiliation: NYU Langone Health
name: Marlena Habal, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Christian P. Larsen, MD, DPhil
role: STUDY_CHAIR
References: