Belatacept Pilot Study in Lung Transplantation Immunosuppression in Lung Transplantation
Condition: Lung Transplant Rejection; Antibody-mediated Rejection
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a pilot randomized controlled trial examining the feasibility of conducting a large
      scale randomized controlled trial of belatacept-based immunosuppression in lung
      transplantation. This pilot study will enroll 40 lung transplant recipients and randomize
      them to belatacept-based immunosuppression or standard of care. The primary endpoint of the
      study is the development of donor-specific HLA antibodies after transplantation. All study
      participants will be followed for a minimum of 12 months after transplantation.
    

Detailed description: 
      Lung transplantation is the ultimate treatment for patients with advanced lung disease.
      However, long-term outcomes remain disappointing and the median survival after
      transplantation is approximately 5.5 years. Beyond the first year after transplantation,
      chronic lung allograft dysfunction is the leading cause of death. The exact mechanisms that
      lead to chronic lung allograft dysfunction are unclear, but the development of donor-specific
      HLA antibodies is an independent risk factor. In fact, studies have consistently identified
      the development of donor-specific HLA antibodies as a significant and independent risk factor
      for chronic lung allograft dysfunction and mortality after transplantation.

      Belatacept is a CTLA4-Ig fusion protein that binds CD80 and CD86 thereby blocking CD28
      co-stimulatory signals. Belatacept has been extensively studied in kidney transplantation. In
      a long-term study, patients treated with Belatacept had better survival than those treated
      with Cyclosporine. Importantly, Belatacept-treated patients were significantly less likely to
      develop donor-specific HLA antibodies than Cyclosporine-treated patients. Nonetheless,
      Belatacept has not been formally evaluated after lung transplantation. The investigators
      hypothesize that Belatacept-based immunosuppression would result in a lower incidence of
      donor-specific HLA antibodies and that this would result in better chronic lung allograft
      dysfunction-free survival after transplantation. Before conducting a large scale randomized
      controlled trial to test this hypothesis, the investigators plan to conduct the current pilot
      randomized controlled trial to examine the feasibility of conducting the large scale
      randomized controlled trial.

      The investigators plan to enroll and randomize 40 lung transplant recipients at 2 sites. All
      recipients will be treated with anti-thymocyte globulin for induction immunosuppression.
      Those randomized to standard of care immunosuppression will be treated with Tacrolimus,
      Mycophenolate mofetil, and prednisone. Those randomized to Belatacept-based immunosuppression
      will be treated with Belatacept, Tacrolimus, and prednisone for the first 89 days; on day 90,
      Mycophenolate mofetil will be substituted for Tacrolimus and patients will be continued on
      Belatacept, Mycophenolate mofetil, and prednisone for the remainder of year 1 after
      transplantation.

      Patients in both groups will be monitored closely for episodes of acute cellular rejection,
      lymphocytic bronchiolitis, and antibody-mediated rejection with surveillance bronchoscopy and
      transbronchial lung biopsies on days 28, 84, 112, 168, 252, and 365 (± 7 days) as part of the
      sites' routine clinical protocols. In addition, patients will be monitored for the
      development of donor-specific HLA antibodies with routine blood tests on on days 10 (± 3
      days), 28, 56, 84, 112, 168, 252, and 365 (± 7 days).

      The primary endpoint of the study is a composite of the development of donor-specific HLA
      antibodies, re-transplantation, and death. Secondary endpoints include acute cellular
      rejection, lymphocytic bronchiolitis, antibody-mediated rejection, chronic lung allograft
      dysfunction, survival, cytomegalovirus infection, bacterial infection, community-acquired
      respiratory viral infection, chronic kidney disease stage 3, malignancy, hypertension,
      diabetes, and hypercholesterolemia.
    

Intervention name(s): Belatacept; Tacrolimus; ATG; Mycophenolate Mofetil; Methylprednisolone; Prednisone
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Belatacept will be dosed at 10 mg/kg of actual body weight on days 0, 7, 14, 28, 56, and 84 then at 5 mg/kg on day 112 and every 28 days through day 364 (i.e., on days 140, 168, 196, 224, 252, 280, 308, 336, and 364); Tacrolimus will be dosed enterally or sublingually within 48 hours of transplantation and the dose will be adjusted to target a trough blood level of 8-15 ng/ml; Anti-thymocyte globulin will be dosed intravenously at 3 mg/kg divided into 3 daily doses starting on day 0 after transplantation; Mycophenolate mofetil will be dosed at 1000 mg twice daily (or if the enteric coated formulation is used, this will be dosed at 720 mg twice daily. In the standard of care arm, mycophenolate mofetil will be initiated on day 0 after transplantation, whereas in the belatacept-based immunosuppression arm, mycophenolate mofetil will be initiated on day 90 after transplantation; Methylprednisolone 500 mg will be given intravenously before perfusion of the allograft during the transplant procedure, then methylprednisolone 0.5 mg/kg will be given intravenously twice daily for 6 total doses; Prednisone will be dosed at 0.5 mg/kg orally daily through day 14, then 0.2 mg/kg orally daily through day 30, then 0.1 mg/kg daily through day 180, then 5 mg daily through day 365
Other intervention name(s): Nulojix; Prograf; Thymoglobulin; Cellcept, Myfortic; Solumedrol
Intervention MeSH terms: Mycophenolic Acid; Prednisone; Methylprednisolone; Methylprednisolone Hemisuccinate; Abatacept; Tacrolimus; Thymoglobulin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Study participants will be randomized to 1 of 2 arms: Belatacept-based immunosuppression or standard of care immunosuppression
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: donor-specific HLA antibodies; lung transplantation