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Belatacept Pilot Study in Lung Transplantation Immunosuppression in Lung Transplantation

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ClinicalTrials.gov Identifier: NCT03388008
Recruitment Status : Not yet recruiting
First Posted : January 2, 2018
Last Update Posted : October 4, 2018
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Bristol-Myers Squibb
Information provided by (Responsible Party):
Ramsey Hachem, Washington University School of Medicine

Study Description
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Brief 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.

Condition or disease Intervention/treatment Phase
Lung Transplant Rejection Antibody-mediated Rejection Drug: Belatacept Drug: Tacrolimus Drug: ATG Drug: Mycophenolate Mofetil Drug: Methylprednisolone Drug: Prednisone Phase 2

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.


Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
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)
Masking Description: Investigators examining lung biopsy results and blood for the development of donor-specific HLA antibodies will be blinded to study participants' treatment arm assignment.
Primary Purpose: Treatment
Official Title: A Pilot Randomized Controlled Trial of De Novo Belatacept-Based Immunosuppression in Lung Transplantation
Estimated Study Start Date : November 15, 2018
Estimated Primary Completion Date : January 31, 2021
Estimated Study Completion Date : April 30, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Belatacept

Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Standard of care
Tacrolimus + Mycophenolate mofetil + prednisone from day 0 through day 365
 Drug: Tacrolimus
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
Other Name: Prograf

Drug: ATG
Anti-thymocyte globulin will be dosed intravenously at 3 mg/kg divided into 3 daily doses starting on day 0 after transplantation
Other Name: Thymoglobulin

Drug: Mycophenolate Mofetil
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
Other Name: Cellcept, Myfortic

Drug: Methylprednisolone
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
Other Name: Solumedrol

Drug: Prednisone
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
Experimental: Belatacept-based immunosuppression
Belatacept + Tacrolimus + prednisone from day 0 through day 89, then Belatacept + Mycophenolate mofetil + prednisone from day 90 through day 365
 Drug: Belatacept
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)
Other Name: Nulojix

Drug: ATG
Anti-thymocyte globulin will be dosed intravenously at 3 mg/kg divided into 3 daily doses starting on day 0 after transplantation
Other Name: Thymoglobulin

Drug: Mycophenolate Mofetil
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
Other Name: Cellcept, Myfortic

Drug: Methylprednisolone
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
Other Name: Solumedrol

Drug: Prednisone
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


Outcome Measures
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Primary Outcome Measures :
  1. Donor-specific HLA antibodies, re-transplantation, or death [ Time Frame: 365 days ]
    Composite primary endpoint


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Provided written informed consent for study participation
  • Underwent single or bilateral lung transplantation
  • Negative urine pregnancy test for women of child bearing potential and willingness to use highly-effective contraception

Exclusion Criteria:

  • Requiring invasive mechanical ventilation immediately before transplantation
  • Requiring extracorporeal life support (ECLS) (i.e., ECMO) immediately before transplantation
  • Received treatment to deplete HLA antibodies before transplantation to improve the possibility of transplantation
  • Having DSA immediately before transplantation (i.e., positive virtual crossmatch)
  • Listed for multi-organ transplant (e.g., heart-lung, liver-lung, kidney-lung)
  • Pregnant or breast-feeding
  • Active infection with Hepatitis B or C virus
  • Active infection with human immunodeficiency virus (HIV)
  • Chronic infection with Burkholderia cepacia complex before transplantation
  • Epstein Barr Virus (EBV) seronegative status
  • Participation in another interventional clinical trial
  • Allograft dysfunction requiring ECMO support after transplantation
  • Delayed chest closure after transplantation
  • Severe coagulopathy and significant bleeding in the opinion of the PI
  • Any condition that in the opinion of the site PI introduces undue risk by participating in this study
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03388008


Contacts
Contact: Ramsey R Hachem, MD (314) 454-8766 Rhachem@wustl.edu
Contact: Katina Richardson (314) 454-8766 k.richardson@wustl.edu

Locations
United States, Texas
Baylor University Medical Center at Dallas Not yet recruiting
Dallas, Texas, United States, 75246
Contact: Howard Huang, MD    214-820-7856    Howard.Huang@BSWHealth.org   
Sponsors and Collaborators
Ramsey Hachem
National Heart, Lung, and Blood Institute (NHLBI)
Bristol-Myers Squibb
Investigators
Principal Investigator: Ramsey R Hachem, MD Washington University School of Medicine
  Study Documents (Full-Text)

Documents provided by Ramsey Hachem, Washington University School of Medicine:
Study Protocol and Statistical Analysis Plan  [PDF] December 8, 2017

More Information
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Publications:

Responsible Party: Ramsey Hachem, Professor of Medicine, Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03388008     History of Changes
Other Study ID Numbers: Bela Lung Pilot
First Posted: January 2, 2018    Key Record Dates
Last Update Posted: October 4, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Ramsey Hachem, Washington University School of Medicine:
donor-specific HLA antibodies
lung transplantation

Additional relevant MeSH terms:
Prednisolone acetate
Methylprednisolone acetate
Prednisone
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Mycophenolic Acid
Tacrolimus
Thymoglobulin
Abatacept
Anti-Inflammatory Agents
Glucocorticoids
Hormones
 Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antiemetics