Belatacept Pilot Study in Lung Transplantation Immunosuppression in Lung Transplantation

NCT03388008 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: Bela Lung Pilot
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 2

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.

Conditions

Lung Transplant Rejection; Antibody-mediated Rejection

Keywords

donor-specific HLA antibodies; lung transplantation

Outcome Measures

Primary Outcomes (1)

• Donor-specific HLA Antibodies, Re-transplantation, or Death

  The Outcome Measure is a composite primary endpoint of the development of donor-specific HLA antibodies, re-transplantation, or death. Testing for donor-specifc HLA antibodies was performed at study-specified time points using the single antigen bead assay at the study core lab. Donor-specific HLA antibodies were defined as reactivity with a mean fluorescence intensity (MFI) ≥ 2,000.

  365 days

Study Arms (2)

Standard of care

ACTIVE COMPARATOR

Tacrolimus + Mycophenolate mofetil + prednisone from day 0 through day 365

Drug: Tacrolimus; Drug: ATG; Drug: Mycophenolate Mofetil; Drug: Methylprednisolone; Drug: Prednisone

Belatacept-based immunosuppression

EXPERIMENTAL

Belatacept + Tacrolimus + prednisone from day 0 through day 89, then Belatacept + Mycophenolate mofetil + prednisone from day 90 through day 365

Drug: Belatacept; Drug: ATG; Drug: Mycophenolate Mofetil; Drug: Methylprednisolone; Drug: Prednisone

Interventions

Belatacept DRUG

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)

Also known as: Nulojix

Belatacept-based immunosuppression

Tacrolimus DRUG

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

Also known as: Prograf

Standard of care

ATG DRUG

Anti-thymocyte globulin will be dosed intravenously at 3 mg/kg divided into 3 daily doses starting on day 0 after transplantation

Also known as: Thymoglobulin

Belatacept-based immunosuppression; Standard of care

Mycophenolate Mofetil DRUG

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

Also known as: Cellcept, Myfortic

Belatacept-based immunosuppression; Standard of care

Methylprednisolone DRUG

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

Also known as: Solumedrol

Belatacept-based immunosuppression; Standard of care

Prednisone DRUG

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

Belatacept-based immunosuppression; Standard of care

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington University School of Medicine: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (2)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Houston Methodist Hospital

Houston, Texas, 77030, United States

Location

Related Publications (24)

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• Meyer KC, Raghu G, Verleden GM, Corris PA, Aurora P, Wilson KC, Brozek J, Glanville AR; ISHLT/ATS/ERS BOS Task Force Committee; ISHLT/ATS/ERS BOS Task Force Committee. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. Eur Respir J. 2014 Dec;44(6):1479-503. doi: 10.1183/09031936.00107514. Epub 2014 Oct 30.

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• Lama VN, Murray S, Lonigro RJ, Toews GB, Chang A, Lau C, Flint A, Chan KM, Martinez FJ. Course of FEV(1) after onset of bronchiolitis obliterans syndrome in lung transplant recipients. Am J Respir Crit Care Med. 2007 Jun 1;175(11):1192-8. doi: 10.1164/rccm.200609-1344OC. Epub 2007 Mar 8.

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• Finlen Copeland CA, Snyder LD, Zaas DW, Turbyfill WJ, Davis WA, Palmer SM. Survival after bronchiolitis obliterans syndrome among bilateral lung transplant recipients. Am J Respir Crit Care Med. 2010 Sep 15;182(6):784-9. doi: 10.1164/rccm.201002-0211OC. Epub 2010 May 27.

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• Singer JP, Singer LG. Quality of life in lung transplantation. Semin Respir Crit Care Med. 2013 Jun;34(3):421-30. doi: 10.1055/s-0033-1348470. Epub 2013 Jul 2.

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• Daud SA, Yusen RD, Meyers BF, Chakinala MM, Walter MJ, Aloush AA, Patterson GA, Trulock EP, Hachem RR. Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2007 Mar 1;175(5):507-13. doi: 10.1164/rccm.200608-1079OC. Epub 2006 Dec 7.

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• Glanville AR, Aboyoun CL, Havryk A, Plit M, Rainer S, Malouf MA. Severity of lymphocytic bronchiolitis predicts long-term outcome after lung transplantation. Am J Respir Crit Care Med. 2008 May 1;177(9):1033-40. doi: 10.1164/rccm.200706-951OC. Epub 2008 Feb 8.

  PMID: 18263803 BACKGROUND

• Hachem RR, Khalifah AP, Chakinala MM, Yusen RD, Aloush AA, Mohanakumar T, Patterson GA, Trulock EP, Walter MJ. The significance of a single episode of minimal acute rejection after lung transplantation. Transplantation. 2005 Nov 27;80(10):1406-13. doi: 10.1097/01.tp.0000181161.60638.fa.

  PMID: 16340783 BACKGROUND

• Le Pavec J, Suberbielle C, Lamrani L, Feuillet S, Savale L, Dorfmuller P, Stephan F, Mussot S, Mercier O, Fadel E. De-novo donor-specific anti-HLA antibodies 30 days after lung transplantation are associated with a worse outcome. J Heart Lung Transplant. 2016 Sep;35(9):1067-77. doi: 10.1016/j.healun.2016.05.020. Epub 2016 May 31.

  PMID: 27373824 BACKGROUND

• Tikkanen JM, Singer LG, Kim SJ, Li Y, Binnie M, Chaparro C, Chow CW, Martinu T, Azad S, Keshavjee S, Tinckam K. De Novo DQ Donor-Specific Antibodies Are Associated with Chronic Lung Allograft Dysfunction after Lung Transplantation. Am J Respir Crit Care Med. 2016 Sep 1;194(5):596-606. doi: 10.1164/rccm.201509-1857OC.

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• Girnita AL, McCurry KR, Iacono AT, Duquesnoy R, Corcoran TE, Awad M, Spichty KJ, Yousem SA, Burckart G, Dauber JH, Griffith BP, Zeevi A. HLA-specific antibodies are associated with high-grade and persistent-recurrent lung allograft acute rejection. J Heart Lung Transplant. 2004 Oct;23(10):1135-41. doi: 10.1016/j.healun.2003.08.030.

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• Girnita AL, Duquesnoy R, Yousem SA, Iacono AT, Corcoran TE, Buzoianu M, Johnson B, Spichty KJ, Dauber JH, Burckart G, Griffith BP, McCurry KR, Zeevi A. HLA-specific antibodies are risk factors for lymphocytic bronchiolitis and chronic lung allograft dysfunction. Am J Transplant. 2005 Jan;5(1):131-8. doi: 10.1111/j.1600-6143.2004.00650.x.

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• Bharat A, Kuo E, Steward N, Aloush A, Hachem R, Trulock EP, Patterson GA, Meyers BF, Mohanakumar T. Immunological link between primary graft dysfunction and chronic lung allograft rejection. Ann Thorac Surg. 2008 Jul;86(1):189-95; discussion 196-7. doi: 10.1016/j.athoracsur.2008.03.073.

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• Jaramillo A, Smith CR, Maruyama T, Zhang L, Patterson GA, Mohanakumar T. Anti-HLA class I antibody binding to airway epithelial cells induces production of fibrogenic growth factors and apoptotic cell death: a possible mechanism for bronchiolitis obliterans syndrome. Hum Immunol. 2003 May;64(5):521-9. doi: 10.1016/s0198-8859(03)00038-7.

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• Maruyama T, Jaramillo A, Narayanan K, Higuchi T, Mohanakumar T. Induction of obliterative airway disease by anti-HLA class I antibodies. Am J Transplant. 2005 Sep;5(9):2126-34. doi: 10.1111/j.1600-6143.2005.00999.x.

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• Mohan S, Palanisamy A, Tsapepas D, Tanriover B, Crew RJ, Dube G, Ratner LE, Cohen DJ, Radhakrishnan J. Donor-specific antibodies adversely affect kidney allograft outcomes. J Am Soc Nephrol. 2012 Dec;23(12):2061-71. doi: 10.1681/ASN.2012070664. Epub 2012 Nov 15.

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• Huang HJ, Schechtman K, Askar M, Bernadt C, Mitter B, Dore P, Goodarzi A, Yau S, Youssef JG, Witt CA, Byers DE, Vazquez-Guillamet R, Halverson L, Nava R, Puri V, Kreisel D, Gelman AE, Hachem RR. A Pilot Randomized Controlled Trial of De Novo Belatacept-based Immunosuppression After Lung Transplantation. Transplantation. 2024 Mar 1;108(3):777-786. doi: 10.1097/TP.0000000000004841. Epub 2024 Feb 20.

  PMID: 37899481 DERIVED

MeSH Terms

Interventions

Abatacept; Tacrolimus; thymoglobulin; Mycophenolic Acid; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisone

Intervention Hierarchy (Ancestors)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins; Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienediols

Results Point of Contact

• Title: Ramsey Hachem, MD
• Organization: Washington University in St. Louis

Rhachem@wustl.edu

(314) 454-7953

Study Officials

• Ramsey R Hachem, MD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Investigators examining lung biopsy results and blood for the development of donor-specific HLA antibodies will be blinded to study participants' treatment arm assignment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Study participants will be randomized to 1 of 2 arms: Belatacept-based immunosuppression or standard of care immunosuppression

Study Record Dates

• First Submitted: December 18, 2017
• First Posted: January 2, 2018
• Study Start: December 17, 2019
• Primary Completion: August 31, 2022
• Study Completion: August 31, 2022
• Last Updated: November 25, 2022
• Results First Posted: November 2, 2021

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)