Selective CD28 Blockade in Renal Transplant Recipients

Study Overview
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Brief Summary
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The aim of this study is to evaluate the safety and efficacy of lulizumab, a CD28-specific domain antibody (CD28 dAb), compared to tacrolimus, as the primary immunosuppressant in first-time renal transplant recipients.

Detailed Description
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This is a phase 2a, open-label, prospective, randomized (1:1), controlled, single center study evaluating the safety and efficacy of lulizumab (a CD28 specific domain antibody [CD28dAb]) compared to tacrolimus as the primary immunosuppressant in first-time renal transplant recipients. The study will take place at Emory University Hospital in Atlanta, Georgia, United States (US). There are two arms/groups in this study, the Control (tacrolimus) group and the Investigational (lulizumab) group. The two arms will be assigned to treatment regimens for the first 12 months after transplantation; at that point, all participants in each arm will be transitioned to a physician directed Standard of Care (SOC) immunosuppressive regimen, and all participants will be assessed at 15 months after transplantation. All participants will receive induction therapy with Thymoglobulin and Methylprednisolone and maintenance therapy with Mycophenolate Mofetil (MMF) and Prednisone.

Official Title
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Selective CD28 Blockade With Lulizumab Compared to CNI Inhibition With Tacrolimus in Renal Transplant Recipients

Conditions
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Kidney Transplantation, Renal Transplant Recipients

Intervention / Treatment
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* Biological: Lulizumab
* Drug: Tacrolimus
* Biological: Thymoglobulin®
* Drug: Methylprednisolone
* Drug: Mycophenolate Mofetil
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals who meet all of the following criteria are eligible for enrollment as study participants: Must be able to understand and provide informed consent; Negative crossmatch (actual or virtual) or a Panel Reactive Antibody (PRA) of 0% on historic and admission sera; First time renal transplant from either a living or deceased donor; Deceased donor recipients only: Deceased donor kidneys with Kidney Donor Profile Indices (KDPI) <85%; Female study participants of childbearing potential must have a negative pregnancy test prior to randomization; 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 percent effective. --Female study participants of child-bearing potential and male study participants must consult with their physician and determine the most suitable method(s) from this list to be used from the time that study treatment begins until after study completion; Study participants must have a negative purified protein derivative (PPD) or negative testing for tuberculosis using an approved interferon-gamma release assay (IGRA) blood test, such as: QuantiFERON®-TB Gold In-Tube test (QFT-GIT) or TSPOT® TB test ---PPD or IGRA testing must be documented to have been performed within 52 weeks before transplant; Documented completion of varicella vaccination series ≥ 8 weeks prior to enrollment, OR verification of a history of varicella or zoster by a physician OR positive laboratory confirmation of varicella immunity or disease; and, Immunizations are up-to-date based on the CDC° adult vaccination recommendations: https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html --°Centers for Disease Control and Prevention (CDC) Exclusion Criteria: Individuals who meet any of these criteria are not eligible for enrollment as study participants: Inability or unwillingness of a study participant to give written informed consent or comply with study protocol; Recipient of previous organ transplant of any type; Need for multi-organ transplant; Calculated panel reactive antibody (cPRA) or panel reactive antibody (PRA) >20% at any time prior to enrollment; Known hypersensitivity to mycophenolate mofetil (MMF) or any of the drug's components; Human immunodeficiency virus (HIV): individuals known to be HIV positive; Known history of Bacillus Calmette-Guérin (BCG) vaccination; Individuals at significant risk of early recurrence of the primary renal disease including: -Focal Segmental Glomerulosclerosis (FSGS) Membranoproliferative Glomerulonephropathy (MPGN) type 2 Hemolytic Uremia Syndrome/Thrombotic thrombocytopenic purpura (HUS/TTP), or any other disease that, in the opinion of the investigator, is at increased likelihood of recurrence and which may result in rapid decline in renal function Known history of high-risk thrombotic events or risk factors; including any of the following: Factor V Leiden, elevated homocysteine, positive lupus anticoagulant, elevated anticardiolipin antibody, heparin induced thrombocytopenia A family history of a heritable thrombotic condition Recurrent Deep vein thrombosis (DVT) or Pulmonary Embolism (PE), or Unexplained stillborn infant or recurrent spontaneous abortion of other congenital or acquired thrombotic disorder History of malignancy within 5 years of enrollment or any history of hematogenous malignancy or lymphoma. --Note: Study participants with curatively treated non-melanomatous skin cancer or curatively treated cervical carcinoma in situ may be enrolled; Study participants who are on biologic treatments for autoimmune disease; Study participants who are involuntarily detained (e.g. prison, jail, compulsory psychiatric or medical therapy); 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 study participant's ability to comply with study requirements, or May impact the quality or interpretation of the data obtained from the study; Human leukocyte antigen (HLA) identical donor/recipient pairing; Use of investigational drugs within 4 weeks of transplant; Study participants who are NOT Epstein-Barr virus (EBV) seropositive -A prior documented EBV seropositive result at enrollment does not need to be repeated --For this study, EBV seropositive patients are defined as having evidence of acquired immunity shown by the presence of immunoglobulin G (IgG) antibodies to viral capsid antigen (VCA) and the presence of antibodies to EBV nuclear antigen (EBNA or EBNA1); Hepatitis C virus (HCV): Study participants who are HCV RNA PCR positive at prerandomization re-evaluation -Study participants who are seropositive must have 2 consecutive negative HCV RNA PCR at least 24 weeks apart; Hepatitis B virus: Individuals with any of the following are NOT eligible: Recipient or donor positive for hepatitis B surface antigen (HBsAg) Recipient or donor with antibodies to hepatitis B core antigen (anti-HBc) Recipient or donor with HBV DNA detectable by PCR; Recipient of a live or live-attenuated vaccine within 8 weeks prior to transplant; Cytomegalovirus (CMV) seronegative individuals accepting an organ from a CMV seropositive donor; Study participants undergoing transplant using: Organs from donation after circulatory death (DCD) donor Donor with Kidney Donor Profile Index (KDPI) >85%, or Anticipated cold ischemia time >28 hours; or, ABO incompatible donor kidney.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lulizumab + SOC<br>N=27 participants will receive a loading dose of lulizumab on Day 0, the day of surgery. This will be followed by a maintenance dose administered on a weekly basis (weeks 1 through 26 post-transplant), followed by administration every two weeks (weeks 28 through 52 post-transplant). Method of administration: subcutaneously. Dose unit of measure: milligrams (mgs). Plus (+) Standard of Care (SOC) Regimen, per protocol- Renal transplant recipients will receive FDA-approved, immunosuppressive medications according to standard of care at Emory Transplant Center: Induction Thymoglobulin: Administered intravenously, dose unit of measure: mgs. Induction Methylprednisolone: Administered intravenously, dose unit of measure: mgs. Maintenance: Mycophenolate mofetil (MMF) administered by mouth twice daily, dose unit of measure: mgs. Maintenance: Beginning the day after methylprednisolone is completed, prednisone will be administered by mouth daily, dose unit of measure: mgs. | Biological: Lulizumab<br>* Lulizumab is a pegylated, humanized monovalent domain antibody construct that is specific for human cluster of differentiation CD28.<br>* Other names: anti-CD28 domain antibody (anti-CD28 dAb);Biological: Thymoglobulin®<br>* Standard of Care: Renal transplant rejection prophylaxis.<br>* Other names: antithymocyte globulin;Drug: Methylprednisolone<br>* Standard of Care: Renal transplant rejection prophylaxis.<br>* Other names: corticosteroid;Drug: Mycophenolate Mofetil<br>* Standard of Care: Renal transplant rejection prophylaxis.<br>* Other names: CellCept®;Drug: Prednisone<br>* Standard of Care: Renal transplant rejection prophylaxis.<br>* Other names: corticosteroid;|
| Active Comparator: Tacrolimus + SOC<br>N=27 participants will receive tacrolimus initiated according to local standard of care and adjusted over time (maintenance) to target optimal trough levels measured in ng/mL: 0 to 6 months, 7 to 12 months and, thereafter, until completion of study participation. Dose unit of measure: mg/kg. Plus (+) Standard of Care (SOC) Regimen, per protocol- Renal transplant recipients will receive FDA-approved, immunosuppressive medications according to standard of care at Emory Transplant Center: Induction Thymoglobulin: Administered intravenously, dose unit of measure: mgs. Induction Methylprednisolone: Administered intravenously, dose unit of measure: mgs. Maintenance: Mycophenolate mofetil (MMF) administered by mouth twice daily, dose unit of measure: mgs. Maintenance: Beginning the day after methylprednisolone is completed, prednisone will be administered by mouth daily, dose unit of measure: mgs. | Drug: Tacrolimus<br>* Standard of Care: Renal transplant rejection prophylaxis.<br>* Other names: Prograf®;Biological: Thymoglobulin®<br>* Standard of Care: Renal transplant rejection prophylaxis.<br>* Other names: antithymocyte globulin;Drug: Methylprednisolone<br>* Standard of Care: Renal transplant rejection prophylaxis.<br>* Other names: corticosteroid;Drug: Mycophenolate Mofetil<br>* Standard of Care: Renal transplant rejection prophylaxis.<br>* Other names: CellCept®;Drug: Prednisone<br>* Standard of Care: Renal transplant rejection prophylaxis.<br>* Other names: corticosteroid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Estimated Glomerular Filtration rate (eGFR) (MDRD) | Efficacy measure. Glomerular Filtration Rate (GFR) will be estimated using the Modification of Diet in Renal Disease (MDRD) equation. MDRD is an equation (calculation) used to estimate GFR in participants with impaired renal function based on serum creatinine, age, race, and gender. | From Month 2 to Month 12 Post Transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Who Remain Free of Biopsy Proven Acute T-Cell Mediated Rejection (aTCMR) | Safety measure. Defined by Banff 2017 kidney criteria. Reference: Haas, M. et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 18(2):293-307. | Up to 15 Months Post Transplantation | 
| Proportion of Participants Who Remain Free of Antibody-Mediated Rejection (ABMR) | Safety measure. Defined by Banff 2017 kidney criteria. Reference: Haas, M. et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 18(2):293-307. | Up to 15 Months Post Transplantation | 
| Cumulative Incidence of Serious Adverse Events | Safety measure. | Up to 15 Months Post Transplantation | 
| Incidence of Serious Infection(s) of Special Interest | Safety measure. Definition: The occurrence of infection(s) requiring participant hospitalization or prolonged therapy, including but not limited to treatment ≥20 days. | Up to 15 Months Post Transplantation | 
| Incidence of Cytomegalovirus (CMV) Viremia | Safety measure. | Up to 15 Months Post Transplantation | 
| Incidence of BK Polyoma Virus (BKV) Viremia | Safety measure. | Up to 15 Months Post Transplantation | 
| Incidence of Any Malignancy, Including but Not Limited to PTLD | Safety measure. Definitions: Malignancy: A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Post-transplant Lymphoproliferative Disorder (PTLD) : A rare but well-known complication of solid organ transplants and hematopoietic stem cell transplantation. | Up to 15 Months Post Transplantation | 
| Proportion of Participants Experiencing the Composite Outcome of Death or Allograft Failure | Efficacy measure. | Up to 15 Months Post Transplantation | 
| Proportion of Participants with Biopsy Proven Acute T-cell Mediated Cellular Rejection (BPaTCMR) | Efficacy measure. Defined by Banff 2017 kidney criteria. Reference: Haas, M. et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 18(2):293-307. | Up to 15 Months Post Transplantation | 
| Proportion of Participants Treated for Kidney Transplant Rejection | Efficacy measure. Definition: Participant requiring treatment for rejection with corticosteroids, T-cell depleting therapy, and/or any other treatment for kidney transplant rejection. | Up to 15 Months Post Transplantation | 
| Proportion of Participants Treated for Acute Rejection Due to Clinical Suspicion | Efficacy measure. Acute rejection due to a clinical suspicion rather than BPaTCMR or BP-aABMR. Definitions: BPaTCMR: Biopsy proven acute T-cell mediated cellular rejection BP-aABMR: Biopsy proven active antibody mediated rejection | Up to 15 Months Post Transplantation | 
| Proportion of Participants with Biopsy Proven Active Antibody Mediated Rejection (BP-aABMR) | Efficacy measure. Defined by Banff 2017 kidney criteria. Reference: Haas, M. et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 18(2):293-307. | Up to 15 Months Post Transplantation | 
| Proportion of Participants with aTCMR Changes in Allograft Biopsies | Efficacy measure. Definitions: aTCMR:acute T-cell mediated cellular rejection Defined by Banff 2017 kidney criteria. Reference: Haas, M. et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 18(2):293-307. | Up to 15 Months Post Transplantation | 
| Time to Event for aTCMR Changes in Allograft Biopsies | Efficacy measure. Definitions: aTCMR:acute T-cell mediated cellular rejection Defined by Banff 2017 kidney criteria. Reference: Haas, M. et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 18(2):293-307. | Up to 15 Months Post Transplantation | 
| Proportion of Participant Who Develop De-Novo Donor Specific Antibody | Efficacy measure. | Up to 15 Months Post Transplantation | 
| Change in Estimated Glomerular Filtration Rate (eGFR) | Efficacy measure. Glomerular Filtration Rate (GFR) will be estimated using the Modification of Diet in Renal Disease (MDRD) equation. MDRD is an equation (calculation) used to estimate GFR in participants with impaired renal function based on serum creatinine, age, race, and gender. | From Month 2 to Month 15 Post Transplantation | 
| Proportion of Participants with Delayed Graft Function | Efficacy measure. | Within 1 Month Post Transplantation | 
| Hemoglobin A1C | Efficacy measure. Definition: HbA1c: Glycosylated hemoglobin, a measure of the average plasma concentration of blood sugar (glucose) over the previous three months. | Month 12 Post Transplantation | 
| Days to Event: TCMR | Efficacy measure. TCMR: T-cell mediated rejection. | Up to 15 Months Post Transplantation | 
| Days to Event: Antibody mediated rejection (ABMR) | Efficacy measure. ABMR: Antibody mediated rejection. | Up to 15 Months Post Transplantation | 
| Days to Event: De-Novo Donor Specific Antibody (DSA) Formation | Efficacy measure. | Up to 15 Months Post Transplantation | 
| Days to Event: Graft Loss | Efficacy measure. | Up to 15 Months Post Transplantation | 
| Standardized Blood Pressure | Efficacy measure. | Month 12 and Month 15 Post Transplantation | 
| Fasting Lipid Profile | Efficacy measure. Included: Total cholesterol, LDL, HDL, and triglyceride. | Month 12 and Month 15 Post Transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD28 blockade, Cluster of Differentiation (CD), CNI inhibition, immune modulation, rejection