Selective CD28 Blockade in Renal Transplant Recipients

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Kidney Transplantation; Renal Transplant Recipients
• Intervention / Treatment: Biological: Lulizumab; Biological: Thymoglobulin®; Drug: Methylprednisolone; Drug: Mycophenolate Mofetil; Drug: Prednisone; Drug: Tacrolimus

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30332
      • Emory University Hospital
      • Principal Investigator: I. Raul Badell, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Individuals who meet all of the following criteria are eligible for enrollment as study participants:

1. Must be able to understand and provide informed consent;
2. Negative crossmatch (actual or virtual) or a Panel Reactive Antibody (PRA) of 0% on historic and admission sera;
3. First time renal transplant from either a living or deceased donor;
4. Deceased donor recipients only: Deceased donor kidneys with Kidney Donor Profile Indices (KDPI) <85%;
5. Female study participants of childbearing potential must have a negative pregnancy test prior to randomization;

6. 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;

7. 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;
8. 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,
9. 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:

1. Inability or unwillingness of a study participant to give written informed consent or comply with study protocol;
2. Recipient of previous organ transplant of any type;
3. Need for multi-organ transplant;
4. Calculated panel reactive antibody (cPRA) or panel reactive antibody (PRA) >20% at any time prior to enrollment;
5. Known hypersensitivity to mycophenolate mofetil (MMF) or any of the drug's components;
6. Human immunodeficiency virus (HIV): individuals known to be HIV positive;
7. Known history of Bacillus Calmette-Guérin (BCG) vaccination;

8. 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

9. 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

10. 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;

11. Study participants who are on biologic treatments for autoimmune disease;
12. Study participants who are involuntarily detained (e.g. prison, jail, compulsory psychiatric or medical therapy);

13. 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;
14. Human leukocyte antigen (HLA) identical donor/recipient pairing;
15. Use of investigational drugs within 4 weeks of transplant;

16. 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);

17. 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;

18. 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;
19. Recipient of a live or live-attenuated vaccine within 8 weeks prior to transplant;
20. Cytomegalovirus (CMV) seronegative individuals accepting an organ from a CMV seropositive donor;

21. 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,
22. ABO incompatible donor kidney.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lulizumab + SOC; 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; Lulizumab is a pegylated, humanized monovalent domain antibody construct that is specific for human cluster of differentiation CD28.; Other Names: BMS-931699; anti-CD28 domain antibody (anti-CD28 dAb); Biological: Thymoglobulin®; Standard of Care: Renal transplant rejection prophylaxis.; Other Names: antithymocyte globulin; Drug: Methylprednisolone; Standard of Care: Renal transplant rejection prophylaxis.; Other Names: corticosteroid; Drug: Mycophenolate Mofetil; Standard of Care: Renal transplant rejection prophylaxis.; Other Names: MMF; CellCept®; Drug: Prednisone; Standard of Care: Renal transplant rejection prophylaxis.; Other Names: corticosteroid
Active Comparator: Tacrolimus + SOC; 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.	Biological: Thymoglobulin®; Standard of Care: Renal transplant rejection prophylaxis.; Other Names: antithymocyte globulin; Drug: Methylprednisolone; Standard of Care: Renal transplant rejection prophylaxis.; Other Names: corticosteroid; Drug: Mycophenolate Mofetil; Standard of Care: Renal transplant rejection prophylaxis.; Other Names: MMF; CellCept®; Drug: Prednisone; Standard of Care: Renal transplant rejection prophylaxis.; Other Names: corticosteroid; Drug: Tacrolimus; Standard of Care: Renal transplant rejection prophylaxis.; Other Names: Prograf®

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Bristol-Myers Squibb; PPD
• Investigators: Study Chair: Christian P. Larsen, MD, DPhil, Emory Transplant Center, Emory University; Principal Investigator: Andrew B. Adams, MD, PhD, Emory Transplant Center, Emory University

Publications and helpful links

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2022
• Primary Completion (Actual): September 22, 2022
• Study Completion (Actual): September 22, 2022

Study Registration Dates

• First Submitted: May 21, 2021
• First Submitted That Met QC Criteria: May 21, 2021
• First Posted (Actual): May 26, 2021

Study Record Updates

• Last Update Posted (Actual): March 22, 2023
• Last Update Submitted That Met QC Criteria: March 20, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: rejection; immune modulation; CD28 blockade; Cluster of Differentiation (CD); CNI inhibition
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Methylprednisolone; Prednisone; Tacrolimus; Mycophenolic Acid; Thymoglobulin; Antilymphocyte Serum
• Other Study ID Numbers: DAIT RTB-011; U01AI138909 (U.S. NIH Grant/Contract); NIAID CRMS ID#: 38687 (Other Identifier: DAIT NIAID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The plan is to share data upon completion of the study in: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
• IPD Sharing Time Frame: On average, within 24 months after database lock for the trial.
• IPD Sharing Access Criteria: Open access.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No