A Study to Evaluate the Safety and Efficacy of Dual Costimulation Blockade With VIB4920 and Belatacept for Prophylaxis of Allograft Rejection in Adults Receiving a Kidney Transplant

Phase 2

Completed

• Conditions: Allografts; Rejection; Transplant, Kidney; Transplant Rejection; Kidney Transplantation
• Interventions: Drug: Belatacept; Drug: VIB4920; Drug: Thymoglobulin; Drug: Methylprednisolone

• Registration Number: NCT04046549
• Lead Sponsor: Amgen

Brief Summary

The purpose of this study is to evaluate the efficacy, safety and tolerability of dual costimulation blockade with VIB4920 in combination of belatacept in adult male or female recipients of a renal allograft from a deceased, living unrelated or human leukocyte antigen (HLA) non-identical living related donor.

Detailed Description

Study with completed results acquired from Horizon in 2024.

Study Timeline

• Study First Submitted: 2019-08-02
• Study First Submitted QC: 2019-08-02
• Study First Posted: 2019-08-06
• Study Start: 2019-10-30
• Primary Completion: 2022-07-18
• Study Completion: 2023-03-22
• Results First Submitted: 2023-06-21
• Results First Submitted QC: 2023-10-09
• Results First Posted: 2023-10-10
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-02
• Last Update Posted: 2024-12-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

• Recipients of a first renal transplant from standard criteria deceased, living unrelated or HLA non-identical living related donor.

• Recipients who are at low immunologic risk:

  1. No donor specific antibodies (DSA), and
  2. Negative cross-match testing.

• Recipients with up to date vaccination as per local immunization schedules.

• Male and female participants who agree to follow protocol defined contraceptive methods.

Exclusion Criteria

• Participants receiving an allograft from an ABO-incompatible donor.

• Participants treated with systemic immunosuppressive drug therapy for more than a total of 2 weeks within 24 weeks prior to informed consent form signature.

• Participants who have undergone lymphodepleting therapy.

• Participants with medical history of confirmed venous thromboembolism, arterial thrombosis, coagulopathy or known platelet disorders.

• Participants with risk factors for venous thromboembolism or arterial thrombosis, prothrombotic status.

• Participants requiring treatment with antithrombotic drugs (clopidogrel, prasugrel, warfarin, others).

• Participants requiring long-term systemic anticoagulation after transplantation, which would interfere with obtaining biopsies.

• Participants with any contraindication to kidney biopsy.

• Cytomegalovirus (CMV)-seronegative recipients of a CMV-seropositive donor kidney, or unknown CMV serostatus.

• Epstein-Barr virus (EBV)-seronegative or with unknown EBV serostatus.

• Receipt of live (attenuated) vaccine within the 4 weeks before screening.

• Participants with high potential of graft loss due to recurrence of underlying kidney disease.

• Prior solid organ transplant or potential to require a concurrent organ or cell transplant.

• Previous treatment with belatacept and cluster of differentiation 40 (CD40) or anti-CD40L agents.

• Use of B cell depleting therapy, non-depleting B cell directed therapy e.g., belimumab or abatacept within 1 year prior to enrolment.

• At screening blood tests any of the following:

  1. Aspartate aminotransferase (AST) > 2.5 × upper limit of normal (ULN)
  2. Alanine aminotransferase (ALT) > 2.5 × ULN
  3. Alkaline phosphatase (ALP) > 2.5 × ULN
  4. Total bilirubin (TBL) > 2 × ULN
  5. Hemoglobin < 75 g/L
  6. Neutrophils < 1.5 × 10^9/L
  7. Platelets < 100 × 10^9/L

• Participants with severe systemic infections, current or within the 2 weeks prior to transplant surgery.

• Positive test for chronic hepatitis B infection at screening or within the last 12 months.

• Positive test for hepatitis C virus antibody at screening or within the last 12 months.

• Positive test for human immunodeficiency viruses antibody at screening or within the last 12 months.

• History of or active tuberculosis (TB), or a positive QuantiFERON®-TB Gold test at screening, unless previously treated for latent tuberculosis.

• History of cancer, except as follows:

  1. In situ carcinoma of the cervix treated with apparent success with curative therapy > 12 months prior to screening; or
  2. Cutaneous basal cell or squamous cell carcinoma treated with apparent success with curative therapy.

• Lactating or pregnant females.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Belatacept+VIB4920	Belatacept	Participants will be admitted to the transplant center for the administration of VIB4920 and belatacept (with Thymoglobulin and corticosteroids) and will be discharged on Day 3/4 at the discretion of the investigator. Participants will return to the study center to receive study drugs (VIB4920 and /or belatacept) weekly for 2 visits, then every 2 weeks for 5 visits, and then monthly for 9 visits for safety monitoring.
Belatacept+VIB4920	VIB4920	Participants will be admitted to the transplant center for the administration of VIB4920 and belatacept (with Thymoglobulin and corticosteroids) and will be discharged on Day 3/4 at the discretion of the investigator. Participants will return to the study center to receive study drugs (VIB4920 and /or belatacept) weekly for 2 visits, then every 2 weeks for 5 visits, and then monthly for 9 visits for safety monitoring.
Belatacept+VIB4920	Thymoglobulin	Participants will be admitted to the transplant center for the administration of VIB4920 and belatacept (with Thymoglobulin and corticosteroids) and will be discharged on Day 3/4 at the discretion of the investigator. Participants will return to the study center to receive study drugs (VIB4920 and /or belatacept) weekly for 2 visits, then every 2 weeks for 5 visits, and then monthly for 9 visits for safety monitoring.
Belatacept+VIB4920	Methylprednisolone	Participants will be admitted to the transplant center for the administration of VIB4920 and belatacept (with Thymoglobulin and corticosteroids) and will be discharged on Day 3/4 at the discretion of the investigator. Participants will return to the study center to receive study drugs (VIB4920 and /or belatacept) weekly for 2 visits, then every 2 weeks for 5 visits, and then monthly for 9 visits for safety monitoring.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) of Grade 1A or Higher, Graft Loss or Death at Week 24	Week 24	Histological grading of acute allograft rejection from biopsy specimens was based on Banff criteria 2017. Grade IA: Moderate tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade IB: Severe tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade II. Arterial intimal fibrosis with mononuclear cell inflammation, formation of neointima.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) of Grade 1A or Higher, Graft Loss or Death at Weeks 12 and 48	Weeks 12 and 48	Histological grading of acute allograft rejection from biopsy specimens was based on Banff criteria 2017. Grade IA: Moderate tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade IB: Severe tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade II. Arterial intimal fibrosis with mononuclear cell inflammation, formation of neointima.
Percentage of Participants With Antibody-Mediated Rejection	Week 12, 24, 48	The diagnosis of antibody-mediated rejection was based on Banff criteria 2017 - a set of standardized guidelines used by pathologists and clinicians to diagnose and classify rejection based on specific features observed in biopsy samples from the transplanted organ, such as the presence of certain types of immune cells, inflammation, and injury patterns.
Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR)	Week 12, 24, 48	Histological grading of acute allograft rejection from biopsy specimens was based on Banff criteria 2017. Grade IA: Moderate tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade IB: Severe tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade II. Arterial intimal fibrosis with mononuclear cell inflammation, formation of neointima. tBPAR was defined as a BPAR which was treated with anti-rejection therapy.
Percentage of Participants With De Novo Donor-specific Antibodies (dnDSA)	Week 12, 24, 48	Serum samples were collected for de novo donor-specific antibodies (dnDSA) using solid phase (bead-based) assays.
Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR), Graft Loss, Death or Loss to Follow-up (LTFU)	Week 12, 24, 48	Histological grading of acute allograft rejection from biopsy specimens was based on Banff criteria 2017. Grade IA: Moderate tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade IB: Severe tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade II. Arterial intimal fibrosis with mononuclear cell inflammation, formation of neointima.
Percentage of Participants With Biopsy Proven Acute Rejection (BPAR)	Week 12, 24, 48	Histological grading of acute allograft rejection from biopsy specimens was based on Banff criteria 2017. Grade IA: Moderate tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade IB: Severe tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade II. Arterial intimal fibrosis with mononuclear cell inflammation, formation of neointima.
Percentage of Participants With Treated Acute Rejections	Week 12, 24, 48	Acute rejections, per clinical judgement of the investigator followed by confirmatory biopsy, were treated with bolus methylprednisolone (other corticosteroids were acceptable at an equivalent dose) according to local practice.

Trial Locations

Locations (4)

University of California, San Francisco; 🇺🇸 San Francisco, California, United States

Keck Medical Center of USC; 🇺🇸 Los Angeles, California, United States

Duke University School of Medicine; 🇺🇸 Durham, North Carolina, United States

University of Texas Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States