Allografts, Rejection; Transplant, Kidney, Transplant Rejection, Kidney Transplantation
Conditions
Keywords
Renal allograft dysfunction, Cell-mediated rejection, Antibody mediated rejection, Immunosuppression, Acute rejection, VIB4920, MEDI4920, Belatacept, Thymoglobulin, Methylprednisolone, Corticosteroids
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.
Interventions
DRUGBelatacept
Protocol versions 1 through 4: Belatacept 10 mg/kg by intravenous (IV) infusion on post-op Day 1, repeated on post-op Day 3 or 4 (timing is at investigator's discretion), and at the end of Weeks 2, 4, 8 and 12; then 5 mg/kg IV every 4 weeks from Week 16 to Week 48.
DRUGVIB4920
Protocol versions 1 and 2: VIB4920 1500 mg by IV infusion on post-op Days 1 and 14, and at the end of Weeks 4, 6, 8 and 10; then 1500 mg every 4 weeks from Week 12 to Week 48. Protocol versions 3 and 4: VIB4920 1500 mg by IV infusion on post-op Days 1, repeated on post-op Day 3 or 4 (timing is at investigator's discretion), Week 2, and at the end of Weeks 4, 6, 8, and 10; then 1500 mg every 4 weeks from Week 12 to Week 48.
DRUGThymoglobulin
Protocol versions 1 and 2: Thymoglobulin 3.0 mg/kg by intravenous (IV) infusion prior to reperfusion of the allograft on the day of transplantation surgery (Day 0) (1 dose). Protocol versions 3 and 4: Thymoglobulin 1.5 mg/kg by intravenous infusion prior to reperfusion of the allograft on the day of transplantation surgery (Day 0), prior to VIB4920+belatacept infusion on post-op Day 1, on post-op Day 2, and prior to VIB4920+belatacept infusion on post-op Day 3 or 4.
DRUGMethylprednisolone
Protocol versions 1 and 2: Methylprednisolone by IV infusion (500, 250, 125 and 60 mg on Days 0, 1, 2 and 3, respectively) followed by oral administration of prednisone 30 mg per day on Days 4, 5, and 6. Protocol versions 3 and 4: Methylprednisolone by IV infusion (500, 250, 125 and 60 mg on Days 0, 1, 2 and 3, respectively) followed by oral administration of prednisone 30 mg per day on Days 4, 5, 6 and 7. Participants may be tapered to at least 20 mg per day on Day 8, to at least 10 mg per day on Day 15, and to at least 5 mg per day on Day 22. Discontinuation of prednisone following the post-op Day 28 visit.
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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 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. |
| 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 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. |
Countries
United States
Participant flow
Pre-assignment details
A total of 25 participants underwent transplant surgery (enrolled); two of these participants were not treated, and are not included in any analysis. A total of 3 participants were enrolled prior to protocol version 3.
Participants by arm
| Arm | Count |
|---|---|
| Belatacept+VIB4920 Belatacept (protocol versions \[v\]1-4): 10 mg/kg by intravenous (IV) infusion on post-op Day 1, repeated on post-op Day 3 or 4, and at the end of Weeks 2, 4, 8, 12; then 5 mg/kg IV every 4 weeks from Week 16 to Week 48.
VIB4920 (protocol v1-2): 1500 mg by IV infusion on post-op Days 1 and 14, and at the end of Weeks 4, 6, 8, 10; then 1500 mg every 4 weeks from Week 12 to Week 48. Protocol v3-4: 1500 mg by IV infusion on post-op Days 1, repeated on post-op Day 3 or 4, Week 2, and at the end of Weeks 4, 6, 8, 10; then 1500 mg every 4 weeks from Week 12 to Week 48.
Thymoglobulin (protocol v1-2): 3.0 mg/kg by IV infusion prior to reperfusion of the allograft on the day of transplantation surgery (Day 0). Protocol v3-4: 1.5 mg/kg by IV infusion prior to reperfusion of the allograft on the day of transplantation surgery (Day 0), prior to VIB4920+belatacept infusion on post-op Day 1, on post-op Day 2, and prior to VIB4920+belatacept infusion on post-op Day 3 or 4.
Methylprednisolone (protocol v1-2): IV infusion (500, 250, 125, 60 mg on Days 0, 1, 2, 3, respectively); oral administration of prednisone 30 mg per day on Days 4, 5, 6. Protocol v3-4: IV infusion (500, 250, 125, 60 mg on Days 0, 1, 2, 3, respectively); oral administration of prednisone 30 mg per day on Days 4, 5, 6 and 7. Participants may be tapered to ≤ 20 mg per day on Day 8, to ≤ 10 mg per day on Day 15, and to ≤ 5 mg per day on Day 22. Discontinuation of prednisone following the post-op Day 28 visit. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Other, Not Specified | 5 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Belatacept+VIB4920 |
|---|---|
| Age, Continuous | 47.7 years STANDARD_DEVIATION 12.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 23 |
| other Total, other adverse events | 20 / 23 |
| serious Total, serious adverse events | 10 / 23 |
Outcome results
Primary
Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) of Grade 1A or Higher, Graft Loss or Death at 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.
Time frame: Week 24
Population: Efficacy Evaluable Set: All participants who received the revised regimen of Thymoglobulin and steroids, and any dose of investigational product (IP). Participants enrolled in protocol v3 - 4 were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Belatacept+VIB4920 | Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) of Grade 1A or Higher, Graft Loss or Death at Week 24 | 25.0 percentage of participants |
Secondary
Percentage of Participants With Antibody-Mediated Rejection
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.
Time frame: Week 12, 24, 48
Population: Efficacy Evaluable Set: All participants who received the revised regimen of Thymoglobulin and steroids, and any dose of IP. Participants enrolled in protocol v3 - 4 were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Belatacept+VIB4920 | Percentage of Participants With Antibody-Mediated Rejection | Week 12 | 10.0 percentage of participants |
| Belatacept+VIB4920 | Percentage of Participants With Antibody-Mediated Rejection | Week 24 | 10.0 percentage of participants |
| Belatacept+VIB4920 | Percentage of Participants With Antibody-Mediated Rejection | Week 48 | 15.0 percentage of participants |
Secondary
Percentage of Participants With Biopsy Proven Acute Rejection (BPAR)
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.
Time frame: Week 12, 24, 48
Population: Efficacy Evaluable Set: All participants who received the revised regimen of Thymoglobulin and steroids, and any dose of IP. Participants enrolled in protocol v3 - 4 were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Belatacept+VIB4920 | Percentage of Participants With Biopsy Proven Acute Rejection (BPAR) | Week 24 | 25.0 percentage of participants |
| Belatacept+VIB4920 | Percentage of Participants With Biopsy Proven Acute Rejection (BPAR) | Week 12 | 25.0 percentage of participants |
| Belatacept+VIB4920 | Percentage of Participants With Biopsy Proven Acute Rejection (BPAR) | Week 48 | 25.0 percentage of participants |
Secondary
Percentage of Participants With De Novo Donor-specific Antibodies (dnDSA)
Serum samples were collected for de novo donor-specific antibodies (dnDSA) using solid phase (bead-based) assays.
Time frame: Week 12, 24, 48
Secondary
Percentage of Participants With Treated Acute Rejections
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.
Time frame: Week 12, 24, 48
Population: Efficacy Evaluable Set: All participants who received the revised regimen of Thymoglobulin and steroids, and any dose of IP. Participants enrolled in protocol v3 - 4 were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Belatacept+VIB4920 | Percentage of Participants With Treated Acute Rejections | Week 12 | 25.0 percentage of participants |
| Belatacept+VIB4920 | Percentage of Participants With Treated Acute Rejections | Week 24 | 25.0 percentage of participants |
| Belatacept+VIB4920 | Percentage of Participants With Treated Acute Rejections | Week 48 | 30.0 percentage of participants |
Secondary
Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR)
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.
Time frame: Week 12, 24, 48
Population: Efficacy Evaluable Set: All participants who received the revised regimen of Thymoglobulin and steroids, and any dose of IP. Participants enrolled in protocol v3 - 4 were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Belatacept+VIB4920 | Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) | Week 12 | 25.0 percentage of participants |
| Belatacept+VIB4920 | Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) | Week 24 | 25.0 percentage of participants |
| Belatacept+VIB4920 | Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) | Week 48 | 25.0 percentage of participants |
Secondary
Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR), Graft Loss, Death or Loss to Follow-up (LTFU)
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.
Time frame: Week 12, 24, 48
Population: Efficacy Evaluable Set: All participants who received the revised regimen of Thymoglobulin and steroids, and any dose of IP. Participants enrolled in protocol v3 - 4 were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Belatacept+VIB4920 | Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR), Graft Loss, Death or Loss to Follow-up (LTFU) | Week 12 | 25.0 percentage of participants |
| Belatacept+VIB4920 | Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR), Graft Loss, Death or Loss to Follow-up (LTFU) | Week 24 | 25.0 percentage of participants |
| Belatacept+VIB4920 | Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR), Graft Loss, Death or Loss to Follow-up (LTFU) | Week 48 | 25.0 percentage of participants |
Secondary
Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) of Grade 1A or Higher, Graft Loss or Death at 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.
Time frame: Weeks 12 and 48
Population: Efficacy Evaluable Set: All participants who received the revised regimen of Thymoglobulin and steroids, and any dose of IP. Participants enrolled in protocol v3 - 4 were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Belatacept+VIB4920 | Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) of Grade 1A or Higher, Graft Loss or Death at Weeks 12 and 48 | Week 12 | 25.0 percentage of participants |
| Belatacept+VIB4920 | Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) of Grade 1A or Higher, Graft Loss or Death at Weeks 12 and 48 | Week 48 | 25.0 percentage of participants |