Antibody Mediated Rejection
Conditions
Keywords
Antibody Mediated Rejection, AMR, Acute Humoral Rejection, AHR, Living Donor, Kidney Transplant
Brief summary
The purpose of this trial was to determine the safety and efficacy of eculizumab in the prevention of antibody-mediated rejection (AMR) in sensitized recipients of a living donor kidney transplant requiring desensitization therapy.
Detailed description
The main objective of this study was to evaluate the safety and efficacy of eculizumab to prevent AMR in sensitized recipients of living donor kidney transplants requiring desensitization therapy prior to transplantation. The primary endpoint focused on acute AMR during the first 9 weeks post-transplantation. Patients were to be vaccinated against N. meningitidis at least 14 days prior to study drug initiation and revaccinated 30 days later. If not vaccinated 14 days prior, prophylactic antibiotics were to be administered. Pre-transplant infectious disease assessment was to be performed as part of the screening assessment. Patients were to undergo desensitization therapy according to the practice of the local transplant center prior to transplantation, and this desensitization practice was to be uniformly applied for all patients at that center throughout the study. The actual length of desensitization for an individual patient was based on the clinical judgment of the Transplant Center team. Rituximab was prohibited in all patients as part of the pre-transplantation desensitization therapy due to potential pharmacodynamic interactions. The control group was designed to test eculizumab against the best available care (referred to as standard of care, or SOC) consisting of plasmapheresis (PP) and/or intravenous immunoglobulin (IVIg). The best available care consisting of PP and IVIg was chosen because these modalities combined represented the most prevalent therapy reported in the literature and were the best available therapies at the time of this protocol's inception as per the transplant community.
Interventions
DRUGEculizumab
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female patients ≥18 years old 2. Patients with Stage IV or Stage V chronic kidney disease who will receive a kidney transplant from a living donor to whom they are sensitized and require desensitization prior to transplantation
Exclusion criteria
1. ABO incompatible with living donor 2. Any medical condition that, in the opinion of the Investigator, might interfere with the patient's participation in the study, poses an added risk for the patient, or confounds the assessment of the patient
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Failure Rate | 9 weeks post-transplantation | The primary efficacy variable was a binary outcome variable where patients meeting the composite endpoint of the occurrence of 1) biopsy-proven acute AMR, 2) graft loss, 3) patient death, or 4) loss to follow-up definition at Week 9 post-transplantation were considered treatment failures and all others were considered treatment successes. |
Countries
Australia, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Recruitment period lasted from Nov 2011 to Mar 2014. Forty-one sites in Australia, the European Union, and North America participated in this study.
Pre-assignment details
Written consent was provided prior to performing any study-required assessments (N = 275). Patients who passed screening (N = 137) underwent desensitization therapy according to local transplant center practice prior to transplantation. A total of 104 patients were randomized; of these, 102 were transplanted and received eculizumab or SOC.
Participants by arm
| Arm | Count |
|---|---|
| Eculizumab Patients in the eculizumab treatment group were to receive eculizumab for 9 weeks according to the following dosing regimen:
Eculizumab 1200 mg prior to allograft transplantation (Day 0, starting approximately one hour prior to kidney allograft reperfusion), eculizumab 900 mg (Days 1, 7, 14, 21, and 28), and eculizumab 1200 mg (Weeks 5, 7 and 9). All doses of eculizumab were administered intravenously. | 51 |
| Standard of Care (SOC) Patients in the standard of care (SOC) treatment group received prophylactic therapy for acute AMR according to the SOC choice at each participating investigative site, which could have included any combination of plasmapheresis (PP) and intravenous immunoglobulin (IVIg). Patients randomized to SOC who were diagnosed with AMR could have received eculizumab for the treatment of AMR after initially receiving PP and/or IVIg. | 51 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Transplantectomy | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Eculizumab | Standard of Care (SOC) |
|---|---|---|---|
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adults (18-64 years) | 96 Participants | 47 Participants | 49 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized From 65 to 84 years | 6 Participants | 4 Participants | 2 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn - gestational age < 37 wk | 0 Participants | 0 Participants | 0 Participants |
| Highest Single Donor-Specific Antibodies (DSA) | 8431.7 mean fluorescence intensity (MFI) STANDARD_DEVIATION 4157.87 | 8135 mean fluorescence intensity (MFI) STANDARD_DEVIATION 4048.08 | 8740.7 mean fluorescence intensity (MFI) STANDARD_DEVIATION 4289.97 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) White | 73 Participants | 37 Participants | 36 Participants |
| Region of Enrollment Australia | 5 Participants | 4 Participants | 1 Participants |
| Region of Enrollment France | 10 Participants | 3 Participants | 7 Participants |
| Region of Enrollment Germany | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Italy | 6 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Netherlands | 3 Participants | 0 Participants | 3 Participants |
| Region of Enrollment Norway | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Spain | 7 Participants | 3 Participants | 4 Participants |
| Region of Enrollment Sweden | 5 Participants | 1 Participants | 4 Participants |
| Region of Enrollment United Kingdom | 15 Participants | 10 Participants | 5 Participants |
| Region of Enrollment United States | 47 Participants | 26 Participants | 21 Participants |
| Sex: Female, Male Female | 67 Participants | 37 Participants | 30 Participants |
| Sex: Female, Male Male | 35 Participants | 14 Participants | 21 Participants |
| Total Donor-Specific Antibodies (DSA) | 16411.1 mean fluorescence intensity (MFI) STANDARD_DEVIATION 13380.16 | 15394.7 mean fluorescence intensity (MFI) STANDARD_DEVIATION 14163.78 | 17469.8 mean fluorescence intensity (MFI) STANDARD_DEVIATION 12573.44 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 51 | 1 / 51 |
| other Total, other adverse events | 51 / 51 | 51 / 51 |
| serious Total, serious adverse events | 43 / 51 | 48 / 51 |
Outcome results
Primary
Treatment Failure Rate
The primary efficacy variable was a binary outcome variable where patients meeting the composite endpoint of the occurrence of 1) biopsy-proven acute AMR, 2) graft loss, 3) patient death, or 4) loss to follow-up definition at Week 9 post-transplantation were considered treatment failures and all others were considered treatment successes.
Time frame: 9 weeks post-transplantation
Population: Full analysis set, defined as patients who were randomized, received a living donor kidney transplant, and were treated (either with eculizumab or SOC), based on randomized treatment groups.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eculizumab | Treatment Failure Rate | 5 Participants |
| Standard of Care | Treatment Failure Rate | 7 Participants |
p-value: 0.7695% CI: [-23.9, 16.3]Fisher Exact