Delayed Graft Function
Conditions
Keywords
DGF, Dialysis, Kidney, Kidney Transplantation, eGFR, Complement, Eculizumab
Brief summary
The purpose of this study was to determine if eculizumab is safe and could be used to prevent delayed graft function (DGF) following kidney transplantation.
Interventions
DRUGEculizumab
Eculizumab is a complement component 5 inhibitor.
DRUGPlacebo
0.9% sodium chloride
Sponsors
CTI Clinical Trial and Consulting Services
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, 18 years or older * Has dialysis-dependent renal failure (initiated more than 2 months prior to transplant) * Participant is to receive a first kidney transplant from a standard criteria donor or expanded criteria donor deceased donor with a DGF risk score using the Irish scale of ≥25% (to be determined prior to surgery and before randomization) * Able to provide written informed consent * Willing and able to comply with the requirements of the study protocol * Female participants of child-bearing potential must have a negative serum pregnancy test (serum beta-human chorionic gonadotropin) and must be practicing an effective, reliable, and medically approved contraceptive regimen at the time of consent and for up to 5 months following discontinuation of treatment
Exclusion criteria
* Participant to receive a multi-organ transplant * Participant to receive kidney(s) from donors \<6 years of age * Participant to receive a dual kidney transplant (from same donor, including en bloc) * Participant to receive a living donor kidney * Participant is highly sensitized (high risk to develop acute antibody-mediated rejection) to the donor (as determined by local center practice). Testing to determine high risk may include but is not limited to flow cytometric cross match, single antigen bead testing and/or complement dependent cytotoxicity * Participant has received a previous transplant * Participant is participating in another investigational study * Participant has a body mass index \>40 kilograms/square meter at screening * Participant will be the recipient of an A, B, O Blood Glycoproteins (ABO) (blood type) incompatible kidney (A2 donors to B and O recipients will be allowed if the site has the ability to confirm A2 subtype) * Participant will receive a kidney from a donation after cardiac death donor * Participant has a predicted Irish model risk of DGF \<25% * Female participants who are pregnant or breast feeding * Female participants of child bearing potential who are unable or unwilling to use a medically acceptable form of contraception * Participants with a history of human immunodeficiency virus, or active hepatitis C virus or hepatitis B virus infection * Participants with active bacterial or other infection which is clinically significant in the opinion of the Investigator * Participants with a history of splenectomy * Participants with unresolved meningococcal disease * Participants with an unresolved systemic bacterial or fungal infection * Participants with known or suspected hereditary complement deficiency (for example, but not limited to: atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria) * Participant has a current malignancy or a history of any malignancy (within the past 5 years), except non-metastatic basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix that has been treated appropriately * Participant has a history of or is believed by the Investigator to have used an illicit drug(s) and/or abused alcohol within 3 months prior to screening * Participant has a psychiatric or physical illness that in the opinion of the Investigator would interfere with the ability of the participant to participate in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Of Participants With Delayed Graft Function (DGF) In The First Seven Days Post-transplant | First 7 days post transplantation | Results are reported for the DGF composite endpoint, defined as the occurrence of DGF (dialysis for any reason in the first 7 days post transplantation), graft loss, death, or loss to follow-up (including discontinuation) in the first 7 days post transplantation and for each item of the composite endpoint. Loss to follow-up included withdrawal due to any reason other than death. The sum of the counts in the events that make up the DGF composite may be greater than the composite count, because a participant who experienced multiple events was only counted once in the composite. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Of Participants With DGF, Functional DGF, And Immediate Graft Function | First 7 days post transplantation | DGF was defined as a requirement for dialysis for any reason in the first 7 days post transplantation; functional DGF was defined as no need for dialysis during the first 7 days post transplantation and either (1) a \<70% reduction in serum creatinine during the first 7 days post transplantation, or (2) failure of serum creatinine to decrease by at least 10% daily on 3 consecutive days, both measured during the first 7 days post transplantation. Blood and urine samples were collected, but because the study failed to demonstrate a treatment effect and the program subsequently lost funding, the collected data from the samples could not be analyzed to generate summary level data. As such, the data set for this secondary outcome measure cannot be summarized. |
| Percentage Of Participants Who Required Dialysis Post Transplantation | First 30 days post transplantation | The need for dialysis was assessed by evaluation of renal function; this included urine volume, blood urea nitrogen, serum creatinine, and, starting on Day 2, the creatinine reduction ratio. Blood and urine samples were collected, but because the study failed to demonstrate a treatment effect and the program subsequently lost funding, the collected data from the samples could not be analyzed to generate summary level data. As such, the data set for this secondary outcome measure cannot be summarized. |
| Estimated Glomerular Filtration Rate (eGFR) | Day 28 post transplantation | The eGFR was calculated by using the Modification of Diet in Renal Disease 7 equation at Day 28 post transplantation. The equation requires serum creatinine, age, ethnicity, gender, blood urea nitrogen, and albumin. The eGFR was calculated retrospectively from participant demographics and laboratory chemistries and is reported in mL/min/square meter (m\^2). |
| Percentage Of Participants With Rejection-free Graft Survival | Week 26 and 52 post transplantation | Graft survival was defined as not having biopsy-proven acute rejection per Banff criteria, graft loss, or participant death. Participants who did not experience graft loss or death were censored at 365 days or the day they withdrew, whichever came first. There were no time-specific protocol mandated biopsies. Kidney biopsy would have been performed for cause at the discretion of the Investigator to assess poor graft function and would have been obtained prior to initiating treatment of suspected allograft rejection. Only summaries of Kaplan-Meier estimates of graft survival at Week 26 (Month 6) and Week 52 (Month 12) are reported. |
Countries
Australia, Brazil, Canada, Czechia, France, Germany, Italy, Spain, United States
Participant flow
Recruitment details
Fifty-nine centers in Australia, Brazil, Canada, Czech Republic, France, Germany, Italy, Spain, and the United States of America participated in this study. The study recruited participants who had been receiving dialysis for a median of approximately 50 months before undergoing transplantation and received a kidney from a deceased donor.
Pre-assignment details
Written consent was provided prior to study-required assessments (N=333). Participants who passed screening (N=314) were vaccinated against Neisseria meningitidis. A total of 314 were randomized; of these, 286 underwent transplantation and received eculizumab or placebo. Two participants received placebo but withdrew prior to transplantation.
Participants by arm
| Arm | Count |
|---|---|
| Eculizumab Participants received 2 doses of eculizumab: the first dose was just prior to reperfusion of the allograft and the second dose was within 18 to 24 h after completion of administration of the first dose. Eculizumab was administered by IV infusion over 25 to 45 min for each dose. The first dose was 1200 mg in 240 mL (5 mg/mL); the second dose was 900 mg in 180 mL (5 mg/mL). | 142 |
| Placebo Participants received 2 doses of placebo: the first dose was just prior to reperfusion of the allograft and the second dose was within 18 to 24 h after completion of administration of the first dose. Placebo was administered by IV infusion over 25 to 45 min for each dose. The first dose was 240 mL of 0.9% NaCl; the second dose was 180 mL of 0.9% NaCl. | 146 |
| Total | 288 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Death | 7 | 7 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Pre-transplant Withdrawal | 0 | 2 |
| Overall Study | Withdrawal by Subject | 5 | 4 |
Baseline characteristics
| Characteristic | Eculizumab | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 12.29 | 57.3 years STANDARD_DEVIATION 12.65 | 57.1 years STANDARD_DEVIATION 13.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 46 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 108 Participants | 221 Participants | 113 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 21 Participants | 10 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 38 Participants | 75 Participants | 37 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 9 Participants | 16 Participants | 7 Participants |
| Race/Ethnicity, Customized Unknown | 4 Participants | 7 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 88 Participants | 180 Participants | 92 Participants |
| Sex: Female, Male Female | 47 Participants | 92 Participants | 45 Participants |
| Sex: Female, Male Male | 95 Participants | 196 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 142 | 7 / 146 |
| other Total, other adverse events | 139 / 142 | 142 / 146 |
| serious Total, serious adverse events | 92 / 142 | 102 / 146 |
Outcome results
Primary
Percentage Of Participants With Delayed Graft Function (DGF) In The First Seven Days Post-transplant
Results are reported for the DGF composite endpoint, defined as the occurrence of DGF (dialysis for any reason in the first 7 days post transplantation), graft loss, death, or loss to follow-up (including discontinuation) in the first 7 days post transplantation and for each item of the composite endpoint. Loss to follow-up included withdrawal due to any reason other than death. The sum of the counts in the events that make up the DGF composite may be greater than the composite count, because a participant who experienced multiple events was only counted once in the composite.
Time frame: First 7 days post transplantation
Population: Full Analysis Set: all participants who were randomized to treatment and received a deceased donor kidney transplant and at least 1 dose of study drug (placebo or eculizumab).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eculizumab | Percentage Of Participants With Delayed Graft Function (DGF) In The First Seven Days Post-transplant | DGF | 33.8 percentage of participants |
| Eculizumab | Percentage Of Participants With Delayed Graft Function (DGF) In The First Seven Days Post-transplant | Graft Loss | 0.7 percentage of participants |
| Eculizumab | Percentage Of Participants With Delayed Graft Function (DGF) In The First Seven Days Post-transplant | Death | 0.0 percentage of participants |
| Eculizumab | Percentage Of Participants With Delayed Graft Function (DGF) In The First Seven Days Post-transplant | Lost to Follow-up (including discontinuation) | 3.5 percentage of participants |
| Eculizumab | Percentage Of Participants With Delayed Graft Function (DGF) In The First Seven Days Post-transplant | DGF Composite | 35.9 percentage of participants |
| Placebo | Percentage Of Participants With Delayed Graft Function (DGF) In The First Seven Days Post-transplant | Lost to Follow-up (including discontinuation) | 1.4 percentage of participants |
| Placebo | Percentage Of Participants With Delayed Graft Function (DGF) In The First Seven Days Post-transplant | DGF Composite | 41.7 percentage of participants |
| Placebo | Percentage Of Participants With Delayed Graft Function (DGF) In The First Seven Days Post-transplant | DGF | 39.6 percentage of participants |
| Placebo | Percentage Of Participants With Delayed Graft Function (DGF) In The First Seven Days Post-transplant | Death | 1.4 percentage of participants |
| Placebo | Percentage Of Participants With Delayed Graft Function (DGF) In The First Seven Days Post-transplant | Graft Loss | 3.5 percentage of participants |
Comparison: Analysis of DGF compositep-value: 0.398395% CI: [0.49, 1.33]Regression, Logistic
Secondary
Estimated Glomerular Filtration Rate (eGFR)
The eGFR was calculated by using the Modification of Diet in Renal Disease 7 equation at Day 28 post transplantation. The equation requires serum creatinine, age, ethnicity, gender, blood urea nitrogen, and albumin. The eGFR was calculated retrospectively from participant demographics and laboratory chemistries and is reported in mL/min/square meter (m\^2).
Time frame: Day 28 post transplantation
Population: Safety Set: all participants who received at least 1 dose of study drug (placebo or eculizumab) and made the Day 28 visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eculizumab | Estimated Glomerular Filtration Rate (eGFR) | 42.640 mL/min/1.73 m^2 | Standard Deviation 20.7491 |
| Placebo | Estimated Glomerular Filtration Rate (eGFR) | 39.954 mL/min/1.73 m^2 | Standard Deviation 20.3288 |
Secondary
Percentage Of Participants Who Required Dialysis Post Transplantation
The need for dialysis was assessed by evaluation of renal function; this included urine volume, blood urea nitrogen, serum creatinine, and, starting on Day 2, the creatinine reduction ratio. Blood and urine samples were collected, but because the study failed to demonstrate a treatment effect and the program subsequently lost funding, the collected data from the samples could not be analyzed to generate summary level data. As such, the data set for this secondary outcome measure cannot be summarized.
Time frame: First 30 days post transplantation
Population: Full Analysis Set: all participants who were randomized to treatment and received a deceased donor kidney transplant and at least 1 dose of study drug (placebo or eculizumab). Because the study failed to demonstrate a treatment effect and the program subsequently lost funding, collected data could not be analyzed to generate summary level data.
Secondary
Percentage Of Participants With DGF, Functional DGF, And Immediate Graft Function
DGF was defined as a requirement for dialysis for any reason in the first 7 days post transplantation; functional DGF was defined as no need for dialysis during the first 7 days post transplantation and either (1) a \<70% reduction in serum creatinine during the first 7 days post transplantation, or (2) failure of serum creatinine to decrease by at least 10% daily on 3 consecutive days, both measured during the first 7 days post transplantation. Blood and urine samples were collected, but because the study failed to demonstrate a treatment effect and the program subsequently lost funding, the collected data from the samples could not be analyzed to generate summary level data. As such, the data set for this secondary outcome measure cannot be summarized.
Time frame: First 7 days post transplantation
Population: Full Analysis Set: all participants who were randomized to treatment and received a deceased donor kidney transplant and at least 1 dose of study drug (placebo or eculizumab). Because the study failed to demonstrate a treatment effect and the program subsequently lost funding, collected data could not be analyzed to generate summary level data.
Secondary
Percentage Of Participants With Rejection-free Graft Survival
Graft survival was defined as not having biopsy-proven acute rejection per Banff criteria, graft loss, or participant death. Participants who did not experience graft loss or death were censored at 365 days or the day they withdrew, whichever came first. There were no time-specific protocol mandated biopsies. Kidney biopsy would have been performed for cause at the discretion of the Investigator to assess poor graft function and would have been obtained prior to initiating treatment of suspected allograft rejection. Only summaries of Kaplan-Meier estimates of graft survival at Week 26 (Month 6) and Week 52 (Month 12) are reported.
Time frame: Week 26 and 52 post transplantation
Population: Full Analysis Set: all participants who were randomized to treatment and received a deceased donor kidney transplant and at least 1 dose of study drug (placebo or eculizumab). Eculizumab participants censored: Month 6 = 7; Month 12 = 132. Placebo participants censored: Month 6 = 2; Month 12 = 128.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eculizumab | Percentage Of Participants With Rejection-free Graft Survival | Graft Survival at Month 6 | 94.89 percentage of participants |
| Eculizumab | Percentage Of Participants With Rejection-free Graft Survival | Graft Survival at Month 12 | 92.66 percentage of participants |
| Placebo | Percentage Of Participants With Rejection-free Graft Survival | Graft Survival at Month 6 | 90.96 percentage of participants |
| Placebo | Percentage Of Participants With Rejection-free Graft Survival | Graft Survival at Month 12 | 88.69 percentage of participants |