Kidney; Complications, Allograft
Conditions
Keywords
chronic kidney allograft injury, complement protein, eculizumab, Kidney transplantation
Brief summary
This study is designed to assess the effectiveness of eculizumab in recipients of kidney transplantation with donor-specific antibodies (DSA) and worsening kidney function and to assess if eculizumab improves endothelial cell injury in the kidney. The investigators hypothesize that complement inhibition with eculizumab will reduce allograft injury, resulting from less complement-mediated injury of endothelial cells and less endothelial cell activation.
Detailed description
This study will address the clinical challenge that currently exists in the management of kidney transplant recipients who have developed de novo DSA, have deteriorating graft function, yet have no established treatment alternative. This is a randomized, open-label, pilot intervention trial. Post transplant patients with deteriorating renal function (defined as 20% reduction in GFR) will be screened for the development of DSA and biopsied for the presence of C4d deposition. All patients with DSA and those meeting inclusion/exclusion criteria will undergo protocol renal biopsy and will be assessed for C4d deposition. Participants will be randomized to treatment with eculizumab plus standard of care (SOC) or SOC only. Randomization will be stratified by C4d status (C4d+/C4d-) with 10 subjects (7 eculizumab, 3 SOC only) in each stratum. Eculizumab is an antibody that has been developed to inhibit the complement protein C5. Eculizumab will be delivered via IV according to the following schedule: * Eculizumab Induction 600mg IV every 7 days for 4 doses * Eculizumab 900mg IV 7 days later * Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks
Interventions
DRUGeculizumab
* Eculizumab Induction 600mg IV every 7 days for 4 doses * Eculizumab 900mg IV 7 days later * Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks
Sponsors
Alexion Pharmaceuticals, Inc.
Sanjay Kulkarni
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Kidney transplant recipients greater than 6 months from the date of transplant * Must be on standard immunosuppression: tacrolimus, mycophenolate mofetil, prednisone and have stable tacrolimus trough levels over past 3 months * Deteriorating renal function, as defined by 20% reduction in GFR (MDRD calculation) * Presence of DSA, as defined as MFI \> 1100 * Renal biopsy demonstrating no diffuse, irreversible end-stage organ injury (i.e. stage IV Fibrosis) * Renal biopsy demonstrating C4d deposition (stratum 1) or no C4d deposition (stratum 2)
Exclusion criteria
* History of CMV, BK, HSV or other viral infections * History of chronic, recurrent bacterial infections * Evidence of tubulitis on renal biopsy or other morphological features of acute cellular rejection or acute humoral rejection * Renal biopsy demonstrating diffuse, irreversible end-stage organ injury * Absolute GFR \< 25 (MDRD calculation) * Inability to provide informed consent * History of poor vascular access * Refusal to use double barrier contraception during study participation * Patients actively enrolled in other clinical trials
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline eGFR (Estimated Glomerular Filtration Rate) | Baseline | — |
| Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 | Months 2,3,4,5,6 | Primary statistical analysis of change from baseline was conducted with mixed effects modeling providing calculated estimates. |
| Group Difference Percentage Change in 6-month Estimated Glomerular Filtration Rate (eGFR) | 6 months | These data were calculated by mean 6-month eGFR minus baseline mean eGFR divided by baseline eGFR. Presented below are the between groups results. These results were derived from the results in the outcome Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Eculizumab eculizumab will be given in addition to standard immunosuppression regimen (oral tacrolimus or equivalent, MMF \[mycophenolate mofetil
\], prednisone)
eculizumab: • Eculizumab Induction 600mg IV every 7 days for 4 doses
* Eculizumab 900mg IV 7 days later
* Eculizumab Maintenance 900mg IV every 14 days for total of 26 weeks | 10 |
| no Additional Therapy patients in this arm will receive standard immunosuppression regimen (oral tacrolimus or equivalent, MMF, prednisone only, no additional therapy | 5 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 3 | 1 |
Baseline characteristics
| Characteristic | no Additional Therapy | Total | Eculizumab |
|---|---|---|---|
| Age, Continuous | 44 years | 43 years | 38 years |
| Baseline DSA (Donor Specific Antibody) MFI (mean fluorescent intensity) | 3,100 MFI | 4,600 MFI | 5,000 MFI |
| C4d Status at Randomization Negative | 4 participants | 9 participants | 5 participants |
| C4d Status at Randomization Positive | 1 participants | 6 participants | 5 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 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 | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) White | 2 Participants | 8 Participants | 6 Participants |
| Region of Enrollment United States | 5 participants | 15 participants | 10 participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 9 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 10 | 0 / 5 |
| serious Total, serious adverse events | 4 / 10 | 3 / 5 |
Outcome results
Primary
Baseline eGFR (Estimated Glomerular Filtration Rate)
Time frame: Baseline
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Eculizumab | Baseline eGFR (Estimated Glomerular Filtration Rate) | 30.04 mL/min/1.73 m2 |
| no Additional Therapy | Baseline eGFR (Estimated Glomerular Filtration Rate) | 30.04 mL/min/1.73 m2 |
Primary
Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6
Primary statistical analysis of change from baseline was conducted with mixed effects modeling providing calculated estimates.
Time frame: Months 2,3,4,5,6
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Eculizumab | Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 | Month 4 | 29.78 mL/min/1.73 m2 |
| Eculizumab | Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 | Month 3 | 29.56 mL/min/1.73 m2 |
| Eculizumab | Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 | Month 5 | 29.99 mL/min/1.73 m2 |
| Eculizumab | Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 | Month 6 | 30.21 mL/min/1.73 m2 |
| Eculizumab | Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 | Month 2 | 29.34 mL/min/1.73 m2 |
| no Additional Therapy | Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 | Month 6 | 28.69 mL/min/1.73 m2 |
| no Additional Therapy | Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 | Month 2 | 31.34 mL/min/1.73 m2 |
| no Additional Therapy | Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 | Month 5 | 29.35 mL/min/1.73 m2 |
| no Additional Therapy | Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 | Month 3 | 30.68 mL/min/1.73 m2 |
| no Additional Therapy | Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6 | Month 4 | 30.02 mL/min/1.73 m2 |
Comparison: Analysis used eGFR, group, time, and group-by-time variables.p-value: 0.09Mixed effects model analysis
Primary
Group Difference Percentage Change in 6-month Estimated Glomerular Filtration Rate (eGFR)
These data were calculated by mean 6-month eGFR minus baseline mean eGFR divided by baseline eGFR. Presented below are the between groups results. These results were derived from the results in the outcome Estimated Glomerular Filtration Rate (eGFR) at Months 2,3,4,5,6.
Time frame: 6 months
Population: These are the between groups percent change that represents the difference between groups when controlling for baseline. Outcome measure #2 provides the data by treatment arm where these data are derived.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Eculizumab | Group Difference Percentage Change in 6-month Estimated Glomerular Filtration Rate (eGFR) | Month 2 | 6.66 percentage change |
| Eculizumab | Group Difference Percentage Change in 6-month Estimated Glomerular Filtration Rate (eGFR) | Month 3 | 3.73 percentage change |
| Eculizumab | Group Difference Percentage Change in 6-month Estimated Glomerular Filtration Rate (eGFR) | Month 4 | 0.80 percentage change |
| Eculizumab | Group Difference Percentage Change in 6-month Estimated Glomerular Filtration Rate (eGFR) | Month 5 | -2.13 percentage change |
| Eculizumab | Group Difference Percentage Change in 6-month Estimated Glomerular Filtration Rate (eGFR) | Month 6 | -5.06 percentage change |