Antibody-mediated Rejection
Conditions
Keywords
Antibody-mediated kidney transplant rejection, Renal
Brief summary
This is a double-blind, randomized-withdrawal, placebo-controlled study in kidney transplant patients with AMR to evaluate the efficacy and safety of human plasma-derived C1-esterase inhibitor as add-on to standard of care (IVIG).
Interventions
C1-esterase inhibitor is a human plasma-derived lyophilised powder for reconstitution
DRUGPlacebo
Excipients of C1-INH plus albumin
Sponsors
CSL Behring
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized-withdrawal
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female at least 18 years of age; * Evidence of at least one donor-specific antibody (DSA); * Recipient of a kidney transplant; * Achieved a steady-state, post-transplant eGFR ≥ 40 mL/min/1.73 m2 within 60 days of post-transplant OR a 50% increase in urine output with a 50% decrease in serum creatinine over the first 7 days post-transplant in subjects with slow or delayed graft function; * Acute AMR.
Exclusion criteria
* Recipient of an en bloc kidney transplant; * Current active hepatitis C virus (HCV) infection; * Active bacterial or fungal infection; * Ongoing dialysis \>2 weeks; * Known congenital bleeding or coagulopathy disorder; * Current cancer or a history of cancer; * Female subjects who are pregnant or breast feeding; * Male or female subjects who are unwilling to use contraception or who are not surgically sterile.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Loss-of-response During Treatment Period 2 (TP2) | Up to 38 weeks | Loss of response is defined as 1 of the following, whichever occurs first: * Decline in Estimated Glomerular Filtration Rate (eGFR), or * Allograft failure, or * Subject death by any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With All-cause Allograft Failure During TP2 | Up to 38 weeks | — |
| Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of Treatment Period 1 (TP1) | Baseline and 13 weeks | — |
| Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of TP2 | Baseline and 38 weeks | — |
| The Rate of Change of eGFR During TP2 as Defined by the Slope of the Mean Regression of eGFR Over Time at End of TP2 | Up to 38 weeks | The Sponsor terminated the study due to futility of enrolment. Because of the study termination, limited efficacy results are presented in this report. |
| Time to All-cause Allograft Failure Through the Follow up Period | Up to approximately 208 weeks | The Sponsor terminated the study due to futility of enrolment. Because of the study termination, limited efficacy results are presented in this report. |
| Number of Responders at the End-of-TP1 | Up to 13 weeks | Responders were defined as subjects whose End-of-TP1 eGFR was ≥ 90% of baseline eGFR and ≥ 20 mL/min/1.73 m2. |
| Number of Participants With All-cause Allograft Failure During TP2 | Up to 38 weeks | Allograft failure is defined as 1 of the following: * Allograft nephrectomy, institution of permanent dialysis, or return to the transplant waitlist for renal transplant, whichever occurs first, OR * Subject death by any cause |
| Proportion of Subjects Surviving Through the Follow-up Period | Up to approximately 208 weeks | The Sponsor terminated the study due to futility of enrolment. Because of the study termination, limited efficacy results are presented in this report. |
| Percent of Participants With Any Adverse Event (AE) Assessed as Related to Investigational Product | Up to approximately 42 weeks after the time of first investigational product administration | — |
| Mean Pre-dose C1-esterase Inhibitor Functional Activity | Up to 13 weeks | C1-esterase Inhibitor may play a role in the prevention of antibody-mediated rejection (AMR) following kidney transplant. Low levels of C1 esterase inhibitor concentration and its functional activity may lead to AMR. Patients with AMR may go on to lose their kidney transplant and have other associated health risks. Levels of C1-esterase inhibitor functional activity in plasma is described as a percent. |
| Area Under the Plasma Concentration Time Curve (AUC0-t) for C1-INH Functional Activity | Up to 72 hours after post-dose on Day 10 and on Day 77 of Period 1 | C1-esterase Inhibitor may play a role in the prevention of antibody-mediated rejection (AMR) following kidney transplant. Low levels of C1 esterase inhibitor concentration and its functional activity may lead to AMR. Patients with AMR may go on to lose their kidney transplant and have other associated health risks. Levels of C1-esterase inhibitor functional activity is described as a percent. |
| Time to Maximum Plasma Concentration (Tmax) for C1-INH Functional Activity | Up to 72 hours after post-dose on Day 10 and on Day 77 of Period 1 | — |
| Percent of Responders at the End-of-TP1 | Up to 13 weeks | Responders were defined as subjects whose End-of-TP1 eGFR was ≥ 90% of baseline eGFR and ≥ 20 mL/min/1.73 m2. |
Countries
Belgium, France, Germany, Netherlands, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Only 13 participants that completed Period 1 were eligible to continue to Period 2. Eligibility based on the amendment in place at the time the subject completed Period 1.
Participants by arm
| Arm | Count |
|---|---|
| C1-INH C1-esterase inhibitor (CSL842)
C1-esterase inhibitor: C1-esterase inhibitor is a human plasma-derived lyophilised powder for reconstitution administered at a dose of 60 IU/kg | 63 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 (Open-label) | Adverse Event | 4 | 0 |
| Period 1 (Open-label) | Lost to Follow-up | 1 | 0 |
| Period 1 (Open-label) | Other | 2 | 0 |
| Period 1 (Open-label) | Physician Decision | 2 | 0 |
| Period 1 (Open-label) | Terminated by sponsor | 1 | 0 |
| Period 2 (Randomized, Blinded) | Death | 0 | 1 |
| Period 2 (Randomized, Blinded) | Lack of Efficacy | 1 | 0 |
Baseline characteristics
| Characteristic | C1-INH |
|---|---|
| Age, Continuous | 43.3 years STANDARD_DEVIATION 13.83 |
| Age, Customized >=18 and <65 years | 57 participants |
| Age, Customized >=65 years | 6 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 52 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 39 Participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 63 | 0 / 7 | 1 / 6 |
| other Total, other adverse events | 46 / 63 | 4 / 7 | 5 / 6 |
| serious Total, serious adverse events | 25 / 63 | 1 / 7 | 3 / 6 |
Outcome results
Primary
Percent of Participants With Loss-of-response During Treatment Period 2 (TP2)
Loss of response is defined as 1 of the following, whichever occurs first: * Decline in Estimated Glomerular Filtration Rate (eGFR), or * Allograft failure, or * Subject death by any cause.
Time frame: Up to 38 weeks
Population: Modified Intent-to-Treat Analysis Set (mITT) - All subjects randomized under the original protocol and under all protocol amendments were included in this population except the subjects randomized prior to Amendment 3 who did not satisfy the responder criteria updated in Amendment 3.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C1-INH | Percent of Participants With Loss-of-response During Treatment Period 2 (TP2) | 33.3 percentage of participants |
| Placebo | Percent of Participants With Loss-of-response During Treatment Period 2 (TP2) | 40.0 percentage of participants |
Secondary
Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of TP2
Time frame: Baseline and 38 weeks
Population: mITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| C1-INH | Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of TP2 | 7.75 mL/min/1.73m^2 | Standard Deviation 8.454 |
| Placebo | Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of TP2 | 15.25 mL/min/1.73m^2 | Standard Deviation 10.444 |
Secondary
Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of Treatment Period 1 (TP1)
Time frame: Baseline and 13 weeks
Population: The Run-in Safety (RiS) analysis set comprised all subjects who received at least 1 dose of C1-INH during TP1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| C1-INH | Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of Treatment Period 1 (TP1) | -0.75 mL/min/1.73m^2 |
Secondary
Area Under the Plasma Concentration Time Curve (AUC0-t) for C1-INH Functional Activity
C1-esterase Inhibitor may play a role in the prevention of antibody-mediated rejection (AMR) following kidney transplant. Low levels of C1 esterase inhibitor concentration and its functional activity may lead to AMR. Patients with AMR may go on to lose their kidney transplant and have other associated health risks. Levels of C1-esterase inhibitor functional activity is described as a percent.
Time frame: Up to 72 hours after post-dose on Day 10 and on Day 77 of Period 1
Population: PK (some participants had missing data)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C1-INH | Area Under the Plasma Concentration Time Curve (AUC0-t) for C1-INH Functional Activity | Day 10 | 15229.84819 hours*percent functional activity | Standard Deviation 4149.16754 |
| C1-INH | Area Under the Plasma Concentration Time Curve (AUC0-t) for C1-INH Functional Activity | Day 77 | 12742.20883 hours*percent functional activity | Standard Deviation 4445.31881 |
Secondary
Mean Pre-dose C1-esterase Inhibitor Functional Activity
C1-esterase Inhibitor may play a role in the prevention of antibody-mediated rejection (AMR) following kidney transplant. Low levels of C1 esterase inhibitor concentration and its functional activity may lead to AMR. Patients with AMR may go on to lose their kidney transplant and have other associated health risks. Levels of C1-esterase inhibitor functional activity in plasma is described as a percent.
Time frame: Up to 13 weeks
Population: The pharmacokinetic analysis set (PK) comprised all subjects who consented to provide rich PK sampling, who received ≥ 1 dose of C1-INH, and who had ≥ 1 measurable level of C1-INH functional activity. (some participants had missing data) or C1-INH antigen concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C1-INH | Mean Pre-dose C1-esterase Inhibitor Functional Activity | week 2 | 168.86 percent functional activity | Standard Deviation 64.059 |
| C1-INH | Mean Pre-dose C1-esterase Inhibitor Functional Activity | week 11 | 179.32 percent functional activity | Standard Deviation 58.551 |
Secondary
Number of Participants With All-cause Allograft Failure During TP2
Allograft failure is defined as 1 of the following: * Allograft nephrectomy, institution of permanent dialysis, or return to the transplant waitlist for renal transplant, whichever occurs first, OR * Subject death by any cause
Time frame: Up to 38 weeks
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C1-INH | Number of Participants With All-cause Allograft Failure During TP2 | 0 number of participants |
| Placebo | Number of Participants With All-cause Allograft Failure During TP2 | 1 number of participants |
Secondary
Number of Responders at the End-of-TP1
Responders were defined as subjects whose End-of-TP1 eGFR was ≥ 90% of baseline eGFR and ≥ 20 mL/min/1.73 m2.
Time frame: Up to 13 weeks
Population: RiS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C1-INH | Number of Responders at the End-of-TP1 | 33 participants |
Secondary
Percent of Participants With All-cause Allograft Failure During TP2
Time frame: Up to 38 weeks
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C1-INH | Percent of Participants With All-cause Allograft Failure During TP2 | 0 percentage of participants |
| Placebo | Percent of Participants With All-cause Allograft Failure During TP2 | 20 percentage of participants |
Secondary
Percent of Participants With Any Adverse Event (AE) Assessed as Related to Investigational Product
Time frame: Up to approximately 42 weeks after the time of first investigational product administration
Population: RiS and RWS \[The Randomized Withdrawal Safety (RWS) analysis set included all subjects in the ITT analysis set who received at least 1 dose of the investigational product after randomization during TP2\]
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C1-INH | Percent of Participants With Any Adverse Event (AE) Assessed as Related to Investigational Product | 20.6 percentage of participants |
| Placebo | Percent of Participants With Any Adverse Event (AE) Assessed as Related to Investigational Product | 0 percentage of participants |
| Placebo | Percent of Participants With Any Adverse Event (AE) Assessed as Related to Investigational Product | 16.7 percentage of participants |
Secondary
Percent of Responders at the End-of-TP1
Responders were defined as subjects whose End-of-TP1 eGFR was ≥ 90% of baseline eGFR and ≥ 20 mL/min/1.73 m2.
Time frame: Up to 13 weeks
Population: RiS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C1-INH | Percent of Responders at the End-of-TP1 | 52.4 percentage of responders |
Secondary
Proportion of Subjects Surviving Through the Follow-up Period
The Sponsor terminated the study due to futility of enrolment. Because of the study termination, limited efficacy results are presented in this report.
Time frame: Up to approximately 208 weeks
Population: The Sponsor terminated the study due to futility of enrolment. Because of the study termination, limited efficacy results are presented in this report. Due to study termination, data was not collected for this endpoint.
Secondary
The Rate of Change of eGFR During TP2 as Defined by the Slope of the Mean Regression of eGFR Over Time at End of TP2
The Sponsor terminated the study due to futility of enrolment. Because of the study termination, limited efficacy results are presented in this report.
Time frame: Up to 38 weeks
Population: The Sponsor terminated the study due to futility of enrolment. Because of the study termination, limited efficacy results are presented in this report. Due to study termination, data was not collected for this endpoint.
Secondary
Time to All-cause Allograft Failure Through the Follow up Period
The Sponsor terminated the study due to futility of enrolment. Because of the study termination, limited efficacy results are presented in this report.
Time frame: Up to approximately 208 weeks
Population: The Sponsor terminated the study due to futility of enrolment. Because of the study termination, limited efficacy results are presented in this report. Due to study termination, data was not collected for this endpoint.
Secondary
Time to Maximum Plasma Concentration (Tmax) for C1-INH Functional Activity
Time frame: Up to 72 hours after post-dose on Day 10 and on Day 77 of Period 1
Population: PK (some participants had missing data)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C1-INH | Time to Maximum Plasma Concentration (Tmax) for C1-INH Functional Activity | Day 10 | 9.9298 hours | Standard Deviation 16.3288 |
| C1-INH | Time to Maximum Plasma Concentration (Tmax) for C1-INH Functional Activity | Day 77 | 37.9251 hours | Standard Deviation 22.8543 |