Efficacy and Safety of Human Plasma-derived C1-esterase Inhibitor as add-on to Standard of Care for the Treatment of Refractory Antibody Mediated Rejection (AMR) in Adult Renal Transplant Recipients

Study Overview
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Brief Summary
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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).

Official Title
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A Double-blind, Randomized-withdrawal, Placebo-controlled Study to Evaluate the Efficacy and Safety of Human Plasma-derived C1-esterase Inhibitor as add-on to Standard of Care for the Treatment of Refractory Antibody Mediated Rejection in Adult Renal Transplant Recipients

Conditions
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Antibody-mediated Rejection

Intervention / Treatment
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* Drug: C1-esterase inhibitor
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Randomized-withdrawal
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: C1-INH<br>C1-esterase inhibitor | Drug: C1-esterase inhibitor<br>* C1-esterase inhibitor is a human plasma-derived lyophilised powder for reconstitution<br>* Other names: C1-INH;|
| Placebo Comparator: Placebo<br>Excipients of C1-INH plus albumin | Drug: Placebo<br>* Excipients of C1-INH plus albumin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 38 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Up to 38 weeks | 
| 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 | The Sponsor terminated the study due to futility of enrolment. Because of the study termination, limited efficacy results are presented in this report. | Up to 38 weeks | 
| 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. | Up to approximately 208 weeks | 
| 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. | Up to 13 weeks | 
| 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. | Up to 13 weeks | 
| 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. | Up to approximately 208 weeks | 
| 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 | 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. | Up to 13 weeks | 
| 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. | Up to 72 hours after post-dose on Day 10 and on Day 77 of Period 1 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antibody-mediated kidney transplant rejection, Renal