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

Phase 3

Terminated

• Conditions: Antibody-mediated Rejection
• Interventions: Drug: Placebo; Drug: C1-esterase inhibitor

• Registration Number: NCT03221842
• Lead Sponsor: CSL Behring

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-07-17
• Study First Submitted QC: 2017-07-17
• Study First Posted: 2017-07-19
• Study Start: 2017-11-06
• Primary Completion: 2021-01-20
• Study Completion: 2021-01-20
• Results First Submitted: 2021-11-18
• Results First Submitted QC: 2021-12-17
• Results First Posted: 2022-01-18
• Status Verified: 2022-07
• Last Update Submitted: 2022-07-25
• Last Update Posted: 2022-07-29

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 63

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Excipients of C1-INH plus albumin
C1-INH	C1-esterase inhibitor	C1-esterase inhibitor

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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
Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of TP2	Baseline and 38 weeks
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.
Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of Treatment Period 1 (TP1)	Baseline and 13 weeks
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.
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.
Percent of Participants With All-cause Allograft Failure During TP2	Up to 38 weeks
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
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.
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.
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
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.

Trial Locations

Locations (26)

California Pacific; 🇺🇸 San Francisco, California, United States

University of Illinois Chicago; 🇺🇸 Chicago, Illinois, United States

St. Barnabas Medical Center; 🇺🇸 Livingston, New Jersey, United States

Hospital Edouard Herriot Lyon; 🇫🇷 Lyon, France

CHU de Bordeaux. Hôpital Pellegrin; 🇫🇷 Bordeaux, France

Necker Hospital; 🇫🇷 Paris, France

Columbia University; 🇺🇸 New York, New York, United States

University of Alabama Hospital (at Birmingham); 🇺🇸 Birmingham, Alabama, United States

CHU de Grenoble - Hôpital Michalon; 🇫🇷 Grenoble, France

Hopital saint Louis Paris; 🇫🇷 Paris, France

Centre Regional Hospitalier Universitaire de Lille; 🇫🇷 Lille, France

CHU Rangueil; 🇫🇷 Toulouse, France

NYU; 🇺🇸 New York, New York, United States

Charite Berline; 🇩🇪 Berlin, Germany

Mayo Clinic (Rochester); 🇺🇸 Rochester, Minnesota, United States

Vanderbilt University; 🇺🇸 Nashville, Tennessee, United States

Mayo Clinic Arizona; 🇺🇸 Phoenix, Arizona, United States

Yale New Haven Hospital; 🇺🇸 New Haven, Connecticut, United States

Brigham & Women's; 🇺🇸 Boston, Massachusetts, United States

Universitair Ziekenhuis Gasthuisberg; 🇧🇪 Leuven, Belgium

Leiden University Medical Center; 🇳🇱 Leiden, Netherlands

University of Wisconsin; 🇺🇸 Madison, Wisconsin, United States

Houston Methodist; 🇺🇸 Houston, Texas, United States

Hospital Universitari Vall d'Hebron; 🇪🇸 Barcelona, Spain

Hospital Clinic de Barcelona; 🇪🇸 Barcelona, Spain

Guy's Hospital; 🇬🇧 London, United Kingdom