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

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

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).

Study Overview

• Status: Terminated
• Conditions: Antibody-mediated Rejection
• Intervention / Treatment: Drug: C1-esterase inhibitor; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Universitair Ziekenhuis Gasthuisberg
• France
  • Bordeaux, France, 33000
    • CHU de Bordeaux. Hôpital Pellegrin
  • Grenoble, France, 38043
    • CHU de Grenoble - Hôpital Michalon
  • Lille, France, 59000
    • Centre Regional Hospitalier Universitaire de Lille
  • Lyon, France, 69003
    • Hospital Edouard Herriot Lyon
  • Paris, France, 75743
    • Necker Hospital
  • Paris, France, 75010
    • Hôpital Saint Louis Paris
  • Toulouse, France, 31059
    • CHU Rangueil
• Germany
  • Berlin, Germany, 10117
    • Charite Berline
• Netherlands
  • Leiden, Netherlands, 2300
    • Leiden University Medical Center
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic De Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
• United Kingdom
  • London, United Kingdom, SE19RT
    • Guy'S Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama Hospital (at Birmingham)
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
  • California
    • San Francisco, California, United States, 94115
      • California Pacific
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale New Haven Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic (Rochester)
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • St. Barnabas Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10016
      • NYU
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist
  • Wisconsin
    • Madison, Wisconsin, United States, 53705-2281
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: C1-INH; C1-esterase inhibitor	Drug: C1-esterase inhibitor; C1-esterase inhibitor is a human plasma-derived lyophilised powder for reconstitution; Other Names: C1-INH
PLACEBO_COMPARATOR: Placebo; Excipients of C1-INH plus albumin	Drug: Placebo; Excipients of C1-INH plus albumin

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: CSL Behring

Publications and helpful links

General Publications

• Viklicky O, Slatinska J, Novotny M, Hruba P. Developments in immunosuppression. Curr Opin Organ Transplant. 2021 Feb 1;26(1):91-96. doi: 10.1097/MOT.0000000000000844.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 6, 2017
• Primary Completion (ACTUAL): January 20, 2021
• Study Completion (ACTUAL): January 20, 2021

Study Registration Dates

• First Submitted: July 17, 2017
• First Submitted That Met QC Criteria: July 17, 2017
• First Posted (ACTUAL): July 19, 2017

Study Record Updates

• Last Update Posted (ACTUAL): July 29, 2022
• Last Update Submitted That Met QC Criteria: July 25, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Renal; Antibody-mediated kidney transplant rejection
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins; Complement C1s
• Other Study ID Numbers: CSL842_3001; 2017-000348-17 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No