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

• ClinicalTrials.gov Identifier: NCT03221842
• Recruitment Status: Terminated
• First Posted: July 19, 2017
• Results First Posted: January 18, 2022
• Last Update Posted: July 29, 2022
• Sponsor: CSL Behring
• Information provided by (Responsible Party): CSL Behring

Tracking Information

• First Submitted Date: July 17, 2017
• First Posted Date: July 19, 2017
• Results First Submitted Date: November 18, 2021
• Results First Posted Date: January 18, 2022
• Last Update Posted Date: July 29, 2022
• Actual Study Start Date: November 6, 2017
• Actual Primary Completion Date: January 20, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 17, 2021)

Percent of Participants With Loss-of-response During Treatment Period 2 (TP2) [ Time Frame: 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.

Original Primary Outcome Measures (submitted: July 17, 2017)

Time to loss of response during Treatment Period 2 [ Time Frame: Up to approximately 25 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.

Current Secondary Outcome Measures (submitted: July 25, 2022)

• Number of Participants With All-cause Allograft Failure During TP2 [ Time Frame: 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
• Percent of Participants With All-cause Allograft Failure During TP2 [ Time Frame: Up to 38 weeks ]
• Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of Treatment Period 1 (TP1) [ Time Frame: Baseline and 13 weeks ]
• Absolute Change From Baseline in Estimated Glomerular Filtration Rate at End of TP2 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 Responders at the End-of-TP1 [ Time Frame: 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.
• Proportion of Subjects Surviving Through the Follow-up Period [ Time Frame: 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 [ Time Frame: Up to approximately 42 weeks after the time of first investigational product administration ]
• Mean Pre-dose C1-esterase Inhibitor Functional Activity [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to 72 hours after post-dose on Day 10 and on Day 77 of Period 1 ]

Original Secondary Outcome Measures (submitted: July 17, 2017)

• Time to all-cause allograft failure after randomization into Treatment Period 2 [ Time Frame: Up to approximately 195 weeks ]
  Allograft failure is defined as 1 of the following, whichever occurs first:

  • Allograft nephrectomy.
  • Permanent dialysis.
  • Return to the transplant waitlist.
• Percentage of subjects with response to treatment at the end of Treatment Period 1 [ Time Frame: Up to approximately 13 weeks ]
  Response is defined as an increase in eGFR.
• Percentage of subjects with sustained improvement of eGFR during Treatment Period 2 [ Time Frame: Up to approximately 25 weeks ]
  Sustained improvement is defined as an increase in eGFR
• Change from screening in Banff category scores at up to 38 weeks [ Time Frame: Screening and up to approximately 38 weeks ]
  Banff category scores are used to grade the histopathology of kidney allograft biopsies using a scoring system of 0 (best possible) to 3 (worst possible)
• Percentage of subjects with new or worsening chronic active AMR during Treatment Period 2 [ Time Frame: Up to approximately 25 weeks ]
  New or worsening chronic active AMR during Treatment Period 2, as defined by the Banff 2015 criteria [Loupy et al, 2017]
• Percentage of subjects with splenectomy during Treatment Period 1 and during Treatment Period 2 [ Time Frame: Up to approximately 38 weeks ]
• Percentage of subjects surviving at the end of Treatment Period 2 [ Time Frame: Up to approximately 38 weeks ]
• Percentage of subjects with a surviving allograft at the end of Treatment Period 2 [ Time Frame: Up to approximately 38 weeks ]
• Time to subject death after randomization into Treatment Period 2 [ Time Frame: Up to approximately 195 weeks ]
• Percentage of subjects 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 ]
• Pre-dose C1-INH functional activity [ Time Frame: Day 1, approximately Week 12, and approximately Week 38 ]
• Time to maximum plasma concentration (Cmax) for C1-INH functional activity [ Time Frame: Up to 72 hours after dose ]
• Area under the plasma concentration time curve (AUC0-t) for C1-INH functional activity [ Time Frame: Up to 72 hours after dose ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Randomized-withdrawal

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

• Condition: Antibody-mediated Rejection

Intervention

• Drug: C1-esterase inhibitor
  C1-esterase inhibitor is a human plasma-derived lyophilised powder for reconstitution
  Other Name: C1-INH
• Drug: Placebo
  Excipients of C1-INH plus albumin

Study Arms

• Experimental: C1-INH
  C1-esterase inhibitor
  Intervention: Drug: C1-esterase inhibitor
• Placebo Comparator: Placebo
  Excipients of C1-INH plus albumin
  Intervention: Drug: Placebo

• 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 22, 2021): 63
• Original Estimated Enrollment (submitted: July 17, 2017): 90
• Actual Study Completion Date: January 20, 2021
• Actual Primary Completion Date: January 20, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, France, Germany, Netherlands, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03221842
• Other Study ID Numbers: CSL842_3001; 2017-000348-17 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: CSL Behring
• Original Responsible Party: Same as current
• Current Study Sponsor: CSL Behring
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Program Director; CSL Behring

• PRS Account: CSL Behring
• Verification Date: July 2022