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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

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ClinicalTrials.gov Identifier: NCT03221842
Recruitment Status : Terminated (The study was terminated early due to futility of enrolment and not for safety reasons.)
First Posted : July 19, 2017
Results First Posted : January 18, 2022
Last Update Posted : July 29, 2022
Sponsor:
Information provided by (Responsible Party):
CSL Behring

Tracking Information
First Submitted Date  ICMJE July 17, 2017
First Posted Date  ICMJE July 19, 2017
Results First Submitted Date  ICMJE November 18, 2021
Results First Posted Date  ICMJE January 18, 2022
Last Update Posted Date July 29, 2022
Actual Study Start Date  ICMJE November 6, 2017
Actual Primary Completion Date January 20, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE 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  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Randomized-withdrawal
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Antibody-mediated Rejection
Intervention  ICMJE
  • 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  ICMJE
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: January 22, 2021)
63
Original Estimated Enrollment  ICMJE
 (submitted: July 17, 2017)
90
Actual Study Completion Date  ICMJE January 20, 2021
Actual Primary Completion Date January 20, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   France,   Germany,   Netherlands,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03221842
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Current Responsible Party CSL Behring
Original Responsible Party Same as current
Current Study Sponsor  ICMJE CSL Behring
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Program Director CSL Behring
PRS Account CSL Behring
Verification Date July 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP