A Pilot Study to Evaluate the Use of C1 Esterase Inhibitor (Human) in Patients With Acute Antibody-Mediated Rejection

• ClinicalTrials.gov Identifier: NCT01147302
• Recruitment Status: Completed
• First Posted: June 22, 2010
• Results First Posted: July 9, 2015
• Last Update Posted: August 13, 2015
• Sponsor: Shire
• Information provided by (Responsible Party): Shire

Tracking Information

• First Submitted Date: June 16, 2010
• First Posted Date: June 22, 2010
• Results First Submitted Date: June 16, 2015
• Results First Posted Date: July 9, 2015
• Last Update Posted Date: August 13, 2015
• Study Start Date: November 2010
• Actual Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 22, 2015)

Change From Baseline in Histopathology Endpoints [ Time Frame: Within 72 hours prior to first dose of study drug, Day 20 ]

The protocol-specified Day 20 (post-treatment) biopsy was compared to the qualifying biopsy to assess changes in histopathology for light and immunofluorescence microscopy. The Central Pathologist provided the following categorical information from the qualifying biopsy in an AMR Scorecard: C4d Score (0-100), Margination Score (0-100) Glomerulitis Score (0-100), Vasculitis Score (0-100), Glomerulosclerosis Score (0-100), Chronic Glomerulopathy Score (0-100), Interstitial Fibrosis Score (0-100), and the Chronic Vasculitis Score (0-100), with 0 being absence of abnormal histopathology. The "qualifying" renal allograft biopsy was performed as standard of care (SOC) within 12 months after transplant and prior to screening for this study. The first dose of study drug (Day 1) was administered within 72 hours after qualifying biopsy. A negative change from baseline indicates that histopathology has improved. Endpoint includes subjects with both Qualifying and Day 20 Biopsies.

• Original Primary Outcome Measures (submitted: June 16, 2010): Effect of C1 Esterase Inhibitor (human) on histopathology in AMR [ Time Frame: 3 weeks ]

Current Secondary Outcome Measures (submitted: July 22, 2015)

• Number of Participants With Resolution of The Qualifying Episode of Antibody-Mediated Rejection (AMR) [ Time Frame: 90 days after start of treatment ]
  The "qualifying" renal allograft biopsy was performed as standard of care within 12 months after transplant and prior to screening. The qualifying biopsy was used to establish the diagnosis of AMR and was evaluated for all of the following to obtain baseline assessments: the presence of C4d, and monocyte or neutrophil infiltration around the peritubular capillaries (PTCs) and/or glomeruli. The Central Pathologist provided the following information from the qualifying biopsy in an AMR Scorecard: C4d Score, Glomerulitis Score, Vasculitis Score, Glomerulosclerosis Score, Chronic Glomerulopathy Score, Interstitial Fibrosis Score, and the Chronic Vasculitis Score. The Banff AMR Scoring System was used to summarize these scores. Resolution determination was made based on clinical criteria (improvement of serum creatinine ± decrease of DSA titer, and/or increase in urine output) and histopathology. The first dose of study drug (Day 1) was administered within 72 hours after qualifying biopsy.
• Change From Baseline in Serum Creatinine [ Time Frame: From Day 1 to Days 20 and 90 ]
  Graft function was assessed by measuring serum creatinine. Serum creatinine level was obtained directly from laboratory results. Baseline was the last value collected prior to first dose of study drug. A negative change from baseline indicates that serum creatinine levels have decreased. Values for Day 90 were collected +/= 14 days.
• Change From Baseline in Creatinine Clearance [ Time Frame: From Day 1 to Days 20 and 90 ]
  Graft function was assessed by measuring creatinine clearance. Creatinine clearance was calculated by the Cockcroft-Gault formula. Baseline was the last value collected prior to first dose of study drug. A positive change from baseline indicates that the clearance rate has increased. Values for Day 90 were collected +/= 14 days.
• Number of Plasmapheresis Sessions [ Time Frame: From Day 1 through Days 20 and 90 ]
  If necessary, rescue therapy included plasmapheresis. Participating centers used plasmapheresis for desensitization, if necessary, prior to transplant and also for the treatment of acute AMR. Plasmapheresis therapy was performed for the qualifying episode of AMR according to standards at the investigational site and at the discretion of the investigator. Sessions include those prior to first dose. If plasmapheresis therapy occurred on the same day as study drug dosing, study drug was administered after completion of the plasmapheresis session.
• Number of Participants Who Required Salvage Splenectomy [ Time Frame: From Day 1 to Day 90 ]
  If necessary, rescue therapy included splenectomy.
• Number of Deaths [ Time Frame: From Day 1 to Day 90 ]
• Number of Participants With Allograft Failure [ Time Frame: From the day of enrollment to Day 90 ]
  Allograft failure was determined by the presence of the following criteria: current renal allograft nephrectomy and/or a clinical determination that the allograft irreversibly and irrevocably ceased functioning.
• Serum Concentrations of C1 Inhibitor (C1 INH) Antigen [ Time Frame: Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion ]
  Plasma samples were used for the determination of antigenic C1 INH concentrations. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion.
• Serum Concentrations of C1 INH Functional Activity [ Time Frame: Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion ]
  Plasma samples were used for the determination of functional C1 INH concentrations. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion.
• Time to Maximum Plasma Concentration (Tmax) of C1 INH [ Time Frame: Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion ]
  Plasma samples were used for the determination of antigenic and functional C1 INH concentrations. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion.
• Area Under The Concentration-Time Curve (AUC) of C1 INH Antigen [ Time Frame: Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion ]
  Plasma samples were used for the determination of antigenic C1 INH parameters. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), and area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion.
• Area Under The Concentration-Time Curve (AUC) of C1 INH Functional Activity [ Time Frame: Day 13 pre-plasmapheresis (if performed) and pre-dose then 0.5, 2, 24, 48, 96, 168 and 288 (optional) hours post start of infusion ]
  Plasma samples were used for the determination of functional C1 INH parameters. Primary pharmacokinetic (PK) parameters were calculated using baseline-corrected concentration-versus-time data following the last dose and noncompartmental techniques, as appropriate. The following PK parameters were calculated: baseline concentration (Cbaseline), maximum concentration (Cmax), average concentration at steady-state (Cav,ss), time to maximum concentration (tmax), minimum concentration (Cmin), and area under the concentration-time curve from time zero to last quantifiable concentration at time t (AUC0-t). Blood was collected on Day 13 at the indicated timepoints. If plasmapheresis was performed on a dosing day, blood samples were obtained before plasmapheresis, prior to study drug administration (post-plasmapheresis), and at time points relative to the start of infusion.

• Original Secondary Outcome Measures (submitted: June 16, 2010): Change in renal function [ Time Frame: 3 weeks, 90 days, and 6 months ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Pilot Study to Evaluate the Use of C1 Esterase Inhibitor (Human) in Patients With Acute Antibody-Mediated Rejection
• Official Title: A Randomized Double-Blind Placebo-Controlled Pilot Study to Evaluate the Safety and Effect of CINRYZE® (C1 Esterase Inhibitor [Human]) for the Treatment of Acute Antibody-Mediated Rejection in Recipients of Donor-Sensitized Kidney Transplants
• Brief Summary: The purpose of this research study is to evaluate the safety, effect, and pharmacology of C1 Esterase Inhibitor (human) in kidney transplant patients with acute Antibody-Mediated Rejection (AMR).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Graft Rejection

Intervention

• Biological: Placebo
• Biological: C1 Esterase Inhibitor (Human)
  Other Name: C1 INH-nf

Study Arms

• Experimental: C1 Esterase Inhibitor (Human)
  Subjects were to receive C1 esterase inhibitor intravenously at a rate of approximately 1 mL per minute as tolerated. Subjects were to receive a total of 7 doses over a 2-week period: an initial IV infusion of 5000 U (not to exceed 100 U/kg) on Day 1, followed by 2500 U (not to exceed 50 U/kg) IV on Days 3, 5, 7, 9, 11, and 13
  Intervention: Biological: C1 Esterase Inhibitor (Human)
• Placebo Comparator: Normal Saline
  placebo infused as above
  Intervention: Biological: Placebo

• Publications *: Montgomery RA, Orandi BJ, Racusen L, Jackson AM, Garonzik-Wang JM, Shah T, Woodle ES, Sommerer C, Fitts D, Rockich K, Zhang P, Uknis ME. Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study. Am J Transplant. 2016 Dec;16(12):3468-3478. doi: 10.1111/ajt.13871. Epub 2016 Jun 27.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 22, 2015): 18
• Original Estimated Enrollment (submitted: June 16, 2010): 10
• Actual Study Completion Date: June 2013
• Actual Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria include:

• ≥18 years of age.
• Weigh ≥50 kg.
• Donor specific antibody identified.

Exclusion Criteria include:

• Any surgical or medical condition that could interfere with the administration of study drug or interpretation of study results.
• History of allergic reaction to C1 Esterase Inhibitor or other blood products.
• Participation in the active dosing phase of any other investigational drug study within 30 days prior to dosing with study drug.
• Pregnancy or lactation.
• Receipt of any experimental agents for AMR within 1 month prior to the first dose of study drug.
• Any infection that causes hemodynamic compromise.
• History of bleeding or clotting abnormality.

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: Germany, United States

Administrative Information

• NCT Number: NCT01147302
• Other Study ID Numbers: 0624-201; 2012-000441-12 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Shire
• Study Sponsor: Shire
• Collaborators: Not Provided

Investigators

• Study Director: Marc E Uknis, MD; ViroPharma Incorporated

• PRS Account: Shire
• Verification Date: March 2014