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A Multicenter Study to Evaluate the Efficacy and Safety of Cinryze® for the Treatment of Acute Antibody-mediated Rejection in Participants With Kidney Transplant

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ClinicalTrials.gov Identifier: NCT02547220
Recruitment Status : Terminated (Following a pre-scheduled interim analysis performed by the DMC, it was determined that the study met the pre-specified criteria for futility.)
First Posted : September 11, 2015
Results First Posted : July 13, 2020
Last Update Posted : July 13, 2020
Sponsor:
Information provided by (Responsible Party):
Takeda ( Shire )

Tracking Information
First Submitted Date  ICMJE September 2, 2015
First Posted Date  ICMJE September 11, 2015
Results First Submitted Date  ICMJE May 29, 2020
Results First Posted Date  ICMJE July 13, 2020
Last Update Posted Date July 13, 2020
Actual Study Start Date  ICMJE May 20, 2016
Actual Primary Completion Date May 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 9, 2020)
Percentage of Participants With New or Worsening Transplant Glomerulopathy (TG) at Month 6 Post-Treatment [ Time Frame: Month 6 ]
New or worsening TG at month 6 by the standard score was defined as an increase in one or more between qualifying biopsy and 6-month biopsy. New or worsening TG was measured by Banff 2013 criteria (standard score) using allograft glomerulopathy (Cg0-Cg3): Cg0- No GBM double contours by light microscopy (LM) or electron microscopy (EM); Cg1- no GBM double contours by LM but GBM double contours in at least 3 glomerular capillaries by EM; Cg2- Double contours affecting 26 to 50% of peripheral capillary loops in the most affected of nonsclerotic glomeruli; Cg3- Double contours affecting more than 50% of peripheral capillary loops in the most affected of nonsclerotic glomeruli with a score range of 0 (no allograft glomerulopathy) and 3 (severe glomerulopathy). Percentage of participants with new or worsening TG at Month 6 post-treatment was reported.
Original Primary Outcome Measures  ICMJE
 (submitted: September 10, 2015)
Proportion of subjects with new or worsening transplant glomerulopathy (TG) within 6 months post-treatment as determined by Banff criteria [ Time Frame: Screening to Month 6 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 9, 2020)
  • Number of Participants With All-Cause Graft Failure at Month 48 [ Time Frame: Month 48 ]
    Graft failure was determined as the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment more than [>] 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and estimated glomerular filtration rate (eGFR) less than or equal to (<=) 15 milliliter (mL)/minute (min)/1.73 meter (m)^2.
  • Change From Baseline in Renal Function up to Month 48 [ Time Frame: Baseline, up to Month 48 ]
    Renal function was measured as glomerular filtration rate calculated by the modification of diet in renal disease (eGFRMDRD).
  • Change From Baseline With Pre-Antibody-Mediated Rejection (AMR) in Renal Function up to Month 48 [ Time Frame: Pre-AMR Baseline, up to Month 48 ]
    Renal function was measured as glomerular filtration rate calculated by the modification of diet in renal disease (eGFRMDRD). Pre-AMR baseline was the highest eGFRMDRD value obtained following the kidney transplant and within 30 days prior to the qualifying AMR episode.
  • Number of Participants With Proteinuria Levels at Month 48 [ Time Frame: Month 48 ]
    Proteinuria included spot urine protein, urine creatinine, and urine protein/urine creatinine ratio.
  • Change From Pre-Antibody-Mediated Rejection (AMR) Baseline in Histopathology Per Banff Criteria at Month 6 [ Time Frame: Pre-AMR Baseline, Month 6 ]
    Histopathological diagnosis of acute rejection was measured by Banff 2013 criteria: Glomerulitis score (g0-g3), allograft glomerulopathy (Cg0-cg3), Tubulitis score (T0-T3), Intimal arteritis score (V0-V3), peritubular capillaritis (PTC) (ptc0-ptc3) and Interstitial Inflammation score (i0-i3). The histopathology was a composite of the sub-scores. Each of the sub-scores or histopathology score ranges from 0 ( no histopathology) to 3 (more severe histopathology).
  • Number of Participants With All-Cause Graft Failure at Month 6 [ Time Frame: Month 6 ]
    Graft failure was determined by the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment more than [>] 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and estimated glomerular filtration rate (eGFR) less than or equal to (<=) 15 milliliter (mL)/minute (min)/1.73 meter (m)^2.
  • Number of Participants With Graft Failure Due to Antibody-Mediated Rejection (AMR) Episodes at Month 48 [ Time Frame: Month 48 ]
    Graft failure was determined by the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment more than [>] 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and estimated glomerular filtration rate (eGFR) less than or equal to (<=) 15 milliliter (mL)/minute (min)/1.73 meter (m)^2.
  • Time to All-Cause Graft Failure up to Month 48 [ Time Frame: Up to Month 48 ]
    Graft failure was determined by the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment more than [>] 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and estimated glomerular filtration rate (eGFR) less than or equal to (<=) 15 milliliter (mL)/minute (min)/1.73 meter (m)^2. Time to all-cause graft failure in months was calculated as (Date of graft failure - Date of first dose + 1)/30.25.
  • Time to Graft Failure Due to Antibody-Mediated Rejection (AMR) Episodes up to Month 48 [ Time Frame: Up to Month 48 ]
    Graft failure was determined by the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment > 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and eGFR <=15 mL/ min/1.73m^2. Time to graft failure due to AMR episodes in months was calculated as (Date of graft failure due to AMR - Date of first dose + 1)/30.25.
  • Number of Participants With Resolution of the Qualifying Antibody-Mediated Rejection (AMR) Episodes at Month 48 [ Time Frame: Month 48 ]
    Number of participants with resolution of the qualifying AMR episodes at Month 48.
  • Time to Resolution of Qualifying Antibody-Mediated Rejection (AMR) Episodes up to Month 48 [ Time Frame: Up to Month 48 ]
    Time to resolution of qualifying AMR episodes was calculated as (Date of qualifying AMR resolution - Date of first dose + 1)/30.25. Participants who didn't had resolution of qualifying AMR episodes and still on-study were censored at the date of last visit; Participants who had completed the study without resolution of qualifying AMR were censored at the date of study completion; participants who discontinued from the study without resolution of qualifying AMR were censored at the date of early discontinuation.
  • Number of Participants Who Were Alive at Month 36 [ Time Frame: Month 36 ]
    Number of participants who were alive at Month 36 (study terminated instead of Month 48) were reported.
  • Time to All-Cause Mortality up to Month 48 [ Time Frame: Up to Month 48 ]
    Time to all-cause mortality was calculated as (Date of discontinuation due to death - Date of first dose + 1)/30.25. Participants who are alive and still on-study were censored at the date of last visit; Participants who had completed the study were censored at the date of study completion; Participants who discontinued from the study but not due to death were censored at the date of early discontinuation.
  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From start of study drug administration up to study termination (Month 36) ]
    An adverse event (AE) was any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurred in a participant participating in a clinical study with the sponsor's product, regardless of causal relationship. TEAEs were defined as events that started or worsened on or after the date of the first dose of investigational product, but no later than 30 days following the last dose of investigational product, within a treatment period.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 10, 2015)
  • Proportion of subjects with all-cause graft failure) [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • Time to all-Cause Graft Failure [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • Proportion of subjects with graft failure due to AMR [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • Change from baseline in renal allograft function (eGFR as calculated by the Modification of Diet in Renal Disease (MDRD formula) [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • Change from baseline in histopathology at Month 6 post-treatment per Banff criteria [ Time Frame: Screening to Month 6 ]
  • Time to first recurrence of biopsy-proven acute AMR after dosing [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • Change from baseline in serum Cr [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • Proportion of subjects with salvage splenectomy [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • Overall subject survival [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • Frequency of donor- specific antibody (DSA) reduction therapy beyond protocol-mandated treatment [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • Treatment-emergent adverse events (TEAEs) [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • Change in Vital Signs (Heart Rate) [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • Change in Vital Signs (Blood Pressure) [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • antibodies to C1inhibitor (INH) [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • clinical safety laboratory testing (Hematology) [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • clinical safety laboratory testing (Serum Chemistry) [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • clinical safety laboratory testing (Serum Blood urea nitrogen/Cr) [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
  • time to graft failure due to AMR [ Time Frame: Screening to Month 48(+/- 14 days) EOS ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Multicenter Study to Evaluate the Efficacy and Safety of Cinryze® for the Treatment of Acute Antibody-mediated Rejection in Participants With Kidney Transplant
Official Title  ICMJE A Randomized Double-blind Placebo-controlled Study to Evaluate the Efficacy and Safety of Cinryze® (C1 Esterase Inhibitor [Human]) for the Treatment of Acute Antibody-mediated Rejection in Kidney Transplant Patients
Brief Summary The main purpose of the study is to evaluate the efficacy of CINRYZE administered with plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free immunoglobulin (IVIg) for the treatment of acute antibody-mediated rejection (AMR) of renal allograft in kidney transplant recipients as measured by the proportion of participants with new or worsening transplant glomerulopathy (TG) at 6 months after treatment initiation.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Acute Antibody-Mediated Rejection (AMR)
Intervention  ICMJE
  • Biological: Cinryze®
    Participants will receive 5000 Units of CINRYZE (50 millilitre [mL] of CINRYZE/ 50 mL of normal saline) on Day 1 and 2500 Units of CINRYZE (25 mL of CINRYZE/ 75 mL of normal saline) on Day 3, 5, 7, 9, 11, and 13 respectively.
  • Drug: Placebo
    Participants will receive 7 doses of matched placebo over 13 days of treatment.
Study Arms  ICMJE
  • Experimental: Cinryze®
    Participants will receive 5000 Units of CINRYZE (50 millilitre [mL] of CINRYZE/ 50 mL of normal saline) on Day 1 and 2500 Units of CINRYZE (25 mL of CINRYZE/ 75 mL of normal saline) on Day 3, 5, 7, 9, 11, and 13 respectively.
    Intervention: Biological: Cinryze®
  • Placebo Comparator: Placebo
    Participants will receive 7 doses of matched placebo over 13 days of treatment.
    Intervention: Drug: Placebo
Publications * Not Provided

*   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: July 9, 2020)
39
Original Estimated Enrollment  ICMJE
 (submitted: September 10, 2015)
112
Actual Study Completion Date  ICMJE May 31, 2019
Actual Primary Completion Date May 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Be greater than or equal to (>=) 18 and less than or equal to (<=) 70 years of age.
  2. Weigh >= 45 kg with a body mass index (BMI) less than (<) 35 kilogram (kg)/meter (m)^2 at screening.
  3. Have human leukocyte antigen (HLA) donor-specific antibody (DSA) identified at the time of diagnosis of AMR. If it is anticipated that the local DSA results will not be available within the screening period, previously obtained local DSA results can be used to assess eligibility, if obtained after kidney transplant and within 30 days prior to the qualifying AMR episode. In any instance, a local DSA test should still be performed at the time of AMR diagnosis.
  4. Have a first qualifying episode of AMR in the participant's current renal allograft between 72 hours (h) and 12 months after transplant defined by a renal allograft biopsy demonstrating neutrophil and/or monocyte infiltration in the peritubular capillaries (PTC) and/or glomeruli with or without evidence of 4th complement protein degradation product (C4d) deposition by immunohistopathology according to 2013 Banff criteria.
  5. Have achieved adequate renal function defined as: Pre-AMR baseline estimated glomerular filtration rate calculated by the Modification of Diet in Renal Disease (eGFRMDRD) >=20 millilitre (mL)/minute (min) /1.73m^2 for a qualifying AMR episode occurring <=21 days after transplant or pre-AMR baseline eGFRMDRD >=30 mL/min/1.7m^2 for a qualifying AMR episode occurring greater than (>) 21 days after transplant. The pre-AMR baseline is the highest eGFRMDRD value obtained following the kidney transplant and within 30 days prior to the qualifying AMR episode. If more than 1 eGFRMDRD value is available, a mean of the 2 highest values (at least 1 day apart and both prior to the AMR episode) will be used as the pre-AMR baseline value. If no eGFRMDRD was obtained within 30 days prior to biopsy, it can be evaluated within a 60 day period.
  6. Receive first dose of investigational product after 7 days after the kidney transplant procedure and within 7 days after the qualifying renal allograft biopsy procedure that was positive for AMR.
  7. Be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.
  8. If female and of child-bearing potential, must have a negative urine pregnancy test confirmed by a negative serum beta human chorionic gonadotropin (beta-HCG) pregnancy test at the Screening Visit and must have a negative urine pregnancy test at the Day 1 visit.
  9. Agree to comply with any applicable contraceptive requirements of the protocol.

Exclusion Criteria:

  1. Have received pediatric en bloc kidney transplant.
  2. Have primary Focal Segmental Glomerulosclerosis, rapidly progressive glomerulonephritis, membrano-proliferative glomerulonephritis type 1 (including C3 glomerulopathy), "dense deposit disease", or thrombotic microangiopathy as the cause of native kidney failure.
  3. Have prior or concurrent non-renal solid organ transplant or hematopoietic stem cell transplant (HSCT) or have more than 2 completed kidney transplant procedures (note: 1 double kidney transplant procedure is considered to be 1 procedure).
  4. Have a known neoplastic lesion in the transplanted allograft
  5. Have, any ongoing infection that causes hemodynamic compromise or as determined by the investigator, any surgical or medical condition that could interfere with the administration of investigational product, interpretation of study results, or could compromise participant safety, including (as determined by the transplanting surgeon and documented in the operative report) any major technical complications of the renal artery, renal vein, or ureteral anastomosis
  6. Have ongoing treatment for hepatitis C virus (HCV) infection.
  7. Have had a recent myocardial infarction (MI) within the past 6 months and/or at the time of screening are treated with anticoagulants and/or antiplatelet agents (excluding aspirin) for a previous myocardial infarction.
  8. Have a history of: abnormal bleeding, clotting events or disorders (excluding a history of clotted hemodialysis access or superficial thrombophlebitis in the absence of medically confirmed coagulopathy), any coagulopathy (documented or clinically suspected) For example, participants should be excluded if they have a history of renal allograft arterial or venous thrombosis, deep vein thrombosis, pulmonary embolism, ischemic cerebrovascular accident (stroke) or transient ischemic attack (TIA), any large vessel thrombosis.
  9. Have a history of allergic reaction to CINRYZE or other blood products.
  10. Have had any change in androgen therapy (example, danazol, oxandrolone, stanozolol, testosterone), tranexamic acid, epsilon-aminocaproic acid, or other fibrinolytics within 3 months before the first dose of investigational product.
  11. Have participated in the active dosing phase of any other investigational drug study within 30 days prior to dosing with investigational product.
  12. Have any of the following local laboratory values reported prior to dosing with investigational product: Within 24 h prior to participant dosing, white blood cell (WBC) count <0.5×109/litre (L) or >20×109/L (the value of >20×109/L should be excluded if obtained during steroid treatment), Within 24 h prior to participant dosing platelet count <25×109/L or >600×109/L
  13. Be pregnant or breastfeeding.
  14. Have received any of the following agents within 1 month prior to the first dose of investigational product: Sucrose-containing intravenous immunoglobulin (IVIg), Any C1 inhibitor (C1 INH) (plasma-derived [example, CINRYZE®, Berinert®, Cetor®] or recombinant [example, Rhucin®]), Eculizumab (Soliris®), Ecallantide (Kalbitor®).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (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 Canada,   France,   Germany,   Netherlands,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02547220
Other Study ID Numbers  ICMJE SHP616-302
2015-000726-11 ( 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: Yes
Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers
Responsible Party Takeda ( Shire )
Study Sponsor  ICMJE Shire
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Study Director Shire
PRS Account Takeda
Verification Date May 2020

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