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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 : Recruiting
First Posted : September 11, 2015
Last Update Posted : June 28, 2018
Sponsor:
Information provided by (Responsible Party):
Shire

September 2, 2015
September 11, 2015
June 28, 2018
October 1, 2015
February 1, 2022   (Final data collection date for primary outcome measure)
Number of Participants With new or Worsening Transplant Glomerulopathy (TG) at 6 Months Post-treatment [ Time Frame: Month 6 ]
Number of participants with new or worsening TG at 6 months post-treatment will be assessed
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 ]
Complete list of historical versions of study NCT02547220 on ClinicalTrials.gov Archive Site
  • Number of Participants With all-Cause Graft Failure [ Time Frame: Month 48 ]
    Participants with all-cause graft failure such as return to permanent dialysis and/or removal of the transplanted kidney and/or clinical determination of cessation of graft function at 4 years following treatment of the initial qualifying antibody-mediated rejection (AMR) episode will be assessed.
  • Renal Function at Month 6 [ Time Frame: Month 6 ]
    Renal function will be measured by glomerular filtration rate calculated by the modification of diet in renal disease (eGFRMDRD).
  • Renal Function [ Time Frame: Pre-AMR Baseline, 1,2,3 and 4 years post AMR episode ]
    Renal function will be measured by glomerular filtration rate calculated by the modification of diet in renal disease (eGFRMDRD).
  • Change From pre-Antibody-Mediated Rejection (AMR) Baseline in Renal Function [ Time Frame: Pre-AMR Baseline, 6 months, 1,2,3 and 4 years post AMR episode ]
    Change from pre-AMR (30 days prior to the biopsy for the qualifying AMR episode) baseline in renal function will be assessed.
  • Change From Baseline in Renal Function [ Time Frame: Baseline, 6 months, 1,2,3 and 4 years ]
    Change from baseline in renal function will be assessed.
  • Proteinuria [ Time Frame: Baseline, 6 months; 1,2,3 and 4 years post AMR episode ]
    Proteinuria will be measured.
  • Change From Baseline in Proteinuria [ Time Frame: Baseline, 6 months; 1,2,3 and 4 years post AMR episode ]
    Change from baseline in proteinuria will be assessed.
  • Change From pre-AMR Baseline in Histopathology per Banff Criteria at Month 6 [ Time Frame: Pre-AMR Baseline, Month 6 ]
    Change from pre-AMR (30 days prior to the biopsy for the qualifying AMR episode) baseline in histopathology per Banff criteria will be assessed.
  • Number of Participants With all-Cause Graft Failure at 6 Months [ Time Frame: Month 6 ]
    Participants with all-cause graft failure such as return to permanent dialysis and/or removal of the transplanted kidney and/or clinical determination of cessation of graft function at 6 months following treatment of the initial qualifying AMR episode will be assessed.
  • Number of Participants With Graft Failure due To AMR [ Time Frame: 48 months ]
    Graft failure is 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 millilitere [mL]/minute [min]/1.73 meter [m]^2.
  • Time to all-Cause Graft Failure [ Time Frame: Baseline to 48 months ]
    Time to all-cause graft failure will be assessed.
  • Time to Graft Failure due to AMR [ Time Frame: Baseline to 48 months ]
    Time to graft failure due to AMR will be assessed. Graft failure is 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.
  • Number of Participants With Resolution of the Qualifying AMR Episodes [ Time Frame: Baseline to 48 months ]
    Number of participants with resolution of the qualifying AMR episodes will be assessed.
  • Time to Resolution of AMR Episodes [ Time Frame: Baseline to 48 months ]
    Time to resolution of AMR episodes will be assessed.
  • Number of Participants Alive at 4 Years [ Time Frame: Year 4 ]
    Number of participants alive at 4 years will be assessed.
  • Time to all-Cause Mortality [ Time Frame: Baseline to 48 months ]
    Time to all-cause mortality will be assessed.
  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Baseline to 49 months ]
    An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.
  • 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 ]
Not Provided
Not Provided
 
A Multicenter Study to Evaluate the Efficacy and Safety of Cinryze® for the Treatment of Acute Antibody-mediated Rejection in Participants With Kidney Transplant
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
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.
Not Provided
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Acute Antibody-Mediated Rejection (AMR)
  • 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.
  • 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
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
112
Same as current
February 1, 2022
February 1, 2022   (Final data collection date for primary outcome measure)

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®).
Sexes Eligible for Study: All
18 Years to 70 Years   (Adult, Older Adult)
No
Contact: Shire Contact clinicaltransparency@shire.com
Canada,   France,   Germany,   Netherlands,   Spain,   United States
 
 
NCT02547220
SHP616-302
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
Shire
Shire
Not Provided
Study Director: Shire Study Physician Shire
Shire
June 2018

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