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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

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.

Condition or disease Intervention/treatment Phase
Acute Antibody-Mediated Rejection (AMR) Biological: Cinryze® Drug: Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 112 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 1, 2015
Estimated Primary Completion Date : February 1, 2022
Estimated Study Completion Date : February 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/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.
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.

Placebo Comparator: Placebo
Participants will receive 7 doses of matched placebo over 13 days of treatment.
Drug: Placebo
Participants will receive 7 doses of matched placebo over 13 days of treatment.




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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.

  2. 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).

  3. 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).

  4. 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.

  5. 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.

  6. Proteinuria [ Time Frame: Baseline, 6 months; 1,2,3 and 4 years post AMR episode ]
    Proteinuria will be measured.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Time to all-Cause Graft Failure [ Time Frame: Baseline to 48 months ]
    Time to all-cause graft failure will be assessed.

  12. 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.

  13. 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.

  14. Time to Resolution of AMR Episodes [ Time Frame: Baseline to 48 months ]
    Time to resolution of AMR episodes will be assessed.

  15. Number of Participants Alive at 4 Years [ Time Frame: Year 4 ]
    Number of participants alive at 4 years will be assessed.

  16. Time to all-Cause Mortality [ Time Frame: Baseline to 48 months ]
    Time to all-cause mortality will be assessed.

  17. 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.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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®).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02547220


Contacts
Contact: Shire Contact clinicaltransparency@shire.com

  Show 48 Study Locations
Sponsors and Collaborators
Shire
Investigators
Study Director: Shire Study Physician Shire

Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT02547220     History of Changes
Other Study ID Numbers: SHP616-302
First Posted: September 11, 2015    Key Record Dates
Last Update Posted: June 28, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Additional relevant MeSH terms:
Antibodies
Complement C1 Inhibitor Protein
Complement C1 Inactivator Proteins
Immunologic Factors
Physiological Effects of Drugs
Complement Inactivating Agents
Immunosuppressive Agents