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

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ClinicalTrials.gov Identifier: NCT02547220
Recruitment Status : Recruiting
First Posted : September 11, 2015
Last Update Posted : August 15, 2017
Sponsor:
Information provided by (Responsible Party):
Shire

Brief Summary:
To evaluate the efficacy of Cinryze® given for the treatment of acute antibody-mediated rejection (of renal allograft) (AMR) in kidney transplant recipients as measured by the proportion of subjects 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
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®
eligible subjects with biopsy-proven AMR will be randomized (56 per arm) to receive either IV Cinryze® or placebo
Biological: Cinryze®
7 doses of study drug over 13 days

Placebo Comparator: Placebo
eligible subjects with biopsy-proven AMR will be randomized (56 per arm) to receive either IV Cinryze® or placebo
Drug: Placebo
7 doses of placebo over 13 days




Primary Outcome Measures :
  1. Evaluate efficacy for the treatment of acute AMR of renal allograft in kidney transplant recipients as measured by the proportion of subjects with new or worsening transplant glomerulopathy (TG) at 6 months after treatment initiation using Banff criteria [ Time Frame: Screening to Month 6 ]
    Administer CINRYZE with plasmapheresis, plasma exchange, or immune absorption treatments and sucrose-free immunoglobulin (IVIg).


Secondary Outcome Measures :
  1. Proportion of subjects with all-cause graft failure [ Time Frame: Screening to Month 48 (End of Study [EOS]) (+/- 14 days) ]
  2. Time to all-cause graft failure [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  3. Proportion of subjects with graft failure due to AMR [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  4. Change in renal allograft function (eGFR) as calculated by the Modification of Diet in Renal Disease (MDRD formula) [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  5. Change from baseline in histopathology at Month 6 post-treatment per Banff criteria [ Time Frame: Screening to Month 6 ]
  6. Time to first recurrence of biopsy-proven acute AMR after dosing [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  7. Change from baseline in serum Cr [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  8. Overall subject survival [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  9. Treatment-emergent adverse events (TEAEs) [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  10. Change in Vital Signs (Heart Rate) [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  11. Change in Vital Signs (Blood Pressure) [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  12. antibodies to C1inhibitor (INH) [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  13. clinical safety laboratory testing (Hematology) [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  14. clinical safety laboratory testing (Serum Chemistry) [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  15. clinical safety laboratory testing (Serum Blood urea nitrogen/Cr) [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]
  16. time to graft failure due to AMR [ Time Frame: Screening to Month 48 (EOS) (+/- 14 days) ]


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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 >=18 and <=70 years of age.
  2. Weigh >=45 kg with a body mass index (BMI) <35 kg/m^2 at screening.
  3. Have HLA 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 subject's current renal allograft between 72 hours and 12 months after transplant defined by a renal allograft biopsy demonstrating neutrophil and/or monocyte infiltration in the PTC and/or glomeruli with or without evidence of C4d deposition by immunohistopathology according to 2013 Banff criteria.
  5. Have achieved adequate renal function defined as: Pre-AMR baseline eGFRMDRD >=20 mL/min/1.72m^2 for a qualifying AMR episode occurring <=21 days after transplant or pre-AMR baseline eGFRMDRD >=30 mL/min/1.72m^2 for a qualifying AMR episode occurring >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 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.
  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 patient 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 HCV infection.
  7. Have had a recent myocardial infarction (MI) or transient ischemic attack (TIA) within the past 6 months.
  8. Have a history of abnormal bleeding, clotting, or any coagulopathy (excluding a history of clotted hemodialysis access or superficial thrombophlebitis in the absence of medically confirmed coagulopathy).
  9. Have a history of allergic reaction to CINRYZE or other blood products.
  10. Have had any change in androgen therapy (eg, 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 prior to dosing with investigational product:

    • Within 24 hours prior to subject dosing, white blood cell (WBC) count <0.5×10^9/L or >20×10^9/L (the value of >20×10^9/L should be excluded if obtained during steroid treatment)
    • Within 72 hours prior to subject dosing platelet count < 25×10^9/L or >600×10^9/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 IVIg
    • Any C1 INH (plasma-derived [eg, CINRYZE®, Berinert®, Cetor®] or recombinant [eg, 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
Principal Investigator: 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: August 15, 2017
Last Verified: August 2017

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