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

NCT ID: NCT02547220

Last Updated: 2020-07-13

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 39 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-05-20
• Study Completion Date: 2019-05-31

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.

Conditions

Acute Antibody-Mediated Rejection (AMR)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Cinryze®

Intervention Type: BIOLOGICAL

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

Participants will receive 7 doses of matched placebo over 13 days of treatment.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Participants will receive 7 doses of matched placebo over 13 days of treatment.

Interventions

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 Type: BIOLOGICAL

Placebo

Participants will receive 7 doses of matched placebo over 13 days of treatment.

Intervention Type: DRUG

Eligibility 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®).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shire

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

Shire

Locations

Kidney Transplant Research Office at UCLA

Los Angeles, California, United States

Keck School of Medicine at USC

Los Angeles, California, United States

University of California San Francisco

San Francisco, California, United States

University Of Colorado School Of Medicine

Aurora, Colorado, United States

MedStar Georgetown University Hospital

Washington D.C., District of Columbia, United States

Jackson Memorial Hospital

Miami, Florida, United States

Florida Hospital Transplant Institute

Orlando, Florida, United States

Piedmont Hospital

Atlanta, Georgia, United States

Northwestern Memorial Hospital

Chicago, Illinois, United States

University of Maryland Medical Center

Baltimore, Maryland, United States

Johns Hopkins University

Baltimore, Maryland, United States

Brigham and Womens Hospital

Boston, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Saint Barnabas Medical Center

Livingston, New Jersey, United States

Mount Sinai Hospital

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

New York Presbyterian Hospital - Weill-Cornell

New York, New York, United States

NYU Longone Medical Center

White Plains, New York, United States

University of Cincinnati

Cincinnati, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

Ohio State University Medical Center

Columbus, Ohio, United States

INTEGRIS Nazih Zuhdi Transplant Institute

Oklahoma City, Oklahoma, United States

University of Pittsburgh Medical Center

Monroeville, Pennsylvania, United States

University of Pennsylvania Health System

Philadelphia, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Baylor All Saints Medical Center

Fort Worth, Texas, United States

Houston Methodist Hospital

Houston, Texas, United States

University of Utah Health Sciences Center

Salt Lake City, Utah, United States

Providence Health Care Research Institute

Vancouver, British Columbia, Canada

Royal Victoria Hospital

Montreal, Quebec, Canada

Hotel Dieu

Nantes, Loire-Atlantique, France

Hopital Henri Mondor

Créteil, Val-De-Marne, France

CHU Michallon

Grenoble, , France

Centre Hospitalier Universitaire de Bicêtre

Le Kremlin-Bicêtre, , France

Hôpital Saint Louis

Paris, , France

Groupe Hospitalier Necker Enfants Malades

Paris, , France

Hôpital de Rangueil

Toulouse, , France

Universität Heidelberg

Heidelberg, Baden-Wurttemberg, Germany

Universitätsklinikum Frankfurt

Steinbach, Hesse, Germany

Universitätsklinikum Hamburg Eppendorf

Hamburg, , Germany

Universitair Medisch Centrum Groningen

Groningen, , Netherlands

Erasmus MC

Rotterdam, , Netherlands

Hospital Universitario Germans Trias i Pujol

Badalona, Barcelona, Spain

Hospital Universitari de Bellvitge

Barcelona, , Spain

Hospital Clinico San Carlos

Madrid, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Countries

United States; Canada; France; Germany; Netherlands; Spain

References

Karpman D, Bekassy Z, Grunenwald A, Roumenina LT. A role for complement blockade in kidney transplantation. Cell Mol Immunol. 2022 Jul;19(7):755-757. doi: 10.1038/s41423-022-00854-5. Epub 2022 Mar 24. No abstract available.

Reference Type: DERIVED

PMID: 35332298 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2015-000726-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

SHP616-302

Identifier Type: -

Identifier Source: org_study_id