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

NCT02547220 | Terminated Phase 3 Results DMC FDA Drug

• 2 other identifiers: SHP616-3022015-000726-11
• Study Type: interventional
• Target: 39
• Locations: 6 countries
• Sites: 47

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)

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With New or Worsening Transplant Glomerulopathy (TG) at Month 6 Post-Treatment

  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.

  Month 6

Secondary Outcomes (14)

• Number of Participants With All-Cause Graft Failure at Month 48

  Month 48

• Change From Baseline in Renal Function up to Month 48

  Baseline, up to Month 48

• Change From Baseline With Pre-Antibody-Mediated Rejection (AMR) in Renal Function up to Month 48

  Pre-AMR Baseline, up to Month 48

• Number of Participants With Proteinuria Levels at Month 48

  Month 48

• Change From Pre-Antibody-Mediated Rejection (AMR) Baseline in Histopathology Per Banff Criteria at Month 6

  Pre-AMR Baseline, Month 6

Study Arms (2)

Cinryze®

EXPERIMENTAL

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®

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Cinryze® 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.

Cinryze®

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be greater than or equal to (\>=) 18 and less than or equal to (\<=) 70 years of age.
• Weigh \>= 45 kg with a body mass index (BMI) less than (\<) 35 kilogram (kg)/meter (m)\^2 at screening.
• 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.
• 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.
• 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.
• 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.
• Be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.
• 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.
• Agree to comply with any applicable contraceptive requirements of the protocol.

You may not qualify if:

• Have received pediatric en bloc kidney transplant.
• 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.
• 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).
• Have a known neoplastic lesion in the transplanted allograft
• 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
• Have ongoing treatment for hepatitis C virus (HCV) infection.
• 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.
• 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.
• Have a history of allergic reaction to CINRYZE or other blood products.
• 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.
• Have participated in the active dosing phase of any other investigational drug study within 30 days prior to dosing with investigational product.
• 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
• Be pregnant or breastfeeding.
• 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®).

Sponsors & Collaborators

• Shire: lead

Study Sites (47)

Kidney Transplant Research Office at UCLA

Los Angeles, California, 90024, United States

Location

Keck School of Medicine at USC

Los Angeles, California, 90033, United States

Location

University of California San Francisco

San Francisco, California, 94110, United States

Location

University Of Colorado School Of Medicine

Aurora, Colorado, 80045, United States

Location

MedStar Georgetown University Hospital

Washington D.C., District of Columbia, 20057, United States

Location

Jackson Memorial Hospital

Miami, Florida, 33136, United States

Location

Florida Hospital Transplant Institute

Orlando, Florida, 32804, United States

Location

Piedmont Hospital

Atlanta, Georgia, 30309, United States

Location

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Brigham and Womens Hospital

Boston, Massachusetts, 02115, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55414, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Saint Barnabas Medical Center

Livingston, New Jersey, 07039, United States

Location

Mount Sinai Hospital

New York, New York, 10029, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

New York Presbyterian Hospital - Weill-Cornell

New York, New York, 10065, United States

Location

NYU Longone Medical Center

White Plains, New York, 10605, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45220, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Ohio State University Medical Center

Columbus, Ohio, 43210, United States

Location

INTEGRIS Nazih Zuhdi Transplant Institute

Oklahoma City, Oklahoma, 73112, United States

Location

University of Pittsburgh Medical Center

Monroeville, Pennsylvania, 15146, United States

Location

University of Pennsylvania Health System

Philadelphia, Pennsylvania, 19104, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37204, United States

Location

Baylor All Saints Medical Center

Fort Worth, Texas, 76104, United States

Location

Houston Methodist Hospital

Houston, Texas, 77030, United States

Location

University of Utah Health Sciences Center

Salt Lake City, Utah, 84132, United States

Location

Providence Health Care Research Institute

Vancouver, British Columbia, V6Z 2K5, Canada

Location

Royal Victoria Hospital

Montreal, Quebec, H4A 3J1, Canada

Location

Hotel Dieu

Nantes, Loire-Atlantique, 44093, France

Location

Hopital Henri Mondor

Créteil, Val-De-Marne, 94010, France

Location

CHU Michallon

Grenoble, 38043, France

Location

Centre Hospitalier Universitaire de Bicêtre

Le Kremlin-Bicêtre, 94275, France

Location

Hôpital Saint Louis

Paris, 75010, France

Location

Groupe Hospitalier Necker Enfants Malades

Paris, 75015, France

Location

Hôpital de Rangueil

Toulouse, 31059, France

Location

Universität Heidelberg

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

Universitätsklinikum Frankfurt

Steinbach, Hesse, 61449, Germany

Location

Universitätsklinikum Hamburg Eppendorf

Hamburg, 20246, Germany

Location

Universitair Medisch Centrum Groningen

Groningen, 9713 GZ, Netherlands

Location

Erasmus MC

Rotterdam, 3015 CE, Netherlands

Location

Hospital Universitario Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain

Location

Hospital Universitari de Bellvitge

Barcelona, 8907, Spain

Location

Hospital Clinico San Carlos

Madrid, 28040, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Related Publications (1)

• 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.

  PMID: 35332298 DERIVED

MeSH Terms

Interventions

SERPING1 protein, human

Limitations and Caveats

This study was prematurely terminated at Month 36 due to futility issue.

Results Point of Contact

• Title: Study Director
• Organization: Shire

ClinicalTransparency@takeda.com

+1 866 842 5335

Study Officials

• Study Director

  Shire

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 2, 2015
• First Posted: September 11, 2015
• Study Start: May 20, 2016
• Primary Completion: May 31, 2019
• Study Completion: May 31, 2019
• Last Updated: July 13, 2020
• Results First Posted: July 13, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

FR (7); DE (3); NL (2); ES (4); CA (2); US (29)