Clinical trial NCT02547220: A Multicenter Study to Evaluate the Efficacy and Safety of Cinryze® for the Treatment of Acute Antibody-mediated Rejection in Participants With Kidney Transplant
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Antibody-Mediated Rejection (AMR)
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2015-09-11
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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®).

Primary outcomes:
measure: Percentage of Participants With New or Worsening Transplant Glomerulopathy (TG) at Month 6 Post-Treatment
timeFrame: Month 6
Secondary outcomes:
measure: Number of Participants With All-Cause Graft Failure at Month 48
timeFrame: Month 48
measure: Change From Baseline in Renal Function up to Month 48
timeFrame: Baseline, up to Month 48
measure: Change From Baseline With Pre-Antibody-Mediated Rejection (AMR) in Renal Function up to Month 48
timeFrame: Pre-AMR Baseline, up to Month 48
measure: Number of Participants With Proteinuria Levels at Month 48
timeFrame: Month 48
measure: Change From Pre-Antibody-Mediated Rejection (AMR) Baseline in Histopathology Per Banff Criteria at Month 6
timeFrame: Pre-AMR Baseline, Month 6
measure: Number of Participants With All-Cause Graft Failure at Month 6
timeFrame: Month 6
measure: Number of Participants With Graft Failure Due to Antibody-Mediated Rejection (AMR) Episodes at Month 48
timeFrame: Month 48
measure: Time to All-Cause Graft Failure up to Month 48
timeFrame: Up to Month 48
measure: Time to Graft Failure Due to Antibody-Mediated Rejection (AMR) Episodes up to Month 48
timeFrame: Up to Month 48
measure: Number of Participants With Resolution of the Qualifying Antibody-Mediated Rejection (AMR) Episodes at Month 48
timeFrame: Month 48
measure: Time to Resolution of Qualifying Antibody-Mediated Rejection (AMR) Episodes up to Month 48
timeFrame: Up to Month 48
measure: Number of Participants Who Were Alive at Month 36
timeFrame: Month 36
measure: Time to All-Cause Mortality up to Month 48
timeFrame: Up to Month 48
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: From start of study drug administration up to study termination (Month 36)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Kidney Transplant Research Office at UCLA
state: California
city: Los Angeles
country: United States
facility: Keck School of Medicine at USC
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Aurora
country: United States
facility: University Of Colorado School Of Medicine
state: Colorado
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Miami
country: United States
facility: Jackson Memorial Hospital
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Transplant Institute
state: Florida
city: Atlanta
country: United States
facility: Piedmont Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Brigham and Womens Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Livingston
country: United States
facility: Saint Barnabas Medical Center
state: New Jersey
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital - Weill-Cornell
state: New York
city: White Plains
country: United States
facility: NYU Longone Medical Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: INTEGRIS Nazih Zuhdi Transplant Institute
state: Oklahoma
city: Monroeville
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Fort Worth
country: United States
facility: Baylor All Saints Medical Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Vancouver
country: Canada
facility: Providence Health Care Research Institute
state: British Columbia
city: Montreal
country: Canada
facility: Royal Victoria Hospital
state: Quebec
city: Nantes
country: France
facility: Hotel Dieu
state: Loire-Atlantique
city: Créteil
country: France
facility: Hopital Henri Mondor
state: Val-De-Marne
city: Grenoble
country: France
facility: CHU Michallon
city: Le Kremlin-Bicêtre
country: France
facility: Centre Hospitalier Universitaire de Bicêtre
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Groupe Hospitalier Necker Enfants Malades
city: Toulouse
country: France
facility: Hôpital de Rangueil
city: Heidelberg
country: Germany
facility: Universität Heidelberg
state: Baden-Württemberg
city: Steinbach
country: Germany
facility: Universitätsklinikum Frankfurt
state: Hessen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
Study officials:
affiliation: Shire
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.