A Study of THR-184 in Patients at Risk of Developing Cardiac Surgery Associated-Acute Kidney Injury (CSA-AKI)

Acute Kidney Injury Clinical Trial

Official title:

A Multi-Center, Parallel-Group, Randomized, Double Blind, Adaptive Study Investigating the Safety and Efficacy of THR-184 in Patients at Increased Risk of Developing Cardiac Surgery Associated-Acute Kidney Injury (CSA-AKI)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01830920
• Other study ID #: A-003
• Secondary ID: 2741202
• Status: Completed
• Phase: Phase 2
• First received: April 10, 2013
• Last updated: April 19, 2016
• Start date: May 2013
• Est. completion date: October 2015

Study information

• Verified date: April 2016
• Source: Thrasos Innovation, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health Canada
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether THR-184 when administered around the time of cardiac surgery that requires cardiopulmonary bypass can prevent or ameliorate the development of acute kidney injury.

Description:

The study has been designed to include patients scheduled for cardiac surgery who are considered at increased risk for developing CSA-AKI. The eligibility criteria are intended to enrich the study population with such patients.

Stage 1 consisted of 140 patients randomized in a 1:1:1:1 ratio (approximately 35 patients per treatment arm) to Placebo or to one of three (3) THR-184 dose arms:

• initial pre-surgery low dose of THR-184 by three (3) post-surgery doses at the low dose, or

• initial pre-surgery middle dose of THR-184 followed by three (3) post-surgery doses at the low dose, or

• initial pre-surgery high dose of THR-184 followed by three (3) post-surgery doses at the low dose

An interim analysis (IA) was performed by the Independent Statistical Center (ISC) and presented to the Independent Data Monitoring Committee (IDMC). The IDMC indicated no safety concerns and recommended that the study continue with the placebo arm and the initial pre-surgery high dose arm. Additionally, another dosing arm will be added, which will increase the dose post-surgery.

Stage 2 will consist of approximately 270 patients randomized in a 1:1:2 ratio to Placebo or to a dose selected from one of the two (2) THR-184 dose arms:

• initial pre-surgery high dose of THR-184, followed by (3) post-surgery doses at the original low dose;

• initial pre-surgery high dose of THR-184, followed by (3) post-surgery doses at ~80% of the pre-surgery dose

Study treatment (THR-184 or placebo) will consist of one 60-minute IV infusion administered prior to surgery, followed by a 60-minute IV infusion administered, beginning in the early post-operative period, and followed by two (2) additional 60-minute IV infusions administered, on consecutive days post-cardiac surgery.

The primary endpoint for the evaluation of efficacy in patients receiving THR-184, as compared to patients receiving Placebo, will be the proportion of patients developing CSA-AKI as measured by the Kidney Disease Improving Global Outcomes (KDIGO) criteria, as follows:

• Increase in Serum creatinine (SCr) by ≥0.3 mg/dl (>26.5 µmol/l) within 48 hours post-surgery; or

• Increase in SCr to ≥1.5 times a baseline which has been measured in the previous 7 days; or

• Urine volume <0.5 ml/kg/h for 6 hours post-operatively

If at least one of these measures is present by the 7 day assessment, a patient will be considered to have developed CSA-AKI.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 452
• Est. completion date: October 2015
• Est. primary completion date: October 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• Male or female and >18 years of age.

• Scheduled for a non-emergent coronary and/or valve surgery procedure requiring CPB, to include:

• coronary artery bypass graft (CABG) alone;

• aortic valve replacement or repair alone, with or without aortic root repair;

• mitral, tricuspid, or pulmonic valve replacement or repair alone;

• simultaneous replacement of several cardiac valves;

• CABG with aortic, mitral, tricuspid, or pulmonic valve replacement or repair;

• CABG with combined cardiac valve replacement or repair.

• Have the following risk factors for CSA-AKI:

• eGFR = 20 and < 30 ml/min/1.73m2 OR

• eGFR = 30 and < 60 ml/min/1.73m2 and ONE of the following additional risk factors (other than age = 75 years) OR

• eGFR = 60 ml/min/1.73m2 and TWO of the following additional risk factors

Additional Risk Factors:

• Age = 75 years;

• Combined valve & coronary surgery;

• Previous cardiac surgery with sternotomy;

• Documented NYHA Class III or IV within 1 year prior to surgery;

• Left ventricular ejection fraction (LVEF) = 35% by invasive or noninvasive diagnostic cardiac imaging - echocardiography, nuclear imaging, computed tomography, magnetic resonance imaging or angiography performed within 90 days prior to surgery. (If LVEF = 35% by any invasive or noninvasive imaging procedure, patient meets the risk factor.)

• Insulin-requiring diabetes;

• Non-insulin-requiring diabetes and the presence of =+2 proteinuria on urinalysis (medical history or dipstick);

• Preoperative anemia (hemoglobin <11g/dl for men and women).

Exclusion Criteria:

If any of the following criteria apply prior to surgery, the patient will be excluded from the study:

• Age > 85 years;

• Weight >174 kg or 383 lbs;

• The presence of AKI (KDIGO criteria) at the time of screening ;

• Surgery to be performed without CPB;

• Surgery to be performed under conditions of circulatory arrest or hypothermia with rectal temperature < 28°Celsius (82.4° Fahrenheit);

• eGFR (MDRD) <20 ml/min/1.73m2;

• Surgery for aortic dissection;

• Surgery to correct a major congenital heart defect (e.g., Tetralogy of Fallot, transposition of the great vessels, single ventricle, Ebsteins anomaly. Bicuspid aortic valve is not to be considered a congenital heart defect.);

• Prior organ transplantation;

• Dialysis-dependence;

• Administration of iodinated contrast media within 24 hours prior to cardiac surgery;

• If received contrast media prior to 24 hours and have AKI as defined by KDIGO criteria;

• Cardiogenic shock or haemodynamic instability within the 24 hours prior to surgery, including the anesthesia induction period; as defined by a systolic BP <80 mm Hg and pulse >120 beats per minute (bpm) and requirement for inotropes or vasopressors or other mechanical devices such as intra-aortic balloon counter-pulsation (IABP);

• Requirement for any of the following within seven (7) days prior to cardiac surgery:

• defibrillator or permanent pacemaker,

• mechanical ventilation,

• intra-aortic balloon counter-pulsation (IABP),

• left ventricular assist device (LVAD),

• other forms of mechanical circulatory support (MCS);

• Cardiopulmonary resuscitation within 14 days prior to cardiac surgery;

• Known history of cancer within the past 5 years, except for carcinoma in situ of the cervix or adequately treated basal cell carcinoma of the skin;

• Known or suspected sepsis at time of screening;

• Known or suspected glomerulonephritis or interstitial nephritis at time of screening;

• Confirmed or treated endocarditis within previous 30 days prior to cardiac surgery;

• Other current active infection requiring antibiotic treatment;

• Patients with known active human immunodeficiency virus infection;

• Documented history of HIV antibodies;

• Patients with known active Hepatitis B (HBV) or Hepatitis C (HCV) infection;

• Documented history of HCV antibodies;

• Documented history of HBV antigens;

• Patients on immunosuppressant drugs or prednisone over the dose of 20 mg per day;

• Inadequate hepatic function, defined as total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times the upper limit of normal (ULN) at time of screening or Child Pugh Class C liver disease ( see appendix 6) or higher;

• Any congenital coagulation disorder;

• Pregnancy or lactation;

• If patient has "Do Not Resuscitate" (DNR) status;

• Known hypersensitivity to the study drug or any of its excipients;

• Treatment with an investigational drug or participation in an interventional trial within 60 days prior to 1st dose of study drug;

• In the opinion of the investigator any disease processes or confounding variables that would inappropriately alter the outcome of the study;

• Inability to comply with the requirements of the study protocol.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Kidney Injury

Intervention

Drug:
• THR-184
THR-184 is a synthetic oligopeptide administered intravenously.
• Placebo
A normal saline solution identical in appearance to the active drug solution

Locations

Country	Name	City	State
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	Hamilton Health Sciences Corporation	Hamilton	Ontario
Canada	Centre hospitalier de l'université de Montréal(CHUM)- Hôtel-Dieu	Montréal	Quebec
Canada	Institut de Cardiologie de Montréal	Montréal	Quebec
Canada	MUHC - Royal Victoria Hospital	Montréal	Quebec
Canada	Sacre Cœur Hospital	Montréal	Quebec
Canada	University of Ottawa Heart Institute	Ottawa	Ontario
Canada	Institut Universitaire de Cardiologie et de Pneumologie de Québec	Québec	Quebec
Canada	St-John Regional Hospital Facility	St-John	New Brunswick
Canada	St. Michael's Hospital	Toronto	Ontario
United States	St. Peter's Hospital	Albany	New York
United States	John Hopkins University	Baltimore	Maryland
United States	Suburban Hospital	Bethesda	Maryland
United States	University of Alabama-Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Erlanger Health System	Chattanooga	Tennessee
United States	Memorial Hospital	Chattanooga	Tennessee
United States	University of Chicago	Chicago	Illinois
United States	Lindner Research Center-Christ Hospital	Cincinnati	Ohio
United States	The Ohio State University Medical Center	Columbus	Ohio
United States	Baylor University Medical Center, Soltero Cardiovascular Research Center	Dallas	Texas
United States	Danbury Hospital	Danbury	Connecticut
United States	Duke University Medical Center	Durham	North Carolina
United States	Durham VA Medical Center	Durham	North Carolina
United States	Indiana Ohio Heart	Fort Wayne	Indiana
United States	University of Texas, Houston	Houston	Texas
United States	Indiana Heart-St. Vincent Medical Group	Indianapolis	Indiana
United States	River City Clinical Research	Jacksonville	Florida
United States	University of Southern California	Los Angeles	California
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Columbia University	New York	New York
United States	Advocate Christ Medical Center	Oak Lawn	Illinois
United States	St. Joseph's Regional Medical Center	Paterson	New Jersey
United States	Cardiac and Vascular Research Center of Northern Michigan	Petoskey	Michigan
United States	Maine Medical Center	Portland	Maine
United States	Cardiothoracic Surgical Associates	Richmond	Virginia
United States	Covenant Medical Center	Saginaw	Michigan
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Washington University	St. Louis	Missouri
United States	Stanford University	Stanford	California
United States	Harbor - University of California Los Angeles Medical Center	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
Thrasos Innovation, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Composite of death, dialysis, or sustained impaired renal function		Day 30 and Day 90	Yes
Primary	Incidence of acute kidney injury (AK)		7 days	Yes
Secondary	Duration, severity, and incidence (SCr based) of AKI		7 days	Yes