Nitrite Infusion in High Risk Patients Undergoing Cardiopulmonary Bypass

• ClinicalTrials.gov Identifier: NCT03331146
• Recruitment Status: Withdrawn
• First Posted: November 6, 2017
• Last Update Posted: September 27, 2018
• Sponsor: University of Alabama at Birmingham
• Information provided by (Responsible Party): Ahmed Zaky, University of Alabama at Birmingham

Tracking Information

• First Submitted Date: October 20, 2017
• First Posted Date: November 6, 2017
• Last Update Posted Date: September 27, 2018
• Estimated Study Start Date: October 1, 2018
• Estimated Primary Completion Date: June 1, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 4, 2017)

• Nitrite Metabolome Levels [ Time Frame: baseline to 73 hrs post-operatively ]
  Measuring nitrite, nitrate, and nitrosothiols levels
• Biomarkers of Hemolysis [ Time Frame: baseline to 73 hrs post-operatively ]
  Measuring hemolysis indicators heme, Hb, hemopexin, and hemopectin
• Biomarkers of Kidney Injury [ Time Frame: baseline to 73 hrs post-operatively ]
  Measuring kidney injury indicators creatine, neutrophil-associated gelatinase, lipocalin (NGAL)
• Cell Cycle Stress [ Time Frame: baseline to 73 hrs post-operatively ]
  Measuring cell cycle arrest biomarkers TIMP-2, IGFBP-7

Original Primary Outcome Measures (submitted: October 31, 2017)

• Nitrite Metabolome [ Time Frame: baseline to 73 hrs post-operatively ]
  Measuring nitrite, nitrate, and nitrosothiols levels
• Hemolysis [ Time Frame: baseline to 73 hrs post-operatively ]
  Measuring hemolysis indicators heme, Hb, hemopexin, and hemopectin
• Kidney Injury [ Time Frame: baseline to 73 hrs post-operatively ]
  Measuring kidney injury indicators creatine, neutrophil-associated gelatinase, lipocalin (NGAL)
• Stress [ Time Frame: baseline to 73 hrs post-operatively ]
  Measuring cell cycle arrest biomarkers TIMP-2, IGFBP-7

Current Secondary Outcome Measures (submitted: December 4, 2017)

• Biomarkers of Hepatic injury [ Time Frame: baseline to 24 hours post-operatively ]
  Measuring serum AST and ALT
• Biomarkers of Kidney Injury [ Time Frame: baseline to 24 hours post-operatively ]
  Measuring kidney injury indicators creatine, neutrophil, lipocalin (NGAL)
• Cell Cycle Stress [ Time Frame: baseline to 24 hours post-operatively ]
  Measuring cell cycle arrest biomarkers TIMP-2, IGFBP-7
• Biomarkers of Myocardial Injury [ Time Frame: baseline to 24 hours post-operatively ]
  Measuring myocardial injury indicators troponin and CKMB
• Urine Output [ Time Frame: baseline to 73 hrs post-operatively ]
  Measuring total urine output
• Vasopressors Usage [ Time Frame: baseline to 73 hrs post-operatively ]
  Percentage of vasopressor usage between the control and intervention

Original Secondary Outcome Measures (submitted: October 31, 2017)

• Hepatic injury [ Time Frame: baseline to 24 hours post-operatively ]
  Measuring serum AST and ALT
• Kidney Injury [ Time Frame: baseline to 24 hours post-operatively ]
  Measuring kidney injury indicators creatine, neutrophil, lipocalin (NGAL)
• Stress [ Time Frame: baseline to 24 hours post-operatively ]
  Measuring cell cycle arrest biomarkers TIMP-2, IGFBP-7
• Myocardial Injury [ Time Frame: baseline to 24 hours post-operatively ]
  Measuring myocardial injury indicators troponin and CKMB
• Urine Output [ Time Frame: baseline to 73 hrs post-operatively ]
  Measuring total urine output
• Vasopressors [ Time Frame: baseline to 73 hrs post-operatively ]
  Determining the use of vasopressors in both treatment groups

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Nitrite Infusion in High Risk Patients Undergoing Cardiopulmonary Bypass
• Official Title: Randomized, Controlled, Double-blinded Pilot Study: Nitrite Infusion in High Risk Patients Undergoing Cardiopulmonary Bypass
• Brief Summary: The main objective of this study is to evaluate the efficacy of intravenous sodium nitrite compared with placebo in reducing the occurrence of CSA-AK as diagnosed by KDIGO criteria during the first 72 hrs after cardiac surgery in high-risk patients undergoing cardiac surgery. Secondary objectives are to determine whether IV sodium nitrite achieves adequate pharmacokinetics (PK) in patients undergoing cardiac surgery with the use of CPB.

Detailed Description

Acute kidney injury is one of the most untoward consequences of cardiac-surgery with the use of CPB. As such it is associated with a high mortality and morbidity and health care expense. Unfortunately, currently, there is no effective preventive or treatment strategy for cardiac surgery-associated (CSA) AKI other than renal replacement therapy.

It is postulated that a major mechanism of CSA-AKI is created by the ischemia reperfusion injury (IRI) resulting from aortic cross clamping and unclamping. This creates a cascade of events culminating in inflammation, microvascular dysfunction and tubular cell maladaptation and eventually renal tissue damage. Current treatment modalities that target the microcirculation such as blood pressure and cardiac output fails to prevent renal abnormalities and as such may be deleterious to the renal tissue microcirculation. The PI hypothesizes that a therapeutic strategy that limits IRI such as the administration of inhaled nitric oxide (NO) or sodium nitrite (NaNO2) would ameliorate CSA-AKI by limiting inflammatory injury to the kidney.

The anion nitrite (NO2-) releases NO in biological systems and has been demonstrated to inhibit IR injury in the heart, liver and kidneys created by various pathologic states1-3 and improve outcomes in patients with acute myocardial infarction, in patients with pulmonary hypertension and is the putative active mediator of protection in liver-transplantation patients receiving inhaled nitric oxide4.

The objective of this study is to determine whether the NO donor, nitrite will prevent I/R injury in patients at high risk of development of CSA-AKI undergoing open-heart surgery with cardiopulmonary bypass.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Prevention
• Condition: Acute Kidney Injury

Intervention

• Drug: Saline
  A placebo (saline infusion) will be administered after induction of general anesthesia.
• Drug: Sodium Nitrite
  Sodium nitrite infusion at a 267 mcg/kg/hr. will start after induction of general anesthesia via a dedicated IV line for 6 hrs.
  Other Name: NaNO2

Study Arms

• Placebo Comparator: Control group
  saline infusion will be administered after induction of general anesthesia
  Interventions:

  • Drug: Saline
  • Drug: Sodium Nitrite
• Active Comparator: Sodium Nitrite
  sodium nitrite will start after induction of general anesthesia via a dedicated IV line for 6 hrs.
  Interventions:

  • Drug: Saline
  • Drug: Sodium Nitrite

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: September 25, 2018): 0
• Original Estimated Enrollment (submitted: October 31, 2017): 40
• Estimated Study Completion Date: December 1, 2020
• Estimated Primary Completion Date: June 1, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients CCFS score ≥ 6 (Table 1)
• Patients admitted to UAB cardiac intensive care unit (CICU) following elective cardiac surgery with cardiopulmonary bypass under general endotracheal anesthesia
• 19 years old
• Estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2

Exclusion Criteria:

• Prisoners directly admitted from a correctional facility.
• Children < 19 years or under 50 kg body weight if age is unknown.
• Patients enrolled in a concurrent ongoing interventional, randomized clinical trial.
• Patients with end stage renal disease or preexisting GFR <30 mL/min/1.73 m2 or need for dialysis. 34
• Patients with end stage heart disease on the cardiac transplant list.
• Patients undergoing procedures without the use of CPB
• All transplant patients.
• Patients on ventricular assist devices.
• Patients undergoing emergency procedures.
• Patients with glucose 6-dehydrogenase deficiency
• Pregnancy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 19 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03331146
• Other Study ID Numbers: 1709284471
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

• IPD Sharing Statement: Not Provided
• Responsible Party: Ahmed Zaky, University of Alabama at Birmingham
• Study Sponsor: University of Alabama at Birmingham
• Collaborators: Not Provided

Investigators

• Principal Investigator: Ahmed F Zaky, MD; University of Alabama at Birmingham

• PRS Account: University of Alabama at Birmingham
• Verification Date: September 2018