NITRATE-CIN: The Use of Inorganic Nitrate for the Prevention of Contrast-induced Nephropathy

Sponsor

Barts & The London NHS Trust (Other)

Overall Status

Recruiting

CT.gov ID

NCT03627130

Collaborator

(none)

640

Enrollment

Location

Arms

34.1

Anticipated Duration (Months)

18.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Contrast-induced nephropathy (CIN), an acute kidney injury resulting from the administration of intravascular iodinated contrast media, is an important cause of morbidity/mortality following coronary angiographic procedures in high-risk patients. Despite preventative measures intended to mitigate the risk of CIN, there remains a need for an effective intervention. Dietary inorganic nitrate therapy, which through its chemical reduction in the body delivers nitric oxide has shown promise in attenuating CIN, but its effectiveness in preserving long-term renal function is unknown.

Condition or Disease	Intervention/Treatment	Phase
Contrast-induced Nephropathy Acute Kidney Injury Acute Coronary Syndrome	Drug: Potassium Nitrate Drug: Potassium Chloride	Phase 2

Detailed Description

The NITRATE-CIN trial is a single-centre, randomised double-blinded placebo-controlled trial, which plans to recruit, over a period of 2 years, 640 patients presenting with acute coronary syndromes (ACS) who are at risk of CIN.

Patients will be randomised to either dietary inorganic nitrate therapy or placebo.

The primary endpoint will be the development of CIN (KDIGO criteria). A key secondary endpoint will be whether nitrate therapy impacts upon persistent renal impairment over a 3-month follow-up period. Additional secondary endpoints include the measurement of serum renal biomarkers (e.g. neutrophil gelatinase-associated lipocalin) and urinary albumin at 6, 48 h and 3 months following administration of contrast.

Findings from NITRATE-CIN will potentially demonstrate that nitrate attenuates contrast-induced acute and chronic kidney injury and influence future clinical practice guidelines in at-risk patients undergoing coronary angiographic procedures.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

640 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

IMP and placebo will be identical

Primary Purpose:

Treatment

Official Title:

Effect of Inorganic Nitrate on Contrast-induced Nephropathy in Patients Undergoing Coronary Angiography/Percutaneous Coronary Intervention for Acute Coronary Syndrome (ACS): A Randomised Single-centre, Double-blind Placebo-controlled Trial

Actual Study Start Date :

Nov 29, 2018

Anticipated Primary Completion Date :

Oct 1, 2021

Anticipated Study Completion Date :

Oct 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Potassium Nitrate Potassium nitrate capsules (KNO3: 12 mmol giving 744 mg of nitrate) for 5 days	Drug: Potassium Nitrate Potassium nitrate capsules (KNO3: 12 mmol giving 744 mg of nitrate) for 5 days
Placebo Comparator: Potassium Chloride Potassium Chloride	Drug: Potassium Chloride Potassium Chloride capsules for 5 days

Arm

Intervention/Treatment

Active Comparator: Potassium Nitrate

Potassium nitrate capsules (KNO3: 12 mmol giving 744 mg of nitrate) for 5 days

Drug: Potassium Nitrate

Potassium nitrate capsules (KNO3: 12 mmol giving 744 mg of nitrate) for 5 days

Placebo Comparator: Potassium Chloride

Potassium Chloride

Drug: Potassium Chloride

Potassium Chloride capsules for 5 days

Outcome Measures

Primary Outcome Measures

Contrast Induced Nephropathy [48-72 hours]
Defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria

Secondary Outcome Measures

Demonstration of a persistent benefit of dietary inorganic nitrate against long-term renal impairment [3 months]
Difference in real function as measured by eGFR (estimated glomerular filtration rate) at 3 months post-contrast exposure
Measurement of Circulating Nitrite and Nitrate levels [Baseline, and at 6 hours, 48 hours and 3 months following treatment.]
Plasma Nitrite/Nitrate levels
Major Adverse Cardiac Events [3 and 12 months follow-up]
Defined as death, non-fatal myocardial infarction, revascularisation, acute heart failure, non-fatal stroke
Cost effectiveness of dietary inorganic Nitrate [1 year]
Incremental Cost Effectiveness Ratio (ICER)
To determine if dietary inorganic nitrate ingestion decreases sub-clinical renal injury as measured by urinary renal biomarkers [4-6 hours]
Measurement of urinary IGFB7/TIMP-2
To determine if dietary inorganic nitrate ingestion decreases sub-clinical renal injury as measured by serum biomarkers [4-6 hours]
Measurement of serum Neutrophil gelatinase-associated lipocalin (NGAL)
To determine if dietary inorganic nitrate decreases rates of post-procedural Myocardial Infarction [6-12 hrs]
Definition as per Society for Cardiovascular Angiography and Interventions (SCAI)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients undergoing coronary angiography+/-Percutaneous Coronary Intervention (PCI) for NSTE-ACS
Requirement for CIN prophylaxis as per Barts Heart Centre Criteria for CIN prophylaxis:

eGFR<60ml/min OR 2 of the following: diabetes, liver failure (cirrhosis), age > 70yr, exposure to contrast in last 7 days, heart failure (or LVEF<40%), concomitant renally active drugs (ACEi, ARB, NSAIDs, aminoglycosides, diuretics)

Aged >18
Patients able and willing to give their written informed consent.

Exclusion Criteria:

ST segment myocardial infarction undergoing Primary PCI.
Patients with eGFR<30ml/min or on renal replacement therapy
Subjects presenting with cardiogenic shock (systolic blood pressure <80 mmHg for >30 minutes, or requiring inotropes or emergency intra aortic balloon pump for hypotension treatment) or cardiopulmonary resuscitation
Current life-threatening condition other than vascular disease that may prevent a subject completing the study.
Use of an investigational device or investigational drug within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of study medication.
Patients considered unsuitable to participate by the research team (e.g., due to medical reasons, laboratory abnormalities, or subject's unwillingness to comply with all study related procedures).
Severe acute infection
Pregnancy
Breast-feeding mothers.
Any Inclusion Criteria not met