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

Primary Purpose

Contrast-induced Nephropathy, Acute Kidney Injury, Acute Coronary Syndrome

Status

Completed

Phase

Phase 2

Locations

United Kingdom

Study Type

Interventional

Intervention

Potassium Nitrate

Potassium Chloride

About this trial

This is an interventional treatment trial for Contrast-induced Nephropathy focused on measuring Percutaneous Coronary Intervention, Nitric Oxide, Nitrite, Acute Kidney Injury, Acute Coronary Syndrome

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

Barts Heart Centre

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Potassium Nitrate

Potassium Chloride

Arm Description

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

Potassium Chloride

Outcomes

Primary Outcome Measures

Contrast Induced Nephropathy

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

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

Plasma Nitrite/Nitrate levels

Major Adverse Cardiac Events

Defined as death, non-fatal myocardial infarction, revascularisation, acute heart failure, non-fatal stroke

Cost effectiveness of dietary inorganic Nitrate

Incremental Cost Effectiveness Ratio (ICER)

To determine if dietary inorganic nitrate ingestion decreases sub-clinical renal injury as measured by urinary renal biomarkers

Measurement of urinary IGFB7/TIMP-2

To determine if dietary inorganic nitrate ingestion decreases sub-clinical renal injury as measured by serum biomarkers

Measurement of serum Neutrophil gelatinase-associated lipocalin (NGAL)

To determine if dietary inorganic nitrate decreases rates of post-procedural Myocardial Infarction

Definition as per Society for Cardiovascular Angiography and Interventions (SCAI)

Full Information

NCT ID

NCT03627130

First Posted

January 17, 2018

Last Updated

December 15, 2022

Sponsor

Barts & The London NHS Trust

1. Study Identification

Unique Protocol Identification Number

NCT03627130

Brief Title

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

Acronym

NITRATE-CIN

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Completed

Study Start Date

November 29, 2018 (Actual)

Primary Completion Date

May 30, 2022 (Actual)

Study Completion Date

May 30, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Barts & The London NHS Trust

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Contrast-induced Nephropathy, Acute Kidney Injury, Acute Coronary Syndrome

Keywords

Percutaneous Coronary Intervention, Nitric Oxide, Nitrite, Acute Kidney Injury, Acute Coronary Syndrome

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

IMP and placebo will be identical

Allocation

Randomized

Enrollment

640 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Potassium Nitrate

Arm Type

Active Comparator

Arm Description

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

Arm Title

Potassium Chloride

Arm Type

Placebo Comparator

Arm Description

Potassium Chloride

Intervention Type

Drug

Intervention Name(s)

Potassium Nitrate

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Potassium Chloride

Intervention Description

Potassium Chloride capsules for 5 days

Primary Outcome Measure Information:

Title

Contrast Induced Nephropathy

Description

Defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria

Time Frame

48-72 hours

Secondary Outcome Measure Information:

Title

Demonstration of a persistent benefit of dietary inorganic nitrate against long-term renal impairment

Description

Difference in real function as measured by eGFR (estimated glomerular filtration rate) at 3 months post-contrast exposure

Time Frame

3 months

Title

Measurement of Circulating Nitrite and Nitrate levels

Description

Plasma Nitrite/Nitrate levels

Time Frame

Baseline, and at 6 hours, 48 hours and 3 months following treatment.

Title

Major Adverse Cardiac Events

Description

Defined as death, non-fatal myocardial infarction, revascularisation, acute heart failure, non-fatal stroke

Time Frame

3 and 12 months follow-up

Title

Cost effectiveness of dietary inorganic Nitrate

Description

Incremental Cost Effectiveness Ratio (ICER)

Time Frame

1 year

Title

To determine if dietary inorganic nitrate ingestion decreases sub-clinical renal injury as measured by urinary renal biomarkers

Description

Measurement of urinary IGFB7/TIMP-2

Time Frame

4-6 hours

Title

To determine if dietary inorganic nitrate ingestion decreases sub-clinical renal injury as measured by serum biomarkers

Description

Measurement of serum Neutrophil gelatinase-associated lipocalin (NGAL)

Time Frame

4-6 hours

Title

To determine if dietary inorganic nitrate decreases rates of post-procedural Myocardial Infarction

Description

Definition as per Society for Cardiovascular Angiography and Interventions (SCAI)

Time Frame

6-12 hrs

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

99 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Amrita Ahluwalia, PhD

Organizational Affiliation

Queen Mary University of London

Official's Role

Principal Investigator

Facility Information:

Facility Name

Barts Heart Centre

City

London

ZIP/Postal Code

EC1A 7BE

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

The trial protocol will be published prior to the commencement of the study

IPD Sharing Time Frame

Mid-late 2018

IPD Sharing Access Criteria

Freely available via journal

Citations:

PubMed Identifier

33764198

Citation

Beirne AM, Mitchelmore O, Palma S, Andiapen M, Rathod KS, Hammond V, Bellin A, Cooper J, Wright P, Antoniou S, Yaqoob MM, Naci H, Mathur A, Ahluwalia A, Jones DA. NITRATE-CIN Study: Protocol of a Randomized (1:1) Single-Center, UK, Double-Blind Placebo-Controlled Trial Testing the Effect of Inorganic Nitrate on Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography for Acute Coronary Syndromes. J Cardiovasc Pharmacol Ther. 2021 Jul;26(4):303-309. doi: 10.1177/1074248421000520. Epub 2021 Mar 25.

Results Reference

derived

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

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