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Safety and Effectiveness of Intra-coronary Nitrite in Acute Myocardial Infarction (NITRITE-AMI)

Primary Purpose

Myocardial Infarction, Reperfusion Injury, Myocardial Ischemia

Status

Completed

Phase

Phase 2

Locations

United Kingdom

Study Type

Interventional

Intervention

Sodium Nitrite

Sodium Chloride Placebo

About this trial

This is an interventional treatment trial for Myocardial Infarction

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients aged at least 18 years
Acute STEMI with ECG showing ST-segment elevation of 1mm or more in two adjacent limb leads or 2mm or more in at least two contiguous precordial leads or new left bundle branch block;
Haemodynamically stable
Estimated symptom to balloon or aspiration time < 6 hours
Angiographically i) PPCI indicated for revascularisation ii) Single epicardial artery to be treated iii) Expected ability to use over the wire balloon

Exclusion Criteria:

Patients on organic nitrate treatment (Nicorandil, isosorbide mononitrate)
Previous history of AMI, systolic dysfunction or CABG
Subjects presenting with cardiogenic shock (systolic blood pressure <80 mmHg for > 30 minutes, or requiring inotropes/emergency intra aortic balloon pump or cardiopulmonary resuscitation
Current diagnosis of or treatment for malignancy, other than non-melanoma skin cancer.
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, or significant trauma (burns, fractures).
Pregnancy.
Contra-indications to CMR scanning i) Pacemakers, intracranial clips or other metal implants ii) Claustrophobia iii) Renal failure (eGFR < 30mls/min)
History of alcohol or drug abuse within the past 6 months.
History of congenital methaemoglobinaemia.
Angiographically severe vessel tortuosity, diffuse disease or severe calcification which may impede successful delivery of the the over the wire balloon.

Sites / Locations

London Chest Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Sodium Nitrite

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Infarct size measured by CK area under the curve

AUC measured over the 1st 48 hours after PPCI (0,4,8,12,18,24,36 and 48 hours)

Secondary Outcome Measures

Infarct size measured by Troponin T Area under the curve

AUC measured over the 1st 48 hours after PPCI (0,4,8,12,18,24,36 and 48 hours)

Infarct size, assessed by CMR at 6 months ± 2 weeks.

Infarct size as a proportion of area at risk measured at 48 hours by CMR.

The acute safety and tolerability of intra-coronary nitrite in STEMI

Safety profile of IC nitrate (death, MI, CVA, arrhythmia, hypotension, methaemoglobinaemia)

Assessment of MACE endpoints at 6 and 12 months (death, heart failure, myocardial infarction, stroke, need for repeat revascularisation)

Markers of inflammation measured at baseline, 30 minutes, 4 and 24 hours post PCI

hs-CRP, MCP-1

Assessment of platelet reactivity at baseline, 30 minutes, 4 and 24 hours post PCI

ADP, collagen, PBS

Plasma nitrite and cyclic guanosine monophosphatase (cGMP) concentrations measured at baseline, post procedure, at 4 hours and 24 hours post-PCI

Cost-utility of Nitrite over at 3 years

ICER based on outcome and QoL (EQ5D)

Full Information

NCT ID

NCT01584453

First Posted

April 23, 2012

Last Updated

November 28, 2017

Sponsor

Barts & The London NHS Trust

Collaborators

Queen Mary University of London

1. Study Identification

Unique Protocol Identification Number

NCT01584453

Brief Title

Safety and Effectiveness of Intra-coronary Nitrite in Acute Myocardial Infarction

Acronym

NITRITE-AMI

Official Title

A Randomised, Double-blind, Placebo-controlled Trial Assessing the Safety and Efficacy of Intracoronary Nitrite Infusion During Acute Myocardial Infarction

Study Type

Interventional

2. Study Status

Record Verification Date

July 2015

Overall Recruitment Status

Completed

Study Start Date

April 2012 (Actual)

Primary Completion Date

November 2013 (Actual)

Study Completion Date

January 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Barts & The London NHS Trust

Collaborators

Queen Mary University of London

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Despite advances in the treatment of heart attacks the complications and death rates from failure of the heart to pump properly after treatment remain high. A heart attack occurs when one or more of the arteries that supply blood to the heart become blocked, causing the heart to be starved of oxygen and nutrients. This results in damage to the heart and so the the heart pumps less well. The main treatment for a heart attack is balloon treatment to open the blocked artery (called primary angioplasty). Whilst re-opening the artery is essential and allows blood to flow to the area of the heart starved of oxygen, this process also causes damage itself (called reperfusion injury) and increases the size of the heart attack further. Currently there are no treatments available that reduce this reperfusion injury. The investigators and others have shown that a substance called sodium nitrite reduces reperfusion injury in experimental models of a heart attack. The aim of this research is to perform a trial to investigate whether during a heart attack, an infusion of sodium nitrite into the damaged artery protects against reperfusion injury and reduces heart attack size in patients.

Detailed Description

Coronary heart disease is still the commonest cause of death in the UK (in the main as a consequence of acute myocardial infarction (AMI)). Presently, timely and effective reperfusion with primary percutaneous coronary intervention (PPCI) remains the most effective treatment strategy for limiting infarct size, preserving left ventricular ejection fraction (LVEF), and improving the clinical outcomes in such patients. However, substantial mortality and morbidity rates still persist with respect to longer term outcome. One of the main determinants of prognosis after AMI is the size of the infarct. Thus, identification of additional strategies that might decrease infarct size is desirable. Evidence from pre-clinical studies suggests that inorganic nitrite administration reduces infarct size in animal models of AMI. In this study we aim to translate these findings into man. We will test the hypothesis that in patients with STEMI undergoing PPCI, an intra-coronary injection of nitrite, initiated prior to establishment of full reperfusion reduces infarct size through prevention of ischemia-reperfusion injury.

6. Conditions and Keywords

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

Myocardial Infarction, Reperfusion Injury, Myocardial Ischemia, Cardiovascular Diseases

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

80 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sodium Nitrite

Arm Type

Experimental

Arm Title

Placebo

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

Sodium Nitrite

Intervention Description

A bolus of sodium nitrite solution (1.8 micromol in 10 ml PRe-diluted in 0.9% sodium chloride in a syringe) will be delivered over 30-60 seconds via intracoronary injection initiated during the re-establishment of antegrade epicardial flow with PPCI.

Intervention Type

Drug

Intervention Name(s)

Sodium Chloride Placebo

Intervention Description

The control intervention is a bolus of 0.9% sodium chloride solution (prepared with an identical appearance to the sodium nitrite).

Primary Outcome Measure Information:

Title

Infarct size measured by CK area under the curve

Description

AUC measured over the 1st 48 hours after PPCI (0,4,8,12,18,24,36 and 48 hours)

Time Frame

1st 48 hours after AMI

Secondary Outcome Measure Information:

Title

Infarct size measured by Troponin T Area under the curve

Description

AUC measured over the 1st 48 hours after PPCI (0,4,8,12,18,24,36 and 48 hours)

Time Frame

1st 48 hours post AMI

Title

Infarct size, assessed by CMR at 6 months ± 2 weeks.

Description

Infarct size, assessed by CMR at 6 months ± 2 weeks.

Time Frame

6 months ± 2 weeks.

Title

Infarct size as a proportion of area at risk measured at 48 hours by CMR.

Description

Infarct size as a proportion of area at risk measured at 48 hours by CMR.

Time Frame

48 hours

Title

The acute safety and tolerability of intra-coronary nitrite in STEMI

Description

Safety profile of IC nitrate (death, MI, CVA, arrhythmia, hypotension, methaemoglobinaemia)

Time Frame

1st 48 hours

Title

Assessment of MACE endpoints at 6 and 12 months (death, heart failure, myocardial infarction, stroke, need for repeat revascularisation)

Time Frame

12 months

Title

Markers of inflammation measured at baseline, 30 minutes, 4 and 24 hours post PCI

Description

hs-CRP, MCP-1

Time Frame

24 hours

Title

Assessment of platelet reactivity at baseline, 30 minutes, 4 and 24 hours post PCI

Description

ADP, collagen, PBS

Time Frame

24 hours

Title

Plasma nitrite and cyclic guanosine monophosphatase (cGMP) concentrations measured at baseline, post procedure, at 4 hours and 24 hours post-PCI

Time Frame

24 hours

Title

Cost-utility of Nitrite over at 3 years

Description

ICER based on outcome and QoL (EQ5D)

Time Frame

3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients aged at least 18 years Acute STEMI with ECG showing ST-segment elevation of 1mm or more in two adjacent limb leads or 2mm or more in at least two contiguous precordial leads or new left bundle branch block; Haemodynamically stable Estimated symptom to balloon or aspiration time < 6 hours Angiographically i) PPCI indicated for revascularisation ii) Single epicardial artery to be treated iii) Expected ability to use over the wire balloon Exclusion Criteria: Patients on organic nitrate treatment (Nicorandil, isosorbide mononitrate) Previous history of AMI, systolic dysfunction or CABG Subjects presenting with cardiogenic shock (systolic blood pressure <80 mmHg for > 30 minutes, or requiring inotropes/emergency intra aortic balloon pump or cardiopulmonary resuscitation Current diagnosis of or treatment for malignancy, other than non-melanoma skin cancer. 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, or significant trauma (burns, fractures). Pregnancy. Contra-indications to CMR scanning i) Pacemakers, intracranial clips or other metal implants ii) Claustrophobia iii) Renal failure (eGFR < 30mls/min) History of alcohol or drug abuse within the past 6 months. History of congenital methaemoglobinaemia. Angiographically severe vessel tortuosity, diffuse disease or severe calcification which may impede successful delivery of the the over the wire balloon.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Anthony Mathur, FRCP, PhD

Organizational Affiliation

Barts and the London NHS Trust/QMUL

Official's Role

Principal Investigator

Facility Information:

Facility Name

London Chest Hospital

City

Bethnal Green

State/Province

London

ZIP/Postal Code

E2 9JX

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

27683405

Citation

Jones DA, Khambata RS, Andiapen M, Rathod KS, Mathur A, Ahluwalia A. Intracoronary nitrite suppresses the inflammatory response following primary percutaneous coronary intervention. Heart. 2017 Apr;103(7):508-516. doi: 10.1136/heartjnl-2016-309748. Epub 2016 Sep 28.

Results Reference

derived

PubMed Identifier

25512434

Citation

Jones DA, Pellaton C, Velmurugan S, Rathod KS, Andiapen M, Antoniou S, van Eijl S, Webb AJ, Westwood MA, Parmar MK, Mathur A, Ahluwalia A. Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction. Circ Res. 2015 Jan 30;116(3):437-47. doi: 10.1161/CIRCRESAHA.116.305082. Epub 2014 Dec 15. Erratum In: Circ Res. 2015 Mar 27;116(7):e55.

Results Reference

derived

PubMed Identifier

23550096

Citation

Jones DA, Andiapen M, Van-Eijl TJ, Webb AJ, Antoniou S, Schilling RJ, Ahluwalia A, Mathur A. The safety and efficacy of intracoronary nitrite infusion during acute myocardial infarction (NITRITE-AMI): study protocol of a randomised controlled trial. BMJ Open. 2013 Apr 2;3(4):e002813. doi: 10.1136/bmjopen-2013-002813. Print 2013.

Results Reference

derived

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Safety and Effectiveness of Intra-coronary Nitrite in Acute Myocardial Infarction

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