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Investigating the Effects of Dietary Nitrate on Vascular Function, Platelet Reactivity and Restenosis in Stable Angina (NITRATE-OCT)

Primary Purpose

Cardiovascular Diseases

Status

Active

Phase

Phase 2

Locations

United Kingdom

Study Type

Interventional

Intervention

Beetroot Juice

About this trial

This is an interventional treatment trial for Cardiovascular Diseases focused on measuring Stable Angina, Angioplasty, Optical Coherence Tomography, Nitrate

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with stable angina diagnosed by a cardiologist on optimal medical therapy undergoing angioplasty to treat residual symptoms.
Aged 18-85
Patients able and willing to give their written informed consent.
Patients undergoing successful PCI procedure.

Exclusion Criteria:

Unstable ischaemic heart disease, with an episode of chest pain in less than 24 hours.
Patients who have had previous coronary artery bypass surgery (CABG), if they are undergoing angioplasty within a non-native vessel.
Patients undergoing angioplasty with a bio-absorbable stent.
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. This will be tested by urine human chorionic gonadotropin (hCG) measurement
History of alcohol or drug abuse within the past 6 months.
A history of heart failure New York Heart Association (NYHA) class 3-4 or severe left ventricular dysfunction (left ventricular ejection fraction of <30%) regardless of symptom status.
Systemic autoimmune disease such as rheumatoid arthritis, connective tissue disease, or other conditions known to be associated with chronic inflammation such as inflammatory bowel disease.
Patients who have donated > 500mls blood within 56 days prior to study medication administration.
Anaemia with Hb <10g/dl, or any other known blood disorder or significant illness that may affect platelet function, and coagulation.
A history of chronic viral hepatitis (including presence of hepatitis B surface antigen or hepatitis C antibody or other chronic hepatic disorder) or HIV.
Abnormal liver function due to acute or chronic liver conditions 3 x upper limit of normal at screening.
Renal impairment with creatinine clearance (eGFR) of 35ml/min at screening.
If patients are on mouthwash, they must be willing to stop using this at least 1 week before the start of the study and throughout the duration that they are involved in the study.

Sites / Locations

William Harvey Research Institute, Barts and The London School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Nitrate-rich beetroot juice

Nitrate-deplete beetroot juice

Arm Description

70 ml of a beetroot juice concentrate containing ~5 mmol nitrate

70 ml of a beetroot juice concentrate that is nitrate-depleted

Outcomes

Primary Outcome Measures

Difference between groups in In-stent late loss, where late loss is defined as the difference between the minimum luminal diameter (MLD).

Secondary Outcome Measures

Difference from baseline within the group and between groups in endothelial function assessed by flow-mediated dilatation of the brachial artery at 6 months compared to pre-procedure assessment.

Difference from baseline within the group and between groups in target vessel revascularisation (TVR).

Difference from baseline within the group and between groups in restenosis rate (diameter >50%).

Difference from baseline within the group and between groups in in-segment late loss.

Difference from baseline between groups in major adverse cardiac events (i.e. Myocardial Infarction, death, Cerebrovascular Accident, Target Vascular Revascularisation).

Difference from baseline within the group and between groups in inflammatory markers.

Difference from baseline within the group and between groups in plasma and erythrocyte nitrite reductase.

Difference from baseline within the group and between groups in changes in plasma xanthine oxidase activity.

Difference from baseline within the group and between groups high-sensitivity C-reactive protein (hsCRP).

Difference from baseline within the group and between groups in Interleukin-6 (IL-6).

Difference from baseline within the group and between groups in platelet activation (P-Selectin and platelet-monocyte aggregates).

Difference from baseline within the group and between groups in platelet aggregation ex vivo (ADP, collagen, arachidonic acid).

Full Information

NCT ID

NCT02529189

First Posted

August 7, 2015

Last Updated

September 14, 2023

Sponsor

Queen Mary University of London

Collaborators

Imperial College London

1. Study Identification

Unique Protocol Identification Number

NCT02529189

Brief Title

Investigating the Effects of Dietary Nitrate on Vascular Function, Platelet Reactivity and Restenosis in Stable Angina

Acronym

NITRATE-OCT

Official Title

A Randomised, Double-blind, Placebo-controlled Study Investigating the Effects of Dietary Nitrate on Vascular Function, Platelet Reactivity and Restenosis in Stable Angina

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

November 2015 (Actual)

Primary Completion Date

December 2022 (Actual)

Study Completion Date

December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Queen Mary University of London

Collaborators

Imperial College London

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The mainstay treatment for reducing the symptoms of angina and long-term risk of heart attacks in patients with heart disease is stent implantation in the diseased coronary artery. Whilst this procedure has revolutionised treatment the incidence of secondary events remains a concern. These repeat events are due in part to continued enhanced platelet reactivity, endothelial dysfunction and a phenomenon called 'restenosis' i.e. the stent becomes blocked ultimately requiring another expensive and risky procedure. In this study it will be determined whether a once daily inorganic nitrate administration might favourably modulate platelet reactivity and endothelial function leading to a decrease in restenosis.

Detailed Description

To address the aims a proof-of-concept study will be conducted to ascertain whether a dietary nitrate approach might prove useful adjunctive therapy improving vascular function in patients with stable angina post elective angioplasty. Design: A prospective randomised, single-centre, double-blind, placebo-controlled trial Setting: Patients with stable angina and single/multiple coronary artery stenosis undergoing elective percutaneous coronary intervention (PCI) who are haemodynamically stable (systolic BP>100 mmHg). These patients will be recruited at The Barts Health Heart Centre, based at St. Bartholomew's Hospital. This is one of the biggest centres in the United Kingdom, serving a population of almost two million people from The City of London and The North East up to the M25 and is a 24/7 centre performing approximately 2000 non-primary angioplasties a year. The study will take place in the Clinical Trials Unit, William Harvey Heart Centre. Target population: A total of 300 patients (male and female, age 18-85) with stable angina as per requirements indicated above. Follow-up will take place in the Clinical Trials Unit, William Harvey Research Institute. Treatment: Patients will be randomised (using an on line randomisation database) to receive 70 ml of a beetroot juice concentrate containing 4-5 mmol nitrate or nitrate-deplete placebo juice concentrate. This intervention will be taken by the patient daily from one day prior to re-establishment of flow with PCI and stent implantation. Analysis: We will analyse the results based on an intention to treat analysis. We will also carry out further per protocol analyses and a subgroup analysis on patients who are on organic nitrates as part of their routine therapy and a comparison of DES (drug-eluting stents) versus BMS (bare-metal stents).

6. Conditions and Keywords

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

Cardiovascular Diseases

Keywords

Stable Angina, Angioplasty, Optical Coherence Tomography, Nitrate

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

300 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Nitrate-rich beetroot juice

Arm Type

Active Comparator

Arm Description

70 ml of a beetroot juice concentrate containing ~5 mmol nitrate

Arm Title

Nitrate-deplete beetroot juice

Arm Type

Placebo Comparator

Arm Description

70 ml of a beetroot juice concentrate that is nitrate-depleted

Intervention Type

Dietary Supplement

Intervention Name(s)

Beetroot Juice

Intervention Description

70 ml of beetroot juice containing ~5 mmol of inorganic nitrate

Intervention Type

Dietary Supplement

Intervention Name(s)

Beetroot Juice

Intervention Description

70 ml of beetroot juice which is nitrate-depleted

Primary Outcome Measure Information:

Title

Difference between groups in In-stent late loss, where late loss is defined as the difference between the minimum luminal diameter (MLD).

Time Frame

6 months +/- 1 month post intervention

Secondary Outcome Measure Information:

Title

Difference from baseline within the group and between groups in endothelial function assessed by flow-mediated dilatation of the brachial artery at 6 months compared to pre-procedure assessment.

Time Frame

6 months and 12 months post intervention

Title

Difference from baseline within the group and between groups in target vessel revascularisation (TVR).

Time Frame

6 months post intervention

Title

Difference from baseline within the group and between groups in restenosis rate (diameter >50%).

Time Frame

6 months post intervention

Title

Difference from baseline within the group and between groups in in-segment late loss.

Time Frame

6 months post intervention

Title

Difference from baseline between groups in major adverse cardiac events (i.e. Myocardial Infarction, death, Cerebrovascular Accident, Target Vascular Revascularisation).

Time Frame

6 months, 12 months and 24 months post intervention

Title

Difference from baseline within the group and between groups in inflammatory markers.

Time Frame

6 months and 12 months post intervention

Title

Difference from baseline within the group and between groups in plasma and erythrocyte nitrite reductase.

Time Frame

6 months and 12 months post intervention

Title

Difference from baseline within the group and between groups in changes in plasma xanthine oxidase activity.

Time Frame

6 months and 12 months post intervention

Title

Difference from baseline within the group and between groups high-sensitivity C-reactive protein (hsCRP).

Time Frame

6 months and 12 months post intervention

Title

Difference from baseline within the group and between groups in Interleukin-6 (IL-6).

Time Frame

6 months and 12 months post intervention

Title

Difference from baseline within the group and between groups in platelet activation (P-Selectin and platelet-monocyte aggregates).

Time Frame

6 months and 12 months post intervention

Title

Difference from baseline within the group and between groups in platelet aggregation ex vivo (ADP, collagen, arachidonic acid).

Time Frame

6 months and 12 months post intervention

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with stable angina diagnosed by a cardiologist on optimal medical therapy undergoing angioplasty to treat residual symptoms. Aged 18-85 Patients able and willing to give their written informed consent. Patients undergoing successful PCI procedure. Exclusion Criteria: Unstable ischaemic heart disease, with an episode of chest pain in less than 24 hours. Patients who have had previous coronary artery bypass surgery (CABG), if they are undergoing angioplasty within a non-native vessel. Patients undergoing angioplasty with a bio-absorbable stent. 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. This will be tested by urine human chorionic gonadotropin (hCG) measurement History of alcohol or drug abuse within the past 6 months. A history of heart failure New York Heart Association (NYHA) class 3-4 or severe left ventricular dysfunction (left ventricular ejection fraction of <30%) regardless of symptom status. Systemic autoimmune disease such as rheumatoid arthritis, connective tissue disease, or other conditions known to be associated with chronic inflammation such as inflammatory bowel disease. Patients who have donated > 500mls blood within 56 days prior to study medication administration. Anaemia with Hb <10g/dl, or any other known blood disorder or significant illness that may affect platelet function, and coagulation. A history of chronic viral hepatitis (including presence of hepatitis B surface antigen or hepatitis C antibody or other chronic hepatic disorder) or HIV. Abnormal liver function due to acute or chronic liver conditions 3 x upper limit of normal at screening. Renal impairment with creatinine clearance (eGFR) of 35ml/min at screening. If patients are on mouthwash, they must be willing to stop using this at least 1 week before the start of the study and throughout the duration that they are involved in the study.

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

William Harvey Research Institute, Barts and The London School of Medicine

City

London

ZIP/Postal Code

EC1M 6BQ

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

25421976

Citation

Kapil V, Khambata RS, Robertson A, Caulfield MJ, Ahluwalia A. Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study. Hypertension. 2015 Feb;65(2):320-7. doi: 10.1161/HYPERTENSIONAHA.114.04675. Epub 2014 Nov 24.

Results Reference

background

PubMed Identifier

23589565

Citation

Ghosh SM, Kapil V, Fuentes-Calvo I, Bubb KJ, Pearl V, Milsom AB, Khambata R, Maleki-Toyserkani S, Yousuf M, Benjamin N, Webb AJ, Caulfield MJ, Hobbs AJ, Ahluwalia A. Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential. Hypertension. 2013 May;61(5):1091-102. doi: 10.1161/HYPERTENSIONAHA.111.00933. Epub 2013 Apr 15.

Results Reference

background

PubMed Identifier

27998900

Citation

Rathod KS, Jones DA, Van-Eijl TJ, Tsang H, Warren H, Hamshere SM, Kapil V, Jain AK, Deaner A, Poulter N, Caulfield MJ, Mathur A, Ahluwalia A. Randomised, double-blind, placebo-controlled study investigating the effects of inorganic nitrate on vascular function, platelet reactivity and restenosis in stable angina: protocol of the NITRATE-OCT study. BMJ Open. 2016 Dec 20;6(12):e012728. doi: 10.1136/bmjopen-2016-012728.

Results Reference

derived

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Investigating the Effects of Dietary Nitrate on Vascular Function, Platelet Reactivity and Restenosis in Stable Angina

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