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

• ClinicalTrials.gov Identifier: NCT02529189
• Recruitment Status: Recruiting
• First Posted: August 20, 2015
• Last Update Posted: August 23, 2018
• Sponsor: Queen Mary University of London
• Collaborator: Imperial College London
• Information provided by (Responsible Party): Amrita Ahluwalia, Queen Mary University of London

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.

Condition or disease	Intervention/treatment	Phase
Cardiovascular Diseases	Dietary Supplement: Beetroot Juice	Phase 2

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 246 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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 246 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: November 2015
• Estimated Primary Completion Date: April 2019
• Estimated Study Completion Date: April 2021

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Nitrate-rich beetroot juice; 70 ml of a beetroot juice concentrate containing ~5 mmol nitrate	Dietary Supplement: Beetroot Juice; 70 ml of beetroot juice containing ~5 mmol of inorganic nitrate
Placebo Comparator: Nitrate-deplete beetroot juice; 70 ml of a beetroot juice concentrate that is nitrate-depleted	Dietary Supplement: Beetroot Juice; 70 ml of beetroot juice which is nitrate-depleted

Outcome Measures

Primary Outcome Measures :

1. 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 Measures :

1. 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 ]
2. Difference from baseline within the group and between groups in target vessel revascularisation (TVR). [ Time Frame: 6 months post intervention ]
3. Difference from baseline within the group and between groups in restenosis rate (diameter >50%). [ Time Frame: 6 months post intervention ]
4. Difference from baseline within the group and between groups in in-segment late loss. [ Time Frame: 6 months post intervention ]
5. 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 ]
6. Difference from baseline within the group and between groups in inflammatory markers. [ Time Frame: 6 months and 12 months post intervention ]
7. Difference from baseline within the group and between groups in plasma and erythrocyte nitrite reductase. [ Time Frame: 6 months and 12 months post intervention ]
8. 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 ]
9. Difference from baseline within the group and between groups high-sensitivity C-reactive protein (hsCRP). [ Time Frame: 6 months and 12 months post intervention ]
10. Difference from baseline within the group and between groups in Interleukin-6 (IL-6). [ Time Frame: 6 months and 12 months post intervention ]
11. 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 ]
12. 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 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

1. Unstable ischaemic heart disease, with an episode of chest pain in less than 24 hours.
2. Patients who have had previous coronary artery bypass surgery (CABG), if they are undergoing angioplasty within a non-native vessel.
3. Patients undergoing angioplasty with a bio-absorbable stent.
4. Current diagnosis of or treatment for malignancy, other than non-melanoma skin cancer.
5. Current life-threatening condition other than vascular disease that may prevent a subject completing the study.
6. 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.
7. 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).
8. Severe acute infection, or significant trauma (burns, fractures).
9. Pregnancy. This will be tested by urine human chorionic gonadotropin (hCG) measurement
10. History of alcohol or drug abuse within the past 6 months.
11. 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.
12. 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.
13. Patients who have donated > 500mls blood within 56 days prior to study medication administration.
14. Anaemia with Hb <10g/dl, or any other known blood disorder or significant illness that may affect platelet function, and coagulation.
15. A history of chronic viral hepatitis (including presence of hepatitis B surface antigen or hepatitis C antibody or other chronic hepatic disorder) or HIV.
16. Abnormal liver function due to acute or chronic liver conditions 3 x upper limit of normal at screening.
17. Renal impairment with creatinine clearance (eGFR) of 35ml/min at screening.
18. 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.

Contacts and Locations

Contacts

Contact: Amrita Ahluwalia, BSc PhD; a.ahluwalia@qmul.ac.uk

Contact: Anthony Mathur, MB BChir PhD; a.mathur@qmul.ac.uk

Locations

United Kingdom

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

London, United Kingdom, EC1M 6BQ

Contact: Amrita Ahluwalia, BSc, PhD k.s.rathod@qmul.ac.uk

Contact: Krishnaraj Rathod, MBBS k.s.rathod@qmul.ac.uk

Principal Investigator: Anthony Mathur, MB BChir PhD

Sub-Investigator: Krishnaraj S Rathod, MBBS

Sub-Investigator: Daniel A Jones, MBBS PhD

Sub-Investigator: Amy Robertson, BSc

Sub-Investigator: Shanti Velmurugan, MBBS PhD

Sponsors and Collaborators

Queen Mary University of London

Imperial College London

Investigators

• Principal Investigator: Amrita Ahluwalia, PhD; Queen Mary University of London

More Information

Publications:

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Amrita Ahluwalia, Principal Investigator Investigator: Amrita Ahluwalia [aahluwalia] Official Title: Deputy Director of The William Harvey Research Institute, Prof of Vascular Pharmacology, Queen Mary University of London
• ClinicalTrials.gov Identifier: NCT02529189
• Other Study ID Numbers: 15/LO/0555
• First Posted: August 20, 2015
• Last Update Posted: August 23, 2018
• Last Verified: August 2018

Keywords provided by Amrita Ahluwalia, Queen Mary University of London:

Stable Angina; Angioplasty; Optical Coherence Tomography; Nitrate

Additional relevant MeSH terms:

Cardiovascular Diseases; Angina, Stable; Angina Pectoris; Myocardial Ischemia; Heart Diseases; Vascular Diseases; Chest Pain; Pain; Neurologic Manifestations