Investigation of Dietary Nitrate Effects in Hypertension-induced Target Organ Damage

Prior treatment

• Use of an investigational device or investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
• Subjects who will commence or who are likely to commence regular treatment with non-steroidal anti-inflammatory drugs (NSAIDs) (other than aspirin), from screening until study completion.
• Any non-stable dosing of ongoing medication regimens throughout the study trial.
• Drug abuse within the past 6 months.
• The subject has a three-month prior history of regular alcohol consumption exceeding an average weekly intake of \> 28 units (or an average daily intake of greater than 3 units) for males, or an average weekly intake of \> 21 units (or an average daily intake of greater than 2 units) for females. 1 unit is equivalent to a half-pint (284mL) of beer/lager; 25mL measure of spirits or 125mL of wine.
• Subjects who have donated more than 500 mL of blood within 56 days prior to the study medication administration.
• Concomitant xanthine oxidase inhibitors (such as allopurinol).
• Known history of significant claustrophobia, previous intolerance of CMR imaging or known (or suspected) incompatible metallic implant.
• Patients with known LVH caused by another established pathology diagnosed prior to or at screening e.g. severe aortic stenosis, hypertrophic cardiomyopathy, amyloidosis and Fabry's disease.
  • Exceptions to the exclusion criteria:

Other illness

• History of chronic viral hepatitis (including presence of hepatitis B surface antigen or hepatitis C antibody), or other chronic hepatic disorders.
• History of heart failure defined as NYHA class II - IV or those with known LV dysfunction (EF\<40%) regardless of symptomatic status
• History of malignancy within the past 5 years, other than non-melanoma skin cancer.
• Current life-threatening condition other than vascular disease (e.g. very severe chronic airways disease, HIV positive, life-threatening arrhythmias) that may prevent a subject from completing the study.
• Subjects with rheumatoid arthritis, connective tissue disorders and other conditions known to be associated with chronic inflammation (e.g. Inflammatory Bowel Disease).
• Subjects with any acute infection, or recent systemic (oral or IV) antibiotics within 1 month of screening, or significant trauma (burns, fractures).
• Allergy to gadolinium-based contrast agents used for CMR.

Lab values

• History of increased liver function tests (ALT, AST) due to acute or chronic liver conditions, 3x above the upper limit of normal or bilirubin 1.5x above the upper limit of normal at screening.
• Renal impairment with creatinine clearance (eGFR) of \<50 ml/min at screening.
• Patients with diabetes mellitus, defined by previous history of diabetes or HbA1c \>6.5% (\>48 mmol/mol) at screening.
• Subjects with LDLc, \>7.5 mmol/l. TG level \>10mmol/l.
• Any other subject whom the Investigator deems unsuitable for the study (e.g. due to other medical reasons, laboratory abnormalities, expected study medication noncompliance, or subject's unwillingness to comply with all study-related study procedures).

Other

• Unless specified, a subject will not be eligible for inclusion in this study if any of the following criteria apply:
• Self reported use of anti-microbial mouthwash or tongue scrapes.
• Pregnancy.
• For criteria 18, patients can enter the trial if they discontinue the use of anti-microbial mouthwash for the duration of the clinical trial.
• nCriteria 20 and 22 do not apply to participants who will not have a CMR scan in the NITRATE-CBP arm

• Patients will be enrolled following an informed consent. The subject will be able to understand and comply with protocol requirements, instructions and protocol restrictions.
• Aged 18-80 years.
• The study subjects will be hypertensives with evidence of difficulty treating to target BP (daytime ABPM 135-170/85-105 mmHg) on 1 or more antihypertensive agents, with insufficient efficacy or intolerance of medications.
• For NITRATE LVH, echocardiographic evidence of LV hypertrophy (LV mass indexed to body surface area (BSA); males \>115g/m2; females \>95 g/m2).
• Patients will have been established on an antihypertensive treatment regime for at least 1 month by the time of participation in the study and will not require changes in pharmacological intervention for the duration of the trial.