Nitrite in Hypertrophic Cardiomyopathy (HCM) Study

Study Overview
=================
Brief Summary
-----------------
Inorganic nitrate, which is found at high levels in green leafy vegetables, is reduced to nitrite by bacteria in the mouth, swallowed, and absorbed in the stomach into the blood. Studies have shown that increasing the blood levels of nitrite improves the way that muscles use oxygen and energy during exercise, and potentially blood flow. Some people ( 1 in 500) suffer from a type of genetic heart condition known as hypertrophic cardiomyopathy (HCM). This condition means that the muscle in the heart does not use energy well and becomes larger than average, meaning that they have to tap into the heart's 'energy reserves'. It is not known if nitrite has the same beneficial effects on heart muscle as on other muscles in the body. Our study will explore the mechanism by which nitrite may improve the function and energy status of the heart in HCM.

Official Title
-----------------
Mechanistic Study of the Effect of Inorganic Sodium Nitrate on Cardiac and Skeletal Muscle Metabolic Efficiency in Patients With Hypertrophic Cardiomyopathy

Conditions
-----------------
Cardiomyopathy, Hypertrophic

Intervention / Treatment
-----------------
* Drug: Sodium Nitrate
* Drug: Placebo
* Diagnostic Test: Phosphorous Magnetic Resonance Spectroscopy
* Diagnostic Test: Exercise Stress Transthoracic Echocardiogram


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, aged between 18 and 80 years. Able to provide informed consent. Able to understand basic instructions in English. A diagnosis of hypertrophic cardiomyopathy based on conventional transthoracic echocardiogram guidelines: left ventricular wall thickness >1.5cm in the absence of sufficient alternative cause. Exercise limited by symptoms on exertion (NYHA Class II symptoms or greater). PeakVO2 <80% on baseline CPEX. The absence of resting LV outflow tract obstruction (peak gradient <30 mm Hg) on TTE. Exclusion Criteria: Significant medical, surgical or psychiatric disease that in the opinion of the patient's attending physician would affect subject safety or influence the study outcome. Contraindications for undergoing MRI. Hypotension with a systolic blood pressure <90mmHg. Severe anaemia with a plasma haemoglobin level <8.0g/dL. Known glucose-6-phosphate dehydrogenase (G6PD) deficiency or G6PD deficiency measured at screening in males of African, Asian or Mediterranean decent. Female subjects of childbearing potential. Haemodynamically significant valve disease. Predisposed to acute on chronic limb ischemia evident from a history of claudication or known peripheral arterial disease.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a placebo-controlled, random-order mechanistic study of oral inorganic sodium nitrate versus placebo in cross-over fashion in patients with non obstructive hypertrophic cardiomyopathy and exercise limitation.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sodium Nitrate<br>Following entry into the study, patients will receive a single dose of oral inorganic sodium nitrate (14mmol) on two separate visits, or matching placebo, in random order (i.e. 2x nitrate visits first or 2x placebo visits first) in a cross-over fashion. | Drug: Sodium Nitrate<br>* Single dose of 14mmol oral inorganic sodium nitrate<br>Diagnostic Test: Phosphorous Magnetic Resonance Spectroscopy<br>* On the first visit day of this arm, participants will be lie inside an MRI scanner to take pictures of the heart. The thigh muscle will then be imaged before, during, and after kicking exercises.<br>Diagnostic Test: Exercise Stress Transthoracic Echocardiogram<br>* On the second visit day of this arm, participants will be asked to lie, semi-erect, on an exercise bed for up to 90 minutes. The echocardiogram will be performed at rest and during peak exercise. The exercise will be in the form of a pedal bike. The exercise levels will be worked out from an upright bicycle exercise test completed by the participants prior to randomization.<br>|
| Placebo Comparator: Placebo<br>Following entry into the study, patients will receive a single dose of oral inorganic sodium nitrate (14mmol) on two separate visits, or matching placebo, in random order (i.e. 2x nitrate visits first or 2x placebo visits first) in a cross-over fashion. | Drug: Placebo<br>* Single dose of oral matching placebo<br>Diagnostic Test: Phosphorous Magnetic Resonance Spectroscopy<br>* On the first visit day of this arm, participants will be lie inside an MRI scanner to take pictures of the heart. The thigh muscle will then be imaged before, during, and after kicking exercises.<br>Diagnostic Test: Exercise Stress Transthoracic Echocardiogram<br>* On the second visit day of this arm, participants will be asked to lie, semi-erect, on an exercise bed for up to 90 minutes. The echocardiogram will be performed at rest and during peak exercise. The exercise will be in the form of a pedal bike. The exercise levels will be worked out from an upright bicycle exercise test completed by the participants prior to randomization.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac Energetic Status | Change in cardiac PCr/ATP ratio on phosphorus MRS between inorganic sodium nitrate and placebo | 3 hours post dose of drug or placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skeletal Muscle Mitochondrial Oxidative Capacity/Energetic Status | Change in PCr recovery half-time on dynamic phosphorus MRS between inorganic sodium nitrate and placebo | 3.5 hours post dose of drug or placebo | 
| Cardiac Diastolic and Systolic Function on exercise | Change in measures of diastolic and systolic function on transthoracic echocardiogram at submaximal exercise between inorganic sodium nitrate and placebo | 3 hours post dose of drug or placebo | 
| Cardiac Diastolic and Systolic Function at rest | Change in measures of diastolic and systolic function on transthoracic echocardiogram at rest between inorganic sodium nitrate and placebo | 3 hours post dose of drug or placebo | 
| Plasma levels of Nitrate/Nitrite/NOx | Change in blood plasma levels of Nitrate/Nitrite/NOx between inorganic sodium nitrate and placebo | 3 hours post dose of drug or placebo |