Nitrite in Hypertrophic Cardiomyopathy (HCM) Study

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

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.

Study Overview

• Status: Unknown
• Conditions: Cardiomyopathy, Hypertrophic
• Intervention / Treatment: Drug: Sodium Nitrate; Diagnostic test: Phosphorous Magnetic Resonance Spectroscopy; Diagnostic test: Exercise Stress Transthoracic Echocardiogram; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Norfolk
    • Norwich, Norfolk, United Kingdom, NR4 7UY
      • Recruiting
      • Norfolk and Norwich University Hospitals Nhs Foundation Trust
      • Contact: Brodie L Loudon, MBBS; Phone Number: 44(0) 1603 591 216; Email: b.loudon@uea.ac.uk
      • Principal Investigator: Sunil V Nair, MD
      • Sub-Investigator: Brodie L Loudon, MBBS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Sodium Nitrate; 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; Single dose of 14mmol oral inorganic sodium nitrate; Diagnostic test: Phosphorous Magnetic Resonance Spectroscopy; 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.; Diagnostic test: Exercise Stress Transthoracic Echocardiogram; 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.
PLACEBO_COMPARATOR: Placebo; 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.	Diagnostic test: Phosphorous Magnetic Resonance Spectroscopy; 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.; Diagnostic test: Exercise Stress Transthoracic Echocardiogram; 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.; Drug: Placebo; Single dose of oral matching placebo

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

Collaborators and Investigators

• Sponsor: University of East Anglia
• Collaborators: Norfolk and Norwich University Hospitals NHS Foundation Trust; British Medical Research Council
• Investigators: Study Chair: Michael P Frenneaux, MD, University of East Anglia; Principal Investigator: Sunil V Nair, MD, Norfolk and Norwich University Hospitals Nhs Foundation Trust

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): November 1, 2017
• Primary Completion (ANTICIPATED): December 1, 2018
• Study Completion (ANTICIPATED): January 1, 2019

Study Registration Dates

• First Submitted: August 11, 2017
• First Submitted That Met QC Criteria: August 11, 2017
• First Posted (ACTUAL): August 16, 2017

Study Record Updates

• Last Update Posted (ACTUAL): October 25, 2017
• Last Update Submitted That Met QC Criteria: October 24, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Hypertrophy; Cardiomyopathies; Cardiomyopathy, Hypertrophic
• Other Study ID Numbers: 201323

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No