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Nitrite in Hypertrophic Cardiomyopathy (HCM) Study

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ClinicalTrials.gov Identifier: NCT03251287
Recruitment Status : Unknown
Verified August 2017 by University of East Anglia.
Recruitment status was:  Recruiting
First Posted : August 16, 2017
Last Update Posted : October 25, 2017
Sponsor:
Collaborators:
Norfolk and Norwich University Hospitals NHS Foundation Trust
British Medical Research Council
Information provided by (Responsible Party):
University of East Anglia

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.


Condition or disease Intervention/treatment Phase
Cardiomyopathy, Hypertrophic Drug: Sodium Nitrate Drug: Placebo Diagnostic Test: Phosphorous Magnetic Resonance Spectroscopy Diagnostic Test: Exercise Stress Transthoracic Echocardiogram Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: This will be a double blind study. The placebo and active treatments will appear identical and will be dispensed in identical containers. All trial patients, care providers, outcome assessors and data analysts will remain blind throughout the study.
Primary Purpose: Other
Official Title: Mechanistic Study of the Effect of Inorganic Sodium Nitrate on Cardiac and Skeletal Muscle Metabolic Efficiency in Patients With Hypertrophic Cardiomyopathy
Estimated Study Start Date : November 2017
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : January 2019


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.
Drug: Placebo
Single dose of oral matching placebo

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.




Primary Outcome Measures :
  1. Cardiac Energetic Status [ Time Frame: 3 hours post dose of drug or placebo ]
    Change in cardiac PCr/ATP ratio on phosphorus MRS between inorganic sodium nitrate and placebo


Secondary Outcome Measures :
  1. Skeletal Muscle Mitochondrial Oxidative Capacity/Energetic Status [ Time Frame: 3.5 hours post dose of drug or placebo ]
    Change in PCr recovery half-time on dynamic phosphorus MRS between inorganic sodium nitrate and placebo

  2. Cardiac Diastolic and Systolic Function on exercise [ Time Frame: 3 hours post dose of drug or placebo ]
    Change in measures of diastolic and systolic function on transthoracic echocardiogram at submaximal exercise between inorganic sodium nitrate and placebo

  3. Cardiac Diastolic and Systolic Function at rest [ Time Frame: 3 hours post dose of drug or placebo ]
    Change in measures of diastolic and systolic function on transthoracic echocardiogram at rest between inorganic sodium nitrate and placebo

  4. Plasma levels of Nitrate/Nitrite/NOx [ Time Frame: 3 hours post dose of drug or placebo ]
    Change in blood plasma levels of Nitrate/Nitrite/NOx between inorganic sodium nitrate and placebo



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03251287


Contacts
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Contact: Brodie L Loudon, MBBS 44(0) 1603 591 216 b.loudon@uea.ac.uk
Contact: Michael P Frenneaux, MD 44(0) 1603 593 061 m.frenneaux@uea.ac.uk

Locations
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United Kingdom
Norfolk and Norwich University Hospitals NHS Foundation Trust Recruiting
Norwich, Norfolk, United Kingdom, NR4 7UY
Contact: Brodie L Loudon, MBBS    44(0) 1603 591 216    b.loudon@uea.ac.uk   
Principal Investigator: Sunil V Nair, MD         
Sub-Investigator: Brodie L Loudon, MBBS         
Sponsors and Collaborators
University of East Anglia
Norfolk and Norwich University Hospitals NHS Foundation Trust
British Medical Research Council
Investigators
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Study Chair: Michael P Frenneaux, MD University of East Anglia
Principal Investigator: Sunil V Nair, MD Norfolk and Norwich University Hospitals NHS Foundation Trust

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Responsible Party: University of East Anglia
ClinicalTrials.gov Identifier: NCT03251287     History of Changes
Other Study ID Numbers: 201323
First Posted: August 16, 2017    Key Record Dates
Last Update Posted: October 25, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Cardiomyopathies
Cardiomyopathy, Hypertrophic
Hypertrophy
Heart Diseases
Cardiovascular Diseases
Pathological Conditions, Anatomical
Aortic Stenosis, Subvalvular
Aortic Valve Stenosis
Heart Valve Diseases