Clinical trial NCT03658174: Upregulating the Nitric Oxide Pathway To Restore Autonomic Phenotype (UNTRAP).
Official title: Upregulating the Nitric Oxide Pathway To Restore Autonomic Phenotype (UNTRAP). A Double Blind Randomised First "Proof of Concept" Direct Translational Study to Explore the Effects of Dietary Nitrate Supplementation on Autonomic Function in Heart Failure Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Heart Failure
Arrhythmia
Keywords: Nitrate
Lead sponsor: University of Leicester
Sponsor class: OTHER
Collaborators: name: National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK
name: Loughborough University
name: University Hospitals, Leicester
First posted: 2018-09-05
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Double blind placebo controlled crossover study
Primary purpose: TREATMENT

Brief summary: Autonomic nervous system dysfunction is known to be associated with an increased risk of heart rhythm abnormalities and sudden cardiac death (SCD) in patients with chronic heart failure - a condition affecting millions of people worldwide. The nitric oxide pathway has been identified as being involved in mediating the effects of the autonomic nervous system on the heart. Recent studies have shown that dietary nitrates can increase the availability of nitric oxide in the body.

This study hopes to find out if dietary nitrate supplementation can help to improve cardiac and autonomic function in patients with heart failure and autonomic dysfunction and reduce the risk of arrhythmias.

Detailed description: 20 participants enrolled at the University Hospitals of Leicester NHS Trust will be invited to take a beetroot juice supplement, which naturally contains a high concentration of nitrates, and a nitrate-free (placebo) beetroot supplement. In a double blind way, participants will be randomised to the order in which they receive the 2 treatments with crossover of the treatments. There will be a washout period between the two treatments.

In order to assess cardiac and autonomic function, and risk of heart rhythm abnormalities, tests will be carried out before and after each treatment period

Hypotheses:

* Nitrate supplementation reverses the autonomic dysfunction seen in Chronic Heart Failure (CHF)
* Markers of prognostic significance for predicting SCD, including QT variability index and cardiac restitution properties (R2I2, PERS), are normalised by nitrate supplementation in patients with CHF.
* Nitrate supplementation results in functional improvement in CHF patients.

Eligibility criteria: Inclusion Criteria:

* Participant is willing and able to give informed consent for participation in the study.
* Male or Female.
* Diagnosed with chronic heart failure - NYHA II-III
* Reduced heart rate variability
* Left ventricle ejection fraction (LVEF) of ≤40%
* Sinus rhythm on 12 lead ECG
* Must have an adequate understanding of written and spoken English
* Female participants of child bearing potential must be willing to ensure that they or their partner use effective contraception during the study and for 3 months thereafter
* Able (in the Investigators opinion) and willing to comply with all study requirements

Non-Invasive Programmed Stimulation (NIPS) Sub-Study Inclusion Criteria:

* Participant is willing and able to give informed consent for participation in the study
* Patients has a pre-existing ICD device with right ventricular apical lead

Exclusion Criteria:

* Myocardial infarction or coronary revascularization within the last 6 months before study enrolment
* NYHA class IV heart failure symptoms
* Persistent Atrial Fibrillation (AF)/Atrial flutter, or paroxysmal AF with frequent recent episodes of prolonged AF
* Patients taking any other nitrate containing medication or supplement (e.g. Isosorbide mononitrate, GTN)
* Patients taking proton pump inhibitors
* Severe pulmonary disease
* Significant renal impairment (eGFR\<15)
* Active cancer with life expectancy \< 1year
* Patients with significant diabetic or other autonomic neuropathy
* Current or recent (within the last year) cigarette smokers
* Female participants who are pregnant, lactating or planning pregnancy during the course of the study.
* Due to undergo any scheduled elective surgery or other procedures requiring general anaesthesia during the study.
* Participant who is inappropriate for placebo therapy
* Subjects who do not have an adequate understanding of written and spoken English
* Any other significant disease or disorder, which in the opinion of the investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study.
* Participants who have participated in another research study involving an investigational product in the past 12 weeks

Primary outcomes:
measure: Change in heart rate variability (HRV) from baseline
timeFrame: 4 weeks and 8 weeks
measure: Change in QT variability index (QTVI) from baseline
timeFrame: 4 weeks and 8 weeks
measure: Change in Regional Restitution Instability Index (R2I2) from baseline
timeFrame: 4 weeks and 8 weeks
measure: Change in Peak Electrocardiogram Restitution Slope (PERS) from baseline
timeFrame: 4 weeks and 8 weeks
Secondary outcomes:
measure: Change in left ventricular function from baseline
timeFrame: 4 weeks and 8 weeks
measure: Change in peak oxygen uptake (VO2max) on cardiopulmonary exercise test from baseline
timeFrame: 4 weeks and 8 weeks
measure: Change in total exercise time on cardiopulmonary exercise test from baseline
timeFrame: 4 weeks and 8 weeks
measure: Change in the total score on the Minnesota Living With Heart Failure Quality of Life Questionnaire from baseline
timeFrame: 4 weeks and 8 weeks
measure: Participant compliance with dietary supplement
timeFrame: 4 weeks and 8 weeks
measure: Correlation between Non-Invasive Programmed Stimulation (NIPS) derived and exercise ECG derived R2I2 and PERS values
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Leicester
country: United Kingdom
facility: Glenfield Hospital, University Hospitals of Leicester NHS Trust
state: Leicestershire
Study officials:
affiliation: University of Leicester
name: Andre Ng, MBChB, PhD
role: PRINCIPAL_INVESTIGATOR
References: