Upregulating the Nitric Oxide Pathway To Restore Autonomic Phenotype (UNTRAP). (UNTRAP)

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

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Arrhythmia
• Intervention / Treatment: Dietary supplement: Nitrate-rich beetroot juice; Dietary supplement: Nitrate-free beetroot juice

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE3 9QP
      • Glenfield Hospital, University Hospitals of Leicester NHS Trust

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Nitrate-rich beetroot juice; 70mls of concentrated beetroot juice to be taken twice a day. This contains 5-6 mmol of inorganic nitrate.	Dietary supplement: Nitrate-rich beetroot juice; 70mls of concentrated beetroot juice containing approximately 5-6 mmol of inorganic nitrate
PLACEBO_COMPARATOR: Nitrate-free beetroot juice; 70mls of concentrated nitrate-free beetroot juice to be taken twice a day. This is an identical juice from which the nitrate has been removed using a standard anion exchange resin.	Dietary supplement: Nitrate-free beetroot juice; 70mls of concentrated beetroot juice that has been nitrate-depleted; Other Names: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in heart rate variability (HRV) from baseline	Measure of autonomic function	4 weeks and 8 weeks
Change in QT variability index (QTVI) from baseline	Marker of arrhythmia risk	4 weeks and 8 weeks
Change in Regional Restitution Instability Index (R2I2) from baseline	Marker of ventricular arrhythmia and sudden cardiac death risk	4 weeks and 8 weeks
Change in Peak Electrocardiogram Restitution Slope (PERS) from baseline	Marker of ventricular arrhythmia and sudden cardiac death risk	4 weeks and 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left ventricular function from baseline	LVEF, volumes and filling pressure (E/e ratio)	4 weeks and 8 weeks
Change in peak oxygen uptake (VO2max) on cardiopulmonary exercise test from baseline	Maximum oxygen uptake	4 weeks and 8 weeks
Change in total exercise time on cardiopulmonary exercise test from baseline	Time to exhaustion on exercise test	4 weeks and 8 weeks
Change in the total score on the Minnesota Living With Heart Failure Quality of Life Questionnaire from baseline	Measured using Minnesota Living With Heart Failure Quality of Life Questionnaire, with total score ranging from 0 to 105	4 weeks and 8 weeks
Participant compliance with dietary supplement	Compliance as measured using supplement and food diary	4 weeks and 8 weeks
Correlation between Non-Invasive Programmed Stimulation (NIPS) derived and exercise ECG derived R2I2 and PERS values	Assessment of the correlation between R2I2 and PERS values recorded using NIPS and exercise ECG	4 weeks

Collaborators and Investigators

• Sponsor: University of Leicester
• Collaborators: University Hospitals, Leicester; Loughborough University; National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK
• Investigators: Principal Investigator: Andre Ng, MBChB, PhD, University of Leicester

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 30, 2018
• Primary Completion (ACTUAL): December 31, 2020
• Study Completion (ACTUAL): December 31, 2020

Study Registration Dates

• First Submitted: August 30, 2018
• First Submitted That Met QC Criteria: August 31, 2018
• First Posted (ACTUAL): September 5, 2018

Study Record Updates

• Last Update Posted (ACTUAL): May 3, 2021
• Last Update Submitted That Met QC Criteria: April 29, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Nitrate
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: 0675; Edge ID 108647 (OTHER: University Hospitals of Leicester NHS Trust)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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