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

• ClinicalTrials.gov Identifier: NCT03658174
• Recruitment Status: Completed
• First Posted: September 5, 2018
• Last Update Posted: May 3, 2021
• Sponsor: University of Leicester
• Collaborators: National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK; Loughborough University; University Hospitals, Leicester
• Information provided by (Responsible Party): University of Leicester

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Heart Failure; Arrhythmia	Dietary Supplement: Nitrate-rich beetroot juice; Dietary Supplement: Nitrate-free beetroot juice	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Double blind placebo controlled crossover study
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: August 30, 2018
• Actual Primary Completion Date: December 31, 2020
• Actual Study Completion Date: December 31, 2020

Arms and Interventions

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 Name: placebo

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United Kingdom

Glenfield Hospital, University Hospitals of Leicester NHS Trust

Leicester, Leicestershire, United Kingdom, LE3 9QP

Sponsors and Collaborators

University of Leicester

National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK

Loughborough University

University Hospitals, Leicester

Investigators

• Principal Investigator: Andre Ng, MBChB, PhD; University of Leicester

More Information

• Responsible Party: University of Leicester
• ClinicalTrials.gov Identifier: NCT03658174
• Other Study ID Numbers: 0675; Edge ID 108647 ( Other Identifier: University Hospitals of Leicester NHS Trust )
• First Posted: September 5, 2018
• Last Update Posted: May 3, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Leicester:

Nitrate

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases