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

Primary Purpose

Heart Failure, Arrhythmia

Status
Completed
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
Nitrate-rich beetroot juice
Nitrate-free beetroot juice
Sponsored by
University of Leicester
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring Nitrate

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Glenfield Hospital, University Hospitals of Leicester NHS Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Nitrate-rich beetroot juice

Nitrate-free beetroot juice

Arm Description

70mls of concentrated beetroot juice to be taken twice a day. This contains 5-6 mmol of inorganic nitrate.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Change in left ventricular function from baseline
LVEF, volumes and filling pressure (E/e ratio)
Change in peak oxygen uptake (VO2max) on cardiopulmonary exercise test from baseline
Maximum oxygen uptake
Change in total exercise time on cardiopulmonary exercise test from baseline
Time to exhaustion on exercise test
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
Participant compliance with dietary supplement
Compliance as measured using supplement and food diary
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

Full Information

First Posted
August 30, 2018
Last Updated
April 29, 2021
Sponsor
University of Leicester
Collaborators
National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK, Loughborough University, University Hospitals, Leicester
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1. Study Identification

Unique Protocol Identification Number
NCT03658174
Brief Title
Upregulating the Nitric Oxide Pathway To Restore Autonomic Phenotype (UNTRAP).
Acronym
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

2. Study Status

Record Verification Date
April 2021
Overall Recruitment Status
Completed
Study Start Date
August 30, 2018 (Actual)
Primary Completion Date
December 31, 2020 (Actual)
Study Completion Date
December 31, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Leicester
Collaborators
National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK, Loughborough University, University Hospitals, Leicester

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure, Arrhythmia
Keywords
Nitrate

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Model Description
Double blind placebo controlled crossover study
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nitrate-rich beetroot juice
Arm Type
Active Comparator
Arm Description
70mls of concentrated beetroot juice to be taken twice a day. This contains 5-6 mmol of inorganic nitrate.
Arm Title
Nitrate-free beetroot juice
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Nitrate-rich beetroot juice
Intervention Description
70mls of concentrated beetroot juice containing approximately 5-6 mmol of inorganic nitrate
Intervention Type
Dietary Supplement
Intervention Name(s)
Nitrate-free beetroot juice
Other Intervention Name(s)
placebo
Intervention Description
70mls of concentrated beetroot juice that has been nitrate-depleted
Primary Outcome Measure Information:
Title
Change in heart rate variability (HRV) from baseline
Description
Measure of autonomic function
Time Frame
4 weeks and 8 weeks
Title
Change in QT variability index (QTVI) from baseline
Description
Marker of arrhythmia risk
Time Frame
4 weeks and 8 weeks
Title
Change in Regional Restitution Instability Index (R2I2) from baseline
Description
Marker of ventricular arrhythmia and sudden cardiac death risk
Time Frame
4 weeks and 8 weeks
Title
Change in Peak Electrocardiogram Restitution Slope (PERS) from baseline
Description
Marker of ventricular arrhythmia and sudden cardiac death risk
Time Frame
4 weeks and 8 weeks
Secondary Outcome Measure Information:
Title
Change in left ventricular function from baseline
Description
LVEF, volumes and filling pressure (E/e ratio)
Time Frame
4 weeks and 8 weeks
Title
Change in peak oxygen uptake (VO2max) on cardiopulmonary exercise test from baseline
Description
Maximum oxygen uptake
Time Frame
4 weeks and 8 weeks
Title
Change in total exercise time on cardiopulmonary exercise test from baseline
Description
Time to exhaustion on exercise test
Time Frame
4 weeks and 8 weeks
Title
Change in the total score on the Minnesota Living With Heart Failure Quality of Life Questionnaire from baseline
Description
Measured using Minnesota Living With Heart Failure Quality of Life Questionnaire, with total score ranging from 0 to 105
Time Frame
4 weeks and 8 weeks
Title
Participant compliance with dietary supplement
Description
Compliance as measured using supplement and food diary
Time Frame
4 weeks and 8 weeks
Title
Correlation between Non-Invasive Programmed Stimulation (NIPS) derived and exercise ECG derived R2I2 and PERS values
Description
Assessment of the correlation between R2I2 and PERS values recorded using NIPS and exercise ECG
Time Frame
4 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andre Ng, MBChB, PhD
Organizational Affiliation
University of Leicester
Official's Role
Principal Investigator
Facility Information:
Facility Name
Glenfield Hospital, University Hospitals of Leicester NHS Trust
City
Leicester
State/Province
Leicestershire
ZIP/Postal Code
LE3 9QP
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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

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