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Trial registered on ANZCTR


Registration number
ACTRN12615000906550
Ethics application status
Approved
Date submitted
5/08/2015
Date registered
1/09/2015
Date last updated
20/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of Dietary Inorganic Nitrate Supplementation on Exercise Performance in Heart Failure
Scientific title
Effects of Dietary Inorganic Nitrate Supplementation on Exercise Performance in Heart Failure
Secondary ID [1] 287082 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure Preserved Ejection Fraction (HFpEF) 295590 0
Heart Failure Reduced Ejection Fraction (HFrEF)
295591 0
Condition category
Condition code
Cardiovascular 295867 295867 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants will consume 210mL of inorganic beetroot juice per day:
-Two 70mL bottles of inorganic beetroot juice
-One 70mL bottle of sport inorganic beetroot juice)
Beetroot juice is sourced from :BEET IT shot, James White Drinks, Ipswich, UK

Participants will consume the the sport shot in the morning, and one of each of the other two bottles midday and at night. The sport shot contains approximately 6.4mmol of nitrate and each organic shot contains approximately 4.8mmol of nitrate per bottle, with a total daily dosing of 16mmol nitrate.

Participants will be required to have at least 7 days of supplementation with the beetroot juice, but depending on subject availability, the total days dosing could vary between subjects. One subject might have availability to complete all round 1 testing visits within a week, whereas another subject could require a week and a half to complete all visits. Previous research does not indicate any further benefits of nitrate dosing beyond 6 days, so we do not expect the total days dosing to affect the study outcome providing all subjects meet the minimum of 7 days supplementation.

Following supplementation, subjects will undergo a minimum of two week wash-out period.

Adherence will be managed by reminder phone calls to subjects during the supplementation period. They will also be asked to keep a record of when they consumed the supplement. and return the empty bottles to the research team.
Intervention code [1] 292322 0
Treatment: Other
Intervention code [2] 292610 0
Lifestyle
Comparator / control treatment
Participants will consume 140mL (two 70mL bottles) of the placebo beetroot juice twice per day for 7-10 days.

The placebo has been specifically manufactured by James White Drinks, Ipswich, UK, to be identical to the active drink, with the only difference between the two being that the placebo has been made inactive by removing the nitrate.

The study employs a cross-over design so all participants will supplement with both the beetroot juice and the placebo, with the order of supplementation randomized, and the dosing remaining double-blinded.
Control group
Placebo

Outcomes
Primary outcome [1] 295544 0
To determine group differences in VO2peak during a maximal graded treadmill cardiopulmonary exercise test (CPX) following beetroot juice (BTR) or placebo (PL) treatment both within and between the heart failure groups.

VO2peak will be determined via using a metabolic cart.
Timepoint [1] 295544 0
During the screening visit participants will complete a maximal CPX. The VO2peak obtained from this test, however, will not be used in final analysis. This screening visit will be used to determine the appropriate workloads for the testing CPX visits and will act as a familiarisation for the participants.

VO2peak will be assessed following a minimum of 7 days of beetroot juice supplementation and again following a minimum of 7 days placebo supplementation.
Primary outcome [2] 295545 0
To determine group differences in time to exhaustion during a maximal graded treadmill cardiopulmonary exercise test (CPX) following beetroot juice (BTR) or placebo (PL) treatment both within and between the heart failure groups.
Timepoint [2] 295545 0
During the screening visit participants will complete a maximal CPX. The time to exhaustion obtained from this test, however, will not be used in final analysis. This screening visit will be used to determine the appropriate workloads for the testing CPX visits and will act as a familiarisation for the participants.

Time to exhaustion will be assessed following a minimum of 7 days of beetroot juice supplementation and again following a minimum of 7 days placebo supplementation.
Primary outcome [3] 295546 0
To determine the segment of Heart Failure patients that can achieve the desired level of plasma nitrite (>400nM) over the course of the 7-10 day dosing regimen.
Timepoint [3] 295546 0
Plasma nitrite levels in response to the nitrate supplementation will be assessed following a minimum of 7 days of nitrate dosing.

Blood samples will be taken at the maximal CPX and vascular testing visits following both placebo and nitrate dosing. To assess plasma nitrite concentrations, however, only the blood data collected following nitrate supplementation will be required.
Secondary outcome [1] 315827 0
To determine group differences between HFpEF and HFrEF in exercise tissue oxygenation (by NIRS) following BTR or PL treatment.
Timepoint [1] 315827 0
Following a minimum of 7 days of BTR and PL supplementation. The placebo supplementation will act as the baseline measures (or the control measures) for the nitrate intervention.
Secondary outcome [2] 315828 0
To determine group differences (HFpEF v HFrEF) in NO-derived species (plasma and RBC nitrite, nitrate, nitrosothiol) following BTR or PL treatment.
Timepoint [2] 315828 0
Following a minimum of 7 days of BTR and PL supplementation. The placebo supplementation will act as the baseline measures (or the control measures) for the nitrate intervention.
Secondary outcome [3] 316138 0
To determine group differences (HFpEF v HFrEF) in mitochondrial function via a muscle biopsy following BTR or PL treatment.
Timepoint [3] 316138 0
Following a minimum of 7 days of BTR and PL supplementation. The placebo supplementation will act as the baseline measures (or the control measures) for the nitrate intervention.
Secondary outcome [4] 316139 0
To determine group differences (HFpEF v HFrEF) in endothelial function assessed via brachial flow mediated dilation using an ultrasound following BTR or PL treatment.
Timepoint [4] 316139 0
Following a minimum of 7 days of BTR and PL supplementation. The placebo supplementation will act as the baseline measures (or the control measures) for the nitrate intervention.
Secondary outcome [5] 316737 0
To determine group differences (HFpEF v HFrEF) in cardiac function following BTR or PL treatment.


Cardiac function will be determine via use of an echocardiograph.
Timepoint [5] 316737 0
Following a minimum of 7 days of BTR and PL supplementation. The placebo supplementation will act as the baseline measures (or the control measures) for the nitrate intervention.
Secondary outcome [6] 316738 0
To determine group differences (HFpEF v HFrEF) in VO2 onset kinetics following BTR or PL treatment.

VO2 onset kinetics will be calculated from data collected via the metabolic cart.
Timepoint [6] 316738 0
Following a minimum of 7 days of BTR and PL supplementation. The placebo supplementation will act as the baseline measures (or the control measures) for the nitrate intervention.
Secondary outcome [7] 316739 0
To determine group differences (HFpEF v HFrEF) in vascular stiffness assessed via a SphygmoCor machine following BTR or PL treatment.

Timepoint [7] 316739 0
Following a minimum of 7 days of BTR and PL supplementation. The placebo supplementation will act as the baseline measures (or the control measures) for the nitrate intervention.
Secondary outcome [8] 316740 0
To determine group differences (HFpEF v HFrEF) in lower limb blood flow assessed via plethysmography following BTR or PL treatment.
Timepoint [8] 316740 0
Following a minimum of 7 days of BTR and PL supplementation. The placebo supplementation will act as the baseline measures (or the control measures) for the nitrate intervention.

Eligibility
Key inclusion criteria
Recruitment will be for individuals between the ages of 18 and 85 who have diagnosed stable Heart Failure ((HF) with either reduced ejection fraction of less than or equal to 40 percent (HFrEF) or preserved ejection fraction of greater than or equal to 50 percent (HFpEF) andno major changes in medications for at least 3 months.


Additional inclusion criteria include: NYHA class II-III HF; receiving optimal medical therapy and a peakVO2 between 10 and 30 ml/kg/min. Furthermore HFpEF inclusion criteria includes: evidence of diastolic dysfunction via an echocardiography (ECHO) or brain natriuretic peptide (BNP).
Minimum age
18 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
A major cardiovascular event or procedure within the previous 6 weeks or plans for hospitalisation or cardiac transplantation within the next 2 months; foot ulcers/Advanced neuropathy; abnormal responses to cardiopulmonary exercise testing (CPX) as defined by AACVPR or other co-morbidities or limitations that preclude safe participation in the exercise testing; inability to walk on treadmill; Allergy to beets, beet juice, milk or soy; Refusal or inability to abstain from the use of proton pump inhibitors for 24 hours prior to testing visits.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The project will be double-blind, with the only un-blinded person being someone who is not directly involved in the collection of data. This individual will color code the placebo and beetroot juice bottles so that only he/she is aware of the color link to the active verse inactive treatment. In this way both the subjects and the research team involved in testing will be blinded to the treatment order.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated coding software will be used to randomly allocate participants to group one or group two.

This study is a double-blind crossover design, so all participants will undergo both the treatment and placebo intervention, but in a randomized order. Group 1 will supplement with placebo (PL) for the first week followed by a washout and then beetroot (BTR) juice supplementation. Group 2 will begin with BTR supplementation followed by a washout period and then placebo supplementation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary endpoint is exercise capacity during the maximal CPX. A repeated measure ANOVA will be used to determine the time × group effect and paired t-tests will be used to determine whether time to exhaustion is greater compared to baseline within each group. Similar analyses will be performed on the secondary endpoints/variables listed in the Specific Aims. Post-hoc comparisons of change scores for relevant variables between HFpEF and HFrEF will be performed.

This is a pilot study, and the results will be used to develop power calculations for a large double blind randomized controlled trial. An important goal of the pilot study is to examine feasibility and potential effectiveness of the intervention. A samples size of 15 patients in each group, or 30 in total, was determined as this is a realistic number of patients that can be recruited from a single site within the time frame of the study.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 291646 0
University
Name [1] 291646 0
Central Research Scheme Grant
Victoria University
Address [1] 291646 0
Victoria University
Ballarat Rd, Footscray VIC 3011
Country [1] 291646 0
Australia
Funding source category [2] 297045 0
Charities/Societies/Foundations
Name [2] 297045 0
Australian Heart Foundation
Address [2] 297045 0
Level 12/500 Collins Street
Melbourne VIC 3000
(03) 9329 8511
Country [2] 297045 0
Australia
Primary sponsor type
Individual
Name
Jason Allen
Address
Jason Allen
L317 Footscray Park, Victoria University
Ballarat Rd, Footscray VIC 3011
Country
Australia
Secondary sponsor category [1] 290392 0
University
Name [1] 290392 0
Victoria University
Address [1] 290392 0
Ballarat Rd, Footscray VIC 3011
Country [1] 290392 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293174 0
Melbourne Health HREC
Ethics committee address [1] 293174 0
PO Royal Melbourne Hospital
300 Grattan Street,
Parkville Victoria, 3050
Ethics committee country [1] 293174 0
Australia
Date submitted for ethics approval [1] 293174 0
29/04/2015
Approval date [1] 293174 0
30/06/2015
Ethics approval number [1] 293174 0
HREC/15/MH/166
Ethics committee name [2] 293311 0
Victoria University Human Research Ethics Committee
Ethics committee address [2] 293311 0
Ethics committee country [2] 293311 0
Australia
Date submitted for ethics approval [2] 293311 0
Approval date [2] 293311 0
24/07/2015
Ethics approval number [2] 293311 0
HREC/15/MH/166

Summary
Brief summary
This project will investigate if 7 days of dietary inorganic nitrate supplementation (beetroot juice) versus placebo in a randomized, double blind, cross-over design, can improve exercise tolerance in heart failure (HF) patients with preserved ejection fraction (HFpEF, n=15) and with reduced ejection fraction (HFrEF, n=15).

The testing protocols are designed to investigate the oxygen consumption system at multiple levels that may mediate exercise performance. These include assessments during exercise of gas exchange, cardiac function, VO2kinetics, skeletal tissue oxygen extraction and nitric oxide metabolism.

Additional resting measures of vascular function and stiffness, tissue perfusion and mitochondrial function (biopsy) will be performed.

The hypothesis of this proposal is that in subjects with HFpEF and HFrEF, regular consumption of beetroot juice for 7-10 days will produce a clinical benefit in exercise tolerance (increase in VO2peak and time to exhaustion) versus a placebo.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58706 0
Prof Jason D Allen
Address 58706 0
Department of Kinesiology | Curry School of Education
Division of Cardiovascular Medicine | School of Medicine
203 Memorial Gymnasium, University of Virginia
Charlottesville, VA 22904
Country 58706 0
United States of America
Phone 58706 0
+1,434,9246207
Fax 58706 0
Email 58706 0
ja6af@virginia.edu
Contact person for public queries
Name 58707 0
Prof Jason D. Allen
Address 58707 0
Department of Kinesiology | Curry School of Education
Division of Cardiovascular Medicine | School of Medicine
203 Memorial Gymnasium, University of Virginia
Charlottesville, VA 22904
Country 58707 0
United States of America
Phone 58707 0
+1,434,9246207
Fax 58707 0
Email 58707 0
ja6af@virginia.edu
Contact person for scientific queries
Name 58708 0
Prof Jason D Allen
Address 58708 0
Department of Kinesiology | Curry School of Education
Division of Cardiovascular Medicine | School of Medicine
203 Memorial Gymnasium, University of Virginia
Charlottesville, VA 22904
Country 58708 0
United States of America
Phone 58708 0
+1,434,9246207
Fax 58708 0
Email 58708 0
ja6af@virginia.edu

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary