Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000489493
Ethics application status
Approved
Date submitted
17/04/2025
Date registered
20/05/2025
Date last updated
20/05/2025
Date data sharing statement initially provided
20/05/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of beetroot juice on blood pressure in unmedicated adults with high blood pressure
Scientific title
Dose-Response Effects of Nitrate-Rich Beetroot Drink on Blood Pressure in Adults with Untreated High Blood Pressure (systolic blood pressure 120-159/ diastolic blood pressure 80-99 mmHg): A Randomised Controlled Trial
Secondary ID [1] 312978 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
High blood pressure 335159 0
Condition category
Condition code
Cardiovascular 331654 331654 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The Intervention is nitrate-rich beetroot juice. This study is an acute dose-response, crossover, double-blinded, randomised, placebo-controlled trial (RCT).

Materials:
Nitrate-Rich Beetroot Juice: The beetroot juice was prepared at the FoodBowl in Auckland, New Zealand. The concentrated beetroot juice drink, which includes natural flavours and contains no added sweeteners or preservatives, is pasteurised at 90°C for 5 seconds and then filled into Polyethylene Terephthalate (PET) bottles under aseptic conditions. The drinks are stored at -20°C until use and tested for microbial safety.
Quality Control: Drinks are stored at -20°C. Thawing will be done at 4°C before administration, and disposed of if not used on the trial day.
Placebo Drink: Similar in appearance and taste to beetroot juice but with minimal nitrate content. Each drink contains varying nitrate concentrations:
* Placebo: less than 62 mg (1 mmol)
* Low Dose: 400 mg (6.45 mmol) nitrate.
* Medium Dose: 600 mg (9.68 mmol) nitrate.
* High Dose: 800 mg (12.9 mmol) nitrate.
Health Screening Questionnaire: Used to assess participants' eligibility.
Blood Pressure Monitor: Riester Ri-champion 'Registered Trademark' N monitor.
Ultrasonographic Cardiac Output Measurement Device: For haemodynamic measurements.
Two-Day Food Diary: To record dietary intake before trial visits.
Informed Consent Forms: Detailed participant information and consent documentation.
These materials are provided to participants during the study visits and can be accessed through the study team at Massey University.

Procedures:
Screening Visits: The study consists of two health screenings and familiarisation sessions to confirm the eligibility of participants.
Trial Visits: The study consists of four trial visits. Each participant will consume all four nitrate concentrations across separate visits, with one specific concentration consumed per visit. The order of the concentrations will be randomised for each participant. At the end of the first trial visit, the participant will be asked to visit for the next trial date (second) after at least a 7-day washout period. On the subsequent trial visits, these steps will be repeated with the remaining beetroot juice doses.
Participants will complete pre-supplementation (baseline) measures, and then will be provided a randomly assigned (double blind) beetroot juice.
Dosage: Participants consume a single shot of 100 ml of beetroot juice within 10 minutes.
Administration: Participants consume the randomly assigned drink on-site with a standardised breakfast. A waiting time for 2.5-3.5 hours (the time it takes for the plasma nitrate and nitrite levels to peak) will be followed, and then post-supplementation measures will be taken.
* The standardised isocaloric breakfast consists either cereal with milk or toast with peanut butter, designed to provide a balanced macronutrient intake of approximately 15 grams of protein, 30 grams of carbohydrates, and 10 grams of fat; this meal will be consumed alongside 100 ml of one of four different nitrate dosages of beetroot juice.
* The total duration of each trial visit is approximately 4 hours.
The pre-supplementation (baseline) assessment comprises measures that will be repeated post-supplementation, including:
* Data Collection: Recording of blood pressure and haemodynamic measurements (heart rate, stroke volume, cardiac output, and systemic vascular resistance).
* Blood Sample Collection: For plasma nitrate and nitrite analysis, serving as biomarkers for nitric oxide bioavailability

Personalisation: The intervention is not personalised or titrated. All participants receive the same four doses of BRJ in a randomised order.

Intervention Providers:
* Co-ordinating Investigator: Prof Ajmol Ali, expertise in sport and exercise science.
* PhD Candidate: Reder Mohammedsalih (10+ years academic experience, nutritionist registered in NZ, Medically Laboratory Registered (MLT) in NZ, certified in Comprehensive First Aid), responsible for day-to-day study management.
* Study Management Group: Experienced researchers and academic staff from Massey University.
* Medically Qualified Clinician: Dr. Sadiq Al-Sakini, MBChB, MSc, FRCPA, MCNZ Registration Number: 23030. Dr. Al-Sakini will review blood pressure results, medical history, and other relevant data to ensure participant safety.

Location: The study will be conducted at the Sport and Exercise Science Research Laboratory, School of Sport, Exercise and Nutrition, Massey University, Auckland. The facility is equipped with the necessary infrastructure for conducting clinical trials, including private rooms for health screenings and laboratory space for trial visits.

Adherence and fidelity will be assessed through direct observation by the research team and participant self-reports. Participants will be monitored during each visit to ensure they follow the study protocols, including the consumption of the assigned beetroot juice dose and adherence to pre-visit instructions (e.g., fasting, avoiding certain foods). Additionally, participants will have the opportunity to contact the researcher to provide feedback and report any issues. The research team, including the Co-ordinating Investigator, PhD candidate, study management group, and medically qualified clinician, will be responsible for assessing adherence and fidelity.

To maintain or improve fidelity, several strategies will be employed. Participants will receive reminders about study protocols and the importance of adherence during each visit. All procedures, including the preparation and administration of the beetroot juice, will follow standardised protocols to ensure consistency. During the pre-assessment baseline, participants with blood pressure outside the predefined range (120-159/80-99 mmHg) at screening or subsequent visits will be withdrawn, considering pre- and post-supplementation readings and the rate of blood pressure change. The clinician will review blood pressure results, medical history, and other relevant data to ensure participant safety during the screening process and throughout the study.
Intervention code [1] 329516 0
Lifestyle
Comparator / control treatment
The control treatment in this study is a placebo.
Details;
* Placebo Drink: The placebo is designed to be similar in appearance and taste to the nitrate-rich beetroot juice used in the intervention.
* Composition: Beetroot juice concentrate with added sweeteners and acidulants but no added preservatives.
* Nitrate Concentration: Less than 62 mg (1 mmol) per 100 ml serving, significantly lower than the active doses.
* Mode of Administration: Oral ingestion, served in a PET bottle at 7-10°C, consumed within 10 minutes of having a standardised breakfast. Consumed once per trial visit.
* Form: Same as the BRJ, served in Polyethylene Terephthalate bottles.
* Storage: Handled and stored under the same conditions as the beetroot juice.
Control group
Placebo

Outcomes
Primary outcome [1] 339385 0
Systolic Blood Pressure (SBP)
Timepoint [1] 339385 0
* Pre-supplementation: At baseline during visits 3, 4, 5, and 6. * Post-supplementation: 2.5 hours and 3.5 hours after the consumption of the beetroot juice during visits 3, 4, 5, and 6.
Secondary outcome [1] 439729 0
Assessment of haemodynamic parameters, including heart rate (HR), cardiac output (CO), stroke volume (SV), and systemic vascular resistance (SVR). This will be assessed as a composite outcome.
Timepoint [1] 439729 0
* Pre-supplementation: At baseline during visits 3, 4, 5, and 6. * Post-supplementation: 2.5 hours and 3.5 hours after the consumption of the beetroot juice during visits 3, 4, 5, and 6.
Secondary outcome [2] 447446 0
Plasma Nitrate Levels
Timepoint [2] 447446 0
* Pre-supplementation: At baseline during visits 3, 4, 5, and 6. * Post-supplementation: 2.5 hours and 3.5 hours after the consumption of the beetroot juice during visits 3, 4, 5, and 6.
Secondary outcome [3] 447846 0
Plasma Nitrite Levels
Timepoint [3] 447846 0
* Pre-supplementation: At baseline during visits 3, 4, 5, and 6. * Post-supplementation: 2.5 hours and 3.5 hours after the consumption of the beetroot juice during visits 3, 4, 5, and 6.

Eligibility
Key inclusion criteria
All participants are required to meet the following criteria:
* High blood pressure individuals with SBP greater than 120-159 mmHg and/or DBP less than 81–99 mmHg
* BMI range greater than or equal to 18 kg/m2 and less than or equal to 35 kg/m2
* Do not take antihypertensive medications [e.g., diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers (ARBs), beta-blockers, alpha-blockers, nitrate-derived agents, or calcium channel blockers (CCBs)]
* Not diagnosed with any heart (e.g., congestive heart failure), vascular (e.g., atherosclerosis of peripheral vascular disease) or cerebrovascular (e.g. stroke) conditions.
* Not diagnosed with a metabolic disease (e.g., diabetes mellitus, Cushing’s Syndrome), or gastrointestinal disease or disorder (e.g., chronic gastritis).
* Do not use supplements that may affect study outcomes (e.g., tetrahydrobiopterin [BH4], a cofactor involved in the synthesis of NO, and amino acid supplements such as L-arginine and L-citrulline, which may influence NO production and vascular function)
* Do not take other non-hypertension medications that could interfere with the study's mechanisms and outcomes (e.g., oral corticosteroids, laxatives, anticoagulants, and antimuscarinic medications)
* Do not use hormonal therapies (e.g., cortisol treatments, hormone replacement therapy)
* Not currently pregnant or breastfeeding
* Not currently using or having used any form of hormonal contraceptive therapy (e.g., oral contraceptives, intrauterine devices, patches, or hormonal injections) within the past 6 months.
* Follow a sedentary lifestyle, participants must perform no more than one 60-minute dedicated exercise session (e.g., running, cycling, swimming) per week for at least 6 months before the study. This does not include regular physical activities that maintain a normal heart rate, such as walking, gardening, low-intensity cycling (e.g., commuting), and general household chores.
Minimum age
30 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Individuals with SBP less than or equal to 120 mmHg or greater than or equal to 160 mmHg, and/or DBP less than or equal to 80 mmHg or greater than or equal to 100 mmHg.
* Self-reported diagnosis of any heart (e.g. congestive heart failure), vascular (e.g. atherosclerosis of peripheral vascular disease) or cerebrovascular (e.g. stroke) conditions.
* Self-reported diagnosis of a metabolic disease (e.g., diabetes mellitus, Cushing’s Syndrome) or gastrointestinal disease or disorder (e.g., chronic gastritis).
* Use of supplements (e.g., BH4, L-arginine and L-citrulline), or other non-hypertension medications (e.g., oral corticosteroids, laxatives, anticoagulants, and antimuscarinic medications) that may affect study outcomes
* Currently using hormonal therapies
* Be pregnant or breastfeeding
* Currently using or having used any form of hormonal contraceptive therapy (e.g., oral contraceptives, intrauterine devices, patches, or hormonal injections) within the past 6 months.
* Have menstrual cycles that typically occur more than 60 days apart.
* Engaging in physical activity that exceeds 60 minutes on more than one day per week.
* Be unable to consume the study beverage due to allergy or intolerance to BRJ
* Currently smoke or vape, or have done so in the last 6 months
* Have a bleeding disorder that would prevent blood draws by venipuncture.

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)
Central randomisation by computer: The randomisation process is conducted independently and remotely using an online tool called Research Randomizer. This ensures proper concealment of randomisation and maintains separation from the investigators involved in the trial. The drinks are labelled with a 3-digit code, known only to a senior laboratory technician or another designated academic member who is not part of the study, ensuring the integrity and objectivity of the research
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software: The sequence code for randomisation is generated using the online tool Research Randomizer. This ensures that the allocation of participants to different groups is random and unbiased
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
Efficacy
Statistical methods / analysis
Sample Size Determination: The number of participants needed to achieve the study objectives was determined using G-Power software. The calculation targeted a moderate effect size (Cohen’s f = 0.25), with a power of 80% and a significance level of 0.05. Based on these parameters and the selected statistical test, Repeated Measures Analysis of Variance (ANOVA), a minimum of 24 participants was deemed sufficient to detect meaningful dose-response effects of nitrate-rich beetroot juice on blood pressure in untreated high blood pressure adults. To account for a potential 20% dropout rate, the final target sample size is set at 30 participants. This sample size ensures that the study is adequately powered to detect significant differences and achieve its objectives.

Statistical Methods and Analysis Plan: IBM SPSS (Statistical Package for the Social Sciences) software version 26 will be used for statistical analysis of the data. Participant characteristics will be presented as means and standard deviations (SD). The data will be assessed for normal distribution and constant variance. If these assumptions are not met, a log-transformation will be applied to normalise the data and stabilise variance for accurate analysis.

Primary Analysis:
* Repeated Measures ANOVA will be used to evaluate within-subject differences in blood pressure reduction across the four doses of nitrate-rich beetroot juice. This method is appropriate for analysing dose effects in a crossover design, where the same participants receive all treatments.
* Statistical significance will be set at a level of p < 0.05 for all analyses. To control for multiple comparisons across secondary outcomes (e.g., heart rate, stroke volume, cardiac output, and systemic vascular resistance), the Holm-Bonferroni correction will be applied.

Secondary Analysis:
* Sphericity will be assessed to ensure equal variance in the differences between conditions. If sphericity is violated, the Greenhouse-Geisser correction will be applied to adjust the degrees of freedom, providing a more accurate test of significance across doses.
* Post-hoc pairwise comparisons using Bonferroni adjustment will be performed if the ANOVA reveals a significant effect across doses. This approach will identify which specific dose levels differ significantly from each other, such as between each dose and the placebo.
* Effect sizes (partial eta-squared) will be reported to quantify the magnitude of the treatment effects, providing insight into the strength of each dose's impact on blood pressure reduction.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/06/2025
Actual
Date of last participant enrolment
Anticipated
1/03/2026
Actual
Date of last data collection
Anticipated
1/05/2026
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment outside Australia
Country [1] 26917 0
New Zealand
State/province [1] 26917 0
Auckland

Funding & Sponsors
Funding source category [1] 317418 0
University
Name [1] 317418 0
Massey University, School of Sport, Exercise and Nutrition
Country [1] 317418 0
New Zealand
Primary sponsor type
University
Name
Massey University
Address
Country
New Zealand
Secondary sponsor category [1] 320984 0
None
Name [1] 320984 0
None
Address [1] 320984 0
Country [1] 320984 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316138 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 316138 0
Ethics committee country [1] 316138 0
New Zealand
Date submitted for ethics approval [1] 316138 0
20/01/2025
Approval date [1] 316138 0
02/05/2025
Ethics approval number [1] 316138 0
Ethics reference 2025 EXP 19717,

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 136910 0
Prof Ajmol Ali
Address 136910 0
Massey University, School of Sport, Exercise and Nutrition, SNW Extension Building, Private Bag 102904, North Shore, Auckland 0745
Country 136910 0
New Zealand
Phone 136910 0
+64 92136414
Fax 136910 0
Email 136910 0
[email protected]
Contact person for public queries
Name 136911 0
Ajmol Ali
Address 136911 0
Massey University, School of Sport, Exercise and Nutrition, SNW Extension Building, Private Bag 102904, North Shore, Auckland 0745
Country 136911 0
New Zealand
Phone 136911 0
+64 92136414
Fax 136911 0
Email 136911 0
[email protected]
Contact person for scientific queries
Name 136912 0
Ajmol Ali
Address 136912 0
Massey University, School of Sport, Exercise and Nutrition, SNW Extension Building, Private Bag 102904, North Shore, Auckland 0745
Country 136912 0
New Zealand
Phone 136912 0
+64 92136414
Fax 136912 0
Email 136912 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers

• * Review committees for publication and scientific communication
* Authorised representatives from the Sponsor
* Regulatory/ethics authorities for trial-related audits and inspections


Conditions for requesting access:
• Yes, conditions apply:
• Requires review on a case-by-case basis by the trial custodian, sponsor or data sharing committee
• Requires a scientifically sound proposal or protocol
What individual participant data might be shared?
• De-identified individual participant data:
• All outcomes data
• Published results
• Primary outcome(s)
What types of analyses could be done with individual participant data?
• Systematic reviews and meta-analyses
• Studies exploring new research questions
• Health economic analyses
• Studies testing whether findings can be repeated or confirmed
• Teaching research methods or developing new statistical techniques
When can requests for individual participant data be made (start and end dates)?
From:
At the end of the study
To:
No end date
Where can requests to access individual participant data be made, or data be obtained directly?
• Email of trial custodian, sponsor or committee: [email protected] and [email protected]

Are there extra considerations when requesting access to individual participant data?
No


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
24715Ethical approval    6. Ethic approved 02052025.pdf



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