Rice Vinegar as an Intervention to Lower Blood Pressure in Adults With Prehypertension and 10-year CVD Risk <10%

Approximately 75 million American adults have hypertension with nearly one in every three
adults experiencing a condition known as prehypertension (1). In 2013, more than 360,000
American deaths involved high blood pressure as a primary or co-morbid cause (2). In
hypertensive patients, the probability of a first occurrence of heart attack and/or stroke is
70% and 80%, respectively (2). Dietary and lifestyle modifications may help some individuals
maintain BP within normal ranges.

Studies of acetic acid, main component of vinegar, conducted with rat and human revealed
mechanisms of potential blood pressure lowering (3-7). Also several human clinical trials to
assess the efficacy of vinegar on blood pressure have previously been conducted in Japan.
Kajimoto et al (2001, 2003) reported that continuous intake of 750 mg of acetic acid daily
(approximately 15 mL of vinegar) reduces systolic blood pressure of adults with
prehypertension as well as adults with hypertension (8-9). Sadou et al (2006) also reported
similar effects with tomato vinegar in adults with prehypertension (750 mg daily acetic acid
intake)(10).

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC7) published by U.S. Department of Health and Human
Services in 2003 defines prehypertension as blood pressure ranging from 120-139 mmHg systolic
and 80-89 mmHg diastolic (11). JNC7 states that "prehypertension is not a disease category".
Individuals with prehypertension are not candidates for drug therapy, rather they are
recommended to practice lifestyle modification to reduce the risk of developing hypertension
in the future. The Centers for Disease Control (CDC) shows the same position to JNC7 that a
person who have SBP (120-139 mmHg) or DBP (80-89 mmHg) are prehypertension at risk stage
(https://www.cdc.gov/bloodpressure/measure.htm). U S Food and Drug Administration (FDA) shows
similar position in 21 C.F.R. § 101.74(a)(1) that "Hypertension, or high blood pressure,
generally means a systolic blood pressure of greater than 140 millimeters of mercury (mm Hg)
or a diastolic blood pressure of greater than 90 mm Hg. Normotension, or normal blood
pressure, is a systolic blood pressure below 140 mm Hg and diastolic blood pressure below 90
mm Hg.". Recently issued guidance by the American College of Cardiology, the American Heart
Association, and other collaborators (ACC/AHA) has emphasized the importance of 10-year CVD
risk in categorization of blood pressure, which is calculated using an individual's systolic
and diastolic blood pressure values, blood cholesterol levels, and medical history (12). The
recommended treatment for an individual with a 10-year CVD risk <10% and blood pressure ≤139
mmHg systolic and ≤89 mmHg diastolic is lifestyle modification and not pharmacologic
intervention. The target population for this study is not hypertension as defined by FDA and
will align with the blood pressure category of "prehypertension" as defined by JNC7,
recognized by CDC, and an additional inclusion criterion of a 10-year CVD risk <10% in
recognition of the 2017 ACC/AHA report.

Its potential effects on blood pressure of acetic acid in humans with prehypertension (all
clinical trials in Japan) provide a rationale for this evaluation with a Mizkan rice vinegar
fruit drink containing 750 mg acetic acid. The purpose of this trial is to investigate the
effect of vinegar delivering 750 mg acetic acid on blood pressure over a 12-week period in
individuals with prehypertension and a <10% 10-year CVD risk. Additionally, the impact of 750
mg acetic acid as delivered in the vinegar drink on blood markers of the
renin-angiotensin-aldosterone system and a marker of endothelial function will be assessed
after 12-weeks.

Inclusion Criteria:

- Prehypertension (SBP 120-139mmHg and /or DBP 80-89mmHg)

- Males and females

- Must be between 30-65 years of age

- BMI: ≥18.5 kg/m2 and ≤34.9 kg/m2

- Stable body weight [self-reported weight gain or loss <5kg (11 lbs) in the past 3
months]

- Agree to comply with the study procedures

- Able to understand and sign the electronic informed consent

- Has reliable access to the internet and smartphone, and the necessary skills required
to complete study tasks

Exclusion Criteria:

- SBP ≥140mmHg or SBP <120mmHg

- Use of tobacco, illegal drugs, or legal drugs known to impact blood pressure (BP),
including but not limited to: amphetamine-type stimulants, cannabis, cocaine, heroin
and other opioids, and MDMA

- Significant alcohol consumption (women: >3 drinks a day or >7 drinks a week; men: >4
drinks per day or >14 drinks per week)

- Women who are pregnant or nursing, and those planning to become pregnant

- Frequent heartburn, e.g., ≥2 days or more per week

- Use of anti-hypertensives, anti-depressants, immunosuppressants, drugs for
hyperlipidemia, drugs that alter nutrient metabolism, and/or supplements targeting
blood pressure reduction, and/or sustained use of NSAIDs within 30 days before
randomization

- Regular use of polyphenol supplements and unwilling to stop use at the time of
screening and for the duration of the study

- Self-identified as "high" consumer of vinegar-containing foods (e.g., 2 days or more
per week consumption of a vinegar drink or significant volumes from such categories as
salad dressings, pickled foods, etc.)

- History of chronic medical conditions, including but not limited to Type 1 or 2
diabetes, cardiovascular disease (including previous heart attack or stroke), kidney
dysfunction (including chronic kidney disease), cancer

- An ASCVD 10-year risk score of ≥10% based on the ACC/AHA ASCVD calculator as performed
by the Investigator or designee via the ASCVD Risk Estimator website
(http://tools.acc.org//ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/)

- Participation in a clinical research trial within 30 days prior to signing the eIC
during screening

- Clinically significant findings from the laboratory assessments obtained during
screening, as assessed by the Investigator or designee

- Allergy to any component of the vinegar or placebo products

- Unable to understand the study and undergo the informed consent process despite
assistance

- Having more than one individual from a household participate in the study (to ensure
prevention of mistaken consumption of incorrect investigational product)

- Investigator's discretion, e.g., subject deemed unsuitable or unreliable in follow-up
to interaction with Investigator or site staff