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Study of preB Dietary Supplement: A Randomized, Placebo Controlled, Double Blind Trial
February 17, 2010
John C. Nelson, MD, MPH, Principal Investigator
Howard Allen Kadish, MD, MBA, Co-Investigator
Boyd L. Jentzsch, JD, Study Design, Editor
Laura Gontchar, MEd, MBA, Study Coordinator
Vivo Research and Testing
PO Box 1059 Salt Lake City, UT 84065
Background: While many whole-food based products have advanced claims about
moderating Metabolic Syndrome, few have been tested in controlled trials. preB is a
Japanese dietary supplement in wide use there and throughout Asia and South
America. While it has been extensively tested outside the US, it has not been tested for
safety for use in the US. Methods: This study was approved by WIRB #20081790,
Study #1102926. Subjects (n = 75) were recruited from local clinics and from public
advertising. They were randomly assigned to Test and Control groups. Blood, urine, and
other measurements were taken of all subjects before and after the administration of the
test sample. Using a double-blind procedure for assignment, subjects took either
placebo, or the preB (36 mL/day) for six weeks. Results: There were no adverse
reactions, illness or complications detected in either the control of the preB test group.
In addition, several statistically significant results in metabolic variables were noted in
the preB group. Conclusions: preB is safe to use in the US for the dosage and terms
used in the study.
preB has been on the market in Asia and South America for over 7 years. It is used
annually by hundreds of thousands of people (sponsor supplied data). To date no
adverse reactions have been reported (sponsor supplied data). preB is a thick liquid
made of 56 herbs, nuts, seeds, grains, vegetables, and fruits fermented and aged
together for a minimum of six months.
preB has previously been tested and shown to be low glycemic (Final Report, Glycemic
Index Determination, preB Liquid, GI 42.3, Protocol GIL-8042, Glycemic Index
Laboratories, Nov. 15, 2008), and high in antioxidants (Report of Analysis, preB Liquid,
ORAC 79.82 U/g, American Analytical Chemistry Laboratories, Ltd., May 18, 2009).
preB also contains other useful ingredients such as lutein, which is a yellow pigment
contained in green and yellow vegetables and is known to exert anti-oxidative effects,
plus it contains significant carotenoids (pigment group) like â-carotene and lycopene.
A number of studies have been done on the product in Japan, China, and Brazil, that
show the product has potential in moderating Metabolic Syndrome along several
parameters, including a previous Japanese study (Safety Study of preB, Kitasato
Institute Medical Center Hospital, Kitasato University, Tokyo, Japan, September 17,
2008, unpublished) which looked specifically at the safety of preB in healthy subjects
(n=40) and concluded that it was safe. However, preB has not been studied for its safety
in the US.
The purpose of this research was to determine the safety of preB for use in healthy
subjects in the US.
This study was approved by WIRB #20081790, Study #1102926. Subjects were
recruited (N=75) from local clinics and public advertising. Volunteers were initially
screened by telephone to determine if they had any illness, or metabolic disorders, were
on any conflicting medications, or were being treated for depression. Those passing this
screen were then interviewed in person by a trained and experienced interviewer to
examine more closely their answers to questions concerning their present health and
pregnancy status. After signing a disclosure document, they had a number of
measurements taken (height, weight, waist circumference, body fat % using the bioimpedance
device by Tanita, blood pressure, and resting heart rate). Urine and blood
samples were also taken. A total of 43 study variables were tested (see Table 1).
Subjects were then assigned to either a Test or Control group, using a double blind
procedure, and given either a packet of placebo (36 mL/day of a solution of
hydroxypropyl methylcellulose (HPMC), at 0.25 g/100 mL water) in individual serve
packets, or preB. Identical looking packets were given to both groups. Subjects were
given written instruction on when to take the samples (any time they wanted during the
day), the manner of taking (with or without food or drinks), and not to change their daily
eating or exercise habits. Subjects were told to take the samples daily for six weeks.
During that period, an interviewer, blinded as to which group the subjects were
assigned, contacted each subject weekly, by phone or email, and reminded them to
take the samples and to not change their daily exercise or dietary habits. At the end of
six weeks the subjects returned to the clinic and had their measurements, blood, and
urine samples taken again. Subjects were paid a small amount for their time and travel
at the conclusion of the study ($120). Post interviews of the subjects were conducted to
determine their self-reported compliance, and reported tolerability of the test samples
Data Analysis and Statistical Power
Data were analyzed using standard inferential statistical approaches. For continuous
variables, independent samples t-tests were used when parametric assumptions were
met and non-parametric Wilcoxon Rank Sum were used when these assumptions were
not met. Dichotomous variables were analyzed with ÷2 (chi-square) analyses or Fisher.s
exact tests. Due to the exploratory nature of this study, all analyses were conducted
using a 2-tailed approach with á = 0.05. A two group t-test with a 0.050 two-sided
significance level will have 80% power to detect a moderate effect size of 0.661 when
the sample sizes in the two groups are 42 and 33, respectively (total sample size of 75).
A total of 90 healthy subjects began the study, and 75 completed it. Two were dropped
due to incomplete data sets. A total of 13 subjects dropped out the the study, from both
the Control group (n = 2) and Test group (n = 11). There were no significant statistical
differences between those who finished the study (n = 75) and those who dropped out
with the exception of two items: (1) 4.5% of the Control subjects dropped out versus
25% of the Test subjects (p = 0.016). (2) The mean resting heart rate was 66.84 (sd
=7.265) for those who completed the study versus 61.38 (sd = 8.656) for those who
dropped out (p = 0.017). This suggests that there was not a systematic pattern of
dropout, other than it appears that those in the Test group were more likely to drop out
(probably due to tolerability issues, as suggested by post-test interviews).
Of the 43 variables compared in this study (see Table A), three differed significantly (p <
0.05) between the Test and Control groups, with six more having marginally significant
differences (0.05 < p < 0.10).
The statistically significant differences (p < 0.05) occurred among the following
Potassium Serum: While the t1:t2 change in potassium serum went up for the Test
group (0.1758), and decreased for the Control group (-0.0857), and while the difference
in both groups was significant (p = 0.040), both values are in the normal clinical range,
and the difference carries no clinical significance.
LDL Cholesterol: While a change occurred in LDL Cholesterol (p = 0.015), the change
for the Test group (1.3636), and for the Control group (-6.2500), both were within the
normal range for healthy individuals, and has no clinical significance.
Erythrocyte Sedimentation Rate (ESR): This is a test that indirectly measures the level
of inflammation in the body. The Test group change in the sedimentation rate declined
significantly (= -.09394) over the Control group (1.1538), indicating a decline in
inflammation (p = 0.039).
The data supports the null hypothesis on 40 of the 43 variables that there were no
significant differences between the Test and Control groups caused by the test
substance, preB. Two of the variables (Potassium Serum and LDL Cholesterol) showed
statistical changes, but they were not of clinical significance.
The Erythrocyte Sedimentation Rate (ESR) differences between the groups (p = 0.039),
Test group (= -.09394), versus the Control group (1.1538), indicates a significant decline
in inflammation attributable to preB.
Between the groups, the change in C-RP, a more specific measure of inflammation,
while showing a similar directional effect for both groups (Test = -0.2212, Control =
0.3000), did not rise to the level of significance (p = 0.507). Even though the previously
mentioned Kitasato study did report a more significant impact on C-RP, it was not
repeated in this study. The possible effect of preB on C-RP is a good target for a
recommended follow-up dosing study.
The Waist/Height Ratio remained unchanged in the Test group (0.0000) during the study
period, while it increased in the Control group (0.0120) (p = 0.068). Waist
Circumference changes were marginally statistically relevant (p = 0.072), with the Test
group change (0.0227) showing a lower rise than the Control group (0.8095). Taken
together these two variables could indicate a possible effect of preB on waist
circumference, and also waist/height ratio. These relationships need to be tested in
further studies to verify it. It is also possible that there is a dose dependent effect
(meaning a larger dose could create a larger effect), but that too needs to be confirmed
by further clinical study.
Several quintile and inter-variable comparisons were examined. While the results of
these examinations showed interesting relationships between variables, and top-quintile
versus bottom quintile groups, they did not result in any statistically significant results.
They do, however indicate possible directions for further research, especially with larger
doses. Unlike drugs that create biologic changes in small doses, it is possible this
whole-food product needs to be given in larger doses for its effects to be detected more
There were no significant statistical differences between the study groups on 40 of the
43 variables. The observed significant statistical differences between groups on the
three variables may be inferred by the dietary supplement preB. Even when statistically
significant differences occurred between study groups, the overall values are all within
normal clinical range.
Therefore, based on the study results, there is no indication of potentially negative
impact from the dietary supplement sufficient to cause or lead to physiologic damage or
illness to a human. Much higher doses of this product have been consumed in Japan for
longer periods of time with no obvious negative effects. Based upon this study, previous
clinical studies and clinical observations, and with the absence of reported adverse
events among consumers, there is nothing to suggest that such negative effects could
be predicted with higher doses.
These results of this study support the conclusion that preB is safe for consumption by
healthy humans when used in the dose (36 mL/day) and duration (six weeks) studied.
Now that preB has been shown to be safe, further studies should concentrate on dosing
effects at various levels to see if accentuated metabolic relationships develop of clinical
significance, as well as to examine the potential relationship between preB and
inflammation, and waist circumference.
The authors have no relationship past or present, with the sponsor of this study, Brazil
Products Company, (the owner of preB), other than compensation for their contribution
to this study. They therefore declare they have no competing interests.
John C. Nelson, MD, MPH, was the principal investigator and author of this study, coinvestigator
was Howard Kadish, MD, MBA. Stephen Alder, PhD, performed the biostatistical
analysis. Study design, coordination of the draft manuscripts, and editing
services were performed by Boyd L. Jentzsch, JD. The preB Clinical Study Coordinator
was Laura Gontchar, MEd, MBA.
Dr. Nelson is the past-President of the American Medical Association (AMA). He is also
immediate past-Member of the Advisory Committee to the Director of the National
Institutes of Health (NIH), and past-Member of the National Advisory Committee to
Agency for Healthcare Research and Quality (AHRQ).
Dr. Kadish is Professor, Department of Pediatrics, University of Utah School of
Medicine, and Associate Division Chief of the Division of Pediatric Emergency Medicine
at Primary Children.s Medical Center, and author of numerous peer-reviewed articles
and chapters in medical books and journals.
Dr. Alder is Division Chief of the Division of Public Health in the Department of Family
and Preventive Medicine, University of Utah School of Medicine, and author of
numerous peer-reviewed articles in medical journals.
|Table 1: Variables Compared between Test and Control Groups|
- Waist/Height Ra/o
- Glucose Serum: 65.99 mg/dL
- BUN: 5.26
- Crea/nine Serum: 0.57.1.00 mg/dL
- eFGR: >59 mL/min/1.73
- BUN/Crea/nine Ra/o: 8.27
- Sodium Serum: 135.145 mmol/L
- Potassium Serum: 220.127.116.11/L
- Chloride Serum: 97.108 mmol/L
- Carbon Dioxide, total: 20.32 mmol/L
- Calcium Serum: 18.104.22.168 mg/dL
- Protein Total Serum: 22.214.171.124 g/dL
- Albumin Serum: 126.96.36.199 g/dL
- Globulin, Total: 188.8.131.52 g/dL
- A/G Ra/o: 184.108.40.206
- Bilirubin, Total: 0.1.1.2 mg/dL
- Alkaline Phosphatase, Serum: 25.150 IU/L
- AST (SGOT): 0.40 IU/L
- ALT (SGPT): 0.40 IU/L
- Cholesterol, Total: 100.199 mg/dL
- Triglycerides: .149 mg/dL
- HDL Cholesterol: >39 mg/dL
- VLDL Cholesterol Calc: 5.40 mg/dL
- LDL Cholesterol Calc: 0.99 mg/dL
- Sedimenta/on Rate – Westergren: 0.20 mm/hr
- C.Reac/ve Protein, Quant: 0.0.4.9 mg/L
- Urine: Glucose
- Urine: Bilirubin
- Urine: Ketone, mg/dL
- Urine: SG (Specific Gravity)
- Urine: BLD (Blood)
- Urine: PH
- Urine: Protein, mg/dL
- Urine: Urobilinogen, EU/dL
- Urine: Nitrite
- Urine: Leukocytes
- Weight, lbs
- Waist, inches
- Body Fat, %
- Blood Pressure, Systolic
- Blood Pressure, Diastolic
- Res/ng Heart Rate