J Ginseng Res 44 (2020) 697e703

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Journal of Ginseng Research
journal homepage: http://www.ginsengres.org

Research Article

A randomized, double-blind, placebo-controlled pilot study to assess
the effects of protopanaxadiol saponineenriched ginseng extract andpectinase-processed ginseng extract on the prevention of acuterespiratory illness in healthy people
Jeong-Hwan Hwang 1, 2, 3, q, Soo-Hyun Park 4, q, Eun-Kyung Choi 4, Su-Jin Jung 4,
Mi Kyung Pyo 6, Soo-Wan Chae 4, 5, *1

Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea
Research Institute of Clinical Medicine of Jeonbuk National University, Jeonju, Jeonbuk, Republic of Korea
3
Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Jeonbuk, Republic of Korea
4
Clinical Trial Center for Functional Foods, Jeonbuk National University Hospital, Jeonju, Jeonbuk, Republic of Korea
5
Department of Pharmacology, Jeonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea
6International Ginseng and Herb Research Institute, Geumsan, Republic of Korea
2

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 8 May 2018
Received in Revised form
28 November 2018
Accepted 14 January 2019
Available online 11 February 2019

Background: GS-3K8 and GINST, both of which are modiﬁed ginseng extracts, have never been examinedin terms of their effectiveness for the prevention of acute respiratory illness (ARI) in humans. We conducted a pilot study to assess the feasibility of performing a large-scale, randomized, controlled trial.
Methods: This study was a randomized, double-blind, placebo-controlled, pilot study at a single centerfrom October 2014 to March 2015. The 45 healthy applicants were randomly divided into the GS-3K8(n ¼ 15), GINST (n ¼ 15), and placebo groups (n ¼ 15). The study drug was administered as a capsule(500 mg/cap and 3000 mg/day). GS-3K8 contained 6.31 mg/g of Rg1, 15.05 mg/g of Re, 30.84 mg/g of Rb1,
15.02 mg/g of Rc, 12.44 mg/g of Rb2, 6.97 mg/g of Rd, 1.59 mg/g of Rg3, 3.25 mg/g of Rk1, and 4.84 mg/g of
Rg5. GINST contained 7.54 mg/g of Rg1, 1.87 mg/g of Re, 5.42 mg/g of Rb1, 0.29 mg/g of Rc, 0.36 mg/g of
Rb2, 0.70 mg/g of Rd, and 6.3 mg/g of compound K. The feasibility criteria were the rates of recruitment,
drug compliance, and successful follow-up. The primary clinical outcome measure was the incidence of
ARI. The secondary clinical outcome measures were the duration of symptoms.
Results: The rate of recruitment was 11.3 participants per week. The overall rate of completed follow-up
was 97.8%. The mean compliance rate was 91.64  9.80%, 95.28  5.75%, and 89.70  8.99% in the GS-3K8,
GINST, and placebo groups, respectively. The incidence of ARI was 64.3% (9/14; 95% conﬁdence interval[CI], 31.4e91.1%), 26.7% (4/15; 95% CI, 4.3e49.0%), and 80.0% (12/15; 95% CI, 54.8e93.0%) in the GS-3K8,
GINST, and placebo groups, respectively. The average days of symptoms were 3.89  4.65, 9.25  7.63,
and 12.25  12.69 in the GS-3K8, GINST, and placebo groups, respectively.
Conclusion: The results support the feasibility of a full-scale trial. GS-3K8 and GINST appear to have apositive tendency toward preventing the development of ARI and reducing the symptom duration. A
randomized controlled trial is needed to conﬁrm these ﬁndings.
Ó 2019 The Korean Society of Ginseng. Publishing services by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords:
Acute respiratory illness
Clinical trial
GINST
GS-3K8
Pilot study* Corresponding author. Department of Pharmacology, Jeonbuk National University Medical School, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do, 54896, Republicof Korea.
E-mail address: soowan@jbnu.ac.kr (S.-W. Chae).
qJeong-Hwan Hwang and Soo-Hyun Park contributed equally to this work.
https://doi.org/10.1016/j.jgr.2019.01.002
p1226-8453 e2093-4947/$ e see front matter Ó 2019 The Korean Society of Ginseng. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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J Ginseng Res 2020;44:697e703

1. Introduction
Acute respiratory illness (ARI) is mainly caused by respiratory
viruses, and its progress is self-limiting [1]. However, it leads toreduced functioning and work productivity [2]. ARI is also associated with a marked economic burden to the health-care system andsociety because of medical costs and lost work time [3]. According
to the Korean Health Insurance Review and Assessment Service, thecost of medical care for ARI was approximately 920 million dollars
per year from 2007 to 2011 and approximately 1.4 billion dollars
per year from 2012 to 2016 [4].
Infections caused by respiratory viruses, particularly inﬂuenza
and respiratory syncytial virus, remain a signiﬁcant cause of deathin community-dwelling older adults [5]. Inﬂuenza vaccination may
have limited efﬁcacy in this population because of an ageassociated decrease in both humoral and cell-mediated immune
function [6]. In addition, the use of amantadine and rimantadine islimited by their side effects and the development of resistance [7].
Although neuraminidase inhibitors do not have these limitations,the cost of these drugs has been the greatest barrier to their use ininstitutional settings [7].
Ginseng products, including Korean ginseng and American
ginseng, are available over the counter and are often used for theprevention and treatment of ARI [8,9]. Recently, we showed thepreventive effects of Korean ginseng on the development of ARI [8].
However, there is insufﬁcient evidence to conclude that standard
ginseng extracts decrease the incidence of ARI [1]. Therefore,
modiﬁed ginseng extracts that have changes in the composition orabsorbability of ginsenosides, which are mainly attributed to thepharmacological effects of ginseng, are needed [10].
Ginsenoside Rb1, one of the protopanaxadiol (PPD)-type ginsenosides, suppresses viral infection and the proliferation ofvarious viruses in vitro [11e13]. PPD-type ginsenosides Rb1, Rb2,
and Rc are transformed into compound K by the intestinal microﬂora [14]. GINST is a modiﬁed ginseng extract that hydrolyzes theseginsenosides into pectinase and enhances the absorption ofcomponent K [15]. GS-3K8 is another modiﬁed ginseng extract withenhanced PPD-type ginsenoside content [16]. There has been nolarge-scale, randomized, controlled study on the preventive effectsof GS-3K8 and GINST against ARI. Therefore, we conducted a pilot
study on GS-3K8 and GINST to determine the feasibility of a larger
study.

research staff, investigators, and pharmacists until the completionof the study.
At the ﬁrst visit, the enrolled participants were instructed toingest two capsules three times per day (after every meal) for 12
weeks. All participants were educated regarding ARI and instructedto contact the investigators and study physician at the onset of acold. The participants were instructed not to consume any ginseng
products other than those provided for the study or other functional foods or dietary supplements. During the study period, theparticipants who developed ARI received symptomatic treatment
under the direction of the study physician. They were instructed
not to take any other cold medication unless advised by the study
physician. Every 6 weeks, the participants were asked to report any
adverse events or adverse drug reactions, changes in lifestyle oreating patterns, and symptoms of ARI and assess their drug
compliance. Laboratory tests were performed at the ﬁrst visit and
12-week visit. During the 12-week intervention period and 6-weekfollow-up period, ARI-related symptoms were assessed weekly via
telephone. If any symptoms were reported to the study physician,telephone interviews were then conducted daily until the symptoms ended.
2.2. Study population
The participants were recruited through media advertisements,
and those volunteers were screened via a telephone interview for
the inclusion and exclusion criteria. The participants were eligible
to participate in this study if they were in good general health andaged between 39 and 65 years. The participants were excluded
based on the following criteria: (1) vaccinated against inﬂuenza inthe previous 6 months, (2) upper respiratory tract infection at thetime of screening, (3) underlying medical conditions such as humanimmunodeﬁciency virus infection, malignancy, and cardiovascular,
pulmonary, hepatic, renal, neurological, psychiatric, autoimmune,or hematologic diseases, (4) alcohol abuse or drug addiction, (5)gastrointestinal diseases, such as Crohn’s disease, that may interrupt the absorption of the test drug or gastrointestinal surgery,except herniotomy and appendectomy, (6) taking immunomodulators such as immunosuppressants or immunostimulants, (7) hypersensitive to ginseng or currently taking ginseng, (8)participation in another clinical study within 2 months of thescreening test, (9) abnormal hepatic or renal test, (10) psychologicalconditions making it difﬁcult to participate in a study, and (11)pregnant or lactating.

2. Materials and methods
2.3. Study drugs
2.1. Study design
This pilot study was conducted as a randomized, double-blind,placebo-controlled trial to assess the feasibility of a large, randomized, controlled trial to compare GS-3K8 and GINST with placebo. The trial was conducted at the Clinical Trial Center for
Functional Foods at Jeonbuk National University Hospital, which is
a 1,200-bed, university-afﬁliated teaching hospital and the largest
referral center in Jeollabuk-do, a province of Korea. Volunteers were
informed about the study, including the study protocol, after which
the study physician obtained informed consent from each participant. The screening examination was conducted within 4 weeks ofthe study initiation. The participants who passed the screening
process were randomly allocated into one of the three groups (GS3K8, GINST, or placebo) with an allocation ratio of 1:1:1. Random
numbers were generated using the block randomization method in
the Microsoft Ofﬁce Excel 2007 program (Microsoft Corporation,
Redmond, WA, USA) for sequence generation. The randomization
sequence and allocation were concealed from all study participants,

GS-3K8, the PPD saponineenriched ginseng extract used in thisstudy, was obtained from the International Ginseng & Herb
Research Institute (Geumsan, Republic of Korea) and prepared as
described previously with slight modiﬁcations [16]. The preparation method of GS-3K8 was as follows: Ginseng material was prepared from mixtures of ginseng main root and rootlet(root:rootlet ¼ 4:6). Ginseng mixture (1 kg) was extracted with 10 Lof water at 80 C for 6 hours. Each extraction was repeated threetimes. The obtained water extract was concentrated up to 80% of
extraction volume by ultraﬁltration system with a 3-kDa hollow
ﬁber cartridge. Inner fraction of the ginseng extract obtained byultraﬁltration system was further dried in a freeze dryer for the
preparation of PPD saponineenriched ginseng extract and thennamed as GS-3K8. GS-3K8 contained 6.31 mg/g of Rg1, 15.05 mg/g
of Re, 30.84 mg/g of Rb1, 15.02 mg/g of Rc, 12.44 mg/g of Rb2, 6.97
mg/g of Rd, 1.59 mg/g of Rg3, 3.25 mg/g of Rk1, and 4.84 mg/g of
Rg5. GINST, a pectinase-processed Panax ginseng extract, was obtained from ILHWA Co. Ltd., (Guri, Republic of Korea) and preparedJ.-H. Hwang et al / A pilot study for protopanaxadiol saponin-enriched ginseng extract and pectinase-processed ginseng extract
Table 1
Composition of the test drugs.
Component, mg (%)

GS-3K8

Protopanaxadiol saponin
eenriched ginseng extract
Pectinase-processed
ginseng extract
Maltodextrin
Soybean oil
Palm oil
Rice bran wax
ER 290
LecithinAnnatto extract
Cacao color
Total

GINST

Placebo

162 (32.53)

-

-

-

160 (31.94)-

238 (47.79)
40 (8.03)
50 (10.04)
8 (1.61)498 (100)

243 (48.50)
40 (7.98)
50 (9.98)
8 (1.60)
501 (100)

160 (32.00)
241 (48.10)
30 (6.00)
48 (9.60)
11 (2.30)
3 (0.60)
7 (1.40)500 (100)

as described previously with slight modiﬁcations [15]. The preparation method of GINST was as follows: Dried ginseng (1 kg) was
extracted in 5 L of 50% ethanol in water and concentrated with avacuum concentrator. The dry ginseng extract was incubated withan enzyme solution containing 2.4% pectinase (Sigma-Aldrich, St
Louis, MO, USA) at 55oC for 24 hours. GINST contained 7.54 mg/g of
Rg1, 1.87 mg/g of Re, 5.42 mg/g of Rb1, 0.29 mg/g of Rc, 0.36 mg/g of
Rb2, 0.70 mg/g of Rd, and 6.3 mg/g of compound K [17]. The placebo
capsule was composed primarily of maltodextrin, soybean oil, palmoil, lecithin, rice bran wax, cacao color, and annatto extract and wasmatched to the other capsules with regard to energy content, ﬂavor,
appearance, and dosage. The study drug capsules were packaged
indistinguishably and labeled with the participant’s number. The

699

compositions of the study drugs are shown in Table 1. The participants were instructed to bring all remaining supplements at each
visit, and good compliance was deﬁned as 75% or greater. The study
drug was supplied to the participants two times, at the ﬁrst visit
and 6-week visit.
2.4. Outcome measures
All outcome measures were deﬁned a priori. The primary
outcome measures for this pilot study were the recruitment rate,
follow-up rate, and drug compliance rate. The three feasibility objectives would be considered successful if we achieved a recruitment rate of 11 participants per week, completed follow-ups forat least 95% of all recruited participants, and a mean compliance
rate of 90% or greater. Completed follow-up was deﬁned as thepercentage of randomized participants who completed all assessments during the 18-week study period. Compliance was deﬁned
as follows: percent compliance ¼ 100  (number of capsules
dispensed e number of capsules returned)/number of capsulesprescribed. The secondary outcome measures were the clinicaloutcome measures that would be used in a large-scale clinicalstudy. The primary clinical outcome was the incidence of ARI, andthe secondary clinical outcome was the duration of ARI-related
symptoms.
2.5. Safety assessment and tolerability
Safety was assessed through the number of adverse events andadverse drug reactions that were measured using the results ofFig. 1. Flow chart showing the number of participants assessed for eligibility, randomization, follow-up, and analysis.

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J Ginseng Res 2020;44:697e703

laboratory tests and vital signs. Tolerability was evaluated throughthe side effects of GS-3K8, GINST, and placebo capsules. Speciﬁcally,
the participants were asked about gastrointestinal symptoms, suchas nausea, vomiting, loss of appetite, gastrointestinal distress, andintolerance to certain tastes, at each visit.
2.6. Ethical approval
The protocol for this study was approved by the Institutional
Review Board of Jeonbuk National University Hospital (IRB number:
2014-02-011)
andregisteredatwww.clinicaltrials.gov(NCT03028077).
2.7. Sample size and data analysis
Because preliminary data were lacking regarding the ability of
GK-3K8 or GINST to prevent ARI in healthy people, a pilot trial was
performed to generate preliminary data for the design of a largescale clinical trial. Continuous variables were expressed as themean value and standard deviation, and categorical variables wereexpressed as the percentage. The cumulative risk of ARI was estimated using the KaplaneMeier method. Hazard ratios and 95%
conﬁdence intervals (CIs) comparing the incidence rate between
GS-3K8 and placebo or between GINST and placebo were estimatedusing Cox proportional hazards regression models. Calculations ofsample size were based on the ability to detect a 20% difference inthe event rates of ARI between the GS-3K8 and placebo groups with
80% power using a two-sided p value of 0.017 by Bonferroni
correction. SPSS software (version 19.0; IBM, Chicago, Illinois, USA)was used for all statistical analyses.
3. Results
Fig. 1 describes the management of the participants in this pilot
study. The participants were recruited at the Clinical Trial Center for
Functional Foods at Jeonbuk National University Hospital,
Jeollabuk-do, Republic of Korea, in October 2014. The rate ofrecruitment in this feasibility study was 11.3 participants per week.
Initially, 49 participants were enrolled in the study; however, four
participants did not meet the inclusion criteria and were excluded.
The remaining 45 participants were randomly allocated to the GS3K8 (n ¼ 15), GINST (n ¼ 15), and placebo (n ¼ 15) groups. The
participants in each group took the study drug during the 12-weekintervention period and were assessed for ARI occurrence during
the next 6 weeks (follow-up period). During the study period, one
participant in the GS-3K8 group withdrew consent, and theremaining 44 of the 45 randomized participants were followed up
for the entire study period, yielding a follow-up rate of 97.8%.
The demographic characteristics of the participants are presented in Table 2, and Table 3 presents the clinical events, that is,
primary and secondary clinical outcomes, observed in this study.
The incidence of ARI was 64.3% (9/14; 95% CI, 31.4e91.1%) in the GS3K8 group, 26.7% (4/15; 95% CI, 4.3e49.0%) in the GINST group, and80.0% (12/15; 95% CI, 54.8e93.0%) in the placebo group. The average
number of days of symptoms were 3.89  4.65, 9.25  7.63, and12.25  12.69 in the GS-3K8, GINST, and placebo groups, respectively. The KaplaneMeier plots in Fig. 2 show the cumulative incidence of ARI in the GS-3K8, GINST, and placebo groups. The hazard
ratio of ARI was 0.59 (95% CI, 0.28e1.22) in the GS-3K8 group and0.25 (95% CI, 0.01e0.64) in the GINST group. Statistical comparisons
between the groups for clinical outcomes were not conductedbecause this pilot study was not powered for such comparisons andany statistical conclusions from such comparisons would be
misleading.

Table 2
Demographic characteristics of the study participants.
Variables
Sex, n (%)
Male
FemaleAge, mean, yHeight, mean, cm
Body weight,
mean, kg
BMI, mean, kg/m2
Alcohol drinking,
n (%)
Yes
No
Smoking, n (%)
Yes
NoGS-3K8 group(n ¼ 15)

GINST group(n ¼ 15)

Placebo group(n ¼ 15)

1 (6.7)14 (93.3)
54.47  3.40
159.07  6.86
60.89  6.93

2
13
55.00  2.95
159.27  8.88
64.26  10.32

0
15 (100)
53.00  3.66
158.13  5.08
58.82  6.28

24.09  2.30

25.24  2.73

23.58  2.78

5 (33.3)
10 (66.7)

7 (46.7)
8 (53.3)

7 (46.7)
8 (53.3)

015 (100)0
15 (100)

1 (6.7)14 (93.3)

BMI, body mass index.

The mean compliance rate was 91.64  9.80% in the GS-3K8
group, 95.28  5.75% in the GINST group, and 89.70  8.99% in
the placebo group (Table 4). The percentage of participants
achieving 75% or greater compliance was 92.9% in the GS-3K8
group and 100% in the GINST and placebo group. There were no
adverse drug reactions reported in the GS-3K8, GINST, or placebogroups. Five adverse events were observed: one case of herpes
zoster in the GS-3K8 group, one case each of herpes zoster andradial styloid tenosynovitis in the GINST group, and one case eachof vaginitis and rhinitis in the placebo group. Gastrointestinal
intolerance and taste intolerance were not observed in the GS-3K8,
GINST, or placebo groups. During the study period, vital signs were
measured and laboratory tests were performed for the safetyassessment, and the results are shown in Tables 5 and 6.

4. Discussion
We designed this pilot study to determine the feasibility of alarge-scale clinical trial in the future. Korean Red Ginseng is often
taken as a dietary supplement; therefore, we evaluated the successof the study based on the recruitment rate, compliance rate, andcompleted follow-up rate. The results of this study suggest that afull-scale randomized clinical trial is feasible.
The compliance rate was approximately 90% in this study, andmost participants taking the study drugs achieved good compliance
Table 3
Number of clinical events observed in each group.
Variables

GS-3K8 group(n ¼ 14)

GINST group(n ¼ 15)

Primary clinical outcome, n (%; 95% CI)
ARI
9 (64.3; 31.
4 (26.7;
4e91.1)
4.3e49.0)
Secondary clinical outcomes, n, mean days  SD
Symptoms andduration
Sore throat
0
1, 2Coryza7, 2.57  1.13
3, 5.00  3.00
Nasal congestion00
Sneezing
6, 2.33  1.03
0
Hoarseness2, 1.00  0.00
1, 5
Myalgia1, 1
0
Otalgia
0
0
Fever
0
1, 1
Headache
1, 1
1, 1
Cough
3, 7.00  6.93
3, 9.33  9.45
Total
9, 3.89  4.65
4, 9.25  1.22

Placebo group(n ¼ 15)
12 (80.0;54.8e93.0)

5, 3.80  2.49
8, 6.50  3.25
6, 4.00  2.76
3, 7.67  7.23
5, 10.00  9.25
2, 2.00  0.00
01, 1
4, 6.00  6.06
7, 10.43  12.63
12, 12.25  12.69

ARI, acute respiratory illness; CI, conﬁdence interval; SD, standard deviation.

J.-H. Hwang et al / A pilot study for protopanaxadiol saponin-enriched ginseng extract and pectinase-processed ginseng extract

701

Fig. 2. KaplaneMeier estimates of the cumulative risk of acute respiratory illness in the GS-3K8 and GINST groups compared with the placebo group.

(consumption of 75% of the study drug). The reasons for this highcompliance are that the study participants were interested inhealth supplements such as Korean Red Ginseng. Korean Red
Ginseng is readily available in everyday life, and the participants
did not experience drug intolerance or adverse drug reactions inthis study. A similar previous study in our center has a compliance
rate of more than 90% [8]. However, the deﬁnition of goodcompliance in this study is somewhat arbitrary because the use of
categories such as “good” and “poor” compliance is not supported,
as noted by the appropriateness of the cutoff for speciﬁc medications in [18].
We achieved our target follow-up rate and successfully followed
up 97.8% (44/45) of the randomized participants. The recruitment
rate in this study was modest, with 11.3 participants per week.
However, most studies on the effects of ginseng on the preventionof ARI did not report the recruitment rates. A previous large-scalerandomized controlled trialperformed in our center recruited 12.5
Table 4
Drug compliance and tolerability.
Variables
ComplianceCapsules prescribed,
mean  SD
Capsule intake,mean  SD
Compliance rate, %,mean  SD
Achieved 75%
compliance, n (%)
Tolerability
Gastrointestinal
intolerance, nTaste intolerance, nSD, standard deviation.

GS-3K8 group(n ¼ 14)

GINST group(n ¼ 15)

Placebo group(n ¼ 15)498.14  6.49

499.20  8.13

502.80  8.44

456.21  46.36

475.73  31.04

451.20  47.59

91.64  9.80

95.28  5.75

89.70  8.99

13 (92.9)

15 (100)

15 (100)

0

0

0

0

0

0

participants per week, and another large-scale RCT on Panax
quinquefolius recruited 36.6 participants per week [8,19]. The results from this pilot study suggest that a sample of 345 participants(115 in each group) would be required to progress to a full-scale RCTin the future, which allows for a 5% loss of participants during thefollow-up period. If a full-scale RCT was conducted in a single
center, recruitment would take 7e8 months. However, if thenumber of centers was doubled, we estimate that full recruitment
would be achieved in approximately 4 months.
The protective effects of Panax ginseng against infection causedby viruses, such as respiratory syncytial virus, rhinovirus, andinﬂuenza virus causing upper respiratory tract infections, havebeen shown previously in several experimental data [20]. Some
RCTs have documented the clinically favorable effects of standard
ginseng extract, including Panax quinquefolius or Panax ginseng, on
ARI [8,21]. Recently, a study on Panax ginseng at our institution
showed a reduction in the incidence and symptom duration of ARI[8]. However, in other research, Panax quinquefolius did not show aprotective effect against ARI [5]. In addition, previous studies ofPanax quinquefolius or Panax ginseng on ARI in humans have shown
insufﬁcient evidence on their effectiveness in preventing ARI [22].
GINST is a modiﬁed ginseng extract with an increased content ofcompound K formed by fermentation of PPD-type ginsenosides
Rb1, Rb2, and Rc by pectinase [14]. By increasing the content ofcompound K by fermentation, GINST showed excellent pharmacokinetic parameters in a human study rather than the usual
nonfermented ginseng extract [15]. GINST showed higher antiviral
activity against a variety of inﬂuenza viruses than nonfermented
ginseng extract [23]. GS-3K8 also showed an antiviral activity
against inﬂuenza virus A (H1N1) as a modiﬁed ginseng extract witha high proportion of Rb1/Rg1 by increasing the content of PPD-typeginsenosides via ultraﬁltration [24].
Therefore, we conducted a pilot-scale human participant study
using GS-3K8 and GINST, which are made from standard ginseng

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J Ginseng Res 2020;44:697e703

Table 5
Change in laboratory ﬁndings during the study.
GS-3K8 group (n ¼ 14)

Laboratory test

Hematology
WBC
Hemoglobin
Platelets
Chemistry
ALP
GGT
AST
ALT
Total bilirubin
Total protein
Albumin
BUN
Creatinine
Total cholesterol
Triglycerides
GlucoseUrinalysis
Speciﬁc gravity
pH

GINST group (n ¼ 15)

Placebo group (n ¼ 15)

Baseline

12 weeks

Baseline

12 weeks

Baseline

12 weeks

5.72  1.30
13.87  1.16
269.27  58.97

5.27  0.98
13.68  1.14
268.14  55.38

5.36  1.09
13.67  1.07
255.80  49.36

4.71  0.99
13.93  0.98
256.73  38.96

4.70  0.87
13.53  0.86
248.47  37.90

4.60  1.46
13.62  0.70
249.73  54.23

80.73  16.54
24.80  26.43
23.67  4.05
19.00  5.36
0.81  0.23
7.63  0.33
4.44  0.14
14.67  4.37
0.64  0.14
188.73  34.17
126.33  58.08
86.33  5.38

87.57  21.67
23.07  19.03
27.64  8.74
23.43  8.40
0.79  0.17
7.53  0.38
4.38  0.17
14.86  4.04
0.58  0.13
193.07  28.24
109.29  36.59
84.07  6.89

68.00  19.49
17.93  16.33
26.73  6.98
23.40  11.26
0.82  0.20
7.21  0.32
4.35  0.20
13.00  2.39
0.61  0.20
203.93  33.84
118.93  47.62
88.67  8.68

68.47  17.60
16.33  6.11
24.20  4.04
20.67  6.99
0.82  0.33
7.38  0.36
4.43  0.21
13.73  2.52
0.59  0.18
199.80  27.02
123.13  41.95
84.33  6.78

62.80  14.96
15.93  4.06
25.27  5.22
22.27  11.62
0.88  0.25
7.29  0.34
4.31  0.18
12.13  3.20
0.56  0.09
187.40  24.16
100.80  36.28
86.33  10.15

65.87  18.15
14.67  3.02
24.93  4.30
21.60  6.96
0.80  0.26
7.33  0.46
4.39  0.22
13.40  4.07
0.54  0.05
183.20  21.99
99.07  35.78
85.53  6.14

1.02  0.01
6.03  0.92

1.02  0.01
5.86  0.84

1.02  0.01
6.47  1.04

1.02  0.01
6.43  0.65

1.02  0.01
6.37  0.92

1.02  0.01
6.13  0.93

All values are presented as mean  standard deviation.
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate transaminase; BUN, blood urea nitrogen; GGT, gamma-glutamyltransferase; WBC, white blood cell.

Table 6
Change in vital signs during the study.
Vital sign

Systolic BP
Diastolic BP
Heart rate
Body temperature

GS-3K8 group (n ¼ 14)

GINST group (n ¼ 15)

Placebo group (n ¼ 15)

Baseline

12 weeks

Baseline

12 weeks

Baseline

12 weeks

124.00  7.64
79.27  8.54
77.67  10.89
36.42  0.17

127.07  6.63
83.71  7.33
72.71  6.52
36.42  0.15

124.87  7.57
76.80  8.35
74.00  10.95
36.33  0.16

126.87  8.03
79.33  7.96
69.27  8.53
36.34  0.15

116.20  13.96
77.73  12.42
75.47  8.43
36.34  0.17

115.20  13.51
74.47  10.15
71.20  6.90
36.33  0.20

All values are presented as mean  standard deviation.
BP, blood pressure.

extracts by changing the composition or absorbability of ginsenosides and their enzymatic or heat-processed metabolites such ascompound K. This study did not test a formal hypothesis, but thiswas a preliminary study for a future full-scale RCT on GS-3K8 and
GINST. Therefore, statistical analysis of the secondary outcome
measures was not performed. However, this pilot study found apositive trend toward a reduction in the development of ARI and of
symptom duration among the participants in the GS-3K8 and
GINST groups compared with those in the placebo group. The
feasibility criteria were met, indicating that it would be possible toperform a large-scale RCT. Thus, based on the preliminary results
obtained during this pilot study, the usefulness of GS-3K8 and
GINST for the prevention of ARI should be further evaluated byusing a larger randomized controlled trial.
No adverse drug reactions to GS-3K8, GINST, or the placebo
occurred during the intervention or follow-up periods, and no drug
intolerance was observed. Five adverse events developed: one in
the GS-3K8 group, two in the GINST group, and two in the placebogroup. However, there was no causality with the study drugs.
During the study period, both the vital signs and laboratory ﬁndings remained within the normal range for all participants in thethree study groups.
In conclusion, the feasibility results support a full-scale RCT todetermine the efﬁcacy of GS-3K8 and GINST in people with ARI,
which would need to include at least 345 participants. This study
provided encouraging results regarding the effects of GSK-3K8 and
GINST on the development and symptom duration of ARI. The results of this feasibility trial suggest that a full-scale RCT with a

sufﬁcient number of participants to achieve statistical power iswarranted to demonstrate the protective effects of GS-3K8 and
GINST against ARI.
Conﬂicts of interest
The authors declare no conﬂicts of interest.
Acknowledgments
This research was supported by the Export Promotion Technology Development Program of the Ministry of Agriculture, Foodand Rural Affairs (312064-03) of South Korea.
References[1] Allan GM, Arroll B. Prevention and treatment of the common cold: making
sense of the evidence. CMAJ 2014;186:190e9.
[2] Smith A, Thomas M, Whitney H. Effects of upper respiratory tract illnesses onmood and performance over the working day. Ergonomics 2000;43:752e63.
[3] Fendrick AM, Monto AS, Nightengale B, Sarnes M. The economic burden of
non-inﬂuenza-related viral respiratory tract infection in the United States.
Arch Intern Med 2003;163:487e94.
[4] Health Insurance Review and Assessment Service (HIRA). The common cold in
spring during the change of seasons, more attention in young people agegroup [Internet]. Seoul: HIRA; 2013. Mar [cited 2018 Feb 12]. Available from:http://www.hira.or.kr/bbsDummy.do?
pgmid¼HIRAA020041000100&brdScnBltNo¼4&brdBltNo¼8470.
[5] McElhaney JE, Simor AE, McNeil S, Predy GN. Efﬁcacy and safety of CVT-E002,
a proprietary extract of Panax quinquefolius in the prevention of respiratory
infections in inﬂuenza-vaccinated community-dwelling adults: a multicenter,

J.-H. Hwang et al / A pilot study for protopanaxadiol saponin-enriched ginseng extract and pectinase-processed ginseng extract
randomized, double-blind, and placebo-controlled trial. Inﬂuenza Res Treat
2011;2011:759051.
[6] Jefferson T, Rivetti D, Rivetti A, Rudin M, Di Pietrantonj C, Demicheli V. Efﬁcacy
and effectiveness of inﬂuenza vaccines in elderly people: a systematic review.
Lancet 2005;366:1165e74.
[7] Michiels B, Van Puyenbroeck K, Verhoeven V, Vermeire E, Coenen S. The valueof neuraminidase inhibitors for the prevention and treatment of seasonal
inﬂuenza: a systematic review of systematic reviews. PLoS One 2013;8:
e60348.
[8] Lee CS, Lee JH, Oh M, Choi KM, Jeong MR, Park JD, Kwon DY, Ha KC, Park EO,
Lee N, et al. Preventive effect of Korean red ginseng for acute respiratory
illness: a randomized and double-blind clinical trial. J Korean Med Sci
2012;27:1472e8.
[9] McElhaney JE, Gravenstein S, Cole SK, Davidson E, O’neill D, Petitjean S,
Rumble B, Shan JJ. A placebo-controlled trial of a proprietary extract of North
American ginseng (CVT-E002) to prevent acute respiratory illness in institutionalized older adults. J Am Geriatr Soc 2004;52:13e9.
[10] Shin BK, Kwon SW, Park JH. Chemical diversity of ginseng saponins from
Panax ginseng. J Ginseng Res 2015;39:287e98.
[11] Lee MH, Lee BH, Lee S, Choi C. Reduction of hepatitis A virus on FRhK-4 cells
treated with Korean red ginseng extract and ginsenosides. J Food Sci 2013;78:
M1412e5.
[12] Lee MH, Seo DJ, Kang JH, Oh SH, Choi C. Expression of antiviral cytokines in
Crandell-Reese feline kidney cells pretreated with Korean red ginseng extract
or ginsenosides. Food Chem Toxicol 2014;70:19e25.
[13] Liang YY, Wang B, Qian DM, Li L, Wang ZH, Hu M, Song XX. Inhibitory effects
of Ginsenoside Rb1 on apoptosis caused by HSV-1 in human glioma cells. VirolSin 2012;27:19e25.
[14] Bae EA, Kim NY, Han MJ, Choo MK, Kim DH. Transformation of ginsenosides tocompound K(IH-901) by lactic acid bacteria of human intestine. J Microbiol
Biotechnol 2003;13:9e14.
[15] Jin H, Seo JH, Uhm YK, Jung CY, Lee SK, Yim SV. Pharmacokinetic comparisonof ginsenoside metabolite IH-901 from fermented and non-fermented ginseng
in healthy Korean volunteers. J Ethnopharmacol 2012;139:664e7.

703[16] Seol SY, Kim BR, Hong SC, Yoo JH, Lee KH, Lee HJ, Park JD, Pyo MK. The
effective preparation of protopanaxadiol saponin enriched fraction fromginseng using the ultraﬁltration. Nat Prod Sci 2014;20:58e64.
[17] Park SH, Oh MR, Choi EK, Kim MG, Ha KC, Lee SK, Kim YG, Park BH, Kim DS,
Chae SW. An 8-wk, randomized, double-blind, placebo-controlled clinical trial
for the antidiabetic effects of hydrolyzed ginseng extract. J Ginseng Res
2014;38:239e43.
[18] Cramer JA, Roy A, Burrell A, Fairchild CJ, Fuldeore MJ, Ollendorf DA, Wong PK.
Medication compliance and persistence: terminology and deﬁnitions. Value
Health 2008;11:44e7.
[19] High KP, Case D, Hurd D, Powell B, Lesser G, Falsey AR, Siegel R, MetznerSadurski J, Krauss JC, Chinnasami B, et al. A randomized, controlled trial of
Panax quinquefolius extract (CVT-E002) to reduce respiratory infection inpatients with chronic lymphocytic leukemia. J Support Oncol 2012;10:195e
201.
[20] Im K, Kim J, Min H. Ginseng, the natural effectual antiviral: protective effects
of Korean Red Ginseng against viral infection. J Ginseng Res 2016;40:309e14.
[21] Predy GN, Goel V, Lovlin R, Donner A, Stitt L, Basu TK. Efﬁcacy of an extract ofNorth American ginseng containing poly-furanosyl-pyranosyl-saccharides forpreventing upper respiratory tract infections: a randomized controlled trial.
CMAJ 2005;173:1043e8.
[22] Seida JK, Durec T, Kuhle S. North American (Panax quinquefolius) and Asian
ginseng (Panax ginseng) preparations for prevention of the common cold in
healthy adults: a systematic review. Evid Based Complement Alternat Med:eCAM 2011;2011:282151.
[23] Wang Y, Jung YJ, Kim KH, Kwon Y, Kim YJ, Zhang Z, Kang HS, Wang BZ,
Quan FS, Kang SM. Antiviral activity of fermented ginseng extracts against a
broad range of inﬂuenza viruses. Viruses 2018;10.
[24] Pyo MK, Seol SY, Yoo JH, Lee KH, Hong SC, Park JD, International Ginseng &Herb Research Institute. Composition of anti-inﬂuenza H1N1 virus using ultraﬁltration and preparation method thereof. Korean patent KR 101485982B1.
2015 Jan 19. Korean.