Vous êtes sur la page 1sur 7

Journal of Ethnopharmacology 181 (2016) 17

Contents lists available at ScienceDirect

Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep

Prospective, randomized, double-blinded, double-dummy and


multicenter phase IV clinical study comparing the efcacy and safety of
PG201 (Layla) and SKI306X in patients with osteoarthritis
Chul-Won Ha a,b,1, Yong-Beom Park c,1, Byung-Woo Min d, Seung-Beom Han e,
Jae Hyup Lee f, Ye-Yeon Won g, Ye-Soo Park h,n
a
Department of Orthopedic Surgery, Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81
Irwon-ro, Gangnam-gu, Seoul 06351, South Korea
b
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, South Korea
c
Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul 06973,
South Korea
d
Department of Orthopedic Surgery, Keimyung University Dongsan Medical Center, 56 Dalseong-ro, Jung-gu, Daegu 41931, South Korea
e
Department of Orthopedic Surgery, Korea University Medical Center Anam Hospital, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, South Korea
f
Department of Orthopedic Surgery, Seoul Metropolitan Government Seoul National University Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu,
Seoul 07061, South Korea
g
Department of Orthopedic Surgery, Ajou University Medical Center, 164 World Cup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do 16499, South Korea
h
Department of Orthopedic Surgery, Hanyang University Medical Center Guri Hospital, 153 Gyeongchun-ro, Guri-si, Gyeonggi-do 11923, South Korea

art ic l e i nf o

a b s t r a c t

Article history:
Received 14 September 2015
Received in revised form
15 January 2016
Accepted 19 January 2016
Available online 25 January 2016

Ethnopharmacological relevance: This prospective, randomized, double-blinded, double-dummy, multicenter study compared the efcacy and safety of PG201 (Laylas), a new product from extracts of 12 plant
sources and SKI306X (Joinss) which have been well investigated and in relatively wide usage among
herbal medicine, for the treatment of patients with knee osteoarthritis.
Aim of the study: To compare the efcacy and safety of PG201 and SKI306X in patients with knee osteoarthritis.
Materials and methods: A prospective, double-blinded multicenter study was conducted in 124 patients
with Kellgren and Lawrence grade 23 knee osteoarthritis. Patients were randomly assigned to receive
600 mg of PG201 (300 mg, twice daily) and 600 mg of SKI306X placebo (200 mg, thrice daily) or 600 mg
of SKI306X (200 mg, thrice daily) and PG201 placebo (300 mg, twice daily) for 12 weeks. The primary
outcome was the improvement of pain by week 8 as assessed by the 100-mm pain visual analog scale
(VAS). Secondary outcomes included pain VAS improvement level at week 12, pain VAS improvement
rate at weeks 8 and 12, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)
improvement level at weeks 8 and 12, the improvement of the quality of life (EQ-5D), overall symptom
self-assessment score, and rescue medication consumption.
Results: The pain VAS improvement at 8 weeks was 14.27 16.2 in the experimental group and 11.97 13.1
in control group (p 0.557), conrming that the experimental group was not inferior to the control group
as lower limit (-8.38) of 95% CI of the difference of VAS improvement between two groups was well
above the allowed limit (-10 mm). There was no signicant difference in all secondary outcomes including pain VAS, WOMAC, EQ-5D, overall symptom self-assessment score, and rescue medication
consumption. Adverse events were low and similar between the two groups.
Conclusions: The results of this study showed that PG201 signicantly reduced knee pain and improved
knee function and were comparable to SKI306X. PG201 can be suggested as an effective treatment of
knee osteoarthritis.
Trial registration ClinicalTrials.gov:NCT01768468
& 2016 Published by Elsevier Ireland Ltd.

Keywords:
Arthritis
Analgesic
Pain
Traditional medicine Asia & Oceania
Clinical trials

1. Introduction
n

Corresponding author. Tel.: 82 31 560 2316; fax: 82 31 557 8781.


E-mail address: hyparkys@hanyang.ac.kr (Y.-S. Park).
1
These authors contributed equally.

http://dx.doi.org/10.1016/j.jep.2016.01.029
0378-8741/& 2016 Published by Elsevier Ireland Ltd.

Non-steroidal anti-inammatory drugs (NSAIDs) and analgesics


are used for symptom relief in patients with osteoarthritis (OA).
However, the use of these drugs may not be safe and appropriate

C.-W. Ha et al. / Journal of Ethnopharmacology 181 (2016) 17

symptom control may not be accomplished (Jordan et al., 2003;


Zhang et al., 2005; Zhang et al., 2008). Glucosamine and chondroitin sulfate are widely administered as supplementary treatment drugs; however, their efcacy remains disputed (Hochberg,
2006; Wandel et al., 2010).
Herbal medicines have been commonly used to treat osteoarthritis in Asia for centuries (Cameron et al., 2009; Cameron and
Chrubasik, 2014; Chen et al., 2014). Although the mechanism of
action of oral medicinal plant products have not been fully elucidated, their interactions with the mediators of inammation and
cartilage destruction provide a rationale for their use in the
treatment of OA (Cameron et al., 2009).
PG201 (Laylas) is a medicine extracted from 12 herbs which
have been used to treat osteoarthritis in traditional medicine in
Eastern Asia (Kim, 2000; Neung, 1998; Park and Lee, 2000; Shin
et al., 2003). The herbs used for the formulation of PG201 are as
follows: Chaenomeles sinensis (Dum.Cours.) Koehne, fructus (synonym; Chaenomeles chinensis (Dum.Cours.) Koehne), Achyranthes
japonica (Miq.) Nakai, radix (synonym; Achyranthes bidentata
Blume), Acanthopanax sessiliorus (Rupr. & Maxim.) Seem, cortex
(synonym; Eleutherococcus sessiliorus (Rupr. & Maxim.) S.Y.Hu.),
Cinnamomum cassia (L.) J.Presl, cortex (synonym; Cinnamomum
aromaticum Nees), Gentiana macrophylla Pall., radix, (synonym;
Tretorhiza macrophylla (Pall.) Sojk), Clematis chinensis Osbeck,
radix, (synonym; Clematis benthamiana Hemsl.), Angelica gigas
Nakai, radix, (No synonyms), Cnidium ofcinale Makino, rhizoma
(synonym; Ligusticum ofcinale (Makino) Kitag.), Gastrodia elata
Blume, rhizoma (synonym; Gastrodia elata f. pilifera Tuyama),
Carthamus tinctorius L., os (synonym; Carthamus glaber Burm.f.),
Saposhnikovia divaricata (Turcz.) Schischk, radix (synonym; Ledebouriella seseloides (Hoffm.) H.Wolff), Dipsacus asperoides C.Y.
Cheng & T.M.Ai, radix (synonym; Dipsacus inermis Wall.). These
herbs have played an important role in the medical care of for
thousands of years in Korea (Heo, 1999; Lee, 1978). For example,
Chaenomeles sinensis, Achyranthes japonica, Carthamus tinctorius,
Cnidium ofcinale and Cinnamomum cassia have been known for
maintaining or assisting blood circulation. Angelica gigas and
Gastrodia elata have been used as a tonifying the blood and promoting blood circulation. Saposhnikovia divaricata has been used
for headache, vertigo and arthralgia. Gentiana macrophylla has
been frequently used to treat rheumatoid arthritis. Acanthopanax
sessiliorus has been used for arthralgia due to activity in
strengthening muscle and bone. Clematis chinensis and Dipsacus
asperoides have been used for protection against degeneration of
cartilage and regeneration of damaged tissue. These 12 medicinal
herbal extracts used PG201 has demonstrated anti-inammatory
and cartilage protective effects in in vitro and in vivo studies (Park
et al., 2005; Shin et al., 2003; Choi. et al., 2012; Choi et al., 2013).
These results indicate that the application of PG201 in the treatment of patients with OA may be promising.
SKI306X (Joinss) is another drug prepared from the ethanol
extract of 3 medicinal plants, Clematis manshurica Rupr., radix,
(synonym; Clematis terniora var. manshurica (Rupr.) Ohwi), Trichosanthes kirilowii Maxim, radix, (synonym; Trichosanthes kirilowii
var. japonica Kitan.) and Prunella vaulgaris L., spica, (synonym;
Prunella asiatica f. albiora (Nakai) Kitag.), which has been widely
and traditionally used to decrease pain and improve functional
capacity in patients with OA (Kim et al., 2005). SKI306X also
showed the effects of cartilage protection and anti-inammation in
vitro and in vivo (Choi et al., 2002; Hartog et al., 2008; Kim et al.,
2005). The clinical safety and efcacy of SKI306X has been well
investigated, as evidenced by several studies (Jung et al., 2001; Lung
et al., 2004; Song et al., 2007). SKI306X is currently the most widely
used herb-derived medicine for OA in Korea.
The objective of this study was to evaluate the efcacy and
safety of PG201 in knee OA, compared to the herb-derived medicine

that currently is widely used. We hypothesized that PG201 was not


inferior to SKI306X with respect to safety and efcacy for the
treatment of patients with OA.

2. Methods
2.1. Study design
This prospective, randomized, double-blinded, double dummy,
active drug-comparative, and multi-center phase IV study was
conducted at 6 University Hospitals from October 26, 2012 to June
27, 2013. Each participating hospital obtained the approval of its
respective Institutional Review Board and written informed consent was obtained from all subjects.
2.2. Study population
Eligible patients were aged between 40 and 80 years, diagnosed as primary OA according to the American College of Rheumatology criteria (Altman et al., 1986), had radiographic evidence
of tibiofemoral OA (Kellgren and Lawrence grade 2 or 3), exhibited
similar OA symptoms for at least 3 months, had less than 80 mm
on a 100 mm pain visual analogue scale (VAS) during screening,
and had greater than 40 mm on the VAS at baseline. Patients were
excluded from the study if they had spinal or lower extremity joint
diseases that could signicantly affect the indicator knee, history
of upper gastrointestinal ulcers within 6 months before screening,
history of upper gastrointestinal hemorrhage (including hematemesis) within 12 months prior to the screening, or history of
lower gastrointestinal hemorrhage (excluding hemorrhoids)
within 12 months before screening. The full list of inclusion and
exclusion criteria is detailed in the supplemental Table 1.
2.3. Preparation of PG201
PG201 was prepared using the formulation on the basis of the
known functions of the composing herbs described previously
(Shin et al., 2003). The moisture content of each herb was less
than 10% by weight, and the herbs were air-dried. The herbs used
were as follows: Chaenomeles sinensis (Dum.Cours.) Koehne,
fructus (synonym; Chaenomeles chinensis (Dum.Cours.) Koehne),
Achyranthes japonica (Miq.) Nakai, radix (synonym; Achyranthes
bidentata Blume), Acanthopanax sessiliorus (Rupr. & Maxim.)
Seem, cortex (synonym; Eleutherococcus sessiliorus (Rupr. &
Maxim.) S.Y.Hu.), Cinnamomum cassia (L.) J.Presl, cortex (synonym; Cinnamomum aromaticum Nees), Gentiana macrophylla Pall.,
radix, (synonym; Tretorhiza macrophylla (Pall.) Sojk), Clematis
chinensis Osbeck, radix, (synonym; Clematis benthamiana Hemsl.),
Angelica gigas Nakai, radix, (No synonyms) Cnidium ofcinale
Makino, rhizoma (synonym; Ligusticum ofcinale (Makino) Kitag.), Gastrodia elata Blume, rhizoma (synonym; Gastrodia elata f.
pilifera Tuyama), Carthamus tinctorius L., os (synonym; Carthamus glaber Burm.f.), Saposhnikovia divaricata (Turcz.) Schischk,
radix (synonym; Ledebouriella seseloides (Hoffm.) H.Wolff), Dipsacus asperoides C.Y.Cheng & T.M.Ai, radix (synonym; Dipsacus
inermis Wall.), 8:8:8:8:5:5:5:5:5:5:4:4 (w/w), respectively. All
herbs were nely cut to 10  15 mm in size, mixed, and extracted
with 25% (v/v) ethanol at room temperature for 72 hr. The supernatant was ltered with 10mm cartridge lter and concentrated under reduced pressure below 60 C to remove ethanol. As a result of specic plant extract, PG201 was manufactured
by blending, mixing, compressing, and coating. Each tablet of
PG201 tablet is tasteless and odorless, yellow oval lm-coated
and contains 300 mg of PG201. The quality of tablets was controlled in various methods such as purity evaluation, identity and

C.-W. Ha et al. / Journal of Ethnopharmacology 181 (2016) 17

Enrollment

Assessed for eligibility (n=133)

Excluded (n=9)
Meet exclusion criteria (n=1)
Declined to participate (n=7)
Lost to follow-up (n=1)

Randomized (n=124)

Allocation
Allocated to PG201 (n=63)
Received allocated intervention (n=63)
Did not receive allocated intervention (n=0)

Allocated SKI306X (n=61)


Received allocated intervention (n=61)
Did not receive allocated intervention (n=0)

ITT population

ITT population

Follow-Up
Drop-out due to Adverse event (n=3)

Drop-out due to Adverse event (n=6)

Withdrawal of Informed Consent (n=4)

Withdrawal of Informed Consent (n=5)


Lost to follow-up (n=1)
Dissatisfied with efficacy of drug (n=2)

Completed (n=52)

Analysis

Completed (n=44)

Excluded from PP analysis (n=4)

Excluded from PP analysis (n=3))

(Out of window period visits(2),


Low compliance rate(1),
Concomitant medication(1*))

(Out of window period visits(3))

*One case overlap between deviation of


Protocol and excluded from PP
PP population

PP population
Fig. 1. Flow diagram of study population

quantitative analysis and so on. For this study, we used tablets of


batch number 12001 (exp.07/10/2013).
2.4. Randomization
Patients were randomly assigned to the experimental or control group at a 1:1 ratio. The subjects in the experimental group
were administered 600 mg of PG201 (300 mg, twice daily) and
600 mg of SKI306X dummy placebo (200 mg, thrice daily) for a
total of 12 weeks. The control group was administered 600 mg of
the SKI306X (200 mg, thrice daily) and 600 mg of PG201 dummy
placebo (300 mg, twice daily) for a total of 12 weeks. The dose and
regimen of PG201 was determined based on a previous preclinical
study and phase 2 and 3 clinical studies (Shin et al., 2003; Yoo
et al., 2014). Both the investigators and patients were blinded to
the drugs provided. The outpatient follow-up observations were

conducted at week 4, 8, and 12. For the NSAID interregnum after


screening, patients were requested to comply with the washout
period according to the provided conversion table; this period did
not exceed a total of 4 weeks from the screening. During the entire
period of the clinical trial (including the washout period), patients
with a severe level of pain were allowed to take the rescue medicine (acetaminophen 650 mg) up to a maximum of 6 tablets in 24
hours. Compliance with prescribed treatment was assessed by
counting the numbers of unused tablets at each visit.
2.5. Outcome measures
All efcacy assessment variables were evaluated for each visit.
The primary assessment variable was the 100 mm pain VAS improvement level at week 8. The secondary efcacy assessment
variables included the 100 mm pain VAS improvement level at

C.-W. Ha et al. / Journal of Ethnopharmacology 181 (2016) 17

2.7. Statistical analysis

Table 1
Baseline characteristics.

Age (years)
Gender
Male
Female
Height (cm)
Body weight (kg)
Location target knee
Left
Right
Other medical
history
Kellgren-Lawrence
scale
Grade 2
Grade 3
100 mm pain VAS
WOMAC Index
Total score
Pain subscale
score
Stiffness subscale
score
Function subscale
score

Experimental group
PG201 (n 63)

Control group
SKI306X (n 61)

p-value

63.8 7 7.2

65.4 7 7.0

0.2021

8(12.7)
55(87.3)
155.5 7 5.8
61.17 7.6

7(11.5)
54(88.5)
156.4 76.7
62.3 7 8.8

0.8352
0.4351
0.3961

40(63.5)
23(36.5)
49(77.8)

35(57.4)
26(42.6)
47(77.1)

0.4862
0.9232

30(47.6)
33(52.4)

23(37.7)
38(62.3)

0.2403

56.4 7 9.8

56.7 7 10.9

0.4714

35.07 14.8
7.0 73.0

36.7 7 15.4
7.5 7 3.1

0.5381
0.3254)

2.9 7 1.8

3.17 1.7

0.6604

25.17 11.5

26.2 7 11.6

0.5511

Note: Data are mean 7 SD or n(%).


1
2
3
4

Independent t-test
Chi-square test
Fishers exact test
Wilcoxons rank sum test

week 12, 100mm pain VAS improvement rate at weeks 8 and 12,
Western Ontario and McMaster Universities Osteoarthritis Index
(WOMAC) improvement level at weeks 8 and 12, level of improvement of the quality of life (EQ-5D) at weeks 8 and 12, improvement in the overall symptom self-assessment score at weeks
8 and 12, and amount of rescue medicine usage at weeks 8 and 12.
The overall symptom self-assessment score was performed using
the 5-point Likert scale with the following questions: Please mark
(select) how you feel with your knee, considering every aspect
inuenced by your knee arthritis for the last 24 hours (1 very
good, 5 very bad).
The status of development of adverse events (AEs) was conrmed during each visit based on a physical examination and the
vital signs. Patients were asked to report all AEs by non-leading
questions and cases with signicant symptoms were assessed by
detailed screening. All AEs were recorded in detail based on the
Common Terminology Criteria for Adverse Event v4.03 (Health and
Services (2009)). The laboratory tests including blood tests were
conducted during the screening and the visit at week 12.
2.6. Sample size estimation
Sample size for the two groups was calculated based on the
hypothesis that the average 100 mm pain VAS improvement level
is 29.12 with a standard deviation of 19.96 according to the results
of a previous phase 3 trial of PG201 (Yoo et al., 2014). As minimal
clinically important difference in the change of pain VAS was reported as 10 mm (Ehrich et al., 2000), we dened the non-inferiority margin of the difference between PG201 and SK306X as
10 mm. The sample size needed for the non-inferiority was 49 per
group, which would provide a statistical power of 80% at a signicance level of 0.05. Factoring in the 20% dropout rate, 124
subjects were selected, and 62 were assigned to each group.

Patients who received at least one dose of study medication


were analyzed as Intention-To-Treat (ITT) population. Per Protocol
(PP) population was dened as the randomized patients who
completed the study without major protocol violation (Fig. 1). The
demographic and safety data were analyzed using the ITT population. Efcacy analyses were performed using the ITT population
and PP population. Missing data were processed using the Last
Observation Carried Forward Analysis. After testing the normal
distribution status of the data for the efcacy evaluation variables,
the two groups were compared using the independent t-test or the
Wilcoxons rank sum test, and were tested using the analysis of
covariance (ANCOVA), applying the rescue medicine usage status
as a covariate. The non-inferiority of the experimental group was
tested against the control group when the conrmation of twosided 95% condence interval(CI) showed that the lower limit of
the CI was higher than the permitted limit (  10 mm). Categorical
variables were comparatively tested using the Chi-square test or
Fishers exact test.

3. Results
3.1. Patient characteristics
A total of 133 patients were screened, and 124 were included in
the ITT analysis patient group. Among the 124 patients, 22 patients
were eventually excluded: 9 who withdrew their consent after
registration, 9 who displayed adverse events, 1 who failed to follow up, 1 who violated the protocol, and 2 others. Of the 102 patients who completed the clinical trial, 5 were outside the visit
window and 1 showed less than 70% drug adherence, which met
the PP exclusion criteria resulting in a total of 96 patients for the
PP analysis subject group. Fifty-two patients were included in the
experimental group and 44 in the control group (Fig. 1). Group
sample sizes of 52 and 44 achieved 72% power to detect non-inferiority. No signicant differences were observed between the
two groups with regards to the age, sex, height, body weight, stage
of arthritis (K-L grade), pain VAS, and the WOMAC score at baseline (Table 1). Compliance with prescribed treatment was good:
the proportion of patients who took over 70% of medication was
93.7% in experimental group and 91.8% in the control group
(p 0.7415).
3.2. Efcacy
The 100 mm pain VAS showed an improvement of 14.2 716.2
and 11.9 713.1 mm in the experimental and control groups, respectively, determined by PP analysis at week 8 compared to the
baseline (p o0.001 in experimental and control group), with no
signicant statistical difference between the two groups
(p 0.557). In addition, the lower limit (  8.38) of the 97.5% onesided CI (two-sided 95% CI) of the experimental group improvement level-control group improvement level was greater than the
allowed limit (-10 mm), conrming that the experimental group
was not inferior to the control group (Table 2 and Fig. 2). The ITT
analysis also revealed no signicant differences in the average
improvement level of 100 mm pain VAS at week 8 between the
two groups (p 0.318), with the lower limit of the experimental
group improvement level-control group improvement level being
 8.71 mm, demonstrating non-inferiority (Supplemental Table 2).
The average improvement in 100 mm pain VAS at week 12
determined by PP analysis was 18.8 717.61 and 17.1 715.7 mm in
the experimental and control groups, respectively, showing no
signicant difference (p 0.794, Table 2). In addition, the ITT

C.-W. Ha et al. / Journal of Ethnopharmacology 181 (2016) 17

Table 2
Primary and Secondary efcacy outcomes in per-protocol population.
PP group
Experimental
(n 52)
Primary efcacy outcome
100 mm Pain VAS
(mean 7SD)
Baseline
Weeks 8
Change
Difference between groups (95%
CI)
Secondary efcacy outcomes
100 mm Pain VAS
(mean 7SD)
Baseline
Weeks 12
Rate of 100 mm Pain VAS
change from baseline (%)
Weeks 8
Weeks 12
WOMAC Total score
(mean 7SD)
Baseline
Weeks 8
Weeks 12
Quality of life(EQ-5D)
(mean 7SD)
Baseline
Weeks 8
Weeks 12
Patient assessed overall symptom (mean7 SD)
Baseline
Weeks 8
Weeks 12
Rescue medicine consumption
(mean 7SD)
Baseline
Weeks 8
Weeks 12
1

Control(n 44) p-value1

57.6 7 9.1
58.1 7 9.5
43.4 7 19.0
46.3 7 15.0
 14.2 7 16.2
 11.9 7 13.1
 2.3 (  8.38, 3.70)

0.746
0.557

57.6 7 9.1
38.9 7 19.5

58.1 7 9.5
41.0 7 16.2

0.746
0.794

 25.5 730.7
 33.2 7 32.3

 20.3 7 22.5
 28.9 7 26.3

0.450
0.617

35.2714.9
26.3 7 16.9
24.4716.5

36.6 7 14.7
27.7 7 15.2
22.9 7 14.0

0.383
0.991
0.190

0.737 0.11
0.767 0.12
0.7770.12

0.727 0.14
0.767 0.10
0.79 7 0.11

0.740
0.780
0.528

3.54 7 0.50
3.007 0.84
2.85 7 1.04

3.647 0.61
3.167 0.61
2.93 7 0.70

0.344
0.826
0.766

13.7 722.7
21.1 739.7
22.3 7 35.0

14.5 7 24.1
23.1 7 36.2
24.47 34.9

0.852
0.845
0.840

ANCOVA

Fig. 2. Change from baseline to week 12 in 100 mm pain visual analogue scale.

analysis also showed no signicant difference between the two


groups (p 0.601, Supplemental Table 2). The average rate of improvement of 100 mm pain VAS in the experimental and control
groups compared to the baseline determined by the PP analysis
was 25.5 730.7 and 20.3 722.5% at week 8 (p 0.450, Table 2),
and 33.2 732.3 and 28.9 726.3% at week 12, respectively
(p 0.617; Table 2), showing no signicant difference. The ITT
analysis also showed no signicant differences in the average rate
of improvement of 100 mm pain VAS at week 8 or 12 between the
experimental and control groups (p 0.204 and 0.414,

respectively, Supplemental Table 2). The average improvement in


the WOMAC total scores in the experimental and control groups
compared to the baseline determined by the PP analysis were
8.9 711.3 and 8.9 79.8 at week 8, and 10.9 712.2 and 13.7 79.3 at
week 12, respectively, showing no statistically signicant difference (p 0.991 and 0.190, respectively, Table 2). The ITT analysis
also showed no signicant difference in the average improvement
in WOMAC total score at week 8 or 12 between the two groups
(p 0.665 and 0.542, respectively, Supplemental Table 2).
The average improvement in quality of life (EQ-5D) in the experimental and control groups compared to the baseline determined by the PP analysis was 0.04 70.13 and 0.04 70.09 at
week 8, and 0.05 70.14 and 0.06 70.10 at week 12, respectively,
showing no signicant difference (p 0.780 and 0.528, respectively, Table 2). The ITT analysis also showed no signicant difference in the average improvement of quality of life at week 8 or
12 between the two groups (p 0.740 and 0.959, respectively,
Supplemental Table 2). The average improvement in the self-assessed overall symptom score on the effects of knee arthritis on
overall symptoms over the last 24 hours in the experimental and
control groups compared to the baseline values determined by the
PP analysis was 0.547 0.75 and 0.48 70.76 at week 8 (p 0.826)
and 0.69 70.98 and 0.70 70.82 at week 12 (p 0.766), respectively, showing no signicant difference (Table 2). The ITT analysis
also revealed no signicant differences in the average improvement of the self-assessed overall symptom score at week 8 or 12
between the two groups (p 0.258 and 0.422, respectively, Supplemental Table 2). The dose of rescue medicine administered in
the experimental and control groups compared to the baseline
determined by the PP analysis was increased by 7.4 733.5 and
8.6 734.0 tablets at week 8, and 12 8.6 730.5 and 9.9 737.6 tablets at week 12, respectively (p 0.845 and 0.840), showing no
signicant difference (Table 2). The ITT analysis also showed no
statistically signicant differences in the dose of rescue medicine
between the two groups (p 0.693 and 0.542, respectively, Supplemental Table 2).
3.3. Safety
All the observed AEs occurred in 12 (19.1%) and 19 (31.2%)
subjects in the experimental and control groups, respectively in
the ITT analysis group; 47 AEs were recorded in 31 subjects (Table 3). Serious AEs were observed in 2 subjects (2 cases) in the
control group, which were 1 gastrointestinal disorder and 1 musculoskeletal and connective tissue disorders. Treatment-emergent
AEs (TEAEs) occurred in 6 subjects (7 cases) in the experimental
group and 9 subjects (12 cases) in the control group. No signicant
difference was observed in the AE incidence between the groups
(p 0.120, Table 3). Among the categories of vital signs, the systolic
blood pressure increased in the experimental group but decreased
in the control group at week 8 (1.57 710.51 vs.  2.59 710.21,
p 0.034) and 12 (1.48 712.0 vs.  2.61 711.49, p 0.033). This
difference between the two groups was statistically signicant,
although it did not appear to be clinically signicant. No signicant
differences were observed in any of the other vital sign categories.
In addition, no signicant abnormal result was observed upon
physical examination and in laboratory test results including blood
tests.

4. Discussion
This prospective, randomized, double-blinded, double-dummy,
multicenter, and comparative study showed that the efcacy and
safety of PG201 were comparable to that of SKI306X in patients
with knee OA. During the 12-week follow-up period, the pain VAS,

C.-W. Ha et al. / Journal of Ethnopharmacology 181 (2016) 17

Table 3
Summary of safety including severity and incidence of adverse events.
Experimental group
PG201 (n 63)

Patient of AEs
12
Adverse events (cases)
19
Grade 1(mild)
17
Grade 2(moderate)
2
Grade 3(severe)
0
Grade 4
0
Grade 5
0
Serious AEs (case)
0
Patient of TEAEs
6
TEAEs (case)
7
Constipation
0
Diarrhea
2
Dyspepsia
1
Dyspnoea
0
Face oedema
1
Headache
0
Insomnia
1
Nausea
0
Tongue paralysis 0
Urticaria
2

(19.1)
(30.2)
(89.5)
(10.5)
(0.0)
(0.0)
(0.0)
(0.0)
(9.5)
(11.1)
(0.0)
(3.2)
(1.6)
(0.0)
(1.6)
(0.0)
(1.6)
(0.0)
(0.0)
(3.2)

Control group
SKI306X
(n 61)
19
28
19
4
5
0
0
2
9
12
2
0
5
2
0
1
0
1
1
0

(31.2)
(45.9)
(67.9)
(14.3)
(17.9)
(0.0)
(0.0)
(7.1)
(14.8)
(19.7)
(3.3)
(0.0)
(8.2)
(3.3)
(0.0)
(1.6)
(0.0)
(1.6)
(1.6)
(0.0)

p-value1

0.120

0.372

Data are n(%).


1

Chi-square test

WOMAC, quality of life (EQ-5D), and overall symptom assessment


scores signicantly improved in both groups compared to the
baseline values. However, there was no signicant difference between the two groups. In addition, there was no difference between the two groups in AEs and TEAEs in terms of the safety of
the drug.
PG201 is a herb-derived medicine extracted from 12 herbs, and
has been developed using the information on the known function
of each herb and the traditional herbal medicine theories researched from the literature of traditional Chinese and Korean
medicine (Shin et al., 2003). Recently, the components of PG201
have gained scientic evidences in the treatment of osteoarthritis.
For example, Gentiana Macrophylla and Acanthopanax sessiliorus
were reported to assist in the functions of both muscles and bones
and Clematis chinensis has been used for protection against degeneration of cartilage and regeneration of damaged tissue (Park
et al., 2005; Shin et al., 2003). PG201, containing the 12 medicinal
herbal extracts, exhibited anti-inammatory activity by inhibiting
the production of pro-inammatory cytokines such as tumor necrosis factor (TNF-) and interleukin (IL-1), and by upregulating
the anti-inammatory cytokine IL-4 in in vivo studies (Park et al.,
2005; Shin et al., 2003). In addition, PG201 inhibited the expression of matrix degradation enzymes including matrix metalloproteinase (MMP) (Park et al., 2005). PG201 exhibited anti-inammatory activity by decreasing nitrite production via upregulation of heme oxygenase-1 by regulating phosphatidylinositol
3-kinase and nuclear factor, erythroid 2 (NF-E2)-related factor 2
(Choi et al., 2013). In a recent in vitro study, 14 compounds (coumarin, demethylsuberosin, xanthotoxin, psoralen, decursinol, decursin, decursinol angelate, chikusetsusaponin IVa, chikusetsusaponin IVa methyl ester, ethyl caffeate, syringaresinol, cnidilide,
farnesol, and linoleic acid) were isolated from phytopharmaceutical PG201 by activity-guided fractionation using inhibitory activity on nitric oxide production. All compounds except linoleic
acid showed suppressive effects on nitric oxide and prostaglandin
E2 production (Kim et al., 2015). This study was performed based
on the encouraging results obtained in previous studies showing
the activities and benecial effects of PG201 on symptomatic OA.
In this study, PG201 signicantly improved pain and function in
patients with OA. For the primary efcacy parameter, both groups

showed signicant improvement in pain VAS without signicant


difference between the two groups. The secondary efcacy parameters also showed signicant improvement without signicant
difference between the two groups. In a study comparing SKI306X
activity to that of diclofenac, the daily administration of 600 mg of
SKI306X over 4 weeks signicantly improved the pain symptoms;
and the effect of SKI306X was not different from that of diclofenac
(Lung et al., 2004). An 8-week study comparing PG201 to celecoxib
revealed that treatment with 600 mg of PG201 signicantly improved pain symptoms; and it was not different from the effect of
celecoxib (Yoo et al., 2014). In this study, the efcacy of PG201 was
compared with that of SKI306X, which is known to have clinical
effects and in relatively wide usage among herb-derived medicine
in patients with knee OA (Jung et al., 2001; Lung et al., 2004). The
results of this study showed no signicant differences between
PG201 and SKI306X. Therefore, PG201 could be an effective agent
in the treatment of patients with symptomatic knee OA.
In the safety analysis, the incidence of AEs and TEAEs in the
PG201 group was lower than that observed in the SKI306X group
(19.1 vs. 31.2%, 9.5 vs. 14.8%, respectively). However, this difference
was not statistically signicant (p 0.120; p 0.372). During this
clinical trial, 2 cases of serious AEs were observed in 2 subjects in
the SKI306X group while no serious AEs were observed in the
PG201 group. The previous study comparing SKI306X and diclofenac showed a lower incidence of AEs in SKI306X group (29.6 vs.
34.7%, p 0.390), which was not statistically signicant, but the
incidence of TEAEs was signicantly low in SKI306X group (17.6 vs.
29.0%, p 0.033) (Lung et al., 2004). The previous study comparing
celecoxib and PG201 showed higher incidence of AEs and adverse
drug reactions(ADRs) in patients treated with PG201 than in those
treated with celecoxib but this difference was not statistically
signicant (28.6 vs. 26.5%, p 0.677 in AEs and 14.9 vs 13.6%,
p 0.727 in ADRs) (Yoo et al., 2014). Although a direct comparison
is difcult owing to differences in the study designs, these results
suggest that PG201 can be safely used in the treatment of patients
with knee osteoarthritis in terms of gastrointestinal adverse
reactions.
There were some limitations to this study. Firstly, this study
was designed to demonstrate the non-inferiority of PG201 to
SKI306X in patients with OA. Although the efcacy of SKI306X was
assessed by randomized controlled trials (Jung et al., 2001; Lung
et al., 2004), further high-quality, fully powered studies must be
conducted to conrm the efcacy of herbal medicinal plant products (Cameron and Chrubasik, 2014). This study was a well-designed, double-blinded, double dummy, randomized, and controlled study with sufcient number of patients in the experimental and control groups, according to sample size calculation.
Therefore, the results of this study could be considered reliable.
Secondly, no objective efcacy parameter such as X-ray or magnetic resonance imaging was used in this study. However, the goal
of the administration of the oral medication was to provide pain
relief and effect functional improvement in patients with OA.
Therefore, we believe the composite of several efcacy parameters
in this study should be enough to assess the comparative efcacies
of PG201 and SKI306X.

5. Conclusions
This study showed that PG201 has effects on reducing pain and
improving function of the knee in patients with OA. The results
were comparable to SKI306X, a widely used herb-derived medicine in Korea. PG201 can be suggested as an effective treatment for
knee OA.

C.-W. Ha et al. / Journal of Ethnopharmacology 181 (2016) 17

Role of the funding source


This study was funded by PMG Pharm Co., Ltd, South Korea. The
sponsor did not play any role in the collection, analysis, and interpretation of data, or in the writing of the report and decision to
submit the paper for publication.

Competing interests
The authors declare that they have no competing interests.

Authors' contributions
YBP and CWH analyzed the data and wrote the manuscript.
CWH, BWM, SBH, JYL, YYW, and YSP obtained funding and designed the study. CWH, BWM, SBH, JYL, YYW, and YSP recruited
the participants and conducted the trial. All authors read and
approved the manuscript.

Acknowledgements
All authors thank the study coordinators at the participating
centers for their efforts in collecting clinical data and ensuring the
accuracy and completeness of the data.

Appendix A. Supplementary material


Supplementary data associated with this article can be found in
the online version at http://dx.doi.org/10.1016/j.jep.2016.01.029.

References
Altman, R., Asch, E., Bloch, D., Bole, G., Borenstein, D., Brandt, K., Christy, W., Cooke,
T.D., Greenwald, R., Hochberg, M., et al., 1986. Development of criteria for the
classication and reporting of osteoarthritis. Classication of osteoarthritis of
the knee. Diagnostic and Therapeutic Criteria Committee of the American
Rheumatism Association. Arthritis Rheum 29, 10391049.
Cameron, M., Chrubasik, S., 2014. Oral herbal therapies for treating osteoarthritis.
Cochrane Database Syst Rev 5, CD002947.
Cameron, M., Gagnier, J.J., Little, C.V., Parsons, T.J., Blumle, A., Chrubasik, S., 2009.
Evidence of effectiveness of herbal medicinal products in the treatment of arthritis. Part I: Osteoarthritis. Phytother Res 23, 14971515.
Chen, F.P., Chang, C.M., Hwang, S.J., Chen, Y.C., Chen, F.J., 2014. Chinese herbal
prescriptions for osteoarthritis in Taiwan: analysis of National Health Insurance
dataset. BMC Complement Altern Med 14, 91.
Choi, J.H., Choi, J.H., Kim, D.Y., Yoon, J.H., Youn, H.Y., Yi, J.B., Rhee, H.I., Ryu, K.H.,
Jung, K., Han, C.K., Kwak, W.J., Cho, Y.B., 2002. Effects of SKI 306X, a new herbal
agent, on proteoglycan degradation in cartilage explant culture and collagenase-induced rabbit osteoarthritis model. Osteoarthritis Cartilage 10,
471478.
Choi., J., Kim., S.H., Kim., S., 2012. Suppressive effects of PG201, an antiarthritic
botanical formulation, on lipopolysaccharide-induced inammatory mediators
in Raw264.7 cells. Exp Biol Med (Maywood) 237 (5), 499508.
Choi, J., Lee, J., Lee, J., Kim, S.H., Kim, J., Kim, S., 2013. PG201 downregulates the
production of nitrite by upregulating heme oxygenase-1 expression through
the control of phosphatidylinositol 3-kinase and NF-E2-related factor 2. Nitric
Oxide 33, 4255.
Ehrich, E.W., Davies, G.M., Watson, D.J., Bolognese, J.A., Seidenberg, B.C., Bellamy, N.,
2000. Minimal perceptible clinical improvement with the Western Ontario and

McMaster Universities osteoarthritis index questionnaire and global assessments in patients with osteoarthritis. J Rheumatol 27, 26352641.
Hartog, A., Hougee, S., Faber, J., Sanders, A., Zuurman, C., Smit, H.F., van der Kraan, P.
M., Hoijer, M.A., Garssen, J., 2008. The multicomponent phytopharmaceutical
SKI306X inhibits in vitro cartilage degradation and the production of inammatory mediators. Phytomedicine 15, 313320.
Health, U.D.o., Services, H. National Cancer Institute. Common Terminology Criteria
for Adverse Events (CTCAE). 28 May 2009 (v4. 03: 14 June 2010). http.evs.nci.
nih.gov/ftp1/CTCAE/About.html (October 2010, date last accessed).
Heo, J., (1613 A.D.). 1999. Dong Ui Bo Gam [The precious mirror of oriental medicine]. Namsandang. Seoul.
Hochberg, M.C., 2006. Nutritional supplements for knee osteoarthritisstill no resolution. N Engl J Med 354, 858860.
Jordan, K.M., Arden, N.K., Doherty, M., Bannwarth, B., Bijlsma, J.W., Dieppe, P.,
Gunther, K., Hauselmann, H., Herrero-Beaumont, G., Kaklamanis, P., Lohmander, S., Leeb, B., Lequesne, M., Mazieres, B., Martin-Mola, E., Pavelka, K., Pendleton, A., Punzi, L., Serni, U., Swoboda, B., Verbruggen, G., Zimmerman-Gorska,
I., Dougados, M., 2003. EULAR Recommendations 2003: an evidence based
approach to the management of knee osteoarthritis: Report of a Task Force of
the Standing Committee for International Clinical Studies Including Therapeutic
Trials (ESCISIT). Ann Rheum Dis 62, 11451155.
Jung, Y.B., Roh, K.J., Jung, J.A., Jung, K., Yoo, H., Cho, Y.B., Kwak, W.J., Kim, D.K., Kim, K.
H., Han, C.K., 2001. Effect of SKI 306X, a new herbal anti-arthritic agent, in
patients with osteoarthritis of the knee: a double-blind placebo controlled
study. Am J Chin Med 29, 485491.
Kim, H.C., 2000. Herbalogy. Young Lim Sa, Seoul.
Kim, H.J., Kim, H.M., Ryu, B., Lee, W.S., Shin, J.S., Lee, K.T., Jang, D.S., 2015. Constituents of PG201 (Layla), a multi-component phytopharmaceutical, with inhibitory activity on LPS-induced nitric oxide and prostaglandin E productions in
macrophages. Arch Pharm Res.
Kim, J.H., Ryu, K.H., Jung, K.W., Han, C.K., Kwak, W.J., Cho, Y.B., 2005. SKI306X
suppresses cartilage destruction and inhibits the production of matrix metalloproteinase in rabbit joint cartilage explant culture. J Pharmacol Sci 98,
298306.
Lee, S., (1590 A.D.). 1978. Bon Cho Gang Mok [Compendium of material medica].
ChungKuK ChungEuiHak. Peking.
Lung, Y.B., Seong, S.C., Lee, M.C., Shin, Y.U., Kim, D.H., Kim, J.M., Jung, Y.K., Ahn, J.H.,
Seo, J.G., Park, Y.S., Lee, C.S., Roh, K.J., Han, C.K., Cho, Y.B., Chang, D.Y., Kwak, W.J.,
Jung, K.O., Park, B.J., 2004. A four-week, randomized, double-blind trial of the
efcacy and safety of SKI306X: a herbal anti-arthritic agent versus diclofenac in
osteoarthritis of the knee. Am J Chin Med 32, 291301.
Neung, I.G., 1998. Herbalogy.. Sanitation Press, Seoul
Park, J.H., Lee, C.H., 2000. The encyclopedia of medicinal plants. SinIl Sangsa, Seoul.
Park, K.C., Park, E.J., Kim, E.R., Kim, Y., Chung, S.H., Cho, B.W., Kim, S., Jin, M., 2005.
Therapeutic effects of PG201, an ethanol extract from herbs, through cartilage
protection on collagenase-induced arthritis in rabbits. Biochem Biophys Res
Commun 331, 14691477.
Shin, S.S., Jin, M., Jung, H.J., Kim, B., Jeon, H., Choi, J.J., Kim, J.M., Cho, B.W., Chung, S.
H., Lee, Y.W., Song, Y.W., Kim, S., 2003. Suppressive effects of PG201, an ethanol
extract from herbs, on collagen-induced arthritis in mice. Rheumatology (Oxford) 42, 665672.
Wandel, S., Juni, P., Tendal, B., Nuesch, E., Villiger, P.M., Welton, N.J., Reichenbach, S.,
Trelle, S., 2010. Effects of glucosamine, chondroitin, or placebo in patients with
osteoarthritis of hip or knee: network meta-analysis. BMJ 341, c4675.
Yoo, W.H., Yoo, H.G., Park, S.H., Baek, H.J., Lee, Y.J., Shim, S.C., Kang, S.W., Kim, H.A.,
Song, J.S., Suh, C.H., Choi, S.J., Yoon, B.Y., Tae, D.N., Ko, H.S., Song, Y.W., 2014.
Efcacy and safety of PG201 (Layla) and celecoxib in the treatment of symptomatic knee osteoarthritis: a double-blinded, randomized, multi-center, active
drug comparative, parallel-group, non-inferiority, phase III study. Rheumatol
Int.
Zhang, W., Doherty, M., Arden, N., Bannwarth, B., Bijlsma, J., Gunther, K.P., Hauselmann, H.J., Herrero-Beaumont, G., Jordan, K., Kaklamanis, P., Leeb, B., Lequesne, M., Lohmander, S., Mazieres, B., Martin-Mola, E., Pavelka, K., Pendleton,
A., Punzi, L., Swoboda, B., Varatojo, R., Verbruggen, G., Zimmermann-Gorska, I.,
Dougados, M., 2005. EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing
Committee for International Clinical Studies Including Therapeutics (ESCISIT).
Ann Rheum Dis 64, 669681.
Zhang, W., Moskowitz, R.W., Nuki, G., Abramson, S., Altman, R.D., Arden, N., BiermaZeinstra, S., Brandt, K.D., Croft, P., Doherty, M., Dougados, M., Hochberg, M.,
Hunter, D.J., Kwoh, K., Lohmander, L.S., Tugwell, P., 2008. OARSI recommendations for the management of hip and knee osteoarthritis, Part II:
OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 16,
137162.