Académique Documents
Professionnel Documents
Culture Documents
Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep
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
http://dx.doi.org/10.1016/j.jep.2016.01.029
0378-8741/& 2016 Published by Elsevier Ireland Ltd.
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
Enrollment
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)
ITT population
ITT population
Follow-Up
Drop-out due to Adverse event (n=3)
Completed (n=52)
Analysis
Completed (n=44)
PP population
Fig. 1. Flow diagram of study population
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
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.
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
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
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.
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,
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
Chi-square test
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.
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.
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.