Different Kinds of Acupuncture Treatment for Knee Osteoarthritis：a Multicentre Randomised Controlled Trial
Phase: NA
Conditions: Knee Osteoarthritis
Sponsor: Zhejiang Chinese Medical University

 
 
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  The KeyPlan of Zhejiang Province 
Traditional Chinese Medicine Prevention and 
Treatment of Major Diseases 
 
 
Number：2018ZY008 
Research name: 
Different kinds of acupuncture treatments for Knee 
Osteoarthritis: a Multi-center Randomized controlled 
trial  
 
Responsible investigator： 
Name: Jianqiao Fang 
E-mail: fangjianqiao7532@163.com 
Address: 
Zhejiang 
Chinese 
Medical 
University, 
Hangzhou, China. 548 Binwen Road, Binjiang District, 
Hangzhou, Zhejiang, China  
 
  
 

 
 
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The Study Protocol of the project 
Different kinds of acupuncture treatments for Knee Osteoarthritis: a 
Multi-center Randomized controlled trial  
Research objectives 
(1)The study aims to exam different kinds of acupuncture treatment for treating knee 
osteoarthritis (KOA), compared with the effective drug control group respectively, and 
confirm the efficacy of different acupuncture treatments of KOA, and further a safe, 
effective and easily-spread therapy for KOA. 
(2)To observe and compare the effects between groups of different acupuncture 
treatment: acupuncture group, moxibustion group and warm-needling group, and 
make clear whether the moxibustion play a key role in the acupuncture treatment for 
KOA. 
(3) To compare the effects of acupuncture group and sham-needle group and make 
clear whether acupuncture is effective in KOA treatment. 
(4) To compare the effects of electro-acupuncture group and the warm-needling group, 
to explore whether there are different clinical effects of electric stimulation and warm 
stimulation in acupuncture treatment of KOA. 
Research Methods 
Participants 
1. Case source 
  360 patients with knee osteoarthritis are planned to be recruited from May 2018 to 
December 2021 in the following six hospitals: Jiaxing TCM Hospital, The Third Affiliated 
Hospital of Zhejiang Chinese Medical University,  Zhejiang provincial Hospital of TCM, 
Zhejiang Hospital,  Hangzhou Red Cross Hospital ,Zhejiang Provincial Tongde Hospital. 
2.Diagnostic criteria: The diagnostic criteria of KOA in western medicine refers to the 
diagnostic criteria of American College of Rheumatology (ACR)[1] and Kellgren-Lawrence 
Classification[2]; and the TCM diagnostic criteria refers to the Diagnostic efficacy of TCM 
syndrome [3]. 
 

 
 
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1)The diagnostic criteria of western medicine: Meet the KOA diagnostic criteria, in I-III 
level of K-L classification. 
  According to the American College of Rheumatology (ACR) KOA diagnostic criteria: 
(1)Have knee pain of most days in a month; 
(2) There is a noise in the joint activity; 
(3)Morning knee stiffness lasting less than 30 minutes; 
(4)Over 38 years old; 
(5)Bony swelling and snapping sound of the knee joint; 
(6)Bony swelling and no snapping sound of the knee joint. 
At least 1-4 or 1, 2, 3, 5 or 1 and 6 can be diagnosed. 
The grade of knee osteoarthritis was graded, and the grading evaluation criteria of 
Kellyon-Lawrence (K-L) was adopted (level 5). 
0:Normal; 
I:Doubtful joint space narrow, possible osteophytes ; 
Ⅱ:Definite osteophytes, possible joint space narrow or normal; 
Ⅲ:Moderate osteophytes, definite joint space narrow, some sclerosis of subchondral 
bone , possible deformity; 
Ⅳ:Large osteophytes, marked joint space narrow, severe sclerosis of subchondral 
bone, definite deformity. 
2)The diagnostic criteria of TCM : 
  (1)For the first time, there was dull pain in the knee joint , with unfavorable flexion 
and extension of the knee joint; Knee pain released slightly by mild activity, and 
aggravated when the climate changes, and repeated lingering. 
  (2)The onset of the disease is slow, often among the middle aged or elderly; 
  (3)The joints can be mildly swollen, the joints have the kala or the frictions tone 
during the activity, and the severe ones can see the muscular atrophy and joint 
deformity; 
  (4)X-ray examination showed osteoporosis, irregular joint surfaces, narrow joint 
space, subchondral bone sclerosis, and lip-shaped hyperplasia, osteophyte formation; 
  (5)Check ESR, anti-chain "O", rheumatoid factors and more to identify with 

 
 
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rheumatism and rheumatoid arthritis. 
References: 
[1] Hochberg MC, Altman RD, April KT, et al． American College of Rheumatology 2012 
recommendations for the use of non-pharmacologic and pharmacologic therapies in osteoarthritis of 
the hand, hip and knee[J].Arthritis Care Res,2012,64 ( 4) : 465-474． 
[2] Kohn MD, Sassoon AA, Fernando ND et al., Classifications in Brief Kellgren-Lawrence Classification of 
Osteoarthritis. Clin Orthop Relat Res, 2016. 474: p. 1886-1893. 
[3] State administration of traditional Chinese medicine. Diagnostic efficacy of TCM syndrome[M]. 
Nanjing: Nanjing university press, 1994:48-64. 
3.Inclusion criteria 
1)Aged 40-75 years old; 
2) History of knee pain for more than 3 months, and complain of knee pain on most days of 
the past month; 
3) I-III level in K-L classification; 
4)At visit an average knee pain severity of 4 point or more on an 10-point VAS; 
5)Volunteer for this test and sign informed consent. 
4.Exclusion criteria 
   1) Knee osteoarthritis patients with history of gout, infection, tumor, autoimmune 
diseases, trauma or other causes of knee pain or knee deformities; 
   2)Patients who have local skin damage, poor skin conditions or coagulant dysfunction 
and patients who are not suitable for acupuncture; 
   3)Patients who are accompanied with serious medical problems, mental or shallow 
sensation disorder disorders, cognitive dysfunction or shallow sensation disorder who 
cannot cooperate with the treatment;  
   4)Patients who have received acupuncture or needle knife in the past month; 
   5)Other patients who are not suitable for acupuncture treatment. 
5.Off standard 
1)The patient did not follow this test, quit or lost his visit; 
2)Severe adverse reactions or adverse events occurred during treatment. 
6.Withdrawal criteria   
1)A diagnostic physician at each center assessed the KOA exacerbations that occurred 
during the study. When a patient develops knee pain that cannot be alleviated by 

 
 
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acupuncture (based on VAS score> 8 points), the physician evaluates the severity and 
discontinues the study; 
2)Onset of serious adverse events such as severe infection, coma, shock, death, etc., the 
main investigator should be reported immediately and the study should be suspended 
immediately. 
7. Clinical Ethics and Clinical Trial Registration 
The study follows the “Helsinki Declaration” and other relevant regulations, the clinical 
study was carried out after approved by the Central Ethics Committee. Before each subject 
was enrolled in the study, it was the investigator's responsibility to provide the subject or 
his agent with a complete and comprehensive introduction of the purpose, procedure, and 
potential risks of the study, and to sign an informed consent form so that the subject 
knowing that they have the right to withdraw from this study at any time, informed 
consent should be retained as a clinical research document. Before collecting the first case, 
the central ethics approval was completed and the clinical trial registration was completed. 
Analysis methods 
1. Sample size estimation 
   Sample size estimation was by using PASS(version 11.0) software. According to 
document analysis and trial test, the WOMAC joint function scores could change 
by13.0±5.6 after treatment of positive drug control group.(Qilin Liu. Observation on clinical 
effect of KOA by needling with moxibustion[J]. TCM clinic Research,2016,8(09):108-109.), 
while needling group changed by 8.8±3.7(Acupuncture for Chronic Knee Pain A 
Randomized Clinical Trial),EA group changed by 8.9±4.0(trial test),Moxibustion group 
changed by 10±4.7(trial test), Warm needling group changed by 12.0±6.1(Jianbo 
Wang,Yanlin Wang,Yongqi Lu,Yaochi Wu.Effect analysis of KOA by needling with 
moxibustion[J]. Shanghai acupuncture magzine,2010,29(06):390-392.), Sham acupuncture 
group changed by 5.8±3.0(Acupuncture for Chronic Knee Pain A Randomized Clinical Trial). 
In the condition of α=0.05, the power of test was 1-β=0.9 and the six groups were 
distributed according to 1:1:1:1:1:1 ratio, and the sample amount is at least 42. The sample 
size is to be expanded by estimated 20% dropout rate, and finally, there are at least 53 

 
 
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patients in each group. In view of the equality of the distribution of all cases in six centers, 
there were a total of 360 cases with 60 patients in each group. The following equation was 
used: 
 
2.Random allocation 
    The block randomization is operated by the central randomization system (by 
telephone and online).When the subjects met inclusion exclusion criteria of the study, The 
randomization of the central random system is conducted by assigned personnel or clinical 
investigators of each center. The randomization scheme of this study is produced by the 
Clinical Evaluation and Analysis Center of Zhejiang Provincial Hospital of TCM which is not 
involved in the statistical analysis of this project . The randomization scheme of this study 
and The parameters set during the process of the program are called the bottom of the 
blind, which is generated by the random scheme personnel to sign and seal, and taken care 
of by the specialized personnel not involved in the project of the Clinical Evaluation and 
Analysis Center of Zhejiang Provincial Hospital of TCM. The central random system has 
strict personnel authority, and other than the highest level system management staff, no 
one has access to the random scheme in the central random system.   
3. Design and implementation of blind method 
The blind(patient-blind) design is adopted in this program, and the patients are 
evaluated by blind method. Index evaluation and data recording, treatment operator and 
statistician are all separated. The random member and the therapist know the grouping; 
The curative evaluators and the statisticians were not aware of the grouping.  
4. Interventions 
The six groups of participants (except for western medicine group) will be treated with 
different kinds of acupuncture treatment. The unified needle is the single-use, sterile steel, 
size 0.30×25mm or 0.30×40mm needle(Huatuo brand disposable acupuncture needle, 
Suzhou Medical Co., Jiangsu, China),it will be used in Ordinary acupuncture group, 

 
 
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electro-acupuncture group and Warm-needling acupuncture group；The unified moxa is 
the 2cm Yufu brand Qing Ai(Jiangsu Kangmei Pharmaceutical Co. Ltd. Jiangsu, 
China,Z32020253 ),it will be used in Mild moxibustion group and Warm-needling 
acupuncture group; The unified Electro-acupuncture apparatuses is the Huatuo 
SDZ-IIB  electro-acupuncture apparatus(Jiangsu Suzhou Medical Supplies Factory LTD. 
Jiangsu China ),it will be used in electro-acupuncture group; The unified  Leather 
measuring tape is: Type 8214 ,Size 1.5m*7.5mm produced by Deli Group Limited; The 
unified acupuncture time and therapy course were: Each treatment lasts for 30 minutes 
which will be applied 3 times a week(ideally every 1 or 2 days ) for consecutive 4 weeks, 12 
sessions in total; Operator and attention: Acupuncture treatments will be operated by the 
attending doctor and should pay attention to the disinfection of operator's hands and local 
skin before and after treatment. The treatment of acupuncture and moxibustion will be 
mainly aimed at the knee joint with pain symptoms, such as single or bilateral knee pain, 
the treatment of single / bilateral knee joint. The unified emergency medication and 
treatment: If the participants have unbearably knee pain during the study, we will allow 
them to take temporary emergency medication: oral Celebrex capsules (Celebrex, Capsules, 
Pfizer Pharmaceuticals Ltd), which will be applied once a day (0.2g a time orally).The 
situation of drug use should be recorded in detail; swelling of the knee joint during the test 
and temporary receiving treatment, but it should be recorded in detail. 
swelling in the knee joint effusion shown during test, allowed to accept fluid pumping 
treatment, but it should also be recorded in detail. 
(1)Acupuncture group 
1)Acupoints：Liangqiu(ST34),Xuehai(SP10),Neixiyan（EX-LE4）,Dubi (ST35),Yanglingquan 
(GB 34)and Yinlingquan (SP9) 
2)Point location: According to the National Standard of The People’s Republic of China, 
the Name and Location of Acupoints, issued in 2006 (GB/T 12346-2006). 
3) Location and operation of acupoints 
Liangqiu（ST34）is located in the anterior femoral region, the medial end of the 
patellar base was 2 cun and the medial femoral muscle was raised. Operation: 

 
 
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straight 1.0-1.5 cun. 
Xuehai（SP10）is located in  the anterior femoral region, 2 cun of the patellar 
base, the lateral femoral muscle and the tendon of the rectus femoris. 
Operation: straight 1.0-1.5 cun. 
Neixiyan (EX-LE4) is located in the center of the depression of the patellar ligament 
of the knee . Operation: Once outside and within the frontal plane at an angle of 
45 degrees inclined 0.5-1 cun. 
Dubi (ST35) is located in a depression lateral to the patellar ligament. Operation: 
At 90 degrees, the backward inclined 1-1.5 cun.      
Yanglingquan (GB 34) is located in the depression anterior and inferior to the head 
of the fibula.Operation: straight 1.0-1.5 cun. 
Yinlingquan (SP9) is located in the depression between the lower border of the 
medial condyle of the tibia and the medial border of the tibia. Operation: straight 
1.0-2.0 cun. 
In the Acupuncture group, the inserted needles will be manipulated using techniques 
including lifting, thrusting, twisting, and rotating to reach De Qi (A composite of sensations 
including soreness, numbness, distention, heaviness and other sensations).The treatment 
lasts for 30 minutes.  
(2)Electro-acupuncture group 
Acupoints, location and acupuncture operation are the same to the above 
acupuncture group. 
Operation: The electrode will be connected in Neixiyan (EX-LE4) and Dubi (ST35) and 
electrode wire will be connected to the Huatuo SDZ-IIB electro-acupuncture 
apparatus(Jiangsu Suzhou Medical Supplies Factory LTD. Jiangsu China ), dilatational wave 
with a frequency of 2/100 Hz, the current strength in participants within their tolerance 
(preferably with the skin around the acupoints shivering mildly without pain), for 30 
minutes.  
(3)Mild moxibustion group 
Operation: In this group, Liangqiu（ST34）,Xuehai（SP10） ,Yanglingquan (GB 34) and 
Yinlingquan (SP9) are needled the same to the acupuncture group. At the same time ,mild 

 
 
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moxibustion are applied at the distance of 2-3 cm away from the skin of both the Neixiyan 
(EX-LE4) and Dubi (ST35) by 2 two Zhuang for 30 minutes. 
(4)Warm-needling  group 
Acupoints, location, and acupuncture are the same to the acupuncture group. 
Operation: Warm-needling are applied at both Neixiyan (EX-LE4) and Dubi (ST35). That 
is to insert one zhuang(about 2cm)of Qing Ai on the top of the needle, and burn the moxa 
at the lower end ,each acupoint applied 2 Zhuang. In the process of moxibustion, if the 
participants feel unbearable hot , we should be put some paper between the skin and 
moxa to prevent burns. 
(5)Sham acupuncture group 
The sham Acupoints: Sham Liangqiu(ST34), Sham Xuehai(SP10), Sham   Neixiyan(EX-LE4), 
Sham  Yanglingquan (GB 34),  Sham  Yinlingquan (SP9) 
Positioning and operation: Sham acupuncture group choose a non-meridian and 
non-acupoint needling method, respectively needle 1cm lateral to the above acupoints 
with a 0.18 * 25mm disposable needle with depth of 1-2mm for 30 minutes. 
(6)Celebrex group 
Celebrex capsules (Celebrex, Capsules, Pfizer Pharmaceuticals Ltd), which will be applied 1 
time daily( 1 time oral 0.2g) for 4 weeks. 
5.Outcome measurements and observe time point 
All subjects received a clinical evaluation before treatment (baseline), in treatment (2 
weeks), after treatment (4 weeks), and during follow-up (3 months, 6 months) at five time 
points. The primary outcome measurements includes McMaster University Osteoarthritis 
Index (WOMAC) function score and Visual Analogue Scale (VAS); Secondary outcomes 
measures including WOMAC pain score, WOMAC stiffness score, the Physical Activity Scale 
of the Elderly (PASE), knee joint swelling measurement and WHO-BREF quality of life scale. 
(1) Primary outcomes 
1)Visual Analogue Scale (VAS); 
2)WOMAC function score; 
The primary outcome measurements will take the average of the last three days. 
(2) Secondary outcomes 

 
 
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1)WOMAC pain score, taking the average of the last 3 days. 
2)WOMAC stiffness score, taking the average of the last 3 days; 
3)The Physical Activity Scale of the Elderly (PASE); 
4)Knee joint swelling measurement; 
5)WHO-BREF life quality scale. 
(3) Acupuncture and moxibustion related safety evaluation 
Stabbing pain of needle, faint, local hematoma, infection and abscess, burns, skin 
allergy etc. The safety assessment of acupuncture and moxibustion must be recorded after 
each treatment. 
6. Statistical processing 
1)Full Analysis Set (FAS) : a collection of cases that are randomly enrolled and at least 
treated once. 
  In the analysis of the main curative effect indexes, the missing value of FAS is processed 
by LOCF (Last Observation Carried Forward) method, which was observed at the latest 
point of time. In the Case of secondary curative effect, general situation and safety 
Analysis, the Available Case Analysis principle is adopted to carry out missing value 
processing. 
2) Per-protocol population set(PPS) : a set of cases that meet inclusion criteria and 
complete treatment according to the test plan. Good compliance 
 with the test scheme and compliance ,no drug use, and the completion of efficacy 
evaluation(at least the primary efficacy). 
3) Safety set (SAS) : at least one treatment, and a safety index to record the actual data. 
(2)Statistical analysis  
1) the distribution of cases of six groups: the total loss rate of six groups and the 
loss rate due to adverse events. 
2) comparability analysis: comparison of demographic data and other baseline 
values to measure the comparability of the six groups. 
3) Compliance analysis: compared with the six groups of patients whether they 
meet the appropriate treatment on time and take the drug banned in the 

 
 
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Trial flow chart 
programme. 
4)Effectiveness analysis: main efficacy indexes are analyzed by PP (per protocol)and 
ITT(Intend to treat); Since this study is a multicenter clinical trial, the effect of the 
central effect and baseline on the efficacy index should be considered. 
5)Effect factor analysis: such as age, sex, course of disease, and combination of 
drugs, etc. 
6) Safety analysis: first, according to the requirements of adverse reaction 
correlation list ,describes six groups of adverse events and adverse reactions, 
(including the number of cases of adverse events and laboratory test indexes 
before and after the test , abnormal turn cases and different rate). The adverse 
reactions were analyzed by chi-square test. 
(3)Statistical analysis method 
1) Measurement data: first, the normal test is carried out, and t-test, paired t test, 
variance analysis, covariance analysis and other methods are adopted if it's in a 
normal distribution. Rank and inspection, matching rank and check are used for 
data that does not conform to normal distribution. 
2) Counting data: using the chi-square test, Fisher exact test, etc.; The hierarchical 
data were analyzed by Ridit analysis, CMH(Cochran-mantel-Haensel statistics) or 
other non-parametric tests. 
3) Multicenter analysis of comprehensive curative effect: using CMH method for 
counting data while analysis of covariance for measurement data. 
4) All statistical tests were by bilateral inspection, and the P value was less than or 
equal to 0.05, which is statistically significant. 
（4）Statistical software 
 SAS9.3 software analysis. 
 

 
 
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WOMAC 
VAS 
PASE 
 Knee swelling 
measurement  
WHO-BREF quality of 
life scale 
Baseline evaluation 
Eligible participants (n=360) 
Posters, 
television, 
Internet,  
newspapers  
and other open 
recruitment of 
participants 
Specialist diagnosis 
Inclusion criteria 
Exclusion criteria 
Informed consent 
participants recruitment 
screening for eligibility 
Randomized into six groups 
Ordinary 
acupuncture 
（n=60） 
Electro- 
acupuncture  
（n=60） 
Mild 
moxibustion 
（n=60） 
Sham 
acupuncture 
（n=60） 
Warm-needling 
acupuncture 
（n=60） 
Western 
medicine 
（n=60） 
Shedding cases and causes 
Primary outcomes :VAS, 
WOMAC function score; 
Secondary outcomes: 
WOMAC pain score, 
WOMAC stiffness score, 
PASE, knee swelling 
measurement, WHO-BREF 
quality of life scale, 
Acupuncture and 
moxibustion related safety 
Outcome measures 
at four time points 
Outcome analysis 

 
 
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