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The thirty-nine-week open-label clinical study investigates the efficacy of acupuncture for Knee Osteoarthritis (KOA) as adjunctive therapy to analgesics compared to analgesics only and assesses the effects after 9 and 24 weeks, with safety assessment provided.
The study seeks to find possible additional benefits of acupuncture on Kidney Deficiency (KD) while treating KOA with an acupuncture protocol designed to treat KOA following Traditional Chinese Medicine (TCM) theory, which connects KOA with KD as its root cause. The points prescription uses local and Kidney-related points to treat KOA.
The chronic conditions require a higher number of acupuncture treatments. This study will provide acupuncture treatments in three cycles, each three weeks long, with frequency three times weekly. Twenty-seven acupuncture treatments of KOA during fifteen weeks tend to improve KOA and KDS; symptoms are assessed in 10 successive time points, and treatment effects and effect persistence are analysed.
64 patients with symptomatic KOA are randomly allocated into the Acupuncture (A) or Control (C) group according to their permanent, unique, and coincidental Personal Identification Number, which is randomly given to all citizens in Croatia. Before the experiment starts, demographics and disease parameters of all participants are compared. To objectify acupuncture effects, the enrolled physiatrist's measures included knee measures at 3 time points: baseline, at the end of acupuncture (Week 15), and nine weeks later (Week 24). Subjective evaluations of symptoms are assessed by Western Ontario and McMaster University Arthritis Index (WOMAC) total and subscales scores, Numeric Rating Scale (NRS), and Kidney Deficiency Syndrome Questionnaire (KDSQ) every 3 weeks till the 24th week (9 assessments). Analgesics taken by participants (DRUG) in the last three days before the assessments are recorded. Acupuncture treatment was promised to all participants. Therefore, at Week 25, the between-group analysis ended, and the C group crossed over to receive the identical acupuncture protocol. The 10th assessment in Week 39 was used to estimate, by within-group analysis, the immediate effects of the acupuncture in group C and the effect persistence in group A.
The Lequesne index was introduced additionally at Week 24 as another measure of the knee's functional state.
Full description
KOA's high prevalence assures the trial's participation motivation of patients regarding associated pain and functional impairment. Besides pain and stiffness, patients experience muscle weakness, poor balance, and joint distortion in an advanced stage. KOA attacks the diseased ones at the age of 50. Pain worsens with joint loading and becomes relieved by rest. KOA supposes bones remodelling, cartilage thinning, synovial thickening, and joint space narrowing. The advanced stage is presented by joint instability, squaring, and even subluxation.
KOA involves both knees and the contributing symptoms of old age from the scope of Kidney deficiency syndromes, such as weakness, insomnia, depression, tinnitus, forgetfulness, feeling cold, hot, low back pain, thirst at night, and disturbed urination could be manifested.
The acupuncture treatment of KOA follows syndrome differentiation. The treatment principle distinguishes the deficient root (primary Kidney deficiency and secondary Blood deficiency) as the cause, and the excessive branch (knee bone Bi syndrome) when in empty Cou Li spaces, the external factor becomes entraped, consequently. An aspiration with treatment is to tonify the Kidney, nourish Qi, tonify and invigorate Blood, remove Damp and Cold by transferring them toward the deficiency rather than expelling, and relieve the channels and collaterals from the obstruction. Moreover, knee meridians should be dredged to improve knee symptoms by a simultaneous reinforcing-reducing technique on local points and reinforcing on KD-related points. Eventually, the improvements of KD indicate better life quality.
The study's design involves two groups: an acupuncture (A) group that receives acupuncture treatment adjunctive to analgesics, and a control (C) group that receives only analgesics. Participants were recruited from the target population of patients over 50 from 2 Family Medicine practices with confirmed KOA. The study sample was formed with inclusion and exclusion criteria. 64 patients were recruited. All medical data of the participants were available to the investigator. After fulfilling the SOAP form (Subjective, Objective, Assessment, Plan) and getting informed written consent, the study sample was randomly allocated into two groups by size of their permanent, unique eleven-digit long Personal Identification Numbers (OIB), which is assigned to all Croatian citizens. Its first ten digits are accidentally chosen, and the last is a control number. Every second participant ordered by the size of OIB belongs to the same group; odd ones belong to the A group, and even ones to the C group. Demographic and disease parameters are compared at baseline to determine if the groups are comparable. All study participants received analgesics and could modify dosages according to their needs. Analgesics were nonsteroidal anti-inflammatory drugs (NSAIDs) and/or tramadol. Taken analgesics were recorded at Weeks 0, 3, 6, 9, 12, 15, 18, 21, 24, and 39. The dose represents an average daily dose of analgesics from the last three days. The dose was recorded after conversion to the comparable dose of the selected representative (ibuprofen), the most prescribed one. The given data will be statistically processed and analyzed.
Patients in the A group started with acupuncture treatment in September 2021, with the first treatment cycle. Each of the 3 treatment cycles, in total, is three weeks long, each consists of 9 treatments, patients will receive acupuncture three times per week and the two adjacent acupuncture cycles are separated by three weeks without acupuncture.
Acupuncture treatment protocol includes local treatment points Dubi (ST-35), Neixiyan (EX-LE-4) and Heding (EX-LE-2), Xuehai (SP-10), Yanglingquan (GB-34), Yinlingquan (SP-9), Zusanli (ST-36), Sanyinjiao (SP-6), and points targeting Kidney deficiency syndrome Taixi (KI-3), Guanyuan (CV 4), and Shenshu (BL-23).
Disposable sterile acupuncture needles 0.30 × 40 mm are used. The depth and angle procedure predicted straight needling on 1-1.5 inches deep, with a mild reinforcing-reducing method for local points, further straight and 0.5-1 inch deep with the reinforcing method for points based on KD syndromes. Complete treatment lasts 30 minutes, and the manipulations are provided every 10 minutes, three times in total.
The sample size was calculated based on the Berman et al. (1999) study. The sample size was calculated by envisioning a two-sided test with unequal variances: type I error 0,05, power 0,95. Group sample sizes of 16 and 16 (i.e. complete study population of 32 subjects) achieve 95,78% power to reject the null hypothesis of equal means and with a significance level (alpha) of 0,050 using a two-sided two-sample unequal-variance t-test.
From a longer treatment period of this study and higher participants' drop-off expected, the population was doubled to 64 subjects in total.
Research methods were determined upon the clinical question "Could the prolonged design of acupuncture treatments on patients with knee osteoarthritis (KOA) decrease pain and improve the function of the knee joints and additionally achieve positive effects on the debilitating symptoms of a Kidney deficiency as a root cause of KOA, measured by recognized questionnaires?".
Evaluation of the therapeutic effects of acupuncture on KOA included WOMAC, VAS, KDSQ scores, and DRUG at Weeks 0, 3, 6, 9, 12, 15, 18, 21, 24, and 39. WOMAC is a renowned questionnaire for KOA evaluation. It measures 5 items for pain, 2 for stiffness, and 17 for functional limitation. VAS is a continuous numeric rating scale of 100 mm in length that is widely used for pain intensity assessment. The KDSQ questionnaire is a valid and reliable measure constructed in 2012 to evaluate Kidney Yin and Yang deficiency syndromes of Hong Kong Chinese middle-aged women by Chen et al. KDSQ represents a valid questionnaire for KD assessment in this study population.
From a total of 10 assessments, the first 9 compared scores between groups A and C. Participants were promised to receive equal acupuncture treatment if they were randomised into the C group. So, group C crossed over to receive the identical protocol from Week 25 to 39, and the 10th assessment was added to both groups of participants to estimate the immediate effects of the acupuncture treatment in the C group and estimate treatment effect persistence in the A group over 24 weeks, in a within-group manner. The physiatrist's assessments at 3 time-points (baseline, 15th Week, and 24th Week) include the standard physiatrist KOA measurements (knee and thigh circumference, range of motion of the knee). The Lequesne index was added as the knee's functional state measure in Week 24.
Data is stored electronically with secured and restricted access. Data transfer will be encrypted, and all data that could identify individuals has been removed.
Study analysis serves to process the effects of acupuncture treatment. Baseline data are obtained before the experiment starts. Besides immediate effects, effects persistence was assessed at Weeks 24 (9 weeks after acupuncture of group A ended) and 39. WOMAC total score at the end of the acupuncture protocol (Week 15) is a primary outcome, while WOMAC subscales, VAS, and KDSQ scores, DRUG at Weeks 15, 24 and 39, and persistence of WOMAC total were secondary and supportive of the primary one. Secondary outcome measures include physiatrists' measures and the Lequesne index as well. Effect sizes are calculated from data comparison to the control group up to Week 24 or baseline at Week 39. Analyses were performed on 64 participants, randomised for the intention-to-treat (ITT) analysis using the maximum available data set (i.e. excluding the missing values) from repeated measures of variables of interest and their variances. ITT analysis, excluding missing values, was selected regarding dropouts that emerged in the study, completely random without any causal clustering. Dropouts produced missing values. Omitting missing values can compromise the statistics and produce bias. Therefore, sensitivity analyses were provided to compare those who dropped out and those who completed the study to determine if data significantly differed. Also, a test calculation with the Last observation carried forward technique (LOCF) with the imputed last observed value in the missing one was performed to check if the obtained effects still stand. All statistical tests are two-sided. The Shapiro-Wilk test tests the normality distribution. The non-parametric Mann-Whitney U test was used for comparability testing with 95% power and α=0,05. The main efficacy indicators tested the comparability of the groups with the Mann-Whitney U test and quantified observed effects by mean differences and Cohen's d.
A participant will be considered to have withdrawn from the trial when consent is revoked or if the participant cannot be contacted or located. Participants will not be withdrawn from the trial for protocol violations. Withdrawal due to an adverse event should be distinguished from withdrawal due to insufficient response.
All adverse events will be recorded in the Adverse Event Report Form at every treatment. If this happens, an adverse event will be followed until its resolution. The serious adverse event must be reported to the Medical Ethics Committee.
It is expected to relieve pain and increase joint mobility, along with alleviating KD and reducing the use of analgesics and confirming the safety of acupuncture.
This is a prospective, interventional, randomized, open-label, controlled trial. It is supported by recent scholarly, peer-reviewed literature. The research method reflects the approach needed to answer the research questions. Research is addressing a gap in the literature that would contribute new findings. The research topic is based on a tangible and cited problem. The research collects and analyses the data, any deviations are documented and approved by NJUCM. The study was designed originally. The acupuncture treatment plan for KOA is designed with the assistance of Professor Xueping Zhou. The study will be conducted in a Family Medicine practice by the experimenter. All financial and operating burdens will be funded from practice resources.
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64 participants in 2 patient groups
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