This three-arm, randomized, sham-controlled trial has been approved by ethics committees at all 9 hospitals. Eligible KOA participants diagnosed according to the American College of Rheumatology criteria [19] are randomly assigned (1:1:1) to receive 24 sessions of electro-acupuncture, manual acupuncture, or sham acupuncture over 8 weeks. Block randomization with random block size of 6 and 9, is stratified by study centre, and is performed via a web-based randomization system. The nature of acupuncture means that acupuncturists are not blinded to treatment allocation; however, patients, outcome assessors and statisticians remain masked where possible. Informed consent is obtained from each participant before randomization. The trial has been registered with ClinicalTrials.gov (NCT03366363).
Objectives
The objective of current study is to determine if EA and MA improve the outcome at 8 weeks in patients with knee osteoarthritis. The following two null hypotheses are tested: there is no difference in patients’ response rate between EA group and SA group; there is no difference in patients’ response rate between MA group and SA group.
Outcomes
Primary outcome
The primary outcome is the response rate [20] - the proportion of patients who simultaneously achieve minimal clinically important improvement (MCII) in pain and function domains at 8 weeks post-randomization. The average pain over the previous week is assessed using an 11-point Numerical Rating Scale (NRS) [21] with scores ranging from 0 to 10. The MCII in pain domain is defined as 2 points in NRS [11, 22]. The average function over the previous week is measured using Western Ontario and McMaster Universities osteoarthritis index (WOMAC) function subscale [23] with scores ranging from 0 to 68. The MCII in function domain is defined as 6 points in WOMAC function subscale [11, 22]. The criteria of responder are presented in Fig 1. The response rate is also measured at weeks 4, 16, and 26 after randomization.
Secondary outcomes
Numerical Rating Scale [21]: an 11-point patient reported outcome measure (PROM) with scores ranging from 0 (no pain) to 10 (worst pain).
WOMAC [23] pain subscale: a 5-item PROM with total scores ranging from 0 to 20. Higher scores indicate worse pain.
WOMAC [23] function subscale: a 17-item PROM with total scores ranging from 0 to 68. Lower scores indicate better physical function.
WOMAC [23] stiffness subscale: a 2-item PROM with total scores ranging from 0 to 8. Higher scores indicate more stiffness.
Patient global assessment [24]: a 5-point Likert scale. Participants are asked how their knee symptoms were during the past week. The answers include ‘extremely improved’, ‘slightly improved’, ‘not changed’, ‘slightly aggravated’, and ‘extremely aggravated’.
12-item Short Form Health Survey (SF-12) [25] physical dimension: total score range from 0 to 100. Lower scores indicate a worse quality of life.
SF-12 [25] mental dimension: total score range from 0 to 100. Higher scores indicate a better quality of life.
NRS, WOMAC, Patient global assessment and SF-12 is measured at 4, 8, 16, and 26 weeks after randomization. Blinding assessment is measured at 4 and 8 weeks after randomization. Credibility and expectancy of participants are measured 5 minutes after the first acupuncture [26]. The use of rescue medicine is also counted throughout the trial.
Safety outcome
Adverse events are recorded throughout the trial. Based on the potential relationship between acupuncture and adverse events, adverse events are categorized as treatment-related or not.
Sample size
Based on the results of a previous trial [16], the response rates of EA, MA and SA group are assumed to be 70%, 60% and 40%, respectively. With a 2-sided significance level of 2.5% and power of 80%, 128 participants in each group will be required to detect a difference as small as 20% between each acupuncture group and control group. With an estimated loss-to-follow-up rate of 20%, 480 participants in the three groups will be recruited.
Statistical analysis
Statistical analysis population
Full analysis set (FAS), per-protocol set (PPS), and safety set (SS) will be used in current trial.
FAS will consist of all randomized participants who have at least one post-baseline measurement according to modified intention-to-treat principle. Logistic regression will be used to exam whether the data are missing at random or not [27]. If data is missing at random, multiple imputation method will be used [28]. FAS will be the primary analysis set, and all analyses will be conducted for this population if not otherwise stated. Analyses on FAS will provide an estimate of the effect of electro-acupuncture and manual acupuncture.
PPS will include those who complete the treatment and follow-up timely according to protocol without major violations. Major violations of protocol will be judged during the audit of data, including but not limited to: not meeting the inclusion criteria / meeting the exclusion criteria, receiving other treatments which might affect symptoms of KOA during the trial, completing < 20 sessions of acupuncture. PPS will be the secondary analysis set and be used for sensitivity analyses.
Those who receive randomization and at least one session of acupuncture will be defined as SS, which is used for safety analyses.
General analysis principles
All data will be summarized by treatment group. Numbers (percentages) will be used to describe categorical data. Either means (standard deviations) or medians (interquartile ranges) will be used for quantitative data depending on whether the variables are normally distributed or not. If not otherwise stated, the significance level will be set at 0.05. The significance level will be adjusted for the multiple comparisons for the primary outcome. The conclusion will be based on the analysis of primary outcome, and all secondary outcomes will be analyzed to support the primary analysis. All analyses will be carried out using SAS 9.3 (Cary, NC).
Descriptive analyses
The number of participants screened, excluded, randomly assigned to each group, interviewed at each follow up, and analyzed will be summarized using a flow diagram recommended by CONSORT [29] (Fig. 2). Reasons for the losses to follow-up and withdrawals will also be listed by treatment arm.
Demographic characteristics and clinical outcomes at baseline will be presented in Table 1. When testing differences among the three groups, either one-way analysis of variance (ANOVA) or Krusal-Wallis one-way ANOVA (if normality is violated) will be used for continuous variables. Chi-square test or Fisher exact text will be used for categorical variables.
Analysis of primary outcome
For the analysis of primary outcome, the response rates of the three groups at 8 weeks will be calculated and the Z-test for comparisons of proportions will be used with FAS. There will be two comparisons. The first comparison is the one between electro-acupuncture group and sham acupuncture group. The second comparison is the one between manual acupuncture group and sham acupuncture group. The significance level will be adjusted at 0.025 for the multiple comparisons.
Analysis of secondary outcomes
For NRS score, comparisons among three groups will be assessed by mixed-effect model with repeated measurement (MMRM) analysis using NRS scores at all follow up time points as dependent variable, treatment as main factor, baseline value as a covariate. The same approach will be used to analyze WOMAC pain subscale, function subscale, and stiffness subscale, and SF-12. If there is a normality violation in the continuous variables, a transformation will be performed before the comparison. Chi-square test will be used for patient global assessment. These outcomes will be shown in Table 2.
Safety analyses
Based on the potential relationship between acupuncture and adverse events, adverse events are categorized as treatment-related or not. Acupuncture-related adverse events will be summarized by group and compared using Chi-square test (or Fisher exact test).
Blinding analyses
Kappa analysis will be used to determine whether participants correctly guessed their group assignment at a higher rate than would be expected by chance.
Additional analyses
Sensitivity analysis of primary outcome and secondary outcomes will be carried out with PPS to examine the robustness of conclusion. Several researches have shown that the center stratified randomization lead to the correlation among treatment groups. Therefore, we will discuss the generalized linear mixed-effect model for primary outcome to analyze the group effect, in which centre effects is included. Subgroup analysis based on Kellgren - Lawrence grade will be performed.