Study Design and participants. This pilot study was designed according to the CONSORT 2010 statement. This was a prospective, randomized-controlled, observer blinded study with 24-week follow-up done between June 2020 and December 2020. Subjects were recruited through advertisements placed in a rehabilitation department of the Second Affiliated Hospital of Chongqing Medical University. The inclusion and exclusion criteria are shown in Table 1. All subjects gave written informed consent before participating in the study. The study was approved by the Ethics Committee of the Second Affiliated Hospital, Chongqing Medical University. The Chinese Clinical Trial Registry granted full approval of the study protocol, recruitment materials, and consent form (URL: https://www.chictr.org.cn; unique identifier: ChiCTR2000032735; date of registration: 08/05/2020). The procedures conformed with good clinical practice and with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Table 1
Inclusion and exclusion criteria.
Inclusion criteria
|
Age 40–80 years (either sex)
|
Met the criteria for the ACR clinical classification of knee OA
|
Had radiographic evidence of knee OA (weight-bearing views) assessed as Kellgren–Lawrence grade I to grade III
|
Had average knee pain≥3 on an 11-point NRS in the past week
|
Exclusion criteria
|
Knee pain caused by other diseases (rheumatoid arthritis, gouty arthritis, infectious arthritis)
|
A history of knee joint replacement on the study knee; current or past (within 6 months) oral or intra-articular corticosteroid use
|
Physiotherapy, acupuncture treatment, the use of exercises specifically for the knee within the past 6 months
|
A medical condition that precludes safe exercise (such as uncontrolled hypertension, a heart condition, hematological diseases coagulopathy, gastrointestinal ulcers, or a hemorrhage)
|
A history of taking NSAIDs or symptomatic slow-acting drugs for OA (diacerein, hyaluronic acid) within the previous 30 days
|
The inability to complete the study.
|
ACR American College of Rheumatology, OA osteoarthritis, NRS Numerical Rating Scale, NSAIDs nonsteroidal anti-inflammatory drugs.
|
Table 2 The baseline demographics and clinical features of patients.
Variable
|
FLIPUS
(n=57)
|
PSWD
(n=57)
|
P value
|
Age, years
|
62.28±10.88
|
59.93±8.97
|
0.211
|
Women, no. (%)
|
42(73.68%)
|
45(78.95%)
|
0.660
|
BMI, kg/m2
|
25.18±3.26
|
25.29±2.85
|
0.854
|
Duration of disease, months
|
120.32±74.88
|
118.54±89.73
|
0.909
|
Kellgren–Lawrence grade, no. (%)
|
Grade I
|
4(7.01%)
|
6(10.53%)
|
0.205
|
Grade II
|
40(70.18%)
|
45(78.94%)
|
Grade III
|
13(22.81%)
|
6(10.53%)
|
Primary Outcome
|
|
|
|
WOMAC
|
|
|
|
Total
|
34.49±10.26
|
33.70±7.91
|
0.646
|
Pain
|
6.40±2.15
|
7.44±2.61
|
0.551
|
Stiffness
|
2.35±1.13
|
2.56±1.02
|
0.558
|
Physical Function
|
23.89±8.37
|
25.54±6.58
|
0.688
|
Secondary Outcomes
|
|
|
|
NRS
|
5.51±1.28
|
5.81±1.06
|
0.825
|
GROC score
|
-2(2)
|
-1(3)
|
0.066
|
ROM, degree
|
127.39±5.92
|
126.23±6.57
|
0.895
|
TUG test
|
12.91±2.45
|
12.60±2.33
|
0.296
|
FLIPUS focused low-intensity pulsed ultrasound, PSWD pulsed shortwave diathermy, BMI body mass index, WOMAC Western Ontario and McMaster Universities Osteoarthritis Index, NRS Numerical Rating Scales, GROC Global Rating of Change scale, IQR interquartile range, ROM range of motion; TUG Timed Up and Go test. Measurement data are represented as mean ± SD (Normally distributed data) or median (IQR) (Non-normally distributed data). Enumeration data are represented as frequencies (proportion). |
Table 3 Primary and secondary efficacy measures after 12 days of treatment.
Variable
|
FLIPUS
|
PSWD
|
Mean Between-Group Difference:
FLIPUS-PSWD (95% CI)
|
p value
|
n
|
57
|
57
|
|
|
Primary Outcome
|
|
|
|
|
WOMAC
|
|
|
|
|
Total
|
17.86± 9.77
|
28.35± 7.25
|
-10.50(-13.54, -7.45)
|
0.000
|
Change (95% CI) from baseline
|
-16.63(-17.85, -15.42)
|
-5.35(-6.00, -4.71)
|
|
|
Pain
|
3.07± 1.61
|
4.70± 2.13
|
-1.63(-2.30, -0.96)
|
0.005
|
Change (95% CI) from baseline
|
-3.33(-3.69, -2.98)
|
-2.74(-3.03, -2.44)
|
|
|
Stiffness
|
0.70± 0.76
|
1.88± 0.93
|
-1.18(-1.46, -0.89)
|
0.000
|
Change (95% CI) from baseline
|
-1.65(-1.93, -1.36)
|
-0.68(-0.88, -0.49)
|
|
|
Physical Function
|
13.82± 8.29
|
22.04± 6.42
|
-8.21(-11.13, -5.29)
|
0.000
|
Change (95% CI) from baseline
|
-10.07(-11.38, -8.76)
|
-3.51(-4.48, -2.54)
|
|
|
Secondary Outcome
|
|
|
|
|
NRS
|
1.89± 1.01
|
2.65± 1.01
|
-0.76(-1.12, -0.39)
|
0.011
|
Change (95% CI) from baseline
|
-3.61(-3.85, -3.37)
|
-3.16(-3.36, -2.95)
|
|
|
GRC score
|
+4(2)
|
+3(2)
|
|
0.011
|
ROM, degree
|
130.56± 4.65
|
128.30± 6.24
|
2.26(0.21,4.32)
|
0.025
|
Change (95% CI) from baseline
|
3.16(2.41, 3.94)
|
2.07(1.50, 2.64)
|
|
|
TUG test
|
10.61± 2.29
|
11.84± 2.42
|
-1.23(-2.02, -0.44)
|
0.005
|
Change (95% CI) from baseline
|
-2.30(-2.63, -1.97)
|
-0.75(-0.91, -0.60)
|
|
|
FLIPUS focused low-intensity pulsed ultrasound, PSWD pulsed shortwave diathermy, BMI body mass index, WOMAC Western Ontario and McMaster Universities Osteoarthritis Index, NRS Numerical Rating Scales, GROC Global Rating of Change scale, IQR interquartile range, ROM range of motion; TUG Timed Up and Go test, CI confidence interval. Measurement data are represented as mean ± SD (Normally distributed data) or median (IQR) (Non-normally distributed data). |
Table 4 WOMAC total scores and NRS score measures after 12 and 24 weeks of follow-up.
|
WOMAC (Total scores)
|
NRS scores
|
Baseline
|
12 weeks
|
24 weeks
|
P value
|
Baseline
|
12 weeks
|
24 weeks
|
P value
|
FLIPUS
|
34.49±10.26
|
22.89±9.32
|
28.02±9.29
|
0.000
|
5.70±1.24
|
3.05±0.99
|
4.91±0.89
|
0.000
|
PSWD
|
33.70±7.91
|
30.46±6.77
|
34.98±6.72
|
0.000
|
5.61±1.13
|
4.84±0.94
|
6.28±0.96
|
0.000
|
P value
|
0.646
|
0.000
|
0.000
|
|
0.825
|
0.000
|
0.000
|
|
FLIPUS focused low-intensity pulsed ultrasound; PSWD pulsed shortwave diathermy, WOMAC Western Ontario and McMaster Universities Osteoarthritis Index, NRS Numeric Rating Scales. Measurement data are represented as mean ± SD (Normally distributed data). |
The study consisted of a screen visit, a baseline visit-during which FIPUS or PSWD was done- and follow-up visits at 12 days, 12 and 24 weeks post-therapy. Potential study participants returned for a baseline visit after a 1-week washout period for nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics. Before randomization, demographic data and baseline assessments were collected.
Randomization procedures. Enrolled patients were randomized (1:1) to 2 groups. Opaque randomization envelopes with sequentially numbered allocation were generated by a person who was not clinically involved in the study. When a patient consented to the trial, the patient selected one of the envelopes and then was given the allocated therapy 7.
Intervention. The patients in the FLIPUS group received focused low-intensity pulsed ultrasound therapy (The Model CZG200 Ultrasound Therapeutic Device for Arthritis used, Chongqing Haifu Medical Technology Co. Ltd., China) for 20 minutes once daily for a total treatment duration of 12 days 3. The device had an ultrasonic transducer diameter of 25 mm, a radius-of-curvature of 28 mm, a frequency of 0.6 megaherz (MHz), a pulse repetition frequency of 300 herz (Hz), and a spatial and temporal average intensity (Ista) of 120 milliwatts(mW)/cm2, and a duty cycle of 20% 3. All treatments were standardized using a device that placed the participant in a sitting position, and the knee was angled ~90° in the flexion position. The four ultrasound probes were close to the surface skin of the EX-LE 4 acupoint (located in the depression medial to the patellar ligament when the knee was flexed), ST 35 acupoint (located in the depression lateral to the patellar ligament when the knee was flexed), and medial and lateral knee joint spaces, respectively, as previously described3 (Fig. 1).
The patients in the PSWD group received pulsed shortwave diathermy therapy(The Curapulse 970 model, Enraf-Nonius, Rotterdam, the Netherlands) for 20 minutes once daily for a total treatment duration of 12 days7. The machine’s program was set at ‘chronic OA model’ and delivered electromagnetic waves with a frequency of 27.12 MHz, a pulse repetition frequency of 300 Hz, a pulse duration of 300 µs, a peak power of 200 watts (W), and a mean power of 18 W 8. All patients reported a mild but comfortable feeling of warmth.
Patients with symptoms in both knees received treatment in both knees, but trial outcomes were assessed only in the knee with worse symptoms8.
Outcomes Measures. The primary outcome measures were functional capacity, assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)9. The Minimal Clinically Important Difference for knee OA is –7.9 points for WOMAC total score10. Secondary outcomes included the following: (1) Numerical rating scale (Minimal Clinically Important Difference, ≥15% improvements from baseline), (2) Time Up and Go test (Minimal Clinically Important Difference, 1.14 seconds11), (3) Active joint range of motion, and (4) Global Rating of Change scale (Minimal Clinically Important Difference, a score of +3 or higher12). All of them were evaluated at baseline, after 12 days of treatment, and at follow-up after 12 and 24 weeks.
Statistical analysis. The statistical evaluation was carried out after qualified statistical advice. Case number planning was calculated for the primary outcome measure and the reduction in WOMAC total score compared to baseline. Based on a study by Tubach et al10., who found a reduction of 7.9 points with the WOMAC total score (effect size of 0.59), the case number was calculated using a t test-based model in G * Power version 3.1.513. A power of 0.8 with a significance level of 0.05 was chosen and resulted in a required number of 47 cases. We added approximately 10%-20% more participants to account for potential loss to follow-up, resulting in a final enrollment goal of 114 participants (57 per group).
Independent t tests (continuous variables), Mann–Whitney U tests (ordinal variables), and chi-square tests (nominal variables) were used to compare the characteristics of the FLIPUS group and PSWD group.
All outcomes were analyzed using the intention-to-treat approach. We tested the data normality and sphericity using the Shapiro-Walk test and Mauchly’s test, respectively. Repeated measures analysis of covariance (ANCOVA) was used to compare the WOMAC score, Numerical Rating Scale at baseline, after 12 days of treatment, and at follow-up after 12 and 24 weeks, as well as the Time Up and Go test, joint range of motion, and Global Rating of Change scale at baseline and after 12 days of treatment.
Post hoc analyses were conducted within (using paired t tests for comparisons across time) and between (using independent t tests within each time point) groups via pairwise comparisons with Bonferroni correction. ANCOVA using a last-observation-carried forward (LOCF) approach for the imputation of missing data was applied as a supportive analysis.
All statistical analyses were performed using SPSS version 20 (SPSS Inc., Chicago, IL, USA) with a global alpha of 0.05.