Study design
This study will be a prospective, single-blind, randomized, controlled trial conducted in Beijing Chaoyang Hospital. The measurements of several outcomes will be made before and after the interventions and 24 weeks after the interventions begin (Fig. 1). This study was approved by the Ethics Committee of Beijing Sport University (Ethics Approved Number: 2020108H) and registered at the Chinese Clinical Trial Registry (ChinCTR2000037859). We designed this study using the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement [26] (Fig. 2) and the results will be reported in accordance with the CONsolidated Standards of Reporting Trials (CONSORT) guidelines [27].
Participants
In this study, we will recruit 100 patients, both men and women, with the diagnosis of unilateral or bilateral KOA. This group will then randomly be assigned to different interventions. The participants will be recruited using targeted strategies, including social media (WeChat), websites, newspapers, and other community approaches. If an interested patient meets the eligibility criteria, then the informed consent process will be performed. All potential participants will be informed that the study will last for 6 months and they have the right to withdraw at any time. If they are uncertain whether they will be able to participate for the entire 6-month period, we will provide regular healthcare for their KOA rather than include them into the formal study. Figure 1 demonstrates the flow chart for the trial, which includes participant recruitment, eligibility screening, baseline measurements, randomization and allocation, intervention, and outcome assessments. The enrollment of participants, the randomization procedure, and the performance of various measurements will be conducted by four independent physiotherapists. A manual will be developed to standardize the administration of the subjective questionnaires and the objective performance tests.
Inclusion criteria
The inclusion criteria will be as follows: (1) 45–75 years of age, (2) unilateral or bilateral KOA diagnosed according to the American College of Rheumatology clinical classification system [14, 28], (3) radiologic confirmation of KOA demonstrating Kellgren-Lawrence grade II or III [29], (4) average pain intensity of 40 or more on a 100-mm visual analogue scale (VAS) in the last week, and (5) adequate Mandarin language skills to complete the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and a written informed consent.
Exclusion criteria
The exclusion criteria will be as follows: (1) a history of knee surgery or scheduled surgery; (2) a history of any invasive procedure of the affected knee, including arthroscopy or intra-articular injection in the past 12 months; (3) a history of physical therapy/physiotherapy or a strengthening procedure of the affected knee in the past 6 months; (4) use of nonsteroidal anti-inflammatory drugs in the past 3 months; (5) any neurological, heart, or vascular disease, such as blood coagulation disorders; (6) abnormal blood pressure (resting systolic blood pressure [SBP] > 160 or < 100 mmHg or a diastolic blood pressure [DBP] > 100 mmHg); or (7) other acute or chronic disorders or psychiatric conditions that will affect physical or cognitive functions.
Withdrawal criteria and management
KOA patients will be asked, or be allowed, to quit the study in the following cases: (1) participants have such a demand and (2) there is a severe adverse event during the study.
Randomization and allocation concealment
Eligible patients will be randomly assigned to one of the following groups: LL group, High BFR (80% LOP) group, Low BFR (40% LOP) group, and HE group, at a ratio of 1:1:1:1. The research staff will independently use SAS software (SAS Institute, Cary, NC, USA) to generate a randomization sequence and this staff will not participate in the intervention or statistical analyses of this study. The number sequence will then be placed into a sealed opaque sequentially numbered envelope prior to the study by another independent research assistant who will also not participate in other parts of this study. Once eligible patients with KOA finish the informed consent process, the demographic information and baseline measures will be recorded. Next, the research coordinator, who will not be involved in the measurement process, will have the authorization to open the envelopes in ascending order to determine a patient’s intervention group assignment.
Masking
The measurement assessors will be blinded to the assignment group and work in the university remote to where the intervention will be performed. The statistician will be blinded to the group information of original data. Participants will be informed that all interventions have proven efficiency for their knee disorder, but it is still unknown which intervention is better. Moreover, they will be asked to not discuss their intervention and group assignment at any time during the study. Unmasking will only be allowed in the case of severe adverse events and will be reported as a part of the results of this study.
Intervention
All participants of the intervention groups will complete 24 exercise sessions over 12 weeks with 2 sessions per week as described in Table 1. During the 12 weeks, participants may continue their previous activities without aggravating their knee symptoms. In an individual exercise session, each group will perform a warm-up exercise to prevent injuries before the formal exercise protocol. Moreover, the pain intensity will be monitored by a VAS during the exercise, with some pain being acceptable during the exercise. However, the load will decrease by 20% if the pain intensity is higher than 20 mm/100 mm on the VAS [30]. Only if the patients finish more than 80% of their target sessions will they be enrolled into the statistical analyses.
Table 1
Treatment protocol performed by the LL group and the BFR groups.
LL group and BFR groups
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Hamstrings stretching, 3 repetitions of 30 s
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Bridge with isometric contraction of the transversus abdominis-CORE training, 3 repetitions of 30 s+
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Hip abduction with weights (side lying), 3 sets of 10 repetitions+
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Calm exercises (side lying) with elastic band, 3 sets of 10 repetitions+
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Calf raises with weights (standing), 3 sets of 10 repetitions+
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Sensori-motor training (standing) at mini-trampoline, 3 repetitions of 30 s
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Leg press (machine), 0°–60°, 3 sets of 15 repetitions *
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Seated knee extension (machine), 90°–0° of knee flexion, 3 sets of 15 repetitions*
|
*Load is 30% of the 1-repetition maximum. |
+The load will be adjusted every 4 weeks to maintain an effort of perception between 6 and 7 on the Borg scale. |
Each group will conduct a warm-up by cycling for 10 minutes before the LLRT or BFR training. The leg press will be performed between 0° and 60° of knee flexion. And the leg extension will be performed between 90° and 45° of knee flexion [31]. In addition to thigh muscle strength training, distal joint, proximal joint, and core muscle strength training will also be performed for patients with KOA. The reason for this is because the current evidence has shown that biomechanical changes occur in patients with KOA [32] and a combined multi-joint strength exercise is potentially more effective than knee strength training alone in knee musculoskeletal disorders [33]. To avoid possible injuries during the training, we will provide a relative integrated therapeutic exercise program. Thus, stretching exercises and core trainings will also be adopted in this study. During the treatment, we will adopt the 10-point Borg scale to monitor the perceived effort for several exercises[34], as shown in the detailed exercise program in Table 1.
The exercise load will be individually set for each participant and be adjusted every 4 weeks by re-evaluating the participant’s 1RM. Since a direct 1RM test could potentially cause knee pain or injury in patients with KOA, the 1RM will be estimated by performing a 7–10 RM test, which is the maximum load the individual can complete for 7–10 repetitions. Previous studies have shown that the 7–10 RM test can accurately estimate the 1RM for the leg press [35] and knee extension exercises [36]. The formula is as follows [37]: estimated 1RM = weight/(1.0278–0.0278 × reps).
Blood flow restriction exercise
All participants from the High BFR and Low BFR groups will be individually measured for the LOP and re-evaluated every 2 weeks during the study. The LOP will be measured with participants in a relaxed and supine position. The portable color Doppler ultrasound (LOGIQ e, General Electric Company, Boston, USA) will be positioned at the ankle to measure the pedal pulse. A pneumatic cuff (7-cm width and 56-cm length) will be placed on the proximal thigh of the participant and inflated until the pedal pulse vanishes on the Doppler ultrasound. We will then slowly deflate the cuff, and when the pedal pulse returns, we will record the LOP. The Low BFR group will perform at 40% LOP, while the High BFR group will perform at 80% LOP during the exercise. The loads for the leg press and knee extension exercises will be 30% of the 1RM (estimated by 7–10 RM). Furthermore, participants in the High BFR and Low BFR groups will perform 1 set of 30 repetitions (or until exhaustion) and 3 sets of 15 receptions with a 30-second interval between sets [20]. The LOP will be adjusted every time to maintain a similar degree of BFR for each individual.
Standardized resistance exercise
The LL group will conduct a sham BFR in which the pneumatic cuff will be placed on the proximal thigh of the participant with adequate space for two or more fingers between the thigh and cuff. However, there will be no pressure applied in the pneumatic cuff. The exercise protocol of the LL group is the same as the BFR groups. The LL group will perform 3 sets of 15 repetitions with 30% 1RM and 30-second intervals between sets [19, 21, 30].
Health education group
The individuals in the health education group will attend sessions related to protecting their knee joint during daily life. Sessions will meet once a week for 12 weeks. Moreover, we will introduce the basic concept of KOA and the methods used to manage the risks of KOA through various articles from the Internet and leaflets.
Outcome measures
Primary outcome measures
1) Pain
The VAS will be used to evaluate pain intensity at rest and under maximum situations during the last week. The VAS is comprised of a line with a length of 100 mm, in which “0 mm” corresponds to no pain and “100 mm” to the worst pain imaginable [38]. The VAS will be well depicted for pain, and it is easily operated and widely applied in patients with KOA. The VAS will be used at 0, 12, and 24 weeks after randomization of participants. Furthermore, the minimal clinically important improvement for pain is about 20 mm/100 mm [39].
2) Self-report function
The knee function self-report outcomes will be measured using the WOMAC. This is a 24-item self-report questionnaire that assesses joint pain, stiffness, and physical function related to KOA [40]. The maximum score of the WOMAC is 120, where a higher score indicates worse symptoms and functions of the knee. The Chinese version of the WOMAC has been shown to be both valid and reliable and also sensitive to changes for patients with KOA [41]. The WOMAC will be measured at 0, 12, and 24 weeks after the randomization of the participants.
3) Adverse events
All adverse events will be recorded throughout the entirety of the trial. Patients will be made aware of potential adverse events during the consent process and instructed to notify a researcher when adverse events occur. A physiotherapist and related specialists will the categorize adverse events as treatment-related or not and the severity of the adverse events within 24 hours. Common BFR or training-related adverse events include muscle soreness, knee pain, a subcutaneous hemorrhage, and numbness.
Secondary outcome measures
1) Quadriceps femoris strength
The quadriceps muscle strength will be evaluated by an isokinetic knee extension with an isokinetic test system (IsoMed 2000, D&R Ferstl GmbH, Hemau, Germany) device. Before the strength test, the participants will be fastened onto a dynamometric chair in a 90° sitting position with the torso and thighs fixed by rigid belts. Then, the axis of the dynamometer will be adjusted in alignment with the center of the knee. Furthermore, the range of motion will be set individually for participants by asking them to extend and flex their knee to maximum ranges. Participants will need to perform five constant flexion and extension motions using concentric contractions without a gravity-compensation model at three angular velocities of 60°/second, 90°/second, and 120°/second [42]. During the test, the participants will be encouraged to perform at their maximum effort [43]. The data will be recorded and calculated as the peak torque in Newton-meters, peak torque/body weight, and power in watts. Previous studies have demonstrated that the test-retest reliability for an isometric knee muscle strength assessment is 0.83 in patients with KOA [44].
2) Muscle thickness
The muscle thickness of the quadriceps will be measured using a portable color Doppler ultrasound [30, 45]. Intra-rater and inter-rater reliabilities have demonstrated good validation when evaluating the muscle by ultrasound. Furthermore, the correlation between an ultrasound and magnetic resonance imaging (MRI) scans for muscle thickness for the vastus medialis, vastus lateralis, and rectus femoris are 0.86, 0.94, and 0.86, respectively [46, 47]. During the test, the probe will be placed at the mid-belly of these three muscles without depressing the skin. Each muscle will be measured from the adipose tissue-muscle interface to the muscle-bone interface three times. The images will be saved and then averaged. The size of the quadriceps will be estimated as a sum of these three muscles.
3) Physical functional performance
Physical functional performance will be assessed by the timed up and go (TUG) test [48]. Previous studies found that the TUG test has a good intra- and inter-rater reliability (0.97 and 0.96, respectively) for patients with grades 1–3 KOA [49]. During the test, the subject is timed and required to independently rise from an armchair that is 45 cm in height, walk forward following a straight line for three meters, turn, walk back, and sit down again. The average of three measurements will be used for analysis.
4) Quality of life
The 36-item Short Form Health Survey (SF-36) is a brief self-report questionnaire with 36 questions relevant to QoL in eight health dimensions, including vitality, bodily pain, general health, physical functioning, emotional functioning, social functioning, and mental health in psychometric properties. It can be summarized in two health scores, physical and mental components, where higher scores indicate a better health condition. Previous studies have indicated that the Chinese version of the SF-36 is a relative and valid questionnaire for the general population.
Sample size estimation
Previous studies have shown the effect size for pain and function are 0.38–0.49 and 0.41–0.52, respectively [50, 51]. The sample size was estimated by using G-Power software (version 3.1.9.6, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany) with the parameters as follows: analysis of variance (ANOVA) with repeated measures, a type-I error of 5% (α = 0.05), a power of 95% (β = 0.05), group numbers = 4, and the number of measurements = 3. With a possible dropout rate of 15%, it is estimated that a sample size of 25 patients per group will be needed to verify our study hypotheses for the primary outcomes.
Statistical analyses
All data will be expressed as mean ± standard deviation (SD). A linear mixed model with repeated measures will be run to assess the data for fixed factors of the trial (LL group, High BFR group, Low BFR group, and HE group) and time (primary and secondary outcomes). Additionally, two-way ANOVAs will be used to analyze the differences between baseline, post intervention, and follow-up measurements. The analysis will follow an intention-to-treat approach if the subjects drop out during the study. Significance will be set at P < 0.05 for all data. Statistical analyses will be performed using SPSS 22.0 (SPSS Inc., Chicago, USA).
Quality control
The protocol will be reviewed and revised by experts in orthopedics, physiotherapy, methodology, and statistics. The data will be carefully recorded by both printed and electronic case report forms (eCRFs). Only outcome assessors have access to the eCRFs, and all input data will be double checked by two independent assessors. All data will be unmodifiable once inputted and checked through the eCRF. Only statisticians have access to the database to conduct final statistical analyses. In this trial, both online monitoring and on-site monitoring will be adopted to review the trial processes.