Study setting
The study will follow the principles of the Consolidated Standards of Reporting Trials (CONSORT) for randomized, parallel studies, as well as the Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) statement for acupuncture. [28,29]. This will be a single-blinded RCT with a sample size based on published evidence in comparative studies. Seventy AS patients will be blinded to study conditions. The study will be conducted at Guangdong Provincial Hospital of Chinese Medicine (GPHCM), Department of Acupuncture, Guangdong, China, following the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). For the participant timeline, see Figure 1.
Recruitment
A total of 70 AS patients age 18–60 years and 30 healthy volunteers will be recruited for this study. AS participants will be recruited from both the outpatient and inpatient departments of the GPHCM, Department of Rheumatology. Study flyers, bulletin boards at the hospital and online advertisements will also be used for patient recruitment. Healthy volunteers will be recruited from among students of Guangzhou University of Chinese Medicine. Treatment and measurements will be performed at the GPHCM.
Inclusion criteria
Recruitment conditions are as follows: 1) a definite diagnosis of axial AS during a stable disease period; 2) 18–60 years of age, onset age <40 years; 3) currently being treated at a stable dose of medication for ≥4 weeks prior to randomization and have received no biologic therapy within the past 3 months; 4) course of disease ≤10 years; and 5) willingness to sign the informed-consent form. Potential participants who satisfy the inclusion criteria will be sent a more detailed information leaflet for informed consent. They will be contacted few days later to determine whether they are interested in participating, and, if so, an appointment will be made for them to visit the GPHCM.
Exclusion criteria
Potential participants will be excluded for the following reasons: 1) clinically important fracture of the spine; 2) spinal deformity or disability; 3) blood coagulation disorder; 4) presence of viral hepatitis, human immunodeficiency virus (HIV) or other blood infection; 5) pregnancy or lactation; 6) previous history of stroke or transient ischemic attacks; 7) pacemaker or other electrical device implanted; or 8) lack of consent, active pursuit of compensation or with pending litigation.
Dropout criteria
1) Patients who have severe adverse reactions after acupuncture and cannot successfully complete the course of treatment;2) The participant was unable to follow the protocol treatment for personal reasons during the course, or use other traditional Chinese medicine therapies.
Randomization
A computer algorithm [30] generated a permuted block randomization sequence that will allocate participants to either the acupuncture or sham control acupuncture group to ensure balanced group sizes and allocation concealment. We will use opaque, sealed envelopes in sequential order to contain allocation information.
Blinding
As this is a single-blinded trial, patients will not know which treatment approach they will undergo. During the data collection and analysis stages, the clinical researcher, assessor and statistician will not share study information with each other. Blinding will be assessed after the last treatment using a questionnaire that asks participants if they were in the real treatment group or the sham treatment group. The possible responses are “real treatment group,” “sham group” or “do not know.”
INTERVENTION
All practitioners in this trial are licensed TCM acupuncture therapists with at least 5 years’ clinical experience, and they will be trained to master the study protocol. The acupuncturist will be asked to administer the sham intervention as they would administer standard manipulation, with the same enthusiasm. All participants will continue to receive standard rheumatological care.
Acupuncture group
The acupuncture intervention program was designed by a senior acupuncturist. The acupoints will be Shenshu (BL23), Ganshu (BL18), Yanglingquan (GB34), Jizhong (DU6), Jinsuo (DU8), Mingmen (DU4) and Yaoyangguan (DU3). We will use sterile, disposable stainless-steel needles 0.3 mm in diameter and 25 or 40 mm in length, depending on the acupoints. After eliciting the Deqi response, the researcher will apply electro-acupuncture by connecting an acupoint nerve stimulator (HANS-200A) to Shenshu (BL23) and Ganshu (BL18) at a frequency of 2 Hz for 30 min. Electro-acupuncture intensity will be set according to the maximum intensity tolerated by each subject (0.9–3.0 mA). Other needles will be stimulated manually every 10 min. All needles will be left in place for 30 min.
Sham control acupuncture group
The acupuncture points will be lateral to those in the verum acupuncture group. However, instead of using 0.25-mm diameter, 25-mm long, sterile disposable stainless-steel needles inserted into acupoints 2–3 mm deep without manipulation and into non-acupoints, we will include NP1 (1 cm outward horizontally of Shenshu [BL23]), NP2 (Ganshu [BL18] level outward by 1 cm), NP3 (1 cm behind Yanglingquan [GB34]), NP4 (1 cm to the right horizontally of Jizhong [DU6]), NP5 (1 cm to the right horizontally of Jinsuo [DU8]), NP6 (1 cm outward horizontally of Mingmen [DU4]) and NP7 (1 cm outward horizontally of Yaoyangguan [DU3]). Next, electro-acupuncture will be applied to Shenshu (BL23) and Ganshu (BL18; 0.1–0.3 mA). All needles will be left in place for 30 min. The inclusion of a placebo group will allow for comparison of active acupuncture care effects with manifestations of either sham treatment or psychic solace.
Health control group
No acupuncture intervention will be conducted in healthy controls.
OUTCOMES
Primary outcomes
Primary outcomes will be musculoskeletal-ultrasound, ASQoL and BASMI results. Musculoskeletal ultrasound will use two-dimensional (2D) grayscale, SWE and SMI techniques. The 2D grayscale technique will capture muscle thickness changes in the paraspinal and multifidus muscles. Changes in lumbar-muscle thickness can reflect muscle morphological change due to acupuncture treatment for somatic disorders. The lumbar paraspinal muscles play important roles in movement and control of the spine; studies have shown an inverse relationship between lumbar paraspinal-muscle CSA and lower-back disability but not between lumbar paraspinal-muscle CSA and pain intensity, suggesting that treatment strategies directed at increasing paraspinal-muscle size might be effective in reducing lower-back disability [31]. Later, a blinded tester will measure thickness at the levels of the L4–5 zygapophyseal joints using onscreen calipers [32]. SWE is an ultrasound technique that characterizes tissue mechanical properties based on the propagation of remotely induced shear waves [33]. It provides semiquantitative (color map) and quantitative (absolute SWE value) imaging biomarkers that are useful in assessing the elasticity of tendon and muscle composition and stiffness [34,35] and in helping to distinguish between asymptomatic and symptomatic [36], with diseased tendons being significantly softer than healthy ones [37]. SMI is an ultrasound technique for vascular and microvascular examination. It can diagnose diseases associated with angiogenesis in their early phases and has value in grading disease activities and monitoring therapeutic responses [38]. SMI uses an intelligent algorithm that efficiently separates low-speed flow signals from motion artifacts and successfully extracts clinically relevant information [39]. We will test AS participants using SMI, record resistance index (RI), peak systolic velocity (PSV) and end diastolic velocity (EDV) to reflect SIJ inflammation in this trial. Ultrasound tests will be performed at baseline and week 12.
The ASQoL and BASMI scales have anchors of 0 (none) to 10 (severe). Participants will evaluate their conditions over the preceding week. ASQoL records the impact of AS on health-related QoL from the patient’s perspective in terms of sleep, mood, motivation, coping, activities of daily living, independence, relationships and social life [40]. BASMI [41] is associated with QoL, physical function and psychological status and reflect the change of lumbar side flexion sensitive and reproducible.
Secondary outcomes
Secondary outcomes will be BASDAI, BASFI, FS-14, SAS and SDS results. The BASDAI and BASFI were developed in 1994 using the Visual Analog Scale (VAS) [42,43]. The BASDAI is a patient-generated index measuring disease activity in patients with AS. Scores depend on what patients perceive as being related to their AS. The BASFI measures patients’ functional ability to cope with everyday life in terms of bending, reaching, changing position, standing, turning and climbing steps. The FS-14 measures severity of physical and mental fatigue, which correlates positively with fatigue severity in AS. The SAS and SDS, self-evaluation scales that analyze the patient’s emotional state, are widely used in research and in clinical practice for the detection of anxiety and depression.
Other outcomes
Participant characteristics of age, weight, body mass index, current medical issues, current medications and back pain history will be collected using electronic case report forms. Participants will be asked for number and types of medications taken, medication scheduling and the dose used to self-manage AS symptoms at baseline and at weeks 6 and 12.
Follow-up
Follow-up will occur 12 weeks after completion of the treatment program. This time point was selected to assess sustained long-term effectiveness of the intervention.
The trial work plan is summarized in Figure 2.
Sample size
Based on published evidence in comparative studies, a sample size of 24 per group will yield a power of 90% at an alpha (α) value of 0.05. To account for an anticipated dropout rate of 15%, the enrollment target will be 70.
Data analysis
We will use SPSS software version 18.0 (IBM Corp, Armonk, New York, US) to perform data analysis. Demographic and baseline data will be analyzed with standard descriptive statistics. Data will be presented as the mean ± standard deviation (SD). Between-group differences will be tested using repeated-measure analyses of variance (ANOVAs). The entire data analysis process will be performed by statisticians who are independent from the research team and blinded to the group settings. The accepted level of significance for all analyses will be P < 0.05.
Ethics and dissemination
Any participant who discontinues treatment will be asked their reasons for poor compliance or dropout. If a participant reports a severe adverse event, they will be withdrawn from the study and, depending on the nature of the event, referred to the emergency department or receive appropriate treatment. We will collect, assess and report any spontaneously described adverse events from participants.
We will be monitored by the Institutional Ethics Committee (IEC) of GPHCM, which will audit trial conduct every December. The IEC of GPHCM will be independent from the investigators and sponsor. Ethical approval has been obtained from the IEC of GPHCM (YF2019-232-01). All candidates who agree to participate and who meet all of the inclusion criteria and none of the exclusion criteria will be provided informed consent to obtain full understanding of what study participation will entail and the potential risks. Participants have the right to discontinue participation at any time. Data will be used in the aggregate only, and no identifying characteristics of individuals will be published or presented.