Methods/Design
Overview
We are conducting a randomized clinical trial in which individuals with CNLBP are randomly assigned to group SSE and CBT (Figure 1). Participants will be followed for 52 weeks after randomization. The primary outcome we will assess is RMDQ. Participants will be informed that the study researchers are comparing “two different widely used pain self-management programs that have been found helpful for reducing pain and making it easier to carry out daily activities”.
Figure 1 Flowchart of the trial protocol
Study sample and setting
The primary source of participants for this trial will be SGH, a not-for-profit health-care organization with around 3.83 million outpatient visits every year in Shanghai. As needed to achieve recruitment goals, poster advertisement, telephone, social health lecturing, official website and WeChat will be employed. The subjects will be at the age of 20 to 70 years living in the areas served by SGH.
Inclusion and exclusion criteria
We are recruiting individuals from 20 to 70 years of age whose low back pain has persisted for at least 3 months. The inclusion and exclusion criteria were developed to maximize the enrollment of appropriate patients while screening out patients who have low back pain of a specific nature (for example, spinal stenosis) or a complicated nature or who would have difficulty completing the study measures or interventions (for example, psychosis). Tables 1 and 2 list the inclusion and exclusion criteria, respectively, as well as the rationale for each criterion.
In addition, we require that participants be willing and able to attend the CBT or SSE group during the whole intervention period if assigned to one of those treatments, and to respond to follow-up questionnaires according to the protocol.
Recruitment procedures
Based on SGH’s administrative and clinical electronic case history, potentially eligible candidates with a visit in the recent 3 months (or longer than 3 months) can be identified to a provider that resulted in a diagnosis consistent with CNLBP. They will be informed of this trial in different ways including advertisement, social health lecturing, or other recruitment routes. If one is interested, a research specialist will call the potential participant to ask questions; determine eligibility; clarify risks, benefits and requirements of the study; and request informed consent. After the signed informed consent form has been obtained, the baseline telephone assessment is conducted.
To ensure that all these screened study participants remain eligible at the time that the trial begins, those who consent more than 14 days prior to the start of the intervention will be re-evaluated approximately 0 to 14 days prior to the first visit to reconfirm their eligibility. The primary concern is to exclude persons who no longer have at least moderate baseline ratings of pain bothersomeness and pain-related interference with activities. Those individuals who remain suitable to this trial and give their final informed consent will be included.
Randomization
All the volunteers will be trained with procedures and notes of both SSE & CBT by qualified investigators or instructors, and they will also be assessed whether they master these skills. After completing the baseline assessment, participants will be randomized in equal proportions to the SSE or CBT group. Each person will get a random number from 1 to 480 scheduled according to inclusion sequence.
Study treatments
Sinew-strengthening exercise
SSE, a practical exercise method frequently used in Department of Orthopedics in SGH, is conducted as procedures in Table 3.
Cognitive-behavioral therapy
It is reported that CBT is a valid way to deal with chronic pain problems [11], which emphasizes active, structured techniques to teach patients how to identify, monitor and change maladaptive thoughts, feelings and behaviors, with a focus on helping patients to acquire skills that they can apply to a variety of problems and collaboration between the patient and therapist. A variety of techniques are taught, including training in pain coping skills (for example, use of positive coping self-statements, distraction, relaxation and problem-solving). CBT also promotes setting and working toward behavioral goals.
The CBT intervention (Table 4) will consist of eight weekly 2-hour sessions that will provide (1) education about the role of maladaptive automatic thoughts (for example, catastrophizing) and beliefs (for example, one’s ability to control pain, hurt equals harm) common in people with depression, anxiety and/or chronic pain and (2) instruction and practice in identifying and challenging negative thoughts, the use of thought-stopping techniques, the use of positive coping self-statements and goal-setting, relaxation techniques and coping with pain flare-ups. The intervention will also include education about activity pacing and scheduling and about relapse prevention and maintenance of gains. Participants will be given audio recordings of relaxation and imagery exercises and asked to set goals regarding their relaxation practice. During each session, participants will complete a personal action plan for activities to be completed between sessions. These plans will be used as logs for setting specific home practice goals and checking whether they complete during the week to be reviewed at the next week’s session.
Instructors
All SSE instructors will have received either formal training in teaching SSE from a senior doctor who is experienced in treating patients for chronic low back pain in Department of Orthopedics in SGH or equivalent training. They will themselves be practitioners of SSE and will have taught SSE previously. The CBT intervention will be conducted by doctorate-level clinical psychologists with previous experience in providing CBT to patients with CNLBP.
Training and monitoring of instructors
All CBT instructors will be trained in the study protocol for the CBT intervention by qualified investigators from Rehabilitation Department in SGH, who are very experienced in administering CBT to patients with chronic pain. One of the investigators will train the SSE instructors in the adapted SSE protocol and supervise them. Each instructor will attend weekly supervision sessions, which will include discussion of positive experiences, adverse events, concerns raised by the instructor or participants and protocol fidelity. Treatment fidelity checklists highlighting the essential components for each session were created for both arms. A trained research specialist will use the fidelity checklist during live observation of every session. The research specialist will provide feedback to the supervisor to facilitate weekly supervision of the instructors.
Participant retention and adherence to home practice
Participants will receive a reminder call before each visit. They will be asked to record their daily home practice on weekly logs. Questions about their home practice during the prior week will also be included in all follow-up interviews. To maintain interviewer blinding, adherence questions will be asked after all outcome data have been recorded.
Measures
A variety of participant baseline characteristics will be assessed, including sociodemographic characteristics, low back pain history and expectations of the helpfulness of the treatments for CNLBP (Table 5).
We will assess a core set of outcomes for patients with spinal disorders (back-related function, pain, general health status, work disability and patient satisfaction) that are consistent with the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations for clinical trials of chronic pain treatment effectiveness and safety [12]. We will measure both short-term outcomes (8 and 26 weeks) and long-term outcomes (52 weeks). Participants will be paid 20 yuan for each follow-up interview completed to maximize response rates.
Primary outcome measure
The primary outcome measure will be RMDQ. This method has been found to be reliable, valid and sensitive to clinical changes. In RMDQ, 24 questions about low back pain will be asked to the patients. We will analyze and report primary outcomes in two ways. First, for our primary endpoint analyses, we will compare the percentages of participants in the two groups who achieve clinically meaningful improvement (≥30% improvement from baseline) [13] at each time point (with 26-week follow-up being the primary endpoint). We will then examine, in a secondary outcome analysis, the mean differences between groups on these measures at each visit.
Secondary outcome measures
Back pain bothersomeness will be measured by asking participants to rate how bothersome their back pain has been during the previous week on a 0 to 10 scale (0 = “not at all bothersome” and 10 = “extremely bothersome”). A literature showed that this bothersomeness measure is highly correlated with a 0 to 10 measure of pain intensity (r = 0.8 to 0.9) and with measures of function and other outcome measures [14]. As a result, this scale is sensitive enough in detecting changes in pain after treatment.
SF-36, known as a health survey summary, is a universal measurement scale with 8 aspects and 36 questions including physical functioning, role-physical, bodily pain, general health, validity, social functioning, role-emotional and mental health, which is one of the most commonly used standardized life quality assessment tools in the world. It has been translated to different languages since 1980s. Another health index in this short form is health transition to evaluate overall health change status in the previous year [15, 16].
Fat percentage of core muscle group is detected by Magnetic Resonance Hydrolipid Separation Imaging (MRHS), also named Dixon Technology, which is to perform two acquisitions by adjusting the time of echo (TE) in accordance with the difference of the hydrogen proton statnamic frequency in water molecules and fat molecules in the magnetic field. The first acquisition obtains the transverse magnetization vector of the two protons in phase, i.e. the addition of water and fat signals. The second one obtains the transverse magnetization vector with opposed phase, which is the difference image of water and fat signals. The scanning device is high field superconducting nuclear magnetic resonance, Simens skyra 3.0T MRI. The scanning parameters are as follows: horizontal axis Dixon sequence scan: TR5.36ms, TE1.24ms, flip angle: 9 degrees, FOV500mm×500mm, the number of layers: 44-60 layers, layer thickness: 5.0mm, interval: 1.0mm, scanning time: 12s×5. The reason for selecting fat percentage of muscle group as a secondary outcome measure is that skeletal muscle fat infiltration is associated with the onset of spinal degenerative diseases as it leads to the substitution of contractile muscle fibers by non-contracting tissues, which may affect spine stability [17]. Degeneration of paraspinal muscles is also closely related to the recurrence of low back pain [18].
Data collection, quality control and confidentiality
Data will be collected of the questionnaires from participants by trained investigators. We will attempt to obtain outcome data from all participants in the trial, including those who never attend or drop out of the therapies, those who discontinue enrollment in the study and those who move away. We will collect information at every stage of recruitment, randomization and treatment so that we can report patient flow according to the CONSORT (Consolidated Standards of Reporting Trials) guidelines [19]. In each visit, the investigators will ask the subjects to exercise in line with what they do at home to ensure that they practice in a correct way. Although the volunteers know his/her own group, the evaluators will see the baseline and questionnaire data only in order to keep their blind status and make the results reliable. To maintain the confidentiality of patient-related information in the database, unique participant study numbers will be used to identify patient outcomes and treatment data.
Protection of human participants and assessment of safety
Protection of human participants
The SGH Ethics Committee (EC) approved this study.
Safety monitoring
This trial will be monitored for safety by an independent Data and Safety Monitoring Board (DSMB) composed of a primary care physician experienced in CBT, a biostatistician and a clinical psychologist with experience in treating patients with chronic pain.
Adverse events
We will collect data on adverse events (AEs) from several sources: (1) reports from the CBT and SSE instructors of any participants’ experiences of concern to them; (2) safety evaluation from laboratory examination; and (3) spontaneous reports from participants. The project coinvestigators and a SGH primary care internist will review AE reports from all sources weekly. Any serious adverse events (SAEs) will be reported promptly to the SGH EC, the DSMB and National Medical Products Administration (NMPA). AEs that are not serious will be recorded and included in regular DSMB reports. Any identified deaths of participants will be reported to the DSMB chair within 7 days of discovery, regardless of attribution.
Stopping rules
The trial will be stopped only if the DSMB believes that there is an unacceptable risk of SAEs in one or more of the treatment arms. In this case, the DSMB can decide to terminate one of the arms of the trial or the entire trial.
Sample size and detectable differences
Our sample size was chosen to ensure adequate power to detect a statistically significant difference between the two groups. We specified our sample size on the basis of the expected percentage of patients with a clinically meaningful improvement measured with the primary outcome measure (RMDQ) at the 26-week assessment (that is, at least 30% relative to baseline) [13].
A literature showed that 55% of CBT treatment group had clinically meaningful improvement on the RMDQ at 26 weeks [13]. We will have at least 80% power to detect a significant difference between SSE and CBT on the RMDQ if the ratio of SSE that improves with clinical meaning will be 20% higher than that of CBT, which means that 66% (55%+55%*20%) of SSE group will have clinically meaningful improvement on the RMDQ at 26 weeks from our expectation.
The effectiveness rates of these two groups are compared. Assuming a 20% loss to follow-up, we plan to recruit a sample of 576 participants (288 per group). We will need 480 participants (240 in each group) to achieve 80% power to find SSE treatment different from CBT group on the RMDQ according to the formula 
The primary outcome will be tested at the P < 0.05 level at each time point because they address separate scientific questions.
Statistical analyses
In our comparisons of treatments based on the outcome measures, we will analyze outcomes assessed at all follow-up time points. We will conduct the following set of analyses for both the continuous outcome score and the binary outcome (clinically significant change from baseline) including all follow-up time points (4, 8, 26 and 52 weeks). The SSE treatment will be deemed successful only if the 26-week time point comparisons are significant. The other time points will be considered secondary evaluations.
We will use an intent-to-treat approach in all analyses; that is, the assessment of individuals will be analyzed by randomized group, regardless of participation in any classes. In this trial, if a patient does not complete the treatment, the data will be carried forward with the last observation. This analysis minimizes biases that often occur when participants who do not receive the assigned treatments are excluded from analysis.