Study design
The study (http://www.chictr.org.cn/index.aspx ID: ChiCTR2100048507) is a multicenter, randomized, open-label, parallel-group, active-controlled trial that will investigate the clinical outcomes of modified LIF sequence versus conventional LIF sequence in treating patients with lumbar spinal stenosis. It will be conducted following the international Consolidated Standards of Reporting Trials (CONSORT) statement (http://www.consort-statement.org/). Approximately three clinical centers will participate in this study. A brief flow chart of this study is provided in Fig. 1.
Study Patients
A total of 254 eligible patients will be enrolled and randomized after screening at the study sites.
The following are the inclusion criteria:
① Age > 18 and < 80 years;
② Non-pregnant and lactating women;
③The patient is suffering from lumbar spinal stenosis (refers to the clinical syndrome of the nerve root and cauda equina compression caused by factors such as lumbar disc herniation or facet joint hyperplasia and stimulation, which is manifested as low back pain, lower extremity pain, lower extremity numbness, lower extremity weakness, intermittent claudication, and even urine and stool dysfunction).
④Lumbar spine imaging examination (X-ray film, computed tomography, and magnetic resonance imaging) to diagnose lumbar spinal stenosis, herniated disc, or hyperplasia of facet joint leading to nerve tissue (spinal cord or nerve root) compression, or nerve tissue compression caused by the stenosis of nerve root outlet.
⑤With significant clinical symptoms of lumbar spinal stenosis, including low back pain, lower limb numbness and pain, and intermittent claudication; On physical examination, the patient had limited lumbar extension, positive or negative straight leg elevation test, and abnormal knee and tendon reflexes.
⑥More than 6 months of conservative treatment, no significant improvement of symptoms, seriously affect the quality of life of patients.
⑦Patients with a strong desire to undergo surgery and a full understanding of the differences between the two surgical procedures and their complications signed an informed consent form to voluntarily participate in the clinical trial.
The exclusion criteria are as follows:
① Patients with cardiovascular, liver, kidney and hematopoietic systems and other serious primary diseases, mental and malignant diseases such as tumors.
②Combined with congenital lumbar malformation, past infection history, tumor history, and trauma history, leading to significant abnormal changes in the shape of the lumbar spine.
③The existence of compression diseases in other parts of the spine other than the lumbar spine, such as cervical disc degeneration, cervical hyperextension, cervical posterior longitudinal ligament ossification, thoracic posterior longitudinal ligament ossification, thoracic ligament yellow ossification, etc.
④There are other diseases such as piriformis syndrome, sciatic nerve injury, polio, and Guillan-Barre syndrome, which affect neurological function and thus interfere with postoperative efficacy.
Recruitment And Randomization Process
Before enrollment, there will be one pretreatment screening visit at the study site office, during which each subject will be assigned a unique identification number.
Once considered eligible for entry, the patients with lumbar spinal stenosis will be randomly assigned to one of two study treatment groups, e.g. either modified LIF sequence or conventional LIF sequence in a 1:1 ratio. A stratified block randomization with randomly varying block size will be used, stratified by surgical segments of lumbar intervertebral disc (single versus multiple segments), modified Schizas classification of lumbar spinal stenosis (level B versus C/D). Random assignment is generated by an independent statistician and implemented via central randomization mobile phone APP (Shanghai KNOWLANDS MedPharm Consulting Co., Ltd.,). In order to avoid potential selection bias, the randomization sequence is concealed from both clinical staff and patients until assignment. With these, neither site investigators nor study participants can influence which treatment group the study patients are assigned to.
Description Of The Interventions
The enrolled subjects will be randomized to undergo LIF surgery with a modified sequence or a conventional sequence. To minimize the potential bias of the trial data, all subjects would be operated on by senior spine surgeons at each site who have at least five years of spine surgical experience and performed more than 100 cases of LIF surgery annually. All subjects will take the same surgical devices. Representative intraoperative images of modified LIF sequence surgery is provide in Fig. 2.
Allthe consumables used in the operation are from the same manufacturer, and the operations will be carried out in strict accordance with a unified standard. The only difference is that patients in the modified LIFsequence group are to be implanted with the fusion cage before with the titanium rod, as opposed to those in the conventional LIF sequence group which are in the opposite order. A detailed description of the LIF surgery technique can be found in previous studies [8, 11].
Study Visits
Five study visits per subject will be scheduled in the study as follows: pretreatment visit (Day − 14 to Day 0), treatment visit (Day 1), discharge visit (on the day of discharge from hospital), follow-up visit month 1 (Month 1 post-treatment) and follow-up visit month 3 (Month 3 post-treatment). These visits will be made at the patient ward before discharge or study site office after discharge. At scheduled visits, data relating to demography, operation duration, estimated blood loss during operation period, length in days of the stay at hospital, and perioperative complications, visual analogue scale (VAS) pain score and lumbar Japanese Orthopaedic Association (JOA) score, concomitant medication, new-onset adverse events, etc. will be collected. See Fig. 1 for more details.
In case severe adverse events occur, the subjects can decide to drop out any time during the study.
Outcome Measures
Primary outcome
The primary outcome endpoint is the new-onset lower extremity neurological symptoms, including new adverse events of pain, numbness, and foot drop at different severity, which occur on the day of surgery performed until prior to discharge from hospital. In order to exclude the influence of nerve root edema, these new-onset symptoms to be included for analysis should not be significantly relieved three days after conservative treatment of nerve dehydration.
Secondary outcomes
The efficacy endpoints in this study mainly included VAS pain score, and lumbar JOA recovery rate pre and post LIF surgery. The VAS pain score is an ordinal scale of 0 to 10 points, with 0 indicating no pain, a higher value indicating more severe pain, and 10 indicating the most severe one. The lumbar JOA recovery rate is derived from lumbar JOA score per subject visit. Lumbar JOA score involves four aspects: subjective symptoms (a range of 0 to 9 points), clinical signs (a range of 0 to 6 points), daily life activities (a range of 0 to 14 points), and bladder function (a range of -6 to 0 points). The total JOA score ranged from − 6(worst) to 29points (normal), with a lower score indicating more significant dysfunction. The recovery rate of lumbar JOA is calculated by Hirabayashi’s method [12] as follows:
Safety outcomes
The safety outcome endpoints also include other adverse events (AEs), surgery complications and laboratory tests as appropriate. The AEs profile of both treatments will be evaluated by examining the incidence of AEs according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 5.0) [13].
Sample Size Calculation
We used SAS®software, V.9.4 (SAS Institute, North Carolina, USA) to estimate sample size. According to the principle of outcome superiority design, the significance level α was set as 0.05 at two-sided. And the effect size indicates the treatment difference of clinical significance. The primary endpoint is the new-onset neurological symptoms (including pain, numbness and foot drop) of the lower limbs during the perioperative period from LIF surgery until discharge from hospital.
Assuming that the incidence of new-onset lower extremity neurological symptoms before and after the expected improvement [7] was 16% and 5%, respectively, when the two groups with a sample size of 242 subjects are randomly allocated in a 1:1 ratio, a power of 80% to establish superiority of modified LIF sequence over conventional LIF sequence will be reached. If the drop-out rate is 5% or less, a total of 254 eligible subjects would be required to randomly enroll in this study.
Statistical analysis
We will have two analysis populations in this study. Of them, the safety set (SS) is defined as all subjects who have ever received the study-specified operation (regardless of whether they participate in the randomized assignment or not) and will be the primary population for safety data analysis. The subjects in SS would be grouped based on the actual operation received. On the other hand, we will utilize full analysis set (FAS) for baseline and efficacy data; it includes all subjects who are randomized into the study groups and received the study operation. Following the principle of intention to treat, subjects in FAS would be analyzed by their randomly assigned group, regardless of the actual operation received.
The primary endpoint in this study is new-onset lower extremity neurological symptoms. The Cochran mantel Haenszel (CMH) method stratified by random stratification factors as appropriate will be used to test the statistical hypothesis. The incidence and 95% confidence interval (CI, Clopper-Pearson method) will be estimated by treatment group. The CI of incidence difference between the two groups will be obtained by using Newcombe method [15]. Similar statistical analysis will further be carried out for individual events of new-onset lower limb neurological symptoms, or Fisher exact method as appropriate will be used for comparison between groups. Additionally, similar analysis for the relief of old lower extremity neurological symptoms will be conducted for pooled and individual events, namely pain, numbness and foot drop during the perioperative period.
For VAS pain score, we will use analysis of covariance (ANCOVA) to compare the between-group changes of the observed values from baseline values after treatment. The random stratification factors as appropriate and the treatment group will be considered as fixed factors with the baseline value as covariate. The least squares mean (LSM), the difference from the control group and its 95% CI will be also provided. Similarly, 3-month recovery rate of lumbar JOA will be analyzed with the use of ANCOVA method.
In addition, we will use a repeated measures mixed effects model (MMRM) as supportive analysis as appropriate. MMRM analysis has treatment group, time and time treatment group interaction as fixed effects, baseline value as covariate, and subjects as random effects. When missing data occur, the last observation carry forward method (LOCF) will be applied to primary analysis and no data imputation as sensitivity analysis. If data distribution limits the use of ANCOVA, a rank-based analysis will be utilized. The LSM, the difference from the control group and its 95% CI will be also provided.
In the study, we will use a p-value of 0.05 or less at two-sided to indicate significance for any statistical tests with the use of R, V.4.0.4 [14] or SAS® software, V.9.4 (SAS Institute, North Carolina, USA).
Ethics And Dissemination
Ethical considerations
The independent ethics committee (IEC) of Shanghai Changzheng Hospital approved the study protocol (version 1.0, issue date: 2021-05-31) for all three participating centers (Approval No.2021SL030). The IEC agreed that this study will not raise patients’ risk or cause any extra harm to patients. The IEC further agreed that the study is in accordance with the Declaration of Helsinki and that the study will be conducted without ethics problems. All subjects will be required to sign a written informed consent document before their participation in the study.
Relevance And Dissemination
Our retrospective data (2020) [7] revealed that the modified sequence of LIF surgery can significantly reduce the incidence of immediate post-operative symptoms for patients with single-level lumbar disc herniation via installation of rods prior to insertion of cage. For purpose of higher level of evidence, herein it is expected that this multicentre randomized controlled trial will clearly demonstrate the two types of surgery sequence in terms of immediate post-operative symptoms among diverse LSS patients. It is well known that the adverse experience will significantly compromise the quality of patients’ life and sometimes even require revision surgery [7, 16, 17].
In the RCT, the conventional LIF surgery sequence will be changed in order: the intervertebral space is first restored and maintained without any distraction or compression force after facetectomy and discectomy; then, differently, the installing and tightening of rods are to be performed prior to the insertion of the cages. By this modified sequence, the inserted cage would be usually smaller than that in the conventional one. In addition, the modified procedure would make it easier to insert an appropriately small cage and even avoid smaller cage to insert.
Given that the immediate postoperative symptoms are available soon after surgery, the study is designed short (approximately three months per subject) in follow-up time. However, it makes sure that we can follow up study patients well and obtain higher quality of data. As regards data analysis, in order to control any possible biases resulting from imbalanced confounders among patients, we will then use stratified randomization technique as is appropriate for this study. This had better help set up any statistical modeling for data analysis. A dedicated data management and analysis team is in place for this study.
In summary, the modified LIF surgery sequence with a rod-prior-to-cage order might be considered more reasonable in treating patients with lumbar spinal stenosis. The study findings will be shared with participating hospitals, and the academic community to promote the clinical management of immediate post-operative symptoms after LIF surgery.
Trial Status
The study has been now recruiting subjects as of the date of submission.