Study setting {9}
Participating centers are the University Hospitals of Uppsala (primary site), Stockholm and Gothenburg and the County Hospital of RyHov in Jönköping. Each center has high volumes of CSM patients and complex spine surgery teams to provide the interventions.
Eligibility criteria {10}
All patients diagnosed with CSM referred for surgical consultation to the orthopedic or neurosurgery departments at the participating centers will be eligible for inclusion in the study. Patients will be enrolled if they meet the inclusion criteria (Table 1) and sign informed consent.
Table 1
Inclusion and exclusion criteria
Inclusion criteria
|
Age > 18 years
|
|
1–4 levels of cervical spondylotic myelopathy in the subaxial spine, C3-C7, without or with deformity not exceeding exclusion criteria, see below
|
|
Eligible for both treatments
|
|
Ability to understand and read Swedish language
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|
Symptomatic myelopathy with at least one clinical sign of myelopathy
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|
No previous cervical spine surgery or thoracic/lumbar spinal stenosis surgery
|
|
Psychosocially, mentally, and physically able to fully comply with this protocol, including adhering to scheduled visits, treatment plan, completing forms, and other study procedures
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|
Personally, signed and dated informed consent document prior to any study-related procedures, indicating that the patient has been informed of all pertinent aspects of the trial
|
Exclusion criteria
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Local kyphosis; a modified K-line minimum interval distance (INT) of < 4 mm (26)
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Spondylolisthesis ≥ 4 mm and simultaneous translation ≥ 2 mm on lateral flexion/extension radiographs (11)
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Soft disc herniations only (no signs of osteophyte formation and hypertrophy of the ligamentum flavum)
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Active infection
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Neoplasm
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Trauma
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Inflammatory disease (i.e., rheumatoid arthritis or ankylosing spondylitis or DISH)
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Systemic infectious disease including HIV
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Lumbar or thoracic spinal disease to the extent that surgical consideration is probable or anticipated within 6 months after the cervical surgical treatment (significant lumbar stenosis as defined by Schizas C or worse) (27)
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OPLL
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Parkinson´s disease
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Drug abuse, dementia, or other reason to suspect poor adherence to follow-up
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Previous cervical spine surgery
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Who will take informed consent? {26a}
The consultant spine surgeon will take informed consent during consultation meeting with the patient that is eligible for inclusion.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
No other consent provisions are applicable; no biological specimens are collected.
Interventions
Explanation for the choice of comparators {6b}
Considering the existence of muscle-preserving laminectomy techniques that can maintain cervical lordosis (28), there are reasons to explore the additional value of instrumented fusion in the cervical spine. Although both methods are widely used, they are yet to be compared in a randomized controlled study.
Intervention description {11a}
General set up
Under general anesthesia, the patient is placed in the prone position and the head is fixed in a clamp. The appropriate levels are verified by fluoroscopy when needed. Local anesthetics are applied to the planned incision site.
Muscle-preserving selective laminectomy
A posterior midline incision is made, and the nuchal fascia is divided longitudinally. The spinous process is split using a high-speed drill/ultrasound knife and without disturbing the bilateral deep extensor muscles, the spinous process is divided at its base. Laminectomy is performed with a width not extending more than 2 mm outside the dural borders. The bilateral facet joints are not exposed. Finally, the split fragments of the spinous process are sutured together (18). No collar or restrictions will be used (29).
Posterior decompression and fusion
A midline incision is made over the appropriate levels, defined as the extension of laminectomy plus one level above and below without extending beyond C3-C7 (30). Soft tissue dissection and retraction is performed to identify osseous landmarks. Special care is taken to spare muscle attachments on C2 and C7. Spinal instrumentation is performed with lateral mass or pedicle screws (C3-C7) combined with rod fixation. Laminectomy is performed with a width not extending more than 2 mm outside the dural borders. Facet joint injury should be avoided. Special care is taken to spare the C7 spinous process and distal half of C7 lamina (31). The sagittal alignment is corrected before spinal fixation. No collar or restrictions will be used (29).
Criteria for discontinuing or modifying allocated interventions {11b}
Both stand-alone laminectomy and laminectomy with fusion have been performed on a regular basis for decades. Still, if severe adverse events are noted, the attending spine surgeon will contact the investigator of the study. Analysis of severe adverse events will be conducted to evaluate if the method is harmful and if the trial needs to be discontinued.
Strategies to improve adherence to interventions {11c}
The study nurse will monitor the follow-ups and send up to three reminders if the participant fails to attend. The third reminder will also include a phone call.
Relevant concomitant care permitted or prohibited during the trial {11d}
Postoperative care, pain control and physiotherapy will be identical in both groups. Stiff neck collars that affect range of motion is prohibited.
Provisions for post-trial care {30}
The participants get no provision for participating in the trial. General standard insurance in case of malpractice and harm is provided by the Swedish healthcare system.
Outcomes {12}
The primary endpoint is reoperation for any reason. Reoperation will be considered in case of:
-
Postoperative hematoma or reperfusion injury with neurologic deterioration within hours/days after the primary surgery.
-
Change in sagittal alignment (kyphosis, DJK of more than 40 mm cSVA (13) and/or C2-C7 Cobb < -10°) with corresponding symptoms of camptocormia/increased pain/neurological deterioration.
-
ASP defined as degenerative changes on an adjacent level diagnosed with MRI and concomitant symptoms of myelopathy and/or radiculopathy.
-
Implant failure (clear radiolucency around > 1 screw or rod breakage with increased neck pain and/or neurologic deterioration).
-
Postoperative infection that requires revision surgery.
Secondary outcome measures will be:
- Change from baseline in myelopathy score on the patient derived modified Japanese Orthopedic Association scale (P-mJOA) at two years of follow-up.
- Change of at least 1 in mild myelopathy (>14 p), 2 in moderate myelopathy (12-14 p) and, 3 in severe myelopathy (<12 p).
- Change from baseline in participants disability score on the Neck disability index (NDI) at two years of follow-up.
- Change of at least 17% (32) in the NDI (0-100 %) compared with baseline (adjustable according to results from own minimal clinically important change results for NDI).
- Change from baseline in myelopathy score on the Nurick scale at two years.
- Change from baseline in the patient Quality of life five dimensions (EQ-5D index) at two years.
- Change from baseline in pain scores on the Numeric rating scale (NRS) at two years.
- Pain relief, as defined by ≥2.5 points (33) improvement on a 10 graded numeric rating scale for arm/shoulder pain.
- Change from baseline in number of participants with psychological impairment on the Hospital anxiety and depression scale (HADS) in both groups at two years.
- The cutoff for depression defined as >10 p (34).
- Change in number of satisfied participants on the satisfaction index in both groups at two years.
- Change from baseline in myelopathy on the 10-s grip and release test at two years.
- Change from baseline in myelopathy on the 10-s foot-tapping speed test at two years.
- Difference in number of participants with treatment adverse events in both groups at five years.
- Change from baseline in sagittal alignment described as cSVA and C2-C7 Cobb angle in neutral radiographs at five years.
- Number of participants with change in adjacent segment pathology (ASP) on MRIs from baseline to five years of follow-up.
- Number of participants with change in compression of the spinal cord on the index level on MRIs from baseline to five years of follow-up.
- Change in direct costs between the groups at one year of follow-up.
- Change in indirect societal costs at one year of follow-up.
- Mortality at five years of follow-up.
Participant timeline {13}
Table 2
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STUDY PERIOD
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|
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Enrollment
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Day of intervention
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Post-allocation
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Timepoint
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-4–18 weeks
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0
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1 day
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3 months
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1 y
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2y
|
5y
|
ENROLMENT:
|
|
|
|
|
|
|
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Eligibility screen
|
X
|
|
|
|
|
|
|
Informed consent
|
X
|
|
|
|
|
|
|
Allocation
|
X
|
|
|
|
|
|
|
INTERVENTIONS:
|
|
|
|
|
|
|
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Laminectomy or laminectomy with fusion
|
|
X
|
|
|
|
|
|
ASSESSMENTS:
|
|
|
|
|
|
|
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Baseline variables
|
X
|
|
|
|
|
|
|
Follow-up variables
|
|
|
|
|
X
|
X
|
X
|
X-ray
|
X
|
|
|
|
X
|
X
|
X
|
MRI
|
X
|
|
|
X
|
|
|
X
|
CT
|
X
|
|
X
|
X
|
|
|
X
|
Sample size {14}
Based on data from the national Swedish spine registry on patients with CSM, reoperation was estimated to 3.4% after standalone laminectomy and 7.9% after laminectomy and fusion. Five year mortality was estimated to 16.3% in the same population (35) .
We further determined that excluding a 5% excess rate of reoperation in the laminectomy group vs laminectomy and fusion was a clinically relevant target for the study, and therefore set the non-inferiority margin at 5 percentage points (pp).
With a sample size of 300 participants and with regards to mortality and an additional 5% loss due to dropout and emigration, we end up with 236 analyzable patients. This results in a power of 87% based on simulation using rerandomization.
Recruitment {15}
Patients with CSM are referred by a general practitioner to a consulting spine surgeon at a large center. Four large spine centers in Sweden are participating in the trial with patient enrolment to secure the reach of target sample size.
Assignment of interventions: allocation
Sequence generation {16a}
Participants will be allocated to either standalone laminectomy or laminectomy and fusion through randomization with a 1:1 ratio using the REDcap software (Research Electronic Data Capture), after informed consent and agreement to be included in the study. After inserting the patient´s personal number into REDcap the program reports the random allocation of the patient according to the pre-constructed randomization list. The randomization is stratified for center and participant sex, i.e. using separate lists for each center and sex. The allocation sequence utilizes balanced blocks of three different sizes occurring in random sequence. The principal investigator and study collaborators are blinded to the sequence, the block sizes and block sequence.
Concealment mechanism {16b}
Concealment mechanism is provided by the REDcap software that allows the user to perform randomization without the possibility of knowing the outcome beforehand. The statistician that created the randomization file that was imported to the REDcap randomization module is a separate statistician, not the same as the study statistician and is otherwise not involved in the study.
Implementation {16c}
One accountable spine surgeon at each center has individual logging to REDcap and the logon process is with a two-stage verification using logging and mail code. The accountable spine surgeon implements the allocation.
Assignment of interventions: blinding
Who will be blinded {17a}
Trial participants will not be blinded after assignment to interventions as they have online access to their medical records by a centrally managed system. Radiographic assessment is not possible to blind.
The outcome assessors and data analysts will be blinded by using a coding system for the participants and treatment groups.
Procedure for unblinding if needed {17b}
No blinding
Data collection and management
Plans for assessment and collection of outcomes {18a}
Participant baseline data are collected before the intervention and secured by the study nurse into the REDcap software. Baseline data include routine demographics, smoking habits, work status, sick listing, duration of neck pain, attitude towards returning to work, use of analgesics, fine motor skills and patient reported outcome measures (PROMs) including P-mJOA, NDI, EQ-5D, NRS separately for arm and neck pain and, HADS. The surgeon records data including: diagnosis, 10-s grip and release test, 10-s foot-tapping test, surgical treatment, surgical levels, neurological impairment, Nurick grading (36), instability, type of implant, operation time, blood loss and any perioperative complications. Follow-up questionnaires and PROMs are sent to the participants after 1, 2, and 5 years, postoperatively, according to Swespine routines (37, 38).
Assessment regarding the primary endpoint will be made at the one-, two- and five years of follow-up (study protocol initiated) or at any timepoint when increased pain, deformity, or neurological deterioration is detected (patient initiated).
The most important secondary outcome measure is the P-mJOA (continuous variable), a self-administered questionnaire with four domains, measuring motor (upper and lower extremities), sensor (upper extremities) and sphincter dysfunction in participants with CSM. The first domain is scored from zero to five, second domain from zero to seven, third and four domains from zero to three. The maximum score is 18 points, indicating no deficits and the minimum score is zero, total tetraplegia. The minimum clinically important difference (MCID) in mJOA has been reported to be 2 overall with a threshold of 1 in mild myelopathy (mJOA > 14), 2 in moderate myelopathy (mJOA 12–14) and 3 in severe myelopathy (mJOA < 12) (39). Consistency between P-mJOA and mJOA is demonstrated with identical mean scores and a SD of 1.5 together with a strong agreement of 0.83 with the use of intraclass correlation coefficient and the Spearman correlation (40).
Other secondary outcome measures are the NDI (32) (continuous variable) (ranging from 0-100% with higher scores indicating severe disability), the Nurick scale (categorical variable), a six-grade system (0–5) based on the “difficulty in walking”, EQ-5D index (continuous variable) (ranging from − 0.5 to 1 with higher scores reflecting a better quality of life) (41), EQ VAS (continuous variable) (ranging from 0-100 with higher scores indicating better health), NRS for neck and arm pain (33) (continuous variable) (ranging from 0–10, with higher scores indicating more severe pain), HADS (continuous variable) (ranging from 0–42 with higher scores indicating more anxiety/depression with a cutoff for depression of > 10 p) (34) and patient satisfaction index (categorical variable). The MCID is 15%-17% (32, 33, 42) for NDI, 0.24 for EQ-5D (32) and 2.5 (33) for NRS of the neck and arm (33).
The satisfaction index evaluates the participants´ experienced overall result after surgery. The participant is asked “How is your attitude regarding the treatment result”. The alternative answers are “satisfied”, “uncertain”, “dissatisfied”.
The 10-s grip and release test (continuous variable) is performed with the forearm in pronation and the wrist in mild extension. The participant is asked to grip and release with their fingers as rapidly as possible and the number of completed cycles of movement within 10 seconds is counted. Both hands are tested separately. The test has been correlated to the JOA score and differences between sex and age groups in the normal population have been set (43).
The 10-s foot-tapping speed test (continuous variable) is performed with the participant sitting on a chair adjusted so that the hip and knee are flexed at 90° and the bilateral soles have contact with the floor. The participant is asked to move their toes up and down, tapping the floor as quickly as possible for 10 sec with their heels firmly planted on the floor. The number of completed cycles of movement within 10 seconds is counted and both feet are tested separately. The test has been correlated to the JOA score, Nurick grade, 10-s grip and release test and the 30-m walking test (44).
All adverse events in both groups will be recorded. The adverse events will be graded according to severity (categorical variable): grade 1, any non-life-threatening complication treated without invasive procedures; grade 2, complications requiring invasive management such as surgical, endoscopic, and endovascular procedures; grade 3, life-threatening adverse events requiring treatment in an intensive care unit; and grade 4, death as a result of complications (45).
The C2-C7 Cobb angle, C2-C7 cSVA, C7 slope and T1 slope (continuous variables) are all measured on images taken preoperatively and at one, two and five years of follow-up (14, 46). Development of ASP will be monitored. Participants who develop a progressive kyphosis/DJK of more than 40 mm cSVA (13) and/or C2-C7 Cobb < -10° and neurological deterioration/ASP/restenosis will undergo additional magnetic resonance imaging (MRI) and may be subject to supplementary posterior fusion/revision.
Direct costs include hospital stay related to the surgical procedure, implant related costs, and pain medication usage. Indirect costs include pain medication usage after discharge, societal costs for absence from work and workers compensation.
Imaging
Standing radiographs of the cervical spine in neutral, flexion and extension will be performed preoperatively and at one, two and five years of follow-up. When radiographs of the neutral position are executed, the participant will be in a comfortable standing position with the head facing forward for horizontal gaze. The radiographs will be used to investigate the sagittal alignment by measuring the C2-C7 Cobb angle, C2-C7 cSVA, C7 slope and T1 slope (18).
MRI of the cervical spine with T1- and T2-weighted images in sagittal and T2-weighted in axial planes will be performed preoperatively, after three months and at five years of follow-up. Hereby the compression of the spinal cord can be assessed as well as the performed decompression and the degenerative development over time.
Computed tomography (CT) will be performed pre- and postoperatively and at 3 months and 5 years to control the screw fixation, bony anatomy, and fusion (Table 2).
Plans to promote participant retention and complete follow-up {18b}
Participants that do not reply on the first set of PROMs will get two reminders by mail. If still no response, they will be approached once by telephone. If still no response, information about missing participants that have not left the study will be retrieved from the medical records, radiographs, and the Swedish patient registry.
Data management {19}
The REDcap software, with a two-stage verification login, will also be used for safe data management (project-redcap.org; redcap.vanderbilt.edu). The data will be pseudonymized and all participants will have a specific code. Access to decrypted data and safekeeping of the decryption key will be limited to the principal investigator and the study nurse. The principal investigator is responsible for communicating important protocol modifications and is together with the research nurse responsible for encrypting participant data and protecting the decryption key.
Confidentiality {27}
All data managements and analysis are done using unidentified data. The participating spine surgeons will only have access to data generated on their own site and cannot see the other recruiting centers.
Plans for collection, laboratory evaluation and storage of biological speciments for genetic or molecular analysis in this trial/future use {33}
No laboratory test or biological materials are collected during this trial.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
All endpoints will be analyzed in the per protocol (PP) population, defined as randomized patients who are still alive without having emigrated or left the study after two and five years. Primary outcome
To test for non-inferiority, a two-sided 95% confidence interval (CI) for the difference in failure (reoperation) rates between the two groups will be computed. To account for sparsity of events, the CI will be computed using rerandomization techniques (47), blocked on sex, since the randomization was stratified on sex. Non-inferiority will be claimed if the upper limit of the CI is less than 5 pp. If non-inferiority is demonstrated, superiority will also be tested using the same CI, although the study is likely underpowered to detect this.
Secondary outcomes
The secondary outcomes will be analyzed using ordinal regression models, adjusted for sex. In addition, each secondary endpoint will be dichotomized and analyzed using logistic regression. The dichotomization will be done by comparing baseline and follow-up data, either based on MCID when applicable, or else by defining success as an improvement from baseline. All secondary endpoints will be analyzed at 1, 2 and 5 years of follow-up, but not until the study is closed.
Interim analyses {21b}
An interim analysis regarding adverse events will be performed by an independent observer when 100 participants are included. The results will be reported to the principal investigator and the accountable researchers at each center and the group will make the decision to terminate the trial.
Methods for additional analyses (e.g. subgroup analyses) {20b}
No primary subgroup analyses are planned.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Dropouts may be one out of two entities; 1) the participant actively leaves the study or, 2) the participant has died or do not show up on follow-ups for unclear reasons. In case 1, the participant will not be part of the study anymore and data will not be retrieved from other information sources. In case 2, information about living participants will be retrieved from the medical records, radiographs, and the Swedish patient registry. In case 2, missing PROMs will be imputed using multiple imputation (48). Reoperations, adverse events, and radiographs will not be imputed.
Plans to give access to the protocol, participant level-data and statistical code {31c}
A deidentified dataset will be delivered upon request after completion and publication of the five-year follow-up.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The coordinating center is Uppsala University Hospital.
The steering committee is: Anna MacDowall, study director and overall supervision of the study; Adrian Elmi-Terander and Erik Edström, responsible for the study site in Stockholm; Håkan Löfgren, responsible for the study site in Jönköping; Helena Brisby and Catharina Parai, responsible for the study site in Gothenburg. The steering committee will have meetings once every six months.
Main coordinator and controller: Catarina Strömstedt, responsible for data managing in REDcap.
Independent observer: Prof. Nils Hailer, MD, PhD, responsible for interim analysis and auditing trial conduct.
The study sites have each a coordinator that is in direct contact with the main coordinator and controller.
The study statistician is Lars Lindhagen at Uppsala Clinical Research Center.
Composition of the data monitoring committee, its role and reporting structure {21a}
Data monitoring is performed on a weekly basis by the main coordinator and controller with support of the local coordinator to ensure that all events, PROMs and radiology are performed according to the protocol.
Data monitoring committee comprises of the study director and the main coordinator and controller. The monitoring committee is independent from sponsors and competing interests.
Adverse events reporting and harms {22}
As reoperations due to complications and adverse events is the primary outcome, all adverse events in both groups will be recorded. The adverse events will be graded according to severity (categorical variable): grade 1, any non-life-threatening complication treated without invasive procedures; grade 2, complications requiring invasive management such as surgical, endoscopic, and endovascular procedures; grade 3, life-threatening adverse events requiring treatment in an intensive care unit; and grade 4, death as a result of complications (45).
The adverse events are reported by the senior spine surgeon to the steering committee.
Frequence and plans for auditing trial conduct {23}
Auditing trial conduct will be performed by the independent observer and an interim analysis will be made when 100 participants are included.
Plans for communication important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Any change in the protocol from the primary protocol that is approved by the Swedish Ethical Review Authority must be resubmitted for ethical approval and reported to relevant parties as trial participants and trial registries.
Dissemination plans {31a}
The trial result will be submitted to peer review journals and presented at international meetings.