A Randomised Controlled Trial Comparing the Effectiveness of Surgical and Nonsurgical Treatment for Cervical Radiculopathy
Phase: NA
Conditions: Cervical Radiculopathy
Sponsor: Oslo University Hospital

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Cervical Radiculopathy Trial 
NCT03674619 
December 3, 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 

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This supplement contains the following items: 
1.          Original protocol, final protocol, summary of changes. 
2.          Original statistical analysis plan, final statistical analysis plan, summary of changes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of contents 
Study protocol v. 1.0 ...................................................................................................................................... 4 
Study protocol v. 2.0 ................................................................................................................................... 33 
Summary of changes to the protocol ......................................................................................................... 62 
Statistical analysis plan (SAP) v. 1.0 ............................................................................................................64 
Statistical analysis plan (SAP) v. 2.0 ............................................................................................................76 
Summary of changes to the statistical analysis plan  .................................................................................87 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study protocol v. 1.0 Published: 16 March 2020 
 
A randomised controlled trial comparing the effectiveness of surgical and 
nonsurgical treatment for cervical radiculopathy 
 
Mirad Taso1,2,3*, Jon Håvard Sommernes2, Frode Kolstad2, Jarle Sundseth2, Siri Bjorland1, Are 
Hugo Pripp4, John Anker Zwart3,5, Jens Ivar Brox1,3 
 
1Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Ullevål, Oslo, 
Norway 
2Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway 
3Faculty of Medicine, University of Oslo, Oslo, Norway 
4Oslo Centre of Biostatistics and Epidemiology, Research Support Services, Oslo University 
Hospital, Oslo, Norway 
5Research and Communication Unit for Musculoskeletal Health, Division of Clinical 
Neuroscience, Oslo University Hospital, Oslo, Norway 
*Corresponding author: 
Mirad Taso 
Department of Physical Medicine and Rehabilitation, Oslo University Hospital HF, Ullevål, 
Postboks 4956, Nydalen, 0424, Oslo, Norway,  
E-mail: mirtas@ous-hf.no, Telephone: +47 93838735 
 
 

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E-mail addresses of other authors: 
Jon Håvard Sommernes, haasom@ous-hf.no 
Frode Kolstad, fkolstad@ous-hf.no 
Jarle Sundseth, jsundset@ous-hf.no  
Siri Bjorland, sibjorl@online.no  
Are Hugo Pripp, apripp@ous-hf.no 
John Anker Zwart, UXZWJO@ous-hf.no 
Jens Ivar Brox, jbrox@ous-hf.no 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Abstract 
Background: Cervical radiculopathy is usually caused by disc herniation or spondylosis. The 
prognosis is expected to be good in most patients, but there is limited scientific evidence on the 
indications for nonsurgical and surgical treatments. The aim of the present study is to evaluate 
and compare the effectiveness of surgical and nonsurgical treatment in two trials – including disc 
herniation and spondylosis, respectively, and to evaluate factors that contribute to better decision 
making. 
Methods/Design: Patients with disabling radicular arm pain and MRI-proven cervical disc 
herniation or spondylosis will be randomised to receive nonsurgical or surgical treatment. The 
follow-up period is one year and the sample size is estimated to be 50 for each arm in the two 
trials, giving a total of 200 patients. The primary outcomes are the Neck Disability Index and arm 
pain. Secondary outcomes include neck pain; EQ-5D and costs to evaluate cost-effectiveness; 
prognostic factors; CT and MRI scans, to estimate intervertebral foraminal area and nerve root 
compression; and the expected minimal improvement for willingness to undergo treatment. 
Discussion: The outcomes of this study will contribute to better decision making in the treatment 
of cervical radiculopathy.  
Trial registration: This study has been registered at ClinicalTrials.gov as NCT03674619, on 
September 17, 2018 (https://clinicaltrials.gov/ct2/show/NCT03674619). 
Keywords: Cervical radiculopathy, Treatment, Surgery, Anterior cervical decompression and 
fusion, Nonsurgical, Physical medicine and rehabilitation, Effectiveness, Shared decision 
making, RCT.  
 
 

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Background 
Neck pain is among the leading causes of disability worldwide (1). The yearly prevalence is 48%, 
and 25% of women and 13% of men reported that they suffered from neck pain weekly in two 
Norwegian epidemiological surveys (2, 3). Classifying neck pain in those who consult healthcare 
providers is challenging. Interpreting images is difficult because of the high frequency of 
degeneration in asymptomatic populations (4). For example, in a systematic review, disc 
protrusion was reported in 29% of 20-year-old asymptomatic persons, and in 43% of 80-year-
olds, while facet joint degeneration was reported in 4% and 83%, respectively (4). 
 
In contrast, the yearly prevalence of cervical radiculopathy is relatively low. It was estimated to 
83/100 000, peaking in fourth and fifth decades, in a large epidemiological study applying wide 
criteria, including neck and arm pain, and corresponding MRI findings indicating that one or 
more nerve roots were affected (5). Cervical radiculopathy is caused by disc herniation, 
spondylosis, or a combination of herniation and spondylosis. In 80% of patients, the C6 or C7 
roots are affected (5). Cervical spondylosis refers to degenerative changes that occur in the 
cervical spine with age, most often manifesting as decreased disc height and hypertrophy of the 
intervertebral joint. Symptoms usually develop more gradually than the sudden, intense arm pain 
reported by patients with disc herniation.  
Cervical disc herniation and spondylosis may trigger local ischemia and inflammation, mediated 
by biochemical and immunological factors that contribute to the pathophysiology of 
radiculopathy (6). High levels of IL-6 were found to be a predictor of slow recovery in patients 
with lumbar radicular pain (7).  

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The natural course of cervical radiculopathy is difficult to outline. Recent studies have described 
a favourable course at an average of 6 months, with complete recovery ranging from 24 to 36 
months (8, 9). There is limited evidence on prognostic factors; however, durations greater than 6 
months, higher pain scores, radicular signs, psychosocial factors, sickness absences, and surgery-
related factors are reported to be associated with poorer outcomes (9, 10). Most patients with 
cervical radiculopathy are treated nonsurgically. The effectiveness of different nonsurgical 
treatments in comparison to placebo or the natural course is not known. A recent randomised 
controlled trial (RCT) compared cervical collar, physiotherapy, and a wait-and-see policy in 
patients with cervical radiculopathy lasting 3 weeks or more (11). With any of the three 
interventions, mean arm pain intensity decreased from about 70% of the worst possible pain at 
baseline to about 20% of the worst possible pain at 6 months follow-up (11). Improvement in 
condition at 6 and 12 weeks was significantly better in those who received physiotherapy or a 
collar. In the aforementioned epidemiological study, 561 patients were studied for 5 years, and 
90% were asymptomatic or only mildly incapacitated owing to cervical radiculopathy. Twenty-
six per cent of the patients underwent surgery. The strongest predictor of surgery was a 
combination of radicular pain, sensory loss, and muscle weakness, yielding a hazard ratio of 17.3 
in a multivariable model. 
The most common surgical treatment is discectomy and fusion (12). Anterior cervical discectomy 
is one of the most frequently performed spinal procedures; in the United States, almost 550 000 
patients were operated on between 2005 and 2008 (13). The surgical rates for cervical 
radiculopathy are lower in Norway compared to the United States, but increased by 86.5 % from 
2008 to 2014, and was 2.5 times higher in counties with the highest rates compared to those with 
the lowest rates (14). Neither the observed increase over time nor geographical differences are 
likely to be explained by variations in the prevalence of cervical radiculopathy. A recent review 

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stated that previous studies have led most investigators to conclude that cervical radiculopathy is 
a self-limiting phenomenon in most cases (15). This directly contradicts the increasing surgery 
rates. 
 
The success rates of surgical interventions are reported to range between 80 and 95% (16); 
however, two systematic reviews (SRs) have found no clear benefits of surgery over nonsurgical 
treatments (17, 18). One of the SRs included two small RCTs (19-21), the other included six 
additional controlled clinical trials. The evidence that can be drawn from these systematic 
reviews is considered to be limited. Results suggest that selection criteria, observer bias, the 
natural course and placebo mechanisms play an important role in the reported high success rates 
after surgery. Further, the disc prosthesis (cervical arthroplasty) has been proposed to improve 
results. A recently published Norwegian multicentre trial did not favour discectomy and disc 
prosthesis compared with the traditional discectomy and fusion (22). The trial included patients 
with one-level radiculopathy (C6 or C7) primarily caused by spondylosis. The success rate was 
75%, estimated by the number of patients reaching the minimal clinical important change 
(MCIC). However, reported values of the minimal important clinical change of the Neck 
Disability Index (NDI) differ largely (23). A systematic review reported that MCIC varied from 
10 to 38, on a scale from 0 to 100 (24). An MCIC of 10 is most commonly used in trials 
comparing various surgical procedures for cervical radiculopathy (22). The global perceived 
change is often used as an external criterion for estimating MCIC; however, the improvement 
expected by the patient in order to undergo surgery or non-operative treatments has not been 
examined, to the best of our knowledge.  
 

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There is limited knowledge on the indications for surgery in patients with pain syndromes in 
general, and particularly in patients with cervical radiculopathy caused by disc herniation. It is 
believed that the prognosis of non-operative treatment is better in patients with disc herniation 
than in patients with spondylosis, but there is a lack of clinical trials to corroborate this. One 
reason for this is that a strict classification based on MRI-findings has been difficult to obtain. 
Surgery is conducted to decompress the nerve root, but the correlation between the intervertebral 
foraminal area, root compression, and symptoms has been poorly investigated, and findings are 
questionable because neither the measurement error nor the inter-rater agreement of findings has 
been reported. Albert et al. found no postoperative correlation between surgical graft height and 
symptom relief (25). The intervertebral foraminal area of different segments of the cervical spine 
correlates with disc height and disc degeneration – measured using CT or MRI scans (26) – and is 
increased by cervical flexion (27). More studies have been performed on the lumbar spine. A 
recent study found moderate inter-rater reliability for evaluation of postoperative nerve-root 
thickening and compression, and that postoperative compression or dislocation observed in 
patients operated for disc herniation was not correlated significantly to the outcome (28). 
Therefore, assessing the association of the neuroforaminal area and nerve root compression in the 
cervical spine, including a methodological evaluation, is warranted.  
Further research may improve our understanding and reverse or limit current practice. Forty-two 
per cent of practices believed to be effective, were reversed according to a systematic review 
evaluating trials published in a high impact journal over a 10-year period (29). For example, a 
few years ago, spinal surgeons and radiologists strongly believed that vertebroplasty for 
osteoporotic vertebral fractures was very effective, but two sham-controlled trials found that it 
was not more effective than placebo (30, 31).  

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The current study aims to evaluate the effectiveness of surgical and nonsurgical treatment in two 
separate trials on patients with disc herniation and spondylosis, respectively. The trials will be 
merged to evaluate cost-effectiveness, prognostic factors, radiology, and expected outcome. The 
studies are likely to contribute to better evidence for the treatment of cervical radiculopathy. 
 
Aims  
The primary aim of this study is to compare the effectiveness of surgical and nonsurgical 
treatment in patients with cervical radiculopathy through two separate trials, one including disc 
herniation and the other including spondylosis (Figure 1). Secondary aims are to evaluate the 
cost-effectiveness and factors that predict the success of the two treatments, along with exploring 
the success rate and expectations of patients by asking them to fill in their expected primary 
outcome score at the baseline. 
 
Specific aims 
1. To test the hypothesis that the effectiveness of surgery measured by the mean 
difference in Neck Disability Index (NDI) and arm pain – adjusted for the baseline at a 1-
year follow-up – in patients with cervical radiculopathy does not differ from nonsurgical 
treatment in: 
 
a) Study 1: one-level disc herniation (C5/6 or C6/7) 
 
b) Study 2: one- or two-level spondylosis (C5/6 and/or C6/7) 
 
2. To test the hypothesis that surgery is more effective in patients with more clinical 
findings (dermatomal sensory loss, myotonal weakness, and reflex disturbance) at the 
baseline. 

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3. To estimate the cost-effectiveness for healthcare costs and societal costs (including 
sickness absence) in surgical versus nonsurgical patients. 
 
4. To assess radiological (MRI and CT) measurements of the foraminal area and nerve 
compression, and whether morphological changes at the 1-year mark can predict clinical 
changes (NDI and arm pain). 
 
5. To evaluate treatment-outcome expectations by asking patients to fill in their expected 
improvements at the baseline, and to compare these with previously published MCIC 
values and outcomes at the 1-year mark. 
 
Methods  
Design 
This study is designed as two randomised controlled trials comparing cervical decompression and 
non-operative treatment with cost-effectiveness analysis and the assessment of expectations and 
predictors of outcomes. The main research question will be evaluated through a one-year follow-
up. The trial is registered with the Norwegian ethics committee, REK 2017/2125, and in Clinical 
Trials – as NCT03674619 – on September 17, 2018. The trial follows the recommendations put 
forth by SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) (32). 
 
 
 

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Patients 
All patients referred to Oslo University Hospital for treatment of cervical radiculopathy – from 
levels C5/C6 and C6/C7 – will be screened for inclusion in the study. The patients are primarily 
referred by their general practitioners, private clinics, or neurology departments at other hospitals 
in the Health Region South-Eastern Norway, covering a population of about 2.9 million 
inhabitants. 
  
Inclusion criteria 
This definition of cervical radiculopathy is according to a previously described minimum criteria 
set (5). The inclusion criteria are listed in Table 1.  
 
Table 1 Inclusion criteria  
 
Aged 20 to 65 years. 
 
Study 1: Neck and arm pain for at least 3 months, and a corresponding herniation involving one cervical nerve root (C6 or 
C7)   
Study 2: Neck and arm pain for at least 3 months, with corresponding spondylosis involving C6 and/or C7 
 
Arm pain intensity of at least 4 on a scale from 0 (no pain) to 10 (worst possible pain)  
 
Willing to accept either of the treatment alternatives 
 
Neck Disability Index (NDI ) > 30% 
  
The patients will be informed about the study in detail, both through a standardised written text 
and orally. They will be informed about what is already known, including the natural course and 
the effectiveness of the two interventions.  
 
 

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Exclusion criteria  
Patients with any previous cervical fractures or cervical spine surgery; signs of myelopathy; 
rapidly progressive paresis or paresis < grade 4; pregnancy; arthritis involving the cervical spine; 
infection or active cancer; generalised pain syndrome; serious psychiatric or somatic disease that 
excludes one of the treatment alternatives; concomitant shoulder disorders that may interfere with 
the outcome; abuse of medication/narcotics; inability to understand written Norwegian; and 
unwillingness to accept one of the treatment alternatives. 
 
Randomisation 
The patients will be randomized using Viedoc electronic randomisation. This is an independent 
institution that uses permuted blocks that are unknown to the patient coordinator, which will 
randomise patients in study A and B. The randomisation process is unknown to the patient 
coordinator, who is not involved in treatment and evaluation. The coordinator will accordingly 
make treatment appointments. 
 
Blinding 
The outcome assessor and the statistician will be blinded to treatment allocation. The data will be 
extracted in an unidentifiable manner and will not contain any information that can reveal what 
treatment a single subject or a group were randomised to. 
 
Interventions 
All the interventions will commence within 2–3 weeks after randomisation.  
 
 

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Decompression surgery 
A recent systematic review that included 39 randomised controlled trials concluded that the 
surgeon, patient, and healthcare provider can choose any surgical technique based on experience, 
preference, and cost (33). In the present study, we plan to use anterior discectomy, which is the 
most commonly used procedure at the neurosurgical department of Oslo University Hospital. 
This strategy is supported by a recent randomised controlled trial at our hospital that found no 
clinical benefits of disc prosthesis (22). All operations will be carried out by experienced and 
qualified neurosurgeons.  
 
Anterior discectomy will be performed, and a microscope will be used. After separation of the 
platysma muscle, the pre-vertebral space is reached by an approach medial to the sternocleido-
mastoid muscle and carotid artery, and lateral to the trachea and oesophagus. Subsequently, the 
disc is incised and the corpora are distracted to perform discectomy. Usually, the posterior 
ligament is cut, the spinal root is decompressed, and – if necessary – the arthritic rims are 
removed. An inter-vertebral fusion device then is inserted. Two levels are allowed in the 
spondylosis study. 
 
Nonsurgical intervention 
Patients will first meet an experienced specialist in physical medicine and rehabilitation, who will 
answer their concerns and questions, and repeat the information given before inclusion, if 
necessary. The aim of this brief intervention is to promote a better understanding and coping with 
the condition. The intervention will further include supervision by a physiotherapist (six sessions 
altogether), who will provide advice on how to handle secondary neck muscle pain and 
dysfunction, reduce eventual fear behaviour, and provide advice to stay active.  

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Crossover 
Study subjects randomised to nonsurgical intervention will have the option of crossing over to 
surgery. They will simply have to express their wish to cross over to the treating physician or 
physiotherapist. The expected reasons for cross overs are a rapid decline in the neurological 
status or unbearable pain in the arm. The surgeon will then conduct a new assessment and, after a 
short observation period, these patients will be offered the option of surgery.  
 
Outcome measurements 
Baseline data will be obtained before randomisation and 12, 26, and 52 weeks after 
randomisation.  
The primary outcomes are:  
 The Neck Disability Index, which consists of ten questions about pain-related disability, 
including items such as headaches, concentration problems, reading issues and sleep 
disturbances. Each item is rated by choosing one of five response categories, and then 
transformed into a total score ranging from 0 to 100 (worst possible). The Norwegian 
version has been validated in patients with neck pain and with cervical radiculopathy (34, 
35). 
 Arm pain, measured by a Numeric Rating Scale (NRS) from 0 (no pain) to 10 (worst 
imaginable pain) (36).  
 Follow-up at 52 weeks is the primary endpoint. 
 
 
 

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The secondary outcomes are:  
 Neck pain, measured by a Numeric Rating Scale (NRS) from 0 (no pain) to 10 (worst 
imaginable pain). 
 Perceived recovery or change of the main symptoms, rated on a numeric scale ranging 
from   -9 (worst possible change) to 9 (best possible change) (37). 
 EuroQol (EQ-5D and EQ-VAS). EQ-5D includes five facets: mobility, self-care, daily 
activities, pain/discomfort, and anxiety/depression, and each has three response 
categories. The responses are transformed into and indexed to value the patients’ health-
related quality of life for a cost–utility analysis. Patients score their health from 0 (as bad 
as possible) to 100 (best possible) by EQ-VAS. The Norwegian version has been 
validated in patients with back pain, idiopathic scoliosis, and cervical radiculopathy (35, 
38, 39). 
 Fear-avoidance beliefs, evaluated using the Fear Avoidance Beliefs Questionnaire 
(FABQ) (40-43). 
 Emotional distress will be assessed by the 10-question version of the Hopkins Symptom 
Check List (HSCL-10) (44, 45). 
 Medicine consumption the week before inclusion and the week before each follow-up will 
be registered. 
 Sickness absence data will be collected from the National Social Security Institution for 
the year before and after inclusion.  
 Dysphagia (46). 
 Frequency of complications (dural tears, and disturbances of the larynx recurrent nerve, 
index-level nerve, oesophagus, trachea, or large vessel). 

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 Frequency of reoperation after surgery and frequency of operations in patients allocated to 
nonsurgical treatment.  
 Other treatments. We will register concomitant care and interventions. There are no 
restrictions related to concomitant care. 
 Exploring global success rates by asking the patients about how their arm and neck pain 
are compared to prior to treatment (ranging from much worse to much better). 
 Patient expectations. Exploring patient expectations ahead of treatment. The patients are 
asked to fill out the Neck Disability Index – as if they were at 52 weeks post-treatment – 
and selecting the lowest category they would be content with for each item. The patients 
are also asked to report what they expect their symptoms to be like in 52 weeks (ranging 
from much worse to much better), registered for arm pain, neck pain, and headaches 
separately. 
 
Outcomes of the predictor and cost–utility analyses are briefly outlined in Table 2 and 3, 
respectively.  
Outcomes of the radiology study and the expected-outcome study are briefly outlined in Table 4. 
The timing of the outcome measurements is outlined in Table 5.  
 
 
 
 
 
 

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Table 2 Predictors study 
Neurological (sensory abnormality and weakness) (5) 
MRI findings (disc herniation, spondylosis, and number of levels involved) 
Sickness absence (9) 
Patient expectations (47) 
Emotional distress 
Fear-avoidance beliefs 
Age  
Gender 
Smoking 
Severity of primary outcome at the baseline 
Primary outcome 
Change in the primary outcome of the trial 
Number of patients recovered (mean pain scores 0, 1, and 2) or reached the expected outcome at 52 weeks 
Number of patients working full time at the 1-year mark (adjusted for absence at the baseline) 
 
 
 
 
 
 
 
 
 
 

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Table 3 Cost–utility study  
Direct costs1, 
 
Surgery 
- 
Direct surgical costs 
- 
Implants 
- 
Hospital stay, including eventual complications and emergencies 
 
Nonsurgical treatment 
- 
Consultation 
- 
Physiotherapy      
 
Both groups 
- 
Medication 
- 
Consultations 
- 
Imaging 
Indirect costs 
Sickness absence (9) 
Utility 
EQ-5D 
1A sensitivity analysis of costs will estimate direct costs using prices at private clinics in Norway. 
 
 
 
 
 
 
 
 

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Table 4 Radiology and expected-outcome study  
Radiology  
CT at the baseline and at 1-year follow-up for assessment of foraminal area 
MRI at the baseline and 1-year follow-up for assessment of nerve-root compression and dislocation 
 
Expected outcome 
Expected NDI, NRS for neck and arm pain for willingness to undergo surgery.  
Expected NDI, NRS for neck and arm pain for willingness to undergo nonsurgical treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 5 Outcome measurements 
Outcome 
When they will be evaluated 
 
Baseline 
12 weeks 
26 weeks 
52 weeks 
Primary: 
 
NDI 
x 
x 
x 
x 
Arm pain (NRS) 
x 
x 
x 
x 
Secondary: 
 
Neck pain (NRS) 
x 
x 
x 
x 
Patient 
expectations 
x 
 
 
 
Perceived 
recovery 
 
x 
x 
x 
Success rate 
 
x 
x 
x 
EuroQol (EQ-5D 
and EQ-VAS) 
x 
x 
x 
x 
FABQ 
x 
x 
x 
x 
HSCL-10 
x 
x 
x 
x 
Medicine 
consumption 
x 
x 
x 
x 
Sickness absence 
x 
x 
x 
x 
Dysphagia 
x 
x 
x 
x 
Frequency of 
surgical 
complications 
 
x 
x 
x 
Frequency of 
reoperations 
 
x 
x 
x 
Cross overs in the 
nonsurgical group 
 
x 
x 
x 
Patient 
demographics 
x 
 
 
 
Neurological 
status, incl. grip 
strength 
x 
x 
x 
x 
 
 
 

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Sample size 
 
Including 36 patients in each treatment group is estimated to have 80% power for detecting a 
clinically significant difference (p<0.05) in NDI at a 1-year follow-up of 12, assuming a standard 
deviation of 18. Assuming a 10% drop-out and 20% cross-over rate, we plan to include 50 
patients in each group in each trial, giving a total of 200 patients for evaluation of predictors.   
 
Data analysis 
The principle of ‘intention to treat’ will be applied for the primary analyses comparing outcomes 
between groups. We are also planning to perform an analysis based on the ‘as treated’ principle. 
Multiple imputations will be used for the primary outcome if missing data exceeds 10%. 
ANCOVA or multiple-regression analysis will be used to compare outcomes among the different 
groups at the 1-year mark, adjusting for respective outcome variables at the baseline. In addition, 
we will use mixed models to investigate changes over time. Categorical variables will be assessed 
with Pearson’s chi-square test or logistic regression. Results will be presented as mean 
differences or as odds ratios for categorical data, both with 95% confidence intervals (95% CI). 
Sensitivity analyses, including those with treatments performed according to the protocol, will be 
added. A non-parametric bootstrapping technique will be used for health economic analyses. 
Kappa and limits of agreement will be estimated, and logistic and linear regression will be 
applied to analyse radiology. Predictors will be analysed using multiple-linear and logistic 
regression. The expected primary outcomes will be calculated for each patient; mean values (95% 
CI) will be estimated.   
 
 
 

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Implementation and study group 
The project will involve all the departments (neurosurgery, neurology, and physical medicine and 
rehabilitation) treating patients with cervical radiculopathy at Oslo University Hospital (OUS). 
Because the population covered by OUS is about 2.9 million, we have decided to conduct the 
study at OUS and not involve other neurosurgical institutions in Norway. All referrals will be 
coordinated from the respective units, and possible candidates for inclusion will be evaluated by a 
specialist in physical medicine and rehabilitation (doctoral candidate), along with an experienced 
neurosurgeon (doctoral candidate or equivalent). Only patients with cervical radiculopathy will 
be included in the study. Neck pain itself, even accompanied by radiological findings, is not an 
indication for surgery. A research nurse will handle patients found to be eligible after oral and 
written consent is obtained. The study group consists of experienced researchers who have 
expertise in conducting large, high-quality, randomised controlled trials. Surgeries will be 
performed by an experienced neurosurgeon and non-operative treatment by an experienced 
specialist in physical medicine and rehabilitation. The head of physiotherapy, along with 
physiotherapists who are currently conducting non-operative treatments of these patients at the 
physical medicine and rehabilitation department, have been engaged in the planning and running 
of the non-operative treatment. Two study secretaries at the neurosurgical department have 
coordinated another RCT at the department with great success, which is of importance for the 
quality of the current project.  
 
Patients included in the planned trial are all surgical candidates with high expectations for 
surgery. The physicians recruiting the patients must be trained to inform the patients about the 
lack of evidence of surgery, and that the trial is being conducted to ascertain the best choice in the 
future. This is important when recruiting patients, to reduce bias in favour of surgery.  

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Client participation 
When designing this trial, we discussed several issues with the former leader of the Norwegian 
Patient Organisation for Spinal Pain. They are fully informed about the project. They will be 
involved in further interpretation and implementation of the study, preferably in collaboration 
with other patients who have undergone neck surgery. 
 
Data collection 
The designated investigator staff will enter the data required by the protocol into eCase report 
forms (eCRF). The investigator is responsible for assuring that data entered into the eCRF is 
complete and accurate, and that entries are made in a timely manner. The Clinical Data 
Management System (CDMS) used for eCRF in this study is ViedocTM. The setup of the study-
specific eCRF in the CDMS will be performed by the Clinical Trial Unit, Research Support 
Services, Oslo University Hospital. After database locking, the investigator will receive a digital 
copy of the subject data for archiving at the investigation site. 
 
Database management 
Data management will be performed by the Clinical Trial Unit, Research Support Services, Oslo 
University Hospital. The data-management procedures will be performed in accordance with the 
department’s Standard Operating Procedures (SOPs) and International Council for 
Harmonisation (ICH) guidelines. The data-management process will be described in the study-
specific data handling plan and the study-specific data handling report after database closure. 
After database closure, the data will be stored in a dedicated and secured area at OUS. Data will 
be stored with all identifiers removed, where each study participant can only be recognised by 
his/her unique trial subject number.  

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Ethics and dissemination 
We have been granted approval by The Committee of Medical Ethics in Health Region South-
Eastern Norway and from The Research Board at Oslo University Hospital, Norway. Standard 
informed written consent will be obtained from each participant. The trial is formally registered 
at the National Register, and Clinical Trials and will be reported according to the CONSORT 
(Consolidated Standards of Reporting Trials) statement (48). The findings will be published in 
international journals and presented at national and international conferences. The version 
number of the current protocol is V.2.0 (07.03.2019). The project is sponsored by the Southern 
and Eastern Norway Regional Health Authority. The sponsor had no role in designing this trial. A 
steering committee is responsible for the design and any subsequent amendments to the study 
protocol. A Data Monitoring Committee (DMC), independent from the sponsors of the study, has 
full insight into preliminary data. The DMC has the power to terminate the trial in case the 
interim results suggest a need for this. 
 
Discussion 
Published protocols include a Dutch trial comparing the effectiveness of surgical treatment and a 
wait-and-see approach including information about the nature and prognosis of the problem along 
with trustworthy counselling in patients with cervical radiculopathy caused by disc herniation 
(16). In addition, a Swedish trial compares the effectiveness of a comprehensive neck-specific 
training regimen combined with an additional cognitive behavioural approach to prescribed 
physical activity (49). The results from the trials, including the current protocol, are likely to 
improve our understanding of the treatment and prognosis of patients with cervical radiculopathy. 
The prognostic part of the present study will preferably be able to detect certain patient 

27 
 
characteristics that may aid in improving indications. Finally, the cost–utility analysis is 
important to estimate the healthcare and societal costs, which may help to better distribute 
healthcare resources between surgical and nonsurgical treatment.  
 
List of abbreviations 
MRI: Magnetic resonance imaging, IL: Interleukin, RCT: Randomised controlled trial, SR: 
Systematic review, MCIC: Minimal clinical important change, CT: Computed tomography, NDI: 
Neck Disability Index, REK: Norwegian ethics committee, SPIRIT: Standard Protocol Items 
Recommendations for Interventional Trials, NRS: Numeric Rating Scale, EuroQol (EQ-5D and 
EQ-VAS): Health-related quality of life instrument, FABQ: Fear Avoidance Beliefs 
Questionnaire, HSCL-10: Hopkins Symptom Check List, ANCOVA: Analysis of covariance, 
OUS: Oslo University Hospital, eCRF: eCase report form,  
CDMS: Clinical Data Management System, SOPs: Standard Operating Procedures, ICH: 
International Council for Harmonisation, CONSORT: Consolidated Standards of Reporting 
Trials, 
DMC: Data Monitoring Committee. 
 
 
Declarations 
 
Ethics approval and consent to participate 
Ethics approval has been granted by The Committee of Medical Ethics in Health Region South-
Eastern Norway (REC South East, reference number 2017/2125) and by The Research Board at 
Oslo University Hospital, Norway. Standard informed written consent will be obtained from each 

28 
 
participating patient. Participation in the study is completely voluntary. Participants can choose to 
withdraw from the study at any stage without further explanation. 
 
Consent for publication 
Not applicable 
 
Availability of data and material 
Not applicable 
 
Competing interests 
The authors declare that they have no competing interests. 
 
Funding 
The authors are grateful to the Southern and Eastern Norway Regional Health Authority for 
funding this study. The sponsor had no role in designing this trial, writing the manuscript, or in 
the collection, analysis, and interpretation of data. 
 
Authors' contributions 
JIB had the original idea for this study and secured funding. MT did most of the writing of the 
current manuscript. JHS and MT are recruiting patients for the study. JHS, JS, FK, SB, and JIB 
are treating the patients in this study. AHP conducted the power analysis and wrote the proposed 
statistical approach. JAZ contributed with scientific and clinical expertise. All authors were 
involved in the study design and protocol development. All authors read and approved the final 
manuscript. 

29 
 
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33 
 
Study protocol v. 2.0, 03.12.2024  
 
 
 
 
 
A randomised controlled trial comparing the effectiveness of surgical and 
nonsurgical treatment for cervical radiculopathy 
 
Mirad Taso1,2,3*, Jon Håvard Sommernes2, Frode Kolstad2, Jarle Sundseth2, Siri Bjorland1, Are 
Hugo Pripp4, John Anker Zwart3,5, Jens Ivar Brox1,3 
 
1Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Ullevål, Oslo, 
Norway 
2Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway 
3Faculty of Medicine, University of Oslo, Oslo, Norway 
4Oslo Centre of Biostatistics and Epidemiology, Research Support Services, Oslo University 
Hospital, Oslo, Norway 
5Research and Communication Unit for Musculoskeletal Health, Division of Clinical 
Neuroscience, Oslo University Hospital, Oslo, Norway 
*Corresponding author: 
Mirad Taso 
Department of Physical Medicine and Rehabilitation, Oslo University Hospital HF, Ullevål, 
Postboks 4956, Nydalen, 0424, Oslo, Norway,  
E-mail: mirtas@ous-hf.no, Telephone: +47 93838735 
 
 

34 
 
E-mail addresses of other authors: 
Jon Håvard Sommernes, haasom@ous-hf.no 
Frode Kolstad, fkolstad@ous-hf.no 
Jarle Sundseth, jsundset@ous-hf.no  
Siri Bjorland, sibjorl@online.no  
Are Hugo Pripp, apripp@ous-hf.no 
John Anker Zwart, UXZWJO@ous-hf.no 
Jens Ivar Brox, jbrox@ous-hf.no 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

35 
 
Abstract 
Background: Cervical radiculopathy is usually caused by disc herniation or spondylosis. The 
prognosis is expected to be good in most patients, but there is limited scientific evidence on the 
indications for nonsurgical and surgical treatments. The aim of the present study is to evaluate 
and compare the effectiveness of surgical and nonsurgical treatment in two trials – including disc 
herniation and spondylosis, respectively, and to evaluate factors that contribute to better decision 
making. 
Methods/Design: Patients with disabling radicular arm pain and MRI-proven cervical disc 
herniation or spondylosis will be randomised to receive nonsurgical or surgical treatment. The 
follow-up period is one year and the sample size is estimated to be 50 for each arm in the two 
trials, giving a total of 200 patients. The primary outcome is the Neck Disability Index. 
Secondary outcomes include arm pain, neck pain; EQ-5D and costs to evaluate cost-
effectiveness; prognostic factors; CT and MRI scans, to estimate intervertebral foraminal area 
and nerve root compression; and the expected minimal improvement for willingness to undergo 
treatment. 
Discussion: The outcomes of this study will contribute to better decision making in the treatment 
of cervical radiculopathy.  
Trial registration: This study has been registered at ClinicalTrials.gov as NCT03674619, on 
September 17, 2018 (https://clinicaltrials.gov/ct2/show/NCT03674619). 
Keywords: Cervical radiculopathy, Treatment, Surgery, Anterior cervical decompression and 
fusion, Nonsurgical, Physical medicine and rehabilitation, Effectiveness, Shared decision 
making, RCT.  
 

36 
 
 
Background 
Neck pain is among the leading causes of disability worldwide (1). The yearly prevalence is 48%, 
and 25% of women and 13% of men reported that they suffered from neck pain weekly in two 
Norwegian epidemiological surveys (2, 3). Classifying neck pain in those who consult healthcare 
providers is challenging. Interpreting images is difficult because of the high frequency of 
degeneration in asymptomatic populations (4). For example, in a systematic review, disc 
protrusion was reported in 29% of 20-year-old asymptomatic persons, and in 43% of 80-year-
olds, while facet joint degeneration was reported in 4% and 83%, respectively (4). 
 
In contrast, the yearly prevalence of cervical radiculopathy is relatively low. It was estimated to 
83/100 000, peaking in fourth and fifth decades, in a large epidemiological study applying wide 
criteria, including neck and arm pain, and corresponding MRI findings indicating that one or 
more nerve roots were affected (5). Cervical radiculopathy is caused by disc herniation, 
spondylosis, or a combination of herniation and spondylosis. In 80% of patients, the C6 or C7 
roots are affected (5). Cervical spondylosis refers to degenerative changes that occur in the 
cervical spine with age, most often manifesting as decreased disc height and hypertrophy of the 
intervertebral joint. Symptoms usually develop more gradually than the sudden, intense arm pain 
reported by patients with disc herniation.  
Cervical disc herniation and spondylosis may trigger local ischemia and inflammation, mediated 
by biochemical and immunological factors that contribute to the pathophysiology of 
radiculopathy (6). High levels of IL-6 were found to be a predictor of slow recovery in patients 
with lumbar radicular pain (7).  

37 
 
The natural course of cervical radiculopathy is difficult to outline. Recent studies have described 
a favourable course at an average of 6 months, with complete recovery ranging from 24 to 36 
months (8, 9). There is limited evidence on prognostic factors; however, durations greater than 6 
months, higher pain scores, radicular signs, psychosocial factors, sickness absences, and surgery-
related factors are reported to be associated with poorer outcomes (9, 10). Most patients with 
cervical radiculopathy are treated nonsurgically. The effectiveness of different nonsurgical 
treatments in comparison to placebo or the natural course is not known. A recent randomised 
controlled trial (RCT) compared cervical collar, physiotherapy, and a wait-and-see policy in 
patients with cervical radiculopathy lasting 3 weeks or more (11). With any of the three 
interventions, mean arm pain intensity decreased from about 70% of the worst possible pain at 
baseline to about 20% of the worst possible pain at 6 months follow-up (11). Improvement in 
condition at 6 and 12 weeks was significantly better in those who received physiotherapy or a 
collar. In the aforementioned epidemiological study, 561 patients were studied for 5 years, and 
90% were asymptomatic or only mildly incapacitated owing to cervical radiculopathy. Twenty-
six per cent of the patients underwent surgery. The strongest predictor of surgery was a 
combination of radicular pain, sensory loss, and muscle weakness, yielding a hazard ratio of 17.3 
in a multivariable model. 
The most common surgical treatment is discectomy and fusion (12). Anterior cervical discectomy 
is one of the most frequently performed spinal procedures; in the United States, almost 550 000 
patients were operated on between 2005 and 2008 (13). The surgical rates for cervical 
radiculopathy are lower in Norway compared to the United States, but increased by 86.5 % from 
2008 to 2014, and was 2.5 times higher in counties with the highest rates compared to those with 
the lowest rates (14). Neither the observed increase over time nor geographical differences are 
likely to be explained by variations in the prevalence of cervical radiculopathy. A recent review 

38 
 
stated that previous studies have led most investigators to conclude that cervical radiculopathy is 
a self-limiting phenomenon in most cases (15). This directly contradicts the increasing surgery 
rates. 
 
The success rates of surgical interventions are reported to range between 80 and 95% (16); 
however, two systematic reviews (SRs) have found no clear benefits of surgery over nonsurgical 
treatments (17, 18). One of the SRs included two small RCTs (19-21), the other included six 
additional controlled clinical trials. The evidence that can be drawn from these systematic 
reviews is considered to be limited. Results suggest that selection criteria, observer bias, the 
natural course and placebo mechanisms play an important role in the reported high success rates 
after surgery. Further, the disc prosthesis (cervical arthroplasty) has been proposed to improve 
results. A recently published Norwegian multicentre trial did not favour discectomy and disc 
prosthesis compared with the traditional discectomy and fusion (22). The trial included patients 
with one-level radiculopathy (C6 or C7) primarily caused by spondylosis. The success rate was 
75%, estimated by the number of patients reaching the minimal clinical important change 
(MCIC). However, reported values of the minimal important clinical change of the Neck 
Disability Index (NDI) differ largely (23). A systematic review reported that MCIC varied from 
10 to 38, on a scale from 0 to 100 (24). An MCIC of 10 is most commonly used in trials 
comparing various surgical procedures for cervical radiculopathy (22). The global perceived 
change is often used as an external criterion for estimating MCIC; however, the improvement 
expected by the patient in order to undergo surgery or non-operative treatments has not been 
examined, to the best of our knowledge.  
 

39 
 
There is limited knowledge on the indications for surgery in patients with pain syndromes in 
general, and particularly in patients with cervical radiculopathy caused by disc herniation. It is 
believed that the prognosis of non-operative treatment is better in patients with disc herniation 
than in patients with spondylosis, but there is a lack of clinical trials to corroborate this. One 
reason for this is that a strict classification based on MRI-findings has been difficult to obtain. 
Surgery is conducted to decompress the nerve root, but the correlation between the intervertebral 
foraminal area, root compression, and symptoms has been poorly investigated, and findings are 
questionable because neither the measurement error nor the inter-rater agreement of findings has 
been reported. Albert et al. found no postoperative correlation between surgical graft height and 
symptom relief (25). The intervertebral foraminal area of different segments of the cervical spine 
correlates with disc height and disc degeneration – measured using CT or MRI scans (26) – and is 
increased by cervical flexion (27). More studies have been performed on the lumbar spine. A 
recent study found moderate inter-rater reliability for evaluation of postoperative nerve-root 
thickening and compression, and that postoperative compression or dislocation observed in 
patients operated for disc herniation was not correlated significantly to the outcome (28). 
Therefore, assessing the association of the neuroforaminal area and nerve root compression in the 
cervical spine, including a methodological evaluation, is warranted.  
Further research may improve our understanding and reverse or limit current practice. Forty-two 
per cent of practices believed to be effective, were reversed according to a systematic review 
evaluating trials published in a high impact journal over a 10-year period (29). For example, a 
few years ago, spinal surgeons and radiologists strongly believed that vertebroplasty for 
osteoporotic vertebral fractures was very effective, but two sham-controlled trials found that it 
was not more effective than placebo (30, 31).  

40 
 
The current study aims to evaluate the effectiveness of surgical and nonsurgical treatment in two 
separate trials on patients with disc herniation and spondylosis, respectively. The trials will be 
merged to evaluate cost-effectiveness, prognostic factors, radiology, and expected outcome. The 
studies are likely to contribute to better evidence for the treatment of cervical radiculopathy. 
 
Aims  
The primary aim of this study is to compare the effectiveness of surgical and nonsurgical 
treatment in patients with cervical radiculopathy through two separate trials, one including disc 
herniation and the other including spondylosis (Figure 1). Secondary aims are to evaluate the 
cost-effectiveness and factors that predict the success of the two treatments, along with exploring 
the success rate and expectations of patients by asking them to fill in their expected primary 
outcome score at the baseline. 
 
Specific aims 
1. To test the hypothesis that the effectiveness of surgery measured by the mean 
difference in Neck Disability Index (NDI) – adjusted for the baseline at a 1-year follow-
up – in patients with cervical radiculopathy does not differ from nonsurgical treatment in: 
 
a) Study 1: one-level disc herniation (C5/6 or C6/7) 
 
b) Study 2: one- or two-level spondylosis (C5/6 and/or C6/7) 
 
2. To test the hypothesis that surgery is more effective in patients with more clinical 
findings (dermatomal sensory loss, myotonal weakness, and reflex disturbance) at the 
baseline. 
 

41 
 
3. To estimate the cost-effectiveness for healthcare costs and societal costs (including 
sickness absence) in surgical versus nonsurgical patients. 
 
4. To assess radiological (MRI and CT) measurements of the foraminal area and nerve 
compression, and whether morphological changes at the 1-year mark can predict clinical 
changes (NDI and arm pain). 
 
5. To evaluate treatment-outcome expectations by asking patients to fill in their expected 
improvements at the baseline, and to compare these with previously published MCIC 
values and outcomes at the 1-year mark. 
 
Methods  
Design 
This study is designed as two randomised controlled trials comparing cervical decompression and 
non-operative treatment with cost-effectiveness analysis and the assessment of expectations and 
predictors of outcomes. The main research question will be evaluated through a one-year follow-
up. The trial is registered with the Norwegian ethics committee, REK 2017/2125, and in Clinical 
Trials – as NCT03674619 – on September 17, 2018. The trial follows the recommendations put 
forth by SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) (32). 
 
 
 
Patients 

42 
 
All patients referred to Oslo University Hospital for treatment of cervical radiculopathy – from 
levels C5/C6 and C6/C7 – will be screened for inclusion in the study. The patients are primarily 
referred by their general practitioners, private clinics, or neurology departments at other hospitals 
in the Health Region South-Eastern Norway, covering a population of about 2.9 million 
inhabitants. 
  
Inclusion criteria 
This definition of cervical radiculopathy is according to a previously described minimum criteria 
set (5). The inclusion criteria are listed in Table 1.  
 
Table 1 Inclusion criteria  
 
Aged 20 to 65 years. 
 
Study 1: Neck and arm pain for at least 3 months, and a corresponding herniation involving one cervical nerve root (C6 or 
C7)   
Study 2: Neck and arm pain for at least 3 months, with corresponding spondylosis involving C6 and/or C7 
 
Arm pain intensity of at least 4 on a scale from 0 (no pain) to 10 (worst possible pain)  
 
Willing to accept either of the treatment alternatives 
 
Neck Disability Index (NDI ) > 30% 
  
The patients will be informed about the study in detail, both through a standardised written text 
and orally. They will be informed about what is already known, including the natural course and 
the effectiveness of the two interventions.  
 
 
Exclusion criteria  

43 
 
Patients with any previous cervical fractures or cervical spine surgery; signs of myelopathy; 
rapidly progressive paresis or paresis < grade 4; pregnancy; arthritis involving the cervical spine; 
infection or active cancer; generalised pain syndrome; serious psychiatric or somatic disease that 
excludes one of the treatment alternatives; concomitant shoulder disorders that may interfere with 
the outcome; abuse of medication/narcotics; inability to understand written Norwegian; and 
unwillingness to accept one of the treatment alternatives. 
 
Randomisation 
The patients will be randomized using Viedoc electronic randomisation. This is an independent 
institution that uses permuted blocks that are unknown to the patient coordinator, which will 
randomise patients in study A and B. The randomisation process is unknown to the patient 
coordinator, who is not involved in treatment and evaluation. The coordinator will accordingly 
make treatment appointments. 
 
Blinding 
The outcome assessor and the statistician will be blinded to treatment allocation. The data will be 
extracted in an unidentifiable manner and will not contain any information that can reveal what 
treatment a single subject or a group were randomised to. 
 
Interventions 
All the interventions will commence within 2–3 weeks after randomisation.  
 
 
Decompression surgery 

44 
 
A recent systematic review that included 39 randomised controlled trials concluded that the 
surgeon, patient, and healthcare provider can choose any surgical technique based on experience, 
preference, and cost (33). In the present study, we plan to use anterior discectomy, which is the 
most commonly used procedure at the neurosurgical department of Oslo University Hospital. 
This strategy is supported by a recent randomised controlled trial at our hospital that found no 
clinical benefits of disc prosthesis (22). All operations will be carried out by experienced and 
qualified neurosurgeons.  
 
Anterior discectomy will be performed, and a microscope will be used. After separation of the 
platysma muscle, the pre-vertebral space is reached by an approach medial to the sternocleido-
mastoid muscle and carotid artery, and lateral to the trachea and oesophagus. Subsequently, the 
disc is incised and the corpora are distracted to perform discectomy. Usually, the posterior 
ligament is cut, the spinal root is decompressed, and – if necessary – the arthritic rims are 
removed. An inter-vertebral fusion device then is inserted. Two levels are allowed in the 
spondylosis study. 
 
Nonsurgical intervention 
Patients will first meet an experienced specialist in physical medicine and rehabilitation, who will 
answer their concerns and questions, and repeat the information given before inclusion, if 
necessary. The aim of this brief intervention is to promote a better understanding and coping with 
the condition. The intervention will further include supervision by a physiotherapist (six sessions 
altogether), who will provide advice on how to handle secondary neck muscle pain and 
dysfunction, reduce eventual fear behaviour, and provide advice to stay active.  
Crossover 

45 
 
Study subjects randomised to nonsurgical intervention will have the option of crossing over to 
surgery. They will simply have to express their wish to cross over to the treating physician or 
physiotherapist. The expected reasons for cross overs are a rapid decline in the neurological 
status or unbearable pain in the arm. The surgeon will then conduct a new assessment and, after a 
short observation period, these patients will be offered the option of surgery.  
 
Outcome measurements 
Baseline data will be obtained before randomisation and 12, 26, and 52 weeks after 
randomisation.  
The primary outcomes are:  
 The Neck Disability Index, which consists of ten questions about pain-related disability, 
including items such as headaches, concentration problems, reading issues and sleep 
disturbances. Each item is rated by choosing one of five response categories, and then 
transformed into a total score ranging from 0 to 100 (worst possible). The Norwegian 
version has been validated in patients with neck pain and with cervical radiculopathy (34, 
35). 
 Follow-up at 52 weeks is the primary endpoint. 
 
 
 
The secondary outcomes are:  
 Arm pain, measured by a Numeric Rating Scale (NRS) from 0 (no pain) to 10 (worst 
imaginable pain) (36).  

46 
 
 
 Neck pain, measured by a Numeric Rating Scale (NRS) from 0 (no pain) to 10 (worst 
imaginable pain). 
 Perceived recovery or change of the main symptoms, rated on a numeric scale ranging 
from   -9 (worst possible change) to 9 (best possible change) (37). 
 EuroQol (EQ-5D and EQ-VAS). EQ-5D includes five facets: mobility, self-care, daily 
activities, pain/discomfort, and anxiety/depression, and each has three response 
categories. The responses are transformed into and indexed to value the patients’ health-
related quality of life for a cost–utility analysis. Patients score their health from 0 (as bad 
as possible) to 100 (best possible) by EQ-VAS. The Norwegian version has been 
validated in patients with back pain, idiopathic scoliosis, and cervical radiculopathy (35, 
38, 39). 
 Fear-avoidance beliefs, evaluated using the Fear Avoidance Beliefs Questionnaire 
(FABQ) (40-43). 
 Emotional distress will be assessed by the 10-question version of the Hopkins Symptom 
Check List (HSCL-10) (44, 45). 
 Medicine consumption the week before inclusion and the week before each follow-up will 
be registered. 
 Sickness absence data will be collected from the National Social Security Institution for 
the year before and after inclusion.  
 Dysphagia (46). 
 Frequency of complications (dural tears, and disturbances of the larynx recurrent nerve, 
index-level nerve, oesophagus, trachea, or large vessel). 

47 
 
 Frequency of reoperation after surgery and frequency of operations in patients allocated to 
nonsurgical treatment.  
 Other treatments. We will register concomitant care and interventions. There are no 
restrictions related to concomitant care. 
 Exploring global success rates by asking the patients about how their arm and neck pain 
are compared to prior to treatment (ranging from much worse to much better). 
 Patient expectations. Exploring patient expectations ahead of treatment. The patients are 
asked to fill out the Neck Disability Index – as if they were at 52 weeks post-treatment – 
and selecting the lowest category they would be content with for each item. The patients 
are also asked to report what they expect their symptoms to be like in 52 weeks (ranging 
from much worse to much better), registered for arm pain, neck pain, and headaches 
separately. 
 
Outcomes of the predictor and cost–utility analyses are briefly outlined in Table 2 and 3, 
respectively.  
Outcomes of the radiology study and the expected-outcome study are briefly outlined in Table 4. 
The timing of the outcome measurements is outlined in Table 5.  
 
 
 
 
 
 

48 
 
Table 2 Predictors study 
Neurological (sensory abnormality and weakness) (5) 
MRI findings (disc herniation, spondylosis, and number of levels involved) 
Sickness absence (9) 
Patient expectations (47) 
Emotional distress 
Fear-avoidance beliefs 
Age  
Gender 
Smoking 
Severity of primary outcome at the baseline 
Primary outcome 
Change in the primary outcome of the trial 
Number of patients recovered (mean pain scores 0, 1, and 2) or reached the expected outcome at 52 weeks 
Number of patients working full time at the 1-year mark (adjusted for absence at the baseline) 
 
 
 
 
 
 
 
 
 
 

49 
 
Table 3 Cost–utility study  
Direct costs1, 
 
Surgery 
- 
Direct surgical costs 
- 
Implants 
- 
Hospital stay, including eventual complications and emergencies 
 
Nonsurgical treatment 
- 
Consultation 
- 
Physiotherapy      
 
Both groups 
- 
Medication 
- 
Consultations 
- 
Imaging 
Indirect costs 
Sickness absence (9) 
Utility 
EQ-5D 
1A sensitivity analysis of costs will estimate direct costs using prices at private clinics in Norway. 
 
 
 
 
 
 
 
 

50 
 
Table 4 Radiology and expected-outcome study  
Radiology  
CT at the baseline and at 1-year follow-up for assessment of foraminal area 
MRI at the baseline and 1-year follow-up for assessment of nerve-root compression and dislocation 
 
Expected outcome 
Expected NDI, NRS for neck and arm pain for willingness to undergo surgery.  
Expected NDI, NRS for neck and arm pain for willingness to undergo nonsurgical treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

51 
 
Table 5 Outcome measurements 
Outcome 
When they will be evaluated 
 
Baseline 
12 weeks 
26 weeks 
52 weeks 
Primary: 
 
NDI 
x 
x 
x 
x 
Secondary: 
 
Arm pain (NRS) 
x 
x 
x 
x 
Neck pain (NRS) 
x 
x 
x 
x 
Patient 
expectations 
x 
 
 
 
Perceived 
recovery 
 
x 
x 
x 
Success rate 
 
x 
x 
x 
EuroQol (EQ-5D 
and EQ-VAS) 
x 
x 
x 
x 
FABQ 
x 
x 
x 
x 
HSCL-10 
x 
x 
x 
x 
Medicine 
consumption 
x 
x 
x 
x 
Sickness absence 
x 
x 
x 
x 
Dysphagia 
x 
x 
x 
x 
Frequency of 
surgical 
complications 
 
x 
x 
x 
Frequency of 
reoperations 
 
x 
x 
x 
Cross overs in the 
nonsurgical group 
 
x 
x 
x 
Patient 
demographics 
x 
 
 
 
Neurological 
status, incl. grip 
strength 
x 
x 
x 
x 
 
 
 

52 
 
Sample size 
 
Including 36 patients in each treatment group is estimated to have 80% power for detecting a 
clinically significant difference (p<0.05) in NDI at a 1-year follow-up of 12, assuming a standard 
deviation of 18. Assuming a 10% drop-out and 20% cross-over rate, we plan to include 50 
patients in each group in each trial, giving a total of 200 patients for evaluation of predictors.   
 
Data analysis 
The principle of ‘intention to treat’ will be applied for the primary analyses comparing outcomes 
between groups. We are also planning to perform an analysis based on the ‘as treated’ principle. 
Multiple imputations will be used for the primary outcome if missing data exceeds 10%. 
ANCOVA or multiple-regression analysis will be used to compare outcomes among the different 
groups at the 1-year mark, adjusting for respective outcome variables at the baseline. In addition, 
we will use mixed models to investigate changes over time. Categorical variables will be assessed 
with Pearson’s chi-square test or logistic regression. Results will be presented as mean 
differences or as odds ratios for categorical data, both with 95% confidence intervals (95% CI). 
Sensitivity analyses, including those with treatments performed according to the protocol, will be 
added. A non-parametric bootstrapping technique will be used for health economic analyses. 
Kappa and limits of agreement will be estimated, and logistic and linear regression will be 
applied to analyse radiology. Predictors will be analysed using multiple-linear and logistic 
regression. The expected primary outcomes will be calculated for each patient; mean values (95% 
CI) will be estimated.   
 
 
 

53 
 
Implementation and study group 
The project will involve all the departments (neurosurgery, neurology, and physical medicine and 
rehabilitation) treating patients with cervical radiculopathy at Oslo University Hospital (OUS). 
Because the population covered by OUS is about 2.9 million, we have decided to conduct the 
study at OUS and not involve other neurosurgical institutions in Norway. All referrals will be 
coordinated from the respective units, and possible candidates for inclusion will be evaluated by a 
specialist in physical medicine and rehabilitation (doctoral candidate), along with an experienced 
neurosurgeon (doctoral candidate or equivalent). Only patients with cervical radiculopathy will 
be included in the study. Neck pain itself, even accompanied by radiological findings, is not an 
indication for surgery. A research nurse will handle patients found to be eligible after oral and 
written consent is obtained. The study group consists of experienced researchers who have 
expertise in conducting large, high-quality, randomised controlled trials. Surgeries will be 
performed by an experienced neurosurgeon and non-operative treatment by an experienced 
specialist in physical medicine and rehabilitation. The head of physiotherapy, along with 
physiotherapists who are currently conducting non-operative treatments of these patients at the 
physical medicine and rehabilitation department, have been engaged in the planning and running 
of the non-operative treatment. Two study secretaries at the neurosurgical department have 
coordinated another RCT at the department with great success, which is of importance for the 
quality of the current project.  
 
Patients included in the planned trial are all surgical candidates with high expectations for 
surgery. The physicians recruiting the patients must be trained to inform the patients about the 
lack of evidence of surgery, and that the trial is being conducted to ascertain the best choice in the 
future. This is important when recruiting patients, to reduce bias in favour of surgery.  

54 
 
Client participation 
When designing this trial, we discussed several issues with the former leader of the Norwegian 
Patient Organisation for Spinal Pain. They are fully informed about the project. They will be 
involved in further interpretation and implementation of the study, preferably in collaboration 
with other patients who have undergone neck surgery. 
 
Data collection 
The designated investigator staff will enter the data required by the protocol into eCase report 
forms (eCRF). The investigator is responsible for assuring that data entered into the eCRF is 
complete and accurate, and that entries are made in a timely manner. The Clinical Data 
Management System (CDMS) used for eCRF in this study is ViedocTM. The setup of the study-
specific eCRF in the CDMS will be performed by the Clinical Trial Unit, Research Support 
Services, Oslo University Hospital. After database locking, the investigator will receive a digital 
copy of the subject data for archiving at the investigation site. 
 
Database management 
Data management will be performed by the Clinical Trial Unit, Research Support Services, Oslo 
University Hospital. The data-management procedures will be performed in accordance with the 
department’s Standard Operating Procedures (SOPs) and International Council for 
Harmonisation (ICH) guidelines. The data-management process will be described in the study-
specific data handling plan and the study-specific data handling report after database closure. 
After database closure, the data will be stored in a dedicated and secured area at OUS. Data will 
be stored with all identifiers removed, where each study participant can only be recognised by 
his/her unique trial subject number.  

55 
 
Ethics and dissemination 
We have been granted approval by The Committee of Medical Ethics in Health Region South-
Eastern Norway and from The Research Board at Oslo University Hospital, Norway. Standard 
informed written consent will be obtained from each participant. The trial is formally registered 
at the National Register, and Clinical Trials and will be reported according to the CONSORT 
(Consolidated Standards of Reporting Trials) statement (48). The findings will be published in 
international journals and presented at national and international conferences. The version 
number of the current protocol is V.2.0 (07.03.2019). The project is sponsored by the Southern 
and Eastern Norway Regional Health Authority. The sponsor had no role in designing this trial. A 
steering committee is responsible for the design and any subsequent amendments to the study 
protocol. A Data Monitoring Committee (DMC), independent from the sponsors of the study, has 
full insight into preliminary data. The DMC has the power to terminate the trial in case the 
interim results suggest a need for this. 
 
Discussion 
Published protocols include a Dutch trial comparing the effectiveness of surgical treatment and a 
wait-and-see approach including information about the nature and prognosis of the problem along 
with trustworthy counselling in patients with cervical radiculopathy caused by disc herniation 
(16). In addition, a Swedish trial compares the effectiveness of a comprehensive neck-specific 
training regimen combined with an additional cognitive behavioural approach to prescribed 
physical activity (49). The results from the trials, including the current protocol, are likely to 
improve our understanding of the treatment and prognosis of patients with cervical radiculopathy. 
The prognostic part of the present study will preferably be able to detect certain patient 

56 
 
characteristics that may aid in improving indications. Finally, the cost–utility analysis is 
important to estimate the healthcare and societal costs, which may help to better distribute 
healthcare resources between surgical and nonsurgical treatment.  
 
List of abbreviations 
MRI: Magnetic resonance imaging, IL: Interleukin, RCT: Randomised controlled trial, SR: 
Systematic review, MCIC: Minimal clinical important change, CT: Computed tomography, NDI: 
Neck Disability Index, REK: Norwegian ethics committee, SPIRIT: Standard Protocol Items 
Recommendations for Interventional Trials, NRS: Numeric Rating Scale, EuroQol (EQ-5D and 
EQ-VAS): Health-related quality of life instrument, FABQ: Fear Avoidance Beliefs 
Questionnaire, HSCL-10: Hopkins Symptom Check List, ANCOVA: Analysis of covariance, 
OUS: Oslo University Hospital, eCRF: eCase report form,  
CDMS: Clinical Data Management System, SOPs: Standard Operating Procedures, ICH: 
International Council for Harmonisation, CONSORT: Consolidated Standards of Reporting 
Trials, 
DMC: Data Monitoring Committee. 
 
 
Declarations 
 
Ethics approval and consent to participate 
Ethics approval has been granted by The Committee of Medical Ethics in Health Region South-
Eastern Norway (REC South East, reference number 2017/2125) and by The Research Board at 
Oslo University Hospital, Norway. Standard informed written consent will be obtained from each 

57 
 
participating patient. Participation in the study is completely voluntary. Participants can choose to 
withdraw from the study at any stage without further explanation. 
 
Consent for publication 
Not applicable 
 
Availability of data and material 
Not applicable 
 
Competing interests 
The authors declare that they have no competing interests. 
 
Funding 
The authors are grateful to the Southern and Eastern Norway Regional Health Authority for 
funding this study. The sponsor had no role in designing this trial, writing the manuscript, or in 
the collection, analysis, and interpretation of data. 
 
Authors' contributions 
JIB had the original idea for this study and secured funding. MT did most of the writing of the 
current manuscript. JHS and MT are recruiting patients for the study. JHS, JS, FK, SB, and JIB 
are treating the patients in this study. AHP conducted the power analysis and wrote the proposed 
statistical approach. JAZ contributed with scientific and clinical expertise. All authors were 
involved in the study design and protocol development. All authors read and approved the final 
manuscript. 

58 
 
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62 
 
Summary of changes to the protocol 
 
The following changes are based on recommendations from the editors of NEJM Evidence. 
 
Specific aims: removed arm pain as primary outcome as we did not calculate power based on 
arm pain. Page 38. 
 
Outcome measurements: moved arm pain from primary outcomes to secondary outcomes as we 
did not calculate power based on arm pain. Page 43. 
 
Table 5 Outcome measurements: moved arm pain from primary outcomes to secondary 
outcomes as we did not calculate power based on arm pain. Page 49. 
 
 
 
 

63 
 

64 
 
Statistical analysis plan (SAP) 
Administrative information:   
Trial title  
A randomised controlled trial comparing the effectiveness of 
surgical and nonsurgical treatment for cervical radiculopathy 
Trial registration number  
NCT03674619 
REC no  
REK 2017/2125 
SAP version and date  
This is SAP version 1.0, dated 05.01.2024 
Protocol version  
This document has been written based on information 
contained in the study protocol (1).  
Authors  
Mirad Taso, MD PhD student. Department of Physical  
Medicine and Rehabilitation, Oslo University Hospital. 
Institute of Clinical Medicine, Faculty of Medicine, University 
of Oslo.  
 
Are Hugo Pripp, statistician, PhD. Oslo Centre of Biostatistics 
and Epidemiology, Research Support Services, Oslo University 
Hospital. 
 
Jon Håvard Sommernes, MD, PhD student. Department of 
Neurosurgery, Oslo University Hospital. Institute of Clinical 
Medicine, Faculty of Medicine, University of Oslo. 
 
Frode Kolstad, MD, PhD. Department of Neurosurgery, Oslo 
University Hospital.  
 
Jarle Sundseth, MD, PhD. Department of Neurosurgery, Oslo 
University Hospital. 
 
Siri Bjorland, MD PhD. Department of Physical  
Medicine and Rehabilitation, Oslo University Hospital. 
 
John Anker Zwart, MD PhD. Research and Communication 
Unit for Musculoskeletal Health, Division of Clinical 
Neuroscience, Oslo University Hospital, Oslo, Norway 
 
Jens Ivar Brox, MD, Professor. Department of Physical 
Medicine and Rehabilitation, Oslo University Hospital. 
Institute of Clinical Medicine, Faculty of Medicine, University 
of Oslo. 
  

65 
 
  
  
Table of Contents  
Study protocol v. 1.0 .................................................................................................................................... 4 
Study protocol v. 2.0 .................................................................................................................................. 33 
Summary of changes to the protocol ....................................................................................................... 62 
1.2 Research hypothesis .......................................................................................................................... 67 
2.0 Study methods ...................................................................................................................................... 67 
2.1 Trial design ........................................................................................................................................ 67 
2.2 Randomisation .................................................................................................................................. 68 
2.3 Sample size ........................................................................................................................................ 68 
2.4 Endpoints/outcome .......................................................................................................................... 68 
2.4.1 Primary outcome measure ......................................................................................................... 68 
2.4.2 Secondary outcome measures ................................................................................................... 68 
2.5 Timing of outcome assessments ....................................................................................................... 70 
3.0 General considerations ......................................................................................................................... 71 
3.1 Adherence and protocol deviations .................................................................................................. 71 
3.2 Analysis populations.......................................................................................................................... 71 
3.3 Statistical Framework ........................................................................................................................ 71 
3.4 Statistical interim analyses and stopping guidance .......................................................................... 72 
3.5 Timing of final analysis ...................................................................................................................... 72 
3.6 Baseline patient characteristics ......................................................................................................... 72 
4.0 Analysis methods .................................................................................................................................. 72 
4.1 Statistical methods ............................................................................................................................ 72 
4.1.1 Analysis of primary outcome ...................................................................................................... 72 
4.1.2 Analysis of secondary outcomes ................................................................................................ 73 
4.2 Missing data ...................................................................................................................................... 73 
4.3 Additional analyses ............................................................................................................................ 73 
4.4 Adverse Events .................................................................................................................................. 73 
4.5 Statistical software ............................................................................................................................ 73 
5.0 References ............................................................................................................................................. 74 

66 
 
1.2 Research hypothesis .......................................................................................................................... 78 
2.0 Study methods ...................................................................................................................................... 78 
2.1 Trial design ........................................................................................................................................ 78 
2.2 Randomisation .................................................................................................................................. 79 
2.3 Sample size ........................................................................................................................................ 79 
2.4 Endpoints/outcome .......................................................................................................................... 79 
2.4.1 Primary outcome measure ......................................................................................................... 79 
2.5 Timing of outcome assessments ....................................................................................................... 81 
3.0 General considerations ......................................................................................................................... 82 
3.1 Adherence and protocol deviations .................................................................................................. 82 
3.2 Analysis populations.......................................................................................................................... 82 
3.3 Statistical Framework ........................................................................................................................ 82 
3.4 Statistical interim analyses and stopping guidance .......................................................................... 83 
3.5 Timing of final analysis ...................................................................................................................... 83 
3.6 Baseline patient characteristics ......................................................................................................... 83 
4.0 Analysis methods .................................................................................................................................. 83 
4.1 Statistical methods ............................................................................................................................ 83 
4.1.1 Analysis of primary outcome ...................................................................................................... 83 
4.1.2 Analysis of secondary outcomes ................................................................................................ 84 
4.2 Missing data ...................................................................................................................................... 84 
4.3 Additional analyses ............................................................................................................................ 84 
4.4 Adverse Events .................................................................................................................................. 84 
4.5 Statistical software ............................................................................................................................ 84 
5.0 References ............................................................................................................................................. 85 
The following changes are administrative revision: .............................................................................. 87 
2.4.1 Primary outcome measure ......................................................................................................... 87 
3.6 Baseline patient characteristics ......................................................................................................... 87 
1.2 Research hypothesis .......................................................................................................................... 87 
3.3 Statistical Framework ........................................................................................................................ 88 
4.1.1 Analysis of primary outcome ...................................................................................................... 88 
 
  

67 
 
1.0 Introduction  
   
This document describes the planned statistical analyses for the clinical trial:  “A randomised 
controlled trial comparing the effectiveness of surgical and nonsurgical treatment for cervical 
radiculopathy”. It is intended to supplement the study protocol (1).   
The overall purpose of this study is to evaluate whether surgery or conservative treatment is more 
effective in the treatment of cervical radiculopathy.   
  
1.2 Research hypothesis  
  
Null hypothesis  
H0: The effectiveness of surgery is not different from non-surgical treatment as measured by 
Neck Disability Index (NDI) and arm pain at 1-year follow-up in patients with cervical 
radiculopathy in: 
Study 1: one level disc herniation (C5/6 or C6/7) 
Study 2: one or two level spondylosis (C5/6 and/or C6/7). 
Alternative hypothesis  
H1: There is a difference between effectiveness of surgery and non-surgical treatment as 
measured by Neck Disability Index (NDI) and arm pain at 1-year follow-up in patients with 
cervical radiculopathy in: 
 
Study 1: one level disc herniation (C5/6 or C6/7) 
 
Study 2: one or two level spondylosis (C5/6 and/or C6/7). 
 
 
2.0 Study methods  
  
2.1 Trial design  
The studies are designed as single blind, randomised controlled trials, with two parallel groups. 
The outcome assessor and the statistician will be blinded to treatment allocation. The data will be 
extracted in an unidentifiable manner and will not contain any information that can reveal what 
treatment a single subject or a group were randomised to. When the data is analysed and 
conclusions are drawn, the groups will be revealed before writing up the discussion.  

68 
 
  
2.2 Randomisation  
Eligible patients were randomised in a 1:1 ratio. Treatment allocation was done by a computer 
generated randomisation schedule, (Viedoc Technologies AB.  Viedoc regulatory compliance. 
Version Date 2023-03-24). Based on the stratification diagnosis (herniation vs spondylosis), 
participants were allocated to the surgical arm or nonsurgical treatment arm according to a 
randomised allocation list with random block sizes prepared by a statistician at Clinical Trials 
Unit (CTU) / Oslo University Hospital (OUS). The list is uploaded to the electronic case report 
form system (eCRF) Viedoc, and patient allocation is revealed only when the participant is 
deemed eligible and ready for randomisation, ensuring the blinding of study personnel during the 
randomisation process and for the blinded study personnel during the study conduct. 
 
2.3 Sample size  
The sample size was based on the primary outcome measure Neck Disability Index (NDI) at 1-
year, for a comparison between two of the treatment groups using a two-sided t test.  
Including 36 patients in each treatment group within study 1 and 2 (a total of 144) is estimated to 
have 80% power for detecting a clinically significant difference (p<0.05) of 12 on NDI at a 1-
year follow-up in each study, assuming a standard deviation of 18. We have included 180 patients 
in total, which allows for up to 20% cross over and drop out. 
  
2.4 Endpoints/outcome  
2.4.1 Primary outcome measure  
• 
The Neck Disability Index, which consists of ten questions about pain-related disability, 
including items such as headaches, concentration problems, reading issues and sleep 
disturbances. Each item is rated by choosing one of five response categories, and then 
transformed into a total score ranging from 0 to 100 (worst possible). The Norwegian 
version has been validated in patients with neck pain and with cervical radiculopathy (2, 
3). 
• 
Arm pain, measured by a Numeric Rating Scale (NRS) from 0 (no pain) to 10 (worst 
imaginable pain) (4). We asked the patients to rate their arm pain the last week.  
2.4.2 Secondary outcome measures  
• 
Neck pain and headache, measured by a Numeric Rating Scale (NRS) from 0 (no pain) to 
10 (worst imaginable pain). 
• 
Perceived recovery or change of the main symptoms, rated on a numeric scale ranging 
from   -9 (worst possible change) to 9 (best possible change) (5). 
• 
EuroQol (EQ-5D-5L and EQ-VAS). EQ-5D-5L includes five dimensions: mobility, self-
care, daily activities, pain/discomfort, and anxiety/depression, and each has five levels of 
severity. The responses are transformed into and indexed to value the patients’ health-
related quality of life for a cost–utility analysis. Patients score their health from 0 (as bad 
as possible) to 100 (best possible) by EQ-VAS. The Norwegian version has been 

69 
 
validated in patients with back pain, idiopathic scoliosis, and cervical radiculopathy (3, 6, 
7). 
• 
Fear-avoidance beliefs, evaluated using the Fear Avoidance Beliefs Questionnaire 
(FABQ) (8-11). 
• 
Emotional distress will be assessed by the 10-question version of the Hopkins Symptom 
Check List (HSCL-10) (12, 13). 
• 
Medicine consumption the week before inclusion and the week before each follow-up will 
be registered. 
• 
Sickness absence data will be collected from the National Social Security Institution for 
the year before and after inclusion.  
• 
Dysphagia; The Dysphagia Short Questionnaire (14). 
• 
Frequency of complications (dural tears, and disturbances of the larynx recurrent nerve, 
index-level nerve, oesophagus, trachea, or large vessel). 
• 
Frequency of reoperation after surgery and frequency of operations in patients allocated to 
nonsurgical treatment.  
• 
Other treatments. We will register concomitant care and interventions. There are no 
restrictions related to concomitant care. 
• 
Exploring global success rates by asking the patients about how their arm and neck pain 
are compared to prior to treatment (ranging from much worse to much better). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

70 
 
 
2.5 Timing of outcome assessments  
  
Outcome measurements 
Outcome 
When they will be evaluated 
 
Baseline 
12 weeks 
26 weeks 
52 weeks 
Primary: 
 
NDI 
x 
x  
x 
x 
Arm pain (NRS) 
x 
x 
x 
x 
Secondary: 
 
Neck pain (NRS) 
x 
x 
x 
x 
Patient 
expectations 
x 
 
 
 
Perceived 
recovery 
 
x 
x 
x 
Success rate 
 
x 
x 
x 
EuroQol (EQ-5D 
and EQ-VAS) 
x 
x 
x 
x 
FABQ 
x 
x 
x 
x 
HSCL-10 
x 
x 
x 
x 
Medicine 
consumption 
x 
x 
x 
x 
Sickness absence 
x 
x 
x 
x 
Dysphagia 
x 
x 
x 
x 
Frequency of 
surgical 
complications 
 
x 
x 
x 
Frequency of 
reoperations 
 
x 
x 
x 
Cross overs in the 
nonsurgical group 
 
x 
x 
x 
Patient 
demographics 
x 
 
 
 
Neurological 
status, incl. grip 
strength 
x 
x 
x 
x 

71 
 
 
3.0 General considerations  
  
3.1 Adherence and protocol deviations  
The number and proportion of patients that received the intervention they were randomized to 
will be presented. The following are pre-defined major protocol deviations regarded to affect the 
efficacy of the intervention:   
- 
Compliance of interventions: For the conservative treatment, the patients have to 
complete at least 2 out of 6 sessions. For the surgical treatment, the patients have to go 
through surgery. 
- 
Timing of follow-up visits: Patients not completing post baseline follow-up within +/- 4 
weeks for the 3 months follow-up, +/- 4 weeks for the 6 months follow- up, and +/- 8 
weeks for the 12 month follow- up.    
  
3.2 Analysis populations  
We define the following patient population in this trial:   
- 
Intention- to- treat analysis set: All patients that have been randomised will be analysed 
according to the group they were originally assigned, regardless what treatment (or not) 
they received.    
- 
Per protocol analysis set: All patients that were randomised, received treatment according 
to protocol without deviations (as described for in “compliance of interventions” and 
“timing of follow-up visits” above) were analysed according to the treatment they were 
randomised to.  
- 
As treated analysis: All patients will be analysed according to treatment they actually 
received. 
- 
We will calculate the proportion of patients reaching the predefined clinical important 
outcome. A percentage change of 30 has been defined as clinically important for the 
Norwegian patients as reported by the Norwegian registry for spine surgery (15).    
- 
In addition, we will calculate the proportion of patients reaching their own minimal 
expected improvement as answered at baseline immediately before randomisation. 
  
3.3 Statistical Framework  
Superiority hypothesis testing will be performed to test the effectiveness of the interventions 
according to the null hypothesis as stated above. Superiority of a treatment will be claimed if the 
two-sided p-value in the test comparing 12 months score between groups is less than 5 %. This 
protocol is designed to address two primary endpoints; NDI and arm pain using NRS at 12 
months. A difference in the effect between the interventions will be claimed if null hypothesis is 
rejected, that is if the two-sided p- value is less than 5%.  
  

72 
 
3.4 Statistical interim analyses and stopping guidance  
There will be no interim analyses in this trial.   
If severe medical events occur, the treating surgeon and physiatrist have access to unblind that 
particular patient.   
  
3.5 Timing of final analysis  
When all patients have completed a minimum of 12 months follow- up the analysis of the 
primary outcomes will be performed. When all patients have completed a minimum of 12 months 
follow-up the secondary analysis will be performed.   
  
     3.6 Baseline patient characteristics  
Baseline characteristics of the study population will be summarized separately with each 
randomized group in the cohort of spondylosis (Study 1) and in the cohort of disc herniation 
(Study 2). For continuous variables, means and standard deviations will be presented, unless the 
variable has a highly skewed distribution, in which case, medians, 25th and 75th percentiles and/or 
range will be presented. For categorical (binary or ordinal) variables, the number and percentage 
of participants within each category will be presented. For each variable (continuous or 
categorical), the percentage of missing values will be reported.   
  
4.0 Analysis methods  
4.1 Statistical methods  
 The results of the trial will be presented following the standard CONSORT recommendations 
(16). A CONSORT diagram will be used to show patient flow with number of patients 
considered and total numbers randomized.  
All calculated p-values will be two-sided and compared to a 5% significance level. If a p-value is 
less than 0.05, the null hypothesis in the test will be rejected. Efficacy estimates for the 
comparison of treatment interventions will be presented with two-sided 95% confidence intervals.   
P-values will be rounded to three decimal places. P-values less than 0.001 will be reported as 
<0.001 in tables. There will be no adjustment to secondary outcomes for multiple testing.  
  
4.1.1 Analysis of primary outcome  
ANCOVA (i.e., multiple-regression analysis) will be used to compare primary outcomes at 12 
months follow-up among the different groups, adjusting for respective outcome variables at the 
baseline. The analysis will be performed for the two studies separately in addition to an analysis 
of the entire study population as one. 
 

73 
 
In addition, we will use  linear mixed effects model for repeated measurements to assess 
difference between groups at each follow-up time and investigate changes over time. The model 
will include fixed effects for time, group and treatment x time interaction and a subject-specific 
random intercept. To assess difference between groups, we will include the outcome variable at 
baseline as a covariate in the model. The primary efficacy outcome of between-group differences 
in changes from baseline to 12 months follow-up will be estimated. This approach allows for 
comparison between surgical treatment and conservative treatment. The primary effect analysis 
will use the intention- to treat population. The secondary analysis will include per protocol and as 
treated populations.  
  
4.1.2 Analysis of secondary outcomes  
Secondary outcomes, assessed at multiple time points (baseline, 3, 6 and 12 months) will be 
analysed by using a linear mixed effect model approach as described in section 4.1.1 on both the 
intention-to treat population, the per protocol and as treated population   
  
4.2 Missing data  
Imputations will be used for the primary outcome if missing data exceeds 10%.   
Missing data for repeated measured continuous endpoints will be implicitly handled by the linear 
mixed-effects models under the assumption of missing at random observations; thus no 
imputation is required.   
  
4.3 Additional analyses  
We will apply a multivariable logistic and linear regression analysis to explore predictive factors 
as demographics, clinical and radiological findings for primary and secondary outcomes. Model 
building will be done in a way that is appropriate for the given sample sizes, by restricting the 
number of potential predictive factors and considering shrinkage methods to stabilise predictions.   
  
  
4.4 Adverse Events  
Any complications and adverse events were continuously registered.   
  
4.5 Statistical software  
All statistical analysis will be done using SPSS, STATA, R or other appropriate software.  

74 
 
 
 
5.0 References  
1. 
Taso M, Sommernes JH, Kolstad F, Sundseth J, Bjorland S, Pripp AH, et al. A 
randomised controlled trial comparing the effectiveness of surgical and nonsurgical treatment for 
cervical radiculopathy. BMC Musculoskeletal Disorders. 2020;21(1):171. 
2. 
Johansen JB, Andelic N, Bakke E, Holter EB, Mengshoel AM, Røe C. Measurement 
Properties of the Norwegian Version of the Neck Disability Index in Chronic Neck Pain. 
2013;38(10):851-6. 
3. 
Sundseth J, Kolstad F, Johnsen LG, Pripp AH, Nygaard OP, Andresen H, et al. The Neck 
Disability Index (NDI) and its correlation with quality of life and mental health measures among 
patients with single-level cervical disc disease scheduled for surgery. Acta Neurochir (Wien). 
2015;157(10):1807-12. 
4. 
Downie WW, Leatham PA, Rhind VM, Wright V, Branco JA, Anderson JA. Studies with 
pain rating scales. Ann Rheum Dis. 1978;37(4):378-81. 
5. 
Brox J, E G, G U, A SB, Brevik J, AE L, Staff P. Arthroscopic surgery versus supervised 
exercises in patients with rotator cuff disease (stage II impingement syndrome): A prospective, 
randomized, controlled study in 125 patients with a 2 1/2 year follow-up. J Shoulder Elbow Surg. 
1999;8:102-11. 
6. 
Adobor RD, Rimeslatten S, Keller A, Brox JI. Repeatability, reliability, and concurrent 
validity of the scoliosis research society-22 questionnaire and EuroQol in patients with 
adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2010;35(2):206-9. 
7. 
Solberg TK, Olsen JA, Ingebrigtsen T, Hofoss D, Nygaard OP. Health-related quality of 
life assessment by the EuroQol-5D can provide cost-utility data in the field of low-back surgery. 
EurSpine J. 2005;14(10):1000-7. 
8. 
Waddell G, Newton M, Henderson I, Somerville D, Main CJ. A fear-avoidance beliefs 
questionnaire (FABQ) and the role of fear-avoidance beliefs in chronic low back pain and 
diasability. Pain. 1993;52:157-68. 
9. 
Grotle M, Vollestad NK, Veierod MB, Brox JI. Fear-avoidance beliefs and distress in 
relation to disability in acute and chronic low back pain. Pain. 2004;112(3):343-52. 
10. 
Dedering A, Borjesson T. Assessing fear-avoidance beliefs in patients with cervical 
radiculopathy. Physiotherapy research international : the journal for researchers and clinicians in 
physical therapy. 2013;18(4):193-202. 
11. 
Halvorsen M, Kierkegaard M, Harms-Ringdahl K, Peolsson A, Dedering A. Dimensions 
Underlying Measures of Disability, Personal Factors, and Health Status in Cervical 
Radiculopathy: A Cross-Sectional Study. Medicine. 2015;94(24):e999. 
12. 
Sirpal MK, Haugen W, Sparle K, Haavet OR. Validation study of HSCL-10, HSCL-6, 
WHO-5 and 3-key questions in 14-16 year ethnic minority adolescents. BMC family practice. 
2016;17:7. 
13. 
Dalgard OS, Thapa SB. Immigration, social integration and mental health in Norway, 
with focus on gender differences. Clinical practice and epidemiology in mental health : CP & 
EMH. 2007;3:24. 
14. 
Skeppholm M, Ingebro C, Engstrom T, Olerud C. The Dysphagia Short Questionnaire: an 
instrument for evaluation of dysphagia: a validation study with 12 months' follow-up after 
anterior cervical spine surgery. Spine. 2012;37(11):996-1002. 

75 
 
15. 
Austevoll IM, Gjestad R, Grotle M, Solberg T, Brox JI, Hermansen E, et al. Follow-up 
score, change score or percentage change score for determining clinical important outcome 
following surgery? An observational study from the Norwegian registry for Spine surgery 
evaluating patient reported outcome measures in lumbar spinal stenosis and lumbar degenerative 
spondylolisthesis. BMC Musculoskelet Disord. 2019;20(1):31. 
16. 
The L. CONSORT 2010. The Lancet. 2010;375(9721):1136. 
 
 
 
 

76 
 
Statistical analysis plan (SAP)  
Administrative information:   
Trial title  
A randomised controlled trial comparing the effectiveness of 
surgical and nonsurgical treatment for cervical radiculopathy 
Trial registration number  
NCT03674619 
REC no  
REK 2017/2125 
SAP version and date  
This is SAP version 2.0, dated 03.12.2024 
Protocol version  
This document has been written based on information 
contained in the study protocol (1).  
Authors  
Mirad Taso, MD PhD student. Department of Physical  
Medicine and Rehabilitation, Oslo University Hospital. 
Institute of Clinical Medicine, Faculty of Medicine, University 
of Oslo.  
 
Are Hugo Pripp, statistician, PhD. Oslo Centre of Biostatistics 
and Epidemiology, Research Support Services, Oslo University 
Hospital. 
 
Jon Håvard Sommernes, MD, PhD student. Department of 
Neurosurgery, Oslo University Hospital. Institute of Clinical 
Medicine, Faculty of Medicine, University of Oslo. 
 
Frode Kolstad, MD, PhD. Department of Neurosurgery, Oslo 
University Hospital.  
 
Jarle Sundseth, MD, PhD. Department of Neurosurgery, Oslo 
University Hospital. 
 
Siri Bjorland, MD PhD. Department of Physical  
Medicine and Rehabilitation, Oslo University Hospital. 
 
John Anker Zwart, MD PhD. Research and Communication 
Unit for Musculoskeletal Health, Division of Clinical 
Neuroscience, Oslo University Hospital, Oslo, Norway 
 
Jens Ivar Brox, MD, Professor. Department of Physical 
Medicine and Rehabilitation, Oslo University Hospital. 
Institute of Clinical Medicine, Faculty of Medicine, University 
of Oslo. 
  

77 
 
  
  
Table of Contents  
1.0  Introduction.................................................................................... Feil! Bokmerke er ikke definert. 
1.2 Research hypothesis ................................................................... Feil! Bokmerke er ikke definert. 
2.0  Study methods ............................................................................... Feil! Bokmerke er ikke definert. 
2.1  Trial design ................................................................................. Feil! Bokmerke er ikke definert. 
2.2  Randomization ........................................................................... Feil! Bokmerke er ikke definert. 
2.3  Sample size ................................................................................. Feil! Bokmerke er ikke definert. 
2.4  Endpoints/outcome.................................................................... Feil! Bokmerke er ikke definert. 
2.4.1 Primary outcome measure ................................................... Feil! Bokmerke er ikke definert. 
2.4.2 Secondary outcome measures ............................................. Feil! Bokmerke er ikke definert. 
2.5 Timing of outcome assessments ................................................. Feil! Bokmerke er ikke definert. 
3.0  General considerations .................................................................. Feil! Bokmerke er ikke definert. 
3.1  Adherence and protocol deviations ........................................... Feil! Bokmerke er ikke definert. 
3.2  Analysis populations ................................................................... Feil! Bokmerke er ikke definert. 
3.3  Statistical Framework ................................................................. Feil! Bokmerke er ikke definert. 
3.4  Statistical interim analyses and stopping guidance ................... Feil! Bokmerke er ikke definert. 
3.5  Timing of final analysis ............................................................... Feil! Bokmerke er ikke definert. 
3.6 Baseline patient characteristics .................................................. Feil! Bokmerke er ikke definert. 
4.0  Analysis methods ........................................................................... Feil! Bokmerke er ikke definert. 
4.1  Statistical methods ..................................................................... Feil! Bokmerke er ikke definert. 
4.1.1 Analysis of primary outcome ................................................ Feil! Bokmerke er ikke definert. 
4.1.2 Analysis of secondary outcomes .......................................... Feil! Bokmerke er ikke definert. 
4.2  Missing data ............................................................................... Feil! Bokmerke er ikke definert. 
4.3 Additional analyses ..................................................................... Feil! Bokmerke er ikke definert. 
4.4 Adverse Events ............................................................................ Feil! Bokmerke er ikke definert. 
4.5 Statistical software ...................................................................... Feil! Bokmerke er ikke definert. 
5.0 References ....................................................................................... Feil! Bokmerke er ikke definert. 
 
  

78 
 
1.0 Introduction  
   
This document describes the planned statistical analyses for the clinical trial:  “A randomised 
controlled trial comparing the effectiveness of surgical and nonsurgical treatment for cervical 
radiculopathy”. It is intended to supplement the study protocol (1).   
The overall purpose of this study is to evaluate whether surgery or conservative treatment is more 
effective in the treatment of cervical radiculopathy.   
  
1.2 Research hypothesis  
  
Null hypothesis  
H0: The effectiveness of surgery is not different from non-surgical treatment as measured by 
Neck Disability Index (NDI) at 1-year follow-up in patients with cervical radiculopathy in: 
Study 1: one level disc herniation (C5/6 or C6/7) 
Study 2: one or two level spondylosis (C5/6 and/or C6/7). 
Alternative hypothesis  
H1: There is a difference between effectiveness of surgery and non-surgical treatment as 
measured by Neck Disability Index (NDI) at 1-year follow-up in patients with cervical 
radiculopathy in: 
 
Study 1: one level disc herniation (C5/6 or C6/7) 
 
Study 2: one or two level spondylosis (C5/6 and/or C6/7). 
 
 
2.0 Study methods  
  
2.1 Trial design  
The studies are designed as single blind, randomised controlled trials, with two parallel groups. 
The outcome assessor and the statistician will be blinded to treatment allocation. The data will be 
extracted in an unidentifiable manner and will not contain any information that can reveal what 
treatment a single subject or a group were randomised to. When the data is analysed and 
conclusions are drawn, the groups will be revealed before writing up the discussion.  

79 
 
  
2.2 Randomisation  
Eligible patients were randomised in a 1:1 ratio. Treatment allocation was done by a computer 
generated randomisation schedule, (Viedoc Technologies AB.  Viedoc regulatory compliance. 
Version Date 2023-03-24). Based on the stratification diagnosis (herniation vs spondylosis), 
participants were allocated to the surgical arm or nonsurgical treatment arm according to a 
randomised allocation list with random block sizes prepared by a statistician at Clinical Trials 
Unit (CTU) / Oslo University Hospital (OUS). The list is uploaded to the electronic case report 
form system (eCRF) Viedoc, and patient allocation is revealed only when the participant is 
deemed eligible and ready for randomisation, ensuring the blinding of study personnel during the 
randomisation process and for the blinded study personnel during the study conduct. 
 
2.3 Sample size  
The sample size was based on the primary outcome measure Neck Disability Index (NDI) at 1-
year, for a comparison between two of the treatment groups using a two-sided t test.  
Including 36 patients in each treatment group within study 1 and 2 (a total of 144) is estimated to 
have 80% power for detecting a clinically significant difference (p<0.05) of 12 on NDI at a 1-
year follow-up in each study, assuming a standard deviation of 18. We have included 180 patients 
in total, which allows for up to 20% cross over and drop out. 
  
2.4 Endpoints/outcome  
2.4.1 Primary outcome measure  
• 
The Neck Disability Index, which consists of ten questions about pain-related disability, 
including items such as headaches, concentration problems, reading issues and sleep 
disturbances. Each item is rated by choosing one of six response categories, and then 
transformed into a total score ranging from 0 to 100 (worst possible). The Norwegian 
version has been validated in patients with neck pain and with cervical radiculopathy (2, 
3). 
 2.4.2 Secondary outcome measures  
• 
Arm pain, measured by a Numeric Rating Scale (NRS) from 0 (no pain) to 10 (worst 
imaginable pain) (4). We asked the patients to rate their arm pain the last week. 
• 
Neck pain and headache, measured by a Numeric Rating Scale (NRS) from 0 (no pain) to 
10 (worst imaginable pain). 
• 
Perceived recovery or change of the main symptoms, rated on a numeric scale ranging 
from   -9 (worst possible change) to 9 (best possible change) (5). 
• 
EuroQol (EQ-5D-5L and EQ-VAS). EQ-5D-5L includes five dimensions: mobility, self-
care, daily activities, pain/discomfort, and anxiety/depression, and each has five levels of 
severity. The responses are transformed into and indexed to value the patients’ health-
related quality of life for a cost–utility analysis. Patients score their health from 0 (as bad 
as possible) to 100 (best possible) by EQ-VAS. The Norwegian version has been 

80 
 
validated in patients with back pain, idiopathic scoliosis, and cervical radiculopathy (3, 6, 
7). 
• 
Fear-avoidance beliefs, evaluated using the Fear Avoidance Beliefs Questionnaire 
(FABQ) (8-11). 
• 
Emotional distress will be assessed by the 10-question version of the Hopkins Symptom 
Check List (HSCL-10) (12, 13). 
• 
Medicine consumption the week before inclusion and the week before each follow-up will 
be registered. 
• 
Sickness absence data will be collected from the National Social Security Institution for 
the year before and after inclusion.  
• 
Dysphagia; The Dysphagia Short Questionnaire (14). 
• 
Frequency of complications (dural tears, and disturbances of the larynx recurrent nerve, 
index-level nerve, oesophagus, trachea, or large vessel). 
• 
Frequency of reoperation after surgery and frequency of operations in patients allocated to 
nonsurgical treatment.  
• 
Other treatments. We will register concomitant care and interventions. There are no 
restrictions related to concomitant care. 
• 
Exploring global success rates by asking the patients about how their arm and neck pain 
are compared to prior to treatment (ranging from much worse to much better). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

81 
 
 
2.5 Timing of outcome assessments  
  
Outcome measurements 
Outcome 
When they will be evaluated 
 
Baseline 
12 weeks 
26 weeks 
52 weeks 
Primary: 
 
NDI 
x 
x  
x 
x 
Secondary: 
 
Arm pain (NRS) 
x 
x 
x 
x 
Neck pain (NRS) 
x 
x 
x 
x 
Patient 
expectations 
x 
 
 
 
Perceived 
recovery 
 
x 
x 
x 
Success rate 
 
x 
x 
x 
EuroQol (EQ-5D 
and EQ-VAS) 
x 
x 
x 
x 
FABQ 
x 
x 
x 
x 
HSCL-10 
x 
x 
x 
x 
Medicine 
consumption 
x 
x 
x 
x 
Sickness absence 
x 
x 
x 
x 
Dysphagia 
x 
x 
x 
x 
Frequency of 
surgical 
complications 
 
x 
x 
x 
Frequency of 
reoperations 
 
x 
x 
x 
Cross overs in the 
nonsurgical group 
 
x 
x 
x 
Patient 
demographics 
x 
 
 
 
Neurological 
status, incl. grip 
strength 
x 
x 
x 
x 

82 
 
 
3.0 General considerations  
  
3.1 Adherence and protocol deviations  
The number and proportion of patients that received the intervention they were randomized to 
will be presented. The following are pre-defined major protocol deviations regarded to affect the 
efficacy of the intervention:   
- 
Compliance of interventions: For the conservative treatment, the patients have to 
complete at least 2 out of 6 sessions. For the surgical treatment, the patients have to go 
through surgery. 
- 
Timing of follow-up visits: Patients not completing post baseline follow-up within 
+/- 4 weeks for the 3 months follow-up, +/- 4 weeks for the 6 months follow- up, and +/- 
8 weeks for the 12 month follow- up.    
  
3.2 Analysis populations  
We define the following patient population in this trial:   
- 
Intention- to- treat analysis set: All patients that have been randomised will be analysed 
according to the group they were originally assigned, regardless what treatment (or not) 
they received.    
- 
Per protocol analysis set: All patients that were randomised, received treatment according 
to protocol without deviations (as described for in “compliance of interventions” and 
“timing of follow-up visits” above) were analysed according to the treatment they were 
randomised to.  
- 
As treated analysis: All patients will be analysed according to treatment they actually 
received. 
- 
We will calculate the proportion of patients reaching the predefined clinical important 
outcome. A percentage change of 30 has been defined as clinically important for the 
Norwegian patients as reported by the Norwegian registry for spine surgery (15).    
- 
In addition, we will calculate the proportion of patients reaching their own minimal 
expected improvement as answered at baseline immediately before randomisation. 
  
3.3 Statistical Framework  
Superiority hypothesis testing will be performed to test the effectiveness of the interventions 
according to the null hypothesis as stated above. Superiority of a treatment will be claimed if the 
two-sided p-value in the test comparing 12 months score between groups is less than 5 %. This 
protocol is designed to address one primary endpoint; NDI at 12 months. A difference in the 
effect between the interventions will be claimed if null hypothesis is rejected, that is if the two-
sided p- value is less than 5%.  
  

83 
 
3.4 Statistical interim analyses and stopping guidance  
There will be no interim analyses in this trial.   
If severe medical events occur, the treating surgeon and physiatrist have access to unblind that 
particular patient.   
  
3.5 Timing of final analysis  
When all patients have completed a minimum of 12 months follow- up the analysis of the 
primary outcomes will be performed. When all patients have completed a minimum of 12 months 
follow-up the secondary analysis will be performed.   
  
     3.6 Baseline patient characteristics  
Baseline characteristics of the study population will be summarized separately with each 
randomized group in the cohort of disc herniation (Study 1) and in the cohort of spondylosis 
(Study 2). For continuous variables, means and standard deviations will be presented, unless the 
variable has a highly skewed distribution, in which case, medians, 25th and 75th percentiles and/or 
range will be presented. For categorical (binary or ordinal) variables, the number and percentage 
of participants within each category will be presented. For each variable (continuous or 
categorical), the percentage of missing values will be reported.   
  
4.0 Analysis methods  
4.1 Statistical methods  
 The results of the trial will be presented following the standard CONSORT recommendations 
(16). A CONSORT diagram will be used to show patient flow with number of patients 
considered and total numbers randomized.  
All calculated p-values will be two-sided and compared to a 5% significance level. If a p-value is 
less than 0.05, the null hypothesis in the test will be rejected. Efficacy estimates for the 
comparison of treatment interventions will be presented with two-sided 95% confidence intervals.   
P-values will be rounded to three decimal places. P-values less than 0.001 will be reported as 
<0.001 in tables. There will be no adjustment to secondary outcomes for multiple testing.  
  
4.1.1 Analysis of primary outcome  
ANCOVA will be used to analyse differences in NDI at 12 months, adjusting for the baseline 
value. The analysis will be performed for the two studies separately in addition to an analysis of 
the entire study population as one. 
 

84 
 
In addition, we will use linear mixed effects model for repeated measurements to assess 
difference between groups at each follow-up time and investigate changes over time. The model 
will include fixed effects for time, group and treatment x time interaction and a subject-specific 
random intercept. To assess difference between groups, we will include the outcome variable at 
baseline as a covariate in the model. The primary efficacy outcome of between-group differences 
in changes from baseline to 12 months follow-up will be estimated. This approach allows for 
comparison between surgical treatment and conservative treatment. The primary effect analysis 
will use the intention- to treat population. The secondary analysis will include per protocol and as 
treated populations.  
  
4.1.2 Analysis of secondary outcomes  
Secondary outcomes, assessed at multiple time points (baseline, 3, 6 and 12 months) will be 
analysed by using a linear mixed effect model approach as described in section 4.1.1 on both the 
intention-to treat population, the per protocol and as treated population   
  
4.2 Missing data  
Imputations will be used for the primary outcome if missing data exceeds 10%.   
Missing data for repeated measured continuous endpoints will be implicitly handled by the linear 
mixed-effects models under the assumption of missing at random observations; thus no 
imputation is required.   
  
4.3 Additional analyses  
We will apply a multivariable logistic and linear regression analysis to explore predictive factors 
as demographics, clinical and radiological findings for primary and secondary outcomes. Model 
building will be done in a way that is appropriate for the given sample sizes, by restricting the 
number of potential predictive factors and considering shrinkage methods to stabilise predictions.   
  
  
4.4 Adverse Events  
Any complications and adverse events were continuously registered.   
  
4.5 Statistical software  
All statistical analysis will be done using SPSS, STATA, R or other appropriate software.  

85 
 
 
 
5.0 References  
1. 
Taso M, Sommernes JH, Kolstad F, Sundseth J, Bjorland S, Pripp AH, et al. A 
randomised controlled trial comparing the effectiveness of surgical and nonsurgical treatment for 
cervical radiculopathy. BMC Musculoskeletal Disorders. 2020;21(1):171. 
2. 
Johansen JB, Andelic N, Bakke E, Holter EB, Mengshoel AM, Røe C. Measurement 
Properties of the Norwegian Version of the Neck Disability Index in Chronic Neck Pain. 
2013;38(10):851-6. 
3. 
Sundseth J, Kolstad F, Johnsen LG, Pripp AH, Nygaard OP, Andresen H, et al. The Neck 
Disability Index (NDI) and its correlation with quality of life and mental health measures among 
patients with single-level cervical disc disease scheduled for surgery. Acta Neurochir (Wien). 
2015;157(10):1807-12. 
4. 
Downie WW, Leatham PA, Rhind VM, Wright V, Branco JA, Anderson JA. Studies with 
pain rating scales. Ann Rheum Dis. 1978;37(4):378-81. 
5. 
Brox J, E G, G U, A SB, Brevik J, AE L, Staff P. Arthroscopic surgery versus supervised 
exercises in patients with rotator cuff disease (stage II impingement syndrome): A prospective, 
randomized, controlled study in 125 patients with a 2 1/2 year follow-up. J Shoulder Elbow Surg. 
1999;8:102-11. 
6. 
Adobor RD, Rimeslatten S, Keller A, Brox JI. Repeatability, reliability, and concurrent 
validity of the scoliosis research society-22 questionnaire and EuroQol in patients with 
adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2010;35(2):206-9. 
7. 
Solberg TK, Olsen JA, Ingebrigtsen T, Hofoss D, Nygaard OP. Health-related quality of 
life assessment by the EuroQol-5D can provide cost-utility data in the field of low-back surgery. 
EurSpine J. 2005;14(10):1000-7. 
8. 
Waddell G, Newton M, Henderson I, Somerville D, Main CJ. A fear-avoidance beliefs 
questionnaire (FABQ) and the role of fear-avoidance beliefs in chronic low back pain and 
diasability. Pain. 1993;52:157-68. 
9. 
Grotle M, Vollestad NK, Veierod MB, Brox JI. Fear-avoidance beliefs and distress in 
relation to disability in acute and chronic low back pain. Pain. 2004;112(3):343-52. 
10. 
Dedering A, Borjesson T. Assessing fear-avoidance beliefs in patients with cervical 
radiculopathy. Physiotherapy research international : the journal for researchers and clinicians in 
physical therapy. 2013;18(4):193-202. 
11. 
Halvorsen M, Kierkegaard M, Harms-Ringdahl K, Peolsson A, Dedering A. Dimensions 
Underlying Measures of Disability, Personal Factors, and Health Status in Cervical 
Radiculopathy: A Cross-Sectional Study. Medicine. 2015;94(24):e999. 
12. 
Sirpal MK, Haugen W, Sparle K, Haavet OR. Validation study of HSCL-10, HSCL-6, 
WHO-5 and 3-key questions in 14-16 year ethnic minority adolescents. BMC family practice. 
2016;17:7. 
13. 
Dalgard OS, Thapa SB. Immigration, social integration and mental health in Norway, 
with focus on gender differences. Clinical practice and epidemiology in mental health : CP & 
EMH. 2007;3:24. 
14. 
Skeppholm M, Ingebro C, Engstrom T, Olerud C. The Dysphagia Short Questionnaire: an 
instrument for evaluation of dysphagia: a validation study with 12 months' follow-up after 
anterior cervical spine surgery. Spine. 2012;37(11):996-1002. 

86 
 
15. 
Austevoll IM, Gjestad R, Grotle M, Solberg T, Brox JI, Hermansen E, et al. Follow-up 
score, change score or percentage change score for determining clinical important outcome 
following surgery? An observational study from the Norwegian registry for Spine surgery 
evaluating patient reported outcome measures in lumbar spinal stenosis and lumbar degenerative 
spondylolisthesis. BMC Musculoskelet Disord. 2019;20(1):31. 
16. 
The L. CONSORT 2010. The Lancet. 2010;375(9721):1136. 
 
 
 

87 
 
Summary of changes to the statistical analysis plan 
The following changes are administrative revision: 
 
 
2.4.1 Primary outcome measure  
The Neck Disability Index, which consists of ten questions about pain-related disability, 
including items such as headaches, concentration problems, reading issues and sleep 
disturbances. Each item is rated by choosing one of six response categories, and then transformed 
into a total score ranging from 0 to 100 (worst possible). 
Comment: Changed from five to six response categories as this was incorrect. Page 75. 
 
3.6 Baseline patient characteristics  
Baseline characteristics of the study population will be summarized separately with each 
randomized group in the cohort of disc herniation (Study 1) and in the cohort of spondylosis 
(Study 2). 
Comment: Corrected the names of study 1 and study 2. Page 79. 
 
 
The following changes are based on recommendations from the editors of NEJM 
Evidence: 
1.2 Research hypothesis  
Comment: removed arm pain as primary outcome as we did not calculate power based on arm 
pain. Page 74. 
 
2.4 Endpoints/outcome 
Comment: moved arm pain from primary outcomes to secondary outcomes as we did not 
calculate power based on arm pain. Page 75. 
 
 
 

88 
 
2.5 Timing of outcome assessments 
Comment: moved arm pain from primary outcomes to secondary outcomes as we did not 
calculate power based on arm pain. Page 77. 
 
3.3 Statistical Framework  
Comment: removed arm pain as primary outcome as we did not calculate power based on arm 
pain. Page 78. 
 
4.1.1 Analysis of primary outcome  
ANCOVA will be used to analyse differences in NDI at 12 months, adjusting for the baseline 
value. 
Comment: Adapted the description to fit NDI as the only primary endpoint.  Page 79.