Transforaminal Epidural Injection in Acute Sciatica
Phase: NA
Conditions: Sciatica, Sciatica Due to Intervertebral Disc Disorder, Sciatic Radiculopathy
Sponsor: C.L.A.Vleggeert-Lankamp

Official title of the study: 
Transforaminal Epidural Injection in Acute Sciatica 
 
NCT: ID not yet assigned 
 
Date of the document: 14 February 2019 
 
Approved by the Medical Ethics Committee: 25 March 2019 

NL6757.058.18 / TEIAS: Transforaminal Epidural Injection in Acute Sciatica 
 
 
 
 
 
 
 
 
 
 
 
 
Transforaminal Epidural Injection in Acute 
Sciatica (TEIAS) 
 
 
 
  

NL6757.058.18 / TEIAS: Transforaminal Epidural Injection in Acute Sciatica 
 
 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE ........................................................................... 8 
2. 
OBJECTIVES ............................................................................................................10 
3. 
STUDY DESIGN ........................................................................................................12 
4. 
STUDY POPULATION ...............................................................................................14 
4.1 
Population (base) ...................................................................................................14 
4.2 
Inclusion criteria .....................................................................................................14 
4.3 
Exclusion criteria ....................................................................................................14 
4.4 
Sample size calculation ..........................................................................................15 
5. 
TREATMENT OF SUBJECTS ...................................................................................16 
5.1 
Investigational product/treatment ............................................................................16 
5.2 
Use of co-intervention ............................................................................................16 
5.3 
Escape medication .................................................................................................16 
6. 
METHODS .................................................................................................................17 
6.1 
Study parameters/endpoints ...................................................................................17 
6.1.1 
Main study parameter/endpoint .......................................................................17 
6.1.2 
Secondary study parameters/endpoints ..........................................................17 
6.1.3 
Other study parameters ...................................................................................19 
6.2 
Randomisation, blinding and treatment allocation ..................................................19 
6.3 
Study procedures ...................................................................................................19 
6.4 
Withdrawal of individual subjects ............................................................................20 
6.5 
Replacement of individual subjects after withdrawal ...............................................20 
6.6 
Follow-up of subjects withdrawn from treatment .....................................................20 
6.7 
Premature termination of the study .........................................................................20 
7. 
SAFETY REPORTING ...............................................................................................21 
7.1 
Temporary halt for reasons of subject safety ..........................................................21 
7.2 
AEs, SAEs and SUSARs ........................................................................................21 
7.2.1 
Adverse events (AEs) ......................................................................................21 
7.2.2 
Serious adverse events (SAEs) .......................................................................21 
7.3 
Follow-up of adverse events ...................................................................................22 
8. 
STATISTICAL ANALYSIS ..........................................................................................23 
8.1 
Primary study parameter(s) ....................................................................................23 
8.2 
Secondary study parameter(s) ...............................................................................23 
8.3 
Other study parameters ..........................................................................................23 
9. 
ETHICAL CONSIDERATIONS ...................................................................................25 
9.1 
Regulation statement .............................................................................................25 
9.2 
Recruitment and consent........................................................................................25 
9.3 
Incentives ...............................................................................................................25 
10. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................26 
10.1 
Handling and storage of data and documents ........................................................26 
10.2 
Monitoring and Quality Assurance ..........................................................................26 
10.3 
Annual progress report ...........................................................................................26 

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10.4 
Temporary halt and (prematurely) end of study report ............................................26 
11. 
STRUCTURED RISK ANALYSIS...............................................................................28 
11.1  Potential issues of concern .....................................................................................28 
11.2 
Synthesis ...............................................................................................................28 
12. 
REFERENCES ..........................................................................................................29 
 
 
 
 
 
 
 
 
 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
DSMB 
GP 
GRP 
 
Adverse Event 
Data Safety Monitoring Board 
General Practitioner 
Good Research Practice 
IC 
Informed Consent 
METC 
 
LRS 
LUMC 
NRS 
(S)AE 
Sciatica 
SIPS 
Medical Research Ethics Committee (MREC); in Dutch: Medisch-Ethische 
Toetsing Commissie (METC) 
Lumbosacral radicular syndrome 
Leiden University Medical Center 
Numerical Rating Scale 
(Serious) Adverse Event 
Condition of radicular pain in the leg 
Spine Intervention Prognostic Study Group 
Sponsor The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party that 
provides funding for a study but does not commission it is not regarded as the 
sponsor, but referred to as a subsidising party. 
TEI 
TEIAS 
VAS 
WMO 
Transforaminal Epidural Injection 
Transforaminal Epidural Injection in Acute Sciatica 
Visual Analogue Scale 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 

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SUMMARY 
 
Rationale: To study (cost) effectivity of the transforaminal epidural injection with analgesic 
and anti-inflammatory medication (TEI) in order to relieve the symptoms and to evaluate the 
intervention as a predictor tool for symptoms of sciatica in the long term. 
Objective: To evaluate the percentage of patients that experiences satisfactory (long term) 
decrease in leg pain in the TEI group in comparison to the conservative care group. 
Study design: Randomised controlled trial 
Study population: Patients that suffer 3-8 weeks from sciatica (Numeric Rating Scale ≥ 6, 
on a 10 point scale) 
Intervention: transforaminal epidural injection with analgesic and anti-inflammatory 
medication  
Main study parameters/endpoints: the percentage of patients that experiences satisfactory 
decrease (NRS lower than 4) in leg pain after 2, 10 and 21 weeks after randomization in both 
treatment arms 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: the participants fill in questionnaires at baseline, at 1, 2, 4, 10 and 21 
weeks after randomization. Participants will also fill in cost-diaries during this period. TEI as 
an intervention tool is considered usual care for sciatica patients, though the timing of the 
injection is not clearly defined. The extent of risk from TEI is comparable to usual care. 

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1. INTRODUCTION AND RATIONALE 
 
Sciatica is a condition of radicular pain in the leg and is usually caused by herniation of a 
lumbar intervertebral disc. The herniated disc compresses a lumbar nerve root that continues 
its route into the sciatic nerve. About 13% to 40% of all people will suffer from sciatica at 
least once during their lifetime [1]. Sciatica can have severe socio-economic effects; patients 
are immobilised by the pain they experience and therefore cannot go to work or participate in 
social events. 
Most cases resolve spontaneously with conservative therapy using only standard analgesics 
and/or physiotherapy. In a large RCT it was demonstrated that outcome of conservative and 
surgical therapy was comparable after 26 weeks [2]. 40% of patients randomized to the 
conservative care group crossed over and was treated surgically, with a mean delay of 15 
weeks. With this knowledge the guidelines for surgical treatment of sciatica were adjusted 
and it is nowadays usual care to offer surgery only after at least 8 weeks of conservative care 
and preferably after 14-16 weeks of conservative care. This decision is made together with 
the patient in a process of Shared Decision making [3,4].  
Although this treatment regimen has been demonstrated to be efficacious and cost effective, 
the burden for a patient during these weeks of conservative care is usually high. We seek to 
find a type of conservative care to reduce the discomfort due to the pain and to enable the 
patient to remain physically active. Not only will this add to the quality of life of the patient, 
but it will also prevent the patient from taking a sick-leave.  
 
Rationale for this study 
We would like to explore the effectivity of the transforaminal epidural injection (TEI) with 
analgesic and anti-inflammatory medication to relieve the symptoms. Theoretically, such an 
injection would have a painkilling effect within the first two weeks after injection, and this 
effect may last for months, but we know that some patients do not experience this beneficial 
effect [5]. Some patients report initial pain reduction but report a re-arousal of pain after 
several hours, days or weeks [6].  
There has been extensive research on TEI, but these studies generally include patients with 
chronic sciatica or a mixed population of patients with acute and chronic symptoms. We 
performed a systematic review on TEI specifically in the acute phase and it occurred that we 
could find only one article on the efficacy of epidural injections administered to patients with 
acute sciatica (<8 weeks of symptoms) [6]. This study, conducted by Spijker et al., 
randomized 63 patients with a duration of symptoms of at least 2 weeks and a maximum of 4 
weeks. Patients were divided over an intervention group (receiving TEI with triamcinolone) 
and a control group (usual care with non-iv medication). It was demonstrated that 

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functionality and pain relief in the back were more beneficial in the group that received an 
injection, but that differences were (too) small. However, the analysis of the effect was 
averaged over all patients in the treatment group. It is known that there is a group of non-
responders after TEI, averaging 33% of patients [5]. If the outcome values of all patients are 
averaged, no effect will be retrieved, while there could be a clear effect for the responders. In 
the study of Joswig [5] recruiting 63 patients with radicular pain in the leg, 66% of patients 
responded well to TEI within hours after the injection and in the first 14 days after injection 
the VAS leg pain remained around 30 mm on a 100 mm scale. In the non-responders the 
VAS pain was on average 55 mm and persisted on that level for at least 14 days.  
Not only was in Spijker’s study no distinction made between responders and non-
responders, the injection was lacking a painkilling component, like xylocaine. Moreover, the 
baseline values for VAS leg pain, VAS back pain and Roland Disability score were lower 
(better) in the control group, and the group of patients evaluated was relatively small. It 
appears that there is only little literature on TEI in the acute phase of sciatica and therefore 
additional research is obligatory. 
Furthermore, it is not yet understood why some patients experience more pain than other 
patients. From literature it is known that pain score does not correlate with the size of the 
herniated lumbar disk, but there are indications that degree of infection is related [7]. It has 
been demonstrated that at the site of the herniated disc several inflammatory cytokines can 
be found leading to prostaglandin synthesis and macrophage recruitment [8-9]. For this 
reason, disc material will be retrieved from patients undergoing lumbar surgery during this 
study and histological analysis will be performed. 
 
 

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2. OBJECTIVES 
 
Primary study objective:  
To study effectivity of the epidural injection with analgesic and anti-inflammatory medication 
to relieve the symptoms within two weeks follow up. 
It will be evaluated what the average leg pain score is in both treatment arms at two weeks 
follow up. It will be evaluated how long the effect lasts. 
The leg pain and functionality at 4 weeks after randomization will also be evaluated to get 
informed on the responsiveness on TEI in a somewhat later stage. 
 
Secondary study objectives:  
To evaluate the outcome of TEI in the first two weeks after randomization as a predictor of 
NRS leg pain at 14-16 and ca 26 weeks after onset of leg pain.  
Ideally, responsiveness to TEI can predict the clinical condition at 14-16 weeks after onset of 
sciatica. The hypothesis is that being non-responsive to TEI within two weeks, predicts an 
unsatisfactory condition after 14-16 weeks of suffering. This is the category of patients that in 
contemporary care in the Netherlands will be offered a surgical intervention. If our hypothesis 
is correct, in the future, this population of patients can be offered a surgical intervention at an 
earlier time point. 
The ca 26-week time point is chosen since in the Sciatica trial [2], both the conservative and 
the surgical group demonstrated comparable outcome data. 
Patients in this study are included while suffering from severe leg pain for 3-8 weeks. 
Presumably most patients will enter the study with 4-6 weeks of leg pain. This means that on 
average 10 weeks after randomization, the 14-16 week leg pain time point is reached. This 
means that 21 weeks after randomization the ca 26-week leg pain time point is reached. 
The response in NRS leg pain, ODI and patient satisfaction at 1 week after injection and at 2 
weeks after injection will be correlated to the value of these parameters at 10 and 21 weeks 
after randomisation. 
 
To evaluate the cost-effectivity of analgesic/anti-inflammatory epidural injections to relieve 
symptoms of early sciatica. 
 
A substantial portion of the patients in this study will eventually have an MRI of the lumbar 
spine. These MRIs will be evaluated according to our standard MRI evaluation protocol, that 
has been proven to generate additional successful conclusions and subsequent publications 
in the past [10-15]. Protruding disc, disc and vertebral end plate changes (MODIC) will be 
correlated to clinical data.  

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A portion of the patients in this study will eventually be operated. Disc material from these 
patients will be evaluated for the presence (and type) of macrophages and these data will be 
correlated to MRI and clinical data. These additional outcome measures can be combined 
with the research lines on etiology of sciatica that are executed in the Neurosurgery 
Department of the LUMC [16]. 

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3. STUDY DESIGN 
 
This is a prospective, open-label, randomized controlled trial on patients suffering from acute 
sciatica (3-8 weeks pain in the leg with a NRS ≥ 6) (see inclusion and exclusion criteria) in 
which consecutive patients who meet the inclusion criteria are invited to participate in the 
trial. The trial will take place at the Spaarne Gasthuis Hospital (SG) in Hoofddorp and 
Haarlem, the Netherlands in cooperation with researchers from Leiden University Medical 
Center (LUMC), Leiden, the Netherlands. Patient recruitment will occur at GP practices (GP 
collective Haarlemmermeer and Kennemerland, 185 GP’s). The GP will diagnose the patient 
and, if the patient is diagnosed with sciatica, refer to the study investigator. 
Eligible patients that are willing to participate are randomized to treatment with transforaminal 
epidural injections (treatment group) or standard conservative care (control group). 
Randomization will take place using block randomization in a 1:1 allocation ratio. Patients 
from the treatment group will be treated with TEI, oral pain medication and, if deemed 
necessary by the GP, physiotherapy. The control group will only receive oral pain medication 
and if deemed necessary additional physiotherapy. For this study, the control group will not 
include placebo injections since we want to compare treatment with injections to treatment 
without injections. The focus will not be on the type of medication that is contained in the 
injection. Furthermore, a control group without injections will demonstrate what percentage of 
patients will experience spontaneous relief of symptoms (only using medication and/or 
physiotherapy) as it is known that in a significant part of the patients sciatica resolves without 
any intervention. 
At baseline, clinical and demographic data are gathered for patients in both groups. Patients 
from the treatment group will receive TEI within 4 days after randomization. Patients from this 
group can receive multiple injections but an injection is only repeated after a certain interval 
time according to usual anaesthesiological guidelines. For all injections, details on timing, 
frequency and prevailing complications will be gathered. 
NRS leg pain that decreases below the value of 4 (on a 10 point scale) within two weeks 
after TEI is documented as successful effect of TEI. NRS leg pain that remains higher than a 
value of 4 at a time interval of two weeks after TEI makes a patient eligible for surgery if the 
patient requests for surgery. If surgery is requested by the patient (either in the control or 
intervention group), general guidelines for timing of surgery will be conducted, meaning that 
the patient is encouraged to postpone surgery till 14-16 weeks after onset of pain. This 
decision is made using Shared Decision Making and it is possible that the patient is operated 
before the 14-16 week time point. The patients who are randomized cannot be operated in 
the first two weeks after randomization, unless sudden loss of strength or a cauda equina 
syndrome is reported. We expect that during these two weeks TEI will have its effect. Four 

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weeks after randomization the outcome parameters are measured again to be informed on 
the late effect of TEI. Patients will be followed up for a total duration of 21 weeks starting 
from the moment of randomization. Questionnaires will be filled in at baseline, 1, 2, 4, 10 and 
21 weeks follow-up. A schematic overview of the study procedures is outlined in figure 1. 
Note that this figure does not hold into account that it is possible for patients randomized to 
the treatment group to receive additional injections if necessary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig.1 Flow diagram of study procedures 
 
 
Diagnosis sciatica by GP 
Inclusion/exclusion criteria 
Randomisation 
Transforaminal Epidural 
Injection by anaesthesiologist 
Oral pain medication by family 
doctor 
Follow up 1 week: NRS leg pain, NRS back pain, ODI, Likert, TEI data 
Follow up 2 weeks: NRS leg pain, NRS back pain, ODI, EQ-5D, Likert, Euro-QoL, TEI 
Follow up 4 weeks: NRS leg pain, NRS back pain, ODI, Likert, TEI data 
Follow up 10 weeks: NRS leg pain, NRS back pain, ODI, EQ-5D, Likert, Euro-QoL, TEI 
Baseline data/questionnaires 
Follow up 21 weeks: NRS leg pain, NRS back pain, ODI, EQ-5D, Likert, Euro-QoL, TEI 

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4. STUDY POPULATION 
 
4.1 Population (base)  
Patients suffering from sciatica that visit the general practitioner (GP collective 
Haarlemmermeer (60 GP) and Kennemerland (125 GP) referring to the Spaarne Gasthuis 
location Haarlem and location Hoofddorp (adherence 750.000 patients) are evaluated to be 
candidates for this study. If the general practitioner diagnoses a lumbar radicular syndrome 
(LRS) (sciatica) with an NRS leg pain of 6 points or more on a 10 points scale, and the 
duration of pain is longer than 3 weeks and shorter than 8 weeks, the patients are offered to 
participate in the RCT. If they are willing to consider participating in the RCT, the GP will 
send the contact details to the study investigator. Patients will be offered at least 48 hours to 
decide whether they want to be enrolled in the study. The study investigator will contact the 
patients and explain the study again. If patients are deciding to cooperate, informed consent 
will be signed. If patients are randomized to continue usual care, the GP will be informed and 
he/she will conduct conservative treatment as deemed suitable. If the patient is randomized 
to TEI, the patient is referred to the anaesthesiologist to receive TEI. TEI treatment will be 
received within 4 days. 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
▪ 
Sciatica; 
▪ 
Leg pain of 6 or more on a 10 point NRS (Numeric Rating Scale) scale with a 
duration of >3 and <8 weeks; 
▪ 
Patient is willing to accept the possible costs for the treatment by the pain 
physician 
▪ 
Informed consent. 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
▪ 
Age under 18 years;  
▪ 
Condition preventing to receive TEI (for instance, allergy for lidocaine); 
▪ 
Severe scoliosis; 
▪ 
TEI received in 6 months before randomization date; 
▪ 
Surgery for sciatica at the same level; 
▪ 
Surgery for sciatica at another level within one year before inclusion; 

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▪ 
Pregnancy. 
4.4 Sample size calculation 
We hypothesize that patients in the intervention group will have a mean NRS for leg pain of 
4.0 on a 10-point scale at two weeks after treatment with TEI and patients in the control 
group will have a mean NRS for leg pain of 5.5 two weeks after randomization. A difference 
of 1.5 points on the NRS scale will be considered clinically relevant [17]. With a standard 
deviation of 2.6 (according to results of Joswig [18]), a power of 90% and a level of 
significance of 5% 64 patients are needed per group. This is a total of 128 patients. With a 
loss to follow-up of 10% we aim to include 142 patients. 
 
 
 

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5. TREATMENT OF SUBJECTS 
 
5.1 Investigational product/treatment 
Patients are referred to the anaesthesiologist to receive TEI within 4 days after 
randomization. 
For injections below L3, where the space around the nerve root is larger and thus dilution of 
the injectable is more than in the area around the nerve root in the higher lumbar area 
(above L3), the dosage of the medication will be higher. 
For injections at L3 or below :1,5 ml lidocaine 2% and 40mg methylprednisolone acetate is 
injected transforaminally in close proximity of the nerve root, according to usual care 
For injections above L3: 1,5 ml lidocaine 1% and 10mg dexamethasone is injected 
transforaminally in close proximity of the nerve root, according to usual care. 
Administration of the injection will be performed in an outpatient clinic setting and will take 15 
minutes. After the procedure, the patient will stay at the recovery room for 30 minutes for 
monitoring. 
 
 
5.2 Use of co-intervention 
Oral pain reducing medication according to usual care is allowed. This is prescribed, if 
necessary, by the GP. Since it is a randomized controlled trial, it is reasonable to expect that 
participants in both treatment arms will demonstrate comparable variation in oral pain 
medication. 
 
5.3 Escape medication 
N.a. 

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6. METHODS 
6.1 Study parameters/endpoints 
6.1.1 Main study parameter/endpoint 
 
NRS leg pain: The pain intensity in the leg and the back will be measured with a 10-point 
horizontal Numeric Rating Scale (NRS), ranging from 0 (no pain) to 10 (worst imaginable 
pain). During each visit the NRS leg pain and NRS back pain will be scored. The patient is 
not entitled to see the pain scores indicated during previous visit(s). The NRS scores will be 
measured at baseline and at 1, 2, 4, 10 and 21 weeks after randomization. 
 
The average score for NRS leg pain at two weeks after injection is compared to the average 
score for NRS leg pain in the prolonged conservative care group, 2 weeks after 
randomization. This will be calculated again at 4 weeks after randomization. 
6.1.2 Secondary study parameters/endpoints  
 
Sciatica is not only characterized by pain in the leg, but also by discomfort in functioning. 
Therefore the following parameters will also be evaluated.  
 
NRS back pain: The pain intensity in the leg and the back will be measured with a 10-point 
horizontal Numeric Rating Scale (NRS), ranging from 0 (no pain) to 10 (worst imaginable 
pain). During each visit the NRS leg pain and NRS back pain will be scored. The patient is 
not entitled to see the pain scores indicated during previous visit(s). The NRS scores will be 
measured at baseline and at 1, 2, 4, 10 and 21 weeks after randomization. 
 
Oswestry Disability Index (ODI): The functionality of the patient with a focus on walking 
and daily activities will be measured with the Oswestry Disability Index that is usually 
measured for sciatica complaints. The scale ranges from 0 (no disability) to 50 (worst 
disability possible). During each visit the ODI will be scored. The patient is not entitled to see 
the scores indicated during previous visit(s). The ODI scores will be measured at baseline 
and at 1, 2, 4, 10 and 21 weeks after randomization. 
 
EuroQoL (EQ-5D): The EuroQoL (five point EQ-5D) will be used for the cost utility analysis. 
The tool measures five dimensions: mobility, self-care, daily activities, pain/discomfort, and 
anxiety/depression. Each dimension consists of one item, while three levels are distinguished 
(no problems, some problems, many problems). Use of the EuroQol needs to be registered 

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(euroqol.org). The EuroQol scores will be measured at baseline and at 2, 10 and 21 weeks 
after randomization. 
 
Quality of Life VAS (Health state utility VAS): To represent the patients perspective, utility 
will also be estimated using a VAS for the valuation of the patient’s health state (ranging from 
0 = as bad as death to 100 = perfect health), measured at baseline and at 2, 10 and 21 
weeks after randomization. 
 
Likert perceived recovery patient: To measure the perceived recovery a seven-point Likert 
scale will be used. The score on this scale varies from ‘completely recovered’ to ‘worse than 
ever’. The Likert scores will be measured at baseline and at 1, 2, 4, 10 and 21 weeks after 
randomization. 
 
Costs (Cost intervention, health care use, and loss of productivity): Cost diaries will be filled 
out at 10 and 21 weeks after randomisation. Health care utilization (including physiotherapy, 
visits to GP and specialists, nursing care and medication), patient costs, and absenteeism 
will be measured using cost diaries filled out by the patient.  
 
Complications: Post-TEI exacerbation of NRS leg pain (>1 point additional leg pain) that 
lasts for at least 24 hours will be documented as a clinically relevant complication of TEI. 
Other rare adverse events from treatment with TEI such as pain at site of injection, persisting 
numbness, vasovagal reaction, accidental discal puncture, accidental dural puncture or 
headache will be recorded as well. 
 
Radiological parameters: the level of disc herniation, the size and shape of disc herniation, 
disc degeneration (Pfirrmann scale), vertebral end plate changes, and facet degeneration 
(Weishaupt scale) will be evaluated by two independent researchers, blinded to clinical and 
histological data, on T2 weighted sagittal and transversal MRI. 
 
Histology: During surgery, the herniated disc material will be collected and fixed in 4% 
formaldehyde solution. For evaluation, the tissue will be subsequently embedded in paraffin 
blocks. These blocks will be stained with Hematoxylin and used for general macrophage 
staining (CD68), and subtype macrophage staining: M1(iNOS & CD40) and M2 (Arg1 & 
CD163), T cell staining (CD45-RO) and B cell staining (CD20). Furthermore, presence of 
Propionibacterium Acnes and Staphylococcus Epidermidis will be verified by PCR analysis 
for 16S rDNA. Positive samples will be gram stained for further identification of the bacteria. 

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All histological data will be quantified by two independent researchers, blinded to clinical and 
MRI data, and an inter-agreement analysis will be conducted. 
6.1.3 Other study parameters 
Data with respect to the following variables will be collected at baseline: 
- 
Demographic data; 
- 
Age, gender, length, weight, BMI, tobacco exposure, alcohol abuse; 
- 
History of previous radicular symptoms in the legs; 
- 
Usage of pain medication. 
 
Data with respect to the following items will be collected concerning TEI: 
- 
Timing of administration (days after randomization); 
- 
Number of injections and timing of those; 
- 
NRS leg pain after injection; 
- 
Other complications. 
Data during follow up will be collected: 
- 
If an MRI is performed: MRI data; 
- 
If surgery is performed: disc material for histology. 
 
 
6.2 Randomisation, blinding and treatment allocation 
Randomisation will take place using block randomisation in a 1:1 allocation ratio in order to 
obtain equal study groups. When the patient is enrolled, a randomization envelope will be 
opened to determine patient allocation. Since this is an open-label randomized controlled trial  
allocation is not concealed.  
 
6.3 Study procedures 
Patients that are diagnosed by the GP with acute sciatica (3-8 weeks after onset of pain, 
NRS ≥ 6) that meet in- and exclusion criteria will be offered the study. If patients are willing to 
be randomized, they will be contacted by the study investigator. The study investigator will 
inform the patients again and checks whether patients have access to e-mail. This is done to 
make sure that they can fill in the questionnaires online (a web-based database with 
questionnaires is used for data collection (Castor, LUMC)). The study investigator will ask for 
informed consent. Randomization will take place. If patients are randomized to the 
intervention group, they will be sent to the anaesthesiologist and planned for TEI within 4 
days after randomization without visiting the neurologist. If patients are randomized to the 

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control group, they will receive oral pain medication according to the care of the general 
practitioner. 
The patient will be invited to the hospital where baseline data will be gathered and 
questionnaires will be filled in. During this contact the study investigator will guide the patient 
through the online questionnaire fill-in procedure to get the patient accustomed with this 
procedure.  
Questionnaires will be filled in after 1, 2, 4, 10 and 21 weeks after randomization for both the 
control group and TEI group.  
If leg pain remains severe after the 2 weeks after randomization primary endpoint, patients 
can be referred to the neurologist if the general practitioner deems it necessary. Patients can 
be offered surgery if applicable. 
If an MRI is made during the process, MRI data will be gathered as mentioned above. 
If a lumbar discectomy is performed, disc tissue will be gathered during surgery and 
analysed as mentioned above. 
 
6.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
 
6.5 Replacement of individual subjects after withdrawal 
This will not be done. Subjects that refuse TEI after randomisation to the TEI group, will be 
considered as cross-over subjects. Patients that withdraw during the study will be considered 
lost-to-follow up patients. 
 
6.6 Follow-up of subjects withdrawn from treatment 
These subjects will be followed-up according to study protocol and considered as cross-over 
subjects. 
 
6.7 Premature termination of the study 
N.a. 
 
 

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7. SAFETY REPORTING 
7.1 Temporary halt for reasons of subject safety 
 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardise subject health or 
safety. The sponsor will notify the accredited Medical Ethical Committee (METC) without 
undue delay of a temporary halt including the reason for such an action. The study will be 
suspended pending a further positive decision by the accredited METC. The investigator will 
take care that all subjects are kept informed.  
 
7.2 AEs, SAEs and SUSARs 
7.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to TEI. All adverse events reported spontaneously 
by the subject or observed by the investigator or his staff will be recorded. 
Adverse events from treatment with TEI are rare. The most common adverse events 
reported in literature are [19]: 
- 
Transient exacerbation of pain: 2.4% 
- 
Pain at site of injection: 1.1% 
- 
Persisting numbness: 0.33% 
- 
Vasovagal reaction: 0.14% 
- 
Accidental discal puncture: 0-1% 
- 
Accidental dural puncture: 2.3% 
- 
(Post dura puncture) headache: 0.33-1% 
This includes also includes leg pain/inability as a result of TEI that:  
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in significant disability or incapacity; 
 
7.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 

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- 
any other important medical event that did not result in any of the outcomes listed 
above due to TEI but could have been based upon appropriate judgement by the 
investigator. 
 
In literature, arachnoiditis and ‘nervous system disorder’ have been described as major 
complications. However, despite the lack of exact data, these complications are considered 
to be rare [19]. 
 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the subsidizing party without undue delay after 
obtaining knowledge of the events. 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result in 
death or are life threatening followed by a period of maximum of 8 days to complete the initial 
preliminary report. All other SAEs will be reported within a period of maximum 15 days after 
the sponsor has first knowledge of the serious adverse events. 
 
7.3 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol. 
 
 
 
 

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8. STATISTICAL ANALYSIS 
8.1 Primary study parameter(s) 
The study data will be analysed according to the intention-to –treat principle. The mean NRS 
for leg pain will be compared between the two groups using the unpaired t-test. This will also 
be done at the 4-week time point. 
 
8.2 Secondary study parameter(s)  
The absolute decline in NRS leg pain, NRS back pain and ODI and increase in EQ5D from 
baseline to 2 weeks after randomization will be calculated using t-tests. The same will be 
done for the baseline to 4 weeks after randomization time point (using t-tests).  
Perceived recovery Likert data will be dichotomized (1 and 2 is success, 3-7 is no success) 
and compared at 2 and 4 weeks after randomization or injection and to 14 and 26 weeks 
after start of severe leg pain using Chi-square tests. 
 
The 2-week success data will be correlated to the success data after 14 weeks and 
subsequently for 26 weeks using Chi-square tests to make predictions. Logistic regression 
analysis will be used to correlate 2-week (and 4-week) success data to the absolute data for 
NRS leg pain, NRS back pain, ODI, increase in EQ5D at 14 and 26 weeks. 
 
Cost effectivity analysis:  
The economic evaluation will consist of a cost-effectiveness analysis from a healthcare 
perspective (CEA: costs per extra patient with symptom relieve, i.e. the primary outcome 
measure) and a cost-utility analysis from a societal perspective (CUA: costs per QALY). Both 
analyses will be trial-based, using patient reports, with a half-year time horizon. Healthcare 
use will be valued according to the Dutch guidelines. QALYs will be calculated as the area 
under the utility curve, estimated using the Dutch tariff for the EQ-5D. As sensitivity analysis, 
QALYs will also be calculated using the VAS for quality of life (with power transformation). 
Average costs and patient outcome will be compared according to intention-to-treat, using 
net-benefit analysis, and using multiple imputation to account for missing data. 
 
8.3 Other study parameters 
 
MRI: the level of disc herniation on MRI will be compared to the clinical diagnosis (made 
before MRI) and the percentage of clinical diagnosis prediction success can be calculated. 

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The size and shape of disc herniation, disc degeneration (Pfirrman scale), vertebral end plate 
changes, and facet degeneration (Weishaupt scale) will be correlated to baseline clinical 
data using t-tests. 
Histology: the number of M1 and M2 macrophages will be correlated to NRS leg pain and 
ODI at all time points using t-tests and mixed models analysis. 
 

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9. ETHICAL CONSIDERATIONS 
9.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (version 
2018, 9 July 2018, www.wma.net) and in accordance with the Medical Research Involving 
Human Subjects Act (WMO). 
 
9.2 Recruitment and consent 
Patients that present at the GP with acute sciatica (3-8 weeks after onset of pain, NRS ≥ 6) 
that meet in- and exclusion criteria will be offered the study. If patients are willing to be 
randomized (48 hours’ time of consideration), they will be contacted by the study 
investigator. The study investigator will inform the patients again and checks whether 
patients have access to e-mail. This is done to make sure that they can fill in the 
questionnaires online (a web-based database with questionnaires is used for data collection 
(Castor, LUMC)). The study investigator will ask for informed consent.  
 
9.3 Compensation for injury 
The Spaarne Gasthuis, where the study is conducted has a liability insurance which is in 
accordance with article 7 of the WMO. 
  
The Spaarne Gasthuis (also) has an insurance which is in accordance with the legal 
requirements in the Netherlands (Article 7 WMO). This insurance provides cover for damage 
to research subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
9.4 Incentives  
For each patient that is randomised, the GP, that offered the study to the patient will receive 
a financial compensation of 25 euros.  
 

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10. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
10.1 Handling and storage of data and documents 
Data will be collected using Castor EDC (web based secured system provided by LUMC). 
Baseline data will be collected during inclusion of the participant and directly registered in 
Castor by a researcher from the LUMC. Data on TEI, MRI and lumbar surgery will be 
collected from the electronic patient system Epic in Spaarne Gasthuis by the treating 
physician and by a researcher from the LUMC and processed in Castor. Specific data on the 
TEI procedure will be filled in on a paper CRF by the anaesthesiologist and subsequently 
processed by a researcher from the LUMC in Castor. Other data will be collected at 
predefined follow-up moments through digital questionnaires that the participants will fill in at 
home. These will be processed automatically in Castor. Castor EDC will code the patient 
data into untraceable ID’s. All data will be safeguarded and stored for 15 years after the 
study is finished. All data will be handled according to the guidelines of GRP. This obligates 
all researchers to comply to the quality assurance standards, which include monitoring, risk 
assessment, privacy of patient data, and transparency of information to the patient. The 
LUMC will be responsible for the processing of data. 
In order to warrant privacy patient data and disc material will be coded. Only with the key 
data can be traced back to a specific individual. The key is securely saved at the local 
research site and only the principal investigator, research monitor and Healthcare and Youth 
Inspection (Inspectie Gezondheidszorg en Jeugd) will have access to the key. No traceable 
data will be published. Patients will give permission for these authorities to access the key 
and their personal data through the informed consent. At any moment patients can withdraw 
their permission. Data collected before withdrawal of consent will be used. If disc material 
has been collected, it will be destroyed after withdrawal of consent. Analyses of disc material 
performed before withdrawal of consent will be used. 
 
10.2 Monitoring and Quality Assurance 
Monitoring and quality assurance will be done according to the LUMC standard protocol. The 
monitoring and quality assurance will be done by a member of the SAINTS research group. 
A monitoring plan will be created in cooperation with the monitoring coordinator from the 
LUMC after approval of the protocol by the METC. 
 

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10.3 Amendments 
Amendments are changes made to the research after a favourable opinion by the accredited 
METC has been given. All amendments  will be notified to the METC that gave a favourable 
opinion. 
 
10.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments. 
 
10.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC within 15 
days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC. 
 
10.6 Public disclosure and publication policy 
The results from this trial will be published in international peer reviewed journals. Results 
will be presented on international spine and pain congresses. Furthermore, the results can 
influence the usual care in the Netherlands and will subsequently be offered to be considered 
by (inter)national guideline-authors for treatment of sciatica.  
 
 

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11. STRUCTURED RISK ANALYSIS 
 
 
11.1 Potential issues of concern 
N.a. 
 
11.2 Synthesis 
Administration of TEI with dexamethasone has been tested extensively on human beings 
through numerous (randomized controlled) trials. In the Netherlands, this therapy is now 
considered usual care for patients suffering from sciatica. Dexamethasone is registered to be 
used for TEI therapy. The same holds true for the administration of lidocaine. 
The study population will only consist of sciatica patients that would have been eligible to 
receive TEI through usual medical care. In order to minimize risks from treatment with TEI 
exclusion criteria have been composed: patients that have a condition that prevents them to 
receive TEI, that have received TEI in 6 months before randomisation or that are pregnant 
will be excluded from participation. After administration of the injection, patients will shortly 
stay at the recovery room where they will be monitored. Since TEI treatment is considered 
usual care additional measurements are not necessary. Current monitoring standards are 
believed to be sufficient and therefore we do not establish a DSMB or safety committee.  

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Anesthesiologie. (2016). Protocol Veilig gebruik van epidurale corticosteroïden infiltraties. 
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