Prospective Hounsfield Unit Measurements of Intercorporal Bone Grafts Remodelling Towards Spinal Fusion
Conditions: Spondylolisthesis, Spinal Fusion
Sponsor: Rijnstate Hospital

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TEMPLATE RESEARCH PROTOCOL 
(September 2018) 
 
- 
May 2015: adaptation section 11.5: text in accordance to old and new Measure regarding 
Compulsory Insurance for Clinical Research in Humans  
- 
Sept 2015: adaptation section 9.1, 9.2 and 12.5: text in accordance to WMO amendment 
on reporting SAE and temporary halt (section 10 of WMO) 
- 
Oct 2015: adaptation section 4.4 – comment [CCMO15], 8.2 and 10.1 with respect to 
methodology/statistics 
- 
Sept 2018: adaptation section 12.1 and comment [CCMO46] due to applicability GDPR 
as of May, 2018 
 
 
 

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PROTOCOL TITLE ‘Prospective Hounsfield Unit measurements of intercorporal bone grafts 
remodelling towards spinal fusion’. 
Protocol ID 
NL81678.091.22  
Short title 
Intercorporal Bone Graft Measurement 
Study 
EudraCT number  
N/A  
Version 
4 
Date 
09-09-2022 
Coordinating investigator/project leader 
 
Drs. Joey F.H. Reijmer 
Ziekenhuis Rijnstate 
Secretariaat Orthopedie (1191) 
Antwoordnummer 111 
6800 WC Arnhem 
Principal 
investigator(s) 
(in 
Dutch: 
hoofdonderzoeker/ uitvoerder) 
 
Dr. Job L.C. van Susante 
Ziekenhuis Rijnstate 
Secretariaat Orthopedie (1191) 
Antwoordnummer 111 
6800 WC Arnhem 
 
Dr. Lex D. de Jong 
Ziekenhuis Rijnstate 
Secretariaat Orthopedie (1191) 

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Antwoordnummer 111 
6800 WC Arnhem  
Sponsor 
(in 
Dutch: 
verrichter/opdrachtgever) 
Rijnstate Hospital 
Subsidising party 
Rijnstate Hospital 
Independent expert (s) 
Prof. dr. Eric J. Hazebroek 
Laboratory sites <if applicable> 
N/A 
Pharmacy <if applicable> 
N/A  

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PROTOCOL SIGNATURE SHEET 
Name 
Signature 
Date 
Head of Department: 
 
Drs. 
Claudia 
de 
Swart, 
Manager Zorg Rijnstate Clinics 
 
[Coordinating 
Investigator/Project 
leader/Principal Investigator]: 
Dr. 
Job 
van 
Susante, 
Orthopaedic Surgeon. 
 
 
 
 

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TABLE OF CONTENTS 
1. 
INTRODUCTION AND RATIONALE ...................................................................................... 11 
2. 
OBJECTIVES .................................................................................................................. 14 
3. 
STUDY DESIGN .............................................................................................................. 14 
4. 
STUDY POPULATION ....................................................................................................... 15 
4.1 
Population (base) ...................................................................................................... 15 
4.2 
Inclusion criteria ........................................................................................................ 15 
4.3 
Exclusion criteria ....................................................................................................... 15 
4.4 
Sample size calculation ............................................................................................... 15 
5. 
TREATMENT OF SUBJECTS .............................................................................................. 16 
6. 
INVESTIGATIONAL PRODUCT............................................................................................ 16 
7. 
NON-INVESTIGATIONAL PRODUCT .................................................................................... 16 
8. 
METHODS ..................................................................................................................... 16 
8.1 
Study parameters/endpoints ......................................................................................... 16 
8.1.1 
Main study parameter/endpoint .................................................................................. 16 
8.2 
Randomisation, blinding and treatment allocation ................................................................ 17 
8.3 
Study procedures ...................................................................................................... 17 
8.4 
Withdrawal of individual subjects .................................................................................... 17 
8.4.1 
Specific criteria for withdrawal .................................................................................... 17 
8.5 
Replacement of individual subjects after withdrawal ............................................................. 17 
8.6 
Follow-up of subjects withdrawn from treatment .................................................................. 18 
8.7 
Premature termination of the study ................................................................................. 18 
9. 
SAFETY REPORTING ....................................................................................................... 18 
9.1 
Temporary halt for reasons of subject safety ...................................................................... 18 
9.2 
AEs, SAEs and SUSARs ............................................................................................. 18 
9.3 
Annual safety report ................................................................................................... 18 
9.4 
Follow-up of adverse events ......................................................................................... 19 
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] ................................................... 19 
10. 
STATISTICAL ANALYSIS................................................................................................ 19 
10.1 
Primary study parameter(s) .......................................................................................... 19 
10.2 
Other study parameters ............................................................................................... 20 
10.3 
Interim analysis (if applicable) ....................................................................................... 20 
11. 
ETHICAL CONSIDERATIONS .......................................................................................... 20 
11.1 
Regulation statement .................................................................................................. 20 
11.2 
Recruitment and consent ............................................................................................. 21 
11.3 
Objection by minors or incapacitated subjects (if applicable) ................................................... 21 
11.4 
Benefits and risks assessment, group relatedness ............................................................... 21 
11.5 
Compensation for injury ............................................................................................... 22 
11.6 
Incentives (if applicable) .............................................................................................. 23 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ............................................. 23 
12.1 
Handling and storage of data and documents ..................................................................... 23 
12.2 
Monitoring and Quality Assurance .................................................................................. 24 
12.3 
Amendments ............................................................................................................ 24 

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12.4 
Annual progress report ................................................................................................ 24 
12.5 
Temporary halt and (prematurely) end of study report ........................................................... 24 
12.6 
Public disclosure and publication policy ............................................................................ 25 
13. 
STRUCTURED RISK ANALYSIS ....................................................................................... 25 
14. 
REFERENCES ............................................................................................................ 25 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
ABR 
General Assessment and Registration form (ABR form), the application form 
that is required for submission to the accredited Ethics Committee; in Dutch: 
Algemeen Beoordelings- en Registratieformulier (ABR-formulier) 
AE 
Adverse Event 
AR 
ASA 
Adverse Reaction 
American Society of Anesthesiologists 
AVG 
Algemeen Verordening Gegevensbescherming 
BMD 
BMI 
Bone Mineral Density 
Body Mass Index 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CT 
CV 
Computed Tomography 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
HU 
Hounsfield Units 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
METC 
 
mSv 
 
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
Milliesievert 

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NCS 
 
PIF 
PLIF 
Netherlands Commision for Radiation Dosimetry, in Dutch: Nederlandse 
Commissie voor Stralingdosimetrie 
Patient Information Folder 
Posterior Lumbar Interbody Fusion  
ROI 
(S)AE 
Region Of Interest 
(Serious) Adverse Event  
SOI 
Slide Of Interest 
STZ 
Samenwerkende Topklinische Ziekenhuizen 
SUSAR 
TLIF  
Suspected Unexpected Serious Adverse Reaction 
Transforaminal Lumbar Interbody Fusion 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; in 
Dutch: Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
3D 
Three dimensional 
 
 

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SUMMARY 
Background: Lumbar spinal fusion is a surgical procedure that is widely being used to treat 
spinal pathology. The ultimate goal of this surgical procedure is to achieve bony fusion between 
two adjacent vertebrae throughout the disc space behind an interbody cage. To date there is a 
lack of knowledge about the biological process of intercorporal bone graft remodelling towards 
successful lumbar spine fusion and its association with the development of back and/or leg pain. 
There is also no quantitative and objective tool available to help determine whether solid fusion 
has occurred or is in development. Consecutive Hounsfield Unit (HU) measurements may act 
as a valuable proxy measure for bone graft remodelling and assist in predicting fusion or non-
fusion. Results of a recent feasibility study have shown that it was feasible to establish the HU 
values of the grafted region of interest on consecutive CT-slices using a standardized 
measurement protocol with excellent intraobserver reliability. However, this study was 
conducted using available one-year and two-year CT-data from nine participants only. This 
limited insight into the development of HU values over time and thus the process of bone graft 
remodelling in the first year after surgery. 
 
Aim and objectives: The main aim of this study is to further the knowledge gained during a 
recent feasibility study by exploring the use of HU measurements as a quantitative and reliable 
tool to assess intercorporal bone graft remodelling towards lumbar interbody fusion. Specific 
objectives of this study are: 
1) to explore how the participants’ intercorporal bone grafts HU develop over time in the first two 
years after fusion surgery. 
2) to explore the interobserver reliability of the HU measurements. 
3) to explore if the participants’ upward, downward or no trend in HU values correlate with trends 
of scores on a commonly used interbody fusion classification and the degree of back and leg 
pain. 
 

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Method: This is an exploratory prospective cohort study using 30 patients between the ages of 
45 and 80 with a symptomatic spondylolisthesis (lytic/degenerative/iatrogenic) requiring single-
level lumbar interbody fusion (PLIF/TLIF). Participants will be asked to undergo 4 low-dose 
postoperative CT-scans of the fusion segment over a two year period. 
 
Intervention (if applicable): N/A. 
 
Main study parameters/endpoints: The main outcome of interest will be the participants’ 
individual and group (mean, SD) Hounsfield Unit values of their intercorporal bone graft(s) as 
calculated from their (four) CT-scans. We will use the standardized HU measurement protocol 
developed during a feasibility study. The HU will be determined independently by three 
observers. Secondary outcomes include the Oswestry Low Back Pain Disability Questionnaire 
(ODI), Short Form-36 (RAND-36), Visual Analogue Scale (VAS) for back and leg pain and the 
intercorporal fusion result criteria by Brantigan et al.  
 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness: In this study, participants will be asked to undergo four low-dose CT-scans of their 
instrumented segment over a two year period during their regular care hospital visits. By taking 
several measures, the patient’s effective dose of radiation exposure during the study will be 
around 7.2 mSV compared to the 3.0 mSv during regular care. As such, compared to regular 
care, participants will be exposed to a slightly higher dose of radiation by participating in this 
study. 
 
 
 
 
 
 

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1. INTRODUCTION AND RATIONALE 
Lumbar spinal fusion is a surgical procedure that is widely being used to treat spinal deformities, 
spondylolisthesis, spondylolysis, spinal instability, and degenerative disc disease [1]. To date, 
posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF) are 
the most widely used techniques [2]. Consensus regarding a superior technique is lacking [3]. 
During both these surgical techniques the orthopaedic surgeon uses a dorsal approach to 
remove the intervertebral disc, inserts an intervertebral cage for stability purpose when deemed 
appropriate, and impacts autologous decompressive bone behind the cage [2]. Over time, this 
non-vital bone graft can remodel towards new vital bone and subsequently creates a sustainable 
fusion between two adjacent lumbar vertebral bodies. However, in case of resorption of the bone 
graft or insufficient bone remodelling, solid bridging of bone may fail to develop and this may 
result in a pseudarthrosis or non-union. These clinically important complications appear in 5% 
to 35% of patients treated with spinal fusion and may in turn lead to pain and a decrease in 
functional status [4]. When bone graft remodelling fails and solid fusion does not occur, 
subsequent revision surgery for symptomatic pseudarthrosis is often needed. This occurs in up 
to 24% of patients treated with a fusion [5]. The ultimate goal of a PLIF/TLIF procedure is to 
achieve bony fusion between two adjacent vertebrae throughout the disc space behind the cage. 
In order to monitor and evaluate bony fusion, radiographic evaluation using conventional 
radiographs or CT-scans are commonly used [6-9]. An orthopeadic surgeon can use several 
existing scoring criteria (e.g. [10-12]) to judge and quantify the degree of bone remodelling and 
solid bony bridging based on these radiographs. However, these scoring criteria are rather 
subjective and research has shown that the inter-observer agreement of these scoring criteria 
is relatively low [6, 11]. The problem is that, to date, there is no quantitative and objective tool 
available to quantify the bone remodelling process and to judge whether vertebrae have fused 
or not. In fact, there is an overall dearth of knowledge about the biological process of ongoing 
spinal fusion and its association with the development of back and/or leg pain. 
 

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Hounsfield Units (HU) correlate with bone mineral density (BMD) values and are already used 
to determine bone quality on CT-imaging [13-18]. However, BMD values are generated using 
two-dimensional dual-energy X-ray absorptiometry (DEXA) scans which are hindered by 
overprojection from the iliac crest. This prevents the disc space from being properly scanned. 
As such, CT-based HU measurements in the interbody graft can be considered as a more 
suitable proxy measure for the biological remodelling process after spinal fusion. To quantify 
changes of the grafted disc space over time, repeated CT scans are necessary from early after 
surgery to at least two years after surgery. The four CT-scans taken during this timeframe will 
provide the necessary radiological imagery to measure the bone grafts’ HU and adequately 
capture the participants’ HU trajectories, thereby elucidating the process of bone remodelling 
and monitoring the quality and progression of ongoing interbody fusion [10, 11]. For example, 
patients who clearly show bone remodelling towards fusion (increasing trajectory of HU values) 
may be monitored less frequently after surgery. This may potentially decrease patient burden 
(number of hospital visits, travel expenses, radiation exposure because of less radiographs 
needed) and decrease expenses for health care in general. Conversely, patients who show 
stationary or decreasing trajectories of HU values combined with lasting complaints of back 
and/or leg pain, may be followed-up more regularly in order to monitor the development of 
potential complications (such as pseudarthrosis or non-union) and assist in decision-making 
regarding the need for re-operation. 
 
Because the use of HU measurements as a means to evaluate bone graft formation after lumbar 
interbody fusion surgery is scarce, we explored whether it was feasible to assess intercorporal 
bone graft remodelling by determining CT-based values of HU after lumbar spondylodesis (see 
Figure 1), and to explore trends in the individual changes in HU over time (see Figure 2) [19]. 
The research study proposed in this protocol will build upon the results of this study in an effort 
to further the state of the art in this important field of orthopaedics. 

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Figure 1 An example of the free-hand 
drawn regions of interest (ROI) includ-
ing intercorporal bone graft at one (left) 
and two (right) years after surgery. The 
cage markers, which acted as refer-
ence points beyond which the ROI was 
demarcated (posteriorly), are clearly 
visible on both scans. In this example 
HU increased from 488 HU to 536 HU 
over time. 
 
 
To date only two feasibility studies with relatively small sample sizes have reported on the value 
of HU measurements to evaluate bone graft remodelling after lumbar interbody fusion surgery. 
In one previous cross-sectional study [20] published almost 18 years ago, HU measurements 
were only performed once in the first year after spinal fusion surgery. As such, no information 
with regards to the evolution of bone graft HU over time after fusion surgery were obtained. This 
study prompted us to perform a retrospective feasibility study [19] during which we i) explored 
whether it was feasible to quantify intercorporal bone graft remodelling over time by determining 
CT-based values of HU after lumbar spondylodesis, and ii) to explore trends in the individual 
changes in HU over time in the second year after fusion surgery as a proxy measure of the bone 
graft remodelling process towards intercorporal fusion or non-fusion. The results of this study 
showed that the HU measurement procedure developed for the study had excellent 
intraobserver reliability. The results also suggested that prospective follow-up of CT-based HU 
measurements could potentially be used as a way to judge whether the patients’ bone 
remodelling process is developing towards successful fusion or non-fusion (see Figure 2). 
However, limitations of this study included a small sample (n = 9), the absence of postoperative 
CT-images made during the first weeks after surgery and the absence of information about the 
participants’ postoperative back and leg pain. This limited insight into the progression of pain 
and the process of bone graft remodelling, over time in the first year after surgery. To overcome 
these limitations we want to conduct a prospective study using a larger sample (n = 30) and 
incorporate CT-scanning in the first week after surgery, and again after 6, 12 and 24 months. 

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This method is also well suited to explore the interobserver reliability of our measurement 
procedure. 
 
 
 
 
 
 
 
 
 
 
 
Figure 2 Changes in bone graft HU over time. The 
change in HU from one- to two-years postoperative. 
Each line represents a unique patient. Source:[19] 
 
2. OBJECTIVES 
This study has three specific objectives: 
1) to explore how the participants’ intercorporal bone grafts HU develop over time in the first two 
years after fusion surgery. 
2) to explore the interobserver reliability of the HU measurements. 
3) to explore if the participants’ upward, downward or no trend in HU values correlate with trends 
of scores on a commonly used interbody fusion classification and the degree of back and/or leg 
pain. 
 
3. STUDY DESIGN 
This is a single-center prospective exploratory study. During this study a convenience sample 
of participants, who have undergone lumbar spinal fusion in Rijnstate Hospital and who have 
agreed to participate in the study, will have (four) CT-scans of the lumbar spine taken in the first 
two years after surgery: one in the first week after surgery and one again after 6, 12 and 24 
months. Clinical outcome questionnaires will also be obtained during those set times. 
 

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4. STUDY POPULATION 
4.1 Population (base)  
We 
will 
recruit 
30 
patients 
with 
a 
symptomatic 
spondylolisthesis 
(lytic/degenerative/iatrogenic) who have an indication for single level lumbar interbody fusion 
(PLIF/TLIF).  
4.2 Inclusion criteria 
Patients are only eligible for participation if they i) were non-responsive to non-operative 
treatment in the six months prior to study enrolment, ii) have fusion indicated for only one 
segment in the L1 to S1/ilium region and iii) are between the age of 45 and 80.  
4.3 Exclusion criteria 
Patients will be excluded from participation if they i) will receive revision spine surgery, ii) do 
not want to provide informed consent or when iii) pregnant or expecting to be pregnant within 
in the next two years.  
4.4 Sample size calculation 
To our knowledge, no previous studies have evaluated differences in HU values of 
intercorporal bone grafts over time. Because of the lack of data, establishing the sample 
size needed is challenging. However, the results of our recently conducted feasibility study 
(n = 9) [19] have shown that participants had a mean HU value of around 448 (SD ± 145) 
after one year, and a mean HU value of around 483 (SD ± 142) after two years, 
respectively. The expected mean of the paired differences was approximately 35 and the 
expected standard deviation of the paired differences was approximately 64. Although it is 
not the aim of this study to calculate whether there are statistically significant differences in 
the participants’ HU values over time (but rather to evaluate if and how HU values change 
over time postoperatively) we chose to perform a sample size calculation (for comparing 

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paired differences) as to prevent inviting too little or too many participants for the CT-scans. 
To achieve a power of 80% and a level of significance of 5% (two-sided) for detecting a 
mean of the differences of 35 between pairs, 29 participants would be needed 
(http://statulator.com/SampleSize/ss2PM.html). To compensate for possible participant 
drop-out (which in our experience is minimal in these types of studies) we aim to recruit 30 
participants. 
 
5. TREATMENT OF SUBJECTS 
N/A 
6. INVESTIGATIONAL PRODUCT  
N/A  
7. NON-INVESTIGATIONAL PRODUCT 
N/A 
8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
The main outcome of interest will be the participants’ individual and group (mean, SD) 
Hounsfield Unit values of their intercorporal bone graft(s) as calculated from their (four) 
CT-scans. We will use the standardized HU measurement protocol developed during a 
feasibility study. The HU will be assessed independently by three observers. 
8.1.2 Secondary study parameter/endpoint 

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Secondary outcomes include the Oswestry Low Back Pain Disability Questionnaire 
(ODI), Research and Development-36 (RAND-36), Visual Analogue Scale (VAS) for 
back and leg pain and the intercorporal fusion result criteria by Brantigan et al. (figure 
3). The questionnaires can be found in the Appendix section of this protocol.  
8.2 Randomisation, blinding and treatment allocation 
N/A 
8.3 Study procedures 
After surgery, participants will undergo a total of four postoperative CT-scans of the lumbar 
spine: one in the first week after surgery and one again after 6, 12 and 24 months. 
8.4 Withdrawal of individual subjects 
Participants 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 participant from the study for any 
medical reasons.  
8.4.1 Specific criteria for withdrawal 
Participants who have received a too low amount of intervertebral bone graft that 
precludes proper assessment of HU (as judged by a radiologist) will be withdrawn from 
the study after the first study CT-scan. These participants will subsequently be followed-
up as per regular care. 
8.5 Replacement of individual subjects after withdrawal 
N/A 

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8.6 Follow-up of subjects withdrawn from treatment 
N/A 
8.7 Premature termination of the study 
The study will be terminated if no more than 15 participants have provided their Informed 
Consent (IC) within nine months after the start of the study. All included participants will be 
notified in case of premature termination of the study. 
9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance with 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 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.  
9.2 AEs, SAEs and SUSARs 
All serious or life-threatening SAEs will be directly reported to the principal investigator and 
this will also be presented to the reviewing adjudication committee within the set dates of 7 
days. Non-life-threatening SAEs will be presented to the reviewing committee within 15 days 
after notification.  
9.3 Annual safety report 
N/A 

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9.4 Follow-up of adverse events 
N/A 
9.5 [Data Safety Monitoring Board (DSMB) / Safety Committee] 
N/A 
10. STATISTICAL ANALYSIS 
The participant characteristics, spinal fusion surgery-related data and secondary outcomes will 
be summarized in terms of frequencies (percentages of total), medians (interquartile range ) or 
means (standard deviations). 
The HU measurement values will be presented descriptively in terms of individual values and 
group means (standard deviations). We will also plot the HU trajectories using line graphs to 
illustrate how the HU of individual participants have developed over time. 
To evaluate the interobserver reliability of the HU measurements we will calculate Intraclass 
Correlation Coefficients (95% confidence interval) between the three observers using the single-
rating, absolute agreement, two-way random-effects model. 
To calculate the association between the participants’ upward, downward or no trend in HU 
values, the trend in scores on the interbody fusion classification by Brantigan and pain scores 
we will calculate Chi-square tests for trend. 
 
10.1 Primary study parameter(s) 
The main outcome of interest will be the participants’ individual and group (mean, SD) 
Hounsfield Unit values of their intercorporal bone graft(s) as calculated from their (four) CT-
scans. We will use the standardized HU measurement protocol developed during a feasibility 
study. The HU will be determined independently by three observers. 
 

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10.2 Other study parameters 
The secondary outcomes include the Oswestry Low Back Pain Disability Questionnaire 
(ODI), Research and Development-36 (RAND-36), Visual Analogue Scale (VAS) for back 
and leg pain and the intercorporal fusion result criteria by Brantigan et al. [10] (see Figure 3). 
The baseline questionnaires are sent to the patient within 2 days after enrollment and follow-
up questionnaires are sent to the patients within 2 days upon completion of the follow-up CT-
scan.  
 
Figure 3 The 5-point intercorporal fusion criteria by Brantigan et al. 
10.3 Interim analysis (if applicable) 
N/A  
11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki (as 
adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended 
by the 64th WMA General Assembly, October 2013, Fortaleze, Brazil) and in accordance 
with the Dutch Medical Research Involving Human Subjects Act (WMO). 

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11.2 Recruitment and consent 
First, potential eligible participants will be approached by their treating orthopedic surgeon 
who will introduce the study and thereafter handing or sending them a Patient Information 
Form (PIF) which includes the Informed Consent Form (IC, see Appendix C). One week 
after handing or sending the PIF/IC, the coordinating researcher will contact the patient by 
phone to ask whether the patient has any questions about the study, and whether he/she 
is willing to participate. Participants willing to participate will be asked to sign and return the 
IC to the coordinating researcher. 
11.3 Objection by minors or incapacitated subjects (if applicable) 
N/A 
11.4 Benefits and risks assessment, group relatedness 
Participating in this study has no benefits for participants. 
 
Participants will be asked to undergo four low-dose CT-scans of the instrumented segment 
over a two year period. During standard care, fusion patients undergo three conventional 
lumbar radiographs (after 6 weeks, 3 months, and 1 year) and one CT-scan (after 1 year). In 
our hospital, the effective median exposure doses of standard lumbar radiographs and CT-
scans are 0.2 mSv and 2.4 mSv, respectively. This exposes each patient to a total radiation 
dose of (3 x 0.2 + 1 x 2.4) = 3.0 mSv in one year. Without taking any additional measures, 
four ‘study’ CT-scans would expose the participants to a total radiation dose of (4 x 2.4 =) 9.6 
mSv over a two year period. To mitigate this increased radiation risk, and to lower the 
participants’ radiation exposure during the study, we will: 
1) focus the CT-scan of the lumbar region on the instrumented segment only (2 instead of 
the regular 6-7 vertebral bodies). This measure will reduce the radiation dose by 0.6 mSv 

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(and to a total of 1.8 mSv per CT-scan), and hence reduce the overall CT-based radiation 
dose by (4 x 0.6 =) 2.4 mSv. 
2) replace the conventional lumbar radiographs by the study CT-scans. This measure will 
prevent participants from also receiving a standard radiation dose of 3 x 0.2 = 0.6 mSv from 
the radiographs. 
 
By taking the above two measures, the patient’s effective dose of radiation exposure during 
the study will be around 7.2 mSV compared to the 3.0 mSv during regular care. As such, 
compared to regular care, participants will be exposed to a slightly higher dose of radiation 
by participating in this study. It is also of note that we will only recruit patients over the age of 
45. In this age group the lifetime risk of radiation induced carcinogenesis is known to decline 
rapidly [21, 22]. 
 
Considering the above, and applying the risk classification as proposed by the Dutch 
Commission for Radiation Dosimetry (NCS) [23] the additional radiation risk is moderate 
(“matig risico”, category IIb). We believe that the benefits, of gaining insight in how patients’ 
intercorporal bone grafts HU develop over time in the first two years after fusion surgery, and 
if the patients’ upward, downward or no trend in HU values correlate with trends of scores on 
a commonly used interbody fusion classification and the degree of back and leg pain, 
outweighs this risk. 
11.5 Compensation for injury 
This research falls under the scope of the WMO. Rijnstate has a liability insurance which is 
in accordance with article 7 of the WMO. The sponsor (also) has an insurance which is in 
accordance with the legal requirements in the Netherlands (Article 7 of the WMO). This 
insurance provides cover for the unlikely damage to research subjects through injury or 
death caused by the study. 

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11.6 Incentives (if applicable) 
N/A  
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
All data handling and storage will comply with the EU General Data Protection Regulation 
and the Dutch Act on Implementation of the General Data Protection Regulation (Dutch: 
Uitvoeringswet AVG). All data collected during this study will be managed according to the 
FAIR principles in order to enhance and improve Findability, Accessibility, Interoperability 
and Reuse of research data. All research and patient related data will be stored in Research 
Manager, a cloud based data storage system with ISO 27001: 2013 certification as well as 
Good Clinical Practice (GCP) and NEN7510 compliancy. 
The coordinating investigator/project leader (JFHR) will collect the patient source data from 
the electronic patient records. These data comprise the participant’s hospital identification 
number, their patient characteristics and spinal fusion surgery-related data. All patient data 
will be handled confidentially. Each subject will be given an identification code and only the 
investigators involved in this study will have access to the subject identification code list 
which can be used to link the data to the patient. After full data collection data will be 
transferred to an IBM Statistical Package for the Social Sciences (SPSS, version 25.0; IBM 
Corp, Armonk, NY) spreadsheet. In this spreadsheet the participants data will be non-
identifiable / anonymous. The code is based on consecutive numbers. The data files will be 
securely saved in a research folder on the hospital’s computer mainframe. All data collected 
during this study will be kept under secure conditions at Rijnstate Hospital for 15 years after 
the research has ended and then it will be destroyed. Any information collected will be treated 
as confidential and used only in this study unless otherwise specified. All source data relating 
to consented study participants will be stored and processed in line with Rijnstate Hospital 

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requirements. All source data held in paper form (Informed Consents) will be scanned and 
securely stored as soon as possible after the participants has signed it. Paper copies will be 
stored in the secured research lockable cabinet at the department of Orthopaedics. 
12.2 Monitoring and Quality Assurance  
Monitoring of the study will take place during the total study duration according to guidelines 
set out by the Samenwerkende Topklinische Ziekenhuizen (STZ) and as described in 
Standard Operating Procedure ‘STZ SOP VC12 Monitoringplan’ (STZ version 21-02-2019; 
Rijnstate version 8-5-2019). Monitoring will be performed by Rijnstate’s own local Research 
Ethics Office. 
12.3 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.  
12.4 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.  
12.5 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.  

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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 
credited METC. 
12.6 Public disclosure and publication policy 
This study will be prospectively registered in a public trial registry before the first patient is 
recruited. All data will be the property of Rijnstate. Publication will be the responsibility of the 
coordinating and principal investigators. It is planned to publish the results of this study in a 
peer-reviewed journal and to present results at national and international meetings. It will not 
be possible to identify any individuals from any publication or presentation. 
13. STRUCTURED RISK ANALYSIS  
In this study, participants will be asked to undergo four low-dose CT-scans of their instrumented 
segment over a two year period during their regular care hospital visits. By taking several 
measures, the patient’s effective dose of radiation exposure during the study will be around 7.2 
mSV compared to the 3.0 mSv during regular care. As such, compared to regular care, 
participants will be exposed to a slightly higher dose (4.2 mSv additional radiation) of radiation 
by participating in this study. According to the Dutch Radiation Committee for Radiation 
Dosimetry, this additional radiation poses a moderate risk (“matig risico”) to participants [23]. 
 
14. REFERENCES 
 
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