Analysis of Lumbar Intervertebral Motion During Flexion and Extension Cinematographic Recordings in Asymptomatic Male Participants.
Phase: NA
Conditions: Lumbar Intervertebral Motion
Sponsor: Zuyderland Medisch Centrum

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RESEARCH PROTOCOL 
Analysis of lumbar intervertebral motion during 
flexion and extension cinematographic 
recordings in asymptomatic male participants 
 
Version 2.0 
(September 2018) 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 6 
2. 
OBJECTIVES ................................................................................................................. 7 
3. 
STUDY DESIGN ............................................................................................................ 8 
4. 
STUDY POPULATION ................................................................................................... 9 
4.1. 
Population ............................................................................................................... 9 
4.2. 
Inclusion criteria ...................................................................................................... 9 
4.3. 
Exclusion criteria ..................................................................................................... 9 
4.4. 
Sample size calculation ......................................................................................... 10 
5. 
TREATMENT OF SUBJECTS ...................................................................................... 11 
5.1. 
Investigational product/treatment ........................................................................... 11 
5.2. 
Use of co-intervention ........................................................................................... 11 
5.3. 
Name and description of investigational product(s) ............................................... 11 
5.4. 
Summary of findings from non-clinical studies ....................................................... 11 
5.5. 
Summary of findings from clinical studies .............................................................. 11 
5.6. 
Summary of known and potential risks and benefits .............................................. 14 
6. 
METHODS ................................................................................................................... 15 
6.1. 
Study parameters/endpoints .................................................................................. 15 
6.1.1. Main study parameter/endpoint .......................................................................... 15 
6.2. 
Randomization, blinding and treatment allocation ................................................. 15 
6.3. 
Study procedures .................................................................................................. 15 
6.4. 
Withdrawal of individual subjects ........................................................................... 16 
6.5. 
Replacement of individual subjects after withdrawal .............................................. 16 
6.6. 
Follow-up of subjects withdrawn from treatment .................................................... 16 
6.7 
Premature termination of the study ........................................................................ 16 
7. 
SAFETY REPORTING ................................................................................................. 17 
7.1. 
Section 10 WMO event ......................................................................................... 17 
7.2. 
AEs and SAEs ....................................................................................................... 17 
7.2.1. Adverse events (AEs) ......................................................................................... 17 
7.2.2. Serious adverse events (SAEs) .......................................................................... 17 
7.3. 
Follow-up of adverse events .................................................................................. 18 
8. 
STATISTICAL ANALYSIS ............................................................................................ 19 
8.1. 
Primary study parameter(s) ................................................................................... 19 

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8.2. 
Secondary study parameter(s) .............................................................................. 19 
8.3. 
Interim analysis ..................................................................................................... 20 
9. 
ETHICAL CONSIDERATIONS ..................................................................................... 21 
9.1. 
Regulation statement ............................................................................................ 21 
9.2. 
Recruitment and consent....................................................................................... 21 
9.3. 
Objection by minors or incapacitated subjects ....................................................... 21 
9.4. 
Benefits and risks assessment, group relatedness ................................................ 21 
9.5. 
Compensation for injury ........................................................................................ 22 
9.6. 
Incentives .............................................................................................................. 22 
10. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ........................ 23 
10.1. Handling and storage of data and documents ....................................................... 23 
10.2. Monitoring and Quality Assurance ......................................................................... 23 
10.3. Amendments ......................................................................................................... 23 
10.4. Annual progress report .......................................................................................... 24 
10.5. Temporary halt and (prematurely) end of study report ........................................... 24 
10.6. Public disclosure and publication policy ................................................................. 24 
11. 
STRUCTURED RISK ANALYSIS.............................................................................. 25 
12. 
REFERENCES ......................................................................................................... 26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
Adverse Event 
BMI 
Body Mass Index 
CT 
Computer tomography 
F-e angle 
Flexion-extension angle 
IVFE 
Intervertebral Flexion-Extension 
METC 
  
Medical Research Ethics Committee (MREC); in Dutch: Medische Ethische 
Toetsingscommissie (METC) 
MRI 
Magnetic Resonance Imaging 
ODI 
Oswestry Disability Index (Functional scale used for low back disorders 
(current version 2a) 
ROM 
Range Of Motion 
(S)AE 
(Serious) Adverse Event  
TPDR 
Translation Per Degree of Rotation 
VAS 
Visual Analogue Scale 
Wbp 
Personal Data Protection Act (in Dutch: Wet bescherming persoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen) 
 
 
 
 
 
 
 
 
 
 
 
 

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SUMMARY 
 
Rationale: Physiological motion of the lumbar spine is a subject of interest for doctors and 
allied health professionals. So far, nobody knows exactly what physiological motion means. 
Many researchers have described ranges of motion of the lumbar spine, but only a few have 
mentioned specific motion patterns of each individual segment in healthy individuals. These 
motion patterns describe the sequence of initiation of segmental motion in rotation during 
flexion and extension. However, previous studies have not described the sequence of 
segmental contribution in rotation during flexion and extension. 
Objective: Defining the lumbar spines’ physiological motion pattern of each vertebra L1, L2, 
L3, L4, L5 and S1 by using cinematographic recordings in asymptomatic male participants. 
Study design: Fundamental research 
 
Study population: Eleven asymptomatic male participants (based on VAS-, and ODI-score 
of zero) aged 18 to 25 without a medical history of back problems. 
Intervention: Two flexion and extension cinematographic recordings of the lumbar spine 
with a two week interval between recordings. 
Main study parameters/endpoints: Primary endpoint: Defining the lumbar spines’ 
physiological motion pattern by analysing sequence of initiation of motion and sequence of 
segmental contribution in rotation of each vertebra L1, L2, L3, L4, L5 and S1 during flexion 
and extension.  
Secondary endpoint: Exploring the possibility to analyse intervertebral horizontal and vertical 
translation of each vertebra L1, L2, L3, L4, L5 and S1 during flexion and extension. If mean 
intra-class correlation coefficient is higher than 0.60 the sequence of initiation of motion and 
sequence of segmental contribution of intervertebral horizontal and vertical translation will be 
defined. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness:  Participants receive cinematographic recordings twice in two weeks’ 
time, if they are included based on the VAS-, and ODI-scores. There will be no follow-up. 
 
 
 
 
 
 
 
 
 
 
 

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1. INTRODUCTION AND RATIONALE 
 
Physiological motion of the lumbar spine is a subject of interest for medical specialists and 
allied health professionals. Although the term ‘physiological motion’ is being used in many 
instances, a proper definition is lacking. More knowledge about physiological motion is 
essential to recognize abnormal motion caused by specific diseases or complaints. 
In 1929 Virchow et al. were first to use sagittal radiographs to analyse normal range of 
flexion and extension of the cervical spine [1]. Dittmar et al. were the first in 1931 to perform 
this type of research for the lumbar spine [2]. Troke et al. developed a database with ranges 
of motion from thoracic vertebra 12 to sacral vertebra 1 for asymptomatic patients between 
16 and 90 years old [3]. They found a maximum flexion of 68 to 73 degrees, and a minimum 
flexion of 40 degrees. For extension they found a maximum of 28 to 29 degrees and 
minimum of 6 to 7 degrees [3].  
After these studies, more (range of) motion research followed, not only using radiographs but 
later on using CT- or MRI-based 3D images [4-6]. The latest studies described individual 
motions of segments and initiation of motion in flexion and extension. However, none of 
these studies have described a number of important aspects we would like to consider in our 
study. These aspects include description of flexion and extension of each individual 
participant instead of pooled data for the entire group, extension analysis and sequence of 
segmental contribution besides sequence of initiation of motion per segment during flexion 
and extension. 
 
By addressing these specific aspects, our study aims to assess and understand the 
sequence of initiation of motion in each individual segment and the sequence of segmental 
contribution in rotation of the lumbar spine, during maximum flexion and extension in 
asymptomatic male participants, in order to learn more about physiological motion of the 
lumbar spine. Additionally, we want to explore the possibility of analysing intervertebral 
horizontal and vertical translation to enable determination of sequence of initiation of motion 
and sequence of segmental contribution of translation. 
Eventually, we hope to compare this physiological motion to potential abnormal motion in 
patients suffering from lumbar spinal pathology or postoperative patients, for example after 
fusion surgery, to determine if (adjacent) segments have to contribute more in flexion and 
extension, which could explain (adjacent segment) diseases due to abnormal segmental 
motion patterns. 
 
 
 
 
 
 
 
 

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2. OBJECTIVES 
 
Primary Objective: Defining the lumbar spines’ physiological motion by analysing sequence 
of initiation of motion and sequence of segmental contribution in rotation of each vertebra L1, 
L2, L3, L4, L5 and S1 by using flexion and extension cinematographic recordings in 
asymptomatic male participants.  
 
Secondary objective: Exploring the possibility to analyse intervertebral horizontal and vertical 
translation of each vertebra L1, L2, L3, L4, L5 and S1 by using flexion and extension 
cinematographic recordings in asymptomatic male participants. If mean intra-class 
correlation coefficient is higher than 0.60, sequence of initiation of motion and sequence of 
segmental contribution of intervertebral horizontal and vertical translation will be analysed. 
 
 

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3. STUDY DESIGN 
 
This is a fundamental research project in which asymptomatic male participants without any 
medical history of back pain will be included. Participants will be recruited at Zuyd 
Hogeschool Sittard/Heerlen and Zuyderland Medical Center Sittard-Geleen/Heerlen by using 
posters notifying about the study. Males interested in participation can email the researcher, 
which will inform them verbally and in writing. Informed consent will be signed if males meet 
the inclusion criteria and are willing to participate. 
During our literature research we came across studies confirming the feasibility of sagittal 
cinematographic recordings in analysing flexion and extension of the lumbar spine [7-9]. For 
this reason, we decided not to perform a feasibility study, but to include 11 male participants 
based on previous articles using the same method of cinematographic recordings to analyse 
motion of the spine. Boselie et al., Kanayama et al. and Harada et al. have used eight to ten 
participants and were able to perform adequate analysis and draw solid conclusions [7-9]. 
Interim analysis will be performed after cinematographic recordings of two patients to 
determine if the images acquired with  the Alura Xper are appropriate to perform computer 
software analysis. Taking a possible loss to follow up of 10% into account, our study 
population will consist of 11 participants. 
Each participant receives a flexion and extension cinematographic recording twice to 
determine reproducibility and consistency of sequence between the two time points (T1 and 
T2) [10, 11]. Recordings will be done with an interval of two weeks (T1 and T2), resulting in 
22 cinematographic recordings. Inclusion is expected to take approximately three months. 
Possible participants have to complete the Oswestry Disability Index and Visual Analogue 
Scale for back pain with a score of zero to be included. Cinematographic recordings will be 
scored based on the Kellgrens’ classification by two neurosurgeons to avoid inclusion of 
participants with asymptomatic degeneration. This score has to be zero or one meaning 
there is no or ‘doubtful’ degeneration. Participants with a Kellgrens’ score of two or higher, 
indicating possible degeneration of the spine, will be excluded [12]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4. STUDY POPULATION 
 
4.1. Population  
Male participants with a normal height-weight ratio (BMI under 25), without spinal 
problems defined as ODI-, and VAS-scores of zero, and without a medical history of 
visiting general practitioners, allied health professionals, or medical specialists for spinal 
problems.  
We exclude females from participation to protect ovaries from direct radiation exposure.  
Previous studies did not show significant differences in motion between males and 
females. Lower radiation dosage for proper cinematographic recordings is needed if 
males have a BMI under 25.  
Participants will be recruited using posters shown in Zuyd Hogeschool Sittard/Heerlen and 
Zuyderland Medical Center Sittard-Geleen/Heerlen.  
 
4.2. Inclusion criteria 
To be included in the study, participants have to meet the following criteria:  
 
1. Male  
 
2. Age between 18 and 25 years old. 
` 3. BMI under 25 
4. Participants have to be able to perform flexion and extension over a full range of motion 
without complaints of pain.  
5. Participants have no medical history of spinal problems based on anamneses and an 
ODI-, and VAS-score of zero.  
6. Kellgrens’ classification on cinematographic recordings is zero or one. 
7. Signed informed consent.   
8. Ability to read and understand Dutch. 
 
4.3. Exclusion criteria 
To be excluded from the study, participants have to meet the following criteria: 
1. Medical history of visiting general practitioners, allied health professionals or 
specialists for spinal problems. 
2. Former spine surgery. 
3. Radiographs of abdomen, pelvis, hips, lumbar spine or sacral spine in last year. 
4. Degenerative abnormalities of the lumbar spine. 
5. Active spinal infection. 
6. Immature bone. 
7. Lumbar tumour processes. 
8. Former lumbar radiotherapy. 
9. Congenital lumbar spine abnormalities, for example spina bifida. 
10. Planning pregnancy for the coming year. 
 

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4.4. Sample size calculation 
Sample size is based on previous articles using the same method of cinematographic 
recordings to analyse spine motion. Boselie et al., Kanayama et al. and Harada et al. used 
eight to ten participants to perform adequate analysis and draw solid conclusions [7-9]. 
Our study population comprises 11 participants, assuming a possible loss to follow-up of 
10%. Flexion and extension cinematographic recordings are acquired twice for each 
participant, in order to determine reproducibility and consistency of sequence of motion 
between two time points (T1 and T2) [10]. Recordings will be performed with an interval of 
two weeks, resulting in 22 cinematographic recordings. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5. TREATMENT OF SUBJECTS 
5.1. Investigational product/treatment 
Cinematographic recordings during flexion and extension of the lumbar spine in 
asymptomatic male participants. 
5.2. Use of co-intervention 
Not applicable. 
5.3. Name and description of investigational product(s)  
Not applicable. 
5.4. Summary of findings from non-clinical studies 
Not applicable. 
 
5.5. Summary of findings from clinical studies 
- 
Pearcy (1984): Mean range of flexion for healthy participants (n=11) was 8º for L1-L2, 
10º for L2-L3, 12º for L3-L4, 13º for L4-L5 and 9º for L5-S1. Mean range of extension 
was 5º for L1-L2, 3º for L2-L3, 1º for L3-L4, 2º for L4-L5 and 5º for L5-S1. Mean 
cumulated range for flexion and extension in L4-L5 is significant higher compared to 
segments above [13].  
- 
Dvorak (1991): Healthy participants (n=41) performed passive flexion and extension. 
Ranges of motion from flexion to extension were 11.9o in L1-L2, 14.5o in L2-L3, 15.3o 
in L3-L4, 18.2o in L4-L5 and 17.0o in L5-S1. Segmental rotation was higher in lower 
levels, but variation of these values was also higher. There was no statistically 
significant difference between levels and genders [14].  
- 
Kanayama (1996): Segmental translation of healthy participants (n=8) during flexion 
was smaller in L5-S1 (1.1 mm) compared to L3-L4 (3.1 mm) and L4-L5 (3.3 mm) 
(P<0.001). Segmental rotation was largest in L4-L5 (15.3o) and smallest in L3-L4 
(9.8o) (P<0.05). There was no significant difference between individual levels in 
segmental translation during extension. Segmental rotation was smaller in L3-L4 
(1.6o) and L4-L5 (0.6o) compared to L5-S1 (8.5o) (P<0.05). L3-L4 and L4-L5 had 
significantly smaller translation and rotation during extension compared to flexion 
(P<0.05 and P<0.005, respectively). Translation and rotation were not significantly 
smaller during flexion and extension in L5-S1. 
Flexion started in L3-L4, continued to L4-L5 when L3-L4 had rotated 6o and ended 
with rotation of L5-S1 when L3 to L5 had rotated 8o [8]. 
- 
Okawa (1998): Two motion patterns were observed in healthy participants (n=13) 
during flexion from neutral position. One involved sequential lumbar segmental 
rotation starting from L2 and spreading gradually downward to L4. The other involved 
simultaneous motion-spreading pattern with motion curves of L2 to L4, except L5, 
showing almost the same course. Of 13 healthy participants, six exhibited a 
sequential motion-spreading pattern, four exhibited the simultaneous pattern and in 
three patients the segments did not move in any of the abovementioned orders. Six of 

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eight patients with chronic low back pain showed a sequential or simultaneous 
pattern. In seven of the eight patients with spondylolisthesis, the slipped level seemed 
to move first. 
Three motion patterns were observed when participants returned from flexion to 
neutral position. In one pattern, all segments returned simultaneously to normal 
position. In the other two patterns, lower segments returned earlier than upper 
segments (low-high type) or upper segments returned earlier than lower segments 
(high-low type). Seven out of eight patients with spondylolisthesis showed high-low 
type motion, most of all with prolonged deflection of the slipped L4, which was 
defined as ‘abnormal’. Most patients with ‘normal’ motion tended to have low-high 
type [15]. 
- 
Harada (2000): Healthy male participants (n=10) were trained to perform maximum 
flexion and extension each in six seconds, which were recorded by cinematographic 
recordings at a rate of 30 frames/second. Flexion started in L3-L4 and continued 
step-by-step to lower segments. Extension started in L5-S1 and continued step-by-
step to higher segments. Rate for change of angle improved significantly with each 
lower segment during initiation of flexion; 3.9±1.5 in L3-L4, 5.4±2.3 in L4-L5 and 
8.1±2.1 in L5-S1 in grades per second. There was no significant difference between 
segments regarding rates for change of angle during start of extension. Greatest 
angle changes were -6.3±2.5 in L3-L4, -7.5±2.8 in L4-L5 and -7.3±2.8 in L5-S1 in 
grades per second [9]. 
- 
Takayanagi (2001): Healthy participants (n=20) showed a simultaneous start in 
segments L2 to L5 for f-e angle (flexion-extension angle) and translation. Segment 
L5-S1 showed initial delay. F-e angle and translation changed symmetrically between 
segments. Patients with spondylolisthesis L4-L5 with a slip less than 15% (n=21) 
showed a larger change of f-e angle in this segment than healthy individuals, 
indicating disc dysfunction. Patients with spondylolisthesis L4-L5 with a slip over 15% 
(n=20) showed less change of f-e angle and translation than healthy individuals, 
supporting the identification of the restabilization stage in degenerative processes 
[16].  
- 
Lee (2002): L1-L2, L2-L3, L3-L4, L4-L5 and L5-S1 of healthy participants (n=30) 
showed a steady increase and linear pattern of the intervertebral flexion-extension 
(IVFE) curve from 10o extension to 40o flexion (except for L5-S1 for 10o extension). 
IVFE decreased in the descending order of L1-L2 to L5-S1 at all points of flexion. 
There was no statistically significant difference in slope of IVFE curves in different 
ROMs between genders [17]. 
- 
Wong (2004): Results of healthy participants (n=100) showed a linear-liked motion 
pattern of IVFE with alignment of L2-L3 curve with L3-L4 curve during flexion. (The 
slope of) IVFE curves decreased from L1-L2 to L5-S1 in descending order, 
suggesting less flexibility in lower levels. Initiating of flexion starts in upper segments 
and continues to lower segments, but all segments initiated extension simultaneously. 
Extension-slope for L5-S1 was less steep than the rest. Increased IVFE was found in 
flexion and extension for older participants compared to younger participants. The 

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slope of the IVFE curve was significantly steeper in the oldest group compared to 
younger groups in all levels (P<0.05). There was no statistically significant difference 
between genders [18]. 
- 
Wong (2006): IVFE curves and slopes of healthy participants (n=30) showed a 
decreased linear pattern in descending order from L1-L2 to L5-S1 during flexion, but 
motion is unevenly contributed. Extension is evenly contributed. There was no 
statistically significant difference between genders [19]. 
- 
Wu (2014): Anterior-posterior translation in healthy participants (n=10) showed 
significantly more horizontal translation in segment L4-L5 than in segment L5-S1, 
respectively, 2.9±1.5 versus 1.4±1.1 mm. Vertical translation was 1.5±0.4 mm in L2-
L3, 1.0±0.4 mm in L3-L4, 1.7±0.7 mm in L4-L5 and 2.8±0.9 mm in L5S1. Largest 
proximal-distal translation was found in segment L5-S1, 2.8±0.9 mm. Rotation in L2 
relative to S1 was 29.8o±8.2o from maximum flexion to maximum extension [20]. 
- 
Staub (2015): Individual segments of healthy participants (n=162) showed a 
translation of 1.88 mm in L1-L2, 2.42 mm in L2-L3, 2.69 mm in L3-L4, 2.66 mm in L4-
L5 and 0.53 mm in L5-S1. Intervertebral rotation of individual segments was 12.38o in 
L1-L2, 12.38o in L2-L3, 13.02o in L3-L4, 14.45o in L4-L5 and 12.72o in L5-S1. 
Translation per degree of rotation (TPDR) at every level was 0.55%, except for L5-S1 
were TPDR was 0.18% [12]. 
- 
Boselie (2017): Consistent sequence of contribution of sagittal rotation of the three 
lower cervical motion segments C4-C7 was especially identified in the last phase of 
extension movement in healthy participants (n=20). First peak was found for C4-C5, 
followed by C5-C6 and finally in C6-C7. This sequence was only present in 10% of all 
participants (n=10) with cervical degenerative disc disease [10]. 
 
Above-mentioned small scaled studies provide information about translation and rotation 
of lumbar spine segments from L1 to S1. Extension seems to be correlated to a smaller 
translation and range of motion compared to flexion, where most studies describe 
segment L5-S1 as least mobile. 
Kanayama et al., Wong et al., Lee et al., Takayanagi et al., Okawa et al. and Harada et al. 
described motion of individual segments L1/2/3 to S1 [8, 9, 16-19]. Wong et al., Lee et al., 
Takayanagi et al., and Harada et al. only mentioned means of the study population, 
whereas Kanayama et al. and Okawa et al. mentioned individuals separately. All studies 
described sequence of onset of motion, but not sequence of segmental contribution. They 
all described cumulative rotation of each individual segment on specific time points or at 
specific lumbar ROMs’, which can result in missing drastic changes in intervertebral 
rotation between successive frames. Besides, Kanayama et al., Takayanagi et al. and 
Okawa et al. only described flexion, not extension [8, 15, 16]. Wong et al. and Lee et al. 
limited flexion to 40o and extension to 10o [17-19]. 
We want to describe segmental contribution during maximum flexion and extension in 
asymptomatic participants. Eventually, we hope to compare this physiological motion to 
potential abnormal motion in patients suffering from lumbar spinal pathology or 
postoperative patients, for example after fusion surgery, to determine if (adjacent) 

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segments have to contribute more in flexion and extension, which could explain (adjacent 
segment) diseases due to abnormal segmental motion patterns. 
 
5.6. Summary of known and potential risks and benefits 
Based on the above-mentioned studies, there is no information on potential risks or 
benefits. Radiation experts determined a radiation dosage per cinematographic recording 
of 0.21 mSv. Participants will perform cinematographic recordings twice, resulting in a 
total radiation dosage of 0.42 mSv. This amount of radiation can be categorized in 
category IIa using the NCS guidelines about risks of radiation dosage (0.1 to 1 mSv) [21]. 
This category includes moderate risk which can be justified if there is a potential health 
benefit for future patients. 
 
 

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6. METHODS 
 
6.1. Study parameters/endpoints 
6.1.1. Main study parameter/endpoint 
Defining the lumbar spines’ physiological motion pattern by analysing sequence of 
initiation of motion and sequence of segmental contribution in rotation of each 
vertebra L1, L2, L3, L4, L5 and S1 by using flexion and extension cinematographic 
recordings in asymptomatic male participants. 
 
6.1.2. Secondary study parameter/endpoint 
Secondary objective: Exploring the possibility to analyse intervertebral horizontal 
and vertical translation of each vertebra L1, L2, L3, L4, L5 and S1 by using flexion 
and extension cinematographic recordings in asymptomatic male participants. If 
mean intra-class correlation coefficient is higher than 0.60, the sequence of initiation 
of motion and sequence of segmental contribution of intervertebral horizontal and 
vertical translation will be analysed. 
 
6.2. Randomization, blinding and treatment allocation 
Not applicable. 
 
6.3. Study procedures 
This study does not use invasive procedures, but is not regular care: 
- 
Cinematographic recordings (twice): participants are seated while their pelvis is 
fixated by belts to prevent additional pelvic motion. Cinematographic recordings will 
be made from a lateral perspective to obtain sagittal images. Participants are asked 
to perform maximum extension, followed by maximum flexion and returning to 
maximum extension. Cinematographic recordings will be made twice with an interval 
of two weeks. 
Cinematographic recordings will be made using the Philips Alura Xper FD20 X-ray 
system. To stay below the limit of 1 mSv per participant,  the 0.9 mm Cu + 1 mm Al 
filter will be used for the entire study. The Alura Xper automatically selects correct 
tube voltage, with an expected maximum between 75 and 90 kV for lumbar 
cinematographic recordings. Kellgrens’ classification of cinematographic recordings 
will be determined by two neurosurgeons. 
- 
Questionnaires for inclusion:  
o VAS (Visual Analogue Scale) Back 
o VAS (Visual Analogue Scale) Leg 
o ODI (Oswestry Disability Index) 
 
 
Kellgrens’ classification: a scoring method to determine severity of osteoarthritis in joints, 
using five gradations: 

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- 
Grade zero: no radiological abnormalities indicating osteoarthritis. 
- 
Grade one: discussable joint space narrowing and beginning of osteophyte 
formation. 
- 
Grade two: clear joint space narrowing and osteophyte. 
- 
Grade three: joint space narrowing, multiple osteophytes, sclerosis and bone 
deformity. 
- 
Grade four: joint space narrowing, large and multiple osteophytes, severe 
sclerosis and bone deformity [22].  
 
Visual Analogue Scale: back pain and leg pain will be indicated on a scale of 100 points 
were zero points represents no pain and hundred points represents worst pain imaginable 
[23].  
 
Oswestry Disability Index: tool to measure functional invalidity of patients with low back 
problems. ODI-questionnaire consists of ten questions. Each question will be scored 
between zero and five points. A total of zero points stands for no invalidity and a total of 
50 points for worst invalidity imaginable [24]. 
 
6.4. Withdrawal of individual subjects 
Participants can cease study participation at any time for any reason if they wish to do so, 
without any consequences. If participants leave the study before second recording, only 
the first recording will be included and analysed. 
Researchers cannot decide to withdraw participants from the study, unless participants do 
not respond to calls before the first cinematographic recording is made.  
 
6.5. Replacement of individual subjects after withdrawal 
If a participant withdraws before the first cinematographic recording is made, researchers 
are allowed to replace this participant. 
 
6.6. Follow-up of subjects withdrawn from treatment 
Participants who withdraw from the study will not be actively recalled. 
 
6.7  Premature termination of the study 
Interim analysis will be performed after cinematographic recordings of two patients to 
determine if the image quality with the maximum allowable settings of the Alura Xper have 
sufficient quality and are appropriate to perform computer software analysis. If this is not 
possible, the study will be terminated prematurely. 
 
 
 
 

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7. SAFETY REPORTING 
7.1. Section 10 WMO event 
In accordance to section 10, subsection 4, of the WMO, sponsor and investigator will 
inform the participant and the METC if there is sufficient ground that continuation of the 
study will jeopardize participants’ health or safety. The study will be suspended pending 
further review by the accredited METC. 
 
7.2. AEs and SAEs 
7.2.1.Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a participant 
during the study, whether or not considered related to experimental intervention. All 
adverse events reported spontaneously by participant or observed by the 
investigator or his staff will be recorded. 
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 event); 
- 
Requires hospitalization or prolongation of existing inpatients’ hospitalization; 
- 
Results in persistent or significant disability or incapacity; 
- 
Is a congenital anomaly or birth defect; 
That required medical or surgical intervention to preclude of any other important 
medical event that did not result in any of the outcomes listed above due to medical 
or surgical intervention but could have been based upon appropriate medical 
judgment. 
 
An elective hospital admission will not be considered as a serious adverse event. 
The investigator will report all SAEs to the sponsor without undue delay of obtaining 
knowledge of the events. 
 
Sponsor will report these SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days for SAEs that result in 
death or life threatening event, 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 sponsor has first knowledge of the serious adverse 
events. 

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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 event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to general physician or medical specialist. 
SAEs need to be reported till end of study (last follow up moment for last subject), as 
defined in the protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8. STATISTICAL ANALYSIS 
 
8.1. Primary study parameter(s) 
Primary study parameter is to define the lumbar spines’ physiological motion by analysing 
sequence of initiation of motion and sequence of segmental contribution in rotation of 
each vertebra L1, L2, L3, L4, L5 and S1 by using flexion and extension cinematographic 
recordings in asymptomatic male participants.  
Before recordings are made, participants will be taught to perform the prescribed motion 
over 14 seconds using a metronome. Participants are seated with their pelvis fixated 
during sagittal cinematographic recordings and are asked to perform maximum extension, 
followed by maximum flexion and returning to maximum extension. Participants perform 
this procedure twice with an interval of two weeks. If segment L1 does not remain in the 
field of view, we will start analysing downwards from segment L2. 
Images will be analysed using computer software that uses an algorithm to follow motion 
of the vertebrae during complete flexion and extension [25]. This will be done by two 
researchers for 10 cinematographic recordings to determine reproducibility using two way 
mixed, absolute agreement, intra-class correlation coefficient. 
Graphs will be made for flexion and extension in which segmental rotation (cumulative 
and between each pair of successive frames) of each individual segment L1 to S1 will be 
plotted against the cumulative rotation in segments L1 to S1 together to describe the 
sequence of segmental contribution during flexion and extension. These graphs will be 
made and analysed for each individual participant to identify specific patterns in sequence 
of segmental contributions. If possible, we will describe a sequence definition for initiation 
of motion and segmental contribution in flexion and extension of the lumbar spine. This 
above-mentioned procedure will first be done for T1, which will be tested against T2 using 
coefficient of variation and intra-individual standard deviation to determine if the defined 
sequence is consistent between two recordings in the intra-individual variability.  
 
8.2. Secondary study parameter(s)  
Secondary parameter is to explore the possibility to analyse intervertebral horizontal and 
vertical translation of each vertebra L1, L2, L3, L4, L5 and S1 by using flexion and 
extension cinematographic recordings in asymptomatic male participants. Previous 
studies of the cervical spine described the possibility to determine intervertebral horizontal 
and vertical translation, with an intra-class correlation coefficient higher than 0.60 [26]. 
However, a few previous studies of the lumbar spine described pooled data for 
intervertebral horizontal translation and/or only for specific parts of the flexion-extension 
motion. Only one study described vertical translation [8, 12, 13, 20, 27]. 
To explore the possibility to analyse intervertebral horizontal and vertical translation of the 
lumbar spine for each individual participant, we use the same procedure for recording and 
computer-analysis as mentioned above. If mean intra-class correlation coefficient is higher 
than 0.60, sequence of initiation of motion and sequence of segmental contribution of 
intervertebral horizontal and vertical translation will be determined. 

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8.3. Interim analysis 
Interim analysis will be performed after cinematographic recordings of two patients to 
determine if the image quality with the maximum allowable settings the Alura Xper have 
sufficient quality and are appropriate to perform computer software analysis. These filter 
and tube voltage settings are used for lumbar cinematographic recordings in daily practice 
and will not overstep the limit for radiation dosage of 1 mSv per participant. If appropriate 
computer software analysis is not possible, the study will be stopped. 
.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9. ETHICAL CONSIDERATIONS 
 
9.1. Regulation statement 
This research is conducted according to principles enshrined in the Declaration of Helsinki 
(3th edition 2013) and in accordance with the Medical Research Involving Human Subjects 
Act (WMO, version 1 July 2012). 
 
9.2. Recruitment and consent 
Male participants will be recruited from Zuyd Hogeschool Sittard/Heerlen and Zuyderland 
Medical Center Sittard-Geleen/Heerlen using posters. Possible participants have to send 
an email to the researcher if they are interested in participation. Further information will be 
given verbally and in writing, followed by a thinking time of seven days. If people are 
willing to participate and meet the inclusion criteria, informed consent will be signed during 
the first meeting between researcher and participant.  
Participants can terminate their participation at all times, without giving a reason. For any 
questions regarding the study, an independent physician is available throughout the 
duration of the study. 
 
9.3. Objection by minors or incapacitated subjects 
Not applicable.  
 
9.4. Benefits and risks assessment, group relatedness 
Participants do not directly benefit from participating in this study. They make significant 
contribution to knowledge in the field of motion of the lumbar spine. Increased knowledge 
of physiological motion enables us to recognize abnormal motion in future. 
Phantom measurements of the Alura Xper in Zuyderland Sittard were used to determine 
radiation dosage. According to radiation experts, radiation dosage per cinematographic 
recording will be 0.21 mSv. Settings used for calculation are exposed tissue factor of 0.54 
mSv/Gy (based on ICRP 103), tube voltage of 75-90 kV, record-duration of 20 seconds, 
filter of 0.9 mmCu + 1 mm Al, 7.5 pulses per second, focus-detector distance of 48 cm 
and field of view of 520 cm2. Participants will perform cinematographic recordings twice, 
resulting in a total radiation dosage of 0.42 mSv. This amount of radiation can be 
categorized in category IIa using the NCS guidelines about risks of radiation dosage (0.1 
to 1 mSv) [21]. This category includes moderate risk which can be justified if there is a 
potential health benefit for future patients. 
We exclude females from participation to protect ovaries from direct radiation exposure.  
Lower radiation dosage for proper cinematographic recordings is needed if males have a 
BMI under 25. 
 

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9.5. Compensation for injury 
Sponsor/researcher has a liability insurance which is in accordance with article 7 of the 
WMO. This insurance provides cover for damage to research participants through injury or 
death caused by the study. 
 
9.6. Incentives 
Participants will be reimbursed for extra time that is needed to fill out the questionnaires 
and undergo cinematographic recordings. They will receive €50 for participating in T1 and 
T2. 
 
 

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10. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
10.1. Handling and storage of data and documents 
Data will be stored in two ways; cinematographic recordings on CDs and questionnaires 
on paper. Both of them will be coded with participant-number for example participant 9. 
Cinematographic recordings will also be coded with recording-number, for example 
recording 2. CDs and questionnaires will be locked up in a secured room. Data will be 
kept for 15 years after ending the study. Handling of personal data will comply with the 
Dutch Personal Data Protection Act (Wbp).  
 
10.2. Monitoring and Quality Assurance  
Monitoring will be performed by trained and qualified monitors. According to Good Clinical 
Practice (GCP) guidelines main task of the monitor is ensuring that: 
-      Rights and well-being of human participants are protected. 
-      Reported trial data are accurate, complete and verifiable from source documents. 
- 
Conduct of trial is in compliance with currently approved protocol, GCP and 
applicable regulatory requirements. 
- 
Prior to the study start a monitoring plan will be assembled, specifying Source 
Document Verification Plan, frequency of monitoring visits and frequency of checking 
Trial Master Files/Investigator Site Files. 
 
Monitoring will be performed remotely and on site.  
 
There are several kinds of monitoring visits: 
- 
Site initiation visit (SIV): SIV will be performed after all approvals have been obtained 
and prior to enrolling the first subject in that center. 
- 
Interim monitoring visit (IMV): Several IMV’s will be performed during the trial. 
Frequency of visits is determined in monitoring plan. 
- 
Close out visit (COV): COV will be performed at the end of the trial, after collection of 
all data. 
 
Monitoring visits will be planned in agreement with study site personnel. According to 
GCP guidelines, the investigators must provide the monitor with all necessary information 
and documents. Furthermore, the investigators are obliged to answer all queries raised by 
monitor in eCRF in timely manner. After each monitoring visit, a follow-up email with all 
action points will be sent to the study site. These action points will be addressed at 
beginning of the next monitoring visit. 
 
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.  
 

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10.4. Annual progress report 
Sponsor/researcher will submit a summary of progress of the trial to the accredited METC 
once a year. Information will be provided on date of inclusion of the first subject, numbers 
of subjects included and numbers of subjects that have completed the trial, serious 
adverse events, other problems, and amendments.  
 
10.5. Temporary halt and (prematurely) end of study report 
Sponsor/researcher 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 participants’ last visit.  
Sponsor/researcher will notify METC immediately of a temporary halt of the study, 
including reason of such an action.  
In case of ending the study prematurely, sponsor/researcher will notify the accredited 
METC within 10 days, including reasons for premature termination. 
Within one year after the end of the study, sponsor/researcher will submit a final study 
report with results, including any publications/abstracts, to the accredited METC. 
 
10.6. Public disclosure and publication policy 
This trial will be registered in a public trial register before recruitment of the first 
participant. Results will preferable be published in open access, peer-reviewed journals. 
Data of participants will be anonymous for publication and cannot be traced to an 
individual. In case of negative results, data will also be published. Funder has through 
contractual agreement no effect on publication. There is no veto over whether or not to 
publish data by one of the parties. In case of patent applications, funder is entitled to 
postpone publication for a maximum period of 90 days after analysing data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11. STRUCTURED RISK ANALYSIS  
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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