A Randomized Intra-Patient Controlled Trial of MagnetOs™ Granules vs. Autograft in Instrumented Posterolateral Spinal Fusion
Phase: NA
Conditions: Spinal Fusion
Sponsor: M.C. Kruyt, MD, PhD

RESEARCH PROTOCOL 
‘A Randomized Intra-Patient Controlled Trial  
of MagnetOsTM Granules vs. Autograft  
in Instrumented Posterolateral Spinal Fusion’ 
Updated: May 2018 

ABR number NL64652.041.18  
 
MagnetOsTM Granules vs. Autograft in PLF 
Version number: 2, date 23th of May 2018 
 
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PROTOCOL TITLE ‘A Randomized Intra-Patient Controlled Trial of MagnetOsTM 
Granules vs. Autograft in Instrumented Posterolateral Spinal Fusion’ 
 
Protocol ID 
METC protocol number 18-311 
ABR number NL64652.041.18 
Short title 
MagnetOsTM 
Granules 
vs. 
Autograft 
in 
Instrumented Posterolateral Spinal Fusion 
Version 
02 
Date 
May 2018 
Project leader 
 
 
Coordinating investigator 
 
F.C. Oner, MD, PhD 
f.c.oner@umcutrecht.nl  
+31 88 75 712 62 
A.M. Lehr, MSc 
a.m.lehr@umcutrecht.nl  
+31 88 75 585 11 
Principal investigator 
 
M.C. Kruyt, MD, PhD 
m.c.kruyt@umcutrecht.nl 
+31 88 75 745 17 
Participating sites 
St. Antonius Ziekenhuis Utrecht 
OLVG Amsterdam 
Rijnstate Arnhem 
Amphia Ziekenhuis Breda 
Sponsor 
UMC Utrecht 
Subsidising party 
Kuros, Kuros Biosciences BV 
Independent expert 
R.M. 
Castelein, 
MD, 
PhD, 
Department 
of 
Orthopaedics 
R.M.Castelein@umcutrecht.nl 
+31 88 75 583 27 

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PROJECT TEAM 
 
This multicenter clinical trial will be performed and coordinated by the University Medical Center (UMC) Utrecht, in cooperation with the 
following four participating sites: St. Antonius Hospital Utrecht, Onze Lieve Vrouwe Gasthuis (OLVG) Amsterdam, Rijnstate Hospital Arnhem 
and Amphia Hospital Breda. The project team exists of a multidisciplinary group from the UMC Utrecht and the affiliated Julius Center for Health 
Sciences and Primary Care. 
Name  
Position 
Task 
 
Located 
Contact details 
F.C. Öner, MD, PhD 
Professor, Head of Spine 
Unit, Orthopaedic surgeon 
Project leader  
Dept. of Orthopaedics, UMC 
Utrecht, Utrecht 
f.c.oner@umcutrecht.nl 
+31 88 75 712 62 
M.C. Kruyt, MD, PhD  
Orthopedic surgeon 
Principal investigator 
Dept. of Orthopaedics, UMC 
Utrecht, Utrecht 
m.c.kruyt@umcutrecht.nl 
+31 88 75 745 17 
A.M. Lehr, MSc 
Clinical Research 
Coordinator 
Project coordinator 
Dept. of Orthopaedics, UMC 
Utrecht, Utrecht 
a.m.lehr@umcutrecht.nl 
+31 88 75 585 11 
H.W. Stempels, MSc 
Research assistant 
Research assistant 
Dept. of Orthopaedics, UMC 
Utrecht, Utrecht 
h.w.stempels@umcutrecht.nl 
+31 88 75 673 93 
R.K. Stellato, MSc, 
PhD 
Assistant Professor 
Methodology and statistical 
analysis 
Dept. of Biostatistics, Julius Center, 
UMC Utrecht, Utrecht 
r.k.stellato@umcutrecht.nl 
+31 88 75 507 94 
D.H.R. Kempen, MD, 
PhD 
Orthopedic Surgeon 
Local Principal Investigator 
Dept.  of Orthopedics, OLVG 
Amsterdam 
d.h.r.kempen@olvg.nl 
 
M. van Dijk, MD, PhD 
Orthopedic Surgeon 
Local Principal Investigator 
Dept. of Orthopedics, St. Antonius 
Utrecht 
m.van.dijk@antoniusziekenhuis.nl  
 
J.L.C. van Susante, 
MD, PhD 
Orthopedic surgeon 
Local Principal Investigator 
Dept. of Orthopaedics, Rijnstate, 
Arnhem 
jvansusante@rijnstate.nl  
 
E.A. Hoebink, MD 
Orthopedic surgeon 
Local Principal Investigator 
Dept. of Orthopaedics, Amphia, 
Breda 
hoebine@amphia.nl  
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................11 
2. 
OBJECTIVES ................................................................................................................14 
2.1 
Primary objectives ..................................................................................................14 
2.2 
Secondary objectives .............................................................................................14 
2.3 
Rationale for secondary objectives .........................................................................14 
3. 
STUDY DESIGN ...........................................................................................................16 
4. 
STUDY POPULATION ..................................................................................................19 
4.1 
Population (base) ...................................................................................................19 
4.2 
Inclusion criteria .....................................................................................................19 
4.3 
Exclusion criteria ....................................................................................................20 
4.4 
Sample size calculation ..........................................................................................20 
5. 
TREATMENT OF SUBJECTS .......................................................................................22 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................23 
6.1 
Name and description of investigational product ....................................................23 
6.2 
Summary of findings from non-clinical studies ........................................................23 
6.3 
Summary of findings from clinical studies ...............................................................25 
6.4 
Summary of known and potential risks and benefits ...............................................25 
6.5 
Description and justification of route of administration and dosage .........................25 
6.6 
Product storage and accountability .........................................................................26 
7. 
METHODS ....................................................................................................................27 
7.1 
Study outcomes .....................................................................................................27 
7.1.1 
Primary study outcomes ..................................................................................27 
7.1.2 
Secondary study outcomes .............................................................................27 
7.1.3 
Other study outcomes .....................................................................................27 
7.2 
Randomization, blinding and treatment allocation ..................................................27 
7.3 
Study procedures ...................................................................................................28 
7.3.1 
Baseline data ..................................................................................................29 
7.3.2 
Surgical and postoperative procedures ...........................................................30 
7.3.3 
Planned follow-up moments ............................................................................31 
7.4 
Radiologic evaluation .............................................................................................34 
7.4.1 
X-rays .............................................................................................................34 
7.4.2 
CT-scans .........................................................................................................34 
7.5 
Withdrawal of individual patients ............................................................................35 
7.6 
Replacement of individual subjects after withdrawal ...............................................35 
7.7 
Follow-up of subjects after withdrawal ....................................................................35 
7.8 
Failures ..................................................................................................................35 
7.9 
Premature termination of the study .........................................................................36 
8. 
SAFETY REPORTING ..................................................................................................37 
8.1 
Temporary halt for reasons of subject safety ..........................................................37 
8.2 
AEs and SAEs ........................................................................................................37 
8.2.1 
Adverse events (AEs) ......................................................................................37 

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8.2.2 
Serious adverse events (SAEs) .......................................................................37 
8.3 
Follow-up of adverse events ...................................................................................38 
9. 
STATISTICAL ANALYSIS .............................................................................................39 
9.1 
Primary efficacy analysis ........................................................................................39 
9.2 
Primary safety analysis ..........................................................................................39 
9.3 
Analysis of secondary outcomes ............................................................................40 
9.4 
Other study parameters ..........................................................................................40 
10. 
ETHICAL CONSIDERATIONS ...................................................................................42 
10.1 
Regulation statement .............................................................................................42 
10.2 
Recruitment and consent........................................................................................42 
10.3 
Objection by minors or incapacitated subjects ........................................................42 
10.4 
Benefits and risks assessment, group relatedness .................................................42 
10.5 
Compensation for injury .........................................................................................43 
11. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................44 
11.1 
Handling and storage of data and documents ........................................................44 
11.2 
Monitoring and Quality Assurance ..........................................................................44 
11.3 
Amendments ..........................................................................................................45 
11.4 
Annual progress report ...........................................................................................45 
11.5 
End of study report .................................................................................................46 
11.6 
Public disclosure and publication policy ..................................................................46 
12. 
STRUCTURED RISK ANALYSIS...............................................................................47 
12.1 
Potential issues of concern .....................................................................................47 
12.2 
Synthesis ...............................................................................................................47 
13. 
REFERENCES ..........................................................................................................48 
APPENDIX A. STATISTICAL ANALYSIS .............................................................................52 
APPENDIX B. SUGGESTED SURGICAL TECHNIQUE .......................................................56 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
 
ABR 
ABR form, General Assessment and Registration form, is the application 
form that is required for submission to the accredited Ethics Committee (In 
Dutch, ABR = Algemene Beoordeling en Registratie) 
AE 
Adverse Event 
ASA 
American Society of Anesthesiologists 
BMP 
Biphasic Calcium Phosphate 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CE 
Conformité Européenne 
CRF 
Clinical Report Form 
CRO 
Clinical Research Organization 
CT 
Computer Tomography 
CV 
Curriculum Vitae 
EU 
European Union 
EQ-5D 
EuroQol Five Dimensions 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEE 
General Estimating Equations 
HA 
Hydroxy Apatite 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
METC  
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsingcommissie (METC) 
NFU 
Dutch Federation of University Medical Centers; in Dutch: Nederlandse 
Federatie van Universitair Medische Centra 
NRS 
Numeric Rating Scale 
NSAID 
Non-Steroidal Anti-Inflammatory Drugs 
ODI 
Oswestry Disability Index 
OLVG 
Onze Lieve Vrouwe Gasthuis 
PLF 
Posterolateral Lumbar Fusion 
PLIF 
Posterior Lumbar Interbody Fusion 
SAE 
Serious Adverse Event  
SOP 
Standard Operating Procedure 

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Sponsor The sponsor is the party that commissions the organization or performance 
of the research, for example a pharmaceutical company, academic hospital, 
scientific organization 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 subsidizing party. 
SPSS 
Statistical Package for the Social Sciences 
Sv 
Sievert 
TCP 
Tricalcium Phosphate 
TLIF 
Transforaminal Lumbar Interbody Fusion 
TM 
Trademark 
UMC 
University Medical Center 
VAS 
Visual Analogue Scale 
Wbp 
Personal Data Protection Act (in Dutch: Wet BeschermingPersoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Posterolateral spinal fusion is currently performed by using large amounts of 
autologous bone graft. Drawbacks of bone grafting include the need for an additional surgical 
procedure, limited supply, sub-optimal bone quality in osteoporotic patients and harvesting 
morbidity, which led to the development of numerous bone graft substitutes. Recently, we 
completed enrollment and one-year follow-up for a clinical trial to evaluate such a bone graft 
substitute (AxA study, METC number 13-192). The product, AttraX® Putty, is a bioresorbable 
tricalcium phosphate (TCP), mixed with a fast resorbing polymer carrier to improve surgical 
handling. The preliminary results are promising in terms of no adverse events related to the 
product and a first impression of similar fusion rates. However, especially in more 
challenging conditions, both the autograft and the material may resorb too fast and bone 
formation by induction was limited. Recently an improved version of the TCP granules has 
been developed, named MagnetOsTM Granules, which has shown favorable results 
especially of these resorption and induction characteristics in pre-clinical studies. 
MagnetOsTM Granules are CE-marked (2115660CE01) and received 510(k) clearance from 
the US Food and Drug Administration (K161859). 
Objective: The primary objective is to demonstrate non-inferiority of MagnetOsTM Granules 
compared to autograft in instrumented posterolateral spinal fusion, in terms of efficacy and 
safety by means of an intra-patient model. 
Study design: This study is designed as a multicenter, observer blinded, randomized, 
controlled non-inferiority trial with intra-patient comparisons. 
Study population: 100 adult patients qualified for posterolateral spinal fusion in the 
thoracolumbar and lumbosacral region (T10-S2) will be recruited and enrolled in this study. 
Intervention: According to a randomization scheme, one side of the spine will be grafted 
with the MagnetOsTM Granules and the other side with bone harvested from the iliac crest 
and local bone. The rest of the surgical procedure will be according to standard care. 
Main study parameters/endpoints: The primary efficacy outcome is the rate of successful 
posterolateral spinal fusion after one year, assessed on CT-scans. Non-inferiority of the 
MagnetOsTM condition compared to the autograft condition will be assessed using a 
McNemar’s test. The primary safety outcome is the number and nature of (serious) adverse 
events related to the surgical procedure compared to control populations from literature. 
Secondary outcomes are the comparison to its predicate (AttraX® Putty), relation between 
posterolateral fusion and interbody fusion after one-year, posterolateral spinal fusion rate 
after two years, relevance of iliac crest donor site pain and the incidence of long-term 
complication and relation with risk factors in the combined population of this study and the 
AxA study. 
Nature and extent of the burden and risks associated with participation: Patient burden 
and risks are expected to be minimal. The first-year follow-up will be according to the 

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standard of care at the UMC Utrecht. Additional procedures for this study include the 
completion of short patient reported outcome measurements at five time points and, 
depending on the local follow-up protocol, a CT-scan at one-year follow-up and/or X-ray at 
two years follow-up. In case the one-year CT-scan shows a doubtful fusion or non-union in 
any of the relevant levels, an additional CT-scan will be made at two years follow-up. Based 
on pre-clinical investigations, and the results of the AxA study, the risk for inferior 
performance of MagnetOsTM Granules is expected to be minimal. Even if this appears to be 
the case, it will have minimal consequences for the patient as the other side of the spine will 
be fused with autologous bone graft and the spine is rigidly instrumented with screws and 
bars. All patients may benefit from the study in terms of reduced surgical time, since only half 
of the required bone graft will be harvested from the iliac crest. 

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1. INTRODUCTION AND RATIONALE 
Spinal fusion is a surgical procedure frequently used for many spinal conditions requiring 
stabilization of the vertebral column, with or without correction of deformities. The primary 
surgical aim of this procedure is to establish bony fusion between one or more vertebral 
segments. Many fusion techniques are available ranging from anterior interbody fusion to 
posterior or posterolateral procedures and combinations of these. Especially in conditions of 
mechanical instability, the bony fusion is facilitated by rigid instrumentation of the vertebrae. 
Bony fusion will develop in time between the immobilized vertebrae when the bone surfaces 
are denuded and graft material is added. This process of fusion is a relatively slow process 
that takes months to years before complete fusion. Therefore, higher fusion rates are 
observed after one year as compared to six months. Autologous bone grafting (or 
autografting) with bone harvested from the iliac crest is the gold standard to achieve bony 
fusion. This is a reliable and well known technique for many indications.1 Whether the bone 
formation after autografting is the result of direct bone formation from the graft, induction by 
the graft, or conduction of host bone remains a matter of debate.2 It is a fact however, that 
alternatives like allograft and ceramics generally perform less good than autologous bone 
from the iliac crest. Bone morphogenic proteins (BMP-2, OP-1) were a popular alternative, 
however, these growth factors have been related to serious complications and may not 
perform as good as autograft.3,4 Especially when more extensive and challenging fusions are 
performed, large amounts of graft are required. This can be problematic since the amount of 
available bone graft from the iliac crest is limited and large quantities may lead to more 
morbidity.3 If extensive decompression is not required, fusion procedures on a single spinal 
level are nowadays often performed with less invasive techniques, combining interbody 
cages with relatively low amounts of bone graft and/or percutaneous pedicle screw 
instrumentation. The real value of an autograft bone substitute is therefore mainly for the 
more extensive surgical procedures where large amounts of autograft are required. Such 
cases include the treatment of multilevel spinal stenosis, primary or secondary scoliosis and 
other deformities. A graft substitute will reduce donor site morbidity and surgery time in those 
cases. At the same time, these conditions are less forgiving and require a graft substitute 
that has at least the same bone forming potential as the autograft. Consequently, the graft 
substitute has to perform like autograft in terms of both generating bone volume and bony 
fusion.  
 
For decades, a suitable alternative to the autologous bone graft has been the subject of 
extensive research. Initially, allogeneic and xenogeneic bone grafts from a human donor and 
animal donor respectively were investigated. Although still very often applied, allogeneic 
grafts do not perform as good as autografts in many situations and they carry a theoretical 

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risk of disease transmission.5–7 Since the 1970s synthetic ceramics have been investigated 
as a more safe and predictable graft substitute. As most ceramics represent the anorganic 
mineral-phase of bone tissue, this strategy seems logical and attractive. Major concerns with 
ceramics are the brittleness and resistance to resorption and remodeling. An alternative is to 
use the organic-phase of donor bone, the so-called demineralized bone matrix (DBM). 
However, also this material has disadvantages of which unpredictable effectiveness is one of 
the major concerns.8,9 Since the 1990s, bone morphogenetic proteins (BMP’s) have been 
introduced and applied at a large scale, especially in the United States. Most well-known are 
BMP-2 and BMP-7, which have shown effectiveness in several preclinical and clinical 
studies. However, these effects could only be accomplished when extremely high dosages 
were applied. These extreme doses may be the cause of the recently reported serious side 
effects.4 
 
Since the late 1990s, a specific group of ceramics has been identified and developed that 
possesses osteoinductive activity in some animal models without the addition of any 
substance.10,11 The exact mechanism behind this characteristic has not yet been elucidated, 
but several important parameters like microporosity and surface characteristics have been 
identified.11,12 Furthermore, it has been shown that osteoinductive characteristics are 
associated with enhanced bone formation in several pre-clinical animal models.13 Such a 
ceramic has been commercialized under the name AttraX® Putty (NuVasive, San Diego, CA) 
and is investigated by us in a similar multicenter, randomized, controlled trial (AxA study, 
METC number 13-192).This study started in October 2013. The last patient was operated in 
July 2016 and one-year follow-up was completed in July 2017. A total of 108 patients were 
included and 100 patients were operated according to the study protocol. The current study 
will be according the same intra-patient design which has many advantages as explained 
below. The preliminary results of the AxA study indicate favorable results in terms of a 
perceived similarity between autograft and AttraX® Putty and the absence of product related 
(serious) adverse events. During the AxA study we did observe that, especially in challenging 
conditions with long fusion trajectories, both the autograft and AttraX® Putty placed around 
the instrumentation and in the posterolateral gutters resorbed too fast and intertransverse 
fusion did not occur, or only between the facet joints. That observation was confirmed by the 
steep reduction in graft density between 3 and 6 months observed with DEXA-scanning. 
 
Recently the composition and manufacturing of AttraX (which was originally developed by 
Progentix Orthobiology, the Netherlands) has been changed by the same research group 
(Prof. de Bruijn and Dr. Yuan, Kuros Biosciences BV, The Netherlands). These changes 
involve a higher hydroxyapatite (HA) content which causes a lower resorption rate, and a 

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surface modification which has shown more favorable osteoinductive activity in several 
studies, as well as less rapid resorption compared to autologous bone.14–18 In a preclinical 
posterolateral spinal fusion study in sheep, the fusion rate was comparable to autograft and 
not influenced by adding a binder.16 This new version has received a CE-mark (number 
2115660CE01) followed by 510(k) clearance from the US Food and Drug Administration 
(FDA) under the name MagnetOsTM Granules and is produced by Kuros Biosciences BV. 
 
The aim of the current study is to clinically investigate MagnetOsTM Granules as an 
alternative to autologous bone graft in adult patients qualified for instrumented posterolateral 
fusion of the thoracolumbar or lumbosacral spine by means of an intra-patient model. This 
patient population will benefit most from such a graft substitute. We expect that MagnetOsTM 
Granules will perform as good as autograft, while eliminating the morbidity and increased 
surgical time associated with harvesting of autologous bone from the iliac crest. 
 

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2. OBJECTIVES 
2.1 Primary objectives 
The primary objective of this study is to demonstrate the non-inferiority of MagnetOsTM 
Granules as compared to autologous bone graft in instrumented posterolateral fusion of the 
thoracolumbar and lumbosacral spine, in terms of efficacy and safety. 
1. Efficacy will be based on the posterolateral spinal fusion rate assessed at one-year 
CT-scans; 
2. Safety will be evaluated by documenting the number and nature of all (serious) 
adverse events that may in any way be related to the surgical procedure. The 
complication rate will be compared to the rate in control populations from literature. 
 
2.2 Secondary objectives 
1. To compare the quantitative primary and secondary results of MagnetOsTM Granules 
to the results of Attrax® Putty from the AxA study (unpaired); 
2. To investigate the relation between successful posterolateral fusion and interbody 
fusion, assessed at the one-year CT-scans used for the primary objective; 
3. To compare the posterolateral spinal fusion rate of both MagnetOsTM Granules and 
autograft at one year with the fusion rates after two years, by using CT-scans; 
4. To investigate the effect of blinding on perceived donor site pain, based on outcome 
measures reported by patients unblinded to the iliac crest donor site in comparison to 
these outcomes of the blinded patients from the AxA study; 
5. To combine the study populations of the current study and the AxA study to 
investigate a) adjacent segment disease, in relation to length of construct and sagittal 
balance and b) risk factors for failures. 
 
2.3 Rationale for secondary objectives 
Besides the primary research question on efficacy and safety, this study gives the 
opportunity to investigate very relevant scientific questions that can only be answered in 
human patients. Furthermore, combining the study data with the data obtained from de AxA 
study increases the power to study phenomena that occur less frequently. 
 
1. Comparison of the quantitative results of MagnetOsTM Granules to AttraX® Putty 
Since both the study designs are the same and have the same in- and exclusion criteria, it 
will be possible to compare the groups in a standard unpaired fashion. We did not power this 
comparison since it is a secondary aim, but the findings will be indicative with a considerable 

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sample size of 200 individuals (each with autograft at one side of their spine and 
MagnetOsTM Granules (n=100) or AttraX® Putty (n=100) at the other side). 
 
2. Relation between posterolateral fusion and interbody fusion 
Since this study will not exclude interbody fusions, and the effect of such interbody fusions 
on the posterolateral fusion masses is unknown, it is desired to determine the statistical 
relation between the posterolateral and interbody fusions. 
 
3. Fusion rate after 2 years 
There are indications that the percentage bony fusion continues to increase between 1 and 2 
years.26–28 Whether this is graft related or a result of immobilization due to instrumentation is 
unclear. Nevertheless, it is important to determine the long-term fusion potential and 
behavior of MagnetOsTM Granules and autograft, and to compare these conditions. To limit 
the number of CT-scans at 2 years follow-up, only those patients that scored a doubtful 
fusion or non-union in any of the relevant levels at the one-year CT-scan will undergo an 
additional CT-scan.   
 
4. Relevance of donor site pain 
Although iliac crest donor site morbidity is often reported by patients, the relevance of donor 
site pain is disputable when the bone is harvested via the same incision as used for the 
spinal fusion.3 The preliminary results of the AxA study indeed indicate that there is no 
relation between the real donor site and the iliac crest that is indicated by blinded patients. 
To determine if the often reported high incidence of donor site pain can be explained by the 
knowledge of the patient where the bone graft was taken, we will not blind the patients for the 
donor site in this study. The outcomes measures reported by patients unblinded to the iliac 
crest donor site will be compared to the outcomes of the blinded patients from the AxA study. 
 
5. Combine the study populations of the current study and the AxA study  
To combine the study data of both the current study and the AxA study will allow 
investigations on more infrequent phenomena on a relatively large population. Such a 
phenomenon is for example adjacent segment disease. This is a longterm complication 
where the adjacent joints and intervertebral disc may wear faster and cause degenerative 
disease. The occurrence of adjacent segment disease may be related to length of the 
construct and restoration of the sagittal balance. The occurrence of typical complications like 
infection and pseudoarthrosis can be related to risk factors like comorbidities, smoking, 
length of instrumented segment and so on.  

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3. STUDY DESIGN 
This study is a multicenter, observer blinded, randomized, intra-patient controlled, non-
inferiority trial with intra-patient comparisons, which is initiated and will be coordinated by the 
department of Orthopaedics from the UMC Utrecht, the Netherlands. A multicenter design is 
necessary to include the required number of patients (n=100) in an acceptable and feasible 
timeframe. Due to the experience with the AxA trial we have an established cooperation with 
the other centers which will make implementation in all centers relatively easy. 
 
Adult patients qualifying for instrumented posterolateral spinal fusion of one to six levels in 
the thoracolumbar and lumbosacral region (T10-S2) with the use of autograft will be recruited 
by their treating orthopaedic surgeon or his/her assistant. After obtaining informed consent, 
they will be operated locally according to normal planning and the surgical techniques 
suggested in Appendix B. Per-operatively, after instrumentation of the spine and preparation 
of the bilateral trajectory for grafting, the randomized allocation of the graft type (left or right) 
will be disclosed. So in each patient, each side of the fusion trajectory will be one of the two 
conditions: the autograft condition, a combination of local bone obtained from 
decompression and/or preparation for fusion (facetectomy and denudement), supplemented 
with at least 50% corticocancellous bone harvested from the iliac crest, or the MagnetOs 
condition. Allocation of the conditions will always be to only one side of the spine, also when 
multiple levels are incorporated. Corticocancellous bone will be taken from only one iliac 
wing at the side of the autograft condition, unless this side is inappropriate due to previous 
harvesting or anatomical reasons. If possible, harvesting is done via the same posterior 
incision for spinal fusion. In case of an additional interbody fusion procedure, the cage is 
preferably filled with local autograft bone and positioned before opening of the randomization 
envelope. If the surgeon decides to use iliac crest bone for this device, the cage can only be 
inserted after the randomization and related harvesting side has been disclosed. All patients 
will be evaluated radiologically and clinically at several time points pre- and postoperatively 
(see Figure 3.1), and all (serious) adverse events that in any way may be related to the 
procedure will be carefully documented and evaluated to meet the objectives described in 
Chapter 2. 
 
The expected duration of the study is approximately 4 years from the commencement of 
patient enrollment; enrollment is expected to take two years, followed by two years follow-up. 
After completion of one-year follow-up, the analysis for the primary outcomes will be done by 
the investigators at the UMC Utrecht.  

ABR number NL64652.041.18  
 
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Figure 3.1: Schematic overview of study design. 
 
Rationale for intra-patient design 
To investigate the efficacy of a bone graft substitute like MagnetOsTM Granules in the patient 
group that will benefit most from it, is challenging as these patients and surgeries are quite 
unique. The types of fusion in terms of location and number are highly variable and difficult to 
compare. Also, several surgical techniques are applied in addition to the posterolateral fusion 
at various levels. For example, posterior lumbar interbody fusion (PLIF) or transforaminal 
lumbar interbody fusion (TLIF). The solution to these impediments is to use a model where 
the patient is its own control. This is a recognized option in posterolateral spinal fusion 
investigations, because the right and left side of the spine are subject to similar procedures 
but physically separated.29,30 Moreover, the assessment of spinal fusion in terms of bone 
continuity and bone volume of both sides can be done independently. By using an intra-
patient comparison model, the number of patients required for sufficient study power will be 
even less than half the number needed for traditional inter-patient comparisons. This is 
Yes: enroll in study 
Intake and pre-operative 
data collection 
Surgical treatment 
6 weeks, 3 months,  
1 year follow-up 
Analyses and report 
1 year results 
2 years follow-up 
Analyses and report 
2 year results 
 
No: exclude from study 
In- and exclusion criteria met and informed consent given  
Adult patients qualifying for instrumented posterolateral spinal fusion  
of one to six levels between T10 and S2 with the use of autograft 

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because inter-patient variability of confounders for bony fusion is irrelevant with this 
approach. Finally, an important ethical advantage of this model is that the patient always 
receives the gold standard treatment for posterolateral fusion at one side of the spine, and 
for interbody fusion as well when an additional PLIF or TLIF procedure is performed. When 
the bone graft substitute would unexpectedly fail to establish a bony fusion, the implications 
will be much less severe because the contralateral side will have the gold standard treatment 
and a unilateral fusion of the spine is sufficient.  
 
A frequently mentioned disadvantage of an intra-patient comparison model can be a 
disturbing effect of one condition on the other.31 This is definitely a concern when the 
stabilizing effect of fusion on one side of the spine might affect the other side. However, 
when spinal instrumentation is used, motion is drastically limited and not likely to be a factor 
of importance. Another disadvantage of an intra-patient model is when bioactive factors like 
BMPs are used, as these may influence the contralateral site. However, this is not a concern 
in the case of the current ceramic material, as it does not contain any bioactive additives. 
The main concern with the intra-patient model is that it does not allow assessment of the 
clinical effect of the intervention. This is a very important limitation that should be recognized. 
However, it is not an issue with respect to our research questions. The clinical outcome of 
spinal fusion is a matter on itself, which actually does not really reflect the functional and 
radiological presence of fusion especially not in the first years.32 Therefore, this study aims to 
evaluate the efficacy of in terms of percentage bony fusion, assessed at one year CT-scans.

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4. STUDY POPULATION 
4.1 Population (base) 
Adult patients, both males and females, qualifying for instrumented posterolateral spinal 
fusion of one to six levels between T10 and S2 with the use of autograft will be recruited by 
their treating orthopaedic surgeon or his/her assistant at the UMC Utrecht, OLVG 
Amsterdam, St. Antonius Hospital Utrecht, Rijnstate Arnhem or Amphia Hospital Breda. All 
patients will have had at least one conservative treatment attempt prior to enrollment. Based 
on the sample size calculation described in Paragraph 4.4 and Appendix A, the total number 
of patients to be enrolled is 100. Based on our experience with the AxA study, patient 
enrollment is expected to take two years. 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a patient must meet all of the following 
criteria: 
 
To be treated with instrumented posterolateral thoracolumbar spinal fusion with the 
use of iliac crest bone, with or without additional posteriorly inserted interbody 
devices (PLIF, TLIF), because of (1) deformity, (2) structural instability and/or (3) 
expected instability as a result of decompression for spinal stenosis; 
1. Deformity is defined as a scoliosis in the coronal plane of >20° and/or a 
sagittal balance disturbance according the SRS/Schwab classification33 on 
standardized standing full spine radiographs;  
2. Preoperative instability is defined as a progressive angular deformity or 
spondylolisthesis in standing radiographs; 
3. Decompression for spinal stenosis is done in the occurrence of radiological 
evidence of stenosis on MRI and clinical leg and/or back pain with one or 
more of the following phenomena: radiculopathy, sensory deficit, motor 
weakness, reflex pathology or neurogenic claudication. 
 
Non-responsive to at least 6 months of non-operative treatment prior to study 
enrollment; 
 
Fusion indicated for one to six levels in the T10 to S2 region. In case of vertebral 
osteotomies (PSO or VCR) the osteotomized segment will not be included in the 
assessment of the fusion rate; 
 
Willing and able to understand and sign the study specific Patient Informed Consent; 
 
Skeletally mature between 18 and 80 years of age. 
 

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4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation 
in this study: 
 Any previous surgical attempt(s) for spinal fusion (revision surgery) of the intended 
segment(s); 
 Previous treatments that compromise fusion surgery like irradiation; 
 Previous autologous bone grafting procedures that compromise the quality and 
amount of iliac crest bone grafting; 
 Indication for spinal fusion because of an acute traumatic reason, like a spinal 
fracture; 
 Active spinal and/or systemic infection; 
 Spinal metastasis in the area intended for fusion; 
 Systemic disease or condition, which would affect the subjects ability to participate in 
the study requirements or the ability to evaluate the efficacy of the graft (e.g. active 
malignancy, neuropathy, pregnancy); 
 At risk to be non-compliant e.g.: (recently treated for) substance abuse, detainee, 
likely to immigrate 
 Participation in clinical trials evaluating investigational devices, pharmaceuticals or 
biologics within 3 months of enrollment in this study; 
 Female patients who intend to be pregnant within 1.5 year of enrollment in the study; 
 Body mass index (BMI) larger than 36 (morbidly obese); 
 Being expected to require additional surgery to the same spinal region within the next 
6 months; 
 Current or recent (<1yr) corticosteroid use equivalent to prednisone ≥5mg/day, 
prescribed for more than 6 weeks. 
 
4.4 Sample size calculation 
The primary objective of this study is to demonstrate that treatment with MagnetOsTM 
Granules is non-inferior to autograft to obtain bony fusion in the spine. The primary outcome 
is the rate of successful posterolateral bony fusion after one year, assessed at CT-scans. 
Fusion will be scored binomially and non-inferiority of fusion in the MagnetOs condition will 
be assessed using a McNemar's test. 
 
Based on literature6,28–30,34 and the preliminary results of the AxA study, we estimate a fusion 
percentage of 50% for unilateral grafting after one year, and a 70% concordance between 
the left and right side of the fusion trajectory (i.e. both sides fused or non-fused). The non-

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inferiority margin is set at an absolute 15% less effectiveness in the MagnetOs condition after 
one year, which corresponds with 15% less posterolateral sides that are judged as fused. In 
other words, the rate of fused posterolateral sides in the MagnetOs condition should be more 
than 35% if the autograft condition shows 50% fusion. We argued that the percentage of the 
iliac crest graft related complications, ranging from 5% major complications to 40% minor 
complications, may justify 15% less fusion in a condition that eliminates these complications. 
 
Based on a 1:1 paired assignment of MagnetOsTM Granules to the control condition with 
autograft, a power of 80%, a one-sided alpha of 0.05 and the non-inferiority margin of 15%, 
the required sample size for the primary outcome is 84 patients (see Appendix A). We 
assume that approximately 15% of the included patients will not be evaluable after one year. 
The intra-patient analyses are not possible when the fusion area has to be revised or when a 
deep wound infection has occurred and considerable amounts of graft material have to be 
removed (expected percentage 2-5%). Other failures are lost to follow-up or bad scan 
quality. Therefore, the total number of patients to be enrolled will be 100. 
 

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5. TREATMENT OF SUBJECTS 
As explained in the introduction, autologous bone grafting is the gold standard to achieve 
bony fusion in (instrumented) spinal fusion procedures. In this study, according to a 
randomization scheme, one side of the spine will be grafted with the synthetic ceramic 
material MagnetOsTM Granules instead of local bone mixed with bone harvested from the 
iliac crest. The rest of the surgical procedure will be according to standard care. The 
investigational product is described more detailed in the next Chapter; the treatment 
procedure and follow-up are described in Chapter 7. 
 

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6. INVESTIGATIONAL PRODUCT 
6.1 Name and description of investigational product 
MagnetOsTM Granules is a synthetic ceramic that has a CE-mark (2115660CE01) as well as 
FDA 510(k) clearance (K161859). It is comprised of calcium phosphate granules with a 
tricalcium phosphate (ß-TCP) and hydroxyapatite (HA) ratio of 70/30. The calcium phosphate 
granules have shown to be bioactive, osteoconductive and osteoinductive.11 
 
MagnetOsTM Granules is intended for use as a bone void filler for voids and gaps of the 
skeletal system that are not intrinsic to the stability of the bony structure, and not too large 
that they would fail to heal spontaneously in the surgeon’s opinion. The device may be 
combined with autogenous bone, blood, platelet-rich plasma, and/or bone marrow. In load-
bearing situations, MagnetOsTM Granules is to be used in conjunction with internal or external 
fixation devices.  
 
6.2 Summary of findings from non-clinical studies 
Biocompatibility of MagnetOsTM Granules has been established through testing and 
evaluation per ISO 10993 standards for permanent implant contacting bone/tissue. The 
material was found to be non-cytotoxic, non-sensitizing, non-irritating, non-genotoxic, and 
non-toxic. 
 
To test device performance, MagnetOsTM Granules has been compared to predicates 
including AttraX Granules (a.k.a. CuriOsTM), VitossTM BA (Orthovita) and ActifuseTM ABX 
(Apatech) in a series of benchtop and animal studies. Benchtop degradation tests show that 
MagnetOsTM Granules are resorbable. The resorption rate of MagnetOs is situated within the 
range of other commercially available calcium phosphate bone void fillers. From the quickest 
to slowest resorbable material: Vitoss>AttraX>MagnetOs>Actifuse ~ Pro-Osteon ~ OsSatura. 
Testing of the structure of the calcium phosphate components using mercury intrusion 
porosimetry showed that MagnetOsTM Granules have a total porosity of 70±15%. The total 
surface area of MagnetOsTM Granules is larger than that of CuriOsTM, VitossTM BA and 
ActifuseTM ABX. These surface features have shown to be important in promoting bone 
formation. 
Ectopic implantation in a dog intramuscular model showed the osteoinductive potential and 
biocompatibility of MagnetOsTM compared to OsOpia (REGEDENT AG) and CuriOsTM. After 
12 weeks implantation, no necrosis and inflammation were seen in any of the explants. 
MagnetOsTM gave rise to earlier bone formation than CuriOsTM and OsOpia14,15 while bone% 

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U
B
FR
U
B
FR
U
B
FR
Autograft 1/5 0/5 10%
1/6  4/6 75%  1/5  4/5
90%
BCP  0/5 0/5
0%
1/6
5/6 92%  0/5  5/5 100%
BCP + Binder  0/5 0/5
0%
 2/6  4/6 83%  1/5  4/5
90%
6 wks 
12 wks 
26 wks 
and cellular activity on the different microstructures were equivalent for all groups at 12 
weeks. 
 
Two preclinical studies in spine posterolateral models showed efficacy of MagnetOsTM 
Granules. In a sheep model of instrumented posterolateral spinal fusion, of MagnetOsTM 
Granules with or without a binder showed to have similar fusion rates at different time points 
compared to autograft. At 12 weeks, the fusion rate assessed by manual palpation and 
histology showed a high fusion performance (see table 1). The tissue responses were similar 
for all implanted bone grafting materials. Material resorption and bone formation were 
quantified by histomorphometry. An equivalent amount of bone was formed and a slower 
resorption of of MagnetOsTM Granules was observed, as compared to CuriOsTM granules. 
Distant organs and blood analyses confirmed the lack of systemic toxicity.16 
 
Table 1. Fusion by histology (instrumented Sheep spine posterolateral fusion) 
U=unilateral fusion; B=bilateral fusion; FR=Fusion rate. BCP= MagnetOs 
 
 
 
 
 
 
As an autograft extender, MagnetOsTM Granules achieved similar fusion rates compared to 
autograft alone in a rabbit bilateral un-instrumented posterolateral spinal fusion. At 6, 9 and 
12 weeks, the animals were essentially equivalent based on all end point evaluations 
(manual palpation, radiography, micro-CT, histology). Progression of fusion was also seen 
for all end points at 6, 9 and 12 weeks. Mechanical testing (flexion-extension and lateral 
bending) at 12 weeks demonstrated fusion of the treated level, which was comparable to the 
autograft group and in line with the manual palpation results. Histology and 
histomorphometry versus time demonstrated the normal features of bone healing and 
progression to spinal fusion. An osteoconductive response was noted at 6 weeks with newly 
formed bone formation both on and between the resorbing calcium phosphate mineral as 
well as with the residual autograft particulate. The normal concert of new bone formation, 
implant resorption and remodeling occurred with time as the newly formed bone remodeled 
together the material resorption and normal marrow spaces developing to mature fusion 
space at 12 weeks. No adverse reactions were observed. 
 

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Table 2. Fusion by histology (Rabbit spine posterolateral fusion) 
 
 
 
6.3 Summary of findings from clinical studies 
No clinical investigations of MagnetOsTM Granules have been performed to-date. 
 
6.4 Summary of known and potential risks and benefits 
Spinal fusion with a synthetic bone graft substitute is a widely available surgical treatment 
option for patients with a spinal deformity. However, there are some short and long-term risks 
that one has to be aware of. 
 
Short term risks of a bone graft substitute include, but are not limited to: 
 
Migration of the device from the site of implantation 
 
An allergic reaction to the implanted material 
 
Long term risks of a bone graft substitute include, but are not limited to: 
 
Failure to promote bone fusion 
 
Excessive bone growth, or bone growth in unwanted locations 
 
As mentioned above, MagnetOsTM Granules has shown in preclinical animal models to result 
in increased fusion potential and quicker fusion than similar commercially available materials. 
Potential benefits in the clinical setting might include higher fusion rates, and faster fusion 
times than other synthetics, as well as lower complications than autograft, allograft, or 
protein-based treatment options. This study is designed to show non-inferiority of 
MagnetOsTM Granules as compared to autograft for posterolateral spinal fusion as well as to 
determine potential risks in the clinical setting.  
 
6.5 Description and justification of route of administration and dosage 
In this study, MagnetOsTM Granules will be used as an alternative to autograft for 
instrumented posterolateral fusion of the thoracolumbar or lumbosacral spine, to evaluate its 
efficacy and safety. After instrumentation and preparation of the bilateral trajectory for 
grafting, the recommended volume of 8-10cc of per spinal level will be placed at the 
randomized allocation side, without the addition of autogenous bone, blood, plasma or bone 
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marrow. Close contact with vital bone is important for its function as a bone regeneration 
material. The surgeon will place the granules around the instrumentation and in the 
decorticated lateral gutters, bridging the dorsal surfaces of the transverse processes, facets 
and laminae, without destruction of the granules structure.  
 
6.6 Product storage and accountability 
MagnetOsTM Granules will be provided by the subsidizing party in commercially available 
packages of 5cc (vials in a pouch). The product will be stored at each participating site 
according to the recommended storage conditions. Shipment and distribution records as well 
as product accountability logs will be retained. At the end of the study, unused products will 
be returned to the subsidizing party. 

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7. METHODS 
7.1 Study outcomes 
7.1.1 Primary study outcomes 
1. Posterolateral spinal fusion rate at one-year follow-up (assessed on CT-scans); 
2. Rate of (serious) adverse events that are related to the procedure in any way, and 
their potential relation with MagnetOsTM Granules. 
7.1.2 Secondary study outcomes 
1. Comparison of the quantitative primary and secondary results of MagnetOsTM 
Granules to the results of AttraX® Putty from the AxA study (unpaired); 
2. Relation between successful posterolateral fusion and interbody fusion at one-year 
follow-up (assessed on CT-scans); 
3. Posterolateral spinal fusion rate at two years follow-up compared to the fusion rate at 
one-year follow-up (assessed on CT-scans); 
4. Effect of blinding on perceived donor site pain; 
5. Incidence of long-term complications and relation with risk factors in the combined 
population of this study and the AxA study. 
7.1.3 Other study outcomes 
This study provides the opportunity to further investigate several outcomes in a cohort of 
100 spondylodesis patients, not related to the comparison of MagnetOsTM Granules and 
autograft. 
 
1. Changes in EQ-5D-5L, ODI and VAS pain scores over time; 
2. Relation between clinical outcomes and fusion status at one-year follow-up; 
3. Satisfaction with treatment; 
4. Effect of nicotine use on fusion; 
5. Effect of NSAID use on fusion. 
 
7.2 Randomization, blinding and treatment allocation 
Randomization for the allocation of the graft type will be performed with use of a 
computerized random-number algorithm. The randomization scheme will be maintained at 
the UMC Utrecht by the central principal investigator and study coordinator. The orthopaedic 
surgeon will be blinded to the allocation side of MagnetOsTM Granules, and thereby the 
contralateral allocation of autograft, as long as possible. He/she will receive an envelope 
containing the randomization of the patient which should be opened during surgery just 

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before the graft is needed (see suggested surgical technique, Appendix B). The iliac bone 
graft has to be taken from the same side where the autograft will be applied for posterolateral 
fusion according to the randomization. This will not be communicated to the patient. 
Whenever possible, bone harvesting will be done without making an additional skin incision.  
 
In case an intra-operative decision is made to perform something different than what was 
intended for study enrollment, like for example to use local bone graft only or an 
uninstrumented spinal fusion, the patient will be considered a per-operative withdrawal and 
will not be treated with MagnetOsTM Granules. These patients will be replaced as described 
in paragraph 7.5. 
 
7.3 Study procedures 
Figure 7.1 illustrates the timing of the different study procedures that are described below. 
Procedures that are not part of standard care in one or more participating centers are 
marked bold.  
 
All study data will be entered in electronic Case Report Forms (eCRFs) using Castor EDC. 
To limit missing data and ensure timely completion, the patient questionnaires are preferably 
filled out digitally by using the email function in Castor EDC. If patients prefer paper 
questionnaires, they should be completed at the outpatient clinic. 
 
De-identified copy of all corresponding images will be send to the principal investigator at the 
UMC Utrecht. 
 
Table 7.1: Timing of study procedures and data collection. Procedures that are not part of standard care 
in one or more participating centers are marked bold. Abbreviations: d = days, wks = weeks, mos = 
months, yr(s) = year(s).  
 
 
 
 
CRF form 
Preop 
 
 
A 
Perop 
 
 
B 
1-5 d  
 
postop 
C 
6 wks 
(±14d) 
postop 
D 
3 mos 
(±21d) 
postop 
E 
1 yr  
(+3mos) 
postop 
G 
2 yrs  
(±2mos) 
postop 
H 
Demographics  
Baseline data 
x 
 
 
 
 
 
 
Treatment details 
 
x 
 
 
 
 
 
Clinical evaluation 
x 
 
x 
x 
x 
x 
x 
X-rays 
x 
 
x 
x 
x 
x 
x 
CT-scan 
 
 
 
 
 
x 
x1 
Patient questionnaires 
x 
 
 
x 
x 
x 
x 

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1 Only applies to patients that scored a doubtful fusion or non-union in any of the relevant 
levels at the one-year CT scan (see Appendix C) 
 
7.3.1 Baseline data 
After enrollment (see Chapter 10 for the recruitment and consent procedure), a 
preoperative baseline evaluation will be performed and the following data will be collected 
(CRF A): 
 
Month and year of birth 
 
Gender 
 
Smoking 
 
Pre-operative diagnosis 
 
Prior treatment to affected spinal levels 
 
Concurrent medical conditions 
 
ASA classification 
 
Disease related medication use (including NSAID use) 
 
Questionnaires 
o EQ-5D-5L 
o ODI 
 
VAS pain score 
o Back pain related to diagnosis  
o Leg pain related to diagnosis 
o Pain in left iliac crest 
o Pain in right iliac crest 
o Pain drawing 
 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. 
Applicable to a wide range of health conditions and treatments, it provides a simple 
descriptive profile and a single index value for health status that can be used in the clinical 
and economic evaluation of health care as well as population health surveys. The 
Oswestry Low Back Pain Disability Index (ODI) is an evaluation questionnaire related to 
patient perception of the effect of his/her current low back pain on activities of daily living. 
A Visual Analogue Scale (VAS) will be used to record back pain, leg pain and iliac crest 
pain at the left and right side at all evaluation points. As a supplement, patients will be 
asked to make a pain drawing to get a graphic representation of the pain and its physical 
distribution.  

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7.3.2 Surgical and postoperative procedures 
Patients will be operated according to standard surgical procedures for instrumented 
posterolateral fusions between T10 and S2, with the only exception that one side of the 
spine will be grafted with the synthetic ceramic material MagnetOsTM Granules instead of 
bone harvested from the iliac crest. A recommended surgical technique is provided in 
Appendix B. In advance, the participating orthopaedic surgeons of each center will receive 
instructions on appropriate use of MagnetOsTM Granules from the principal investigator. 
Any questions that may arise concerning the surgical aspects of using MagnetOsTM 
Granules or autograft will be answered by the principal investigator. 
 
Standard prophylactic antibiotics will be given for at least 24 hours, according the local 
surgical guidelines of each center. A thrombosis prophylaxis will be used according to the 
surgeons’ preference. If preferred by the surgeon, patients will receive a restraining brace 
or orthosis postoperatively in order to protect the spine from (excessive) movements. 
Mobilization will be encouraged on the first postoperative day; physiotherapy will be 
offered during hospitalization and ambulatory if indicated. 
 
According to standard care, standing anteroposterior and lateral radiographs will be taken 
postoperatively during hospitalization.  
 
During surgery and hospital admission, the following information will be collected (CRF B): 
 
Date of surgery 
 
Surgeon’s name 
 
Surgical technique 
o Instrumented spinal levels 
o Levels of decompression 
o Performance of vertebral osteotomy 
o Use of interbody device 
o Insertion side of TLIF 
o Additional surgical procedures  
 
With the use of a 20ml syringe an estimation of the volumes (in mL) of: 
o 1) obtained local bone and 2) obtained iliac crest bone and 3) the 
ratio of local bone / iliac crest bone used for posterolateral fusion 
o Local bone (or mixed autograft) applied per level for interbody fusion 
o (Mixed) autograft used per posterolateral fusion level 

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 
Estimation of volume of MagnetOs™ Granules per posterolateral fusion level 
(in cc) 
 
Iliac crest side used for bone harvesting (right/left) 
 
Iliac bone harvested via same incision (yes/no) 
 
Additional time required for bone graft harvesting (minutes) 
 
Allocation of MagnetOsTM Granules (left/right) 
 
Surgical time (skin to skin and total anaesthesia time (begin and end of 
sedation) 
 
Estimated blood loss (cc) 
 
Use of vancomycine powder 
 
Intra-operative complications 
 
Postoperative X-rays 
 
Date of discharge 
 
Disease related medication use (including NSAID use) 
 
7.3.3 Planned follow-up moments 
The subsequent follow-up moments will take place at the outpatient clinic and are based 
on the standard care at the UMC Utrecht. The data described below will be collected at 6 
weeks, 3 months, 1 year and 2 years postoperatively. The questionnaires, CT-scan at 2 
years follow-up in case of no or doubtful fusion at 1 year follow-up, and depending on the 
local follow-up protocol the CT-scan at one year follow-up and/or X-ray at two years 
follow-up, are extra for this study. In addition to the baseline questionnaires, treatment 
satisfaction will be assessed with a Numeric Rating Scale (NRS). 
 
6 weeks (±14 days; CRF C) 
 
Complications / (serious) adverse events 
 
Disease related medication use (including NSAID use) 
 
Questionnaires 
o EQ-5D-5L 
o ODI 
o NRS satisfaction 
 
VAS pain score 
o Back pain related to diagnosis  
o Leg pain related to diagnosis 
o Pain in left iliac crest 

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o Pain in right iliac crest 
o Pain drawing 
 
Imaging 
o Standing anteroposterior and lateral radiographs  
 
Radiologic evaluation by treating surgeon (indications for failure or 
deformation / instability) 
 
3 months (±21 days; CRF D) 
 
Complications / (serious) adverse events 
 
Disease related medication use (including NSAID use) 
 
Questionnaires 
o EQ-5D-5L 
o ODI 
o NRS satisfaction 
 
VAS pain score 
o Back pain related to diagnosis  
o Leg pain related to diagnosis 
o Pain in left iliac crest 
o Pain in right iliac crest 
o Pain drawing 
 
Imaging 
o Standing anteroposterior and lateral radiographs  
 
Radiologic evaluation by treating surgeon (indications for failure or 
deformation / instability) 
 
1 year (12-15 months; CRF F) 
 
Complications / (serious) adverse events 
 
Disease related medication use (including NSAID use) 
 
Questionnaires 
o EQ-5D-5L 
o ODI 
o NRS satisfaction 
 
VAS pain score 
o Back pain related to diagnosis  
o Leg pain related to diagnosis 
o Pain in left iliac crest 

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o Pain in right iliac crest 
o Pain drawing 
 
Imaging 
o Standing anteroposterior and lateral radiographs  
o CT-scan 
 
Radiologic evaluation by treating surgeon (indications for failure or 
deformation / instability) 
 
Fusion assessment based on CT-scan by treating surgeon per level and per 
side in three planes, without the distinction between graft-related or non-graft-
related fusion as described in Appendix C. 
 
2 years (22-26 months; CRF G) 
 
Complications / (serious) adverse events 
 
Disease related medication use (including NSAID use) 
 
Questionnaires 
o EQ-5D-5L 
o ODI 
o NRS satisfaction 
 
VAS pain score 
o Back pain related to diagnosis  
o Leg pain related to diagnosis 
o Pain in left iliac crest 
o Pain in right iliac crest 
o Pain drawing 
 
Imaging 
o Standing anteroposterior and lateral radiographs  
o CT-scan of all patients with a doubtful fusion or non-union after 1 
year, as assessed by the blinded observer 
 
Radiologic evaluation by treating surgeon (indications for failure or 
deformation / instability) 
 
Fusion assessment based on CT-scan by treating surgeon per level and per 
side in three planes, without the distinction between graft-related or non-graft-
related fusion as described in Appendix C. 
 

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7.4 Radiologic evaluation 
7.4.1 
X-rays 
The regular standing anteroposterior and lateral radiographs will be evaluated locally by 
the treating surgeon. Indications for failure like material breakage or loosening and 
deformation or instability like osteolysis will be recorded, as well as indications for bone 
bridging. 
7.4.2 
CT-scans 
The CT-scans will be reviewed both locally by the treating surgeon and centrally by an 
assessment panel consisting of at least one spine surgeon and an uninvolved specialist. 
This panel will be blinded to the treatment allocation and perform the assessments 
independently on de-identified CT-scans (see Appendix C).  
 
Each instrumented spinal level, that is not part of an osteotomized segment, will be 
unilaterally assessed for posterolateral fusion according the protocol, based on 
literature35–37 and experience from the AxA study. This grading system consists of three 
categories: 
1. “Fusion” is defined as a continuous bony bridge from one vertebra to the other, in 
absence of any secondary signs of nonunion, such as fracture or loosening of the 
screws or rods (= 2 points); 
2. “Doubtful fusion” indicates doubts about continuity or quality of the bony bridge (= 1 
point); 
3. “No fusion” indicates definite discontinuity or lack of the fusion mass, as well as 
obvious indications of mobitliy like materal failure or apparent pseucoarthrotis (= 0 
points). 
 
Assessement of posterolateral fusion is scored in the coronal, sagittal and axial  plane. A 
segment will be regarded fused if at least one plane shows definite fusion (2 points) and at 
least one other plane a doubtfull fusion (at least 1 point). Interbody fusion will be assessed 
in two planes and scored similarly. 
 
The final assessment panel will score two locations of posterolateral fusion separately: 
between the transverse process and >1mm lateral or above the rod (graft related) and 
directly around the rod or fusion of the facet joint (probably not graft related). See 
Appendix C for a more detailed description of the CT-assessment for the primary and 
secondary outcomes.  

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The CT-scans will also be evaluated for the volume of fusion bone, signs of heterotopic 
ossification (i.e. extension of fusion mass beyond the intended fusion level) and if 
possible, the presence of graft remnants will be recorded. 
 
7.5 Withdrawal of individual patients 
Patients can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigators can decide to withdraw a patient from the study for urgent 
medical reasons. In case an intra-operative decision is made to perform something different 
than what was intended for study enrollment like for example to use local bone graft only or 
an uninstrumented spinal fusion, the patient will be considered a per-operative withdrawal 
and will not be treated with MagnetOsTM Granules. Protocol violations where the (surgical) 
procedure or follow-up (e.g. timing of one-year CT-scan) will influence the primary outcome 
will be regarded individually and may lead to withdrawal. 
 
7.6 Replacement of individual subjects after withdrawal 
Per-operative withdrawals will be replaced. Patients who are withdrawn or lost to follow-up 
post-operatively, i.e. after the treatment with MagnetOsTM Granules, will not be replaced in 
this study, unless the anticipated drop-out rate of 15% is exceeded. 
 
7.7 Follow-up of subjects after withdrawal 
All data collected until withdrawal will be used for the analyses as described in the protocol, 
unless the patient made an explicit objection. All withdrawn patients will be followed 
according to standard care. 
 
7.8 Failures 
Patients that need revision surgery that influences the fusion, will be considered failures and 
only excluded from the primary analysis and secondary outcomes related to the performance 
of MagnetOsTM Granules. This because the treatment effect on one side of the spine cannot 
be distinguished from the effect on the other side, so intention to treat analyses are not 
possible. Patients registered as failure will not be replaced, as the total number of patients 
takes this into account. Follow-up will continue according to the study protocol. 
 

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7.9 Premature termination of the study 
All (serious) adverse advents that can be related to the surgical procedure in any way will be 
reported to the principal investigator as described in Chapter 8 and evaluated. If a relation to 
the performance of MagnetOsTM Granules is suspected, the allocation side can be disclosed. 
These findings will be discussed with the METC.  
 
 

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8. SAFETY REPORTING 
8.1 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 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.  
 
8.2 AEs and SAEs 
8.2.1 
Adverse events (AEs) 
Adverse events are defined as any undesirable medical experience occurring to a subject 
during the study, whether or not considered related to MagnetOsTM Granules. All adverse 
events that can be related to the surgical procedure that are observed by the participating 
investigators or their staff, or reported by the subject between or at the follow up visits, will 
be recorded in the Case Report Form. An overview and analysis of all these adverse 
events will be included in the final study report. AEs that are related to previous known or 
unknown diseases, or conditions that cannot be related to the procedure (like accidents or 
other interventions), will not be recorded. 
 
8.2.2 
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 hospitalization or prolongation of existing inpatients’ hospitalization; 
 
Results in persistent or significant disability or incapacity; 
 
Is a congenital anomaly or birth defect; or 
 
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 judgement by the investigator. 
An elective hospital admission for other reasons will not be considered as a serious 
adverse event. 
 

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All SAEs that can be related to the surgical procedure that are observed by the local 
principal investigators or their staff, or reported by the subject between or at the follow up 
visits, will be recorded in the Case Report Form. The investigator will report all these 
SAEs to the sponsor within 24 hours after obtaining knowledge of the events by sending 
the SAE form. SAEs that are related to a previous known or unknown disease, or 
conditions that cannot be related to the procedure (like accidents or related to other 
interventions) will not be recorded. 
 
The sponsor will report all reported serious adverse events 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. 
 
8.3 Follow-up of adverse events 
All reported AEs will be followed until they have abated, or until a stable situation has been 
reached or until the last study visit. Depending on the event, follow up may require additional 
tests or medical procedures as indicated, and/or referral to the general physician or a 
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9. STATISTICAL ANALYSIS 
The detailed statistical methods and justification are described in Appendix A. 
 
9.1 Primary efficacy analysis 
For the primary efficacy analysis, a comparison will be made between the fusion 
performance of the MagnetOsTM condition and the autograft condition, scored from the one-
year (12-15 months) CT-scans according to the method described in Appendix C. Patients 
that required revision surgery influencing the fusion will be excluded from this analysis. In 
addition, if one side of a fusion-level is considered not evaluable, this level will be excluded. 
All evaluable scores will be dichotomized into fusion and no fusion. To allow inclusion of 
patients with fusion of multiple segments, without increasing the influence of these patients 
on the outcome, each side in these patients will be statistically considered as one condition. 
This means that the possible outcomes in these patients are: no fusion (if none of the levels 
is fused), equal fusion (if an equal number of segments is fused per side) or fusion at one 
side vs. no-fusion at the other side in case one side contains more fused segments than the 
other side. 
 
The basis for the primary efficacy analysis will be the test of non-inferiority by performing a 
McNemar’s test. The null hypothesis is that inferiority in fusion rate of the MagnetOsTM 
Granules compared to the autograft condition is greater than 15% (PAG-PMAG 15%); the 
alternative hypothesis is that the MagnetOsTM Granules fusion rate will not be lower than the 
autograft success rate by more than 15% (PAG-PMAG< 15%).  
 
In addition to the McNemar’s test, a generalized estimating equations (GEE) model will be 
used to examine fusion on each side of a vertebra, while accounting for clustering of 
vertebrae within patients. The outcome will be fusion (yes/no) and the explanatory variable 
will be treatment. Analysis will result in an odds ratio for MagnetOsTM Granules vs. autograft 
and a 95% confidence interval. 
 
9.2 Primary safety analysis 
(Serious) adverse events occurring during the study that may in any way be related to the 
surgical procedure will be reported in adverse event tables. The frequency and nature of 
events will be compared to events in control populations from literature. 
 

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9.3 Analysis of secondary outcomes 
1. To compare the quantitative primary and secondary results of MagnetOsTM Granules 
to Attrax® Putty a McNemar’s test will be used as well as the mentioned GEE model; 
2. As mentioned for the primary analysis, the odds-ratios and 95% confidence intervals 
for fusion rates of MagnetOsTM Granules and autograft will be calculated by using the 
GEE model. This model also allows to assess the effect of an additional interbody 
fusion; 
3. For the comparison of the fusion rate after two years, the same method as for the 
primary efficacy analysis will be used; 
4. VAS pain scores will be analyzed using the paired t-test, or Wilcoxon signed rank test 
in case of not-normally distributed data. To investigate the effect of blinding on 
perceived donor site pain, pain scores reported by the patients of this study and the 
AxA study will be compared using the unpaired t-test or Mann-Whitney U test. 
5. To investigate risk factors of both study populations regression analysis will be done. 
 
9.4 Other study parameters 
The following information will be reported and reviewed, but will not influence the 
comparisons between the treatment conditions as this is an intra-patient model. 
 
Demographics 
 
Nicotine use 
 
Pre-operative diagnosis 
 
Medical history 
 
Concurrent medical issues 
 
ASA classification 
 
Disease related medication use 
 
NSAID use 
 
Perioperative data 
 
Length of hospital stay 
 
EQ-5D-5L 
 
ODI 
 
Pain drawing 
 
NRS satisfaction 
 
The clinical outcome measures, the EQ-5D-5L, ODI and VAS, will be analyzed with repeated 
measurements to assess changes over time. For continuous data, an independent t-test or 
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clinical outcomes of fused and non-fused patients. For categorical data, the Chi-square test 
will be used. A logistic regression analysis will be performed to analyze the effects of 
smoking and NSAID use on fusion status.  
 

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10. ETHICAL CONSIDERATIONS 
10.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki 
(version October 2013) and in accordance with the Medical Research Involving Human 
Subjects Act (WMO), the Medical Device Directive 93/42/EEC and Standard Operating 
Procedures (SOPs) of the UMC Utrecht. 
 
10.2 Recruitment and consent 
Adult patients qualifying for instrumented posterolateral spinal fusion of one or multiple levels 
in the thoracolumbar and lumbosacral region (T10-S2) with the use of autograft will be 
recruited by their treating orthopaedic surgeon or his/her clinical assistant. If the patient 
meets the in- and exclusion criteria and is willing to receive further information, he/she will be 
informed about the study and its objectives by a member of the study team authorized by the 
local principal investigator, and will be asked to participate. In addition to the oral information, 
the patient will get a written information letter (see document E1) and at least one week to 
discuss the study with others (including an independent physician) and consider their 
decision. After obtaining a written informed consent (see document E2), the patient will be 
enrolled in the study and will get a unique study identification-number according to which all 
obtained data will be registered. Informed consent will be recorded in the electronic patient 
dossier. The original signed informed consent form must be retained in the Investigator Site 
File; the patient will receive a copy.  
 
10.3 Objection by minors or incapacitated subjects 
Minors or incapacitated/incompetent subjects will not be recruited or enrolled in this study. 
 
10.4 Benefits and risks assessment, group relatedness 
Enrolled patients have the benefit of shorter surgery time and maintenance of iliac bone 
stock due to reduced bone harvesting from the iliac crest. The risk for a functional adverse 
outcome due to non-union with MagnetOsTM Granules is minimal, as the contralateral side 
will always be treated in the conventional way and both sides of the spine are instrumented. 
If MagnetOsTM Granules appears to perform inferior to the autograft condition, a one-sided 
functional posterolateral spinal fusion as a result of iliac crest bone, together with bilateral 
rigid instrumentation, is likely to compensate for this failure. 
 

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10.5 Compensation for injury 
The sponsor has a liability insurance which is in accordance with article 7, subsection 6 of 
the WMO (see document G2). All participating centers have their own liability insurance. This 
is laid down in the clinical trial agreements. 
 
The sponsor 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 all research 
subjects through injury or death caused by the study (see document G1). The insurance 
applies to the damage that becomes apparent during the study or within 4 years after the end 
of the study. 

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11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
11.1 Handling and storage of data and documents 
Data will be handled confidentially according to the Dutch Personal Data Protection Act. After 
obtaining a written informed consent, the patient will get a unique study identification-number 
(consisting of a hospital ID and consecutive number) according to which all data obtained for 
this study will be registered. Informed consent will be recorded in the electronic patient 
dossier. The original signed informed consent forms will be retained in the Investigator Site 
File, stored in a locked closet or room. The key to the study identification-numbers will be 
safeguarded by the local principal investigators.  
 
All study data will be collected in Castor EDC and exported to SPSS for data analyses. The 
local study teams can enter the data directly in the web-based eCRF or after completing a 
printed version of the eCRF. Patients will receive an email via Castor EDC with a 
personalized link to the digital questionnaires. If patients prefer paper questionnaires, they 
should be completed at the outpatient clinic. To be able to reproduce the study findings and 
to help future users to understand and reuse the data, all changes made to the raw data and 
all steps taken in the analyses will be documented in queries, syntaxes or text documents. 
 
Only the local study team authorized by the local principal investigator, the monitor and 
Health and Youth Care Inspectorate have access to the source data in the medical patient 
dossier; the principal investigator and coordinating investigator will only receive the 
completed CRFs and corresponding images, as well as the (S)AE-forms and relevant 
additional information.  
 
At the UMC Utrecht, research data and files will be stored and archived on the research 
network disc of the division of Surgical Specialties.  
 
All study data will be saved for at least 15 years after the end of the study. 
 
11.2 Monitoring and Quality Assurance 
The study will be monitored by trained and independent monitors from TFS, according to the 
guidelines of the Dutch Federation of University Medical Centers (NFU), adjusted to the UMC 
Utrecht. The purposes of monitoring are to verify that: 
 
1. The rights and well-being of human subjects are protected;  
2. The reported trial data are accurate, complete, and verifiable from source documents;  

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3. The conduct of the trial follows the currently approved protocol/amendment(s), with 
GCP, and with the applicable regulatory requirement(s). 
 
The potential risks associated with participation in this study can be classified as ‘negligible 
risk’. This is because the material (tricalcium phosphate TCP) is biochemically well 
characterized and applied for more than 30 years in millions of patients worldwide. The 
difference of this material is the microstructure which is more porous and therefore more 
bone inductive. A very similar material was investigated in the recently performed AxA study 
(METC nr 13-192) where no material related adverse events were reported. The risk of 
performing less good than autologous bone is mitigated by the bilateral (intrapatient) design, 
where for each fusion level always one side is treated with autologous bone and the other 
side with MagnetOsTM Granules. In addition the fusion is always instrumented with posterior 
fixation which immobilizes the segment and will cause a fusion in the long term. Therefore 
the addition of Magnetos on one side is fundamentally different from a standalone application 
and should be regarded as an augmentation to enhance fusion on that side while traditional 
fusion is achieved with autograft on the other side and the rigid fixation. This negligible risk is 
compensated with the definite advantage of less autologous bone graft donor side morbidity.  
 
The following on-site monitoring strategy (per site) is proposed: 
 
1. One initiation visit;  
2. Three monitor visits;  
3. One close-out visit.  
 
More details on the monitoring strategy are given in document K6a.  
 
11.3 Amendments 
Amendments are changes made to the research after a favorable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
 
11.4 Annual progress report 
The principal investigator/sponsor 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, other problems, and amendments.  

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11.5 End of study report 
The investigator 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.  
 
In case the study is ended prematurely, the investigator 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 principal 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. 
 
11.6 Public disclosure and publication policy 
Kuros’ participation in funding will be disclosed to any audience to which any information or 
results of this study are presented. The local principal investigators are permitted to present 
at symposia, national or regional professional meetings, and to publish in journals, theses or 
dissertations, or otherwise of their own choosing. Kuros will be provided with a manuscript of 
any proposed publication at least forty-five (45) days prior to submission, and with the 
abstract of any proposed presentation at conferences at least thirty (30) days prior to 
submission, in order to review any such manuscript and to request changes therein to protect 
inventions and/or proprietary rights and proprietary interests. See the agreement for more 
detailed information on disclosures and the publication policy. 

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12. STRUCTURED RISK ANALYSIS 
 
12.1 Potential issues of concern 
This study involves the application of a registered product (MagnetOsTM Granules) to be used 
within the indication and not in combination with other products. 
 
12.2 Synthesis 
As previously indicated, the main risk of this study will be inferior performance of 
MagnetOsTM Granules, resulting in a lower (unilateral) posterolateral fusion rate. Based on 
the preclinical studies as described in the Investigator’s Brochure (see Chapter 6), this risk 
can be considered minimal. Furthermore, the most closely related and currently investigated 
MagnetOsTM Granules has shown to perform superior to currently widely applied competitor 
TCPs like Vitoss® and Actifuse®. To minimize risks, MagnetOsTM Granules will only be 
applied unilaterally in instrumented posterolateral spinal fusions. The contralateral side will 
receive autologous bone graft that is considered the gold standard for this surgical 
procedure. Furthermore, instrumentation will stabilize the spinal segments to allow an 
optimal environment for bony fusion. All patients may benefit from the study in terms of less 
surgery time and maintenance of iliac bone stock, since only half of the required bone graft 
will be harvested from the iliac crest. When MagnetOsTM Granules is indeed non-inferior to 
iliac crest bone graft, this harvesting procedure may be abandoned in future patient 
populations. 
 
 
 

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13. REFERENCES 
 
1.  Myeroff C, Archdeacon M, Wright J, et al. Autogenous bone graft: donor sites and 
techniques. J Bone Joint Surg Am. 2011;93(23):2227-2236. 
doi:10.2106/JBJS.J.01513. 
2.  Kruyt MC, Delawi D, Habibovic P, Oner FC, Van Blitterswijk CA, Dhert WJA. Relevance of 
bone graft viability in a goat transverse process model. J Orthop Res. 
2009;27(8):1055-1059. doi:10.1002/jor.20830. 
3.  Delawi D, Dhert WJ a, Castelein RM, Verbout AJ, Oner FC. The incidence of donor site 
pain after bone graft harvesting from the posterior iliac crest may be overestimated: a 
study on spine fracture patients. Spine (Phila Pa 1976). 2007;32(17):1865-1868. 
doi:10.1097/BRS.0b013e318107674e. 
4.  Carragee EJ, Ghanayem AJ, Weiner BK, Rothman DJ, Bono CM. A challenge to integrity 
in spine publications: Years of living dangerously with the promotion of bone growth 
factors. Spine J. 2011;11(6):463-468. doi:10.1016/j.spinee.2011.06.001. 
5.  Boden SD. Overview of the biology of lumbar spine fusion and principles for selecting a 
bone graft substitute. Spine (Phila Pa 1976). 2002;27(16 Suppl 1):S26-31. 
doi:10.1097/00007632-200208151-00007. 
6.  Jorgenson SS, Lowe TG, France J, Sabin J. A prospective analysis of autograft versus 
allograft in posterolateral lumbar fusion in the same patient. A minimum of 1-year 
follow-up in 144 patients. Spine (Phila Pa 1976). 1994;19(18):2048-2053. 
http://www.ncbi.nlm.nih.gov/pubmed/7825044. 
7.  Khan Y, Yaszemski MJ, Mikos AG, Laurencin CT. Tissue engineering of bone: Material 
and matrix considerations. J Bone Jt Surg - Ser A. 2008;90(SUPPL. 1):36-42. 
doi:10.2106/JBJS.G.01260. 
8.  Lee YP, Jo M, Luna M, Chien B, Lieberman JR, Wang JC. The efficacy of different 
commercially available demineralized bone matrix substances in an athymic rat model. 
J Spinal Disord Tech. 2005;18(5):439-444. doi:10.1097/01.bsd.0000175696.66049.f7. 
9.  Lee K, Roper J, Wang J. Demineralized bone matrix for spinal arthrodesis. Spine J. 
2005:217S-223S. doi:doi:10.1016/j.spinee.2005.02.006. 
10.  
Yuan H, Fernandes H, Habibovic P, et al. Correspondence: “Smart” biomaterials and 
osteoinductivity. Nat Rev Rheumatol. 2011;7(4):1. doi:10.1038/nrrheum.2010.210-c1. 
11.  
Yuan H, Fernandes H, Habibovic P, et al. Osteoinductive ceramics as a synthetic 
alternative to autologous bone grafting. Proc Natl Acad Sci. 2010;107(31):13614-
13619. doi:10.1073/pnas.1003600107. 
12.  
Davison NL, Gamblin AL, Layrolle P, Yuan H, de Bruijn JD, Barrère-de Groot F. 
Liposomal clodronate inhibition of osteoclastogenesis and osteoinduction by 

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submicrostructured beta-tricalcium phosphate. Biomaterials. 2014;35(19):5088-5097. 
doi:10.1016/j.biomaterials.2014.03.013. 
13.  
Habibovic P, Yuan H, Van den Doel M, Sees TM, Van Blitterswijk CA, De Groot K. 
Relevance of Osteoinductive Biomaterials in Critical-Sized Orthotopic Defect. J Orthop 
Res. 2006:867-876. doi:DOI 10.1002/jor.20115. 
14.  
Van Dijk L, Van Miegem V, Barbieri D, Yuan H, De Bruijn JB, Barrere-de Groot F. 
Accelerated osteoinduction by biphasic calcium phosphate with epitaxial crystal 
surface structure. In: Annual Meeting of the Dutch Sciety for Biomaterials and Tissue 
Engineering. ; 2015. 
15.  
Van Dijk L, Janssen N, Bakker R, et al. Biphasic calcium phosphate with crystalline 
surface microstructure as bone graft substitute in Ovine model of maxillary sinus floor 
augmentation. In: Annual Meeting of the Dutch Sciety for Biomaterials and Tissue 
Engineering. ; 2015. 
16.  
Van Dijk LA, Duan R, Luo X, et al. Equivalence between autologous bone graft and a 
novel osteoinductive calcium phosphate-based bone void filler in an Ovine 
instrumented posterolateral spinal fusion model. In: European Society for Biomaterials 
Meeting. ; 2017. 
17.  
Duan R, Barbieri D, Van Miegem V, De Groot F, De Bruijn JB, Yuan H. Bone 
Regeneration in Rabbit Condyle Defects with Different Surface Structured Calcium 
Phosphate Ceramics. In: Annual Meeting of the Dutch Sciety for Biomaterials and 
Tissue Engineering. ; 2015. 
18.  
Barbieri D, Duan R, De Bruijn J, Yuan H. Performance of an anhydrous copolymer for 
moldable composites with calcium phosphate ceramic. In: Annual Meeting of 
Advanced Functional Polymers for Medicine. ; 2016. 
19.  
Glazer PA, Spencer UM, Alkalay RN, Schwardt J. In vivo evaluation of calcium sulfate 
as a bone graft substitute for lumbar spinal fusion. Spine J. 2001;1(6):395-401. 
doi:10.1016/S1529-9430(01)00108-5. 
20.  
Ha KY, Lee JS, Kim KW. Bone graft volumetric changes and clinical outcomes after 
instrumented lumbar or lumbosacral fusion: A prospective cohort study with a five-year 
follow-up. Spine (Phila Pa 1976). 2009;34(16):1663-1668. 
doi:10.1097/BRS.0b013e3181aacab5. 
21.  
Jenis LG, Banco RJ. Efficacy of silicate-substituted calcium phosphate ceramic in 
posterolateral instrumented lumbar fusion. Spine (Phila Pa 1976). 2010;35(20):1058-
1063. doi:10.1097/BRS.0b013e3181df196f. 
22.  
Aghi MK, Walcott BP, Nahed B V., et al. Determinants of initial bone graft volume loss 
in posterolateral lumbar fusion. J Clin Neurosci. 2011;18(9):1193-1196. 
doi:10.1016/j.jocn.2011.02.017. 

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23.  
Kim KW, Ha KY, Moon MS, Kim YS, Kwon SY, Woo YK. Volumetric change of the 
graft bone after intertransverse fusion. Spine (Phila Pa 1976). 1999;24(5):428-433. 
doi:10.1097/00007632-199903010-00003. 
24.  
Delawi D, Kruyt MC, Huipin Y, et al. Comparing Autograft, Allograft, and Tricalcium 
Phosphate Ceramic in a Goat Instrumented Posterolateral Fusion Model. Tissue Eng 
Part C Methods. 2013;19(11):821-828. doi:10.1089/ten.tec.2012.0576. 
25.  
Hagenmaier F, Kok D, Hol  a., Rijnders T, Oner FC, van Susante JLC. Changes in 
Bone Mineral Density in the Inter-Transverse Fusion Mass After Instrumented Single-
Level Lumbar Fusion. Spine (Phila Pa 1976). 2012;38(8):1. 
doi:10.1097/BRS.0b013e318276fa27. 
26.  
Kang J, An H, Hilibrand A, Yoon ST, Kavanagh E, Boden S. Grafton and local bone 
have comparable outcomes to iliac crest bone in instrumented single-level lumbar 
fusions. Spine (Phila Pa 1976). 2012;37(12):1083-1091. 
doi:10.1097/BRS.0b013e31823ed817. 
27.  
Abdullah KG, Steinmetz MP, Benzel EC, Mroz TE. The state of lumbar fusion 
extenders. Spine (Phila Pa 1976). 2011;36(20). doi:10.1097/BRS.0b013e318209952b. 
28.  
Cammisa FP, Lowery G, Garfin SR, et al. Two-year fusion rate equivalency between 
Grafton DBM gel and autograft in posterolateral spine fusion: a prospective controlled 
trial employing a side-by-side comparison in the same patient. Spine (Phila Pa 1976). 
2004;29(6):660-666. doi:10.1097/01.BRS.0000116588.17129.B9. 
29.  
Niu C-C, Tsai T-T, Fu T-S, Lai P-L, Chen L-H, Chen W-J. A comparison of 
posterolateral lumbar fusion comparing autograft, autogenous laminectomy bone with 
bone marrow aspirate, and calcium sulphate with bone marrow aspirate: a prospective 
randomized study. Spine (Phila Pa 1976). 2009;34(25):2715-2719. 
doi:10.1097/BRS.0b013e3181b47232. 
30.  
Yamada T, Yoshii T, Sotome S, et al. Hybrid grafting using bone marrow aspirate 
combined with porous β-tricalcium phosphate and trephine bone for lumbar 
posterolateral spinal fusion. Spine (Phila Pa 1976). 2012;37(3):E174-E179. 
doi:10.1097/BRS.0b013e3182269d64. 
31.  
Block JE. Potential effectiveness of novel bone graft substitute materials. Spine (Phila 
Pa 1976). 1995;20(20):2261-2262. 
32.  
Fischgrund JS. The Argument for Instrumented Decompressive Posterolateral Fusion 
for Patients with Degenerative Spondylolisthesis and Spinal Stenosis. Spine (Phila Pa 
1976). 2004;29(2):173-174. doi:10.1097/01.BRS.0000111142.76601.1A. 
33.  
Lowe T, Berven SH, Schwab FJ, Bridwell KH. The SRS classification for adult spinal 
deformity: Building on the King/Moe and Lenke classification systems. Spine (Phila Pa 
1976). 2006;31(19 SUPPL.). doi:10.1097/01.brs.0000232709.48446.be. 

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34.  
Alexander DI, Manson N a., Mitchell MJ. Efficacy of calcium sulfate plus 
decompression bone in lumbar and lumbosacral spinal fusion: Preliminary results in 
40 patients. Can J Surg. 2001;44(4):262-266. 
35.  
Christensen FB, Laursen M, Gelineck J, Eiskj??r SP, Thomsen K, B??nger CE. 
Interobserver and Intraobserver Agreement of Radiograph Interpretation With and 
Without Pedicle Screw Implants. Spine (Phila Pa 1976). 2001;26(5):538-543. 
doi:10.1097/00007632-200103010-00018. 
36.  
Carreon LY, Glassman SD, Djurasovic M. Reliability and agreement between fine-cut 
CT scans and plain radiography in the evaluation of posterolateral fusions. Spine J. 
2007;7(1):39-43. doi:10.1016/j.spinee.2006.04.005. 
37.  
Carreon LY, Djurasovic M, Glassman SD, Sailer P. Diagnostic accuracy and reliability 
of fine-cut CT scans with reconstructions to determine the status of an instrumented 
posterolateral fusion with surgical exploration as reference standard. Spine (Phila Pa 
1976). 2007;32(8):892-895. doi:10.1097/01.brs.0000259808.47104.dd. 

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APPENDIX A. STATISTICAL ANALYSIS 
 
The statistical methods were designed previously for the AxA trial in collaboration with a 
medical statistician, dr. R.K. Stellato of the Julius Center, UMC Utrecht, the Netherlands. 
 
 
Sample size calculation 
The numeric results for a non-inferiority (one-sided) test of a difference are shown in the 
table below. Based on a 1:1 paired assignment of AttraX® Putty to the control condition with 
autograft, a power of 80%, a one-sided alpha of 0.05, a non-inferiority margin of 15%, an 
estimated fusion percentage of 50% for unilateral grafting and 70% concordance between 
both sides of the fusion trajectory, the required sample size for the primary outcome is 84 
patients.  
 
Definitions 
 
Power: probability of rejecting a false null hypothesis; 
 
N: number of subjects, sample size; 
 
De: maximum difference between the two proportions that is still called 'equivalent'; 
 
Da: actual difference between Pt and Ps, i.e. Da = Pt-Ps; 
 
Pt: the response proportion to the treatment (experimental or new) test; 
 
Ps: the response proportion to the standard (reference or old) test; 
 
Nuisance Parameter: value that is needed, but is not a direct part of the hypothesis; 
 
Alpha: probability of rejecting a true null hypothesis; 
 
Beta: probability of accepting a false null hypothesis. 
 

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Power Analysis of Non-Inferiority Tests of Correlated Proportions 
Page/Date/Time 19/4/2012 1:37:28 PM 
 
 
 
Sample 
Equiv. 
Actual Treatment 
Standard Nuisance 
 
 
Size 
Difference 
Difference Proportion Proportion Parameter 
Power 
(N) 
(De) 
(Da) 
(Pt) 
(Ps) (P01+P10) 
Alpha 
Beta 
 
 
130.10000-0.10000 
0.40000 
0.50000 
0.30000 
0.05000 
 
0.80005 
5889 
0.10000 
-0.08000 
0.42000 
0.50000 
0.30000 
0.05000 
0.19995 
0.80003 
1400 
0.10000 
-0.06000 
0.44000 
0.50000 
0.30000 
0.05000 
0.19997 
0.80024 
591 
0.10000 
-0.04000 
0.46000 
0.50000 
0.30000 
0.05000 
0.19976 
0.80037 
315 
0.10000 
-0.02000 
0.48000 
0.50000 
0.30000 
0.05000 
0.19963 
0.80135 
191 
0.10000 
0.00000 
0.50000 
0.50000 
0.30000 
0.05000 
0.19865 
0.80000 
24761 
0.11000 
-0.10000 
0.40000 
0.50000 
0.30000 
0.05000 
0.20000 
0.80009 
2623 
0.11000 
-0.08000 
0.42000 
0.50000 
0.30000 
0.05000 
0.19991 
0.80024 
899 
0.11000 
-0.06000 
0.44000 
0.50000 
0.30000 
0.05000 
0.19976 
0.80050 
436 
0.11000 
-0.04000 
0.46000 
0.50000 
0.30000 
0.05000 
0.19950 
0.80053 
250 
0.11000 
-0.02000 
0.48000 
0.50000 
0.30000 
0.05000 
0.19947 
0.80009 
158 
0.11000 
0.00000 
0.50000 
0.50000 
0.30000 
0.05000 
0.19991 
0.80005 
6202 
0.12000 
-0.10000 
0.40000 
0.50000 
0.30000 
0.05000 
0.19995 
0.80006 
1479 
0.12000 
-0.08000 
0.42000 
0.50000 
0.30000 
0.05000 
0.19994 
0.80009 
626 
0.12000 
-0.06000 
0.44000 
0.50000 
0.30000 
0.05000 
0.19991 
0.80044 
335 
0.12000 
-0.04000 
0.46000 
0.50000 
0.30000 
0.05000 
0.19956 
0.80164 
204 
0.12000 
-0.02000 
0.48000 
0.50000 
0.30000 
0.05000 
0.19836 
0.80170 
134 
0.12000 
0.00000 
0.50000 
0.50000 
0.30000 
0.05000 
0.19830 
0.80009 
2763 
0.13000 
-0.10000 
0.40000 
0.50000 
0.30000 
0.05000 
0.19991 
0.80032 
950 
0.13000 
-0.08000 
0.42000 
0.50000 
0.30000 
0.05000 
0.19968 
0.80046 
462 
0.13000 
-0.06000 
0.44000 
0.50000 
0.30000 
0.05000 
0.19954 
0.80079 
266 
0.13000 
-0.04000 
0.46000 
0.50000 
0.30000 
0.05000 
0.19921 
0.80094 
169 
0.13000 
-0.02000 
0.48000 
0.50000 
0.30000 
0.05000 
0.19906 
0.80255 
115 
0.13000 
0.00000 
0.50000 
0.50000 
0.30000 
0.05000 
0.19745 
0.80000 
1558 
0.14000 
-0.10000 
0.40000 
0.50000 
0.30000 
0.05000 
0.20000 
0.80039 
662 
0.14000 
-0.08000 
0.42000 
0.50000 
0.30000 
0.05000 
0.19961 
0.80043 
355 
0.14000 
-0.06000 
0.44000 
0.50000 
0.30000 
0.05000 
0.19957 
0.80021 
216 
0.14000 
-0.04000 
0.46000 
0.50000 
0.30000 
0.05000 
0.19979 
0.80181 
143 
0.14000 
-0.02000 
0.48000 
0.50000 
0.30000 
0.05000 
0.19819 
0.80338 
96 
0.14000 
0.00000 
0.50000 
0.50000 
0.30000 
0.05000 
0.19662 
0.80029 
1001 
0.15000 
-0.10000 
0.40000 
0.50000 
0.30000 
0.05000 
0.19971 
0.80033 
488 
0.15000 
-0.08000 
0.42000 
0.50000 
0.30000 
0.05000 
0.19967 
0.80093 
282 
0.15000 
-0.06000 
0.44000 
0.50000 
0.30000 
0.05000 
0.19907 
0.80163 
180 
0.15000 
-0.04000 
0.46000 
0.50000 
0.30000 
0.05000 
0.19837 
0.80062 
122 
0.15000 
-0.02000 
0.48000 
0.50000 
0.30000 
0.05000 
0.19938 
0.80098 
84 
0.15000 
0.00000 
0.50000 
0.50000 
0.30000 
0.05000 
0.19902 
0.80005 
697 
0.16000 
-0.10000 
0.40000 
0.50000 
0.30000 
0.05000 
0.19995 
0.80031 
375 
0.16000 
-0.08000 
0.42000 
0.50000 
0.30000 
0.05000 
0.19969 
0.80039 
229 
0.16000 
-0.06000 
0.44000 
0.50000 
0.30000 
0.05000 
0.19961 
0.80183 
152 
0.16000 
-0.04000 
0.46000 
0.50000 
0.30000 
0.05000 
0.19817 
0.80168 
106 
0.16000 
-0.02000 
0.48000 
0.50000 
0.30000 
0.05000 
0.19832 
0.80386 
75 
0.16000 
0.00000 
0.50000 
0.50000 
0.30000 
0.05000 
0.19614 
0.80009 
514 
0.17000 
-0.10000 
0.40000 
0.50000 
0.30000 
0.05000 
0.19991 
0.80095 
298 
0.17000 
-0.08000 
0.42000 
0.50000 
0.30000 
0.05000 
0.19905 
0.80029 
190 
0.17000 
-0.06000 
0.44000 
0.50000 
0.30000 
0.05000 
0.19971 
0.80159 
130 
0.17000 
-0.04000 
0.46000 
0.50000 
0.30000 
0.05000 
0.19841 
0.80146 
84 
0.17000 
-0.02000 
0.48000 
0.50000 
0.30000 
0.05000 
0.19854 
0.80249 
66 
0.17000 
0.00000 
0.50000 
0.50000 
0.30000 
0.05000 
0.19751 
 
 
 

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Primary analysis 
The CT score will be dichotomized into fused and not fused. To allow the inclusion of 
patients with intended fusion of multiple segments, the sum of fusions on each side of the 
spine of these patients will be compared. If one side of a fusion-level is considered not 
evaluable, this will be excluded as well as the contralateral level. In multilevel patients, 
superiority (in number of fused levels) of one side, will be considered fusion and the other 
side non-fusion to prevent an unequal influence of patients with multi-level fusions. Although 
fusion assessment by this method gives more a "relative performance score" than a "fusion 
rate," analyzing the fusion rate of individual levels will not be adequate. There is strong 
reason to believe that the fusion rate will vary from patient to patient, so the fusion of 
individual vertebrae from one patient will not be independent. Since the study is randomized, 
this dependence should have no effect on a point estimate for the difference in fusion rates 
for MagnetOsTM Granules vs. autograft, but will certainly affect the standard error of the 
difference, thereby making standard statistical inference unreliable. 
 
Although we know of no way of generating correct p-values or confidence intervals for 
differences in fusion rates using clustered data, it is possible to use a multi-level model (in 
which the clustering of vertebrae within patients is taken into account) to examine the effect 
of MagnetOsTM Granules and autograft on fusion, and using the vertebrae as the primary 
level of analysis. Such a model will produce an odds ratio instead of a difference in fusion 
rates. Since a sample size calculation based on a multi-level analysis requires a number of 
assumptions that cannot be supported by current data, we decided to perform sample size 
calculation based on the McNemar's test, and to use the multi-level model as a secondary 
analysis since it will make better use of the complete data while correctly taking the 
clustering into account. 
 
 
Secondary Analysis 
A three-level generalized estimating equations (GEE) model will be used to examine fusion 
on each side of a vertebra, while accounting for clustering of measurements (fusion on each 
side of the spine) within spinal levels and within patients. The GEE model will use compound 
symmetry working correlation matrices for correlation of measurements within vertebrae and 
vertebrae within patients. In this model, the presence of interbody fusion can also be 
incorporated as a separate factor. The outcome will be fusion (yes/no) and the explanatory 
variable will be the treatment condition. Analysis will result in an odds ratio for MagnetOsTM 
Granules vs. autograft and a 95% confidence interval. 
 
 

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References 
1. Lewis, J.A., Statistical principles for clinical trials (ICH E9) an introductory note on an 
international guideline. Statistics in Medicine, 1999. 18(15), p. 1903-42. 
2. Liu, J., et al., Tests for equivalence or non-inferiority for paired binary data. Statistics 
in Medicine, 2002.21(2), p. 231-45. 
3. Nam, J., Establishing equivalence of two treatments and sample size requirements in 
matched-pairs design. Biometrics, 1997. 53, p. 1422-30. 
4. Nam, J. and Blackwelder, W.C., Analysis of the ratio of marginal probabilities in a 
matched-pair setting.Statistics in Medicine, 2002. 21(5), p. 689-99. 

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APPENDIX B. SUGGESTED SURGICAL TECHNIQUE 
 
 
Step 1: Patient positioning 
The patient is placed in the prone position. To avoid abdominal compression, separate rolls 
or specific frames can be used. Preferably a foil skin drape is used. 
 
 
Step 2: Exposure 
After sterile draping, a single midline incision centered on the intended fusion area is made in 
both the skin and the fascia. The paraspinal muscles are subperiosteally stripped from the 
spinous processes and retracted laterally. The facet joints and transverse processes are 
exposed. 
 
 
Step 3: Instrumentation 
After partial removal of the involved facet joints, the surgeon determines the exact surgical 
procedure concerning the insertion of the instrumentation. Depending on the surgeon’s 
preference, pedicle screws can be inserted now or after decompression. The rod fixation can 
be inserted at this time or after placement of the graft. 
 
 
Step 4: Decompression 
If necessary, a decompression of the posterior spine is performed according the surgeons 
preference. The decompression may involve a whole or partial laminectomy and may include 
one or more levels.  
 
 
Step 5: Decortication 
The next step is meticulous and thorough decortication of all of the available cortical 
surfaces, including the dorsal, superior and inferior surfaces of the transverse processes. It 
may be necessary to extend the longitudinal incision to get good exposure! In addition, the 
dorsal and lateral aspects of the lamina and pars interarticularis, from the most proximal 
vertebra to the most distal vertebra to be included in the fusion should be denuded. If the 
facet joints remain, these should be prepared for fusion by removing the exposed articular 
surfaces.  
 
 
Step 6: Graft preparation and volume measurement 
All bone obtained from decompression and decortication is stripped from soft tissue and 
morcellized to 2-4mm pieces. The volume is assessed by slight compression in a 20mL 
syringe. 
 

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Step X: Additional interbody fusion procedure 
According the surgeons preference, an interbody cage can be used (PLIF or TLIF). This 
cage is preferably filled with local autograft bone and positioned before disclosure of the 
randomized allocation. If the surgeon prefers iliac graft bone, both sides of the spine have to 
be prepared for posterolateral bone grafting before the allocated side of the autograft (and 
bone graft harvesting) is disclosed. 
 
 
Step 7: Disclosure of the random allocation  
After instrumentation and preparation of the fusion trajectory the envelope containing the 
allocation side of the autograft and MagnetOs condition and thereby the allocation of the iliac 
harvesting side, is opened. 
 
 
Step 8: Harvesting of iliac crest autograft  
Only one side of the pelvis can be used for iliac crest bone harvesting. This must be the 
same side as allocated to the autograft posterolateral spine fusion condition. The surgeon 
can use any technique that exposes the iliac crest to obtain corticocancellous bone, but 
preferably no additional skin incision is made and harvesting through a posterior cortical 
window is advised. A total autograft volume of 8-10cc per side and fusion level is intended. 
The contribution of iliac bone graft to this volume has to be at least 50%. For example in a 
L3-S1 three-level fusion with 10cc of local bone, another 20cc of bone from the iliac crest is 
required to reach 3x10cc. If local bone is 20cc, 5cc of this will not be used as local bone can 
only be 15cc (= 50% of 30cc). If the 10cc per level and side cannot be reached because of 
limited iliac bone graft, the autograft volume has to be extended with local bone. In case the 
volume remains below 8cc per side, this is accepted as a consequence of autologous bone 
grafting. The MagnetOs condition will always be 8-10cc and not combined with local bone. 
 
 
Step 9: Placement of the graft 
Both grafts, the autograft and MagnetOsTM granules, are placed on the allocated side around 
the instrumentation and in the decorticated lateral gutters, bridging the dorsal surfaces of the 
transverse processes, facets and laminae. No graft is placed on the dura. No additional 
substances like blood or bone marrow are added. If not yet done at step 3, the rod fixation is 
inserted at this time. 
 
 
Step 10: Patient closing 
The patient is closed using the technique preferred by the surgeon. If vancomycine or 
another antiseptic procedure is used, this should be recorded on the surgical form of the 
CRF.

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APPENDIX C. CT ASSESSMENT 
 
 
Aim 
To compare the fusion rate of the MagnetOsTM granules side to the autograft side after 1 and 
2 years, by using CT-scans.  
 
 
Method primary analysis 
For the primary analysis, all included patients will be CT-scanned at the treating center. The 
CT-scan will be scheduled at 12-15 months after surgery. The standard local protocol for the 
spine will be used when this provides a slice thickness of ≤1 mm. Otherwise, the slice 
thickness will be adapted. To allow all desired planar reconstructions, the data will be 
captured and stored as volume scans. The raw volume dataset (DICOM scans), and 
preferably reconstructions in the coronal, sagittal and axial, will be de-identified and stored 
on a CD-ROM and send to the principal investigator for assessment by a panel consisting of 
at least one spine surgeon and an uninvolved specialist. Based on literature review and 
experience with the AxA trial we developed the following protocol. 
 
 
Stepwise protocol 
 
All patients will be scanned with a volume scan with ≤1 mm slice thickness; 
 
Data will be captured and stored as volume scans; 
 
All scans will be assessed independently by at least two observers, blinded to the 
treatment allocation; 
 
First, the fusion level and side will be identified and assessed in three planes: 
coronal, sagittal and axial; 
 
Osteotomized segments will be excluded from the analyses. If one side of a fusion-
level is considered not evaluable, this level will be excluded as well; 
 
If obvious indications of mobility like material failure or apparent pseudoarthrosis 
exist, the level will be considered a non-union; 
 
If not, the presence of an obvious bone bridge/fusion between the posterolateral 
vertebra will be determined; 
 
Fusion is scored based on assessment in three planes and at two locations, to 
indicate the probability that the bony bridge is graft related: 
o Likely graft related is a bony bridge between the transverse process and 
>1mm lateral or above the rod; 
o Probably not graft related is a bone bridge directly around the rod, between 
the lamina or fusion of the facet joints;  

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 
An obvious fusion at any of these locations in each plane is scored 2 points, doubtful 
fusion is 1 point and non-union is 0 points; 
 
If the segment is fused in at least one plane (2 points) and does not show obvious 
absence of fusion in both the other planes (scores at least 1 in at least one of the 
other planes) it is regarded as fused; 
 
The points of the graft related and non-graft related locations cannot be accumulated;  
 
Finally, the presence of an interbody fusion as a result of an interbody fusion device 
will be determined in two planes and scored similarly (fusion is at least 3 points). 
 
In case of disagreement on overall fusion between the observers, a third investigator will be 
counseled to get consensus. If disagreement persists, the fusion will be scored as doubtful. 
 
 
Method secondary analysis 
For the other secondary analyses, the 2 year CT-scans will be assessed similarly.