Safety and Efficacy of a Vertebral Body Tethering Technique for Pediatric Idiopathic Scoliosis
Phase: NA
Conditions: Idiopathic Adolescent Scoliosis
Sponsor: Nemours Children's Clinic

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 Title:  
Safety and Efficacy of a vertebral body 
tethering technique for pediatric idiopathic 
scoliosis  
Short Title  
Vertebral Body Tethering Outcomes  
 
Drug or Device Name(s):  
Globus Medical Inc.  
Reflect/Transition™ Stabilization System  
Polyethylene terephthalate (PET) cord  
 
FDA IDE  
XXX-XX  
 
Regulatory Sponsor:  
Suken A. Shah, MD  
 
eIRB Number:  
XX-XXXX  
 
Protocol Date:  
12/1/2017 
Amendment 1 Date: 4/23/2019 
Amendment 3 Date: 02/17/2020 
Amendment 2 Date: 10/16/2019 
Amendment 4 Date: 06/29/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Contents 
ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................................. 3 
ABSTRACT ..................................................................................................................................... 4 
PROTOCOL SYNOPSIS................................................................................................................. 7 
1 BACKGROUND INFORMATION AND RATIONALE .......................................................... 11 
2 STUDY OBJECTIVES ............................................................................................................... 22 
3 INVESTIGATIONAL PLAN ..................................................................................................... 23 
4 STUDY PROCEDURES ............................................................................................................ 26 
5 STUDY EVALUATIONS AND MEASUREMENTS ............................................................... 29 
6 STATISTICAL CONSIDERATIONS ........................................................................................ 34 
7 STUDY DEVICE........................................................................................................................ 37 
8 SAFETY MANAGEMENT ........................................................................................................ 38 
9 STUDY ADMINISTRATION .................................................................................................... 44 
10 PUBLICATION ........................................................................................................................ 50 
11 REFERENCES ......................................................................................................................... 50 
12 APPENDIX ............................................................................................................................... 52 
 
 
 

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ABBREVIATIONS AND DEFINITIONS OF TERMS 
Adams’s Forward Bending 
Test  
 
 
Subject stands with their back to the examiner, and 
bends forward at the waist, with knees in extension. 
The examiner looks at the horizontal plane of the spine, 
and measures angle created between a rib hump and the 
horizontal plane. This is measured with an 
inclinometer. 
Adding on  
 
Phenomenon where there is a worsening of the scoliotic 
curve after spinal fusion. This usually occurs at levels 
distal to the distal end of the spinal fusion.  
AE  
Adverse event  
AIS  
Adolescent Idiopathic Scoliosis  
AT  
Anterior Tethering  
Bending/ Bolster x-ray  
 
Coronal radiograph of the entire spine, with the patient 
positioned in lateral flexion. The lateral flexion is done 
towards the convex side of the curve, to ‘lessen’ the 
appearance of the curve’s magnitude. This is done 
either standing, with the patient bending under their 
own power; or in the lateral decubitus position, with a 
pillow or ‘bolster’ placed at the apex of the convexity 
of the curve.  
Coronal spine x-ray  
 
Radiograph of the coronal plane of the entire spine, 
usually also extending distally to include the femoral 
head/neck  
HRQOL  
Health-Related Quality of Life  
JIS  
Juvenile Idiopathic Scoliosis  
Lenke Classification  
 
Standardized classification system for Idiopathic 
Scoliosis. The system has three components: 1) Main 
Curve type (1-6), 2) Lumbar spine modifier (A, B, C), 
3) Sagittal thoracic modifier (-, N, +)  
OSP  
Office of Sponsored Projects  
PET  
Polyethylene Terepthalate  
PFT 
Pulmonary Function Test  
PSF 
Posterior Spinal Fusion  
Risser Scale  
 
Indirect measure of skeletal maturity, based on the 
ossification of the Iliac crest. Graded on a scale of 0-5; 
1 being ¼ ossified, and 4 being completely ossified. 0 
shows no ossification, and 5 is completely ossified with 
fusion of the iliac apophysis to the iliac crest.  
SAE  
 
Serious adverse event – any undesirable experience 
associated with use of the medical device that results in  
Sagittal spine x-ray  
Radiograph of the entire spine taken in the sagittal 
plane.  
Sanders Bone Age  
 
Standardized method of measuring skeletal maturity 
that is predictive of scoliotic curve progression. This 
method involves analysis of the ossification centers of 
the hand, using an AP radiograph of the entire hand.  
SOC  
Standard of Care  
Thoracic/Lumbar flexion test  
 
Subject stands with trunk erect while measuring tape is 
placed proximally on the spinous process of C7 and 

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distally to S1. The subject then bends forward at the 
waist, with knees in extension. Following flexion of the 
vertebrae, using the same bony landmarks, the 
examiner calculates the difference in distance between 
the starting and ending positions.  
 
Thoracic/Lumbar lateral flexion test  
 
Subject stands erect with the feet flat on the floor. Place 
one end of a measuring tape on the tip of the middle 
finger and the other on the floor on a point directly 
beneath the middle finger. The patient then laterally 
flexes their trunk. The difference following the lateral 
flexion motion is measured.  
TLSO  
Thoraco-lumbo-Sacral Orthosis  
UDI  
Unique Device Identification  
VBT  
Vertebral Body Tethering  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABSTRACT 
Context:  
 
Scoliosis is a condition where the spine is deformed by a curvature in the coronal plane. It is 
generally associated with a twisting (axial plane) deformity as well. It can have a variety of 
underlying etiologies and the etiology is used to classify the types of scoliosis. Idiopathic 
scoliosis is sub-classified in two ways: by age of onset and by magnitude of deformity. Curves 
between 10 and 25 degrees are considered mild. Curves between 25- and 50 degrees are classified 
as moderate. Curves greater than 50 degrees are termed severe. The current standard of care for 

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moderate scoliosis in patients with remaining growth is to utilize a thoracolumbosacral orthosis 
(TLSO brace) to prevent progression of deformity. The scientific evidence has supported the 
efficacy of this intervention in avoiding progression of the Cobb angle to 50 degrees or more.  
 
If treated with a TLSO brace, many idiopathic scoliosis patients would conceivably be subjected 
to years of brace wear and the cost and psychological factors inherent therein. Additional 
downsides of brace treatment include the potentially negative psychosocial impact of wearing an 
external sign of deformity during adolescence, a key period of emotional development. Prior 
research has identified negative psychosocial effects related to wearing a brace in children.  
 
Recent evidence has suggested that certain curve patterns will likely progress to 50 degrees or 
more, despite treatment with a TLSO brace. Sanders, et al. demonstrated a correlation of Cobb 
angle (greater than 35 degrees) and skeletal maturity (bone age 4 or less) to the risk of 
progression to 50 degrees or more, despite TLSO bracing. The evidence supports that the current 
practice of TLSO bracing is not an effective treatment to avoid progression to 50 degrees in these 
patients. It is on this population (thoracic Cobb angle greater than 35 degrees, bone age of 4 or 
less) that we intend to test the safety and efficacy of Anterior Vertebral Body Tethering to avoid 
curve progression to more than 50 degrees.  
 
Objectives:  
 
The objectives of this study are to assess the safety and efficacy of Anterior Vertebral Body 
Tethering Surgery (AVBT) to treat Idiopathic Scoliosis.  
 
Study Design:  
 
This is a Phase II, non-randomized, open label study of the anterior insertion of a Polyethylene 
Terephthalate (PET) cord in pediatric scoliosis. The study will be conducted at a single site- 
Nemours – Alfred I duPont hospital for Children 
 
Setting/Participants:  
 
This is a single-site, Sponsor-Investigator led phase II clinical trial of Vertebral Body Tethering 
for pediatric idiopathic scoliosis in children aged 8-16 years. The study will have a retrospective 
arm to collect data from patients who had the tether surgery prior to approval of the prospective 
study. 
Study Interventions and Measures:  
 
The study intervention is surgical orthopedic implantation of Anterior Vertebral Body Screws 
with PET cord, by way of thoracoscopic surgery under general anesthesia. The primary outcome 
measures include assessments of safety of the insertion procedure and of the device, as well as the 
secondary measure of efficacy by determining the improvement in the angle of deformity. 
Monitoring will be conducted by a data safety committee, who has extensive training and 
experience in surgical procedures. 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
 
 
Study Title  
 
Safety and efficacy of a vertebral body tethering technique for 
pediatric idiopathic scoliosis  
 
Funder  
Departmental Funds  
 
Clinical Phase  
Phase II  
 
Study Rationale  
Anterior surgical approach and instrumentation is an accepted 
standard treatment for idiopathic scoliosis (IS). This study will 
assess whether the intervention (Anterior Vertebral Tethering) is 
a safe and efficacious method of anterior approach surgery for 
spinal deformity in pediatric scoliosis.  
 
Study Objective(s)  
Primary  
To determine the safety of Anterior Vertebral Tethering surgery  
 
Secondary  
To determine the efficacy of Anterior Vertebral Tethering 
surgery  
 
Test Article(s)  
Globus Medical Inc.  
Reflect/Transition™ Stabilization System  
Polyethylene terephthalate (PET) cord  
 
Study Design  
This is a single center prospective, open-label pediatric clinical 
device trial with a single surgical intervention with retrospective 
arm to collect data from patients who already had AVT surgery. 
 
Subject Population  
Key criteria for Inclusion  
and Exclusion:  
Inclusion Criteria  
1. Males or females age 8 to 16 years old at time of enrollment 
(inclusive)  
2. Diagnosis of Idiopathic Scoliosis  
3. Sanders bone age of less than or equal to 4  
4. Thoracic curve of greater than or equal to 35 degrees but not 
larger than 60 degrees  
5. Lumbar curve less than 35 degrees  
6. Spina bifida occulta is permitted  
7. Spondylolysis or Spondylolisthesis is permitted, as long as it 
is non-operative, the patient has not had any previous 
surgery for this, and no surgery is planned in the future  
8. Completed standard-of-care procedures as outlined in 
Section 5  
 

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Subject Population  
Key criteria for Inclusion  
and Exclusion:  
Exclusion Criteria  
1. Pregnancy (current)  
2. Prior spinal or chest surgery  
3. MRI abnormalities (including syrinx >4mm, Chiari 
malformation, or tethered cord)  
4. Neuromuscular, thoracogenic, cardiogenic scoliosis, or 
any other non-idiopathic scoliosis  
5. Associated syndrome, including Marfan Disease or 
Neurofibromatosis  
6. Sanders bone age greater than 4  
7. Thoracic curve less than 35 degrees  
8. Lumbar curve greater than or equal to 35 degrees  
9. Unable or unwilling to firmly commit to returning for 
required follow-up visits  
10. Investigator judgement that the subject/family may not be 
a candidate for the intervention  
 
Number Of Subjects  
The study will be conducted at The Nemours – Alfred I 
duPont hospital for Children, Division of Orthopedics. 
Subject inclusion will be based on interest of patients that 
satisfy the inclusion/exclusion criteria that present to the 
Orthopedic Clinic.  The total study enrollment will be 30 
subjects. In the retrospective arm we will aim to enroll all 
patients who had the tether surgery in the past.The study ends 
when all patients reach skeletal maturity.  
Study Duration  
 
 
 
 
Study Phases:  
 
Screening  
 
 
 
 
 
Study Treatment  
 
 
 
 
 
 
 
 
 
 
Post-op Follow-Up  
 
Each subject’s active participation will last about 5 years 
after surgery. The entire study is expected to last at least 8 
years.  
 
1. Screening phase: Subjects will be screened by study staff 
during a clinical visit in the Orthopedics department. Eligible 
subjects will be approached and if interested, enrolled during 
a routine clinical exam.  
 
 
2. Study Treatment: The subject will undergo surgical 
intervention using accepted standard-of-care anterior 
approach using the Globus Medical Inc. Creo™ Stabilization 
System. Vertebral body tethering  using screws and 
Polyethylene Terepthalate cord (Globus Medical, Inc. 
Reflect/Transition™ Stabilization System) is 
investigational. 
 
 
 
 
3. Post-operative Follow-up: Subjects will be followed at 
regular time points at 45 and 90 days post-op during the post-
operative phase. Patients will also be seen at visits 180, 365, 
730, 1095, 1460, 1825 days post-op during the extended 
follow-up phase.  

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Efficacy Evaluations  
The primary efficacy evaluation measurement is thoracic Cobb 
angle (to nearest degree) at the pre-operative visit to Cobb 
angle during follow-up, especially at two years post-op (POD 
730).  
 
Safety Evaluations  
We will use phase-specific endpoints to measure safety:  
1) Study treatment phase: Any individual-level intraoperative 
events including neuromonitoring events (loss or change in 
neurological signaling or function), unanticipated events 
during surgery, and SAEs.  
2) Post-operative active phase: Incidence of infection (within 
90 days post-op), pneumothorax, bronpulmonary plug, or any 
reportable SAE.  
3) Extended follow-up phase: Incidence of over-correction, 
implant failure (measured on serial x-ray), incidence of curve 
progression to >50 degrees at 5 year follow-up, or incidence of 
secondary surgery or re-operation to correct further spine 
deformity (not related to trauma or other issues not related to 
the initial surgery / disease).  
 
Statistical And Analytic Plan  
Cobb angle is a continuous variable. T-test or repeated 
measures Anova will be used to detect any change in Cobb 
angle post-operatively. Linear regression will be utilized to 
assess which variables are associated with change in post-
operative Cobb angle.  
DATA AND SAFETY 
MONITORING PLAN  
The PI and Data Safety group will meet regularly to discuss 
any safety events. Group’s reports will be forwarded to the 
IRB during continuing review per ORC monitoring 
guidance. Safety reporting will be according to IRB SOP 
408 and governing FDA guidelines. The PI and study team 
will also comply with all ORC monitoring standards. The 
PI will meet with the study team regularly to discuss study 
progress and ensure data fidelity. The first meeting will 
take place before initiation of the study to discuss the 
protocol and establish guidelines to monitor the study. The 
Sponsor-PI will work in conjunction with the DSMB 
members to prepare an agenda to address the review of the 
initiation of the trial, reporting of adverse events, stopping 
rules, etc. 
Meetings will be held before enrolling the 1st, 5th, 9th and so 
forth patient. If a Serious Adverse Event (SAE) occurs, a 
separate meeting will be held.  

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The meetings will be held at the Nemours AIDHC 
Department of Orthopedics using WebEx connectivity for 
attendees who are not in the office. 
Meeting minutes will be recorded by the study coordinator 
and will become part of the study binder.   
DSMB group includes  the following members who do not 
have a financial or other types of conflict of interest related 
to this study: 
1. Michael Wade Shrader, MD 
 
2. Kevin Neal, MD 
 
3.  Hossain, Md Jobayer , Ph.D 
 
Dr. Shah will not lead the DSMB meetings, but help to 
prepare reports/events for the DSMB.  Dr. Shah will be 
present as a participant in the meetings to answer questions 
by the DSMB personnel, but will not be present for a 
closed portion of the meeting.   
Members of the DSMB are: 
Michael Wade Shrader, MD is the director of the Cerebral 
Palsy program at Nemours – AIDHC department of 
Orthopedics.  He is a board certified orthopedic surgeon 
with 14 years of experience.  He has performed posterior 
spinal fusion (PSF) surgeries on patients for 14 years.   
 
Kevin M. Neal, MD is the Program Director of Orthopedics 
Fellowship program at Nemours, Jacksonville.  He is board 
certified orthopedic surgeon with 15 years of experience. 
Dr. Neal has performed posterior spinal fusion surgeries on 
pediatric patients for 15 years.  
 
 
3.   Hossain, Md Jobayer, Ph.D is Senior Research Scientist 
in the Department of Biomedical Research and the Manager 
of the Biostatistics Core at Nemours, as well as an Adjunct 
Associate Professor in the Department of Applied 
Economics and Statistics at University of Delaware. He is a 
lead or co-author for 103 published articles and more than 
160 published abstracts and presentations. He is actively 
involved in scientific, educational, and research activities. 
His academic training and extensive work experience in 
statistics, epidemiology, and biometry. 
 
 
 
 
 

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1 BACKGROUND INFORMATION AND RATIONALE  
 
1.1 Introduction  
 
Scoliosis is a condition where the spine is deformed by a curvature in the coronal plane. It is 
generally associated with a twisting (axial plane) deformity as well. It can have a variety of 
underlying etiologies, and the etiology is used to classify the types of scoliosis. Scoliosis related 
to conditions affecting the nervous system or muscle function are termed neuromuscular 
scoliosis. Neuromuscular scoliosis is often related to conditions such as cerebral palsy, muscular 
dystrophies, spina bifida, or paralysis [1]. Another type of scoliosis is congenital scoliosis; 
scoliosis related to malformation of the bony structures of the spine. Some syndromes are 
associated with a high incidence of scoliosis including Marfan syndrome and neurofibromatosis. 
These forms of scoliosis are termed syndromic scoliosis [2]. Idiopathic scoliosis is scoliosis not 
due to any of the above mentioned causes. It is a diagnosis of exclusion.  
 
Idiopathic scoliosis is sub-classified in two ways: by age of onset and by magnitude of deformity. 
Curves between 10 and 25 degrees are considered mild. Curves between 25- and 50 degrees are 
classified as moderate. Curves greater than 50 degrees are termed severe. Idiopathic scoliosis 
occurs in 2-3% of the population with decreasing frequency at higher magnitudes of deformity. 
Idiopathic scoliosis diagnosed before age 3 is classified as infantile idiopathic scoliosis; between 
3 and 10, juvenile idiopathic scoliosis; 10 to 18 adolescent idiopathic scoliosis; greater than 18 is 
adult idiopathic scoliosis. The diagnosis is retained throughout life; a juvenile idiopathic scoliosis 
patient does not become an adolescent idiopathic scoliosis patient at age 10.  
 
Further classification of surgically treated adolescent idiopathic scoliosis has been derived by 
Lenke et al. [3], in an attempt to guide treatment. The classification system takes into account 
factors such as the location of the deformity (thoracic v. lumbar, v. both), number of curves, the 
flexibility of the deformity, and the sagittal plane. This classification system has been widely 
adopted in medical literature on the condition.  
 
1.1.1 The Principle of Growth Modulation  
 
Although the etiology of idiopathic scoliosis is largely unknown, some genetic factors have been 
implicated [4]. Biomechanical imbalance leading to asymmetrical spinal growth has also been 
postulated as the mechanism for progression, though there is limited evidence to link idiopathic 
scoliosis progression to a biomechanical cause [5]. Many treatments have been proposed to 
manage the progression of idiopathic scoliosis. Among the various treatment methods used, 
bracing and surgical fusion remain the most common treatments to alter the natural history of the 
disease [6]. Although spinal fusion and instrumentation for scoliosis correction has high 
intermediate success rates with few complications, it is among the most invasive procedures. Loss 
of motion following fusion and potential for adjacent segment degeneration is a long-term 
concern.  
In the field of limb deformities, the concept of growth modulation by a staple in a growing child 
(introduced by Blount) is utilized as part of the accepted common practice and as the standard of 
care for management of limb deformity [7]. It is presumed that compressive implants such as 
staples inhibit growth according to the Hueter-Volkmann principle [8]. 2  

12 
 
More recently, similar concepts have been applied successfully for spine growth modulation. 
These devices provide compressive forces on the convex side of the curve utilizing the Heuter-
Volkman principle; slowing the growth on the convex side of the curve and enhancing the growth 
on the concave side. This effect has been demonstrated in animal models [9]. Furthermore, they 
have shown to preserve motion at the instrumented levels. Radiographic and chemical analysis 
performed in the animals have shown that disc function is maintained after the application of such 
a device [9].  
 
1.1.2 Current standard of care  
 
1.1.2.1 Moderate Scoliosis (Curves 25-50 Degrees)  
 
The current standard of care for moderate scoliosis in patients with remaining growth is to utilize 
a thoracolumbosacral orthosis to prevent progression of deformity. Recent evidence has 
supported the efficacy of this intervention in avoiding progression of the Cobb angle to 50 
degrees or more. In 2010, Katz and colleagues [10] examined the efficacy of bracing and 
published a study that utilized heat sensors within braces to quantify brace wear compliance. In 
that study, Katz and colleagues [10] determined the brace success rate to be 82% in patients who 
wore their brace for more than 12 hours per day. In 2013, Weinstein and colleagues [11] 
demonstrated an improvement over the natural history with brace treatment and a correlation 
between hours of brace wear and efficacy of bracing in AIS. The most important difference in the 
results presented by Weinstein and colleagues [11] and Katz and colleagues [10] and the 
proposed study is the level of maturity (and therefore natural history) of the treatment population. 
The average age of initiation of bracing in both the Weinstein et al. and Katz et al. studies was 
12.7 years. In a subsequent study of AIS patients treated with bracing, Karol and colleagues 
demonstrated a more than 5 fold increased risk of bracing failure in Risser 0 patients compared to 
Risser 1 patients [12].  
 
The study results of Karol et al. and others suggest that there may be a level of skeletal 
immaturity below which bracing cannot alter the natural history of moderate idiopathic scoliosis 
[13]. The study reported that 63% of patients with Risser 0 and open triradiate cartilage 
progressed to the point of requiring a fusion. The efficacy of bracing in this cohort was 
significantly less than those with closed triradiate cartilages (P<0.001). Furthermore, those 
patients with Risser 0, open triradiate cartilage, and a Cobb angle of 30 degrees or greater had a 
74% incidence of progression to fusion. Jarvis and colleagues [14] reported that fusion was 
avoided in only 49% of those patients with Juvenile Idiopathic Scoliosis (JIS) treated with 
bracing, which raises the question of whether bracing has any impact the natural history in JIS. 
Charles et al. further stratified JIS by Cobb angle [15]. The study showed that curves more than 
30 degrees prior to the puberty growth spurt progressed to a magnitude requiring surgery in 100% 
of cases despite bracing.  
 
If treated with a brace, many idiopathic scoliosis patients would conceivably be subjected to years 
of brace wear and the cost and psychological factors inherent therein. Additional downsides of 
brace treatment include the potentially negative psychosocial impact of wearing an external sign 
of deformity during adolescence, a key period of emotional development. Prior research has 
identified negative psychosocial effects related to wearing a brace in children [16]. Such 
ramifications were further explored in a recent study by Misterska and colleagues [17], who 
found that the patients experienced a moderate level of 3  

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stress specifically related to brace wear despite only low stress levels related to perceived spinal 
deformity. From a patient reported outcome point of view, the treatment is worse than the disease.  
 
1.1.2.2 Severe Scoliosis (Curves 50 Degrees and Greater)  
Spinal fusion is the current standard of care for curves at or near 50 degrees in AIS and JIS. 
Posterior spinal fusion (PSF) involves a midline approach to the back, placement of spinal 
anchors (usually pedicle screws), and fusion with bone graft across the posterior laminae. The 
course of treatment is predictable and safe. Newton et al. reported on the treatment of the most 
common subtype of AIS – Lenke 1 curves – which comprise about half of all AIS cases. He 
reported that a posterior spinal fusion will require a 4 hour surgery with a 5 day hospital stay with 
a blood loss of approximately 800cc [18]. Anterior Spinal Fusion is often utilized as well and this 
may involve a thoracotomy (open procedure) or thoracoscopy. Thoracoscopic anterior spinal 
fusion also has consistent outcomes in terms of radiographic results and expected course of 
treatment [19].  
 
1.2 Name and Description of Investigational Product or Intervention  
 
1.2.1 Vertebral tethering  
 
Vertebral Body Tethering (VBT) will be performed via an anterior thoracoscopic approach (see 
“Surgical Technique” below). This surgical approach is utilized as a common approach for the 
current standard of care anterior-type spinal fusion [19, 20]. Thoracoscopic anterior approaches 
do not seem to carry any increased risk over other approaches for spinal fusion, namely posterior 
spinal fusion and open anterior spinal fusion. The reason it is not uniformly utilized is that the 
fusion is less reliable in this approach with the pseudo-arthrosis rate in thoracoscopic surgery 
reported at 11% v. 3% in posterior spinal fusion [18]. This concern is irrelevant in VBT as fusion 
is not the goal.  
 
1.2.2 Implant  
 
The implants utilized comprise of two components from Globus Spine, Inc., the Creo™ and 
Reflect/Transition™ (aka Reflect) systems. The Creo™ system is designed and indicated to be 
used in anterior thoracoscopic spinal fusion for spinal deformity. We anticipate placing centering 
staples and screws in a manner identical to how they are approved for use. However, rather than 
performing a discectomy, placing bone graft, and placing a rigid rod, we will place a flexible 
Polyethylene Terephthalate (PET) cord (Globus Spine, Inc. Reflect/Transition™ Stabilization 
System). The cord is approved as part of a posterior spinal stabilization system. Currently, no 
other company has an approved device for the use we are proposing for this clinical study. 
Zimmer Spine, Inc. has a posterior PET cord as part of their Dynesis® system but they do not 
have an anterior thoracoscopic implant system that it can be used with. Some surgeons have 
suggested modifying posterior screws from the Dynesis® system for anterior use for vertebral 
tethering but these screws do not have sizing for pediatric indications, as the Creo™ system does. 
Furthermore, the Dynesis® system does not have a centering/stabilizing staple, which is a 
common component of anterior spinal instrumentation systems.  

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1.2.3 Surgical Technique  
 
The surgical technique has been described by Samdani, et al. [21, 22]:  
The patient is intubated with a double lumen endotracheal tube with fiber optic assistance. A 
Foley catheter is placed. The patient is positioned in a lateral decubitus position with the 
operative (convex curve) side facing up. The operative flank is prepped and draped from midline 
anteriorly to midline posteriorly. Flouroscopic assistance is utilized to mark out the location of 
the various vertebra and three 5mm incisions are made to insert the ports in triangular fashion. 
The apex incision is made at the anterior axillary line at the 5th intercostal space. The other two 
incisions are made at the midaxillary line at the 3rd intercostal space and the 8th intercostal space. 
Through the first port a camera is introduced, harmonic scapel through the second, and 
endoscopic “peanut” is placed through the third incision. The pleura is dissected off the vertebral 
bodies laterally along the length of the curve, and anteriorally to the rib heads. Care is taken to 
identify and coagulate the segmental vessels. A 15mm port is then inserted over the most 
cephalad vertebral body ready to be tethered. Over the anterior aspect of the most cephalad 
vertebral body, a 3 prong staple (Creo™ Stabilization System, Globus Spine, Inc.) is introduced 
while maintaining caution that the staple is not introduced in the foramen. Using fluoroscopy the 
position of the staple is confirmed, and then a 5.2mm tap is used to create a screw hole under 
fluoroscopic guidance. The tap is begun on the convex side of the curve towards the convex side, 
across the anterolateral portion of the vertebral body. Next, an appropriately sized screw (Creo™ 
Stabilization System, Globus Spine, Inc.) is placed, with position of the screw confirmed by 
fluoroscopy. Utilizing the same skin incision, the 15mm port is moved to the next intercostal 
space. The vessel ligation, staple placement, tap, and screw placement are then repeated at the 
next vertebral body- moving cephalad to caudad. Generally, up to 3 intercostal spaces can be 
accessed through the same skin incision. Patients who are instrumented to L3 require a mini-open 
retroperitoneal approach.  
 
After all of the screws are placed, the caudal 15mm port is used to pass the PET cord 
(Reflect/Transition™ Stabilization System, Globus Spine, Inc.) through the tulips of all of the 
screws. The set screw (Creo™ Stabilization System, Globus Spine, Inc.) is then placed on the 
most caudal screw tulip using a T-handle pusher. The set screw is locked in place using a locking 
cap (Creo™ Stabilization System, Globus Spine, Inc.), thereby securing the PET cord on the most 
caudal screw. Correction is achieved by tensioning the PET cord and through translation of the 
spine. Once the correction achieved is satisfactory to the surgeon, the set screws are tightened on 
each screw tulip- moving caudad to cephalad. Flouroscopic images should be obtained after each 
screw is tightened, to confirm curve correction. These fluoroscopic images also confirm that there 
is no pulling out, plowing, or other untoward changes in the screw placements in the vertebral 
bodies.  
 
Once all screws have been tightened, global AP and Lateral X-rays of the spine should be 
performed to confirm correction of the curvature. Once satisfactory correction is  
 

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confirmed in this manner, the PET cord should be trimmed, to leave about 2cm at either end to 
accommodate any future adjustment if necessary. An attempt should be made to re-approximate 
the pleura, though this is difficult with the implant. A chest tube should be placed in one of the 
5mm port sites. The hemithorax is then irrigated, the lung is re-inflated under direct vision, and 
the incisions are closed in layers.  
 
1.3 Findings from Non-Clinical and Clinical Studies  
 
1.3.1 Clinical studies  
 
When anterior spinal fusion is selected it is more often performed in cases where only one curve, 
the thoracic or the lumbar curve, requires a fusion [23]. We are proposing similar indications and 
applications for vertebral tethering – a single thoracic curve requiring treatment. Anterior spinal 
fusion provides good clinical and radiographic results. The approach for anterior spinal fusion for 
AIS is most often performed with thoracoscopic guidance. The thoracoscopic approach is less 
invasive than its alternative, an open thoracotomy. Newton et al. reported on 5 year results of 
thoracoscopic anterior fusion showing that Cobb angle correction averaged 56% [20, 24], and 
total lung capacity at 91% of expected. These results were not different than the 2 year outcomes 
in the same patients, suggesting that any slight negative impact of anterior thoracoscopy did not 
lead to a progressive decline in pulmonary function. Furthermore, although open anterior spinal 
fusion is associated with a significant decline in objective measurements in pulmonary function, 
thoracoscopic anterior surgery was not different in its impact on pulmonary function than 
posterior spinal fusion [25, 26]. Faro et al. demonstrated that pulmonary function declines 3 
months after both open and thoracoscopic anterior scoliosis surgery but recovers by 1 year post-
op in thoracoscopic surgery but not in open anterior surgery [27].  
 
In a comparison of the three approaches for fusion of the thoracic spine for AIS (open anterior, 
thoracoscopic anterior, and posterior), Newton et al. in another study reported that Cobb angle 
correction (57%) was similar in all groups, blood loss and incidence of transfusion was greater 
but surgical time was less in the posterior group, and SRS-22 scores were equivalent [18]. 
Furthermore, they reported decreased pulmonary function in the open anterior groups but similar 
PFTs in posterior and thoracoscopic patients. Lonner et al. also addressed the impact of surgical 
approach on pulmonary function [23]. The authors reported a decrease in forced expiratory 
volume in 1 second (FEV1) and functional vital capacity (FVC) as a percent of expected by 4-5% 
but an increase in total lung capacity (TLC) of 3% (Tables 1 and 2). These changes are of 
minimal clinical significance.  
 
 

16 
 
 
 
Table 1: Demographics (Adapted from Lonner et al, 2015)  
 
Approach Type  
N  
Sex Distribution  
Mean Age at 
Surgery 
(Range)* 
 
Mean Numbers 
Levels Fused  
Lenke Curve 
Type 
Thoracotomy  
68  
61 female, 7 male  
14.3 (10-21) 
6.6 
1 
Thoracoscopic  
44  
39 female, 5 male  
13.9 (10-18) 
6.1 
1 
Thoracoabdominal  
19  
18 female, 1 male  
14.8 (13-18) 
4.1 
5 
 
*Not significantly different.  
 
 
 

1 7  
 
Ta ble 2: Mea n Perce nt -pre dicte d Val ues Pre o perati vel y t o F oll o w -u p ( A da pte d fr o m L o n ner et al, 2 0 1 5)  
 
 
                                                     Perce nt  
                             pre dicte d F E V 1  
Perce nt pre dicte d  
F V C  
Perce nt pre dicte d  
T L C  
T h orac ot o m y  
Mea n pre o perati ve  
8 3. 3  
 8 8. 1  
      8 5. 6  
Mea n f oll o w -u p  
7 2. 3  
 7 5. 1  
      7 7. 6  
 ( Pre-p ost)  
-1 1. 0  
-1 3. 0  
      -8. 0  
P  
< 0. 0 0 1  
< 0. 0 0 1  
    ≤ 0. 0 0 1  
 
T h orac osc o pic  
Mea n pre o perati ve  
8 2. 5  
 8 7. 2  
      8 5. 0  
Mea n f oll o w -u p  
7 8. 1  
 8 2. 5  
      8 8. 2  
  
-4. 4  
 -4. 7  
        3. 2  
P  
< 0. 0 0 4  
 N S  
       N S  
 
T h orac oa b d o mi nal  
Mea n pre o perati ve  
9 0. 3  
 9 3. 7  
      9 4. 7  
Mea n f oll o w -u p  
8 3. 5  
 8 7. 7  
      9 5. 1  
  
-6. 8  
 -6. 0  
       0. 4  
P  
N S  
 N S  
      N S  
 
F E V 1 i n dicates f orce d e x pirat or y v ol u me i n 1 sec o n d; F V C, f orce d vital ca pacit y; N S, n o n- si g nifica nt; T L C, t otal l u n g 
ca pacit y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T here is r o o m f or i m pr o ve me nt o ver t he o utc o mes of p osteri or s pi nal f usi o n. I n partic ular, t he 
d ura bilit y of t he pr oce d ure is c o mi n g i nt o q uesti o n. P osteri or pe dicle scre w c o nstr ucts ca me i nt o 

18 
 
popularity in the early 2000’s and new 10 year post-op data is demonstrating a concerning trend. 
The Harms Study Group, a multicenter consortium of scoliosis practitioners and researchers have 
recently shown that almost 10% of AIS fusions require revision surgery by 10 years post-op and 
that this trend is progressive [28] (Figure 1). 
 
Figure 1: Re-operation rates (“Survival Curve”) of posterior spinal fusion over time. (Personal 
Communication from Peter Newton)  
 
 
Other authors have also reported on high long term re-operation rates following AIS fusion 
surgery ranging from 4.6% to 19% [29-31]. One theory is that a fusion imparts increased stress on 
unfused segments below a fusion. Marks et al. have shown that patients will retain total lumbar 
motion after a posterior spinal fusion by increasing motion in the unfused areas [32]. The authors 
postulate that increased motion may lead to degeneration of discs and facet joints. These findings 
of supraphysiologic motion below a posterior spinal fusion may explain some of the decreasing 
durability of posterior spine fusion. Green et al. have studied the health of intervertebral discs 
below a spinal fusion at an average of 11.8 years following posterior spinal fusion [33]. The 
authors found that disc degeneration was occurring in 85% of patients and the discs when graded 
by the Firman scale, an objective validated measure of disc degeneration [33]. Vertebral tether 
surgery will allow for continued motion of the instrumented levels and thus avoid the long lever-
arm effect of a long fusion that may be contributing to early degeneration. Additional reports 
have questioned the durability of posterior spinal fusion. Upasani et al. reported on increased pain 
in patients at 5 years post-spinal fusion compared to at 2 years [34]. Lastly, posterior spinal fusion 
in patients who have not had their pubertal growth spurt, the population in whom we are 
proposing vertebral tethering, are at increased risk of complications and re-operation. Sponseller 
et al. reported that patients with open triradiate cartilages undergoing spinal fusion surgery have 
an increased rate of “adding on” (development of deformity below a fusion) and the response of 
the uninstrumented lumbar curve is less predictable [35].  
 

19 
 
Ideally, longitudinal outcomes of current standards of care including anterior thoracoscopic and 
posterior pedicle screw instrumented fusion would be used as a standard against which new 
technology can be compared. However, such data is a half century away. Furthermore, the pace 
of change and improvement in spinal deformity instrumentation and surgery tells us that change 
is inevitable [36]. 
1.3.2 Non clinical studies  
 
There have been several animal studies of vertebral tethering. Peter Newton and colleagues at 
The University of California at San Diego and Rady Children’s Hospital have performed spinal 
tethering studies in bovine and porcine models [37-39]. The first study the authors published was 
in an immature bovine model [38]. They utilized a stainless steel tether. They demonstrated those 
animals who had a sham surgery without placement of the tether did not develop a curvature 
while those with placement of two rods did develop a curve. This was offered as a proof of 
concept that tension of a tether could alter growth and change alignment. In the porcine model, 
the investigators demonstrated the ability of a spinal tether to induce deformity in immature 
animals proportionally to the duration it was left in place, offering further evidence of the effect 
of growth in contributing to the deformity rather than tension of the implant alone [40]. Further 
evidence of the effect of growth driving the change in alignment was offered in a subsequent 
study of the bovine model [37]. They demonstrated equivalent deformity magnitude after 12 
months between groups in which the tether was tensioned and those in which it was placed 
without tension.  
 
1.4 Relevant Literature and Data  
 
The natural history of scoliosis after maturity has been described in several populations treated 
non-operatively and followed longitudinally. One cohort is from Scandinavia and was reported by 
Danielsson and Nachemson [41]. The other is from Iowa and was reported by Weinstein and 
colleagues [42, 43]. Nachemson reported a cohort of 117 scoliosis patients with a variety of types 
of scoliosis including those classified as congenital scoliosis, neuromuscular scoliosis, post-
infectious scoliosis, and idiopathic scoliosis [44]. Decreased life expectancy was reported in this 
group. A subsequent sub-analysis of only the idiopathic scoliosis patients in this group revealed 
that there was no increase in mortality compared to the general population. Weinstein et al. 
reported a group of idiopathic scoliosis patients treated with observation [43]. They showed that, 
despite an increase in back pain symptoms, there was no increase in mortality rates compared to 
the aged matched general population. Furthermore, they identified Cobb angle greater than 50 
degrees as a predictor of continued progression in adulthood. Greater than 85% of these patients 
progressed at a rate of ~1.1 degrees per year. Weinstein demonstrated a Cobb angle greater than 
50 degrees as a factor predictive of further progression in adolescents in a subsequent study [42]. 
This forms the basis for current indications of surgical fusion for curves greater than 50 degrees. 
Conversely, curves less than 30 degrees at the end of growth did not progress nor did they exhibit 
any pain or pulmonary dysfunction. The desire to keep curves below thirty degrees forms the 
recommendation for initiation of brace management in curves that are 25- 30 degrees.  
 
1.4.1 Curves below 50 Degrees With A High Likelihood of Progression to 50 Degrees  
 
Further studies have elucidated which curves in immature patients will progress to 50 degrees 
before reaching skeletal maturity. Rather than taking a reactive approach to these curves, we 
propose early treatment of this population with vertebral tethering. Dimeglio et al. demonstrated 
that immature patients with idiopathic scoliosis with a Cobb angle of 30 degrees or greater prior 
to their pubertal growth spurt will universally progress to 50 degrees by the end of growth [45]. 

20 
 
Dimeglio suggests several measures for identifying the onset of 10 pubertal growth spurt 
including the changes of various bone growth centers remote from the spine. These include the 
appearance (radiographically) of the sesamoid bone in the thumb, the presence of two distinct 
ossification centers in the olecranon (elbow), and an open tri-radiate cartilage (hip socket). 
Sanders et al. have also demonstrated a correlation of risk of progression to a Cobb angle of 50 
degrees between markers of skeletal maturity and Cobb angle [46]. They developed an easily 
applied scoring system of 1-7 to a hand x-ray. The advantage of a hand x-ray is that it 
encompasses a large number of growth centers, does not require additional training of radiology 
personnel, and is remote from more radiosensitive organs. The maturity based progression 
assessment derived by Sanders assigns a risk of progression to a Cobb angle of 50 degrees or 
more. It is this risk of progression to 50 degrees on which we base or treatment decision for 
Vertebral Body Tethering. Table 3 illustrates that there is significant risk for progression if a 
patient’s curve is above 35 degrees, and is a Sanders stage of 4 or less. Therefore our inclusion 
criteria for this study are set to include patients with curves above 35 degrees and a Sanders stage 
of 4 or less.  
 
We have selected an upper limit of 60 degrees due to the theoretical concern of achieving higher 
amounts of correction during periods of limited growth. In retrospective series by Samdani et al., 
the average Cobb angle of treated curves was 44 degrees [21, 22].  
 
Table 3: Projected risk of progression of scoliosis to above 50 degrees, based on curve magnitude 
and bone age. (From Sanders, et al. 2008) 
 
1.5 Compliance Statement  
 
This study will be conducted in full accordance with all applicable Nemours Research Policies 
and Procedures and all applicable Federal and state laws and regulations including 45 CFR 46, 21 
CFR Parts 50, 54, 56, 312, 314 and 812 and the Good Clinical Practice: Consolidated Guideline 

21 
 
approved by the International Conference on Harmonization (ICH). All episodes of 
noncompliance will be documented.  
 
The investigators will perform the study in accordance with this protocol, will obtain consent and 
assent, and will report unanticipated problems involving risks to subjects or others in accordance 
with Nemours IRB Policies and Procedures and all federal requirements. Collection, recording, 
and reporting of data will be accurate and will ensure the privacy, health, and welfare of research 
subjects during and after the study.  
 
 
 

22 
 
2 STUDY OBJECTIVES  
The purpose of the study is to determine the safety and efficacy of Anterior Vertebral Body 
Tethering surgery on patients with Idiopathic Scoliosis.  
 
2.1 Primary Objective (or Aim)  
 
The primary objective is to assess the safety of Anterior Vertebral Body Tethering surgery in the 
immediate post-operative period.  
 
2.2 Secondary Objectives (or Aim)  
 
The secondary objective is to assess the post-operative correction of the scoliotic curve, as 
measured by Cobb Angle on Coronal (AP/PA) radiograph of the spine.  
 
 
 

23 
 
3 INVESTIGATIONAL PLAN  
 
3.1 General Schema of Study Design  
 
3.1.1 Screening Phase  
 
Subjects will be screened from patients presenting to the orthopedic clinic for routine clinical 
care. Patients who satisfy the inclusion and exclusion criteria will be approached and presented 
information about the clinical study. Those subjects and families who are interested in pursuing 
the clinical study will be enrolled by providing informed consent/assent.  
Subjects who learn about the study through social media and contact Nemours for additional 
information will be directed to have a scoliosis clinical appointment  After that they will  follow 
the same  research procedure as the subjects who present in the orthopedic clinic for scoliosis 
care. This phase will last 1 day 
 
3.1.2 Study Intervention (Surgery)  
 
Enrolled patients who have completed the pre-operative course for anterior spine surgery (Pre-
operative SOC and Pre-operative study procedures) will undergo the study intervention 
comprising implantation of anterior vertebral body screws and PET cord under general 
anesthesia. This phase will last 1 day (day of surgery). This surgical episode is estimated to last 
about 5.5 hours; 2.5 hours of anesthesia induction and preparation, 2.5 hours of surgery, and 30 
minutes of emergence from anesthesia.  
 
3.1.3 Post-operative follow-up  
 
The Post-operative follow-up phase of the study will last approximately 90 days, beginning with 
the day after the surgical intervention. This period has 2 set time points for follow-up, which will 
occur during standard-of-care clinical follow-up visits for spine patients receiving surgical 
intervention. The two time-points are a POD-45 clinical visit, and a POD-90 clinical visit. During 
these two clinical visits physical exams, radiographs, and AE / SAE data will be collected. POD 
2-44 will be monitored for known complications and AE / SAEs only, as there will be no clinical 
outcomes data to collect during this time. This data will be abstracted from the medical records. 
In addition, the patient will be under SOC post-operative care for patients who have undergone 
Anterior Spinal Surgery. Data from any SOC interventions will also be abstracted from the 
medical record.  
 
3.2 Allocation to Treatment Groups and Blinding  
 
The study will not be blinded, as the patient must make an informed decision to undergo the 
intervention, and the surgeon must perform the intervention. Introduction of a sham or placebo 
group would be impractical and unethical in this context. The study will only enroll one cohort- 
the Anterior Tethering (Intervention) cohort.  
 
3.3 Study Duration, Enrollment and Number of Sites  
 
3.3.1 Duration of Study Participation  
The subject will be followed for at least 10 visits over a 5-year (1825 day) period: 1 day for 
recruitment /consent, 1 day for the study intervention (surgery), 1 day for each visit: POD45, 
POD90, POD180, POD365, POD730, POD1095, POD1460, and POD1825. These visits follow 
the schedule for a patient’s standard-of-care follow-up for anterior spinal surgery. Any off-study 

24 
 
visits within the study window will not be captured, unless they are related to an AE / SAE. There 
is a three-week grace period for post-operative study visits, and a 90 day grace period for 
extended follow-up visits, making the maximum study participation time 1825 + 90 days after the 
day of surgery.  
 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected  
 
The study will be conducted at Nemours – Alfred I duPont Hospital for Children.  
As this is a registry of an approved device being used in an off-label method, we do not have a 
maximum number of patients or target enrollment. Based on a broad review of patient visits over 
the past year, we may expect to enroll up to 15 patients per year. These patients will be followed 
up clinically until skeletal maturity. The total number of enrolled subjects in both retrospective 
and prospective arms will be 30.  
 
3.4 Study Population  
 
3.4.1 Inclusion Criteria  
1) Males or females age 8 to 16 years old at time of enrollment (inclusive)  
2) Diagnosis of Idiopathic Scoliosis  
3) Sanders bone age of less than or equal to 4  
4) Thoracic curve of greater than or equal to 35 degrees, but no bigger than 60 degrees 
 
5) Lumbar curve less than 35 degrees  
6) Spina bifida occulta is permitted  
7) Spondylolysis or Spondylolisthesis is permitted, as long as it is non-operative, the patient has 
not had any previous surgery for this, and no surgery is planned in the future  
8) Completed standard-of-care procedures as outlined in Section 5  
9) Subject consent and (if applicable) assent  
 
3.4.2 Exclusion Criteria  
 
1) Pregnancy (current)  
2) Prior spinal or chest surgery  
3) MRI abnormalities (could include syrinx >4mm, Chiari malformation, or tethered cord)  
4) Neuromuscular, thoracogenic, cardiogenic scoliosis, or any other non-idiopathic scoliosis  
5) Associated syndrome, including Marfan Disease or Neurofibromatosis  
6) Sanders bone age greater than 4  
7) Thoracic curve less than 35 degrees  
8) Lumbar curve greater than or equal to 35 degrees  

25 
 
9) Unable or unwilling to firmly commit to returning for required follow-up visits  
10) Investigator judgement that the subject/family may not be a candidate for the intervention  
 
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations of 
these criteria must be reported in accordance with IRB Policies and Procedures.  
 
 
 

2 6  
 
4 S T U D Y P R O C E D U R E S  
 
4. 1 Scree ni n g P h ase  
 
4. 1. 1 Visit 1 ( S cree ni n g & Pre -o per ati ve Visit)  
 
 Me dical rec or d a n d x -ra y re vie w 
 Ha n d x-ra y t o defi ne b o ne a ge 
 I nf or me d c o nse nt / asse nt  
 P h ysical E xa m  (researc h- i ncl u di n g A da m’s F or war d be n di n g test ( de grees), t h oracic  
    a n d l u m bar fle xi o n (c m), t h oracic a n d l u m bar lateral fle xi o n (c m)  
 Cli nical p h ot os 
 Pre g na nc y Test  ( Uri ne or Bl o o d) as a p plica ble  
 C B C bl o o d test  
 S R S 3 0 Q uesti o n naire  
 
4 . 2 St u d y Tre at me nt P h ase ( S ur ger y)  
 
4. 2. 1 Visit 2 ( S ur gic al I nter ve nti o n)  
 
T his p hase i ncl u des t he s ur gical i nter ve nti o n- Verte bral B o d y Tet heri n g t hr o u g h a nteri or 
t h orac osc o pic a p pr oac h u n der ge neral a nest hesia. T his pr ocess is descri be d i n Secti o n 2.  
Data fr o m t he s ur ger y will be a bstracte d b y me dical rec or d re vie w f or a d verse e ve nts or 
c o m plicati o ns. I ntra o perati ve data (i ncl u di n g ra di o gra p hs) will als o be a bstracte d fr o m t he 
me dical rec or d / s ur gical l o gs. Res ults fr o m t he s ur ger y a n d i n patie nt sta y will be a bstracte d at t he 
ti me of disc har ge, e xce pt f or t h ose e ve nts w hic h fall u n der t he re p orti n g g ui deli nes of A E/ S A Es. 
All A E/ S A Es will be re p orte d acc or di n g t o re p orti n g g ui deli nes liste d i n Secti o n 8.  
 
4. 3 P ost-s ur gic al F oll o w- u p P h ase  
 
T his p hase will i ncl u de m o nit ori n g f or p ost- o perati ve c o m plicati o ns / S A E, as well as t w o S O C 
cli nical visits i n t his p hase, w here t he s u bject will als o u n der g o a researc h visit. I nf or mati o n fr o m 
sta n dar d-of -care pr oce d ures will als o be a bstracte d fr o m t he  me dical rec or ds a n d ra di ol o g y 
data bases.  
 
4. 3. 1 Visit 3 ( P O D 4 5)  
 Me dical rec or d re vie w a n d a bstracti o n  
 X- ra y re vie w a n d a bstracti o n  
 P h ysical E xa m (researc h)  
 C o m plicati o ns Re vie w  
 
4. 3. 2 V isit 4 ( P O D 9 0)  
 Me dical rec or d re vie w a n d a bstracti o n  
 X- ra y re vie w a n d a bstracti o n  
 P h ysical E xa m (researc h)  
 C o m plicati o ns Re vie w  
 
4. 4 E xte n de d F oll o w- u p P h ase  
T his p hase will i ncl u de m o nit ori n g f or p ost- o perati ve c o m plicati o ns /S A E, as well as t hree S O C 
cli nical visits i n t his p hase, w here t he s u bject will als o u n der g o a researc h visit. I nf or mati o n fr o m 

2 7  
 
sta n dar d-of -care pr oce d ures will als o be a bstracte d fr o m t he me dical rec or ds a n d ra di ol o g y 
data bases.  
 
4. 4. 1 Visit 5 ( P O D 1 8 0)  
 Me dical rec or d re vie w a n d a bstracti o n  
 X- ra y re vie w a n d a bstracti o n  
 P h ysical E xa m (researc h, i ncl u di n g A da m’s F or war d be n di n g test ( de grees)) 
 S R S 3 0 Q uesti o n naire  
 C o m plicati o ns Re vie w  
 
4. 4. 2 V isit 6 ( P O D 3 6 5)  
 Me dical rec or d re vie w a n d a bstracti o n  
 X- ra y re vie w a n d a bstracti o n  
 P h ysical E xa m  (researc h- i ncl u di n g A da m’s F or war d be n di n g test ( de grees), t h oracic 
    a n d l u m bar fle xi o n (c m), t h oracic a n d l u m bar lateral fle xi o n (c m)  
 S R S 3 0 Q uesti o n naire  
 Cli nical P h ot os 
 Ha n d x-ra y t o defi ne b o ne a ge 
 C o m plicati o ns Re vie w  
 
4. 4. 3 V isit 7 ( P O D 7 3 0)  
 Me dical rec or d re vie w a n d a bstracti o n  
 X- ra y re vie w a n d a bstracti o n  
 P h ysical E xa m  (researc h- i ncl u di n g A da m’s F or war d be n di n g test ( de grees), t h oracic 
    a n d l u m bar fle xi o n (c m), t h oracic a n d l u m bar lateral fle xi o n (c m)  
 S R S 3 0 Q uesti o n naire  
 Ha n d x-ra y t o defi ne b o ne a ge 
 Cli nical P h ot os 
 C o m plicati o ns Re vie w 
 
4. 4. 4 V isit 7 ( P O D 1 0 9 5)  
 Me dical rec or d re vie w a n d a bstracti o n  
 X- ra y re vie w a n d a bstracti o n  
 P h ysical E xa m (researc h- i ncl u di n g A da m’s F or war d be n di n g test ( de grees), t h oracic 
    a n d l u m bar fle xi o n (c m), t h oracic a n d l u m bar lateral fle xi o n (c m)  
 S R S 3 0 Q uesti o n naire  
 Ha n d x-ra y t o defi ne b o ne a ge 
 Cli nical P h ot os 
 C o m plicati o ns Re vie w  
 
4. 4. 5 V isit 7 ( P O D 1 4 6 0)  
 Me dical rec or d re vie w a n d a bstracti o n  
 X- ra y re vie w a n d a bstracti o n  
 P h ysical E xa m (researc h- i ncl u di n g A da m’s F or war d be n di n g test ( de grees), t h oracic 
    a n d l u m bar fle xi o n (c m), t h oracic a n d l u m bar lateral fle xi o n (c m)  
 S R S 3 0 Q uesti o n naire  
 Ha n d x-ra y t o defi ne b o ne a ge 
 Cli nical P h ot os 
 C o m plicati o ns Re vie w  
 
4. 4. 6 V isit 7 ( P O D 1 8 2 5)  

2 8  
 
 Me dical rec or d re vie w a n d a bstracti o n  
 X- ra y re vie w a n d a bstracti o n  
 P h ysical E xa m E xa m (researc h - i ncl u di n g A da m’s F or war d be n di n g test ( de grees), t h oracic   
a n d l u m bar fle xi o n (c m), t h oracic a n d l u m bar lateral fle xi o n (c m)  
 S R S 3 0 Q uesti o n naire  
 Ha n d x-ra y t o defi ne b o ne a ge 
 Cli nical P h ot os 
 C o m plicati o ns Re vie w  
  
4. 5 U nsc he d ule d Visits  
U nsc he d ule d cli nic visits will be ma de t hr o u g h t he de part me nts / h os pitals cli nical sc he d ulers. As 
part of cli nical care, p h ysical e val uati o ns a n d tests ma y be c o n d ucte d. At t hese visits, t he o nl y 
researc h pr oce d ures perf or me d will be me dical rec or d / ra dio gra p hic rec or d a bstracti o n a n d 
c o m plicati o ns re vie w.  
 
4. 6 S u bject C o m pleti o n/ Wit h dr a w al  
 
S u bjects ma y wit h dra w fr o m t he st u d y at a n y ti me wit h o ut prej u dice t o t heir care. T he y ma y als o 
be disc o nti n ue d fr o m t he st u d y at t he discreti o n of t he I n vesti gat or f or lac k of a d here nce t o st u d y 
treat me nt or visit sc he d ules, A Es, or d ue t o n o n-c o m plia nce. H o we ver, i n or der t o c ollect 
i m p orta nt st u d y-relate d data f or t his i n vesti gati o nal de vice, as m uc h as is feasi ble, t he 
I n vesti gat or will ma ke eff orts t o f oll o w- u p s u bjects w h o d o n ot strictl y a d here t o ti mel y visit 
sc he d ules. T he I n vesti gat or ma y d o t his via e mails, p h o ne calls, or letters. T he I n vesti gat or ma y 
als o wit h dra w s u bjects w h o vi olate t he st u d y pla n, or t o pr otect t he s u bject f or reas o ns of safet y 
or f or a d mi nistrati ve reas o ns. It will be d oc u me nte d w het h er or n ot eac h s u bject c o m pletes t he 
cli nical st u d y. If t he I n vesti gat or bec o mes a ware of a n y seri o us, relate d a d verse e ve nts after t he 
s u bject c o m pletes or wit h dra ws fr o m t he st u d y, t he y will be rec or de d i n t he s o urce d oc u me nts 
a n d o n t he C R F.  
 
4. 6. 1 E arl y Ter mi n ati o n St u d y Visit  
 
S u bjects t hat wit h dra w fr o m t he st u d y pri or t o st u d y c o m pleti o n will ha ve all data c ollecte d t o 
date ke pt o n file. S u bjects w h o wis h t o ha ve t heir data re m o ve d fr o m t he st u d y m ust s u b mit a 
writte n re q uest a d dresse d t o t he site’s PI. A ‘ St u d y C o m pleti o n C R F ’ will be file d f or eac h 
s u bject.  
 
 

2 9  
 
5 S T U D Y E V A L U A TI O N S A N D M E A S U R E M E N T S  
P atie nts will u n der g o st a n d ar d of c are f or a d olesce nt i di o p at hic sc oli osis bef ore rese ar c h 
pr oce d ures are i niti ate d.  
 
Ne w visit i ncl u des t he f oll o wi n g: 
 Me d ical hist or y 
 V itals 
 S ta n di n g x-ra ys (pre - o p C or o nal / Sa gittal / Be n di n g  B olster Fil m) 
C o b b a n gle ( meas ure me nt of s pi nal c ur ve) 
 H a n d x-ra y t o deter mi ne s keletal mat urit y a ge 
S a n ders sc ore ( 0 - 7) t o be use d 
    0 pre-p u bertal s keletal mat urit y  
    7 s keletal mat urit y  
 C li nical P h ot o 
 
F oll o w- u p Visit(s)  
 Me d ical hist or y 
 V itals 
 S ta n di n g x-ra ys (pre - o p C or o nal / Sa gittal Fil m) 
C o b b a n gle ( meas ure me nt of s pi nal c ur ve) 
 C li nical P h ot o 
 
 
Pr e- o p o perati ve disc ussi o n f or s ur gical i n dicati o n 
1.  Pai n  
2.  T h orac o- l u m bar ort h osis i na de q uatel y ma na gi n g c ur ve pr o gressi o n  
 
5. 1 Scree ni n g a n d M o nit ori n g E v al u ati o ns a n d Me as ure me nts  
 
5. 1. 1 Pre- o per ati ve Visit  
 
5. 1. 1. 1 Scree ni n g  
 P ote ntial s u bject i de ntifie d b y treati n g s ur ge o n ( matc h I/ E criteria, s ur gical ca n di date)  
 I nf or me d C o nse nt / Asse nt  
 Re vie w I ncl usi o n / E xcl usi o n Criteria, C o m plete I/ E C hec klist  
 S u bject Scree ni n g C R F  
 
5. 1. 1. 2 P re-o per ative Me dic al Rec or d / R a di o gr a p h Revie w  
N a me  
A g e  
R ace 
Se x  
E t h nicit y 
D ate of Birt h  
M R N  
D ia g n osis  
C li nical a n d S ur gical Hist or y (i ncl u di n g hist or y of pre g na nc y)  
R a di o gra p hic i nf or mati o n a n d re p orts (i ncl u di n g pre- o p C or o nal / Sa gittal / Be n di n g  B olster  
Fil ms; S pi ne M RI)  
C li nical p h ot os 
 P F T Data (if a vaila ble)  

3 0  
 
 
5. 1. 1. 3 Pre- o p P hysic al E x a mi n ati o n  
 Sta n di n g Hei g ht  
 Wei g ht  
 B MI – (re p orte d as %) as calc ulate d b y t he me dical rec or d  
 Tr u n k fle xi bilit y meas ure me nts (sta n dar dize d): A da m’s F or war d be n di n g test / I ncli n o meter     
    ( de grees), t h oracic a n d l u m bar fle xi o n (c m), t h oracic a n d l u m bar lateral fle xi o n (c m)  
 Data a bstracte d fr o m cli nical care e xa m ( me dical rec or ds, ra di ol o g y re p orts, p ul m o n ol o g y 
tests)  
 S R S 3 0 Q uesti o n naire  

3 1  
 
5. 1. 2 S ur gic al I nter ve nti o n a n d P ost -o per ati ve C o urse  
5. 1. 2. 1 I ntr a o per ative D at a ( a bstr acte d fr o m me dic al rec or d)  
 
 O perati ve ti me ( S ur gical Start ti me, S ur gical E n d ti me)  
 I ntra-o perati ve esti mate d bl o o d l oss  
 Bl o o d pr o d ucts utilize d: cell sa ver (cc) gi ve n, ot her tra nsf use d bl o o d pr o d ucts (cc)  
 N u m ber of p ortals  
 I m pla nt trac ki n g I nf or mati o n:  
o Bra n d a n d m o del i nf or mati o n of eac h i m pla nte d de vice  
o Part n u m ber, l ot n u m ber, a n d U DI of de vice c o m p o ne nts:  P E T c or d , set scre ws, verte br al 
scre ws, st a ples. 
o T y pe a n d size of scre ws use d  
o Le n gt h of P E T c or d use d  
 T he e xte nt of a n n ulect o m y (c o m plete or partial) a n d t he prese nce of ple ural cl os ure  
 W het her a t h orac o plast y was perf or me d will be n ote d al o n g wit h n u m ber of ri bs a n d w het her 
t he ple ura was c ut or n ot (i nter nal vs e xter nal t h orac o plast y – if use d)  
 P osteri or base d Discect o m y  
 First Assista nt i nf or mati o n  
 A nti bi otic use  
 T y pe a n d D ose of a ntifi bri n ol ytic  
 Ti me - E x p os ure of Fl o ur osc o pic X-ra y d uri n g pr oce d ure  
 T otal i ntra o perati ve ra diati o n d ose  
 
5. 1. 2. 2 P ost- s ur gic al D at a ( a bstr acte d fr o m me dic al rec or d)  
 
 C hest t u be drai na ge o n da y # 1 - # 5, a n d t otal c ollecte d  
 P ost o perati ve da y of e xt u bati o n as well as c hest t u be re m o val will be n ote d  
 P ost o perati ve da y t he patie nt was c o n verte d e ntirel y t o oral pai n me dicati o n  
 Vis ual A nal o g ue Sc ores ( meas ures t he i nte nsit y of a c hil d’s pai n e x perie nce) at disc har ge will 
be rec or de d. T his is use d t o rec or d t he a m o u nt of bac k pai n a patie nt is e x perie nci n g.  
 Da y of disc har ge will be rec or de d  
 T he use of a p ost o perati ve brace a n d t he n u m ber of m o nt hs utilize d will be rec or de d  
 C o m plicati o ns will be rec or de d: P ost- o perati ve c o m plicati o ns will be rec or de d a n d stat us will 
be u p date d u ntil res ol ve d. T his data c ollecti o n met h o d ol o g y will be sta n dar dize d via t he 
c o m plicati o n f or m i n t he patie nt’s st u d y bi n der.  
 P ost - o p Drai n: t y pe a n d drai na ge a m o u nts dail y u ntil d/c of drai n.  
 Data a bstracte d fr o m me dical rec or ds, ra di ol o g y re p orts, a n d s ur gical l o gs  
 
5. 1. 3 P O D- 4 5 a n d P O D- 9 0 F oll o w- u p  
 
5. 1. 3. 1 P ost- O per ative Visit  
 
 Me dical a n d ra di o gra p hic rec or d re vie w  
 
 Sta n di n g Hei g ht  
 Wei g ht  
 B MI  
 Tr u n k fle xi bilit y meas ure me nts (sta n dar dize d): A d a m’s F or w ar d be n di n g test ( de grees) o nl y  
 Data a bstracte d fr o m cli nical care e xa m ( me dical rec or ds, ra di ol o g y re p orts, p ul m o n ol o g y 
tests)  
 

3 2  
 
5. 1. 4 P O D- 1 8 0, P O D- 3 6 5, P O D - 7 3 0, P O D 1 0 9 5, P O D 1 4 6 0, P O D 1 8 2 5 F oll o w -u p  
 
5. 1. 4. 1 E xte n de d F oll o w- u p Visit  
 
 Me dical a n d ra di o gra p hic rec or d re vie w  
 Sta n di n g Hei g ht  
 Wei g ht  
 B MI  
 Tr u n k fle xi bilit y meas ure me nts (sta n dar dize d): A da m’s F or war d be n di n g test ( de grees), 
t h oracic 
    a n d l u m bar fle xi o n (c m), t h oracic a n d l u m bar lateral fle xi o n (c m)  
 Data a bstracte d fr o m cli nical care e xa m ( me dical rec or ds, ra di ol o g y re p orts, p ul m o n ol o g y 
tests)  
 Cli nical p h ot os f or all of t he e xte n de d f oll o w -u p visits e xce pt P O D - 1 8 0 
 S R S 3 0 Q uesti o n naire  
 
5. 1. 5 L a b or at or y E v al u ati o ns  
 
5. 1. 5. 1 Pre g n a ncy Testi n g: Perf or me d at Pre- o p Visit o nly  
 
A uri ne  or bl o o d pre g na nc y test will be perf or me d f or fe male s u bjects ol der t ha n 1 1 years of a ge, 
or a n y fe male w h o has be g u n me nses will be re q uire d t o c o m plete a uri ne or bl o o d  sa m ple 
pre g na nc y test. Res ults of s uc h testi n g will be pr o vi de d t o t he st u d y partici pa nt, u nless it is 
deter mi ne d t hat s he is u na ble t o u n dersta n d t he si g nifica nce or i m plicati o ns of a p ositi ve test 
res ult. I n t his case, t he pare nt (s) will be i nf or me d of t he p ositi ve res ult. I n t he e ve nt of 
pre g na nc y, t he partici pa nt will n ot recei ve t he st u d y i n ter ve nti o n. Partici pa nts w h o are f o u n d t o 
be pre g na nt will be a d vise d t o c o ntact fa mil y pla n ni n g c o u nseli n g ser vices.  
 
5. 1. 6 Ot her E v al u ati o ns, Me as ures  
 
 Sa n ders B o ne A ge: Attac he d as S u p ple me nt 1  
 A da m’s F or war d Be n di n g Test: S u bject sta n ds wit h t heir bac k t o t he e xa mi ner, a n d be n ds 
f or war d at t he waist, wit h k nees i n e xte nsi o n. T he e xa mi ner l o o ks at t he h oriz o ntal pla ne of t he 
s pi ne, a n d meas ures a n gle create d bet wee n a ri b h u m p a n d t he h oriz o ntal pla ne. T his is 
meas ure d wit h a n i ncli n o meter.  
 T h oracic/ L u m bar Fle xi o n test: S u bject sta n ds wit h tr u n k erect w hile meas uri n g ta pe is place d 
pr o xi mall y o n t he s pi n o us pr ocess of C 7 a n d distall y t o S 1. T he s u bject t he n be n ds f or war d at 
t he waist, wit h k nees i n e xte nsi o n. F oll o wi n g fle xi o n of t he verte brae, usi n g t he sa me b o n y 
la n d mar ks, t he e xa mi ner calc ulates t he differe nce i n dista nce bet wee n t he starti n g a n d e n di n g 
p ositi o ns.  
 T h oracic/ L u m bar Lateral Fle xi o n test: S u bject sta n ds erect wit h t he feet flat o n t he fl o or. Place 
o ne e n d of a meas uri n g ta pe o n t he ti p of t he mi d dle fi n ger a n d t he ot her o n t he fl o or o n a 
p oi nt directl y be neat h t he mi d dle fi n ger. T he patie nt t he n laterall y fle xes t heir tr u n k. T he 
differe nce f oll o wi n g t he lateral fle xi o n m oti o n is meas ure d.  
 S R S 3 0: Attac he d as S u p ple me nt 2  
 
5. 2 S afet y E v al u ati o n  
 
S u bject safet y will be m o nit ore d b y rec or di n g all A Es a n d S A Es, a n d will be rec or de d o n t he 
c o m plicati o n f or m i n t he patie nt’s st u d y bi n der. T he e val uati o n of safet y is a pri mar y o bjecti ve of 

33 
 
this research study. There will be a clear classification of “device-related” adverse events. 
Device-related adverse events are those events directly related to the integrity, safety, or 
biomechanics of the device components: PET cord, staples, set screws and vertebral screws. 
This can include variables like device breakage or device migration. Other adverse events which 
are considered not device-related are those that are related to the act of surgery and medical 
recovery. The type of events will be documented on the CRF.  
 
5.3 Efficacy Evaluation  
 
The mode of efficacy evaluation for this procedure will be measurement of Cobb Angle. Cobb 
Angle is a coronal plane radiographic measurement of curvature of the spine. This angle will be 
recorded for the pre-operative coronal spine radiograph, as well as all subsequent serial 
radiographs. The change in Cobb angle (reduction) will be the primary evaluator of efficacy. 
‘Overall study success’ of the intervention will be defined by a final Cobb angle of less than or 
equal to 50 degrees by the time subject reaches skeletal maturity.  
 
 

34 
 
6 STATISTICAL CONSIDERATIONS  
6.1 Primary Endpoint  
 
The primary endpoint is the rate of Adverse Events/SAEs in Anterior VBT Surgery.  
 
6.2 Secondary Endpoints  
 
The secondary endpoint is change in post-operative Cobb angle compared to pre-operative Cobb 
angle, measured on coronal radiograph of the spine.  
 
6.3 Statistical Methods  
 
6.3.1 Baseline Data  
Baseline and demographic characteristics will be summarized by standard descriptive summaries 
(e.g. means and standard deviations for continuous variables such as age and percentages for 
categorical variables such as gender). Categorical data analysis methods such as chi-square will 
be used for dichotomous variables and repeated measures Anova or t-test for continuous data 
(such as differences in Cobb angle). Logistic regression analysis will be conducted to analyze 
various factors associated with adverse events in anterior tethering surgical procedure.  
 
6.3.2 Safety Analysis  
 
The safety endpoint will be factors associated with the adverse events in patients that have 
undergone Anterior VBT Surgery. Variable reporting for adverse event will be dichotomous. 
Descriptive statistics will be used to report number and type of adverse events. Further, chi-
square or fisher-exact test analysis will be used to identify variables that correlate with adverse 
events following anterior tethering surgery. Further, logistic regression will be conducted to 
clarify which variables are associated with adverse outcomes. Odds ratio along with confidence 
intervals will be reported.  
 
All subjects will begin the safety analysis at Study Day 0 (day of surgery). Intraoperative and 
post-intervention medical events or signs and symptoms of the complications arising after the 
start of study intervention will be captured using list of common events associated with Anterior 
VBT Surgery. Adverse signs, symptoms, and/or laboratory abnormalities already existing prior to 
the baseline visit will be captured in the medical history assessment.  
The date of onset, severity, and end date (if relevant) will be documented.  
 
Medical events resulting from any procedure performed in the study will be collected as adverse 
events (AEs). The event description, date of onset, end date, severity, and outcome will be 
documented for the study-related AEs. The frequencies of AEs by type, body system, severity 
and relationship to study intervention will be summarized. SAEs (if any) will be described in 
detail. A distinction will be made between those AE/SAEs which are “device-related”, those 
which are “not device-related”, and those which are “uncertain to be related”. “Device-related” 
complications will include any events directly related to the integrity, safety, or biomechanics of 
the PET cord. Device-related AE incidence will be summarized along with the corresponding 
exact binomial 95% two-sided confidence intervals. 22  
 

3 5  
 
6. 3. 3 Effic ac y A n al ysis  
 
T he pri mar y a nal ysis will be base d o n a n i nte nti o n t o treat a p pr oac h a n d will i ncl u de all s u bjects 
w h o ha ve u n der g o ne t he i nter ve nti o n.  
 
T he e n d p oi nt use d f or efficac y will be c ha n ge i n p ost- o perati ve C o b b a n gle c o m pare d t o pre-
o perati ve C o b b a n gle, meas ure d o n c or o nal ra di o gra p h of t he s pi ne. C o nsi deri n g c ha n ge i n C o b b 
a n gle is a c o nti n u o us varia ble, re peate d meas ures An o va or t-test will be use d t o detect a n y 
c ha n ge i n C o b b a n gle p ost- o perati vel y. Li near re gressi o n will be utilize d t o assess w hic h 
varia bles are ass ociate d wit h c ha n ge i n p ost -o perati ve C o b b a n gle.  
 
6. 4 S a m ple Size a n d P o wer  
 
T he p ur p ose of t his st u d y is t o l o n git u di nall y f oll o w a c o h ort of patie nts treate d wit h a n o vel use 
of a n i m pla nt, t o e x pl ore safet y a n d efficac y of t he i m pla nt. T he re g ulat or y stat us of s uc h a n 
i m pla nt re q uires t hat we o btai n a n I D E. T here is n o c o m parative gr o u p a n d t h us n o effect size or 
p o wer a nal ysis ass ociate d wit h t he w or k.  
 
6. 5 I nteri m A n al ysis  
 
T he st u d y tea m will perf or m i nteri m a nal yses base d o n t he st o p pi n g r ules liste d i n secti o n 6. 6 
( bel o w). If a n y of t hese r ules are met, t he st u d y will halt e nr oll me nt u ntil a p pr o priate meas ures 
ca n be p ut i n place t o re d uce patie nt ris k. All re p orti n g of A E/ S A Es d uri n g t he st u d y will a d here 
t o t he g ui deli nes i n Secti o n 8 ( Safet y Ma na ge me nt).  
 
6. 6 St o p pi n g R ules  
 
T he st o p pi n g r ules f or t his st u d y will be base d o n t he pre vale nce of S A Es. T here is s pecial 
c o nsi derati o n gi ve n t o S A Es t hat are f o u n d t o be “ de vice-relate d”, as o utli ne d bel o w.  
 
6. 6. 1 St o p pi n g r ules f or a n y S A E rel ate d t o t he st u d y pr oce d ure (s ur ger y)  
 
 S A E i n all of t he first 5 patie nts or  
 S A E i n 7 of first 1 0 patie nts or  
 S A E i n > 5 0 % of patie nts after 2 0 cases  
 
6. 6. 2 S t o p pi n g r ules f or S A Es t h at are de vice-rel ate d  
 
Defi niti o n of Ter ms:  
 Scre w fail ure – scre w a n d/ or ce nteri n g sta ple ha ve l o ose ne d fr o m t he verte bra A N D re q uire re-
o perati o n  
 Tet her fail ure – t he tet her has br o ke n or l ost te nsi o n. Dia g n ose d at a n y ti me p oi nt after 3 
m o nt hs b y i ncrease d a n g ulati o n at a disc s pace o n sta n di n g P A or i ncrease i n disc we d gi n g o n 
si de be n di n g x-ra y t o t he si de a wa y fr o m t he i m pla nt. Als o, it is o nl y a n S A E if n ot e d bef ore 
mat urit y A N D o verall C o b b w orse ns c o m pare d t o t he first erect meas ure me nt  
 I m pla nt re- o perati o n - a n y pr o ble m wit h t he i m pla nt t hat re q uires re -o perati o n i ncl u di n g re -
o perati o n f or o verc orrecti o n wit h a n y of t he f oll o wi n g: a re m o val of all or part of t he i m pla nt, 
l o ose ni n g of t he te nsi o n o n t he i m pla nt, or s pi nal f usi o n.  

3 6  
 
St o p pi n g P oi nts  
 Scre w fail ure st o p pi n g p oi nt: 3 of first 5 cases, 5 of first 1 0, or 2 5 % of patie nts be y o n d 2 0 
cases  
 Tet her fail ure st o p pi n g p oi nt: 3 of first 5 cases, 5 of first 1 0, or 2 5 % of patie nts be y o n d 2 0 
cases  
 I m pla nt fail ure re- o perati o n st o p pi n g p oi nt: occ urs i n 4 of first 5 cases or greater t ha n 5 0 % of 
cases be y o n d 1 0 cases  
 
 

37 
 
7 STUDY DEVICE  
7.1 Description  
 
The device is the use of Polyethylene Terephthalate (PET) cord with pedicle screws and staples 
for vertebral body tethering. The PET cord is part of a 510k-cleared implant system distributed by 
Globus Medical, Inc. called the Reflect/Transition™ Stabilization System. The pedicle screws 
and staples are part of a 510k-cleared implant system distributed by Globus Medical, Inc. called 
the CREO™ Stabilization System. Both systems are classified as Class II under 21 CFR 
888.3070, and are manufactured and distributed according to manufacturer guidelines and in 
compliance with 21 CRF 820. The combined use of screws, staples, and Polyethylene 
Terephthalate cord for vertebral body tethering is investigational. 
 
The entire system is supplied at Nemours as part of routine surgical treatment. The system 
supplied also includes hydroxyapatite-coated titanium alloy Ti6Al4V (ASTM F136) or alloy 
Ti6Al4Nb (ASTM F1295) pedicle screws, polycarbonate urethane spacers and bumpers, titanium 
alloy spools, end spools, and set screw ends. The only article being used from this system is 
the PET cord. The rest of the system will be discarded according to the appropriate NEMOURS 
Operation Room policies and procedures.  
 
7.2 Packaging  
 
The device is part of a commercially marketed system from Globus Medical, Inc. As such, the 
device is packaged according to manufacturer guidelines and in compliance with 21 CFR 
820.130.  
 
7.3 Labeling  
 
The device is part of a commercially marketed system from Globus Medical, Inc. As such the 
device will be labeled according to manufacturer guidelines and in compliance with 21 CFR 801.  
Specific device label parameters will be tracked by the study team to comply with FDA standards 
for investigational device tracking. Those parameters include:  
 
o Manufacturer of device  
o Model name of device  
o Device Part Number  
o Device Lot Number  
o Unique Device Identification (UDI)  
o Length of PET cord used  
 
All parts of the tethering system (vertebral screws, set screws, staples and PET cord) will be 
labeled and tracked in the same manner. 
 
 

3 8  
 
8 S A F E T Y M A N A G E M E N T  
8. 1  Cli nic al A d verse E ve nts  
 
Cli nical a d verse e ve nts ( A Es) will be m o nit ore d t hr o u g h o ut t he st u d y.  
 
8. 2  A d verse E ve nt Re p orti n g  
 
U na ntici pate d pr o ble ms relate d t o t he researc h i n v ol vi n g ris ks t o s u bjects or ot hers t hat occ ur 
d uri n g t he c o urse of t his st u d y (i ncl u di n g S A Es) will be re p orte d t o t he I R B i n acc or da nce wit h 
Ne m o urs  I R B S O P 4 0 8: U na ntici pate d Pr o ble ms I n v ol vi n g Ris ks t o S u bjects. A Es t hat are n ot 
seri o us b ut t hat are n ota ble a n d c o ul d i n v ol ve ris ks t o s u bjects will be s u m marize d i n narrati ve or 
ot her f or mat a n d s u b mitte d t o t he I R B at t he ti me of c o nti n ui n g re vie w.  
 
8. 3  Defi niti o n of a n A d verse E ve nt  
 
A n a d verse e ve nt is a n y u nt o war d me dical occ urre nce i n a s u bject w h o has recei ve d a n 
i nter ve nti o n ( dr u g, bi ol o gic, or ot her i nter ve nti o n). T he occ urre nce d oes n ot necessaril y ha ve t o 
ha ve a ca usal relati o ns hi p wit h t he treat me nt. A n A E ca n t heref ore be a n y  u nfa v ora ble or 
u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g, f or e xa m ple), s y m pt o m, or disease 
te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot c o nsi dere d relate d t o 
t he me dici nal pr o d uct.  
We will use t he Cla vie n - Di n d o Classificati o n s yste m [ 4 7], as well as t he C o m pre he nsi ve 
C o m plicati o n I n de x ( base d off of t he Cla vie n- Di n d o s yste m) [ 4 8] t o classif y a n d a nal yze patie nt 
a d verse e ve nts. Gr a de I a n d Gr a de II e ve nts will be c o nsi dere d A Es. ( See A p pe n di x 1 f or 
cl assific ati o n t a ble)  
 
8. 4 Defi niti o n of a Seri o us A d verse E ve nt ( S A E)  
 
A n S A E is a n y a d verse e ve nt t hat res ults i n a n y of t he f oll o wi n g o utc o mes:  
 deat h,  
 a life-t hreate ni n g e ve nt (at ris k of deat h at t he ti me of t he e ve nt),  
 re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n,  
 a persiste nt or si g nifica nt disa bilit y/i nca pacit y, or  
 a c o n ge nital a n o mal y/ birt h defect i n t he offs pri n g of a s u bject.  
 
Im p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life -t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d a seri o us a d verse e ve nt w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n.  
 
A disti ncti o n s h o ul d be dra w n bet wee n seri o us a n d se vere A Es. A se vere A E is a maj or e ve nt of 
its t y pe. A se vere A E d oes n ot necessaril y nee d t o be c o nsi dere d seri o us. F or e xa m ple, na usea 
w hic h persists f or se veral h o urs ma y be c o nsi dere d se vere na u sea, b ut  
 

39 
 
would not be considered serious. On the other hand, a stroke that results in only a limited degree 
of disability may be considered a mild stroke, but would be considered serious.  
We will use the Clavien-Dindo Classification system [47], as well as the Comprehensive 
Complication Index (based off of the Clavien-Dindo system) [48] to classify and analyze patient 
adverse events. Grade III (a/b), Grade IV (a/b), and Grade V events will be considered 
SAEs. (See Appendix 1 for classification table)  
 
8.4.1 Relationship of AE/SAE to study intervention or device  
 
The relationship of each Event to the study intervention should be characterized using one of the 
following terms in accordance with NEMOURS IRB Guidelines: definitely, probably, possibly, 
unlikely or unrelated. In this case, the “study intervention” in considered to be the surgical 
intervention and implantation of the medical device (Anterior vertebral body tethering surgery 
under general anesthesia with spinal cord monitoring). This includes (but is not limited to) 
induction of anesthesia, incision and surgical approach, device implantation, and recovery. For 
each SAE, the PI and Safety Officer will make a case-by-case determination on the 
relationship of the SAE to the study procedure, which will be documented in the study 
documents.  
 
There will be further classification of the Event as either “device-related”, “not device-related”, 
or “uncertain to be device-related”. Device-related adverse events are those events directly related 
to the integrity, safety, or biomechanics of the implanted device. This can include variables like 
device breakage or device migration. Other adverse events which are considered not device-
related are those that are related to the act of the surgery and medical recovery (anesthesia, 
incision and surgical approach, post-operative recovery, etc.). This distinction will be indicated in 
the study documents. For each Event, the PI and Safety Officer will make a case-by-case 
determination on whether the Event is “device related”, “not device related”, or 
“uncertain”. An event which is classified as “device related” will be considered an Adverse 
Device Effect. Adverse device effects have special reporting guidelines, as outlined below.  
 
8.4 Recording plan for AE / SAEs  
 
Surgery and Post-operative Phase (Day 0 – POD 90):  
For these phases, all AEs (including SAEs) will be noted in the study records and reported per 
IRB and FDA requirements outlined below. The subjects will be encouraged to contact the office 
with any concerns, and the medical record will be monitored by study staff for indications of 
AEs.  
Extended Follow-up Phase (POD 91-POD 1825):  
For this phase, all SAEs will be recorded (regardless of cause). Only AEs which are deemed 
“device related” will be recorded on study documents and reported per IRB and FDA 
requirements outlined below. The subjects will still be encouraged to contact the office with any 
concerns, and the medical record will be monitored by study staff for indications of SAEs or 
device-related AEs.  
 

40 
 
Only the AE/SAEs indicated above will be recorded in a patient-specific study binder, kept in the 
secure Orthopedics research office. The binder will contain a full description of the event, 
including the nature, date and time of onset, determination of non-serious versus serious, intensity 
(mild, moderate, severe), duration, causality, and outcome of the event. Hard copies of the 
primary documents (medical record notes) describing the event and any associated treatment will 
be printed and kept in the patient-specific study binder. A redundant copy of adverse events will 
be kept in the study REDCap database and will be maintained by the study team separately from 
the patient-specific study binder. The study binder will serve as the official record of all Events.  
 
8.6 IRB/IEC Notification of SAEs and Other Unanticipated Problems  
The Investigator will promptly notify the IRB of all on-site unanticipated, serious Adverse Events 
that are related to the research activity. Other unanticipated problems related to the research 
involving risk to subjects or others will also be reported promptly. Written reports will be filed 
using the eIRB system and in accordance with the timeline below. External SAEs that are both 
unexpected and related to the study intervention will be reported promptly after the investigator 
receives the report. External events that do not change the risk to subjects or result in a change to 
the research protocol will be reported to the IRB following IRB recommendations. 
REPORTING REQUIREMENTS TO THE IRB 
 
Type of Unanticipated 
Problem  
Initial Notification (Phone, 
Email, Fax)  
 
Written Report  
Internal (on-site) SAEs Death 
or Life Threatening  
24 hours  
Within 2 calendar days  
 
Internal (on-site) SAEs All 
other SAEs  
 
7 days  
 
Within 7 business days  
 
Unanticipated Problems 
Related to Research  
 
7 days  
 
Within 7 business days  
 
All other AEs  
 
N/A  
 
Brief Summary of important 
AEs may be reported at time 
of continuing review  
 
8.4.1 Follow-up report  
 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant new 
or reassessed information (e.g., concomitant medication, medical history) should be submitted to 
the IRB. The investigator is responsible for ensuring that all SAE are followed until either 
resolved or stable. 
 
 
 
8.7 Investigator Reporting Requirements to IRB, FDA, and Sponsor  

41 
 
 
INVESTIGATOR REPORTING TO THE FDA / DEVICE MANUFACTURER 
Type of Report  
Description of 
Report  
 
Submit to:  
Timeline  
Unanticipated 
Adverse Device 
Effects  
Report of any 
unanticipated adverse 
device effect  
IRB and FDA  
Within 10 working 
days after investigator 
first leans of effect.  
 
Withdrawal of IRB 
approval  
 
If IRB withdrawn 
from study site  
 
Sponsor  
 
Within 5 working 
days  
 
Progress Report  
 
FDA Form 3419  
 
IRB, FDA, Sponsor  
 
Regular intervals, no 
less than yearly  
 
Deviations from the 
investigational plan  
 
If deviation of 
investigational plan 
occurred in order to 
protect subject’s life 
or physical well-
being (i.e. during an 
emergency)  
 
IRB, Sponsor  
 
Within 5 working 
days  
 
Informed Consent  
 
If investigator used 
device without 
obtaining informed 
consent  
 
IRB, Sponsor  
 
Within 5 working 
days  
 
Final Report  
 
Complete and final 
investigative report  
 
IRB, Sponsor  
 
Within 3 months of 
study completion or 
study termination  
 
Other Reports  
 
Any access or reports 
on request  
 
IRB, FDA  
 
Per request  
 
Voluntary Reports  
 
At discretion of 
investigator.  
 
Voluntary adverse 
event reporting is 
done through Form 
3500A.  
 
IRB, FDA  
 
As deemed by 
investigator  
 
 
 
8.8 Sponsor Reporting Requirements to FDA and IRB 
SPONSOR REPORTING TO THE IRB / FDA 
 
Type of Report  
Description of Report  
 
Submit to:  
Timeline  

42 
 
Unanticipated Adverse 
Device Effects  
Report of any 
unanticipated adverse 
device effect  
FDA and reviewing 
IRB(s)  
Within 10 working days 
after sponsor first 
receives notice. May 
submit further reports at 
FDA requests  
 
Withdrawal of IRB 
approval  
If IRB withdraws 
approval of 
investigation or part of 
the investigation  
FDA and reviewing 
IRB(s) and participating 
investigators  
 
Within 5 working days 
of receipt of notice  
Withdrawal of FDA 
approval  
If FDA withdraws 
approval  
Reviewing IRB(s) and 
participating 
investigators  
Within 5 working days 
of receipt of notice  
 
Current Investigator 
List  
Current list of names 
and addresses of all 
participating 
investigators  
 
FDA  
6 month intervals  
Progress Report  
FDA Form 3419  
FDA and reviewing 
IRB(s)  
Regular intervals, no 
less than yearly  
 
Recall and Device 
Disposition  
If Sponsor requests 
return, repair, or 
disposal of device, and 
why  
 
FDA and reviewing 
IRB(s)  
Within 30 working days 
after request is made  
Final Report  
Complete and final 
investigative report  
FDA and reviewing 
IRB(s)  
 
1. Notify FDA within 30 
working days  
2. Submit final report to 
FDA and IRBs within 6 
months  
 
Informed Consent  
If investigator used 
device without 
obtaining informed 
consent 
FDA  
Within 5 working days 
of receipt of notice  
                                      
Significant risk device 
determination  
IRB determination of 
significant risk of the 
medical device  
FDA  
Within 5 working days 
of receipt of notice of 
the determination  
 
Other  
Any access or reports 
on request  
FDA and reviewing 
IRB(s)  
Per request  
 
 
8.9 Medical Emergencies  
 

43 
 
If a medical emergency occurs in the hospital system, it will be reported following the above 
guidelines and timeline. If no emergencies are identified through chart review, subjects will be 
asked at designated follow-up if they have sought medical care for any reason between research 
visits. Any events will be reported through the above policies and procedures. Subjects who 
contact the study team or clinical offices regarding a medical emergency will be referred to the 
appropriate health care professional to manage their emergency, and contact will be documented 
in the medical record. 
 
 

44 
 
9 STUDY ADMINISTRATION  
9.1 Data Collection and Management  
 
1. Confidentiality:  
A master list will be maintained separately from the coded data collection sheet and will contain 
the subject ID number, name, MRN, date of birth and dates of service. The list will be password-
protected so that only the study staff will have access. Data will be collected on each subject 
using the subject’s Study ID number. Data will be managed and stored using the research-focused 
electronic data capture system REDCap, under an agreement with the software’s development 
consortium, led by Vanderbilt University. REDCap supports two secure, web-based applications 
designed exclusively to support data capture for research studies. REDCap is a PHP web 
application served by Apache Tomcat over a 128-bit SSL connection using a signed certificate. 
The application relies on a study-specific data dictionary defined in an iterative self-documenting 
process that will be conducted by all members of the research team. The data dictionary is the 
foundation for custom case report form design and validated coding of variables. Authentication 
of research staff will be performed via LDAP using Nemours’s enterprise Active Directory 
service. The application generates a complete audit trail of user activity, provides reporting, and 
has an automated export mechanism to common statistical packages (SAS, SPSS, Stata, R/S-
Plus).  
A patient-specific study binder will be kept for each enrolled patient. The study binder will 
contain adverse event information, as well as signed consent forms and paper forms collected 
during testing, as well as all relevant documentation. These will be stored in a locked research 
office.  
 
2. Security:  
 
The master sheet will be a password protected excel file kept in the secure orthopedic research 
drive at each institution. The REDCap MySQL database is replicated in real time to a completely 
redundant instance of MySQL. The redundant instance is available for restoration of the primary 
database or for manual failover in the case of primary database failure. Time-stamped backup 
files are made from the replicated database daily by NEMOURS Research Information Systems 
using automated backup routines. Backup files are encrypted and transferred to a secure file 
server accessible only to designated personnel. A rolling seven-day window of backup files is 
maintained in an immediately available online state, with a larger window maintained in a 
compressed file archive available at a reduced speed of access. Daily destructive database backup 
files are stored on the database server and are deleted only after successful backup of the entire 
database to file. In the event of data error, loss or corruption, Research personnel will work with 
Nemours Research Information Systems to determine the most appropriate recovery strategy. 
Data and backups are stored in the NEMOURS Research Information Systems Storage Area 
Network (SAN). Access to the SAN directories where data are stored will be limited to Research 
Information Systems personnel, with authentication performed using NEMOURS’s enterprise 
Active Directory service. The data from the application will be compiled on a secured survey web 
platform that is encrypted using AES 256 bit encryption. The data collected on paper forms 
during testing will be secured in the patient-specific study binders in a locked research office.  
 
 
 
3. Anonymization, de-identification or destruction:  
 
Data will be collected on each subject using the subject’s Study ID number. Study personnel will 
store a list connecting the subject’s PHI to study ID. All PHI collected from this study (master 

45 
 
sheet) will be destroyed 6 years after study closure. All other de-identified data will be retained 
for 6 years following study closure.  
 
9.2 Confidentiality  
 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy and that the Investigator and other site 
personnel will not use such data and records for any purpose other than conducting the study.  
No identifiable data will be used for a future study without first obtaining IRB approval.  
 
9.3 Regulatory and Ethical Considerations  
 
9.3.1 Data and Safety Monitoring Plan  
 
The PI will monitor data and safety throughout the duration of the study and will report any 
adverse events in accordance with IRB policies. The PI, Safety Monitor, and study team will 
perform interim safety analyses as outlined in Section 6.6. Safety monitoring will be handled 
internally by the study Safety Monitor and NEMOURS Office of Research Compliance (ORC). 
We will also submit reports to the FDA, device manufacturer, or both as per medical device 
reporting requirements specified in 21CFR803.  
 
9.3.2 Risk Assessment  
 
This section outlines risks associated with the study procedures.  
 
9.3.2.1 Surgical Procedure: Anterior-approach thoracoscopic vertebral body tethering (greater 
than minimal risk)  
 
1. Investigational devise risks: 
Implant failure (tether breakage, lost tension, screw pullout, screw fracture) overcorrection of 
curve, failure of correction, progression of curve and need for conversion to spinal fusion. 
Reoperation for any of the above listed reasons.  
 
 
2. Anesthesia Risks:  
Anesthesia effects alone or with the effects of surgery can be life threatening. Injury to 
the eyes, lips, teeth, nerves and/or spinal cord, increased or decreased blood pressure, 
irregular heartbeat, abnormal reaction to anesthesia agents. Some other known risk, side 
effects and potential complications include nausea and vomiting after surgery, excessive 
bleeding requiring blood transfusions. There are certain (very rare) risks of anesthesia 
including stroke, blindness, and long-term learning disability, which are unpredictable, not 
well understood and still being studied by doctors.  
 
3. Surgery Risks: 
Infection, bleeding, allergic reaction, significant scarring, need for additional     surgery, 
and even death or disability. Some other known risks, side effects and potential complications 
include neurological deficit, visceral, or vessel injury, blindness, need for transfusion of 

46 
 
blood products, back pain, pulmonary insufficiency, pain and unforeseen medical 
complications. Risks associated with radiation exposure from fluoroscopy and X-rays. 
 
4. Spine surgery risks:   
Implant malposition, implant failure (rod breakage, screw pullout, screw fracture), 
progression of curve above or below corrected spinal region, pseudoarthrosis (non-union), 
need for additional surgery, vertebral body damage, paralysis, and allergic reaction to 
implants. Reoperation for any of the above listed reasons. 
 
 
 
 
It should be noted that the above risks are the same risks that are present for standard-of-care 
surgery for spinal surgery. All appropriate clinical care procedures and pathways followed for 
standard-of-care spine surgeries will take place for these subjects.  
 
9.3.2.2  Other Potential Risks (No greater than minimal risk study procedures):  
 
• 
Review of medical records: There is a risk of breach of confidentiality and privacy as a 
result of medical record review. This risk is minimized as detailed in Section 9.  
• 
Administration of questionnaires: The questionnaires have the potential to make subjects 
feel uncomfortable.  
• 
Reproductive Risks: 
Girls deciding whether or not to be in this study may already have started having periods 
or may begin having periods while they are in this study.  Therefore, we need to tell you 
some important facts.  We often do not know the effects of research procedures (such as 
drugs or tests) on unborn babies.  Your child should not plan to become pregnant while 
participating in this study.  If sexually active, your child should use effective birth control 
to prevent pregnancy while participating in this study.  As appropriate, the study doctor 
will discuss issues of possible sexual activity and use of effective birth control privately 
with your child.  
 
Nemours have the following mitigation strategies in place to minimize the risks listed above: 
    1. Investigational device risks  
Your Nemours surgeon is highly experienced with vertebral body tethering technique and will 
employ his knowledge and skills to prevent any risk associated with the investigational device.  
 
2. Anesthesia risks 
To minimize the possibility of the all anesthesia related risks, the patient will undergo a pre-
operative evaluation by the Anesthesia team. You and your child will have an opportunity to 
discuss these risks with the anesthesiologist. 
3.Surgery risks 
Nemours Orthopedic surgeons and surgeon’s assistants are American Orthopedic board certified 
doctors who strive to minimize all type of risks. To minimize the surgery risk and the risk of 

47 
 
infection on particular all Nemours Standard Operating procedure regarding sterile procedures 
and institutional policies on infection prevention will be followed to prevent infection. The 
patient will be placed on Nemours Orthopedics Standard Operating Procedure for pre- and post-
operative antibiotic regimen for spine surgery patients.  
To minimize the bleeding every reasonable effort will be made by the surgical staff to reduce 
blood loss. Expected Blood Loss during surgery will be recorded on the clinical research form. 
To reduce the need of banked blood transfusion Cell Saver machine will be used to filter lost 
patient’s blood and transfuse back to the patient.  
To reduce and minimize the pain levels, Nemours pain team will be consulted for pain 
management in the time following the surgery, to best manage post-operative pain.  
To monitor for surgery risks related to neurology there will an Intra-operative Neuromonitoring 
in the Operating room. After surgery, the patient will be monitored for pneumothorax by inpatient 
hospital staff. If a pneumothorax is found, it may cause elongation of the patient’s hospital stay, 
or require medical / surgical intervention. After surgery, the patient will be monitored for 
presence of a bronchopulmonary plug by inpatient hospital staff. If a bronchopulmonary plug is 
found, it may cause elongation of the patient’s hospital stay, or require a medical / surgical 
intervention.  Nemours uses low dose x-ray machine for all spinal x-rays to reduce the amount of 
radiation patient receives. The widely-accepted ALARA (as low as reasonably acceptable) 
principle will be used to ensure surgeons are imparting the lowest radiographic dose possible onto 
the patient during fluoroscopy. 
     4. Spine surgery risks 
Your Nemours surgeon- Suken Shah, MD- is a pediatric spine surgeon who performs an average 
of 50 spine surgeries per year. His assistants are clinical fellows who are board certified 
orthopedic surgeons. They will use their knowledge and skills to eliminate or minimize any of the 
surgery related risks. 
 
    5. Other Potential Risks 9.3.2.2 (No greater than minimal risk study procedures) 
 
• 
Nemours make all efforts to protect patient’s privacy. Study data are stored in locked 
cabinets and password protected computers. 
• 
Subjects will be allowed to skip questions which they are not comfortable answering   
without compromising their participation in the study.  
• 
Because girls can become pregnant even when using birth control, we will be doing 
pregnancy tests during the study.  The results of any pregnancy test done during the study 
will be made available only to your child.  By law, all minors have a right to confidentiality 
when discussing issues of pregnancy and birth control with a doctor.  This information will 
be discussed with you only if your child agrees.  If there is any chance that pregnancy could 
have occurred during the study, the study doctors must be told immediately.  Anyone who 
is pregnant may be taken out of the study right away.  You and your daughter should be 
aware that, if this happens, others are likely to realize that she is pregnant.  We encourage 
open honest communication between parents and their children regarding issues of sexual 
activity and possible pregnancy.  It is also important for you to let the study doctor know 
if a young girl starts having periods during this study so that appropriate precautions can 
be taken from that point onward. 
 
 
 

48 
 
 
9.3.3 Potential Benefits of Trial Participation  
 
There is some direct benefit to trial participation. First, studies have shown that there is a lower 
surgical risk in anterior-approach spine surgery compared to the posterior approach [19].  
Vertebral Body Tethering has the theoretical potential for improvement over the outcomes of 
posterior spinal fusion. In particular, the durability of the posterior spinal fusion is coming into 
question. Posterior pedicle screw constructs came into popularity in the early 2000’s and new 10 
year post-op data is demonstrating a concerning trend. The Harms Study Group, a multicenter 
consortium of scoliosis practitioners and researchers have recently shown that almost 10% of AIS 
fusions require revision surgery by 10 year post-op and that this trend is progressive [28]. Other 
authors have also reported on high long term re-operation rates following AIS fusion surgery 
ranging from 4.6% to 19% [29-31]. One theory is that a fusion imparts increased stress on 
unfused segments below a fusion. Marks et al. have shown that patients will retain total lumbar 
motion after a posterior spinal fusion by increasing motion in the unfused areas [32]. The authors 
postulate that increased motion may lead to degeneration of discs and facet joints. These findings 
of supraphysiologic motion below a posterior spinal fusion may explain some of the decreasing 
durability of posterior spine fusion. Green et al. have studied the health of intervertebral discs 
below a spinal fusion at an average of 11.8 years following posterior spinal fusion [33]. The 
authors found that disc degeneration was occurring in 85% of patients and the discs when graded 
by the Firman scale, an objective validated measure of disc degeneration, demonstrated an 
average decrease from 1.1 pre-op to 1.8. Vertebral tether surgery will allow for continued motion 
of the instrumented levels and thus avoid the long lever-arm effect of a long fusion that may be 
contributing to early degeneration. Additional reports have questioned the durability of posterior 
spinal fusion. Upasani et al. reported on increased pain in patients at 5 years post-spinal fusion 
compared to at 2 years [34]. Lastly, posterior spinal fusion in patients who have not had their 
pubertal growth spurt, the population in whom we are proposing vertebral tethering, are at 
increased risk of complications and re-operation. Sponseller et al. reported that patients with open 
triradiate cartilages undergoing spinal fusion surgery have an increased rate of adding on 
(development of deformity below a fusion) and the response of the un-instrumented lumbar curve 
is less predictable [35].  
 
The basic science literature suggests that this study intervention has the potential benefit to 
preserve motion of the spine in long-term follow-up, compared to traditional PSF [37-39].  
 
Indirectly, participation in this trial will benefit the scientific community as a whole. Results from 
this trial will guide standard practice in a novel approach to spinal surgery in the pediatric 
population.  
 
9.3.4 Risk-Benefit Assessment  
 
The known risks and direct (and indirect) benefits will be presented to the patients by the 
investigators without bias. The investigators believe that benefits outweigh the risks based on all 
current knowledge and literature on the subject.  
 
9.4 Recruitment Strategy  
 
Subjects will be recruited by the investigator and clinical staff of the Orthopedic Clinic. Potential 
subjects who may satisfy the inclusion / exclusion criteria will be identified by the clinic staff, 
and will contact a study team member. The study team member will use the “Screening CRF” to 
assess preliminarily whether a potential subject may meet I/E criteria. Then, the study team 

49 
 
member will confer with the PI and/or investigators to determine whether the patient should be 
approached to offer the clinical trial to the subject and family. Potentially eligible patients will 
then be approached for informed consent/assent.  
 
9.5 Informed Consent/Assent and HIPAA Authorization  
 
Eligible patients will then undergo consent / assent during their orthopedic visit. This will take 
place in a private exam room in the clinic. The study will be explained to the patients / families 
and they can decide whether to participate in the study. Subjects and their families will be given 
the opportunity to ask questions and may take as long as they need to make a decision.  
 
A patient advocate will be present while you are discussing the study with the research 
team and before you decide whether to consent for your child’s participation in this study.  
The patient advocate’s name is Gina Hennessy who is an orthopedic nurse practitioner.  
Her role in this study is to answer any questions you have or discuss study options with 
you in an impartial manner. 
 
9.6 Payment to Subjects/Families  
 
No payment will be given to subjects or families.  
 
 

50 
 
10 PUBLICATION  
 
Following the completion of subject enrollment, data collection, and analysis, a manuscript will 
be prepared and submitted to an appropriate journal in order to contribute to the literature on this 
topic.  
 
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3. Lenke, L.G., et al., Adolescent idiopathic scoliosis: a new classification to determine extent of 
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4. Gorman, K.F., C. Julien, and A. Moreau, The genetic epidemiology of idiopathic scoliosis. Eur 
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12 APPENDIX 
12.1 Appendix 1: Clavien-Dindo complications classification system (from Dindo, et al.) 

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