1
BIOS 6648 Group Project
Patrick Carry
Laura Paulson
Linda Jones
Project Title: Use of Ultrasonic Bone Scalpel in Adolescent Idiopathic Scoliosis:
A Randomized Clinical Trial
1. Background and Setting
a. Intended Indication
The intended treatment indication of the proposed trial is to reduce intraoperative blood loss
through use of an ultrasonic bonescalpel (specifically, the Misonix BoneScalpelⓇ) in planned
posterior spine fusion with instrumentation in patients diagnosed with adolescent idiopathic
scoliosis (AIS).
b. Condition & Treatment
AIS is the most common spinal abnormality among children in the United States, affecting
approximately 2-3% of the population1. AIS is a three-dimensional deformity of the spinal
column that often appears during the adolescent growth spurt. Unlike other forms of scoliosis, it
tends to appear by itself without symptoms2. The cause is not well-understood, but it is thought
to be a result of various environmental and genetic factors3,4.
The severity of scoliosis can be measured in multiple ways. The Cobb angle is a means to
classify the severity of scoliosis by the angle of the curvature in one plane; the severity of which
guides appropriate treatment5. The Cobb angle is measured by drawing lines parallel to the upper
border of the upper vertebral body and the lower border of the lowest vertebra of the structural
curve, then erecting perpendiculars from these lines to cross each other. The angle between these
perpendiculars is the “angle of curvature”. The Lenke classification system, which also guides
appropriate treatment, assesses scoliosis in two planes and is more complex than the Cobb
angle6. All three regions of the radiographic coronal and sagittal planes, and the proximal
thoracic, main thoracic, and thoracolumbar/lumbar areas are designated as either the major curve
(largest Cobb measurement) or minor curves with the minor curves separated into structural and
nonstructural types.
In the most severe cases (patients whose Cobb angles are greater than 45° while still growing, or
are continuing to progress greater than 45° when growth has stopped), posterior spinal fusion
surgery with instrumentation (PSF) is needed to correct the deformity and prevent curve
progression. If untreated, severe complications such as mortality and dyspnea are possible,
though rare7. Increased pain as well as mental and social consequences are also prevalent among
untreated patients. It is estimated that about 0.25% of AIS patients have curves severe enough to
warrant treatment7. During PSF surgery, metal implants are attached to the spine, and then
connected to a single rod or two rods. The implants are then used to correct the spine and hold it
in the corrected position until the instrumented segments fuse as a bone8. Based on the Lenke
2
classification, it is recommended that the major and structural minor curves are included in the
instrumentation and fusion and the non-structural minor curves are excluded6.
Posterior spinal fusion surgery, like other spine surgeries, is associated with high intraoperative
blood loss. AIS patients lose an average of 25-30% of their total blood volume9,10. As a result,
50-75% of patients require an allogeneic and/or autologous blood transfusion 10-14. The amount
of blood loss is highly variable, with some research reporting a standard deviation of blood loss
exceeding 50% of the group average10,15. The amount of blood loss can vary by the patient’s
diagnosis, age, sex, weight, body mass index (BMI), bone density, preoperative hemoglobin, and
preoperative Cobb angle, as well as the surgical approach, operative time, and number of levels
fused during the procedure16,17. Levels fused refers to the number of vertebral bodies that are
physically fused together during surgery and is a surrogate marker of both disease severity and
surgery complexity. Operative time and number of levels fused have been shown to be the most
significant predictors of blood loss, of those factors over which the surgeon has control18,19.
Blood transfusions increase the risk of infection, adverse reactions, and directly increase the cost
of the procedure20,21. Increased blood loss is also associated with post-operative complications
such as respiratory depression and wound infections22. Consequently, there is a strong interest in
the development of new methodologies that minimize intraoperative blood loss during PSF.
c. Device
Recent refinements in ultrasonic bonescalpels (USBS) have led to an increase in their usage in
specialized surgical procedures. The Misonix BoneScalpelⓇ (proprietary name Alliger
Ultrasonic Surgical System Model AUSS-7) is an ultrasonic surgical device that purports to
enable safe and controlled bone removal, while minimizing soft tissue damage and blood loss
during surgical procedures (Misonix, 2015). Empirical validation of these claims will be
addressed later in this paper. An electrical signal converts to mechanical oscillations, creating
longitudinal vibrations at a frequency of 22,500 times per second. It differentiates between
osseous (bone) tissue and soft, connective tissue. Additionally, an irrigated tip provides cooling
throughout surgical procedures and reduces the risk of thermal injury.
The BoneScalpel product is a Class II device, meaning it was determined to have an equivalent
safety profile to an approved medical device, and thus it underwent the premarket approval
process (510(k)). The Food and Drug Administration (FDA) reviewed the application in 2007.
and approved the BoneScalpel for use in the fragmentation and aspiration of bone and soft
tissues in several surgical specialties, including orthopedic, plastic and reconstructive, and
general surgeries.
d. Previous Research
Ultrasonic cutting devices have been used extensively in adult populations during a variety of
surgical procedures including maxillofacial surgery 23,24 and tumor resections 25-29. During spine
surgery, several single-arm cohorts have concluded ultrasonic devices are both safe and
effective30,31. However, the lack of a control/comparison group in these studies limits the
inferences that can be drawn regarding safety or efficacy of ultrasonic devices relative to
traditional instrumentation.
3
Empirical evidence examining use of a USBS for spine surgery is limited in pediatric
populations; much of the research does not include control groups and/or does not exclude
patients with multiple diagnoses. Bartley, Bastrom & Newton 32 conducted a retrospective study
to evaluate estimated blood loss (EBL) in patients with AIS who underwent posterior spinal
fusion and instrumentation surgery with and without the use of an USBS. They found that use of
an USBS resulted in significantly less intraoperative bleeding, when compared to a control group
of most recent non-USBS procedures (EBL/level fused= 48±30mL (USBS group); 72±28mL
(MRC); p=0.01) as well as compared to a control group matched by Cobb angle (EBL/level
fused=78±30mL (CMC); p=0.003). However, operating time was not significantly different
among the groups (247±62 min. (USBS), 233±42 min. (MRC), 229±30min. (CMC), both
p>0.05). In another retrospective study examining a cohort of 30 pediatric patients undergoing
thoracolumbar decompression, there was an overall lower incidence of complications in the
USBS group (30%) compared to the high speed drill group (50%)31.
e. Scientific and Clinical Goals
The goal of the proposed randomized trial is to compare the efficacy and safety of an USBS with
standard of care surgical instruments (osteotomes and rongeurs) in planned posterior spinal
fusion with instrumentation, in order to determine if use of the USBS can result in lower
intraoperative blood loss. Minimizing blood loss can lead to fewer postoperative complications,
and thus more successful outcomes for patients. Therefore, the primary outcome of the trial is
estimated blood loss per spine level fused (EBL/level). In order to evaluate safety, secondary
outcomes such as the probability of meeting the intraoperative blood transfusion criteria,
operative time, incidence of adverse events, and incidence of surgical site infections will be
measured.
f. Phase
The proposed trial is planned as a Phase IV trial, as the device has already been approved and the
purpose of this trial is to evaluate post-market effectiveness in an expanded target patient
population.
2. Synopsis
a. Study Population
Subjects with adolescent idiopathic scoliosis undergoing planned posterior spinal fusion with
instrumentation will be recruited from a single tertiary recruitment center, Children’s Hospital
Colorado (CHCO), for this trial.
Inclusion Criteria:



10-18 years of age
Diagnosis of AIS
Scheduled for a posterior spinal fusion (without vertebral column resection)
Exclusion Criteria:


Plan for a posterior column osteotomy
Prior spinal surgery
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



MRI abnormalities (such as syrinx and/or chiari malformations)
Other serious comorbidity
Subjects with bleeding diatheses
Non-idiopathic etiology for scoliosis
b. Study Treatment(s)
This study will be performed within the context of standard clinical care for patients undergoing
posterior spinal fusion with instrumentation. Subjects will be randomized to one of two groups
(see section 3.b). Anesthesia technique and post-operative pain management will be determined
on an individual basis by the attending anesthesiologist according to standard clinical practice.
The surgeries will be performed by one of the two attending surgeons participating in the study.
Peri- and post-operative care will be identical in both groups (addressed in the Study Manual)
with the exception of the use of the USBS or standard surgical instruments during posterior
spinal fusion.
Risks Associated with USBS: Compared to standard surgical instrumentation, concerns have been
raised regarding potential increased risk of thermal injuries and/or dural tears associated with the
ultrasonic bone scalpel. Based on previous reports, the risk of iatrogenic dural tears related to the
USBS is comparable to the risk associated with standard tools23,26,29,31,33. Additional information
about risk of dural tears is described in Table 1. Concern for thermal injury also appears
minimal. Brooks et al 34 found that the heat generated by ultrasonic tools in cadaver bone did not
differ from previously reported temperatures generated by high speed drills and also credits the
irrigation system with reducing potentially high temperatures that could be produced from
ultrasonic devices. Using an ovine model, Sonborn et al27 found no evidence of increased risk of
thermal injury when comparing laminectomy procedures performed with and without the USBS.
The authors concluded the USBS irrigation system is able to adequately cool surrounding tissues
during osteotomies. Overall, research shows the USBS to be a safe alternative to historically
standard tools with the potential for reduced blood loss. Both methods are commonly employed
by pediatric spine surgeons at CHCO for performing a variety of orthopedic procedures,
including the procedures used in this study. Below is a table summarizing incidence of dural tear
associated with the USBS in spinal surgery reported in previous studies.
Table 1. Safety Profile in Previous Studies
Author
Al-Mahfoudh et al.26
Matsuoka et al.28
Bydon et al.29
Bydon et al.33
Hu et al.31
Year
Surgical Use
osteotomy,
2014
laminoplasty
recapping
2012
hemilaminoplasty
Number
62
Age (year)
Not
Provided
Dural Tear
in USBS
Dural Tear in
Non-USBS
1 (1.6%)
N/A
33
4-74
0
N/A
2014 spinal decompression
30
8-19
3 (30%)
9 (45%)
spinal decompression
2013 in achondroplastic
patients
337
41-78
5 (5.7%)
9 (3.6%)
2013 osteotomy
128
12-85
11 (8.6%)
N/A
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c. Study measurements and follow-up
Study data will be collected pre-surgery, intra-operatively, and post-operatively. Study data will
be managed using REDCap (Research Electronic Data Capture). All study variables are outlined
below.
Table 2. Variables and Collection Time Points
Collection Time Point
Variable
Type
One Day
Pre-Op
Intra-Op
Post-Op*
Post-Op†
X
X1
X1
Estimated blood loss/level
[mL/level]
Outcome
X
Intraoperative complications
(events requiring deviations from
routine follow up care)
Outcome
X
Probability of meeting blood
transfusion criteria
Outcome
X
Unplanned return to OR
Outcome
X
Length of Hospital Stay
Outcome
X
Surgical Site Infection
Outcome
Procedure Time (first incision to
close)
Outcome
Age
Covariate
X
Gender
Covariate
X
Cobb angle
Covariate
X
BMI
Covariate
X
Lenke Classification
Covariate
X
Hemoglobin/Hematocrit
Covariate
X
Use of Antifibrinolytics
Covariate
Treating Surgeon
Covariate
X1
X
X
X
X
X
X
*Short term follow up, during initial hospital stay
†Long term follow up, one year post-operative
1
Subjects will be asked to report above events to the Study Coordinator when they occur and will be
asked during clinic follow-up visits if these events have occurred since the last visit. The final visit will
occur at one year post-operative.
Assessment of Estimated Blood Loss: Two clinical research coordinators will be trained by
anesthesia personnel in order to standardize the EBL measurement methodology used in this
study. The EBL estimates will be based on the contents of the blood and fluid collection
canisters. EBL will be calculated in the following manner. First, volume of the contents of all of
the blood and fluid canisters used during the course of the surgical procedure will be recorded. In
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order to increase the accuracy of the canister volume measurement, smaller canisters than are
traditionally used for spine surgery will be used to collect blood and fluid. The surgical team will
have to switch canisters more frequently, but this is not seen as difficult nor does it increase
study risk for the patient. Next, the total irrigation volume used during surgery will be calculated.
The irrigation volume will be estimated as the difference in volume of the irrigation bag at
surgery cut versus surgery close. For subjects in the USBS group, the total irrigation volume will
also include the difference in volume of the USBS irrigation bag at surgery cut versus surgery
close. Estimated blood volume will be calculated as total canister volume minus total irrigation
volume.
To ensure the EBL measurements are accurate and consistent, digital photographs of the
canisters and irrigation saline bags will be obtained immediately following surgery close. The
digital photographs will be obtained by the research team. The digital camera will be positioned
24” from canister or irrigation and the image will be centered with the capture frame. The
photographs will be de-identified and a blinded evaluator will estimate blood loss at a later time.
Determination of Whether the Subject Meets Blood Transfusion Guidelines: CHCO does not
have strict transfusion protocols for patients undergoing posterior spinal fusion surgery.
Therefore, the study team developed a standardized methodology for defining patients that meet
the criteria for a blood transfusion. Subjects will be defined as meeting the criteria for
transfusion if one or more of the following occurs:


Hematocrit levels below 23% at any point during the surgical procedure (Hematocrit will
be checked every 30 minutes)
Hematocrit levels between 23-28% and hypotension and/or tachycardia (>20% different
from baseline) is present despite adequate fluid resuscitation
Additional Data Collection Procedures: All other study interventions and procedures (such as
hospital visits, radiographic analysis, and laboratory procedures) are already performed by the
physician care team as part of a surgical patient’s normal plan of care. Data collected from these
interventions will be extracted from CHCO’s electronic medical record system.
Determination of Surgical Site Infections: When surgical implants are utilized, the Centers for
Disease Control and Prevention defines a surgical site infection as an infection that occurs within
twelve months of the initial surgery35. We will follow all subjects for a minimum of one year
after surgery to determine the incidence of surgical site infections in the two study groups.
d. Study Duration
The pediatric orthopedic surgery practice at CHCO typically has approximately 80 cases of
posterior fusion for AIS per year. Based on previous studies with similar risks, it is anticipated
that 80% of subjects will provide consent to participate in the study, resulting in 64 participants
per year. As we plan to enroll a total of 72 subjects, it is estimated that the study will take 1.5
years to complete enrollment, with the last patient, last visit occurring 2.5 years after study
initiation. If (based on scenario 4 below) up to 48 additional subjects are needed, recruitment
will occur over 2.5 years, with last patient, last visit occurring 3.5 years after study initiation.
7
e. Statistical Design
Trial design: The primary purpose of this single blinded, randomized, controlled, superiority trial
is to compare the efficacy of an ultrasonic bone scalpel (or osteotome device) with standard of
care surgical instruments during posterior spine fusion with instrumentation.
Study endpoints: The primary outcome variable in this trial is estimated blood loss per spine
level fused (EBL/level). Secondary outcome variables include the probability of meeting the
intraoperative blood transfusion criteria, incidence of adverse events, incidence of surgical site
infections, and operative time. Estimated blood loss per level is assumed to follow a normal
distribution. A continuous normal probability model will be used in the primary analysis
described below.
Primary Aim 1: Compare estimated blood loss per level fused
Hypothesis 1: The average estimated blood loss per level fused will be significantly lower in the
ultrasonic bone scalpel (USBS) group compared to the standard of care group.
Secondary Aim 1: Compare the incidence of adverse events in the two groups.
Hypothesis 2: There will be no difference in the incidence of adverse events in the bone scalpel
group compared to the standard of care group.
Secondary Aims 2-3: Compare the proportion of patients meeting intra-operative blood
transfusion criteria and operative time in the two groups.
Sample Size/Power Analysis: The primary aim of this study is to compare differences in
estimated blood loss per fusion level (EBL/level) between the USBS and standard of care groups
(𝜃 = 𝜃𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝑐𝑎𝑟𝑒 − 𝜃𝑈𝑆𝐵𝑆 ).We aim to test the null hypothesis that the difference between
groups is less than or equal to 0 (𝐻∅ 𝜃 ≤ 0). Based on a previous retrospective cohort study in a
similar target population32, we anticipate the EBL/level in the proposed study will be 48
mL/level (±30) in the USBS group (𝜃𝑈𝑆𝐵𝑆 ) and 72 mL/level (±28) in the standard instrument
group (𝜃𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝑐𝑎𝑟𝑒 ). Although there are no universally established thresholds for defining a
clinically meaningful difference in EBL/level, the investigators are confident that the 33%
reduction in blood loss per level observed in the previous study is representative a clinically
meaningful reduction in blood loss (𝐻+ 𝜃 ≥ 24 mL/level or 𝐻+ 𝜃 ≥ 33%). Assuming a group
difference of -24 mL/level and a standard deviation of ±28 in the standard instrument group and
a standard deviation of ±30 in the USBS group, we determined that a sample size of 62 subjects
(31 subjects per group, 1:1 randomization) would provide 90% power to reject the null
hypothesis using a two tailed independent sample T-test with an alpha level of 0.05. Based on an
assumed dropout rate of approximately 10%, we intend to enroll 36 subjects per group.
Statistical Modeling: Intent to treat and per protocol analyses of all randomized subjects will be
performed. Descriptive statistics will be used to compare the distribution of demographics and
clinical characteristics in the two groups. Baseline covariates significantly different between
groups will be considered as potential confounding variables in subsequent statistical models.
Due to the stratified nature of the randomization scheme, randomization strata (surgeon) will be
8
included as a covariate in all statistical models. The primary aim of this study is to compare
differences in estimated blood loss per fusion level (EBL/level) between the USBS and standard
of care groups (𝜃 = 𝜃𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝑐𝑎𝑟𝑒 − 𝜃𝑈𝑆𝐵𝑆 ).We aim to test the null hypothesis that the
difference between groups is less than or equal to 0 (𝐻∅ 𝜃 ≤ 0). Multiple variable linear
regression analysis will be used to compare total EBL/level in the two study groups. For the
secondary outcome variables, multi-variable logistic regression analyses will be used to compare
differences in the categorical variables (the risk of adverse events, proportion of subjects meeting
the intra-operative blood transfusion criteria) between the groups. Multivariable linear regression
models or stratified Wilcoxon rank sum tests will be used to compare differences in the
continuous variables (operative time, post-operative length of stay, and intraoperative irrigation
volume).
Interim Analysis/Adaptive Trial Design: This study will utilize a stepwise two-stage adaptive
trial design. As described by Wan et al36 (see Table 3), an interim analysis (Stage 1) will be
performed once the study has reached 36 participants. The standardized test statistic, 𝑍1 , will be
𝜃
calculated as 𝑍1 =
. As described below, the standardized test statistic
2
2
√𝜎𝑈𝑆𝐵𝑆
/18+𝜎𝑆𝑡𝑎𝑛𝑑𝑎𝑟𝑑
𝑐𝑎𝑟𝑒 /18
(𝑍1 ) will be used to determine how the trial protocol will proceed. All scenarios assume a
standard deviation of ±28 in the standard instrument group and a standard deviation of ±30 in the
USBS group.
Scenario 1: Trial Halts Due to Futility: At stage 1, if the difference in blood loss per level fused
between groups is less than 4.6 mL/Level (𝜃 < 4.6 mL/level ), then a decision will be made to
stop the trial. Under this scenario the difference between groups is minimal, and thus it would
not be ethical to continue with a trial that has little potential for clinically meaningful benefit.
Scenario 2: Trial Halts Due to Superiority: At stage 1, if the difference in blood loss per level
fused between groups is greater than 19.4 mL/level (𝜃 > 19.4 mL/level ), then a decision will
be made to halt the trial. Under this scenario, it would not be ethical to continue with the trial due
to strong evidence supporting the superiority of the USBS relative to the standard care
instrumentation.
Scenario 3: Trial Continue to Stage 2 Based on a Large/Small Effect: At stage 1, if the difference
in blood loss per level fused between groups is greater than or equal to 4.6 mL/level and less
than 6.7 mL/level fused (4.6 mL/level ≤ 𝜃 < 6.7mL/level ) or the difference is greater than
16.4 mL/level and less than or equal to 19.4 mL/level (16.4 mL/level < 𝜃 ≤ 19.4 mL/level)
then the trial will enroll an additional 40 subjects. Once the final enrollment has been achieved
𝜃
(Stage 2), a standardized test statistic 𝑍2 , will be calculated as 𝑍2 =
.
2
2
√𝜎𝑈𝑆𝐵𝑆
/38+𝜎𝑆𝑡𝑎𝑛𝑑𝑎𝑟𝑑
𝑐𝑎𝑟𝑒 /38
At stage 2, if the difference in blood loss per level fused between groups is greater than 11.1
mL/level fused (𝜃 > 11.1 mL/level ), we will reject the null hypothesis and conclude the USBS
is superior to the standard care instrumentation.
Scenario 4: Trial Continue to Stage 2 Based on a Modest Effect: At stage 1, if the difference in
blood loss per level fused between groups is greater than or equal to 6.7 mL/level and less than
or equal to 16.4 mL/level fused (6.7 mL/level ≤ 𝜃 ≤ 16.4mL/level ) then the trial will enroll
9
an additional 48 subjects. Once the final enrollment has been achieved (Stage 2), a standardized
𝜃
test statistic 𝑍2 , will be calculated as 𝑍2 =
. At stage 2, if the difference
2
2
√𝜎𝑈𝑆𝐵𝑆
/42+𝜎𝑆𝑡𝑎𝑛𝑑𝑎𝑟𝑑
𝑐𝑎𝑟𝑒 /42
in blood loss per level fused between groups is greater than 11.1 mL/level fused (𝜃 >
11.6 mL/level ), we will reject the null hypothesis and conclude the USBS is superior to the
standard care instrumentation.
Table 3. Stepwise Two-Stage Sample Size Adaptation Method36
Decision/Adaptation
Stage 2 Efficacy Boundary
𝑍1
<0.48
Halt trial, futility
0.48-0.69
1.67
Continue to enroll 𝑛𝑖𝑛𝑖𝑡𝑖𝑎𝑙 ∗1.07 subjects
0.69-1.70
1.75
Continue to enroll 𝑛𝑖𝑛𝑖𝑡𝑖𝑎𝑙 ∗1.20 subjects
1.70 to 2.01 Continue to enroll 𝑛𝑖𝑛𝑖𝑡𝑖𝑎𝑙 ∗1.07 subjects
1.67
>2.01
Halt trial, efficacy
𝑍1 = test statistic calculated at interim analysis
𝑛𝑖𝑛𝑖𝑡𝑖𝑎𝑙 = sample size estimated prior to the start of the trial
3. Study Implementation and Conduct
a. Recruitment and Consent
Subjects will be recruited from patients requiring surgery for AIS at the pediatric orthopedic
surgery practice at CHCO. At the first office visit where the possibility of surgery is discussed,
the clinic nurse will ask the patient and family if they will allow pre-screening for the study, and
if so, a study HIPAA form will be completed. The Study Coordinator (who is listed under the
COMIRB approved personnel form) will then pre-screen patients for preliminary eligibility after
surgery has been scheduled, and if preliminarily eligible, a COMIRB approved information sheet
and informed consent document will be mailed to the patient and family. Patients will be asked
to contact the Study Coordinator by phone if they have any questions and will be informed that
the study will be discussed at the pre-operative clinical visit, one day prior to the planned
surgery. At the pre-operative visit, the study will initially be presented by the Study Coordinator
to minimize bias (if presented by the PI or Co-PI who is also the operating surgeon, the patients
may feel compelled to participate). If the patient remains interested in participation, the PI or coPI will then be available to answer questions and complete the informed consent process.
As this is a pediatric study, assent will be obtained in one of two ways depending on the patient’s
age and understanding. If the participant is 10-12 years old, or if they are having trouble
understand the details of the study, they will read and sign a separate assent form. If the
participant is aged 13-17 years old, or if they understand completely the details of the study, they
will initial and sign the consent form along with their parents, legal guardians, or legally
authorized representative. The patient’s understanding of the protocol will be assessed by the
research team member who is obtaining consent.
b. Randomization Procedures
Subjects will be randomized 1:1 will occur via a randomization table (see attached). As surgical
technique may vary resulting in greater or lesser baseline blood loss, block randomization by
10
surgeon will occur. Randomization will occur just prior to the surgical procedure to minimize the
potential to inadvertently reveal subject allocation to the study coordinator or the subject and
family. The Study Coordinator will use the randomization table and communicate the
randomization assignment to the surgeon just prior to the surgical procedure. The study
investigators will not be aware of the randomization allocation sequence.
c. Procedures for Blinding
A blinded evaluator will be used to calculate the primary outcome variable of interest, estimated
blood loss per level fused. All other study personnel, including the surgeons, will not be blinded
to participant treatment assignment which is necessary to ensure the correct protocol is followed.
Patients and their families will be blinded to study assignment to minimize the risk of assignment
related study withdrawal. Patients and their families will not have the assignment revealed to
them after the surgery as it will not affect their plan of care. If desired, treatment allocation may
be revealed at the final study visit at one year following surgery.
d. Retention and Procedures for Minimizing Missing Data
All subjects have the right to withdraw from this study at any time. A 10% drop-out has been
accounted for in the study design. There are two time points at which withdrawals are likely to
occur. It is possible that subjects may withdraw after providing informed consent and prior to
surgery, although drop-outs are unlikely as this time period is one day. As the duration of followup is one year, it is possible that subjects will withdraw prior to completed collection of variables
such as hospital length of stay, intraoperative complications, unplanned return to the operating
room, surgical site infection, and the final measurement of the Cobb angle. Subjects will be
encouraged to remain in the study but if a subject elects to withdraw, uncollected data will be
lost.
As this study involves a single intervention with data collection occurring during and
immediately following the surgical procedure, it is not possible for a subject to withdraw after
surgery and prior to data collection for the primary aim or secondary aims 2 and 3. As discussed
in the informed consent, once these data have been collected, they are part of the study record.
Subjects will be compensated for all study costs plus $100 for the outpatient study visit at one
year.
For subjects who are lost to follow-up, two certified letters will be sent two week apart following
the first missed clinic visit. If there is no response, the subject will be contacted twice by phone.
If study staff is unable to contact the subject, they will be considered lost to follow-up.
e. Medical Monitoring
The Medical Monitor will be an orthopedic surgeon who is not affiliated with the study. The
Medical Monitor will review all possibly related severe adverse events within five days of the
event occurring. The Medical Monitor will also review all data with the study statistician at the
interim analysis.
11
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