Extended Follow-up of Investigational Device Exemption (IDE) Subjects Treated With the Simplify Cervical Artificial Disc
Phase: NA
Conditions: Cervical Degenerative Disc Disorder
Sponsor: NuVasive

NuVasive, Inc 
 Post Approval Study Protocol 
Confidential 
POST APPROVAL STUDY PROTOCOL 
for the 
SIMPLIFY® 
CERVICAL ARTIFICIAL DISC 
SPONSOR: 
NuVasive, Inc. 
7475 Lusk Boulevard 
San Diego, 
CA  92121 
Phone: 
858-909-1800
 JUNE 30,  2021 
This submission contains CONFIDENTIAL material and information and should be restricted in its 
distribution.  Do not copy without permission of Sponsor. 
NCT04630626

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                                         PROTOCOL SIGNATURE PAGE 
 
                                                    POST APPROVAL STUDY PROTOCOL 
for the 
SIMPLIFY® CERVICAL ARTIFICIAL DISC 
 
                                                              Version June 30,  2021 
 
I have read the contents of this protocol.  I agree to conduct the study according to the protocol and 
the procedures described. 
 
 
Study Site Number: ______ 
 
Investigator Signature and Date: _______________________________________ 
 
Investigator Printed Name: ____________________________________________ 
 
 
 
 
 

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1. 
NAME AND ADDRESS OF SPONSOR AND REPRESENTATIVES ....................................................... 3 
1.1 
STUDY SPONSOR ...................................................................................................................................... 3 
1.2 
 ................................................................................................................ 3 
1.3 
 ................................................................................................................................. 4 
1.4 
 ................................................................................................................... 4 
2. 
STUDY PLAN ................................................................................................................................................ 5 
2.1 
NAME AND INTENDED USE OF THE DEVICE ............................................................................................... 5 
2.2 
PURPOSE OF STUDY .................................................................................................................................. 5 
2.2.1 
Description of Device .......................................................................................................................... 5 
2.3 
PROTOCOL STUDY CONDUCT .................................................................................................................... 6 
2.3.1 
Study Objective.................................................................................................................................... 6 
2.3.2 
Study Hypothesis ................................................................................................................................. 7 
2.3.3 
Study Description ................................................................................................................................ 7 
2.3.4 
Study Population ................................................................................................................................. 7 
2.3.4.1 
Inclusion Criteria .................................................................................................................................................. 7 
2.3.4.2 
Exclusion Criteria ................................................................................................................................................. 8 
2.3.5 
Study Design ....................................................................................................................................... 8 
2.3.5.1 
Overall Study Design ........................................................................................................................................... 8 
2.3.6 
Study Procedures................................................................................................................................. 8 
2.3.6.1 
Informed Consent ................................................................................................................................................. 8 
2.3.6.2 
Study Evaluations, Procedures and Assessments ................................................................................................ 9 
2.3.7 
Statistical Considerations .................................................................................................................. 12 
2.3.7.1 
Primary Endpoint ............................................................................................................................................... 12 
2.3.7.2 
Study Success ..................................................................................................................................................... 13 
2.3.7.3 
Design of the Observational Study .................................................................................................................... 13 
2.3.7.4 
Justification of Control and Expirmental Group Success Rates ....................................................................... 13 
2.3.7.5 
Sample Size Analysis ......................................................................................................................................... 13 
2.3.7.6 
Superiority Testing ............................................................................................................................................. 14 
2.3.7.7 
Addressing Missing Primary Outcome Data ..................................................................................................... 14 
2.3.7.8 
Analysis of Secondary Endpoints and Adverse Events .................................................................................... 15 
2.3.7.9 
 .......................................................................................................................................... 16 
2.3.7.10 
 ..................................................................................................................................... 17 
2.3.7.11 
Other Outcomes .................................................................................................................................................. 17 
2.3.8 
Safety Assessment .............................................................................................................................. 18 
2.3.8.1 
Adverse Events ................................................................................................................................................... 18 
2.3.8.2 
Serious Adverse Events...................................................................................................................................... 18 
2.3.8.3 
Unanticipated Adverse Device Effects .............................................................................................................. 19 
2.3.8.4 
Potential Relationship of Adverse Events ......................................................................................................... 19 

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2.3.8.5 
Assessment of Severity ...................................................................................................................................... 20 
2.3.8.6 
Clinical Events Committee ................................................................................................................................ 20 
2.4 
RISK ANALYSIS ...................................................................................................................................... 21 
2.4.1 
Risks .................................................................................................................................................. 21 
2.5 
STUDY MONITORING .............................................................................................................................. 22 
2.5.1 
Monitoring Organization ................................................................................................................... 22 
2.5.2 
Monitoring Visits ............................................................................................................................... 22 
2.5.3 
Data Collection ................................................................................................................................. 23 
2.5.4 
Review of Study Documents ............................................................................................................... 23 
2.5.5 
Medical Monitoring ........................................................................................................................... 24 
2.5.6 
Role of Co-Principal Investigators .................................................................................................... 24 
2.5.7 
Disposition of any Explanted Study Devices and Data ....................................................................... 24 
2.6 
INFORMED CONSENT .............................................................................................................................. 24 
 

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2. 
STUDY PLAN 
2.1 
NAME AND INTENDED USE OF THE DEVICE  
 
Device Classification & Generic Name: 
Class III; Total Disc Replacement 
 
Device Trade Name: 
Simplify® Cervical Artificial Disc 
 
Indication: Simplify® Cervical Artificial Disc is indicated for use in skeletally mature patients for 
reconstruction of the disc at one or two levels from C3-C7 following discectomy for 
intractable radiculopathy (arm pain and/or a neurological deficit) with or without neck 
pain, or myelopathy due to abnormality localized to the the disc space and manifested 
by at least one of the following conditions confirmed by radiographic imaging (e.g., X-
rays, computed tomography (CT), magnetic resonance imaging (MRI)): herniated 
nucleus pulposus, spondylosis (defined by the presence of osteophytes), and/or visible 
loss of disc height as compared to adjacent levels. Patients receiving Simplify® Cervical 
Artificial Disc should have failed at least six weeks of non-operative treatment or  
demonstrated progressive signs or symptoms  despite nonoperative treatment  prior to 
implantation.  Simplify® Cervical Artificial Disc is implanted via an open anterior 
approach. 
  
2.2 
PURPOSE OF STUDY 
This study is intended to demonstrate the 5-year long-term safety and efficacy of the Simplify® 
Cervical Artificial Disc (“Simplify Disc”) in subjects enrolled in the non-randomized Simplify Disc 
IDE study.  This study was conducted under IDE G140154. 
2.2.1 DESCRIPTION OF DEVICE 
 
The Simplify Disc is a cervical artificial disc manufactured from PEEK endplates and a mobile, 
zirconia-toughened alumina ceramic core. The PEEK endplates have a plasma-sprayed titanium 
coating. The articulating surfaces on the endplates have a concave surface and the core has two 
convex surfaces. 

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Figure 1. Representative Image of Simplify Disc 
For the Simplify Disc family, two core options (i.e., either small or large) are used for all assemblies. 
The articulating features of superior and inferior endplates are identical and congruent with the 
appropriate core. Superior and inferior endplates are available in three footprints, three thicknesses, 
and two lordosis angles. The superior endplates have a retention ring feature. All endplates are 
titanium coated on the bone interfacing surfaces, with two options available for coating thickness. All 
endplate components, regardless of configuration, have identical manufacturing process flow, 
including packaging and sterilization. 
 
The Simplify Disc is designed to provide a theoretical maximum of ± 12° in any combination of 
flexion-extension and lateral bending, unlimited axial rotation, and 1-2 mm translation. This range is 
intended to permit the patient’s anatomy to determine actual range of motion without imposing an 
artificial limit that may be restrictive to the patient’s kinematic profile. The maximum range of 
motion in vivo will be dictated by the patient’s anatomical boundaries or the device limits, whichever 
is smaller.  
2.3 
 PROTOCOL STUDY CONDUCT 
2.3.1 STUDY OBJECTIVE 
The objective of this clinical study is to evaluate the 5 year long-term safety and effectiveness of the 
Simplify Disc compared to conventional anterior cervical discectomy and fusion (“ACDF”) for 
treatment of intractable radiculopathy (arm pain and/or a neurological deficit) with or without neck 
pain or myelopathy due to a single-level abnormality localized to the level of the disc space at one 
level from C3 to C7 that is unresponsive to conservative management.  

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2.3.2 STUDY HYPOTHESIS 
The study hypothesis is that in subjects with intractable radiculopathy (arm pain and/or a neurological 
deficit) with or without neck pain or myelopathy due to a single-level abnormality localized to the 
level of the disc space at one level from C3 to C7 that is unresponsive to conservative management, 
the Month 60 composite clinical success (CCS) rate of the Simplify Disc will be no worse than 
conventional ACDF. Individual success for Simplify Disc and the historical control ACDF is defined 
as follows: 
 
Improvement on the NDI of at least 15 percentage points compared to baseline (pre-op) in the 
Simplify Disc IDE study, and 
 
No device failures by Month 60, and 
 
No subsequent surgical procedure at the index level (including revision, removal, reoperation, 
or supplemental fixation) by Month 60. 
 
2.3.3  STUDY DESCRIPTION 
This is a prospective, multi-center post-approval study (PAS) evaluating subjects in the non-
randomized Simplify Disc IDE study compared to ACDF subjects in a non-concurrent historical 
control Kineflex®|C Disc study.  The historical control population will only include the subjects who 
were selected using a PS model developed in the Simplify Disc IDE study and reviewed by FDA in 
the approved PMA to establish comparability between the study populations. 
 
2.3.4 STUDY POPULATION 
This will include up to 142 subjects eligible for study enrollment from fifteen (15) sites in the 
Simplify Disc IDE study who consent to long-term follow-up.  Additionally, up to 13 training 
subjects from the Simplify Disc IDE study from thirteen (13) sites will be enrolled.  Up to 106 
historical ACDF control subjects will be included in the PAS population. 
  
2.3.4.1 INCLUSION CRITERIA 
All subjects enrolled in the Simplify Disc IDE study are considered for this long-term follow-up 
study.  
  

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2.3.4.2 EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
 
• 
Subjects who were not implanted with the Simplify Disc during the IDE study 
• 
Subjects who had a secondary surgical intervention at the index level during the IDE study 
• 
Subjects who were withdrawn or withdrew consent to participate in the IDE study 
• 
Subjects who do not consent to participate in long-term follow-up post-approval study 
2.3.5 STUDY DESIGN 
2.3.5.1 OVERALL STUDY DESIGN 
This is a prospective, multi-center post-approval study to evaluate the 5-year long term safety and 
effectiveness of the Simplify Disc.  The historical control population will only include the fusion 
subjects who were selected using a PS model developed in the Simplify Disc IDE study and approved 
PMA. The Simplify Disc data from the training subjects will be summarized separately and not used 
in the primary comparison to control.  Study subjects will be evaluated annually (± 2 months) for 
components of the primary endpoint, secondary study endpoints and safety up through 5-year post-
implantation. Primary study  success will be evaluated at the 5-year timepoint.  
2.3.6 STUDY PROCEDURES 
2.3.6.1 INFORMED CONSENT 
Only patients who sign Informed Consent for participation in PAS will be allowed to participate in 
this clinical study. Subjects who do not speak English must be provided a copy of an IRB approved 
consent in their native language, or (if the process is approved by the site’s IRB) an IRB acceptable 
translator.  The original signed consent will be retained in each subject’s study file.    
 
  
 
  
  
  
  
  

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2.3.6.2 STUDY EVALUATIONS, PROCEDURES AND ASSESSMENTS  
Follow-up evaluations annually at Month 36, Month 48, and Month 60 will include: 
 
AP and lateral X-rays (plain films); 
 
Flexion-extension X-rays (used to determine range of motion); 
 
Lateral bending films (Simplify Disc only); 
 
Radiographic core lab evaluations; 
 
Dysphagia Handicap Index (Simplify Disc only); 
 
NDI assessment; 
 
SF-12v2 Health Survey (Simplify Disc only); 
 
VAS pain assessments (neck and arm; neck, left arm and right arm (Simplify Disc only)); 
 
Neurologic evaluation;  
 
Study related medication status (Simplify Disc Only); 
 
Work status; 
 
Treatment satisfaction assessment and 
 
Adverse events as defined by Section 2.3.8 of this protocol.  
 
 
 
Neurologic status will be evaluated by a qualified evaluator, who may be an MD, DO, an RN or a PA.  
The neurologic evaluation will include a motor and sensory assessment, reflex responses and the 
determination of the presence or absence of dysphagia, dysphonia, clumsiness, foot drop, atrophy, 
cramping, muscle spasms, numbness and gait abnormality. 
  
Muscle strength will be graded for the deltoid (C5), biceps (C6), and triceps (C7) according to a 6-
point scale where 0 = no movement, 1 = trace of muscle contraction; 2 = active movement without 
gravity; 3 = active movement against gravity; 4 = active movement against gravity/resistance; and 5 = 
normal response. 
 
Study related medication status will include only medications taken or administered for the following  
 
Pain (any type); 
 
Inflammation (any type); 

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 
Muscle relaxation; 
 
Numbness &/or tingling;  
 
Hormonal replacement therapy and 
 
Other medications related to or given for the subject’s spinal condition. 
 
All radiographic endpoints will be evaluated independently by one core laboratory.   
 
2.3.6.2.1 
Radiographic Assessments 
 The following radiographic assessments will be made by two independent musculoskeletal 
radiologists at the core lab.  A third independent radiographic reviewer will adjudicate in instances of 
disagreement.  The radiographic assessments will include: 
 
Angular Motion; 
 
Change in Angular Motion; 
 
Translational Motion; 
 
Change in Translational Motion; 
 
Global Range of Motion; 
 
Change in Global Range of Motion; 
 
Disc Height; 
 
Change in Disc Height; 
 
Disc Angle; 
 
Change in Disc Angle; 
 
Spondylolisthesis; 
 
Change in Spondylolisthesis; 
 
Bridging Bone; 
 
Fusion Status; 
 
Device Condition; 
 
Device Subsidence; 
 
Device Migration; 
 
Device Protrusion; 
 
Radiolucency; 
 
Heterotopic Ossification; 

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 
Osteophyte Formation; 
 
Endplate Sclerosis; 
 
Adjacent Level Disc Degeneration; 
 
Change in ALDD and; 
 
Additional Observations. 
  
2.3.6.2.2 
 
  
 
 
 
  
 
 
 
 
 
 
. 
2.3.6.2.3 
Study Completion, Termination or Loss to Follow-up 
Simpliy Disc subjects are expected to remain in the study until the 60 months post implantation 
assessment. The study completion/ termination evaluation will be made at the 60 months assessment, 
or at earlier time point if the subject withdraws or is withdrawn from the study. 
 
Subjects may be withdrawn from a clinical study early due to withdrawal of Informed Consent, loss 
to follow-up, or Investigator medical decision.  Any premature termination from the study will be 
documented, including the primary reason for withdrawal.  In the event of a secondary index surgery 
requiring removal of a spinal system, every effort will be made to retrieve the explanted device for 
analysis.  The instructions for the surgical technique for device removal of the Simplify Disc are 
included in the Study Manuals.  Any subjects with a device removal of the Simplify Disc or who have 
any other secondary index surgery will be discontinued from the study after the next follow-up study 
visit. 

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2.3.7 STATISTICAL CONSIDERATIONS 
2.3.7.1 PRIMARY ENDPOINT 
The study hypothesis is that in subjects with intractable radiculopathy (arm pain and/or a neurological 
deficit) with or without neck pain or myelopathy due to a single-level abnormality localized to the 
level of the disc space at one level from C3 to C7 that is unresponsive to conservative management or 
have the presence of progressive symptoms, the Month 60 composite clinical success (CCS) rate of 
the Simplify Disc will be no worse than conventional ACDF when success of ACDF is evaluated at 
Month 60.  Individual success for Simplify Disc and the historical control ACDF is defined as 
follows: 
 
Improvement on the NDI of at least 15 percentage points compared to baseline in the Simplify 
Disc IDE study, and 
 
No device failures by Month 60, and 
 
No subsequent surgical procedure at the index level (including revision, removal, reoperation, or 
supplemental fixation) by Month 60. 
 
Device failure is defined as breakage, migration, or mechanical failure of the components as defined 
in the Radiographic Evaluation Protocol.  Failure of the allograft will not be counted as device failure 
in the historical ACDF control group. 
  
Per FDA Guidance for the Preparation of IDEs for Spinal Systems, the following definitions apply for 
the PAS: 
 
Reoperation - any surgical procedure at the index level that does not involve modification, 
addition or removal of any components of the device” in the postoperative or follow-up 
period. 
 
Revision - any procedure in the postoperative or follow-up period that adjusts modifies or 
removes part of the original implant configuration with or without replacement of a 
component – may include adjusting the position of the original configuration in the 
postoperative or follow-up period. 
 
Removal - a procedure where the entire device is removed with or without replacement of the 
device in the postoperative or follow-up period. 

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 
Supplemental fixation – a procedure in which additional instrumentation not under study is 
implanted (e.g., supplemental placement of a rod/ screw system). 
 
2.3.7.2 STUDY SUCCESS 
The null hypothesis is that the probability of achieving Month 60 composite clinical success (CCS) 
for patients implanted with the Simplify Disc device is no more than 0.10 smaller than the probability 
of ACDF control patients achieving Month 60 CCS.  This study will be considered a success if the 
PS-quintile adjusted, multiple imputation based, 1-sided p-value for rejecting this null hypothesis is 
less than or equal to 0.05. 
2.3.7.3 DESIGN OF THE OBSERVATIONAL STUDY 
One hundred sixty-six (166) subjects were enrolled in the Simplify Disc IDE population. Of these, 16 
Simplify Disc subjects were training subjects. The historical ACDF control population included 133 
subjects. The 283 available subjects (150 Simplify Disc (excluding training subjects) and 133 
historical ACDF control) were assessed via the Propensity Score (PS) sub-classification process. 
After applying an established heuristic for 3 iterations (6 models), a total of 150 Simplify Disc and 
117 historical ACDF control subjects were retained in the final PS designed sample. Analysis of 
subject demographic and baseline data showed no meaningful differences between the treatment 
groups. The PS-selected population and PS sub classes defined in the IDE study will be utilized for 
the purposes of this study. Per the exclusion criteria, additional subjects are not enrolled into the PAS 
due to reasons that preclude long-term Simplify Disc data collection (e.g., SSI). 
 
2.3.7.4 JUSTIFICATION OF CONTROL AND EXPIRMENTAL GROUP SUCCESS RATES 
Based on multiple imputation and including N=150 Simplify Disc subjects and N=117 historical 
controls, the Month 24 PS adjusted success rates were estimated to be 93.0% and 73.6%, respectively, 
for a group difference of 19.4% (90% LB CI 10.9%). The lower bound of the 90% 2-sided CI is 
equivalent to the lower bound of the 95% 1-sided non-inferiority CI. In the completer’s analysis set, 
132 of 142 Simplify Disc subjects achieved Month 24 overall success, and 68 of 96 Controls achieved 
Month 24 overall success.  
2.3.7.5 SAMPLE SIZE ANALYSIS 
 

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For the purposes of sample size calculation, it is estimated that 85% of the estimated 142 Simplify 
Disc subjects (N=121) who are not terminal failures or lost to follow-up by Month 24 will be 
available at year 5. It is estimated that 60% of the estimated 106 (N=64) Control subjects who are not 
terminal failures or lost to follow-up by Month 24 will be available at year 5. 
 
Based on these results, it was conservatively estimated that the 5-year overall success rates would be 
70% of the observed rates, that is, 65% and 50% for Simplify Disc and historical ACDF control, 
respectively. If the success rates in both groups are larger, statistical power will be larger and so this 
power analysis would be conservative. With sample sizes of 121 and 64, and assuming 65% and 50% 
success, the power to detect non-inferiority is 96% at a one-sided 0.05 significance level.  
 
2.3.7.6 SUPERIORITY TESTING 
If the non-inferiority study success criterion is met, superiority testing will be performed in the 
primary analysis set.  It will be concluded that the Simplify Disc is superior to the ACDF control if 
the PS-quintile adjusted one-sided p-value determined from the multiple imputation is less than 0.05. 
2.3.7.7 ADDRESSING MISSING PRIMARY OUTCOME DATA 
Because of the availability of subject level data in controls that correspond to the subject level data to 
be collected in the prospective study, missing data will be addressed in the same fashion to how 
missing data would have been addressed in a randomized clinical trial. Multiple imputation will be 
used to impute missing final NDI in patients otherwise evaluable for primary CCS. For each of 20 
imputed data sets, the primary PS stratified device group difference will be made resulting in a 
standard error for each.  The final device group difference will be the average of the multiple imputed 
datasets and its standard error will account for both within (usual) and between imputation error.   
 
In addition to multiple imputation, sensitivity analysis will be provided based on tipping point 
analyses. These are analyses in which all possible combinations of successes and failures are assumed 
for patients missing primary CCS and the fraction of scenarios in which the statistical conclusion 
changes is summarized. Best case and worst case, all missing success, and all missing failures 
scenarios will also be summarized.   
 

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2.3.7.8 ANALYSIS OF SECONDARY ENDPOINTS AND ADVERSE EVENTS 
Secondary effectiveness endpoints will be compared between groups over time using group 
differences and 95% confidence intervals for group differences. Adverse events will be summarized 
by event counts and per subject incidence rates for categories of AE, for specific AEs, by relationship 
to device and procedure, and for SAEs. Counts will also be summarized by time of onset category and 
by AE severity. Where applicable, AE summary tables will include 95% confidence intervals for 
group differences in incidence rates. 
For each study group and for important subgroups separately, the primary outcome (i.e., patient 
success) and secondary endpoints, as well as the incidence of specific complications, will be tabulated 
and presented by follow-up interval.  Comprehensive tables will provide frequency and percentage 
distributions and descriptive statistics as appropriate in total and for each study group separately.  
Tables and graphical displays will be provided for both the primary effectiveness and safety 
populations as appropriate. 
Survival analysis methods will be used to describe time to event outcomes including time to 
secondary surgical intervention. 
2.3.7.8.1 
Secondary Endpoints 
Secondary endpoints include: 
 
Clinically significant improvement in one or more radicular symptoms or myelopathy at each 
annual timepoint compared to baseline in the IDE study for the Simplify Disc and for the 
historical control ACDF.    The data collected will reflect the number of patients who 
improved (numbers will be stratified to reflect clinical improvement), who remain 
unchanged, and who deteriorated at each study time point.  These endpoints will be graded 
and defined as follows: 
o A visual analog scale (VAS) will be used to evaluate each of the following pain     
locations: 
 
Neck and arm pain (to allow comparison to ACDF control)  
 
Neck pain (Simplify Disc Only) 
 
Left arm pain;(Simplify Disc Only) 
 
Right arm pain;(Simplify Disc Only 
 Changes of at least 20 mm on a 100 mm scale will be regarded as clinically significant. 
 

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o Motor status - A change of one or more grade levels in muscle strength will be 
regarded as clinically significant. 
o Sensory status - Sensation will be graded as normal or abnormal (diminished or 
absent).  Any changes from abnormal to normal or absent to diminished will be 
regarded as clinically significant improvement.1. 
 
Disc height at each annual timepointcompared to baseline (6 weeks) in the IDE study for the 
Simplify Disc and for the historical control ACDF, as measured by standard lateral 
radiograph (spot film, distance of 6 feet, centered at C5 with patient upright). 
 
Adjacent level deterioration at each annual timepoint compared to baseline in the IDE study  
for the Simplify Disc and for the historical control ACDF. 
 
Displacement or migration of the device; only changes of > 3 mm will be considered 
significant due to the margin of error in radiographic determination of displacement 
distances. 
 
Treatment satisfaction at at each annual timepoint  for the SimplifyDisc and *for the 
historical control ACDF. 
 
Health Survey (SF-12v2) for the Simplify Disc at each annual timepoint compared to baseline 
in the IDE study. 
 
Dysphagia Handicap Index (DHI scale) for the Simplify Disc at each annual timepoint  
compared to baseline in the IDE study. 
 
2.3.7.9
 
   
 
 
 
 
 
 
 
 
 
 
 
 
                                                     
 
1  Hacker et al., supra note 7. 

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o 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
2.3.7.10 
 
 
 
 
2.3.7.11 
OTHER OUTCOMES 
Range of motion in flexion/extension at the operative level.  Cobb angle measurements of the 
functional spinal unit will be made.  Differences in range of motion of at least 2 degrees when 
compared to baseline in the IDE study will be considered clinically significant.  Assessments will 
include comparison of range of motion at 60 months to baseline in the IDE study  for the Simplify 
Disc and for the historical control ACDF and to normal range of motion at the operative level, based 
on White and Panjabi2. Evaluation of these criteria will be based on anterior/posterior, lateral, and 
flexion/extension X-rays.  
 
Radiographs will be used to monitor the occurrence of some of the above adverse events, including 
subsidence of the device into the adjacent disc or other changes in the implant, and spinal instability.  
In addition, at each visit, after the subject has had an opportunity to spontaneously mention any 
                                                     
 
2  White and Panjabi: Clinical Biomechanics of the Spine. 2nd ed. Philadelphia, JB Lippincott 
Co.,1990. 

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problems, the investigator will elicit information concerning adverse events by asking standard 
questions.  Adverse events considered unusual for the patient population (i.e., occurring with greater 
frequency than anticipated or with greater severity than anticipated), key to safety or efficacy, or 
device related will require detailed reporting on the appropriate case report form.    
2.3.8 SAFETY ASSESSMENT 
2.3.8.1 ADVERSE EVENTS 
An adverse event is defined as any clinically significant undesirable clinical occurrence in a subject.  
Adverse events, whether or not device related, must be reported on the appropriate case report form. 
Adverse events will be classified based on seriousness, relationship to device and procedure, and 
severity by the study investigator. Any adverse event that occurred prior to treatment with the medical 
device will be documented in the patient’s pre-operative medical history in the Simplify Disc study.  
Only adverse events which occurred in the Month 36 through Month 60 visits or are continuing from 
Simplify Disc IDE study or are new or have worsened during the course of this study will be 
evaluated in the safety assessment. 
 
Analysis of adverse events will be conducted using the methods specified in section 2.3.7.8. 
 
2.3.8.2 SERIOUS ADVERSE EVENTS  
2.3.8.2.1 
Description 
A Serious Adverse Event (SAE) is an adverse event which: 
1. Led to a death, 
2. Resulted in life threatening illness or injury, 
NOTE: the term “life-threatening” refers to an event in which the patient was at a 
risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
3. Resulted in subject hospitalization or prolongation of existing hospitalization, 
4. Resulted in subject disability or permanent damage or required intervention to 
       prevent permanent impairment/damage.     

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2.3.8.3 UNANTICIPATED ADVERSE DEVICE EFFECTS   
2.3.8.3.1 
Description  
An Unanticipated Adverse Device Effect (UADE) is any serious adverse effect on health or safety or 
any life threatening problem or death caused by, or associated with, a device, if that effect, problem, 
or death is not identified in nature, severity, or degree of incidence in this Protocol; or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
the subjects. 
2.3.8.3.2 
Reporting 
SAEs and UADEs must be reported to the Sponsor, as soon as possible, but in no event later than 10 
working days after the Investigator first learns of the event. SAEs and UADEs must also be reported 
to the approving IRB per the IRB’s reporting requirements. 
2.3.8.4 POTENTIAL RELATIONSHIP OF ADVERSE EVENTS 
Investigators will be asked to assess the potential relationship of the adverse event to the implanted 
device and to the procedure and classify the causality of the event according to the following 
definitions. 
 
Definitely Related:  An adverse event that has a strong causal relationship.  An adverse event 
that follows a strong temporal relationship to the use of the device or the procedure, follows a 
known response pattern, and cannot reasonably be explained by known characteristics of the 
subject’s clinical state or other therapies. 
 
Probably Related: An adverse event that potentially has a causal relationship.  The adverse 
event has a reasonable temporal relationship to the use of the device or the procedure and 
alternative etiology is less likely compared to the potential relationship to the use of the 
device or the procedure. 
 
Possibly Related: An adverse event that potentially has a causal relationship.  The adverse 
event has a reasonable temporal relationship to the use of the device or the procedure but 
alternative etiology is equally likely compared to the potential relationship to the use of the 
device or the procedure.  
 
Not Related: An adverse event without any apparent causal relationship.  The adverse event is 
due to the underlying disease state or is due to concomitant medication or therapy not related 
to the use of the device or the procedure. 

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 
Unknown Relationship: If the adverse event cannot be determined to have a causal 
relationship, it will be classified as unknown. 
2.3.8.5 ASSESSMENT OF SEVERITY 
 
Mild: event/symptom is transient and well tolerated by the patient. 
 
Moderate: event/symptom causes discomfort and interferes with routine activities of the 
patient. 
 
Severe: event/symptom interferes considerably with the routine activities of the patient or 
causes inability to work. 
 
Life-Threatening: refers to an event in which the patient was at a risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe. 
 
2.3.8.6 CLINICAL EVENTS COMMITTEE 
The Clinical Events Committee (“CEC”) will adjudicate all adverse events. This will include all 
UADEs, SAEs, secondary surgeries at the index and adjacent levels, adverse events determined to be 
“severe”, and adverse events deemed definitely, probably and possibly related or with an unknown 
relationship to the device or procedure.  The CEC will review investigator assigned neurological 
status at 60 months for the Simplify Disc group onlyto determine if neurological status has improved, 
maintained or declined compared to baseline in the IDE study. 
The CEC may determine neurologic status has declined based on changes including: 
 
Motor Assessment: shift of -1. 
 
Sensory Examination: shift from normal to abnormal; abnormal to 
 
increased abnormality. 
 
Reflex Response: shift from Normal to anything else; hyporeflexive to 
 
absent; hyporeflexive to hyperreflexive or hyperreflexive to hyporeflexive. 
 
Clumsiness, Atrophy, Cramping, Spasms and Numbness: shift from 
 
absent to present. 
 
Dysphagia (difficulty swallowing) and Dysphonia (difficulty with producing 
 
sounds resulting in hoarseness, weakness, harshness, roughness and/or 
 
breathy sound): any worsening. 

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 
Myelopathic Gait Abnormality Class: any worsening 
 
Assessment: Does the CEC agree with the investigator assessment 
 The CEC will also adjudicate all protocol deviations.  The CEC will consist of three spine surgeons 
who are not affiliated with the Sponsor or who are not participating in the study.  The CEC charter is 
used for adjudication of both Simplify Disc and historical control ACDF patients. The 
recommendations of the CEC override the investigator’s classification and become part of the clinical 
trial data set. 
2.4 
RISK ANALYSIS 
2.4.1 RISKS 
No physical risks are anticipated as a result of participation in the long-term follow-up study. The 
amount of radiation exposure to subjects is relatively small.  
 
Subjects may require additional surgery at the treated spinal level: 
- Reoperation - any surgical procedure at the index level that does not involve 
modification, addition or removal of any components of the device” in the postoperative 
or follow-up period. 
- Revision - any procedure in the postoperative or follow-up period that adjusts modifies or 
removes part of the original implant configuration with or without replacement of a 
component – may include adjusting the position of the original configuration in the 
postoperative or follow-up period. 
- Removal - a procedure where the entire device is removed with or without replacement of 
the device in the postoperative or follow-up period. 
- Supplemental fixation – a procedure in which additional instrumentation not under study 
is implanted (e.g., supplemental placement of a rod/ screw system) 
 
 Risks associated with the use of both the Simplify Disc and control spinal systems are expected to be 
comparable.  All secondary index surgeries will be regarded as failures and reported accordingly. 
   

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2.5 
STUDY MONITORING 
2.5.1 MONITORING ORGANIZATION 
Study monitoring functions, with assistance from the Sponsor or designee for any study training 
visits, will be performed by an independent clinical monitoring organization, in compliance with 
recognized Good Clinical Practices as applied to medical device studies, FDA's IDE guidance 
documents, and as outlined in 21 C.F.R. § 812.43(d) and 21 C.F.R. §812.46.  The monitoring 
organization will act as the Clinical Monitor.  The major function of the Clinical Monitor is to 
observe and assess the quality of the clinical study. 
 
In addition to ensuring adequate communication between the investigators and the study Sponsor, the 
monitor's duties include on-site and remote visits and review of study documents and results.  The 
monitoring organization has been provided with appropriate training regarding the Simplify Disc and 
will operate under written procedures to ensure compliance with the protocol. 
2.5.2  MONITORING VISITS 
Monitoring visits include a pre-study visit, periodic visits and a close-out visit at the end of the site’s 
participation in the study.  The pre-study visit, which may be performed by the Sponsor or designee, 
will be conducted remotely and is intended to provide an opportunity to review the Study Plan and 
associated study documents with the Investigator. and to ensure that the Investigator has IRB 
approval and all required documentation prior to initiating the post approval study: 
  
Periodic visits are intended to assess adherence to the Study Plan, maintenance of Records and 
Reports; and provides for review of source documents for accuracy, completeness, and legibility.  
During these periodic visits, the monitor is required to assess the progress of the study toward 
meeting study objectives; to identify any concerns that stem from observations of device performance 
and/or review of the subject records, study management documents or Informed Consent documents; 
to ensure that the site has assessed adverse events according to protocol requirements; and to ensure 
accountability of all subjects.  A periodic visit may be performed on-site or remotely. 
  
The monitor's final visit at completion of the study is intended to ensure that all the data have been 
properly completed and to have a closing meeting with the Investigator and his/her staff members to 
discuss findings, observed problems and potential solutions. 
 

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Reports of the monitoring visits will be made by the monitor and should include a means of tracking 
resolution of concerns, completion of appropriate follow-up activities, completion of assigned tasks, 
and any necessary corrective actions.  At the close of the study, a final report will be prepared by the 
monitor for each site. 
2.5.3 DATA COLLECTION 
Data will be compiled using an Electronic Data Capture system operated by the Independent 
Monitoring Organization.  The Clinical Monitor will verify that appropriate data are recorded for all 
study subjects for whom Informed Consent is obtained; and that no study evaluations are completed 
without Informed Consent.  Documentation will be provided for study subjects who choose to 
terminate study participation and for subjects terminated by their physicians.  A full explanation of 
the reasons for non-participation will be provided. 
 
Data will be reviewed to identify inconsistent or missing data, SAEs, and UADEs.  Data problems 
will be addressed in calls to the study sites and during site visits.  Electronic Case Report Forms and 
data files will be secured to ensure confidentiality.  Quality assurance procedures are designed to 
ensure that complete, accurate and timely data are submitted, that protocol requirements are followed, 
and that complications and adverse events are reported as required under Section 2.2.6.1 and Section 
2.2.7 of this protocol. 
  
2.5.4 REVIEW OF STUDY DOCUMENTS 
The monitor will review completed data forms and study documentation for accuracy, completeness, 
and protocol compliance. Although not limited to these, the following documents will be audited: 
 
The Clinical Trial (Investigator) Agreement signed by the investigator, indicating his/her 
agreement to participate in the investigation and willingness to comply with all study 
requirements. 
 
Electronic Case Report Forms will be reviewed for errors, omissions, internal consistency, 
and signature and dates in the appropriate sections.  The monitor will assume responsibility 
for any follow-up activities that result from review of these forms.  Subject Informed Consent 
documents will be reviewed for completeness. 
 
Study Monitor Reports by a site monitor will be reviewed by the senior monitor.  The 
monitor will assume responsibility for any corrective action. 

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2.5.5 MEDICAL MONITORING 
NuVasive, Inc.  has appointed a qualified spine surgeon to oversee all medical monitoring issues.  
Duties of the Medical Monitor include, but are not limited to: 
 
 Being available to investigators for questions regarding adverse event reporting; 
 
Being available to the FDA for medically related questions regarding this clinical study. 
 
May attend CEC meetings as a NuVasive, Inc Official. 
2.5.6 ROLE OF CO-PRINCIPAL INVESTIGATORS 
NuVasive, Inc. has appointed experienced spine surgeons to oversee all Co-Principal Investigator 
issues.  Duties of the Co-Principal Investigators include, but are not limited to: 
 
Review the protocol; 
 
Being available to investigators for questions regarding protocol criteria and surgical related 
questions; 
 
Being available to the FDA for medically related questions regarding this clinical study. 
2.5.7 DISPOSITION OF ANY EXPLANTED STUDY DEVICES AND DATA 
Should it be necessary to explant the Simplify Disc, NuVasive, Inc. shall provide surgical instructions 
in the Simplify Disc Surgical Technique Guide and a device retrieval kit and instructions detailing the 
appropriate procedure for handling explanted devices.  All Simplify Disc explant procedures will 
attempt to collect tissues adjacent to the device (e.g., bone-implant interface) for independent 
histopathological and wear examination. 
All information received by the study Sponsor or authorized agents of the study Sponsor pertaining to 
subjects will be held on a confidential basis.  This information may be subject to audit by regulatory 
authorities where appropriate.  Authorized agents of the study Sponsor will have the right to inspect 
and copy information in subject files.  Copies will be blinded to replace subject identifying 
information with subject identifiers. 
  
2.6 
INFORMED CONSENT 
Suitable candidates will be informed about the nature of the study and the possible risks involved, and 
will be provided the opportunity to sign Informed Consent.  The subject will be able to ask questions 
of the investigator, and will be allowed to review the consent form at his/her leisure. The investigator 
or the study coordinator, as appropriate, may answer additional questions the subject may have at an 
additional office visit or by telephone. It is possible that the subject will sign the consent at home, and 

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so the date of signature of the Investigator (if Investigator signature is required by IRB) may be 
different from the date of the subject’s signature. 
 
Only patients who sign Informed Consent will be allowed to participate in this clinical study. Subjects 
who do not speak English will be provided a copy of an IRB approved consent in their native 
language, or (if the process is approved by the site’s IRB) an IRB acceptable translator. 
 
The original of the site’s IRB approved Informed Consent template will be kept in the site’s study 
files.  Each site will provide the study Sponsor with a copy of the IRB approved and stamped 
Informed Consent template.  The original signed consent will be retained in each subject’s study file.