Clinical Study Protocol for the Investigation Of The Two Level Simplify® Cervical Artificial Disc
Phase: NA
Conditions: Cervical Degenerative Disc Disorder
Sponsor: NuVasive

NuVasive, Inc                             Clinical Study Protocol                                   Confidential 
 
 
 
 
CLINICAL STUDY PROTOCOL 
FOR THE 
INVESTIGATION 
Of The TWO LEVEL 
SIMPLIFY® CERVICAL ARTIFICIAL DISC 
 
 
SPONSOR: 
 
 
 
 
NuVasive, Inc. 
 
 
 
 
7475 Lusk, Blvd. 
                                           San Diego, CA  92121 
 
 
 
 
Phone: 
858-909-1800 
 
 
 
 
 
 
 
 
 
 
 
 
JULY 15, 2021 
 
This submission contains CONFIDENTIAL material and information and should be 
restricted in its distribution.  Do not copy without permission of Sponsor. 

NuVasive, Inc                             Clinical Study Protocol                                   Confidential 
 
                                         PROTOCOL SIGNATURE PAGE 
 
                                                    CLINICAL STUDY PROTOCOL 
for the 
INVESTIGATION 
Of The Two Level 
SIMPLIFY® CERVICAL ARTIFICIAL DISC 
 
Version July 15, 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: ____________________________________________ 
 
 
 

NuVasive, Inc                             Clinical Study Protocol                             Confidential 
Version Date July 15, 2021 
000001 
1. 
NAME AND ADDRESS OF SPONSOR AND REPRESENTATIVES .............................4 
1.1. 
STUDY SPONSOR ................................................................................................................4 
1.2. 
 
 ................................................................................................................................4 
1.3. 
 ..........................................................................................4 
1.4. 
 ............................................................................................................5 
1.5. 
 .............................................................................................5 
1.6. 
 .................................................................................................5 
2. 
BACKGROUND .....................................................................................................................6 
2.1. 
DESCRIPTION OF CONDITION ..............................................................................................6 
2.2. 
CURRENT THERAPIES .........................................................................................................6 
3. 
INVESTIGATIONAL PLAN ................................................................................................8 
3.1. 
PURPOSE OF STUDY ............................................................................................................8 
3.2. 
PROTOCOL STUDY CONDUCT .............................................................................................8 
3.2.1. 
Study Description .......................................................................................................8 
3.2.2. 
Study Objectives and Hypothesis ...............................................................................9 
3.2.2.1. 
Objectives ...........................................................................................................9 
3.2.2.2. 
Hypothesis ..........................................................................................................9 
3.2.3. 
Study Population ......................................................................................................10 
3.2.3.1. 
Indications for Use ............................................................................................11 
3.2.3.2. 
Inclusion Criteria ..............................................................................................11 
3.2.3.3. 
Exclusion Criteria .............................................................................................12 
3.2.4. 
Study Design ............................................................................................................14 
3.2.4.1. 
Overall Study Design ........................................................................................14 
3.2.4.2. 
Control Group ...................................................................................................15 
3.2.4.3. 
Study Duration ..................................................................................................16 
3.2.5. 
Study Procedures .....................................................................................................16 

NuVasive, Inc                             Clinical Study Protocol                             Confidential 
Version Date July 15, 2021 
000002 
3.2.5.1. 
Informed Consent .............................................................................................16 
3.2.5.2. 
Pre-treatment Evaluations and Data Collection ................................................17 
3.2.5.3. 
Treatment Procedures and Evaluations ............................................................18 
3.2.5.4. 
Post-treatment Evaluations and Data Collection ..............................................19 
3.2.5.5. 
Data Collection Summary .................................................................................26 
3.2.6. 
Statistical Considerations ........................................................................................27 
3.2.6.1. 
Primary Endpoint ..............................................................................................27 
3.2.6.2. 
Study Success ...................................................................................................28 
3.2.6.3. 
Study Design .....................................................................................................28 
3.2.6.4. 
Sample Size Analysis .......................................................................................33 
3.2.6.5. 
Analysis Sets .....................................................................................................34 
3.2.6.6. 
Non-Inferiority Testing .....................................................................................35 
3.2.6.7. 
Superiority Testing ...........................................................................................36 
3.2.6.8. 
Handling of Missing Data for Primary CCS Endpoint .....................................36 
3.2.6.9. 
Handling of Missing Covariate Data For PS Analyses .....................................38 
3.2.6.10. 
Plans to Assess Site Poolability ........................................................................38 
3.2.6.11. 
 ........................................................................................39 
3.2.6.12. 
 .............................................................41 
3.2.6.13. 
Secondary Effectiveness Endpoints ..................................................................42 
3.2.6.14. 
Other Outcomes ................................................................................................44 
3.2.6.15. 
Analysis of Adverse Events ..............................................................................45 
3.2.7. 
Safety Assessment .....................................................................................................47 
3.2.7.1. 
Adverse Events .................................................................................................47 
3.2.7.2. 
Serious Adverse Events (SAE) .........................................................................47 
3.2.7.3. 
Unanticipated Adverse Device Effects (UADE) ..............................................48 
3.2.7.4. 
Adverse Event Recording .................................................................................48 
3.2.7.5. 
Adverse Event and Unanticipated Adverse Device Effect Reporting ..............48 

NuVasive, Inc                             Clinical Study Protocol                             Confidential 
Version Date July 15, 2021 
000003 
3.2.7.6. 
Clinical Events Committee ...............................................................................49 
3.2.7.7. 
Potential Relationship of Adverse Events ........................................................49 
3.2.7.8. 
Assessment of Severity .....................................................................................50 
3.3. 
RISK ANALYSIS ................................................................................................................50 
3.3.1. 
Risks .........................................................................................................................50 
3.3.2. 
Minimization of Risks ...............................................................................................55 
3.3.3. 
Rationale for the Investigation.................................................................................56 
3.4. 
INVESTIGATOR TRAINING, RESPONSIBILITIES AND OBLIGATIONS .....................................56 
3.4.1. 
Investigator Training ...............................................................................................56 
3.4.2. 
Investigator Responsibilities ....................................................................................56 
3.5. 
DEVICE DESCRIPTION .......................................................................................................57 
3.6. 
STUDY MONITORING ........................................................................................................58 
3.6.1. 
Monitoring Organization .........................................................................................58 
3.6.2. 
On Site Monitoring ..................................................................................................58 
3.6.3. 
Data Collection ........................................................................................................60 
3.6.4. 
Initial Device Implantations ....................................................................................60 
3.6.5. 
Review of Study Documents .....................................................................................61 
3.6.6. 
Medical Monitoring .................................................................................................61 
3.6.7. 
Role of Co-Principal Investigators ..........................................................................62 
3.6.8. 
Disposition of Study Devices and Data ...................................................................62 
3.7. 
LABELING .........................................................................................................................63 
3.8. 
INFORMED CONSENT ........................................................................................................63 
3.9. 
ETHICAL CONSIDERATIONS OF THE CLINICAL INVESTIGATION ...........................................64 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
000004 
1. 
NAME AND ADDRESS OF SPONSOR AND REPRESENTATIVES 
1.1. STUDY SPONSOR 
NuVasive, Inc. 
7475 Lusk Blvd. 
San Diego, CA  92121 
Phone: 858-909-1800 
 
 
 
 
 
 
1.2. 
 
 
  
  
 
 
 
1.3.  
 
 
 
 
 
 
     
 
 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
000005 
 
 
 
 
     
  
 
1.4. 
 
 
 
 
 
 
 
1.5. 
 
 
 
 
       
 
 
1.6. 
 
 
 
 
 
 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
000006 
2. 
BACKGROUND 
2.1. DESCRIPTION OF CONDITION 
Cervical radiculopathy, compression of one or more nerve roots in the cervical spine, or 
myelopathy, spinal cord compression, are conditions that can result from degenerated and/or 
diseased discs in the cervical spine.  The true prevalence of cervical radiculopathy is 
uncertain; however, it is estimated that 51% of adults experience neck and arm pain at some 
time in their life.1  A primary cause of these symptoms is degeneration of cervical 
intervertebral discs due to aging.  The resultant pain and neurologic symptoms may lead to 
significant disability.  These conditions are not always isolated to one vertebral level.2  
Rather, these conditions are documented to manifest in more than one cervical level for a 
number of reasons.3 
2.2. CURRENT THERAPIES 
There are several other alternatives for the treatment of intractable radiculopathy or 
myelopathy due to abnormalities localized to the levels of the two contiguous disc spaces at 
two contiguous levels.  
• Traditional options for managing radiculopathy or myelopathy range from 
conservative modalities, such as rest, wearing a neck brace, heat electrotherapy, 
physical therapy, and analgesics.   
• Surgical alternatives include, but are not limited to, surgical decompression and/or 
fusion using various bone grafting techniques or interbody fusion devices, which may 
or may not be used in conjunction with anterior cervical plating (e.g., plate and 
                                                 
1 Furman MB, Cervical Disc Disease.  Available at http://www.emedicine.medscape.com/article/305720-overview#A6 
2 Bryan VE Jr Cervical motion segment replacement Eur Spine J (2002) 11(Suppl.s):S92-S07 
3 Fay LY, Huang WC, Tsai TY, Wu JC, Ko CC, Tu TH, Wu CL, Cheng H. Differences between arthroplasty and anterior 
cervical fusion in two-level cervical degenerative disc disease. Eur Spine J. 2014 Mar;23(3):627-34. 
 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
000007 
screws, or posterior spinal systems (e.g., rods, hooks, wires).  Anterior cervical 
discectomy and fusion (ACDF) with an interbody graft or spacer is the most 
commonly used method for decompression.  
The significant limitations of traditional options and spinal fusion procedures have resulted in 
on-going efforts to develop motion preserving cervical disc prosthesis for both single level 
and for multi-level use.  There are several commercially available artificial disc prostheses 
for single-level use in the cervical spine.  LDR Spine’s Mobi-C© received FDA approval on 
August 23, 2013, thus becoming the first artificial disc to be commercially available in the 
U.S. for two-level use in the cervical spine. Recently, Medtronic also received FDA approval 
for Prestige LP™ to be used at two contiguous levels (July 7, 2016). 
Each alternative has advantages and disadvantages.4 5 
 
                                                 
4 Sasso RC, Smucher JD, Hacker, RJ, Heller JG, (2007) Artificial disc versus fusion.  Spine 32(26):2933-2940 
5 Veeravagu A, Cole T, Jiang B, Ratliff JK, (2014) The Spine Jour 1125-1131 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
000008 
3. 
INVESTIGATIONAL PLAN 
3.1. PURPOSE OF STUDY 
This study is intended to demonstrate that the Simplify® Cervical Artificial Disc (Simplify 
Disc) is at least as safe and effective as conventional anterior cervical discectomy and fusion 
(ACDF) when used to treat two contiguous discs from C3 to C7 following discectomy at two 
contiguous levels for intractable radiculopathy (arm pain and/or a neurological deficit) with  
neck pain or myelopathy due to abnormalities localized to the levels of the two contiguous 
disc spaces in subjects who are unresponsive to conservative management. 
3.2. PROTOCOL STUDY CONDUCT 
3.2.1. 
STUDY DESCRIPTION 
This study will be a multi-center, non-randomized study of the two-level Simplify Disc 
conducted in the United States.  There will be up to 18 sites in the United States enrolling a 
total of N=182 subjects (exclusive of the training subjects).  This study will utilize a non-
concurrent control with subject-level data in a parallel group design.  The historical control 
group will be formed from the randomized ACDF arm (N=188) of 
 
.  Control 
group subjects are from a similar population in which the investigational device is to be 
studied; therefore, adequate control group comparability is expected. The primary 
effectiveness comparison between the investigational device and the control device will be 
‘designed’ using sub classification through propensity score (PS) quintiles (Rosenbaum and 
Rubin, 1983)6 in order to minimize potential selection bias in the estimated device group 
difference in Month 24 composite clinical success rates.  The PS model will be evaluated 
                                                 
6 Rosenbaum PR and Rubin DB. The central role of the propensity score in observational studies for causal effects. 
Biometrika 1983a, 70:41-55. 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
000009 
according to rigorous criteria (Rubin 20017; Imbens and Rubin 2015)8 using a published 
heuristic (Maislin and Rubin 2010)9.  PS analysis is capable of identifying cases when there 
is inadequate comparability to permit valid statistical inference (Yue 200710). 
3.2.2. 
STUDY OBJECTIVES AND HYPOTHESIS 
3.2.2.1. OBJECTIVES 
The objective of this clinical study is to evaluate the safety and effectiveness of the two-level 
Simplify Disc compared to conventional two-level ACDF in skeletally mature patients for 
reconstruction of two contiguous discs from C3 to C7 following discectomy at two 
contiguous levels for intractable radiculopathy (arm pain and/or a neurological deficit) with  
neck pain or myelopathy due to abnormalities localized to the levels of the two contiguous 
disc spaces that are unresponsive to conservative management.  
3.2.2.2. HYPOTHESIS 
The study hypothesis is that in subjects with intractable radiculopathy (arm pain and/or a 
neurological deficit) with neck pain or myelopathy due to abnormalities localized to the 
levels of the two contiguous disc spaces at two contiguous levels from C3 to C7 that are 
unresponsive to conservative management, the Month 24 composite clinical success (CCS) 
rate of the two-level Simplify Disc is not clinically inferior to conventional two-level ACDF 
when success is evaluated at Month 24.  A non-inferiority margin of δ = -0.10 has been 
specified. 
                                                 
7 Rubin DB. For objective causal inference, design trumps analysis. The Annals of Applied Statistics 2008, 2:3:808-840. 
8 Imbens GW and Rubin DB. Causal Inference in the Social and Biomedical Sciences Cambridge University Press 2015. 
9 Maislin G and Rubin DB. Design of Non-Randomized Medical Device Trials Based on Sub-Classification Using 
Propensity Score Quintiles, Topic Contributed Session on Medical Devices. Proceedings of the Joint Statistical Meetings 
2010, pg 2182-2196. 
10 Yue LQ. Statistical and regulatory issue with the application of propensity score analysis to nonrandomized medical 
device clinical studies, Journal of Biopharmaceutical Statistics 2007, 17: 1-13. 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000010 
Overall success is a composite endpoint which will require the following for success: 
• Neck Disability Index (NDI) score improvement of at least 15 points from pre-
operative; 
• Maintenance or improvement in neurological status; 
• No serious adverse event classified as implant associated or implant/surgical 
procedure associated; and  
• No additional surgical procedure classified as a “failure.” 
Overall success will be determined based on data collected during the initial 24 months of 
follow-up.  
3.2.3. 
STUDY POPULATION 
The investigational device population will include 182 subjects enrolled from up to 18 sites 
in the United States.  Subjects will receive the two-level investigational device (Simplify 
Disc).  Each site will also enroll one patient for the purpose of investigational device training. 
 Clinical results from training cases will be summarized separately from the analysis set used 
in comparisons to the ACDF control.  The candidate ACDF control population includes 188 
subjects enrolled from 
 sites. All enrolled subjects from both device groups will be at least 
18 years of age, and will have had at least six (6) weeks of prior conservative therapy or the 
presence of progressive signs or symptoms (e.g., increasing numbness, tingling or decreased 
reflexes) at two contiguous levels from C3 to C7 for intractable radiculopathy (arm pain and 
/or a neurological deficit) with neck pain or myelopathy due to abnormalities localized to the 
levels of the two contiguous disc spaces. This will include the presence of spondylosis 
(defined by the presence of osteophytes) on computed tomography (CT) or magnetic 
resonance imaging (MRI) and/or herniated nucleus pulposus on CT or MRI.  Prospective 
participants must have a Neck Disability Index (NDI score) of at least 30.  All subjects who 
meet the inclusion criteria and do not meet the exclusion criteria, and who elect to participate 
and sign Informed Consent will be included in the study. 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000011 
3.2.3.1. INDICATIONS FOR USE 
Simplify Disc is indicated for use in skeletally mature patients for reconstruction of two 
contiguous discs from C3-C7 following discectomy at two contiguous levels for intractable 
radiculopathy (arm pain and/or a neurological deficit) with neck pain, or myelopathy due to 
abnormalities localized to the levels of the two contiguous disc spaces and at least one of the 
following conditions confirmed by imaging (e.g., computed tomography (CT), magnetic 
resonance imaging (MRI), X-rays): herniated nucleus pulposus and/or spondylosis (defined 
by the presence of osteophytes).  Patients should have failed at least six weeks of non-
operative treatment or have had the presence of progressive symptoms or signs of nerve 
root/spinal cord compression in the face of continued non-operative management prior to 
implantation of the Simplify Disc.  The Simplify Disc is implanted using an anterior 
approach. 
3.2.3.2. INCLUSION CRITERIA 
Prospective subjects must meet all of the inclusion criteria to participate in this clinical study. 
 To be included in the study, the subject must: 
• Has cervical degenerative disc disease at two (2) adjacent cervical levels (from 
C3-C7) requiring surgical treatment and involving intractable radiculopathy, 
myelopathy, or both; 
• Has a herniated disc and/or osteophyte formation at each level to be treated that is 
producing symptomatic nerve root and/or spinal cord compression. The condition is 
documented by patient history (e.g., neck pain with arm pain, functional deficit and/or 
neurological deficit), and the requirement for surgical treatment is evidenced by 
radiographic studies (e.g., CT, MRI, x-rays, etc.); 
• Has been unresponsive to non-operative treatment for at least six weeks or has the 
presence of progressive symptoms or signs of nerve root/spinal cord compression in 
the face of continued non-operative management; 
• Has no previous surgical intervention at the involved levels or any subsequent 
planned/staged surgical procedure at the involved or adjacent level(s); 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000012 
• Must be at least 18 years of age and be skeletally mature at the time of surgery; 
• Has a preoperative Neck Disability Index (NDI) ≥ 30; 
• Has a preoperative neck pain score > 8 based on the preoperative Neck and Arm Pain 
Questionnaire; 
• If a female of childbearing potential, patient is non-pregnant, non-nursing, and agrees 
not to become pregnant during the study period; 
• Is willing to comply with the study plan and sign the Patient Informed Consent Form. 
Muscle strength will be graded for the deltoid (C5), biceps (C6), and triceps (C7) according 
to a 6-point scale where 0 = total paralysis, 1 = palpable or visible contraction; 2 = active 
movement without gravity; 3 = active movement against gravity; 4 = active movement 
against some resistance; and 9 = normal response (active movement against full resistance). 
11 
 
3.2.3.3. EXCLUSION CRITERIA 
To qualify for enrollment in this study, patients must meet none of the exclusion criteria as 
follows: 
• Has a cervical spinal condition other than symptomatic cervical DDD requiring 
surgical treatment at the involved levels; 
• Has documented or diagnosed cervical instability relative to adjacent segments at 
either level, defined by dynamic (flexion/extension) radiographs showing: 
o Sagittal plane translation > 3.5 mm, or 
o Sagittal plane angulation > 20°; 
• Has more than two cervical levels requiring surgical treatment; 
• Has a fused level (or artificial disc replacement) adjacent to the levels to be treated; 
                                                 
11  See Hacker et al., supra note 7, at 2648; Aids to the Investigation of Peripheral Nerve Injuries (UK Medical Research 
Council, War Memorandum No. 7 (2d ed. Rev. 1943). 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000013 
• Has severe pathology of the facet joints of the involved vertebral bodies; 
• Has had previous surgical intervention at either one or both of the involved levels or 
at adjacent levels; 
• Axial neck pain only (no radicular or myelopathy symptoms); 
• Has been previously diagnosed with osteopenia or osteomalacia; 
• Has any of the following that may be associated with a diagnosis of osteoporosis (if 
“Yes” to any of the below risk factors, a DEXA Scan will be required to determine 
eligibility): 
o Postmenopausal non-black female over 60 years of age who weighs less than 
140 pounds;  
o Postmenopausal female who has sustained a non-traumatic hip, spine, or wrist 
fracture; 
o Male over the age of 70; 
o Male over the age of 60 who has sustained a non-traumatic hip or spine 
fracture. 
o If the level of bone mineral density is a T score of -1.5 or lower (i.e., -1.6, 
-1.7, etc.), then the patient is excluded from the study 
• Has presence of spinal metastases; 
• Has overt or active bacterial infection, either local or systemic; 
• Has insulin-dependent diabetes; 
• Has chronic or acute renal failure or prior history of renal disease; 
• Known PEEK, ceramic, titanium allergy; 
• Is mentally incompetent (if questionable, obtain psychiatric consult); 
• Is a prisoner; 
• Is pregnant12; 
                                                 
12  Pregnancy during participation in this study should also be discouraged, since pregnancy may prohibit exposure to X-
rays during necessary follow-up timeframes. 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000014 
• Is currently an alcohol and/or drug abuser or currently undergoing treatment for 
alcohol and/or drug abuse; 
• Is involved with current or pending litigation regarding a spinal condition; 
• Has received drugs that may interfere with bone metabolism within two weeks prior 
to the planned date of spinal surgery (e.g., steroids or methotrexate), excluding 
routine perioperative anti-inflammatory drugs;  
• Has a history of an endocrine or metabolic disorder known to affect osteogenesis 
(e.g., Paget’s Disease, renal osteodystrophy, Ehlers-Danlos Syndrome, or osteogenesis 
imperfecta); 
• Has a condition that requires postoperative medications that interfere with the 
stability of the implant, such as steroids. (This does not include low-dose aspirin for 
prophylactic anticoagulation and routine perioperative anti-inflammatory drugs); 
• Has received treatment with an investigational therapy within 28 days prior to 
implantation surgery or such treatment is planned during the 16 weeks following 
implantation. 
 
NOTE: If a patient does not meet the entry criteria during the initial enrollment, the patient 
should not be re-evaluated for entry into the study at a later time. 
 
3.2.4. 
 
STUDY DESIGN 
3.2.4.1. OVERALL STUDY DESIGN  
Each site will be asked to target a minimum of 10 subjects depending on patient availability.  
Each US site will not be permitted to enroll more than 25 subjects (includes one training 
subject).  The first procedure at each site will constitute a training set. Data from the training 
set will be summarized separately and not used in the primary comparison to control. 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000015 
Investigators will use an anterior surgical approach.  Surgeons will be trained on the 
technique, selection criteria, and protocol for the two-level Simplify Disc clinical study prior 
to their first implantation procedure. 
Subjects will be considered enrolled in the study for the purposes of an intent-to-treat 
analysis, only after they have been treated as determined by the recording of time of incision. 
 Subjects excluded prior to treatment, due to withdrawal of consent, arising medical 
difficulties (e.g., heart attack), documentation of ineligibility by circumstances unforeseen at 
the time of Consent, etc. will be considered screening failures.  Baseline data, including the 
reason for exclusion, will be collected for screening failures.  However, baseline data for 
screen failures may not be complete, as the patient may be determined to be a screen failure 
early in the screening process.  All patients enrolled in the study with a time of incision will 
be included in the "intent to treat" analysis set, regardless of failure to complete the required 
follow-up examinations. 
All radiographic endpoints, including in vivo endplate thickness analysis, will be evaluated 
independently by one core laboratory.  Range of Motion will be measured by this core lab 
using a protocol to determine this measurement incorporating validated techniques to ensure 
reproducibility. 
Neurologic status will be evaluated by a qualified evaluator, who may be an MD, an RN or a 
PA. 
3.2.4.2. CONTROL GROUP 
The proposed ACDF control group is from 
 multi-center, prospective, 
randomized, non-inferiority clinical trial 
 completed in the US. This 
study compared 
 to conventional ACDF for treatment of subjects with 
two-level DDD who are symptomatic at two contiguous levels from C3 to C7 that is 
unresponsive to conservative management. Subjects were treated between 
 and 
. A total of 
 subjects were treated at 
 investigational sites, 
 
subjects in the investigational 
 treatment group, and 188 subjects in the 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000016 
control group (all randomized in a 1:1 ratio).  The amount of time that has passed is relatively 
modest when considering that medical practice concerning conventional ACDF is relatively 
unchanged during this time interval.   
The control treatment was a bi-level fusion procedure with allograft (cortical ring) bone and 
 
. The use of autograft bone from the iliac crest, cancellous 
bone paste, or DBM with the allograft bone was not permitted in the control treatment.  
Closure will be the same for the control group and the investigational device.  There have 
been no important changes in the surgical methods pertaining to conventional ACDF.  
3.2.4.3. STUDY DURATION 
For the purposes of demonstrating safety and efficacy for marketing approval, each subject 
will be followed for at least twenty-four (24) months post treatment.  Subjects will continue 
to be followed thereafter until follow-up is no longer required by FDA.  
 
 
 
For the purposes of this study, subjects will be evaluated pre-operatively, at 
treatment/hospital discharge, and post-operatively at 6 weeks (± 2 weeks), 3 months (± 2 
weeks), 6 months (± 4 weeks), 12 months (± 2 months), 24 months (± 2 months), 36 months 
(± 2 months) and other annual visits (± 3 months) thereafter until the last subject enrolled has 
completed the 24-month evaluation. 
3.2.5. 
STUDY PROCEDURES 
3.2.5.1. INFORMED CONSENT 
Only patients who sign Informed Consent will be allowed to participate in this clinical study. 
Subjects who do not speak English must be provided a copy of an Institutional Review Board 
(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. 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000017 
3.2.5.2. PRE-TREATMENT EVALUATIONS AND DATA COLLECTION 
Pre-treatment evaluations and data collection will include: 
• Radiographic studies for verification of DDD; 
• AP and lateral X-rays (plain films); 
• Flexion-extension X-rays (used to determine range of motion); 
• Lateral bending films;  
• MRI or CT  
• Radiographic core lab evaluations; 
• Dysphagia Handicap Index13; 
• Study related medical history and physical examination; 
• DXA (if indicated as described in Section 3.2.3.3); 
• NDI assessment; 
• SF-36 Health Survey; 
• Neck and arm pain questionnaires (neck, arm, left arm and right arm); 
• Neurologic evaluation; 
• Gait assessment;  
• Work status; 
• Foraminal compression test; 
• Study related medication history and 
• Preoperative Patient Survey (medication and work status). 
All pre-treatment measurements must be done within 6 months prior to surgery. 
The neurologic evaluation will include a motor and sensory assessment and reflex responses. 
Reflexes that are hypo-reflexic will be considered as normal.  Gait abnormality will be 
assessed. 
                                                 
13 Silbergleit, A.K., Schultz, L., Jacobson, B., Beardsley, T. and Johnson, A. The Dysphagia Handicap Index: Development 
and Validation. Dysphagia 2012, 27:46-52. 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000018 
For the purposes of this clinical study, all medications will be recorded preoperatively but 
only medication taken for neck/arm pain including the class of medication, i.e. non-narcotic, 
narcotic (strong and weak), and muscle relaxant, will be collected postoperatively.   
3.2.5.3. TREATMENT PROCEDURES AND EVALUATIONS 
The surgeon will use a standard anterior cervical approach, known as the Smith-Robinson14 
procedure for anterior approach, to the cervical spine.  Details of the Smith-Robinson 
procedure are contained in the Investigator and Study Manuals.  The diseased discs will be 
completely removed using a standard technique, decompressing the anterior surface of the 
spinal canal.  If the surgeon believes that the posterior longitudinal ligaments are 
hypertrophic, ossified, or compressing a neurologic structure (e.g., nerve root or spinal cord), 
the posterior longitudinal ligaments will be removed. If either of the Simplify Discs cannot be 
visualized during implantation, a contrast media may be used.  The Simplify Discs will be 
inserted following the appropriate procedure. 
3.2.5.3.1. 
Simplify Disc  
The surgical technique for implantation of the two level Simplify Disc is described in the 
surgical technique manual. 
3.2.5.3.2. 
ACDF CONTROL 
The conventional two contiguous level ACDF was performed using cortical ring allograft and 
stabilization with 
.  The anterior cervical plate system was 
fixed into place according to standard technique.  Closure will be the same for both the 
control and the Simplify Disc device groups. 
                                                 
14  Smith GW, Robinson RA (1958).  Treatment of certain cervical spine disorders by anterior removal of the intervertebral 
disc and interbody fusion.  JBJS 40:607-23. 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000019 
3.2.5.3.3. 
TREATMENT/HOSPITAL DISCHARGE EVALUATIONS 
Treatment evaluations and data collection obtained during surgery and prior to hospital 
discharge will include: 
• Levels treated; 
• Length of surgery (skin-to-skin); 
• Amount of blood loss;  
• Length of hospital stay; 
• AP and lateral X-rays (plain films); 
• Radiographic core lab evaluations;  
• Neurologic evaluation; 
• Adverse events as defined by Section 3.2.6.1 and Section 3.2.7 of this protocol. 
• 
 
3.2.5.4. POST-TREATMENT EVALUATIONS AND DATA COLLECTION 
3.2.5.4.1. 
POSTOPERATIVE CARE 
Following completion of the procedure, subjects will receive treatment according to a 
standardized postoperative care protocol.  The recommended postoperative regimen for study 
patients is as follows: 
1. Avoid overhead lifting, heavy lifting, and repetitive neck bending for at least 60 days 
postoperatively.  
2. Avoid high-impact/pounding exercising and/or athletic activity for at least 60 days 
postoperatively. Low impact/non-pounding exercising and/or athletic activity is 
permissible.  
3. Avoid prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs) and steroidal 
drugs.  Low dose aspirin for prophylactic anticoagulation and the short-term 
postoperative use of anti-inflammatory medication are acceptable.  

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000020 
4. Postoperative bracing requirements will be left to the discretion of the investigators; 
however, information regarding the type of orthosis used and duration of use will be 
collected on postoperative CRFs. 
5. Electrical bone growth stimulation should not be used for treatment of the cervical 
spine during the 24-month follow-up period.   
6. Patients who are smokers should be encouraged not to smoke. 
7. Unless not medically feasible, the use of NSAIDS in the investigational group is 
recommended for two weeks postoperatively.     
3.2.5.4.2. 
FOLLOW-UP EVALUATIONS AND DATA COLLECTION 
Follow-up evaluations at 6 weeks will include: 
• AP and lateral X-rays (plain films); 
• Flexion-extension X-rays (used to determine range of motion); 
• Postoperative subject survey (medication and subject satisfaction); 
• Physician perception of results 
• Work status; 
• Dysphagia Handicap Index; 
• NDI assessment; 
• Neck and arm pain questionnaires (neck, arm, left arm and right arm); 
• Foraminal compression test; 
• Neurologic evaluation; 
• Gait assessment;  
• Study related medications; 
• Adverse events as defined by Section 3.2.6.1 and Section 3.2.7 of this protocol. 
• 
 
 
Follow-up evaluations at 3 and 6 months will include: 
• AP and lateral X-rays (plain films); 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000021 
• Flexion-extension X-rays (used to determine range of motion); 
• Lateral bending films (starting at 6 months); 
• Radiographic core lab evaluations; 
• Postoperative subject survey (medication and satisfaction); 
• Physician perception of results; 
• Dysphagia Handicap Index; 
• NDI assessment; 
• SF-36 Health Survey (6 months); 
• Neck and arm pain questionnaires (neck, arm, left arm and right arm); 
• Foraminal compression test; 
• Neurologic evaluation; 
• Gait assessment; 
• Study related medications; 
• Work status and 
• Adverse events as defined by Section 3.2.6.1 and Section 3.2.7 of this protocol. 
• 
 
 
Follow-up evaluations at 12 and 24 months will include: 
• AP and lateral X-rays (plain films); 
• Flexion-extension X-rays (used to determine range of motion); 
• Lateral bending films; 
• MRI assessment for Investigational group (24 month); 
• Radiographic core lab evaluations; 
• Postoperative subject survey (medication and satisfaction); 
• Dysphagia Handicap Index; 
• NDI assessment; 
• SF-36 Health Survey; 
• Neck and arm pain questionnaires (neck, arm, left arm and right arm); 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000022 
• Foraminal compression test; 
• Physician perception of results; 
• Neurologic evaluation; 
• Gait assessment; 
• Study related medications; 
• Work status; 
• Adverse events as defined by Section 3.2.6.1 and Section 3.2.7 of this protocol and 
• 
 
 
Subjects who complete their 24 month visit prior to the last study subject’s completion of the 
24 month visit will continue to be followed annually until the last subject enrolled has 
completed the 24 month evaluation.  However, for the purpose of primary safety and efficacy 
evaluations, the study completion/ termination assessment will be made at 24 months 
postoperatively, or at an earlier time point if the subject withdraws or is withdrawn from the 
study. 
 
Follow-up evaluations annually after 24 months will include: 
• AP and lateral X-rays (plain films); 
• Flexion-extension X-rays (used to determine range of motion); 
• Lateral bending films; 
• Radiographic core lab evaluations; 
• Postoperative subject survey (medication and satisfaction) 
• Dysphagia Handicap Index; 
• NDI assessment; 
• SF-36 Health Survey; 
• Neck and arm pain questionnaires (neck, arm, left arm and right arm); 
• Foraminal compression test; 
• Physician perception of results; 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000023 
• Neurologic evaluation;  
• Gait assessment; 
• Study related medications; 
• Work status; 
• Adverse events as defined by Section 3.2.6.1 and Section 3.2.7 of this protocol and. 
• 
  
3.2.5.4.3. 
RADIOGRAPHIC ASSESSMENTS 
For the purposes of data capture, 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: 
• Intervertebral Angle; 
• Change in Intervertebral Angle; 
• Horizontal Translational; 
• Change in Horizontal Translational; 
• Global Range of Motion; 
• Change in Global Range of Motion; 
• Disc Height (assessed by determining Functional Spinal Unit [FSU] height and by 
directly measuring height of disc space) 
• Change in Disc Height; 
• Disc Angle; 
• Change in Disc Angle; 
• Spondylolisthesis; 
• Change in Spondylolisthesis; 
• Device Condition; 
• Device Bending; 
• Device Breaking; 
• Device Fracture; 

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000024 
• Device Subsidence (can also be derived with FSU Height); 
• Device Migration; 
• Device Protrusion; 
• Radiolucency; 
• Heterotopic Ossification; 
• Bridging Bone; 
• Maintenance of PreOp Motion; 
• Osteophyte Formation; 
• Endplate Sclerosis; 
• Kellgren-Lawrence Adjacent Level Disc Degeneration; 
• Facet Degeneration; 
• Stenosis; 
• Modic Changes; 
• Cysts and 
• Additional Observations. 
 
This in vivo endplate thickness analysis will analyze a consecutive series of the first 25 
subjects who complete the 24 month visit and any subject with an explant and/or SAE/severe 
AE that is judged to be implant-associated or implant/surgical procedure-associated.  The 
analysis will be performed using available x-rays from the discharge, 12 Month, 24 Month 
visits and annually thereafter as set forth in the core lab protocol. 
3.2.5.4.4. 
 
 
 
 
 
  

NuVasive, Inc                                  Clinical Study Protocol                              Confidential 
Version Date July 15, 2021 
0000025 
• 
 
 
 
 
 
 
3.2.5.4.5. 
STUDY COMPLETION, TERMINATION OR LOSS TO FOLLOW-UP 
Subjects are expected to remain in the study for at least 24 months following treatment.  
Subjects who complete their 24 month visit prior to the last study subject’s completion of the 
24 month visit will continue to be followed annually until the last subject enrolled has 
completed the 24 month evaluation. Subjects will continue to be followed thereafter until 
follow-up is no longer required by FDA.  However, for the purpose of primary safety and 
efficacy evaluations, the study completion/ termination assessment will be made at 24 months 
postoperatively, or at earlier time point if the subject withdraws or is withdrawn from the 
study.  Missed patient evaluations after the point of withdrawal will not be considered 
protocol deviations. 
Subjects may be withdrawn from a clinical study early due to withdrawal of Informed 
Consent, death, lost to follow-up, or Investigator medical decision.  Each premature 
termination from the study must have the reason for their withdrawal from the study 
documented in both the source documents and on the applicable case report form. 
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 Investigator and Study 
Manuals.  Any subjects with either or both of the Simplify Discs removed will be followed, 
but follow-up subsequent to these events will be summarized separately, if the subject has not 
withdrawn consent.

NuVasive, Inc. 
        Clinical Study Protocol                                                                        Confidential 
Version Date July 15, 2021 
0000026 
3.2.5.5. DATA COLLECTION SUMMARY 
Time Point 
Pre-op1 
Tx/ 
Discharge2 
6 wks3 
 
3 mo3 
6 mo3 
12 mo3 
24 mo3 
Post 24 mo3 
Informed Consent 
X 
 
 
 
 
 
 
 
DDD assessment (MRI, CT or X-ray) 
X 
 
 
 
 
 
 
 
Medical History & Physical Examination 
X 
 
 
 
 
 
 
 
DXA 
X 
 
 
 
 
 
 
 
AP & Lateral X-rays 
X 
X 
X 
X 
X 
X 
X 
X 
Flexion & Extension X-rays 
X 
 
X 
X 
X 
X 
X 
X 
Lateral bending X-rays 
X 
 
 
 
X 
X 
X 
X 
MRI (or CT at Pre-op only); Investigational 
group only at 24M 
X 
 
 
 
 
 
X 
 
Radiographic Core Lab Assessments 
X 
X 
X 
X 
X 
X 
X 
X 
Preoperative Patient Survey 
X 
 
 
 
 
 
 
 
Dysphagia Handicap Index 
X 
 
X 
X 
X 
X 
X 
X 
NDI 
X 
 
X 
X 
X 
X 
X 
X 
SF-36 Health Survey 
X 
 
 
 
X 
X 
X 
X 
Neck and Arm Pain Questionnaires 
X 
 
X 
X 
X 
X 
X 
X 
Foraminal Compression Test 
X 
 
X 
X 
X 
X 
X 
X 
Physician Perception of Results  
 
 
X 
X 
X 
X 
X 
X 
Neurologic Exam 
X 
X 
X 
X 
X 
X 
X 
X 
Gait Assessment 
X 
 
X 
X 
X 
X 
X 
X 
Medications 
X 
 
X 
X 
X 
X 
X 
X 
Work Status 
X 
 
X 
X 
X 
X 
X 
X 
Treatment Assessments 
 
X 
 
 
 
 
 
 
Postoperative Subject Survey 
 
 
X 
X 
X 
X 
X 
X 
  
 
 
Adverse Event Assessment 
N/A 
As needed 
Study Completion/ Termination 
N/A 
N/A 
As needed 
a. If indicated as described in Section 3.2.3.3 of this Protocol. 
b. Made by two Core labs using radiographs. 
 
c. CT acceptable if MRI not available at Pre-op only. 
Study windows: 
1. 
Pre-treatment evaluations may be taken up to 6 months prior to surgery; pre-op medications should include medications to the subject is currently taking at the time of 
the pre-treatment evaluation. 
2. 
Surgery/discharge evaluations must be taken prior to hospital discharge. 
3. 
Follow-up visit evaluations will be taken at 6 weeks (± 2 weeks), 3 months (± 2 weeks), 6 months (± 4 weeks), 12 months (± 2 months) and 24 months (± 2 months) and 
annually thereafter. The study visit window for 36 months is (± 2 months) visits post 36 months is + 3 months. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000027 
3.2.6. 
STATISTICAL CONSIDERATIONS 
3.2.6.1. PRIMARY ENDPOINT 
The study hypothesis is that in subjects with intractable radiculopathy (arm pain and/or a 
neurological deficit) with neck pain or myelopathy due to abnormalities localized to the 
levels of the two contiguous disc spaces at two contiguous levels from C3 to C7 that is 
unresponsive to conservative management, the Month 24 composite clinical success (CCS) 
rate of the two-level Simplify Disc will be no worse than conventional two-level ACDF when 
success is evaluated at Month 24. 
Individual success for both the investigational and control groups is defined as: 
• Neck Disability Index (NDI) score improvement of at least 15 points from pre-
operative; 
• Maintenance or improvement in neurological status15,16; 
• No serious adverse event classified as implant associated or implant/surgical 
procedure associated; and  
• No additional surgical procedure classified as a “failure.” 
Overall success will be determined based on data collected during the initial 24 months of 
follow-up.  Each element of the neurological study exam will be evaluated for maintenance 
or improvement.  
All secondary index surgeries will be classified as failures.  
Per FDA Guidance for the Preparation of IDEs for Spinal Systems, the following definitions 
apply:* 
                                                 
15 Maintenance or improvement in neurological status will be based on motor, sensory, and myelopathic gait assessments. 
16 Due to COVID-19, not all 24M visits (entire or portion) are able to occur in-person. If a 24M in-person visit does not 
occur, the 12M result will be carried forward to represent unavailable 24M results in the primary endpoint and subsequently 
adjudicated by the CEC. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000028 
• Reoperation - any surgical procedure at the index level(s) that does not involve 
modification, addition or removal of any components of the device and is not 
considered a removal, revision, or supplemental fixation. 
• Revision – any procedure in the postoperative or follow-up period that adjusts or in 
any way modifies either one or both of the original implant configurations (e.g., 
adjusting the position of the original configuration, removal with replacement with 
same type of study implant). 
• Removal – a procedure that removes one or more components of the original implant 
configuration without replacement with the same type of trial implant. 
• Supplemental fixation – a procedure at the index level(s) in which additional spinal 
devices not approved as part of the protocol are placed.  
• Other – any additional surgical procedure not classified as a removal, revision, 
supplemental fixation, or reoperation. 
  
3.2.6.2. STUDY SUCCESS 
The null hypothesis is that the probability of achieving Month 24 composite clinical success 
(CCS) for patients implanted with the Simplify Disc device at two levels is no more than 0.10 
smaller than the probability of two-level ACDF control patients achieving Month 24 CCS.  
This study will be considered a success if the 1-sided p-value for rejecting this null 
hypothesis is less or equal to than 0.05. 
3.2.6.3. STUDY DESIGN 
The 188 control subjects from 
 
will be used to form a valid control group for determining the safety and effectiveness 
of the Simplify Disc device. Effectiveness comparisons will be performed using sub 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000029 
classification through propensity score (PS) quintiles (Rosenbaum and Rubin, 1983)17. This 
approach directly addresses potential selection bias inherent in non-randomized comparisons. 
 The PS model will be evaluated according to rigorous criteria (Imbens and Rubin 2015)18 
using a published heuristic (Maislin and Rubin 2010)19.  Applications of this heuristic have 
been recently published (e.g., Keenan, Maislin, et al 201420; Arnardottir, Lim, Keenan, 
Maislin et al 201421; and Pak, Keenan, Jackson, Grandner, Maislin et al 201422). The 
heuristic is designed to identify 5 sub classes in which the groups to be compared share the 
same multivariate distribution of a comprehensive set of baseline variables. Within each sub 
class, subjects are therefore equally likely to have received the Simplify Disc or conventional 
ACDF. The propensity score is the observational study analogue of complete randomization 
in randomized experiments in the sense that its use is not intended to increase precision but 
only to eliminate systematic biases in treatment-control comparisons (Rubin 2008)23.  
Moreover, the "propensity score technique allows the straightforward assessment [of] 
whether the treatment groups overlap enough regarding baseline covariates to allow for a 
sensible treatment comparison" (Yue 2007)24. 
The PS sub classes will be formed when the prospective enrollment is completed in the 
investigational group.  The standard implementation of the PS sub classification including 
iterative ‘trimming’ of subjects from the extremes of the PS distributions for both the 
                                                 
17 Rosenbaum PR and Rubin DB. The central role of the propensity score in observational studies for causal effects. 
Biometrika 1983a, 70:41-55. 
18 Imbens and Rubin D. Causal Inference in the Social and Biomedical Sciences Cambridge University Press 2015 (in 
press) 
19 Maislin G and Rubin DB. Design of Non-Randomized Medical Device Trials Based on Sub-Classification Using 
Propensity Score Quintiles, Topic Contributed Session on Medical Devices. Proceedings of the Joint Statistical Meetings 
2010, pg 2182-2196. 
20 Keenan BT, Maislin G, Sunwoo BY, Arnardottir ES, Jackson N, Olafsson I, Juliusson S, Schwab RJ, 
Gislason T, Benedikstdottir B, Pack AI. Obstructive sleep apnoea treatment and fasting lipids: a comparative 
effectiveness study. Eur Respir J. 2014 May 15. 
21 Arnardottir ES, Lim DC, Keenan BT, Maislin G, Benediktsdottir B, Juliusson S, Pack AI, Gislason T. Effects of obesity 
on the association between long-term sleep apnea treatment and changes in interleukin-6 levels: the Icelandic Sleep Apnea 
Cohort. J Sleep Res. 2014 Oct 31. doi: 10.1111/jsr.12252. [Epub ahead of print]. 
22 VM Pak, BT Keenan, N Jackson, MA Grandner, G Maislin, K Teff, RJ Schwab, ES Arnardottir, S Júlíusson, B 
Benediktsdottir, T Gislason, AI Pack.  Adhesion molecule increases in sleep apnea: beneficial effect of positive airway 
pressure and moderation by obesity. Int J Obes (Lond). 2014 Jul 21. 
23 Rubin D. For objective causal inference, design trumps analysis. The Annals of Applied Statistics 2008, 2:3:808-840. 
24 Yue LQ. Statistical and regulatory issue with the application of propensity score analysis to nonrandomized medical 
device clinical studies, Journal of Biopharmaceutical Statistics 2007, 17: 1-13. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000030 
investigational device and controls in order for the Imbens and Rubin 2015 PS model 
estimation validity criteria to be met and maximum internal validity of the statistical 
inference. In response to FDA concerns that trimming of investigational device patients can 
lead to challenges with regard to labeling, the heuristic described by Maislin and Rubin 2010 
has been modified to force retention of all investigational device patients.  While it is 
recognized that this may reduce internal validity of the inference, the modified heuristic 
maximizes external validity since the investigational device analysis set corresponds exactly 
to the indicated population.  In general, trimming of control patients are allowed given the 
goal of creating a control population that is as similar as possible to the enrolled 
investigational device patients. We note, however, that it may not be possible to achieve the 
desired Rubin criteria while also retaining every investigational device participant due to bias 
introduced by lack of propensity score overlap which reflects lack of covariate balance.  In 
the case that a final PS designed sample that excludes device participants is required, 
effectiveness results from non-selected investigational device patients will be summarized 
separately, compared to those selected for inclusion into a PS subclass, and evaluated in 
effectiveness sensitivity analyses with implications discussed in the clinical study reports 
submitted for regulatory review. No matter what, all investigational device patients will be 
included in safety analyses in order to maximize the external validity of the observed safety 
profile.   Only the baseline data used in the PS design will be summarized for trimmed 
controls. 
It is important to note that the sequential model building process used to identify an analysis 
data set for which there is adequate covariate balance within subclasses, poses no concern for 
Type I error inflation. This is because the PS model building process makes no use of 
outcome data. To avoid bias, no outcome data will be provided to the statistician who will be 
forming the PS sub classes; and the model identification process will be documented in a 
series of iterations as described in [Maislin and Rubin 2011]. That is, the sequential model-
building heuristic should be viewed as part of the 'design of the observational study'. Here 
'design' may be interpreted as "contemplating, collecting, organizing, and analyzing of data 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000031 
that takes place prior to seeing any outcome data (Rubin 2008)25". At its conclusion, 
verification of balance between device groups within sub class will be done through easily 
interpretable graphical means. 
Given the expected similarity of the populations from which the investigational and control 
groups will be obtained and the specificity of the clinical indication, it is expected that no 
more than 20% of the ACDF controls will require trimming.  The sample size analysis 
described below accounts for up to 20% trimming of ACDF.  It is assumed that no 
investigational device patients will be trimmed and so no adjustment for investigational 
device trimming is included in the sample size analysis.  Should there be investigational 
device trimming, it is expected that the number of investigational device patients requiring 
trimming will be very small with no appreciable effect on statistical power. 
We acknowledge that because the proposed propensity score design can only assess the 
comparability of the two groups after the prospective enrollment has been completed, there 
can be significant risk that in the end the data may not be comparable.  The sample size 
determination accounts for up to 20% of the ACDF subjects to be trimmed in the iterative 
heuristic used to construct PS sub classes that meet Rubin’s validity criteria.  The risk of 
insufficient sample sizes due to more than 20% control group trimming can be mitigated by 
continuing enrollment into one the investigational device group should this be needed to 
obtain the required sample sizes for 80% power to reject the non-inferiority null hypothesis.  
An evaluation of the variable collected in the 
 study indicate that all component 
variables necessary to formulate the relevant composite clinical endpoints will be available.  
Any differences in endpoint evaluation are due to the nature of the difference between 
artificial discs and fusion procedures. The components of the CCS will be evaluated in the 
same fashion for the ACDF control as they are to be evaluated for Simplify Disc enhancing 
comparability of results from the two studies. Although composite clinical success requires a 
threshold improvement in the Neck Disability Index (NDI), the “NDI is the oldest and most 
                                                 
25 Rubin D. For objective causal inference, design trumps analysis. The Annals of Applied Statistics 2008, 2:3:808-840. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000032 
widely used instrument for self-reporting of disability due to neck pain. Its internal 
psychometric properties have been well established in numerous cultural groups with neck 
pain: it is highly reliable, strongly internally consistent, and with a 1-factor structure for 
“physical disability.” It has strong and well-documented convergent and divergent validity 
with other instruments used in the evaluation of patients and subjects with neck pain” 
(Vernon 2008)26.  The minimum clinically important difference in cervical spine fusion 
surgery was established to be 15 points out of 100 (Carreon, Glassman and Campbell 
2010)27. 
Similarly, an evaluation of the baseline variables collected in the 
 study indicate 
that a sufficiently rich set of common baseline covariates were collected in both studies.  A 
key exception to this is the baseline pain instrument.  The 
study utilized a 
numerical rating scale while the Simplify study was originally designed to use a 100 mm 
VAS.  In order to have comparability with regard to this key baseline covariate and for 
evaluations during the follow-up period, the Simplify study will now also utilize a numerical 
rating scale.  The very small number of patients enrolled into the Simplify study evaluated 
with a baseline VAS will be included in the analysis with baseline VAS imputed as missing 
values as described below. 
In summary, the above factors lead to the reasonable expectation that the design of the 
observational study using PS sub classes will result in statistical estimates of treatment group 
differences in Month 24 composite clinical with acceptably low bias.  
At the conclusion of the PS sub-classification but prior to unblinding the statistician 
responsible for the PS analysis, results will be distributed to key stakeholder including model 
building process, summary of optimality criteria, and tabular and graphical summarizes of 
                                                 
26 Vernon H. The Neck Disability Index: State of the Art 1991-2008. Journal of Manipulative and Physiological 
Therapeutics 2008, September 491-502. 
27 Carreon LY, Glassman SD, Campbell MJ et al. Neck Disability Index, short form-36 physical component summary, and 
pain scales for neck and arm pain: the minimum clinically important difference and substantial clinical benefit after cervical 
spine fusion. Spine J. 2010;10:469-74. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000033 
achieved covariate balance.  This will include the use of a “Love Plot” (Ahmed et al 200628 ) 
that compares balance before and after application of the PS sub-classification heuristic, 
adjusting for PS subclasses. 
3.2.6.4. SAMPLE SIZE ANALYSIS 
The current study is designed to demonstrate non-inferiority using a non-inferiority margin 
equal to -10.0% at a 1-sided type 1 error rate of α=0.05.  Subclassification using propensity 
score (PS) quintiles will be used to minimize selection bias arising from the non-randomized 
device group comparison.  Mantel-Haenszel stratified analyses accounting for PS subclass 
will utilized when testing the primary non-inferiority hypothesis. A total of 182 two-level 
investigational subjects will be enrolled and compared to two level ACDF control subjects.  
The pool of two level ACDF control subjects includes a sample size of N=188.  The sample 
size analyses below demonstrate that these sample sizes are sufficient to test the primary non-
inferiority hypothesis after accounting for loss-to-following and PS ‘trimming’ of controls 
during the observational design phase.   
According to Table 28 contained in the 
 SSED, the overall 
success was achieved in 
 controls. Therefore, the control group Month 24 
CCS probability was assumed to be 70%.   The total control sample size reported in the 
SSED is N=188.  Since selection into a PS sub class will be conducted without access to 
outcome data, it is assumed that 85% of the selected controls will have a complete Month 24 
CCS endpoint.  It is also assumed that up to 20% of the controls will be trimmed as part of 
the PS modeling process.  Therefore, for purpose on initial sample size analysis, the control 
sample size is assumed to be N = 188 * .85 * .80 = 128.   
It is noted that the 2-level 
 group experienced an 
 success 
rate.  For the purpose of sample size analysis, it is assumed that the 2-level Simplify disc 
                                                 
28 Ahmed A, Husain A, Love TE, et al. Heart failure, chronic diuretic use, and increase in mortality and hospitalization: an 
observational study using propensity score methods. Eur Heart J 2006; 27(12): 1431-9. 
 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000034 
group will have at least a small true superiority margin of 3.5%.  That is, it was assumed that 
the true probability of Month 24 CCS for the investigational group is 75.0%.  As noted 
above, the primary effectiveness hypothesis is non-inferiority with a non-inferiority margin of 
-0.10 to be tested using at one-sided α=0.05.  With these assumptions, 154 investigational 
device patients are required for 80% statistical power as determined using industry standard 
software (nQuery Advisor 7.0 module PTE0U-1).   
“When the sample sizes in the groups are 128 and 154, a two-group large-sample normal 
approximation test of proportions with a one-sided 0.050 significance level will have 80% 
power to reject the null hypothesis that the test and the standard are not equivalent (the 
difference in proportions, pT - pS, is -0.100 or farther from zero in the same direction) in 
favor of the alternative hypothesis that the proportions in the two groups are equivalent, 
assuming that the expected difference in proportions is 0.035 and the proportion in the 
standard group is 0.700.”  
To account for up to 15% loss-to-follow-up, the total enrolled investigational sample size 
will be N=182.   
 
3.2.6.5. ANALYSIS SETS 
The study contains two treatment arms with patients receiving either two-level Simplify Disc 
or two-level ACDF. The following subject groups or analysis sets will be used to complete the 
analysis of data. 
• Intent-to-treat (ITT) analysis set: The ITT analysis set will include all enrolled patients in 
which treatment was attempted as defined by the recording of incision time and excluding 
training cases.  Patients will be included according to their intended treatment device.  Since 
the investigational and control treatments are to be performed at different institutions, it is 
not possible for subjects to receive the alternative treatment. Therefore, the ITT analysis set 
will be used in safety analyses.  

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000035 
• Primary Effectiveness (PE) analysis set:  The PE analysis set includes all subjects in 
the ITT analysis set that are selected into a propensity score subclass. Primary 
effectiveness analyses will be conducted using the PE analysis set.  Selection into a 
PS subclass is the observational study equivalent to being randomized.  Intraoperative 
failures will be included in primary non-inferiority testing as composite clinical endpoint 
failures.  Patients with no follow-up subsequent to surgery will be treated as having a missing 
primary composite clinical endpoint and will be handled according to the approaches 
outlined below. 
• Per protocol (PP) analysis set: The PP analysis set will include patients in the PE 
analysis set that have no major protocol deviations including clinically significant 
deviations from inclusion or exclusion criteria.  Secondary efficacy analyses will be 
performed using the PP analysis set. 
• Training cases analysis set: Training case safety and effectiveness data will be 
summarized separately. 
• Original Protocol (OP) analysis set: All patients enrolled in the original protocol prior 
to approval of the subject protocol with the 
 historical control will 
be analyzed separately to determine if they would meet the current patient enrollment 
criteria. OP safety and effectiveness will be summarized separately and compared to 
the ITT analysis set. Please note, due to the small sample size, these comparisons will 
lack statistical strength and will be provided for informational purposes only. 
3.2.6.6. NON-INFERIORITY TESTING 
The primary non-inferiority test will be conducted using a Mantel-Haenszel stratified analysis 
approach to pool over PS subclass specific estimated device group differences.  If the one-
sided p-value for non-inferiority is less than or equal to 0.05, it will be concluded that the 
two-level Simplify Disc is non-inferior to the two-level ACDF control.  In addition to 
hypothesis testing, the lower bound of a one-sided 95% confidence for the true difference of 
the device group difference will be determined.  

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000036 
3.2.6.7. SUPERIORITY TESTING 
If the non-inferiority study success criterion is met, superiority testing will be performed in 
the PE analysis set.  It will be concluded that the two-level Simplify Disc is superior to the 
two-level ACDF control if the one-sided p-value for superiority is less than or equal to 0.025. 
By the closed testing principal there is no need for a multiplicity adjustment when testing 
superiority after rejecting the inferiority null hypothesis.  Note that 1-sided α=0.025 is 
specified for testing of superiority rather than 0.05 in order to have more definitive evidence 
to support the stronger claim of superiority. 
3.2.6.8. HANDLING OF MISSING DATA FOR PRIMARY CCS ENDPOINT 
The first approach to be used to handle missing data for the primary CCS endpoint is to limit 
the expected amount of missing data through exceptional study conduct and management and 
this is the goal of all study personnel.  However, some missing data from lost to follow-up is 
inevitable in these types of clinical trials.  Moreover, it is known that some control patients 
were not evaluable for the primary Month 24 CCS endpoint.   
The following two approaches will used in testing of the clinical non-inferiority hypotheses 
stated above.   
1) 
Complete case analysis followed by tipping point sensitivity analysis (see below); and 
2) 
Multiple imputation (MI) (see below).  
The primary non-inferiority test will be conducted using the multiple imputation approach 
described below.  The complete case analysis followed by tipping point analysis will be 
performed as a sensitivity analysis for the assumptions inherent in MI. 
Multiple imputation (MI)29 is a methodology used to address missing values due to LTF and 
possibly other reasons.  The validity of MI depends on an untestable assumption known as 
                                                 
29 Rubin DB and Schenker N. Multiple imputation in health-care databases: An overview and some applications. Statistics 
in Medicine 1991 10:585-598. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000037 
missing at random (MAR)30 which is a much weaker assumption than missing completely at 
random (MCAR) which requires unconditional independence.  Although MAR is likely to 
hold in many more situations than MCAR, in any given situation there is no way to confirm 
whether the assumption of MAR is tenable and consequently, whether or not the MI analysis 
produces valid inference.  For this reason, a complete case analysis followed by a tipping 
point sensitivity analysis will be conducted in sensitivity analyses (see below).  MI will be 
used to impute missing final NDI in patients otherwise evaluable for primary CCS. For each 
imputation, the composite endpoints would be constructed from the imputed NDI values and 
within randomly completed data sets, the device group difference and standard error is 
determined.  For these imputations, the status of the other CCS components will be based on 
available data up to the point of loss-to-follow-up which is essentially a last-observation-
carried forward approach.  In this case, the patient’s Month 24 secondary surgical 
intervention status, major device-related complication status, and neurological success status 
will be inferred from their Month 12 status.  Imputations for NDI will be repeated 20 times to 
produce 20 randomly completed data sets.  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 as described in Rubin and Schenker 1991.  The MI 
standard error will be used in the derivation of the p-value to test the non-inferiority 
hypothesis.  MI analyses will be performed using SAS31 Proc MI and MIANALYZE or their 
equivalent.    
A complete case analysis followed by a tipping point analysis will be conducted to 
complement the primary MI approach in order to evaluate the robustness of statistical 
conclusions to the assumptions inherent in MI analyses.  This includes the untestable 
assumption; namely, that the probability that a value is missing is independent from the value 
itself conditional on baseline values and clinical status up to the point.  In a tipping point 
analysis, missing values in each group are separately assumed to be either successes or 
                                                 
30 Rubin DB Inference and missing data.  Biometrika 1976, 63:581-592. 
31 SAS Institute, Cary NC.  

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000038 
failures.  Treatment group differences will be computed based on all possible combinations 
of assigning success or failure to the primary overall success endpoint to the patients in the 
two groups.  For example, one scenario will be that all missing two-level Simplify values are 
failures and all missing two-level ACDF values are successes. The next scenario would have 
one success and the remaining missing values as failure for two-level Simplify keeping all 
missing two-level ACDF as successes, and so forth. The 1-sided p-value for testing the 
primary non-inferiority hypotheses will be determined for each scenario. These results will be 
plotted using a dot plot with the number of missings assumed as failures for two-level 
Simplify on the x-axis and the number of missing assumed as failures for two-level ACDF on 
the Y-axis.  The dots will be color coded to indicate whether or not the primary statistical 
conclusion changes under each individual scenario.  If the fraction of scenarios in which the 
statistical conclusion changes is small, the primary results will have been shown to be robust 
against assumptions concerning missingness. 
3.2.6.9. HANDLING OF MISSING COVARIATE DATA FOR PS ANALYSES 
The amount of missing baseline covariate to be used in the PS analysis is expected to be very 
small.  This includes the missing numerical rating scores for a very small number of 
investigational device patients (~10) that were enrolled based on VAS pain scores. Prior to 
PS analysis, missing baseline covariates will be imputed using a single imputation based on 
multiple linear regression for continuous baseline covariates and multiple logistic regression 
for missing dichotomous baseline covariates.  
 
3.2.6.10. 
PLANS TO ASSESS SITE POOLABILITY 
Since different institutions are enrolling patients into the investigational and control groups, it 
is not possible to evaluate between site differences in relative efficacy.  Therefore, analyses 
will focus on evaluating site variability in percentages of subjects achieving Month 24 CCS. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000039 
A random effects meta-analysis approach (DerSimonian and Laird32) will be used to evaluate 
whether there is more site variability that can be explained by within site sampling 
variability.  Success rates will be transformed to stabilize variances to meet the normality 
assumptions inherent in this approach.  Site specific transformed success rates are assumed to 
follow a normal distribution with mean µ and variance τ2.  The magnitude of site-to-site 
variability in the transformed success rates will be quantified using the I2 statistics (Higgins et 
al 200433). I2 is the fraction of τ2 that is due to effect size heterogeneity, as opposed to 
sampling variance. Higgins et al indicate that, “A naive categorization of values for I2 would 
not be appropriate for all circumstances, although we would tentatively assign adjectives of 
low, moderate, and high to I2 values of 25%, 50%, and 75%”.  
Therefore, the key quantitative assessment of whether or not site-to-site variability in 
treatment effect is important will involve the comparison of the observed I2 value to the 
above guidelines.  In addition to I2, the statistical significance of the site-to-site variability 
will be determined using the Q statistic with degrees-of-freedom equal to the number of sites 
minus 1.  Sites contributing less than 6 patients will be combined prior to these analyses.  If 
significant site variability is observed, sites will be removed one-at-time to identify site(s) 
contributing significant treatment effect heterogeneity and the identified site subjected to 
additional analyses aimed at understanding the cause of this heterogeneity. 
3.2.6.11. 
 
 
 
 
 
 
                                                 
32 DerSimonian R and Laird NM. Meta-analysis in clinical trials.  Journal of Controlled Clinical Trials, 1986; 7:177-188. 
33 Higgins JP, Thompson SG, Deeks JJ, and Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003, 327(7417): 
557-560. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000040 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000041 
3.2.6.12. 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
 
 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000042 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2.6.13. 
SECONDARY EFFECTIVENESS ENDPOINTS 
Secondary endpoints include: 
• Clinically significant improvement in one or more radicular symptoms or 
myelopathy at each post-operative time point compared to baseline for the 
investigational two-level Simplify Disc and the two-level ACDF control group.  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 Pain questionnaires will be used to evaluate each of the following pain 
locations: 
 Neck pain 
 Arm pain 
 Left arm pain (investigational group only); 
 Right arm pain (investigational group only); 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000043 
Success is predicated on maintenance or improvement in neck and arm pain 
status according to the following equation: 
Preoperative Score - Postoperative Score > 0 
(Score = pain intensity + pain duration). 
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.35 
• Time to recovery (time to first 15-point NDI improvement). 
• Disc height (FSU Height) at each post-operative time point compared to baseline (6 
weeks). Both levels have to be a disc height success to claim success for overall disc 
height.  Disc height success for each level is based on either the anterior or posterior 
measurements meet the following criterions: 
       
Postoperative Height – 6 Week Postoperative Height ≥ -2mm  
• Adjacent level deterioration at 24 months compared to baseline for the 
Investigational group. 
• Displacement or migration of the device for the Investigational group; only changes 
of > 3 mm will be considered significant due to the margin of error in radiographic 
determination of displacement distances. 
• Return to work status postoperative.  
• Subject satisfaction and perceived effect at each applicable postoperative timepoint.  
Success for each satisfaction question (three) will be defined as either a “Definitely 
True” or “Mostly True” response.  Success for the perceived effect will be defined as 
either a “Completely Recovered,” “Much Improved,” or “Slightly Improved” 
response. 
                                                 
35  Hacker et al., supra note 7. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000044 
• Health Survey (SF-36) at each applicable postoperative time point compared to 
baseline.  Success will be expressed in terms of the PCS (physical component 
summary) and MCS (mental component summary) scores and will be defined as a 
maintenance or improvement in status postoperatively as compared to the 
preoperative condition. To be classified as a success for each component summary, 
the following criteria must be met: 
       
PCSPostop - PCSPreop ≥0  
             
MCSPostop - MCSPreop ≥0 
• Dysphagia Handicap Index (DHI scale) at each applicable postoperative time point 
compared to baseline for the Investigational group. 
• Facet deterioration at 24 months compared to baseline for the Investigational group. 
• Adjacent Level Motion (Stability) will be compared at each applicable postoperative 
time point to baseline. 
• Results at each applicable postoperative time point will also be categorized by the 
physician’s perception of the subject’s condition (excellent, good, fair, or poor). 
• Gait assessment at each applicable time point compared to baseline.  This will be 
based on Nurick’s classification.  Success will be defined as maintenance or 
improvement in the postoperative status as compared to the preoperative condition: 
Preoperative Score – Postoperative Score ≥0 
 
3.2.6.14. 
OTHER OUTCOMES 
Other outcomes to be measured include: 
• Duration of hospitalization; 
• Blood loss; 
• Operative time (skin incision to skin closure);  
• In vivo endplate thickness analysis will be completed on a consecutive series of the 
first 25 subject who complete the 24 month follow up visit.      

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000045 
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 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.  
Subgroup Analyses 
Primary and secondary effectiveness endpoints will be evaluated in subgroups defined by 
stratifying the primary effectiveness analysis set.  Safety endpoints will be evaluated in 
subgroups defined by stratifying the safety analysis set.  Subgroups to be evaluated will 
include, but not limited to: 
Gender (Male vs. Female) 
Age (Median cut point, ≥ 55 and < 65 years) 
Height (Median cut-point) 
Weight (Median cut-point) 
BMI (Median cut-point) 
Comorbidities 
3.2.6.15. 
ANALYSIS OF ADVERSE EVENTS 
This section summarizes statistical analysis plans for adverse event endpoints. The following 
section provides details regarding safety assessments including definitions and procedures.   
The safety analysis set will be the ITT analysis set which includes all enrolled patients for 
which treatment was initiated as defined as a recording of an incision time. To enhance 
comparability when comparing safety profiles, only controls selected into a PS subclass will 
be included in primary safety analyses.  Assessment of the safety of the investigational 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000046 
implant will include an evaluation of the incidence and severity of complications and adverse 
reactions associated with the treatment in the safety analysis set. 
Adverse event rates will be summarized by type of AE and for specific AEs in two ways: 1) 
per patient incidence of specific AEs and classes of AEs and 2) by event, summarizing event 
counts by visit interval over time and accordance with FDA Guidance (CDRH 2004)36.  
Device and procedure-related events will be summarized by severity and relatedness.  Event 
listings will be provided that include details such as relatedness, severity, onset and 
resolution status will be provided for all events and relevant subsets of events such as serious 
events and related events. The summary tables will indicate the type of adverse event, the 
total number of such events, and the number and the percentage of patients affected in each 
treatment group (“subject wise evaluation”) and also stratified by relation to device and 
severity.  Data of drop-outs will not be presented separately, but possible bias will be 
discussed in the final report. 
In addition to summary tables, the following AE listings will be constructed:   
• 
AE Listing 1 All AEs Sorted by Device and Event Type 
• 
AE Listing 2 All AEs Sorted by Device and Patient 
• 
AE Listing 3 Unanticipated Adverse Device Effects 
• 
AE Listing 4 Serious AEs 
• 
AE Listing 5 Severe AEs 
• 
AE Listing 6 Device Related AEs 
• 
AE Listing 7 Serious Related AEs 
• 
AE Listing 8 Severe Related AEs 
• 
AE Listing 9 Procedure Related AEs 
• 
AE Listing 10 Other AEs 
• 
AE Listing 11 AEs among patients discontinued early 
• 
AE Listing 12 AEs among patients who died 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000047 
3.2.7. 
SAFETY ASSESSMENT 
3.2.7.1. ADVERSE EVENTS 
An adverse event is defined as any clinically adverse sign, symptom, syndrome, or illness that 
occurs or worsens during the operative and postoperative periods of the trial, regardless of 
causality, that is not otherwise being measured in the trial. This does not necessarily include 
immediate postoperative sequelae (such as chills, sore throat, nausea, vomiting, constipation, 
short-term fever unrelated to infection, straight catheterization, pain or burning during 
urination, etc.), unless it prolongs hospitalization or, in the opinion of the investigator, should 
be reported.  Adverse events, whether or not device related, must be reported on the 
appropriate case report form. Any adverse event that occurred prior to treatment with the 
medical device will be documented in the patient’s pre-operative medical history.  Only 
adverse events which are new or have worsened during the course of this study will be 
evaluated in the safety assessment. 
3.2.7.2. SERIOUS ADVERSE EVENTS (SAE) 
A Serious Adverse Event 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, 
                                                                                                                                                       
 
36 Guidance for Industry and FDA Staff Clinical Data Presentations for Orthopedic Device Applications Document issued on: December 2, 
2004. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000048 
4. 
Resulted in subject disability or permanent damage or required intervention to prevent 
permanent impairment/damage. 
3.2.7.3. UNANTICIPATED ADVERSE DEVICE EFFECTS (UADE) 
An Unanticipated Adverse Device Effect 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. 
3.2.7.4. ADVERSE EVENT RECORDING 
Adverse event information will be collected on all subjects.  All adverse events must be 
reported on the Adverse Event Form.    
If an Investigator is unsure about whether to report a finding as an adverse event, s/he should 
report the event on the AE form.   
The investigator should pay particular attention to the patient’s postoperative neurological 
evaluations.  It is important that any new, significant neurological deficits be reported as an 
AE. 
In the event that a patient experiences an AE involving tumor formation, the investigator 
should provide a pathology report describing the location of the tumor; the histopathology of 
the tumor; other comorbid medical diagnosis; and the age of onset, gender, and ethnicity of 
the patient.  Any information regarding the patient’s family history of cancer should also be 
provided, if available. 
3.2.7.5. ADVERSE EVENT AND UNANTICIPATED ADVERSE DEVICE EFFECT 
REPORTING 
At each subject encounter, the investigator will determine if there has been an AE since the 
last encounter and if any previous AE’s are ongoing or have resolved.  Serious Adverse 
Events and Unanticipated Adverse Device Effects must be reported to the Sponsor and to the 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000049 
approving IRB, if required, as soon as possible, but in no event later than 10 working days 
after the Investigator first learns of the event.  All SAEs have to be reported, whether or not 
they are considered casually related to the investigational medical device. 
All SAEs that are related to the investigational medical device will be subject to expedited 
reporting.  The Sponsor or site should inform IRB about SAEs associated with the use of the 
device, per local requirements. 
3.2.7.6. CLINICAL EVENTS COMMITTEE 
The Clinical Events Committee (CEC) will adjudicate all reported adverse events. This will 
include all SAEs, including secondary surgeries at the index and adjacent levels, primary 
endpoint failure, and neurologic deterioration.  
The CEC may determine neurologic status has declined at 24 months compared to baseline 
based on changes including: 
• Motor Assessment: shift from baseline. 
• Sensory Examination: shift from normal to absent or impaired; impaired to absent. 
• Myelopathic Gait Abnormality Class: any worsening. 
The CEC will also review all UADEs.   Adverse events will be classified by the CEC based 
on seriousness, relationship to device and procedure, and severity.  The CEC will also 
adjudicate 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 recommendations 
of the CEC and become part of the clinical trial data set. 
 
3.2.7.7. POTENTIAL RELATIONSHIP OF ADVERSE EVENTS 
The CEC 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. 
• Implant-associated: An AE for which there is a reasonable possibility that the event 
may have been caused primarily by the implant(s). 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000050 
• Surgical procedure-associated:  An AE for which there is a reasonable possibility that 
the event may have been caused primarily by the surgical procedure. 
• Implant/Surgical procedure-associated:  An AE for which there is a reasonable 
possibility that the event may have been caused both by the implant(s) and surgical 
procedure. 
• Not Related: An AE for which sufficient information exists to indicate that the 
etiology is unrelated to the implant(s) or surgical procedure. 
• Undetermined: An AE for which sufficient information is not available at the time of 
the event to determine its causality. 
3.2.7.8. ASSESSMENT OF SEVERITY 
       The CEC will use the following terms for assessment of severity: 
• Mild (grade 1): The AE is noticeable to the patient, but does not interfere with routine 
activity.  The AE does not require removal of the implant(s). 
• Moderate (grade 2): The AE interferes with routine activities of the patient, but 
responds to symptomatic therapy or rest.  The AE does not require removal of the 
implant(s). 
• Severe (grade 3): The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy and may require hospitalization.  In addition, 
the AE may require removal of the implant(s). 
• Life-Threatening (grade 4): The AE requires removal of the implant(s), or the patient 
is at immediate risk of death, even if not related to the implant(s).  
3.3. RISK ANALYSIS 
3.3.1. 
RISKS 
Information on the adverse events or complications relating to general and cervical surgery or 
the investigational spinal system will be collected during the course of the study.  Adverse 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000051 
events that may be associated with the investigational spinal system, fusion control, and/or 
the surgical procedure required for implantation of each device include the following: 
Potential risks associated with general surgery include: 
• Adverse reaction or allergy to the anesthesia medications or anaphylaxis  
• Heart, pulmonary and vascular complications 
o Cardiac Event including myocardial infarction 
o Vascular complication including excessive bleeding or injury to blood vessels 
with potentially fatal bleeding  
o Edema  
o Soft tissue damage or fluid collections, including hematoma or seroma  
o Hypotension 
o Hypertension  
o Ischemia  
o Embolism including pulmonary embolism 
o Thrombosis  
o Thromboembolism  
o Thrombophlebitis  
o Stroke 
o Pneumonia 
o Atelectasis and other pulmonary complications  
• Wound complications 
o Infection of the surgical wound or surrounding soft tissues (e.g., abscess, 
cellulitis) 
o Wound necrosis  
o Scarring of tissue around the surgical wound 
o Wound dehiscence  
o Wound pain 
o Skin or muscle sensitivity over incision which may cause skin breakdown or 
pain and irritation 
 
• Gastrointestinal or urogenital complications   
o Ileus, bowel obstruction or other gastrointestinal complications 
o Nausea or vomiting 
o Difficulty with urination 
o Urinary tract infection 
o Incontinence 
o Bladder dysfuntion or other urogenital complications 
o Reproductive system complications 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000052 
• Other  
o Systemic infection  
o Seizures or convulsions 
o Inability to resume activities of normal daily living 
o Injury to nerves, including nerve damage or paralysis, muscles, or organs 
o Pregnancy complications, including miscarriage or fetal birth defects 
o Pain 
o Psychological Illness 
o Memory loss, confusion, hallucination or other changes to mental status 
o Reflex Sympathetic Dystrophy (RSD) 
o Death 
Potential risks associated with anterior cervical (neck) spine surgery include: 
• Risks to neurological structures 
o Dural injury 
o Arachnoiditis  
o Compressive neuropathy  
o Neurologic deterioration, including injury to nerves or nerve roots associated 
with the spinal cord, spinal cord, resulting in:  
 pain, such as neck or arm pain  
 weakness, 
 paralysis,  
 altered reflexes,  
 numbness,  
 tingling, or  
 other changes in sensation (such as dysesthesias and paresthesias) 
 bowel/bladder dysfunction 
o Coordination abnormalities 
o Dysphasia 
o Gait disturbance  
o Headache 
o Otitis media 
o Tremors 
o Cerebrospinal fluid leakage 
o Cerebrospinal fistula 
o Reflex Sympathetic Dystrophy (RSD)   
• Risks to spine structures 
o Heterotopic ossification 
o Development of disc degeneration or herniation at adjacent levels  
o Facet joint degeneration  

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000053 
o Infection of the disc, bone, or surrounding soft tissue 
o Inflammatory conditions, such as discitis  
o Loss of disc height 
o Loss of anatomic sagittal plane curvature 
o Scarring 
o Soft tissue damage 
o Spinal instability 
o Spondylosis 
o Spondylolysis 
o Spondylolisthesis or vertebral listhesis  
o Spinal stenosis  
o Other injuries to surrounding structures of the spine including adjacent 
vertebrae 
• Risks to structures of the neck 
o Airway obstruction  
o Dysphagia,  
o Sore throat 
o Recurrent aspiration 
o Dysphonia 
o Hoarseness 
o Laryngeal palsy 
o Vocal cord paralysis 
o Esophageal perforation  
o Pharyngeal perforation 
o Tracheal perforation  
o Vessel damage and/or rupture  
o External chylorrhea  
o Fistula 
o Lymphadenopathy or lymphatic vessel injury 
o Other injuries to organs and structures of the neck 
Potential risks associated with cervical total disc replacement surgery (including with 
the Simplify Disc): 
• Device Position and Condition 
o Breakage, 
o Bending 
o Disassembly, 
o Loosening (early or late), 
o Malposition, 
o Subsidence/loss of disc height  

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000054 
o Migration/displacement 
o Above issues can cause pain or injury to surrounding organs and structures, 
such as spinal cord, nerve roots or other neurologic structures that can result in 
pain, paralysis or numbness. 
o Above issues can cause blood vessel damage or erosion (could cause 
catastrophic or fatal bleeding)  
• Anatomical difficulties during the surgery 
• Technical difficulties implanting the device including trouble sizing the device and/or 
improper sizing of the device  
• Adverse reaction or allergy to the device materials (PEEK, ceramic, titanium) 
o Autoimmune disease  
o Metallosis  
o Adverse tissue reaction (local or systemic)  
o Osteolysis or vertebral inflammation related to wear debris  
o Bone resorption  
o Tumor formation 
o Scarring or other symptoms, such as chronic inflammation  
o Above issues could lead to implant loosening or failure of the device 
• Interference with radiographic imaging because of the presence of the device 
• Adverse reaction or allergy to contrast media 
• Difficulties with Surgical Instrument 
o Improper positioning or placement of surgical instruments 
o Instrument damage or breakage or bending 
o Improperly cleaned instruments 
o Possibility that an instrument fragment may be left in the body 
o Device/joint noise 
• The need for additional surgery at the treated spinal levels (reoperation, revision, 
removal, supplemental fixation, and other spinal surgeries) as defined in 
Section 3.2.6.1.  
• The need for additional surgery at the level above or below the treated spinal levels 
• Vertebral fracture 
• Failure of the device to improve symptoms or function 
• Change in alignment of spine or loss of proper anatomic curvature, correction, 
height or reduction of the spine (including spondylolisthesis, change in lordosis or 
instability of the spine) 
• The development of a new or recurrent spinal problem at the surgery levels, or the 
development of a new spinal problem at the levels above or below the treated spinal 
levels 
o Pain 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000055 
o Neurological deterioration, including muscle weakness or paralysis, changes 
in sensation (including numbness, dysesthesias, or paresthesias), decreased 
reflexes, or loss of bowel and/or bladder control 
o Development of new radiculopathy or myelopathy 
o Heterotopic ossification  
o Spontaneous fusion  
o Degeneration of other parts of the spine including facet joint or adjacent discs 
Risks associated with the use of both the experimental and control spinal systems are 
expected to be comparable.  All secondary index surgeries will be regarded as failures and 
reported accordingly. 
3.3.2. 
MINIMIZATION OF RISKS 
Adequate measures have been taken to minimize all of the above risks prior to initiation of a 
U.S. pivotal clinical study, including proper design specification and review, preclinical 
testing, and clinical evaluations outside the United States.  The study Sponsor will provide 
appropriate training to each investigator prior to each sites respective study initiation.  
Surgeons will be trained on the technique, selection criteria, and protocol for the clinical 
study prior to their first implantation procedure.  The training will address topics such as the 
indications and contraindications for the use of the device, the surgical procedure, and 
selection of appropriate implant sizes, device instrumentation, management of adverse 
events, and postoperative care and follow-up. 
The Sponsor will provide training to the operating room staff at each investigational site.  
This training will be presented by experienced surgeons, operating room staff, and/or 
qualified representatives of NuVasive, and will address topics such as the labeling and 
handling of the Simplify Disc, the implantation instruments, and the selection of appropriate 
implant sizes. 
Investigators will assess the possible presence of the risks associated with the surgery and 
with each device during the study treatment and at each follow-up visit by physical and/or 
radiologic examination and subject interview as applicable. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000056 
3.3.3. 
RATIONALE FOR THE INVESTIGATION 
Although many of these risks are significant, they are infrequent.  If an unforeseen event 
arises the subject may be fused in a standard accepted manner (with or without removing the 
device).  Also, it is believed that the use of an artificial total disc may result in return to 
normal activities of daily living sooner than with fusion, since it is not necessary to wait (at 
least 6 months) for the vertebrae to fuse postoperatively.  In addition, the MRI imaging of the 
Simplify Disc may also be of benefit because it is MR-compatible. 
Moreover, if implantation with the two-level Simplify Disc produces a successful result, it 
may reduce the subject’s symptoms of pain and dysfunction.  While pain may also be relieved 
by two-level fusion, total disc replacement with the two-level Simplify Disc permits normal 
or relatively normal segmental motion at the treatment level, and potentially prevents or 
minimizes the negative impact that two-level fusion has on adjacent vertebral levels.  Thus, 
the potential benefit of the use of the two-level Simplify Disc merits clinical study. 
3.4. INVESTIGATOR TRAINING, RESPONSIBILITIES AND OBLIGATIONS 
3.4.1. 
INVESTIGATOR TRAINING 
The sponsor will provide appropriate training to each investigator prior to study initiation. 
Training will address topics including the surgical procedure, selection of appropriate implant 
sizes, instrumentation for implantation, indications for use of the device, contraindications, 
management of complications, and postoperative subject care.  
The Sponsor will also provide training to the operating room staff at each investigational site. 
 This training will be presented by experienced surgeons, operating room staff, and/or 
qualified representatives of the Sponsor, and will address topics such as the labeling of the 
devices, the implantation instruments, and the selection of appropriate implant sizes. 
3.4.2. 
INVESTIGATOR RESPONSIBILITIES 
The Investigator is responsible for ensuring that the investigation is conducted according to 
this protocol and following the Investigator Agreement.  Prior to study participation, the 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000057 
Investigator is required per 21CFR54 to describe any financial arrangements they have with 
the study Sponsor. This information is to be updated as appropriate for one year after study 
completion. 
The Investigator is responsible for ensuring that Informed Consent is obtained from each 
study subject. The Investigator shall permit the device to be implanted only under his/her 
supervision.  Upon completion or termination of this study, or at Sponsor’s request, the 
Investigator shall return to the sponsor any remaining unused devices or otherwise dispose of 
the device as the Sponsor directs.  The Principal Investigator at each site is responsible for the 
device accountability.  The Study Coordinator, or Principal Investigator’s designee, is 
responsible for maintaining the device accountability log, which will include tracking the 
receipt and return/disposition of the devices.  At each monitoring visit, the study monitors 
will review and reconcile the log, the device inventory and the device shipment records. 
3.5. DEVICE DESCRIPTION 
The Simplify Disc is designed to be used for reconstruction of two contiguous discs from C3 
to C7 following discectomy at two contiguous levels for intractable radiculopathy (arm pain 
and/or a neurological deficit) with neck pain, or myelopathy that is unresponsive to 
conservative management.  The spinal system is a 3-piece design consisting of 2 
polyetheretherketone (PEEK) end-plates with a plasma-sprayed titanium endplate coating and 
a fully articulating ceramic alumina matrix composite (AMC) core.  Each superior/inferior 
endplate pair is specifically designed for each configuration (i.e. footprint and height).  In 
addition to serrated surfaces, the inferior endplate has inline keels and the superior endplate 
has two to three teeth to facilitate endplate fixation.  Each superior endplate features a 
retention ring intended to mat with the retention feature of the Simplify core. The system is 
packed preassembled and placed as one unit, by means of the insertion instrument. 
The Simplify Disc is available in 3 foot print sizes (Size 1 – 12mm x 15mm, Size 2 - 14 mm 
x 16 mm and Size 3 - 16 mm x 18 mm) and 3 heights (4mm, 5mm and 6mm).  Furthermore, 
there are 6 additional lordotic configurations (5 deg., Size 1 (height 4mm and 5mm), and Size 
2 and Size 3, (height 5mm and 6mm) and 2 coatings (original and enhanced-visibility or EV). 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000058 
 For standard Simplify Disc configurations, the Simplify core is 5mm tall, is bi-convex with a 
radius of R 9.6 mm.  The core for the Simplify Disc with lower height configurations is 4 mm 
tall and bi-convex with a radius of R 7.7mm.  When assembled, the maximum range of 
motion of the Simplify Disc (as designed, without anatomic constraints) is ±12° flexion-
extension, ±12° lateral bending. The device is unconstrained in rotation.  
3.6. STUDY MONITORING 
3.6.1. 
MONITORING ORGANIZATION 
Study monitoring functions, with assistance from the Sponsor or designee for pre-study 
training visits, will be performed by an independent clinical monitoring organization, in 
compliance with recognized ethical principles of current Declaration of Helsinki as adopted 
by the World Medical Association Declaration of Helsinki, CPMP/ICH Note for Guidance on 
Good Clinical Practices as applied to medical device studies, the ISO 14155 Clinical 
Investigation of Medical Devices, FDA's IDE guidance documents, as outlined in 21 C.F.R. § 
812.43(d) and 21 C.F.R. §812.46, the National Statement, requirements of the TGA, and any 
requirements of relevant Commonwealth or state/territory laws.  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 visits and review of study documents and 
results.  The monitoring organization will be provided with appropriate training regarding the 
device under investigation and will operate under written procedures to ensure compliance 
with the protocol. 
3.6.2. 
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 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000059 
Sponsor or designee, is intended to provide an opportunity to review the Investigational Plan 
with the Investigator and to ensure that the Investigator: 
• Has appropriate training, facilities, subject load, time and willingness to comply with 
study requirements; 
• Has the approval of the supervising IRB; 
• Has all study documentation and required records on site and 
• Assumes responsibility for the investigation at her/his center. 
Periodic visits are intended to assess adherence to the Investigational Plan, maintenance of 
Records and Reports, accountability of investigational devices; 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 that have been treated under the study.  If a periodic visit cannot 
be performed on-site because of compelling circumstances, such as COVID-19, a remote visit 
may be performed. 
 
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 and review study closure responsibilities. 
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. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000060 
3.6.3. 
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 is recorded 
for all study subjects for whom Informed Consent is obtained; and that no study treatments 
are administered 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. 
All CRF information should be traceable to source documents. Surveys completed by the 
patient will be considered source documents. Other records that will be considered source 
documents are hospital records, clinic charts, x-rays, CTs, MRIs and DEXA scans. Copies of 
source documents that may be collected by NuVasive include, but are not limited to: signed 
and dated patient informed consent documents (redacted); operative summaries; hospital 
discharge summaries/orders; any relevant progress notes pertaining to AEs, reoperations, or 
deaths; and autopsy reports.  In cases where assessments (e.g., foraminal compression test, 
neurological examination) are not dictated in the patient’s clinical charts or documented on 
source worksheets, these CRFs will also be considered source documents.  Surveys collected 
by tablet (if used) do not require source documents. 
Data will be reviewed to identify inconsistent or missing data, Serious Adverse Events, and 
Unanticipated Adverse Device Effects.  Data problems will be addressed in calls to the 
investigational 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 3.2.6.1 and 
Section 3.2.7 of this protocol. 
3.6.4. 
INITIAL DEVICE IMPLANTATIONS 
A Sponsor representative will attend initial device implantations to provide assistance with 
study management issues, such as device record keeping.  A data review with the Investigator 
by the study monitor will be held prior to or after a few initial implantations to assure 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000061 
adherence to the study protocol and to provide guidance to avoid continuing problems with 
study procedures and data collection. 
3.6.5. 
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, including pre-study visits, on-site visits or final visit reports, 
submitted by a site monitor will be reviewed by the Director or Manager.  The 
monitor will assume responsibility for any corrective action. 
3.6.6. 
MEDICAL MONITORING 
NuVasive has appointed a qualified spine surgeon to oversee all medical monitoring issues.  
Duties of the Medical Monitor include, but are not limited to: 
• Review the protocol, CRFs, IDE, and at study completion, the PMA; 
• 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 Official. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000062 
3.6.7. 
ROLE OF CO-PRINCIPAL INVESTIGATORS 
NuVasive 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, CRFs, IDE, and at study completion, the PMA; 
• 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. 
3.6.8. 
DISPOSITION OF STUDY DEVICES AND DATA 
All investigational devices received and used by the investigator will be inventoried and 
accounted for throughout the study.  The Simplify Disc if stored at the investigational site 
will be stored in a secure area with restricted access, separate from other medical devices.  
When instructed by the study Sponsor, the investigator will return any remaining devices, 
accompanied by a Device Return Form supplied by the study Sponsor.  The investigator will 
not supply investigational devices to any person except those designated by him/her as co-
investigators.  Should it be necessary to explant the Simplify Disc, NuVasive 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. 
Results of the study will be analyzed per the Statistical Analysis Plan (SAP) after the 
completion of the study and publicly reported in the FDA’s Summary of Safety Effectiveness 
Decision when the PMA review is complete. Clinical data will also be published on 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000063 
clinicaltrials.gov, including any negative outcomes or any unanticipated termination of the 
study. Furthermore, study progress (e.g., all safety, effectiveness, and radiographic data) is 
reviewed annually and reported to FDA so that any untoward results will be identified early 
on and the study terminated if deemed necessary by the medical monitor. 
3.7. LABELING 
The surgical manual, all implants and instruments will be labeled according to federal 
regulations (21CFR 812.5) and FDA’s Guidance Document for the Preparation of IDEs for 
Spinal Systems, including the following statement: 
 
CAUTION – Investigational device.  Limited by Federal (or United States) law to 
investigational use. 
3.8. INFORMED CONSENT 
The final clinical Investigational Plan (CIP) including the final version of the subject 
Informed Consent must be approved or given a favorable opinion in writing by an 
Institutional Review Board (IRB) before enrollment of any subject into the investigation.  
The Clinical Investigator is responsible for informing the IRB of any amendments to the CIP, 
as per local requirements.   
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.  Since this is elective surgery, this discussion may be held weeks or months 
prior to any study surgery.  The subject may elect to enter the study at this time, or at some 
time later.  The investigator or the study coordinator, as appropriate, may answer additional 
questions the subject may have at an additional office visit or by telephone.  Due to the 
extended time of the consent process, it is possible that the subject will sign the consent at 
home, and 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. 

NuVasive, Inc.                              Clinical Study Protocol                                  Confidential 
Version Date July 15, 2021 
 
0000064 
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. 
3.9.  ETHICAL CONSIDERATIONS OF THE CLINICAL INVESTIGATION 
The Investigation will be conducted in compliance with applicable regulatory requirements  
relating to the conduct of the Study.