The Investigational Plan for the Evaluation of the ACADIA® Facet Replacement System
Phase: NA
Conditions: Lumbar Spinal Stenosis
Sponsor: Globus Medical Inc

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Protocol Number: 1020-9052 
Revision K: 14 February 2013 
 
 
 
 
 
The Investigational Plan for the Evaluation of the  
ACADIA® Facet Replacement System  
Protocol Number: 1020-9052 
IDE#: G060073 
 
 
 
Sponsor:   
Globus Medical, Inc. 
Valley Forge Business Center 
2560 General Armistead Avenue 
Audubon, PA 19403 
610-930-1800 
 
 
 
 
 
 
 
 
 
     Revision K  
 
 
     Confidential  
 
 
 
 
 
 
 
Do Not Copy 
 
This investigational protocol contains confidential information for use by the principal investigators and their designated representatives 
participating in this clinical investigation. It should be held confidential and maintained in a secure location. It should not be copied or 
made available for review by any unauthorized person or firm.

 
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Protocol Number: 1020-9052 
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TABLE OF CONTENTS 
 
 
Protocol Summary  
 
 
 
 
 
4 
 
1.0 
Introduction  
 
 
 
 
 
 
8 
 
1.1 
Background 
 
 
 
 
 
 
8 
1.2 
Device Name  
 
 
 
 
 
9 
1.3  
Purpose 
 
 
 
 
 
 
9 
1.4 
Intended Use  
 
 
 
 
 
9 
1.5 
Study Objectives 
 
 
 
 
 
10 
 
 
2.0 
Device Description and Surgical Technique 
 
 
11 
 
2.1 
Device Description 
 
 
 
 
 
11 
 
2.2 
Surgical Technique 
 
 
 
 
 
11 
 
3.0 
Study Design and Methodology 
 
 
 
 
12 
3.1 
Study Design   
 
 
 
 
 
12 
3.2 
Study Scope  
 
 
 
 
 
12 
3.3 
Study Duration 
 
 
 
 
 
13 
 
3.4 
Control Procedure 
 
 
 
 
 
13 
 
3.5 
Study Endpoints 
 
 
 
 
 
14 
 
3.6 
Control of Bias and Validity  
 
 
 
15 
 
4.0 
Patient Selection and Enrollment  
 
 
 
16 
 
4.1 
Inclusion and Exclusion Criteria 
 
 
 
17 
 
5.0 
Study Procedures 
 
 
 
 
 
 
20 
 
5.1 
Screening/Pre-Procedure 
 
 
 
 
20 
 
5.2 
Randomization Procedure 
 
 
 
 
24 
 
5.3 
Operative Procedure  
 
 
 
 
25 
 
5.4 
Patient Discharge 
 
 
 
 
 
25 
 
5.5 
Hospitalization Charges 
 
 
 
 
26 
 
5.6 
Patient Follow-Up 
 
 
 
 
 
27 
 
5.7 
Patient Discontinuation 
 
 
 
 
30 
 
6.0 
Adverse Event Reporting 
 
 
 
 
 
31 
 
6.1 
Adverse Events 
 
 
 
 
 
31 
 
6.2 
Serious Adverse Events 
 
 
 
 
35 
 
6.3 
Unanticipated Adverse Device Effects 
 
 
35 
 
6.4 
Patient Death  
 
 
 
 
 
36 
 
6.5 
Subsequent Surgical Intervention 
 
 
 
36 
 
7.0 
Committees  
 
 
 
 
 
 
37 
 
7.1 
Clinical Events Committee 
 
 
 
 
37 

 
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8.0 
Statistical Analysis Plan 
 
 
 
 
 
38 
 
8.1 
Analysis Populations  
 
 
 
 
38 
 
8.2 
Primary Objective 
 
 
 
 
 
39 
 
8.3 
Randomization, Sample Size and Analysis Plan 
 
39 
 
8.4 
Predictions 
 
 
 
 
 
 
42 
 
8.5 
Operating Characteristics 
 
 
 
 
45 
 
8.6 
Missing Data and Sensitivity Analyses 
 
 
46 
 
8.7 
Secondary Objectives  
 
 
 
 
47 
 
8.8 
Analysis Methods for Secondary Objectives  
 
56 
 
8.9 
Poolability Analyses  
 
 
 
 
62 
 
9.0 
Risk/Benefit Analysis 
 
 
 
 
 
63 
 
9.1 
Surgical Risks  
 
 
 
 
 
63 
 
9.2 
Implant Risks  
 
 
 
 
 
63 
 
9.3 
Minimizing Study Risks 
 
 
 
 
64 
 
9.4 
Justification for Investigation  
 
 
 
64 
 
10.0 
Administrative Responsibilities 
 
 
 
 
66 
 
10.1 
IRB Considerations 
 
 
 
 
 
66 
 
10.2 
Confidentiality 
 
 
 
 
 
67 
 
10.3 
Data Monitoring and Quality Control  
 
 
67 
 
10.4 
Record Maintenance  
 
 
 
 
68 
 
10.5 
Device Accountability 
 
 
 
            71 
 
10.6 
Protocol Deviations and Medical Emergencies 
 
71 
 
10.7 
Investigational Site Termination 
 
 
 
71 
 
11.0 
References 
 
 
 
 
 
 
 
72 
 
Appendices 
 
 
 
 
 
 
 
 
 
 
1 
Study Summary 
 
 
 
 
 
74 
 
2 
Radiographic Protocol 
 
 
 
 
76 
 
3 
Dermatome Locations  
 
 
 
 
83 
4 
Patient Discharge Instructions 
 
 
 
85 
 
5 
Retrieval Protocol 
 
 
 
 
 
87 
 
6 
Case Report Forms 
 
 
 
 
 
92 
 
7 
Bayesian Simulation Details  
 
 
 
125 
 
8 
Sensitivity of Operating Characteristics 
 
 
130 
 
 

 
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Protocol Number: 1020-9052 
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PROTOCOL SUMMARY 
 
Title: 
The Investigational Plan for the Evaluation of the ACADIA® Facet Replacement 
System  
Protocol ID#: 
Protocol Number: 1020-9052 
Device: 
The ACADIA® Facet Replacement System (AFRS) 
Study Objective: 
The primary objective of this study is to evaluate the safety and effectiveness of 
the AFRS through 24 postoperative months compared to an instrumented 
posterolateral fusion control. 
Study Design: 
• 
Multi-center clinical trial at up to 30 investigational sites 
• 
Prospective, randomized, concurrently-controlled trial 
• 
Control: Instrumented posterolateral fusion 
• 
200 Minimum/500 Maximum Investigational and 100 Minimum/250 
Maximum Control patients using 2:1 randomization 
• 
Up to 60 non-randomized investigational training cases (two per site) 
Study Duration/  
Follow-up Period: 
Study Duration: 48-58 months 
Follow-up: 6 week, 3, 6, 12 and 24 month postoperative time points, and annually 
thereafter as required by FDA 
Indication for Use: 
The AFRS Study will include patients who have lateral, lateral recess and/or 
central stenosis at the L3 to S1 level requiring decompression and facetectomy. 
The operative level will receive either the test or control treatment. Adjacent 
lumbar vertebrae levels may be treated through decompression as required to treat 
stenosis that does not result in complete facetectomy or fusion.   
Inclusion Criteria 
• 
Is 21-85 years of age and skeletally mature; 
• 
Undergone at least six cumulative months of conservative treatment prior to 
surgery including any of the following: medications, NSAIDs, physical 
therapy, bracing, chiropractic manipulation, modified activities of daily living, 
epidural injections, facet block injections; 
• 
Lateral, lateral recess and/or central canal stenosis as demonstrated by 
compression of the thecal sac and/or cauda equina, nerve root impingement by 
either osseous or non-osseous elements or evidence of hypertrophic facets 
with encroachment into the central canal or lateral recess at the involved level 
as determined by MRI, CT scan, plain film or myelography;  
• 
Disc height measuring ≥ 4 mm at the operative level; 
• 
Persistent leg, thigh and/or buttock symptoms, including pain, numbness, 
burning or tingling with a minimum leg pain score of 40mm as measured with 
the Visual Analogue Scale (VAS) Index; 
• 
A score greater than 2 on a scale of 1-5 on the Zurich Claudication 
Questionnaire (ZCQ) Symptom Severity (SS) Score; 
• 
A score greater than or equal to 2 on a scale of 1-4 on the ZCQ Physical 
Function (PF) Score; 
• 
A candidate for a decompression with full facetectomy at the operative level; 
• 
A candidate for an instrumented posterolateral fusion; 
• 
Willing and able to comply with postoperative and routinely scheduled 
clinical and radiographic evaluations; 
• 
Lives in the immediate area and has no plans to relocate to another geographic 

 
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Protocol Number: 1020-9052 
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area before the completion of the study, or lives outside the immediate area 
and is willing to comply with scheduled postoperative visits with a designated 
physician; 
• 
Signed a patient informed consent specific to this study.  
Exclusion Criteria 
• 
Previous surgical procedure at the operative or adjacent level except for one of 
the following: micro-discectomy, laminectomy, lamino/foraminotomy, 
rhizotomy, IDET, and/or interspinous spacer;  
• 
Previous lumbar fusion or disc replacement procedure; 
• 
Osteoporosis as defined by Simple Calculated Osteoporosis Risk Estimation 
(SCORE) screening questionnaire score of 6 or greater and DEXA bone 
density measured T-score ≤ –2.0; 
• 
Greater than Grade I spondylolisthesis or retrolithesis, as defined by the 
Meyerding Grading Classification, at the operative level; 
• 
Spondylolisthesis any grade, as defined by the Meyerding Grading 
Classification at levels other than at the operative level; 
• 
Scoliosis of the lumbar spine (defined as more than 11° Cobb angle), as 
indicated by plain X-ray films;  
• 
Primary diagnosis of discogenic back pain due to torn, herniated, inflamed or 
irritated disc or other pathology where the patient exhibits axial back pain 
from degenerative disc disease;  
• 
Acute traumatic pars fracture at the operative or adjacent level vertebral body; 
• 
Spinal stenosis at more than three lumbar segments; 
• 
Experienced acute trauma to the lumbar spine within the last 24 months; 
• 
Active infection at the operative level, or a systemic infection including prior 
or pending treatment for HIV or Hepatitis C; 
 
• 
Physically or mentally compromised (i.e., being currently treated for a 
psychiatric disorder, senile dementia, Alzheimer's disease, presence of alcohol 
or substance abuse) in a manner that would compromise his or her ability to 
participate in the clinical study; 
• 
Diagnosed systemic disease (i.e., Paget's disease, muscular sclerosis, 
amyotrophic lateral sclerosis (ALS), renal osteodystrophy, metastasis to 
vertebrae, Lupus, or ankylosing spondylosis) that  may affect the patient’s 
welfare or overall outcome of the research study; 
• 
Immunologically suppressed or immunocompromised; 
• 
Insulin-dependent diabetes mellitus (type I diabetes); 
• 
Currently undergoing long-term steroid therapy (treated in the last 6 months 
with systemic corticosteroids);  
• 
Metabolic bone disease (i.e., osteomalacia, and/or osteogenesis imperfecta); 
• 
Is of child-bearing potential, and is either pregnant or interested in becoming 
pregnant during the duration of the study; 
• 
Medically significant obesity as defined by a Body Mass Index (BMI) of > 40 
kg/m2. BMI = (weight in pounds × 703) ÷ (height in inches × height in 
inches); 
• 
Active malignancy: a history of any invasive malignancy (except non-
melanoma skin cancer), unless the patient has been treated with curative intent 
and there have been no clinical signs or symptoms of the malignancy for at 
least 5 years; 

 
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• 
Known allergy to cobalt chromium or titanium; 
• 
Used any investigational drug or device within the past 30 days; 
• 
Pending litigation related to back pain or injury; 
• 
Is a prisoner. 
Primary Endpoint: 
The primary study endpoint for this study is individual patient success at 24 
months. Individual patient success will be defined as follows: 
• 
Improvement in the ZCQ by a minimum of 0.5 for both Symptom Severity 
(SS) and Physical Function (PF) scores at 24 months as compared to baseline. 
• 
Maintenance or improvement in neurological outcome at 24 months.   
• 
No subsequent surgical intervention at the level of treatment (including device 
failures requiring revision, removal, re-operation and supplemental fixation ). 
• 
No serious device-related adverse events.  
Secondary 
Endpoints: 
• 
Maintenance or improvement of the components of the primary ZCQ; 
• 
Maintenance or improvement in patient function, as measured by the Oswestry 
Disability Index (ODI) questionnaire; 
• 
Maintenance or improvement of the leg and back VAS pain scores; 
• 
Maintenance or improvement in the components of the SF-36 Quality of Life 
Questionnaire; 
• 
Changes in quantitative radiographic measures including disc height, vertebral 
range of motion and translation; 
• 
Changes in qualitative radiographic measures including fusion; assessment, 
device migration and presence of radiolucencies; 
• 
Radiographic Success 
• 
Maintenance or improvement in neurological status; 
• 
Incidence, severity and device or procedure relatedness of all adverse events 
over the 24-month study assessment period; 
• 
Components of primary endpoint (surgical revisions, reoperations, removals, 
supplemental fixation); 
• 
Return to normal activities of daily life; 
• 
Change in work status and time to return to work; 
• 
Narcotic medication usage; 
• 
Length of hospital stay; 
• 
Duration of surgical procedure and instrumentation time; 
• 
Blood loss; 
• 
Rehabilitation utilization. 
Investigational 
Sites: 
Up to 30 Investigational Sites 
Study Sponsor: 
Globus Medical, Inc. 
Valley Forge Business Center 
2560 General Armistead Avenue 
Audubon, PA 19403 
610-930-1800 

 
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Protocol Number: 1020-9052 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACRONYM 
 
DESCRIPTION 
AE 
Adverse Event 
AFRS 
ACADIA® Facet Replacement System 
AP 
Anterior-Posterior 
BMI 
Body Mass Index 
CRF 
Case Report Form 
CS 
Clinically Significant 
CT 
Computed Tomography  
DEXA 
Dual Energy X-ray Absorptiometry 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IDET 
Intradiscal Electrothermic Therapy 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MRI 
Magnetic Resonance Imaging 
NCS 
Not Clinically Significant 
NSAIDs 
Nonsteroidal Anti-Inflammatory Drugs 
ODI 
Oswestry Disability Index 
PF 
Physical Functioning 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PLF 
Posterolateral Lumbar Fusion 
QA 
Quality Assurance 
SAE 
Serious Adverse Event 
SLR 
Straight Leg Raise 
SS 
Symptom Severity 
UADE 
Unanticipated Adverse Device Effect 
US 
United States 
VAS 
Visual Analog Scale 
ZCQ 
Zurich Claudication Questionnaire 
 

 
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1.0 
INTRODUCTION 
1.1 
Background 
Chronic spinal pain is the leading cause of disability in the industrialized world.1 It has 
been estimated that 65% to 80% of the people in the United States will suffer an episode 
of low back pain during their lifetime.2 In 1997, low back pain was estimated to have a 
total impact of $171 billion in the industrial setting of the United States. In 1990, the 
estimated cost of medical treatment for low back pain alone was $13 billion.3 Low back 
pain is acknowledged as a large, costly and growing problem in industrialized countries.   
 
The origin of low back and leg pain is varied and may include muscular, neurological and 
skeletal components. The most common indication for elective lumbar surgery is pain 
that is refractory to non-surgical treatment. The indications for reconstructive surgery to 
treat painful spinal conditions include instability, degenerative spondylolisthesis, 
scoliosis, stenosis and degenerative disc disease.4 Many of these conditions are associated 
with degeneration of the spine which often occurs at an early age and progresses as the 
patient gets older.5 This degeneration is associated with the mobile joint segments that 
comprise the lumbar spine. 
 
At each level of the spine there is a three joint complex that allows for motion of the 
segment while preserving stability. This three joint complex consists of the disc and two 
facet joints. While the disc is a fibrocartilagenous joint, the facet joints are synovial joints 
consisting of articular cartilage, synovial fluid and fibrous capsule. The nature of the 
degenerative process differs between the discs and facet joints. However, due to their 
close relationship and function, changes in one joint will invariably affect the remaining 
two. It has been shown that changes to the disc structure are accompanied by facet 
osteoarthritis.6 The two lowest motion segments of the lumbar spine are most affected by 
this degeneration process with disc degeneration and facet osteoarthritis increasing with 
age.7,8,9 The degeneration of the motion segment leads to abnormal motion, instability and  
joint collapse. Eventually this can lead to spondylolisthesis due to asymmetric alignment 
of the facets with associated facet osteoarthritis and stenosis that contributes to increased 
pain and loss of function.  
 
Facet joint osteoarthritis due to wear and motion is characterized by facet hypertrophy, 
thickening of the joint and osteophyte formation resulting in lateral, lateral recess and/or 
central canal stenosis. Mooney and Robertson demonstrated that the facet joint 
contributed to pain through the use of intra-articular facet injections.10 It is estimated that 
15-40% of low back pain is attributed to the facet joint.11,12 Treatments for facet 
generated problems include decompression, facetectomy and posterior fusion. Although 
these treatments address the symptoms of pain, they may result in further destabilization 
and in the case of fusion loss of motion. It has also been reported that fusion with loss of 
motion transfers stresses to the adjacent motion segments creating additional 
degeneration and instability in these adjacent segments.13, 14 
 
 

 
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Historically, degeneration and instability of the joint and associated stenosis has been 
addressed with fusion. There could be a meaningful patient benefit by replacing the 
current practice of posterior fusion with facet arthroplasty. This approach involves the 
replacement of the degenerated facet with an articulating joint while resolving the 
associated stenosis. A facet arthroplasty system allows for an anatomic reconstruction of 
the facet joint after decompression and removal of the degenerated facet. Like the original 
facet joint, the replacement implant is designed to reproduce facet motion while restoring 
normal stability and kinematics. Instrumentation allows for precise and reproducible 
placement of the inferior and superior articulating implants.  The cobalt chrome 
articulating components are aligned and secured at their natural anatomical position on 
the pedicle.  
 
The ACADIA® Facet Replacement System (AFRS) has been designed on the principals 
that have allowed other total joint arthroplasty procedures to provide significant patient 
benefits. These guiding principals include: 
• Anatomically-based implant design 
• Reproducible surgical technique 
• Elimination of pain 
 
Globus Medical acquired the ACADIA® Facet Replacement System from Facet Solutions, 
Inc., in January 2011, and is now the sponsor of the associated Investigational Device 
Exemption (IDE) clinical trial. 
 
1.2 
Device Name 
The device under clinical investigation is the ACADIA® Facet Replacement System 
(AFRS). 
  
1.3 
Purpose 
The purpose of this study is to evaluate the safety and effectiveness of the AFRS in 
patients with lateral, lateral recess and/or central canal stenosis due to facet degeneration 
at a single level from L3 to S1 who require a lumbar decompression and facetectomy 
compared to an instrumented posterolateral fusion control group.  Safety of the AFRS 
device will be evaluated by the incidence, severity and device or procedure relatedness of 
all adverse events over the 24 month assessment period as compared to the control group. 
Effectiveness of the AFRS will be based on the improvement in symptom-related 
questionnaire scores, function, and neurological status. 
 
 
1.4 
Intended Use  
The AFRS device is intended for use in patients with acquired degenerative lateral, lateral 
recess and/or central canal stenosis at a single level from L3 to S1 that require 
decompression and facetectomy and have failed to improve with at least six cumulative 
months of conservative treatment.   
 

 
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Acquired Degenerative Stenosis is defined as a narrowing of the lateral, lateral recess 
and/or central canal resulting in compression of the thecal sac and/or cauda equina, nerve 
root impingement by either osseous or non-osseous elements or evidence of hypertrophic 
facets with encroachment into the central canal or lateral recess at the involved level as 
determined by MRI, CT scan, plain film or myelography.   
 
In addition, patients should be candidates for, and willing to undergo, an instrumented 
posterolaterol fusion control procedure for the treatment of their acquired degenerative 
stenosis. 
 
1.5 
Study Objectives 
The primary objective of this study is to evaluate the safety and effectiveness of the 
AFRS device through 24 postoperative months compared to an instrumented 
posterolateral fusion procedure. 
 
More specifically, the primary study objective is to demonstrate that patient success, 
evaluated at 24 months in patients treated with the investigational device, is not inferior 
to subject success at 24 months in patients treated with the control procedure, where 
patient success is based on the following defined measures: The Zurich Claudication 
Questionnaire (ZCQ), neurological deficit, and the need for subsequent surgical 
intervention (at the level of treatment) and/or device removal and absence of serious, 
device-related adverse events.  
 
Patients will also be evaluated during the course of the study for all adverse events and 
surgical interventions, and the relationship of these events and interventions to the 
investigational device.  All adverse events and surgical interventions will be tabulated 
and reported for each assessment time period. 

 
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2.0 
DEVICE DESCRIPTION AND SURGICAL TECHNIQUE 
2.1 
Device Description 
The ACADIA® Facet Replacement System (AFRS) implant design is based on a 
morphology study of more than 40 high-resolution CT scans evaluating more than 80 
facet joints. By analyzing the inferior and superior articular surfaces of the facet joints, a 
bi-planar implant was designed to restore and mimic natural kinematics and range of 
motion. The implant is machined from cobalt chrome alloy with highly polished 
articulating surfaces. This replicates the established metal on metal constructs of total 
knees and hips. The backing of the implant that interfaces with the bone is plasma 
sprayed and coated with hydroxyapatite to promote bony in-growth. The implant is 
secured to the bone with pedicle screws secured with locking nuts. Separate implants are 
used for both inferior and superior facets and come in a variety of sizes to meet the 
subject’s specific anatomy and requirements. Crosslink members affixed with clamps are 
also provided to offer added coupled and rotational support to the left and right inferior 
implants. The AFRS implants are provided in a sterile package. The associated fixation 
screws, crosslinks, clamps and nuts are provided in a kit in a non-sterile format that is 
autoclaved prior to use. Implant trials are provided to verify proper implant sizing.  
 
A complete set of instrumentation provides the alignment and cutting tools to measure 
implant location, proper resection and removal of the existing facet joint, placement of 
the aligning pedicle screws and securing the implant.  All instruments are fabricated from 
stainless steel and are provided in a reusable format.  
 
2.2 
 Surgical Technique 
The AFRS device is implanted through a posterior midline incision approach. A 
decompression is completed followed by a complete facetectomy, provided ample bone-
to-implant interface is maintained. The AFRS device does not present any limitations on 
the boundaries of the decompression. The bone is prepared with the instruments provided 
and the implants placed. A full surgical technique manual is available and will be 
provided to all investigational sites. Please refer to the Surgical Technique Manual for the 
proper handling and use of these systems.   
 
All participating investigators and co-investigators will receive instruction on appropriate 
use of the investigational device. Only investigators and co-investigators qualified by 
training or experience in performing instrumented posterolateral fusions will be selected 
for this clinical trial. If during the surgical procedure it is determined that the randomized 
treatment and any components of the selected treatment is unsuitable for a patient’s 
treatment, the patient will be considered a treatment failure. 
 

 
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3.0  
STUDY DESIGN AND METHODOLOGY 
 
3.1 
Study Design  
The pivotal evaluation of the AFRS investigational device will incorporate a multi-center, 
prospective, randomized, and concurrently controlled study design. Up to 30 sites will 
enroll and treat a minimum of 300 patients and a maximum of 750 patients into the study. 
In addition, up to 60 training cases (two per clinical site) may be completed by 
participating investigators, at the discretion of the Sponsor and participating site 
clinicians. 
 
The investigational group will consist of at least 200 patients who receive the AFRS 
device.  The control group will consist of at least 100 patients who will receive an 
instrumented posterolateral fusion. This number is based upon the sample size required to 
provide reasonable assurance of safety and effectiveness using the concurrent control and 
allowing for 15 percent loss to follow-up. The patients will be allocated to treatment 
assignment using a 2:1 randomization scheme. 
 
The outcome measures in this study will include the following: the SF-36 questionnaire, 
the ZCQ, the ODI, a neurological assessment, a symptomatic pain assessment, as 
measured with the VAS Index, a patient satisfaction questionnaire, and an independent 
radiological assessment. In addition, outcome measures will be included to support 
potential reimbursement with healthcare providers.  Patients in both treatment groups will 
be followed for 24 months postoperatively.  
 
3.2 
Study Scope 
 
3.2.1  Participating Institutions 
The pivotal trial will utilize a maximum of 30 clinical sites. A list of participating 
institutions will be provided semi-annually to the FDA as required by regulations. 
3.2.2 Patient Population 
The AFRS Study will include patients as specified in the Inclusion/Exclusion criteria. 
Study patients will have lateral, lateral recess and/or central stenosis at a single level from 
L3 to S1 requiring decompression and facetectomy. Detailed enrollment criteria can be 
found in the Patient Selection section of this Protocol.  
Patients will receive either the investigational or control treatment, using a posterior 
approach through a midline incision to treat lateral, lateral recess and/or central canal 
stenosis. All patients will receive a decompression and complete facetectomy. The 
operative level will receive either the test or control treatment. Up to two adjacent 
additional levels may be treated through decompression as required to treat stenosis that 
does not result in complete facetectomy or fusion.   

 
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Patients randomized into the investigational group will receive the AFRS device. Those 
randomized to the control group will receive an instrumented posterolateral fusion.   
If the assigned device cannot be placed in the patient during the surgical procedure, this 
patient will be considered a treatment failure. This patient should receive treatment at the 
discretion of the principal investigator and must be followed per the protocol through 
hospital discharge and/or the resolution of any procedure-related adverse events that have 
occurred.  
3.3 
Study Duration 
It is anticipated that the overall duration of the pivotal phase of the AFRS study will be 
approximately 8 years. This estimate is based upon a projected patient enrollment period 
of 4-5 years, including the period of time (~2 years) under the previous sponsor, Facet 
Solutions. Follow-up visits will occur for the subsequent 24 months while all patients 
reach the 24 month postoperative time point, with data analysis and report generation 
accounting for an additional 4-6 months. The follow-up period may increase up to 10 
years as needed to address postmarketing studies that may be required by the FDA during 
the approval process. 
3.4 
Control Procedure  
Upon completion of the decompression procedure, patients randomized to the control 
procedure will undergo an instrumented posterolateral fusion (PLF), Autograft bone 
recovered from the decompression procedure and/or the iliac crest, if necessary, will be 
used to support the fusion procedure. The autograft will be supported with allograft bone, 
including demineralized bone matrix, as needed based on the Investigator’s determination 
of required volume. The use of bone morphogenetic protein (BMP) will be prohibited.  
The study protocol will require that either the Globus Medical REVERE®, Medtronic 
Legacy™, or DePuy Expedium™ pedicle screw and rod systems be used for the control 
procedures by each participating surgeon. These systems are FDA-cleared and are 
commercially available across the United States.  
Instrumented posterolateral fusion was selected as the control arm for this study because 
there are currently no other facet arthroplasty devices approved for use in this type of 
procedure. An instrumented posterolateral fusion is considered the current treatment 
standard for patients who require surgical correction of spinal stenosis. In addition, the 
surgical technique is consistent with that utilized for the AFRS. Please refer to the 
selected instrumentation package inserts for the proper handling and use of these systems.  
Only investigators and co-investigators qualified by training or experience in performing 
instrumented posterolateral fusions will be selected for this clinical trial. If during the 
surgical procedure it is determined that the randomized treatment and any components of 
the selected treatment is unsuitable for a patient’s treatment, the patient will be 
considered a treatment failure. 
 

 
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3.5  
Study Endpoints 
3.5.1  Primary Endpoint 
The primary study endpoint for this study is individual patient success at 24 months.   
Individual patient success will be defined as follows and each component of the primary 
endpoint will be adjudicated by the Clinical Event Committee: 
• Improvements in the ZCQ score by a minimum decrease of 0.5 versus baseline for 
both Symptom Severity (SS) and Physical Function (PF) scores. 
• Maintenance or improvement in neurological outcome at 24 months.  
• No subsequent surgical intervention at the level of treatment (including device failures 
requiring revision, removal, re-operation and supplemental fixation). 
• No serious device-related adverse events (see paragraph below.) 
The trial will be deemed successful (Study Success) if the proportion of successes at 24 
months for the investigational group is not inferior to the proportion of successes for the 
control group.  
For the purposes of defining the primary endpoint, serious device-related adverse events 
are defined as those that are listed below and meet the definition of a serious adverse 
event per Section 6.2 of this protocol:  
• Implant wear, including osteolysis, tumor or other adverse response to wear 
debris. 
• Mechanical failure of the implant. 
• Migration or displacement of the implant. 
• Nerve damage or entrapment. 
• Pedicle screw loosening, backing out. 
• Pedicle screw breakage. 
• Pedicle fracture or other bony fracture. 
• Toxic/allergic response to the device. 
• Other serious adverse events determined by the CEC to have a direct relationship 
to the insertion, presence or performance of the device. 
Additionally, patients receiving post-procedure denervation procedures, at the index 
level, within the 24 month follow up evaluation period will be considered study failures. 
 
3.5.2 Secondary Endpoints 
 
The secondary study effectiveness endpoints include:  
• Improvement of the components of primary ZCQ. 
• Improvement in patient function, as measured by the ODI questionnaire. 
• Improvement of the leg and back VAS pain scores. 
• Improvement in the components of the SF-36 Quality of Life Questionnaire. 
• Changes in quantitative radiographic measures including disc height, vertebral 
range of motion and translation. 
• Changes in qualitative radiographic measures including fusion assessment, device 
migration and presence of radiolucencies. 

 
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• Radiographic Success 
• Maintenance or improvement in neurological status. 
The secondary study safety endpoints include: 
• Incidence, severity and device or procedure relatedness of all adverse events over 
the 24 month study assessment period. 
• Components of primary endpoint (surgical revisions, re-operations, removals, 
supplemental fixation.) 
The secondary clinical practice endpoints for insurance related reimbursement include: 
• Return to normal activities of daily life 
• Change in work status and time to return to work 
• Narcotic medication usage 
• Length of hospital stay 
• Duration of surgical procedure and instrumentation time 
• Blood loss 
• Rehabilitation utilization 
 
3.6 
Control of Bias and Measures to Increase Validity 
The following measures have been included in the study to control bias and increase 
study validity:  
1. 
The study design is a two-arm, controlled study. 
2. 
The study design utilizes multiple investigators. 
3. 
The study design utilizes objective endpoints that are measured by validated test 
methods.  These include the ZCQ, VAS Index, SF-36, ODI, and standardized 
radiographic assessments.  Standardized methods and protocols for performing and 
evaluating tests and examinations have been incorporated into the study protocol.   
4. 
The study design will utilize a randomization plan in which one out of three patients 
will be assigned to the control group.   
5. 
The study monitor will review and source verify case report forms maintained at the 
study sites to assure there are no missing, illegible or incorrect data.  Missing, 
illegible or incorrect data will be corrected following ICH/GCP guidelines and 
Globus Medical Standard Operating Procedures.  Site re-training will take place as 
needed to assure compliance with the protocol. Patients will be contacted prior to 
their scheduled study visits to increase adherence to the reporting schedule. 
6. 
Radiographic film analysis will be performed based on independent review by an 
independent core laboratory. Radiographic films must be taken in accordance with 
the guidelines specified by the radiographic core laboratory (See Appendix 2). The 
analysis by the core laboratory will be used in all cases for purposes of data 
analysis. 

 
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4.0 
PATIENT SELECTION AND ENROLLMENT 
All patients presenting with acquired degenerative lateral, lateral recess and/or central 
canal stenosis at a single level from L3 to S1 who require decompression and facetectomy 
and have failed to improve with at least six months of conservative treatment are 
potential study candidates and will be approached for consent prior to any data collection 
by a member of the institution’s research team.  A screening and enrollment log will be 
provided to study sites to maintain a cumulative log of all screened patients. 
 
Every effort will be made to establish eligibility of the participants prior to enrollment. 
Only patients who meet all eligibility criteria and have signed an IRB/IEC approved 
consent form are considered to be enrolled in the study. Patients who are consented but 
not randomized or randomized but are withdrawn prior to initiation of surgical procedures 
are considered a screen failure for this study. Reasons for screening failure will be 
documented on the site screening log.  All treated patients will be evaluated, as defined 
by protocol through 24 months, and annually thereafter as required by FDA.  
Patients may not be enrolled in the AFRS study without first granting their consent. No 
study specified procedures may be completed until patient has signed an approved 
Informed Consent form. The informed consent process is accomplished by providing the 
patient with a copy of and allowing the patient adequate time to review, the Informed 
Consent Form. The contents of this form are discussed by the participating clinical trial 
site staff with the patient, while allowing adequate time for questions. Patients indicate 
they are willing to participate in the study, by signing and dating the site’s current 
IRB/IEC approved Informed Consent form.  
A patient should not sign the Informed Consent Form if s/he is not willing to accept either 
the investigational or control treatment as established by the randomization process. 
Following consent, the patient will be randomized into either the AFRS (investigational) 
or posterolateral fusion (control) group.  
All patients screened for this study should be recorded but only consented patients will 
receive a study number. All consented patients will be assigned a unique patient number 
where the first two digits represent the investigative site and the last three digits represent 
the patient number (e.g. 01-001 represents the first consented patient at site 01).  Patients 
are considered enrolled only after they have signed the informed consent and met all 
eligibility requirements. Patients will be identified by this assigned number for the 
duration of their participation in the study.  
Randomization will be performed on a per-patient basis, blocked by center to maintain a 
2:1 mix of patients in the investigational and control groups at each institution. 
Randomization must occur  prior to surgery and only after the patient provides written 
informed consent, completes all baseline procedures and meets the requirements of the 
study inclusion and exclusion criteria. Sites are reminded that enough time should remain 
between randomization and surgery to allow sufficient time for insurance authorization. 

 
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As specified earlier, each Investigational Site may complete up to two training cases in 
advance of randomizing patients into the study. These cases provide an opportunity for 
the Investigator to become familiar with the technique and instrumentation. Training 
cases will not be randomized but will be followed per the protocol and analyzed as a 
separate population.  
Any patient enrolled , whether randomized or not,  will be assigned a patient number. The 
reason for failure to randomize or failure to treat will be recorded in his/her study records. 
For enrolled (consented & eligible) patients who are not treated, the following 
information will be recorded in the patient’s study file:  
• Demographic information 
• Inclusion/exclusion criteria 
• Reason for failure to randomize 
If a randomized patient is withdrawn prior to treatment, the next patient will be assigned 
the next randomly determined treatment as per the study randomization plan until a 
sufficient number of patients have been treated per each group.  
All patients treated in the study are considered to be “follow-up eligible” and will be 
required to adhere to the follow-up schedule as outlined in Appendix 1.  Patients that 
withdraw consent after receiving treatment will not be required to undergo follow-up 
after withdrawal; however, these patients will still be considered part of the patient 
cohort. No patient will be removed from the study unless the patient has withdrawn his or 
her consent before treatment or no treatment was ever attempted. 
 
 
4.1 
Inclusion/Exclusion Criteria 
Before entry into this study, each patient will be evaluated by the investigator to 
determine if s/he satisfies the eligibility criteria for this trial. To be eligible, the patient 
must meet all of the characteristics in the “Inclusion Criteria” and none of the 
characteristics listed in the “Exclusion Criteria” as listed below. 
 
4.1.1 Inclusion Criteria 
• 21-85 years of age and skeletally mature; 
• Undergone at least six cumulative months of conservative treatment prior to 
surgery including any of the following: medications, NSAIDs, physical therapy, 
bracing, chiropractic manipulation, modified activities of daily living, epidural 
injections, facet block injections; 
• Lateral, lateral recess and/or central canal stenosis as demonstrated by 
compression of the thecal sac and/or cauda equina, nerve root impingement by 
either osseous or non-osseous elements or evidence of hypertrophic facets with 
encroachment into the central canal or lateral recess at the involved level as 
determined by MRI, CT scan, plain film or myelography;  
• Disc height measuring ≥ 4 mm at the operative level; 
• Persistent leg, thigh and/or buttock symptoms, including pain, numbness, burning 
or tingling with a minimum leg pain score of 40mm as measured with the VAS; 

 
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• Score greater than 2 on a scale of 1-5 on the ZCQ Symptom Severity Score 
• Score greater than or equal to 2 on a scale of 1-4 on the ZCQ Physical Function 
Score; 
• Candidate for a decompression with full facetectomy at the operative level; 
• Candidate for an instrumented posterolateral fusion; 
• Willing and able to comply with postoperative and routinely scheduled clinical 
and radiographic evaluations; 
• Lives in the immediate area and has no plans to relocate to another geographic 
area before the completion of the study, or lives outside the immediate area and is 
willing to comply with scheduled postoperative visits with a designated physician; 
• Has signed a patient informed consent, specific to this study. 
 
4.1.2 Exclusion Criteria 
• Previous surgical procedure at the operative or adjacent level except for one of the 
following: micro-discectomy, laminectomy, lamino/foraminotomy, rhizotomy, 
IDET, and/or interspinous spacer;  
• Previous lumbar fusion or disc replacement procedure; 
• Osteoporosis as defined by Simple Calculated Osteoporosis Risk Estimation 
(SCORE) screening questionnaire score of 6 or greater and DEXA bone density 
measured T-score ≤ –2.0; 
• Greater than Grade I spondylolisthesis or retrolithesis, as defined by the 
Meyerding Grading Classification, at the operative level; 
• Spondylolisthesis any grade, as defined by the Meyerding Grading Classification 
at levels other than at the operative level; 
• Scoliosis of the lumbar spine (defined as more than 11° Cobb angle), as indicated 
by plain X-ray films;  
• Primary diagnosis of discogenic back pain due to torn, herniated, inflamed or 
irritated disc or other pathology where the patient exhibits axial back pain from 
degenerative disc disease;  
• Acute traumatic pars fracture at the operative or adjacent level vertebral body; 
• Spinal stenosis at more than three lumbar segments; 
• Experienced acute trauma to the lumbar spine within the last 24 months; 
• Active infection at the operative level, or a systemic infection including prior or 
pending treatment for HIV or Hepatitis C; 
 
• Physically or mentally compromised (i.e., being currently treated for a psychiatric 
disorder, senile dementia, Alzheimer's disease, presence of alcohol or substance 
abuse) in a manner that would compromise his or her ability to participate in the 
clinical study; 
• Diagnosed systemic disease (i.e., Paget's disease, muscular sclerosis, amyotrophic 
lateral sclerosis (ALS),renal osteodystrophy, metastasis to vertebrae, Lupus, or 
ankylosing spondylosis) that  may affect the patient’s welfare or overall outcome 
of the research study; 

 
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• Immunologically suppressed or immunocompromised; 
• Insulin-dependent diabetes mellitus (type I diabetes); 
• Currently undergoing long-term steroid therapy (treated in the last 6 months with 
systemic corticosteroids);  
• Metabolic bone disease (i.e., osteomalacia, and/or osteogenesis imperfecta); 
• Is of child-bearing potential, and is either pregnant or interested in becoming 
pregnant during the duration of the study; 
• Medically significant obesity as defined by a Body Mass Index (BMI) of > 40 
kg/m2. BMI = (weight in pounds × 703) ÷ (height in inches × height in inches); 
• Active malignancy: a history of any invasive malignancy (except non-melanoma 
skin cancer), unless the patient has been treated with curative intent and there 
have been no clinical signs or symptoms of the malignancy for at least 5 years; 
• Known allergy to cobalt chromium or titanium; 
• Used any investigational drug or device within the past 30 days; 
• Pending litigation related to back pain or injury;  
• Is a prisoner. 

 
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5.0 
STUDY PROCEDURES  
The AFRS device will be clinically evaluated utilizing a standardized protocol as 
described below. The protocol has been designed to minimize variations in patient 
selection, surgical technique, postoperative management, patient evaluation, and 
documentation of results. To further assure consistency, each investigator will be trained 
in all aspects of the protocol, including the surgical technique and appropriate 
documentation. 
 
Study patients will be evaluated pre-operatively, postoperatively and upon discharge, and 
at 6-weeks, 3, 6, 12 and 24 months postoperatively. In addition, patient follow-up will be 
completed annually after the 24-month time point as required by the FDA.  The 
evaluations to be completed at each study visit will include radiographic, pain, function 
and neurological assessments.  A summary of the data collection requirements is 
presented in Appendix 1.  Included in the summary is a list of acceptable time windows 
for patient follow-up to be completed at each study time point.  A detailed description of 
the assessment to be performed at each study visit is provided below. 
 
5.1 
Screening/Pre-Procedure 
Patients presenting with stenosis will potentially be eligible for participation in the study. 
Before being considered for enrollment into this clinical evaluation or receiving any 
study-specific diagnostic tests and/or questionnaires to further determine eligibility, the 
Informed Consent Form must be completed and signed by the patient.  
 
Once an Informed Consent Form has been successfully completed, the patient will be 
evaluated for his or her ability to meet the inclusion and exclusion criteria. Only those 
individuals who meet all of the inclusion criteria and none of the exclusion criteria are to 
be enrolled in the study.  A list of consented patients excluded from enrollment into this 
study, or considered patient screen failures will be maintained for each investigation site. 
The following screening procedures and baseline data are collected for all patients. 
 
5.1.1 Patient History  
Patient demographics and medical history will be completed by the physician or assigned 
medical personnel. Specific parameters include: 
• Age  
• Gender 
• Height/weight 
• Smoking status 
• Work status 
• Education level 
• Duration of pain 
• Concurrent health conditions 
• Medication use 
• Previous surgeries/treatments 

 
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• Previous conservative treatment modalities 
 
The patient should demonstrate failure to improve with conservative, non-surgical 
treatment for a minimum period of six months. Conservative, non-surgical treatment 
options may include, but is not limited to, medications, NSAIDs, physical therapy, 
bracing, chiropractic manipulation, modified activities of daily living, epidural injections, 
facet block injections; 
 
Those patients who are smokers will be advised that they need to stop smoking for a 
period of 6 weeks after the procedure in order to be eligible for study participation. 
Female patients of childbearing potential must have a negative pregnancy test within 14 
days prior to treatment and must agree to avoid pregnancy during the course of the study 
For those patients that enter the study with a previous surgery, information is collected on 
the case report form to provide as much detail as possible on the nature of the surgery 
including type, date, parameters of bone or device removal or other information that may 
be useful in analyzing the procedure and its affect on the patient. 
A comprehensive physical examination will be conducted at baseline and any abnormal 
findings will be recorded on the CRF. Physical examinations at follow-up visits will be 
symptom directed only. 
5.1.2 MRI, CT Scan, Plain Film, Myelography  
Radiographic methods will be completed pre-procedure to verify the presence of lateral, 
lateral recess and/or central canal stenosis per the criteria outlined in inclusion/exclusion 
section above. If a study candidate has received a CT scan or MRI of his/her spine within 
six months prior to study screening, the Investigator may use CT/MRI to verify study 
eligibility for this criteria. 
 
5.1.3 DEXA Scan 
Patients will be administered the Simple Calculated Osteoporosis Risk Estimation 
(SCORE) questionnaire. Those patients who receive a total score of 6 or greater will need 
to have a DEXA scan completed. Patients with a T-score equal to or less than (-) 2.0 will 
be excluded from the study. If a study candidate has received a DEXA scan of his/her 
spine within the previous six months of study screening, the Investigator may use the T-
score results to determine study eligibility for this criteria. 
 
5.1.4 Disc Height   
Radiographic assessment of the disc height will be used to screen out patients with a 
compromised disc and potential degenerative disc disease. The operative-level disc height 
must be greater than or equal to 4.0 mm in order for patients to qualify for enrollment into 
the study. For the purposes of patient eligibility the determination of this measurement 
will be made by the Investigator.  

 
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5.1.5 Radiographic Assessment 
The following radiographs will be taken during pre-procedure screening to establish a 
baseline for future follow up visits: 
 
 
 
 
 
 
 
The radiographs will be independently evaluated for the following quantitative 
measurements at the operative and adjacent levels:   
• Range of Motion: Calculated from the flexion-extension and lateral bending 
radiographs 
• Intervertebral Translation: Calculated from the flexion-extension radiographs  
• Disc Height: Calculated from the static lateral and AP radiographs.  
 
The recommended radiographic protocol detailing the procedures is found in Appendix 
2.  
 
5.1.6 Function 
A pre-operative assessment of function will be made to establish a baseline for 
comparison to postoperative results.  Specifically, the patient will complete the ZCQ and 
ODI questionnaires in order to measure pain and function. These forms are completed by 
the patient only.  
 
5.1.7 Neurological Assessment 
A neurological assessment15 will be completed and is performed by the physician or 
designee (as specified on the site delegation/ signature log). Whenever possible, every 
effort should be made to use the same individual to perform a patient neurological 
assessment for the duration of the study. Specific pre-operative neurological evaluation 
parameters include: 
 
• Reflexes (patellar (L2, L3, L4) and Achilles tendon (S1)) will be measured (left and 
right) and recorded using a 3-point scale: 0 (absent, trace); 1 (normal) or 2 
(hyperreflexic, clonus). 
 
• Straight Leg Raising (SLR) (L4, L5) will be measured (left and right, sitting and 
supine) and recorded using a 2-point scale: 0 (0°-70° positive test) or 1 (70°+ negative 
test). 
 
View 
Position 
Image Type 
Lateral 
Standing Neutral 
Lateral 
Lateral 
Flexion-Extension 
Flexion, Extension 
AP 
Standing Neutral 
AP 
AP 
Lateral Bending 
Left Lateral Bending, Right Lateral Bending 

 
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• Sensory Function will be measured by nerve root distribution using a light touch 
technique with results recorded using a 2-point scale: 0 (decreased, anesthetic or 
hyperesthetic) or 1 (normal). The following dermatomes will be evaluated based on 
level of use: 
 
 
L1 
Anterior Quadriceps 
 
 
L2  
Anterior Thigh 
 
 
L3 
Anterior Knee 
 
 
L4 
Medial Foot 
 
 
L5 
Dorsal Foot 
 
 
S1 
Lateral Foot 
 
A figure detailing the location of the required dermatomes is located in Appendix 3. 
 
• Muscle Strength will be measured for individual muscle groups and recorded using a 
5-point scale: 0 (No evidence of contractility), 1 (Slight contractility, no joint motion), 
2 (Joint motion with gravity eliminated), 3 (Some joint motion against gravity), 4 
(Full joint motion against gravity, some resistance) or 5 (Full joint motion against 
gravity, full resistance). 
 
 
The following muscles will be evaluated based on the level of use using the noted 
motor evaluations: 
 
 
 
L1-L2  
Iliopsoas 
 
 
Hip Flexion 
 
 
L2-L4  
Quadriceps 
 
 
Knee Extension 
 
 
L4-L5  
Anterior Tibial Group  
Ankle Dorsal flexion 
 
 
L4-S1  
Gluteus Maximus 
 
Hip Extension 
 
 
L5 
 
Hallucis Longus 
 
Great Toe Dorsiflexion 
 
 
 
L5-S1  
Hamstrings 
 
 
Knee Flexion 
 
 
S1 
 
Flexor Hallucis 
 
Ankle Plantar Flexion 
 
5.1.8 Pain  
A pre-operative assessment of bilateral leg and back pain will be made to establish a 
baseline for comparison to postoperative results.  Right leg, left leg and back pain will be 
evaluated by the patient using a 100 mm Visual Analog Scale (VAS). The VAS consists 
of three horizontal lines, one each for the right leg, left leg and back. The patient denotes 
his/her pain level by placing a vertical line along its length. To qualify for the study, one 
leg VAS score must be equal to or greater than 40 mm as measured and recorded by the 
clinical staff on the VAS questionnaire document. 
 
5.1.9 Quality of Life  
The patient’s quality of life information will be captured using the SF-36 Quality of Life 
questionnaire. This questionnaire is to be completed by the patient.  
 

 
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5.2 
Randomization Procedure 
Patients will be randomly assigned on a two to one (2:1) basis to either the treatment or 
control group. Randomization will be stratified by clinical center and permuted block 
randomization will be performed within strata. The block size will be variable and 
randomly chosen from small multiples of 3. The randomization schedules for the study 
will be prepared in advance by the study statistician or designee. Investigational sites and 
the Sponsor will not have access to the randomization schedules.  
 
Treatment assignments will be provided by the statistician for each site completed either 
by sealed envelopes or an electronic web-based program. If envelopes are used, they will 
be sealed and sequentially numbered with one envelope per patient. Once distributed to 
the sites, they will remain sealed until a prospective patient had passed all study criteria. 
The study coordinator or designee will open the envelope to determine treatment 
assignment prior to the procedure, allowing sufficient time for insurance authorization. 
The assignment card will be attached to the Case Report Form. Patient will be blinded to 
treatment until after the procedure.  
 
Alternatively, a web-based randomization program may be utilized by sites where 
treatment assignment is made after verification of proper informed consent execution and 
study eligibility.  
 
Any patient consented, whether randomized or not,  will be assigned a patient number. 
The reason for failure to randomize or failure to treat will be recorded in his/her study 
records.  
 
If a randomized patient is withdrawn prior to treatment, the next patient will be assigned 
the next randomly determined treatment as per the study randomization plan until a 
sufficient number of patients have been treated for each group.  
 
5.3 
Operative Procedure 
Following the surgery, details of the surgical procedure are documented including: 
• Operative date, time, clinical site location, investigator performing surgery 
• Treatment assigned, device used and traceability  
• Vertebral levels treated, decompression performed, procedure and instrumentation 
time, blood loss 
• Source of bone for fusion 
• Antibiotics and/or deep vein thrombosis prophylaxis used pre-, intra-, and/or post-
operatively, if applicable 
• Intra-operative complications 
 
Immediately following surgery, the patient is transported to the surgical recovery area and 
monitored according to the hospital/physician protocol for surgeries of this nature. The 
patient may be released from the recovery room to the nursing unit when s/he has met the 

 
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hospital’s criteria for discharge from the recovery area. Immediate postoperative care will 
be dictated by the hospital or physician’s standard care protocol regarding post-anesthesia 
recovery.  Patients shall be encouraged to ambulate after surgery as soon as is medically 
reasonable.   
 
Unforeseen events (findings or procedures) may occur during decompression/spinal 
preparation procedure(s) prior to implantation of the ACADIA®   Facet Replacement 
System or Control System. These unforeseen events are those that are not planned as part 
of this surgery (eg, a drop in oxygen saturation intraoperatively, evidence of an acute 
myocardial infarction, allergic reaction to an antibiotic, etc). Unforeseen events that are 
emergent in nature should be recorded as AEs and the investigator should reassess the 
patient’s suitability for continued participation in this study.  
 
If an intraoperative decision is made to perform a procedure other than what was intended 
for study enrollment, the patient will be withdrawn from the study and will be followed 
for safety as a separate “Not Treated” cohort.  If a randomized patient is withdrawn prior 
to treatment, the next patient will be assigned the next randomly determined treatment as 
per the study randomization plan until a sufficient number of patients have been treated 
per each group.  
 
5.4 
Patient Discharge  
Prior to discharge, patients are examined and evaluated for the presence of any adverse 
events that may have occurred between the operative procedure and discharge. Patient 
discharge from the hospital will be accomplished according to standard hospital/physician 
practice. Patients are eligible for discharge based on the following criteria: 
• Patient is able to ambulate 
• Surgical wound is confirmed as intact, with no signs of infection 
• Patient bodily functions are active 
 
Patient discharge from the hospital will be accomplished according to standard 
hospital/physician practice. Prior to discharge the patient may be fitted with a brace at the 
investigator’s discretion. The brace will be removed at the 6-week follow up visit or 
earlier based on the Investigator’s discretion. 
The following data is collected at discharge: 
• Static AP radiographs 
• Static lateral radiographs 
• Duration of hospital-stay and hospital discharge date 
• Pain and antibiotic medication use 
• Adverse events 
 
Bone growth stimulators are not to be used during the course of this study.  This study 
does not specify the use of prophylactic antibiotic medications. Medications may be 
administered at the discretion of the physician. After discharge, patients are not to receive 

 
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epidural spinal injections or nerve blocks for pain relief within six weeks of a scheduled 
study visit, as this will confound the collection of pain and function data.  
 
Additionally, patients receiving post-procedure denervation procedures, at the index 
level, within the 24 month follow up evaluation period will be considered study failures. 
 
Patients will be instructed to avoid smoking and use of systemic (IV, PO or transdermal 
patch) steroidal therapy during the first six weeks of post procedure bone healing and 
informed that this may affect their recovery. For the purposes of this study, use of inhalers 
containing steroids are not considered systemic use. 
 
All patients will receive postoperative rehabilitation therapy as directed by the 
investigator with the objective or improving strength, flexibility and mechanics. This 
therapy will not be standardized as the program is required to be specific for each 
patient’s need. Bending and lifting should be avoided during the first 6 week period 
postoperative period.  
 
The discharge instructions contained in Appendix 4 (or site equivalent) will be explained 
and provided to the patient upon hospital discharge.  
 
 
5.5  
Hospitalization Charges 
The cost and intensity of service for the index treatment and control hospitalizations, as 
well as any additional hospitalizations during the study, will be tracked. This data will be 
collected to meet the requirements of the Centers for Medicare and Medicaid (CMS) for 
making coverage and reimbursement determinations for new devices.  Because this data 
does not support the safety and efficacy of the investigational device, it will not be 
provided to the Food and Drug Administration (FDA) as part of the IDE reporting 
requirements or the Pre-Market Approval (PMA) process.   
The data to be collected may include, but is not limited to:  copies of the patients’ hospital 
bills (UB04), corresponding Explanation of Benefits (EOB), physician’s bill (HCFA 1500 
form), or itemized hospital bills.  The un-redacted economic form(s) are collected then 
provided to the Sponsor.  
The following personal health information from the UB04 will be collected: 
• 
Patient’s hospital identification number 
• 
Patient’s birth date 
• 
Hospital’s provider identification number 
• 
Patient’s hospital admission date 
• 
Patient’s hospital discharge date 
• 
Patient’s procedure date 
• 
ICD-9 diagnosis and procedure codes (all) 
• 
DRG assignment 
• 
Total charges for the hospitalization 

 
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5.6 
Patient Follow-Up 
Patient follow-up will be completed postoperatively; at hospital discharge, at 6 weeks and 
3, 6, 12, and 24 months as outlined in the Assessment Schedule located in Appendix 1.  
After 24 months, patients will be evaluated annually, as required by FDA.  The study 
assessments required at each follow-up visit are detailed below. 
 
All questionnaires related to patient outcome will be completed at each visit 
independently by the patient prior to any clinical evaluations and will be administered by 
study personnel who are not healthcare providers directly associated with the study. 
 
Patients who undergo removal, revision, or reoperation of, or supplemental fixation to, 
the investigational or control device will continue to be followed for safety and 
effectiveness outcome data. 
  
5.6.1 Radiographic Assessment 
 
The following radiographs will be taken during the follow-up visits. At the 6 week 
follow-up visit, only the standing neutral lateral and AP radiographs are taken. At the 3, 
6, 12, 24 month time points, and annually as required by FDA, all listed radiographs are 
taken.  
 
View 
Position 
Image Type 
Lateral 
Standing Neutral 
Lateral 
Lateral 
Flexion-Extension 
Flexion, Extension 
AP 
Standing Neutral 
AP 
AP 
Lateral Bending 
Left Lateral Bending, Right Lateral Bending 
 
The radiographs will be sent by the sites to Globus Medical, and then to a core radiology 
laboratory for independent review. The radiographs will be independently evaluated for 
the following quantitative measurements at the operative and adjacent levels:   
 
• Range of Motion: Calculated from the flexion-extension and lateral bending 
radiographs 
 
• Intervertebral Translation: Calculated from the flexion-extension radiographs  
 
• Disc Height: Calculated from the static lateral and AP radiographs.  
 
 
 
 
 

 
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In addition, the following qualitative assessments will be made: 
 
• Device Displacement: Graded as Yes or No, where “Yes” is defined as 3mm or 
more displacement of hardware from initial operative placement.   
 
• Radiolucency:  Graded as None, Mild (<25%), Moderate (25-50%) or Severe 
(>50%) based on the amount of radiolucency along the device hardware. 
 
• Bridging Bone: Presence of bridging bone will be graded as “Yes” or “No” based 
upon bone creating a continuous connection between the vertebral endplates.  
 
• Fusion/Non Fusion: A determination of fusion status based upon the following 
criteria: 
 
For the investigational group, radiographic success is defined by the following 
measures at the index level. Each criterion will be evaluated independently:  
 
1. No evidence of bridging trabecular bone between the involved treated   
motion segments, and ≥5º +/-1º of angular motion from flexion to 
extension. 
 
2. No evidence of bridging trabecular bone between the involved treated 
motion segments, and ≥3º +/-1º of angular motion from flexion extension. 
For patients who enter the study with less than or equal to 3º +/-1º of 
angular motion: No evidence of bridging trabecular bone and maintenance 
(+/-1 º) or improvement in angular motion from baseline. 
 
For the control group, radiographic success is defined as evidence of fusion by 
demonstrating all of the following measures at the index level: 
 
1. Evidence of bridging trabecular bone between the involved motion 
segments; and 
 
2. Translational motion < 3mm; and 
 
3. Angular motion <5º +/-1º 
 
For determining success, the definition of angular motion incorporates a +/-1° accuracy 
factor in the analysis. This represents the accuracy of the analysis within 2 standard 
deviations as determined by the core radiology laboratory. The radiographic protocol 
detailing the procedures is found in Appendix 2.  
 

 
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5.6.2 Function 
The patient will complete the ODI and ZCQ Questionnaires for the purposes of 
measuring function.  Both evaluations will be completed by the patient at their 6 week, 3, 
6, 12 and 24 month follow-up visits, and annually as required by FDA. 
 
5.6.3 Neurological Assessment 
The neurological assessment will be completed and is performed by the physician or 
designee as specified on the site delegation/ signature log. Whenever possible, every 
effort should be made to use the same individual to perform a patient neurological 
assessment for the duration of the study. The specific postoperative neurological 
evaluation parameters are outlined in section 5.1.7 above. The evaluation will be 
completed at 6 weeks, 3, 6, 12 and 24 months, and annually as required by FDA. A 
decrease in any one of the measures compared to baseline will be considered an adverse 
event and should be documented on the appropriate CRF. 
 
For the purposes of determining patient success for the primary endpoint, a successful 
neurological outcome is defined as: Maintenance or improvement in sensory, motor 
function, reflexes and muscle strength.   
 
The results of this exam will be adjudicated by the CEC for the purposes of defining 
patient success. 
 
5.6.4 Pain  
Bilateral leg and back pain will be recorded by the patient and measured using the VAS 
Index. This evaluation will be completed by the patient at their 6 week, 3, 6, 12 and 24 
month study follow-up visits, and annually as required by FDA. 
 
5.6.5 Patient Satisfaction 
Patient satisfaction with the procedure s/he received AFRS (investigational) or 
posterolateral fusion (control) will be assessed by the use of a brief satisfaction 
questionnaire. The questionnaire will be completed by the patient at 6 weeks, 3, 6, 12 and 
24 months postoperatively, and annually as required by FDA. 
 
5.6.6  Quality of Life  
Quality of life indicators will be evaluated through the use of the SF-36 Quality of Life 
Questionnaire. This questionnaire will be administered to and completed by the patient at 
the 6 week, 3, 6, 12 and 24 months postoperative study visit time points, and annually as 
required by FDA. 
 
 
5.6.7 Medication Use 
Patient medication use, including pain injections, will be recorded and categorized by 
group. Medication evaluations will be completed at 6 weeks, 3, 6, 12 and 24 months, and 
annually as required by FDA.  
 

 
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Antibiotics and pain medications administered while the patient is in the recovery room 
after the spinal fusion surgery will not be recorded. Other medications, taken while in the 
recovery room, do not need to be recorded unless they are given for an AE. If a patient is 
medicated or receives other non-study therapy for an abnormal clinical laboratory 
evaluation (unless this is standard of care or for a pre-existing condition), it will be 
recorded as an AE. All pain medications and use of postoperative epidural injections and 
denervation procedures will be recorded. Patients receiving denervation procedures at the 
index level before the 24 month follow up visit will be considered study failures.  
5.6.8  Return to Normal Activities/Work 
Patient’s ability to return to normal activities of daily living, utilization of rehabilitation 
and ability to return to work will be will be assessed by the use of a brief questionnaire. 
The questionnaire will be completed at 6 weeks, 3, 6, 12 and 24 months postoperatively 
and annually as required by FDA. 
 
5.6.9  Adverse Events 
Adverse events (AEs), including Serious Adverse Events (SAEs), will be captured 
intraoperatively and during all study follow-up visits. Adverse event definitions and 
reporting requirements are detailed in Section 6.0: Adverse Event Reporting. All reported 
AEs will be followed until resolution or completion of the study or postmarket study, as 
required by FDA.  
 
5.6.10  Symptom Directed Physical Exam 
A symptom directed physical examination will only be conducted during follow-up visits 
if a patient has reported signs or symptoms not previously identified during the previous 
study visit.  Any abnormal findings will be recorded on the appropriate CRF.  
 
5.7 
Patient Discontinuation                                                                      
All patients enrolled into the current study and who have undergone one of the study 
treatments, will be followed for 24 months postoperative and until all FDA requirements 
are met, potentially up to 10 years postoperative.  Acceptable reasons for not evaluating a 
patient through the follow-up period include: 
a) 
Patient Lost to Follow-Up:  Unable to locate patient despite documented attempts to 
notify the patient via telephone and by certified mail.  A patient will not be 
considered lost to follow-up until the last scheduled follow-up visit (24 month study 
time point). 
b) 
Patient Request to Terminate:  The patient requests to terminate his/her involvement 
in the study, therefore withdrawing his/her consent to participate in the study (the 
investigator must thoroughly document the reasons for termination).  
c) 
Patient Death:  If possible, an autopsy and/or death certificate should be obtained in 
order to document the cause of death. 

 
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If a patient discontinues from the study (regardless of the reason), the investigator will 
record the reason for withdrawal on the appropriate CRFs.  Every effort shall be made to 
have discontinued patients (as appropriate) return for an “Early Termination Visit” to 
collected the required safety evaluations as detailed in the protocol.  
 
6.0 
ADVERSE EVENT REPORTING  
6.1 
Adverse Events  
An Adverse Event (AE) is defined as any undesirable clinical occurrence in a patient, 
whether it is considered to be device-related or not.  Adverse events may occur 
intraoperatively or postoperatively, and are reported on the Adverse Event Form (SA10).  
Conditions that existed or occurred prior to treatment in this study may only be 
considered adverse events if the patient’s condition worsens or requires additional 
treatment. 
AEs will be classified and tabulated by the following: 
1. Their relationship to the investigational device (AFRS implant) or control 
(posterolateral fusion) procedure, depending on the patient’s randomization 
into the trial; 
2. Their relationship to the AFRS implant (investigational arm) or posterolateral 
fusion hardware (control arm) itself,  
3. The severity of clinical event;  
4. The action taken to treat the event; and 
5. The outcome of the event. 
 
Serious adverse events and deaths are considered adverse events, and will be listed and 
reported separately.  Unanticipated adverse device effects will be recorded and reported in 
accordance with FDA regulations.  
 
The determination of whether an adverse event is classified as a Serious Adverse Event 
(SAE) or Unanticipated Adverse Device Effect will be based on the definitions contained 
in this section, while also taking into account the clinical judgment of the investigator.  
 
Adverse events will be coded by the Clinical Events Committee, based on the body 
system (e.g. gastrointestinal) and categorization of events appropriate to the condition. 
 
6.1.1 Adverse Event Term 
An adverse event term is determined by the investigator/site coordinator, based on the 
patient’s symptom or condition, and is described on the form.  Potential adverse events 
may include, but are not limited to, the following: 
• Implant breakage; 
• Component disarticulation; 
• Component degradation;  
• Implant displacement/dislocation; 

 
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• Pedicle disruption/failure; 
• Allergic reaction to implant materials; 
• Reaction to implant wear debris;Fracture/damage to pedicle; 
• Fracture/damage to spinous process; 
• Failure of bone to heal around implant; 
• Bone resorption; 
• Non-union, delayed union; 
• Bursitis; 
• Vessel damage/bleeding; 
• Nausea and/or vomiting; 
• Superficial infection; 
• Deep wound infection; 
• Hematoma at surgical site; 
• Incisional pain; 
• Pulmonary embolism; 
• Stroke; 
• Myocardial infarction; 
• Coronary episode; 
• Pneumonia; 
• Kidney failure; 
• Bowel obstruction 
• Dural tear; 
• Thrombosis; 
• Nerve injury; 
• Neuropathy 
• Cauda equina syndrome; 
• Transverse process fracture; 
• Pseudomeningocele; 
• Paralysis; 
• Spinal fluid leakage; 
• Spinal cord damage; 
• Bone fracture; 
• Spinous process fracture; 
• Spondylosis; 
• Heterotopic bone formation; 
• Scoliosis; 
• Kyphosis; 
• Segmental instability; 
• Decrease in neurological function; 
• Worsening leg and/or back pain; 
• Worsening pain associated with stenosis; 
• Degeneration at adjacent level(s); 

 
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• Respiratory distress; 
• Wound dehiscence; 
• Wound swelling; 
• Death 
 
6.1.2 Relationship to Procedure 
The relationship between an adverse event and the surgical procedure (investigational or 
control treatment) will be assessed on the basis of the following definitions: 
 
• Definitely Related:  Clear-cut temporal association and no other possible cause. 
 
• Probably Related: Clear-cut temporal association and a potential alternative 
etiology that is not apparent. 
 
• Possibly Related: Temporal association is less clear and other etiologies are also 
possible. 
 
• Probably Not Related:  Temporal association and the nature of the event is such 
that the surgical procedure is not likely to have had any association with the 
observed event (cause and effect relationship improbable but not impossible) 
 
• Definitely Not Related:  There is no temporal association and/or evidence exists 
that the event is definitely related to another etiology 
 
6.1.3 Relationship to Device 
The relationship between an adverse event and the implanted device (investigational or 
control) will be assessed on the basis of the following definitions: 
 
• Definitely Related:  Clear-cut temporal association and no other possible cause. 
 
• Probably Related: Clear-cut temporal association and a potential alternative 
etiology that is not apparent. 
 
• Possibly Related: Temporal association is less clear and other etiologies are also 
possible. 
 
• Probably Not Related:  Temporal association and the nature of the event is such 
that the device is not likely to have had any association with the observed event 
(cause and effect relationship improbable but not impossible) 
 
• Definitely Not Related:  There is no temporal association and/or evidence exists 
that the event is definitely related to another etiology 
 

 
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6.1.4 Severity 
The severity of an adverse event will be assessed according to the World Health 
Organization (WHO) Recommendations for Grading of Acute and Subacute Toxic 
Effects. The following definitions are used: 
 
• Mild (Grade 1): The adverse event is noticeable to the patient but does not 
interfere with routine activity. The adverse event does not require implant 
removal. 
 
• Moderate (Grade 2): The adverse event interferes with routine activity but 
responds to symptomatic therapy or rest.  The adverse event does not require 
implant removal. 
 
• Severe (Grade 3): The adverse event significantly limits the patient’s ability to 
perform routine activities despite symptomatic therapy.  In addition, the adverse 
event may require removal of the implant. 
 
• Life-threatening (Grade 4): The adverse event may require removal of the 
implant.  The patient is at immediate risk of death. 
 
6.1.5 Action Taken 
Adverse events or treatment failures may lead to further actions as required to resolve the 
adverse event.  The following actions will be identified for each adverse event:  
 
• None: No further actions taken to resolve adverse event 
 
• Medication:  Medications are prescribed to treat the adverse event 
 
• Index Level Surgery:  A procedure at the original involved level in which all 
or part of the original implant configuration is modified or removed, with or 
without replacement, or additional surgical instrumentation is implanted.  This 
includes decompression, surgical repair of a dural tear, wound debridement, 
irrigation and drainage at the original level.  (Details are submitted on a 
Surgical Intervention Form SA11.) 
 
• Other:  Any additional procedure that is not one of the above categories 
 
An index level surgery that is a revision, removal, reoperation, or supplemental fixation 
will be classified as a treatment “failure”. Other index level surgery, such as debridement, 
irrigationa and drainage, and repair of a dural tear, will not be classified as a treatment 
“failure”.  All patients having secondary surgical procedures will be followed for the 
duration of the study for safety, in accordance with Section 5.6. 
 
6.1.6 Outcome 

 
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The outcome of each adverse event will be identified as one of the following categories: 
 
• Resolved:  The adverse event has been resolved and is no longer continuing 
 
• Temporary Disability: Disability that is short term and is not considered a 
permanent disability 
 
• Permanent Disability: Disability that has been determined to be permanent 
and not temporary 
 
• Death:  Death of the patient due to the adverse event 
 
6.2 
Serious Adverse Events 
Serious adverse events (SAEs) are defined as adverse events that are life-threatening, or 
ones that result in permanent impairment of a body function or permanent damage to a 
body structure, or they necessitate medical or surgical intervention to preclude permanent 
impairment of a body function or permanent damage to a body structure.  
 
An SAE is any untoward medical occurrence that:  
• Results in death,  
• Is life-threatening,  
• Requires inpatient hospitalization or prolongation of existing hospitalization,  
• Results in persistent or significant disability/incapacity, or  
• Is a congenital anomaly/birth defect.  
 
Any Serious Adverse Event must be reported to Globus Medical, Inc. by the investigator 
within 24 hours of first learning about the event. An Adverse Event Case Report Form 
must be sent to Globus Medical within ten working days of knowledge of the event to the 
fax number listed on the case report form.  The event is documented on the Adverse 
Event Case Report Form, with SAE denoted on the form.  Participating Institutional 
Review Boards will be notified in accordance with their respective procedures.  
 
6.3 
Unanticipated Adverse Device Effects 
An Unanticipated Adverse Device Effect (UADE) is defined as any serious adverse effect 
on health or safety or any life threatening problem or death caused by or associated with 
the device if that effect, problem or death was not previously identified in nature, 
severity or degree of incidence in the investigational plan, or any other unanticipated 
serious problem associated with the device that relates to the rights, safety or welfare of 
subjects.  
 
Any unanticipated adverse device effects must be reported to Globus Medical, Inc. within 
24 hours of first learning about the event. A written report must be made to Globus 
Medical, Inc. within ten working days of knowledge of the event to the fax number listed 

 
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on the case report form.  The event is documented on the Adverse Event Case Report 
Form, with UADE denoted on the form.  The Institutional Review Board must also be 
notified within ten working days or sooner depending on their requirements. 
Globus Medical, Inc. will also notify the appropriate regulatory agencies, and all 
participating investigators and Institutional Review Boards in writing within ten working 
days after learning of any unanticipated adverse device effects.  
 
 
6.4 
Patient Death                                                                                 
Patient death during the investigation must be reported by fax to Globus Medical, Inc. 
within 24 hours of the Investigator’s knowledge of the death.  Notification of death must 
include a brief statement of the relevant details and be signed by the Investigator or Co-
Investigator.  A copy of the death records, death certificate and an autopsy report (if 
performed) must be sent to Globus Medical, Inc. 
 
6.5 
Subsequent Surgical Interventions 
All additional surgeries are to be reported, and are reported according to Section 6.1.5 
Action Taken.  Details are reported on the Surgical Intervention Form (SA11).  Surgical 
procedures subsequent to the original surgery will be categorized as follows: 
 
• A revision is a procedure that adjusts or in any way modifies or removes part the 
original implant configuration with or without replacement of a component, and 
may also include adjusting the position of the original configuration.  
 
• A removal is a procedure where all of the original implant configuration is 
removed with or without replacement. 
 
• A reoperation is any surgical procedure at the involved level that does not require 
removal, modification, or addition of any components of the system (excluding 
surgical repair of a dural tear, irrigation and drainage, or wound debridement). 
 
• A supplemental fixation is a procedure in which additional instrumentation not 
under study in the protocol is implanted at the involved level. 
 
An implant removal study will be conducted during the length of the investigational 
study. Investigators will retrieve any explanted devices during this time period, place the 
specimen in 70% alcohol, place in a leak-proof container, and send the specimen to 
Globus Medical, Inc. Globus will then complete a thorough evaluation of the implant to 
determine an assignable cause for the device removal, if any.   A complete protocol to 
address analysis of removed implants is detailed in Appendix 5. 
 
If an adverse tissue reaction is suspected before or during revision, report specific 
observations (operative site and device), any histological data (biopsy), MRI/CT, and 
metal allergy data on SA11, in addition to the operative report and chart notes. 

 
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7.0 
COMMITTEES 
 
7.1 
Clinical Events Committee 
An independent Clinical Events Committee (CEC) will be established to oversee study 
progress, review clinical data/safety parameters and to adjudicate study endpoints. The 
CEC will consist of a minimum of three independent physicians.  The group may be 
multidisciplinary (e.g. orthopedic surgeons, neurosurgeons and radiologists) and 
membership will include individuals not participating in the AFRS clinical study. The 
CEC members will be independent from both the Sponsor and the study investigators.  
Efforts shall be made to maintain anonymity of the committee membership to reduce any 
potential bias. The CEC will function under the following general guidelines (detailed 
guidelines may be found in the CEC charter): 
• Meetings will be called to periodically review study data and/or evaluate the 
impact of identified adverse events. The CEC will be responsible for the review 
and adjudication of all adverse events that occur over the course of the study and 
the subsequent classification of these events by level of seriousness and 
relationship to the device or procedure.   
• The CEC will recommend interrupting, stopping or continuation of study 
enrollment after assessing the rate of complications encountered and their impact 
on patient safety and welfare.  
• The CEC may recommend revising the protocol, ICF or other study documents if 
it is determined necessary to maintain the safety or welfare of the involved 
subjects. 
 
If the study is stopped study enrollment / treatment may resume after a safety review by 
the CEC, the sponsor and other experts as needed, has been completed and it is 
determined that it is safe to continue. Submission of a supplement to the IDE identifying 
issues, reviews and rationale for restarting enrollment must be approved by the FDA prior 
to resuming study enrollment. Individual site IRB/IECs may review the CEC’s related 
meeting minutes and rationale for study continuation prior to allowing the clinical site to 
resume enrollment. 
 
The final analysis of individual events shall be based on the CEC adjudicated events.  
During the review of events, the members of the CEC will be blinded to the 
investigational site as much as possible.  
 
The CEC will also participate in evaluation of data for endpoint adjudication and protocol 
deviation review for purposes of determining the per protocol analysis patient population.  
 
The CEC will establish consistent definitions for each type of adverse event and define 
the documentation required to review the adverse events at their first meeting.   

 
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8.0 
STATISTICAL ANALYSIS PLAN 
 
8.1 
Analysis Populations 
 
Primary Analysis Population:   
 
The principal analysis of the primary and secondary endpoints will utilize the intent-to-
treat (ITT) patient population.  The ITT population will include all randomized subjects 
for whom surgery is attempted.  Subjects for whom surgery is attempted but not 
successfully completed will be considered treatment failures.  Randomized subjects in 
whom surgery is not attempted will be described in detail in a separate section of the 
study report. 
 
Secondary Analysis Populations:   
 
The primary and secondary objectives will be further analyzed using an as-treated (AT) 
analysis performed on all randomized subjects according to the treatment actually 
received.   
 
The primary and secondary objectives will be further analyzed using a per protocol (PP) 
analysis performed on an evaluable patient population.  The evaluable population will 
consist of all ITT subjects that:  [1] meet critical study eligibility criteria and have no 
significant protocol deviations based on Clinical Events Committee assessment; [2] have 
the assigned procedure completed; and [3] completed the 24-month follow-up 
assessment.   
 
Training Population:   
 
This patient population will include all non-randomized AFRS treated patients enrolled 
during the pivotal phase of the trial as training cases at the site.  A maximum of two 
patients per site for a total of 60 patients will be included in this cohort.  Training cases 
will be described separately from randomized patients in the final study report and will be 
presented primarily using descriptive statistics.  This patient population will be used to 
understand the learning curve in the use of the device by assessing the results of the 
Training cases relative to those obtained in the Treatment group arm of the randomized 
study.   
 
An additional presentation of the safety data in which all of the patients treated with the 
AFRS device (non-randomized and randomized) are combined as one cohort and 
compared to the control group will be included. 
 

 
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8.2 
Primary Objective 
 
The primary objective is to establish that AFRS (treatment) is non-inferior to fusion 
(control) at 24 months as assessed by subject success.  Using the definition of treatment 
success as presented in Section 3.5, the hypothesis of interest is 
 
H:     pt – pc > –δ, 
 
where pt and pc represent the proportions of treatment successes in the treatment and 
control groups, respectively, and δ = 0.15 is the margin of non-inferiority.  AFRS will be 
declared to be non-inferior to control if it can be established that the posterior probability 
Pr( Hδ=0.15 | data) > Ψ, where Ψ is a pre-specified threshold value.  If, in addition, it can be 
shown that Pr(Hδ=0 | data) > Ψ, AFRS will be declared to be superior to control.  The 
value chosen for Ψ is described below. 
 
8.3 
Randomization, Sample Size, and Analysis Plan  
 
This study is designed to adaptively determine the proper sample size.  Possible sample 
sizes are 300, 450, 600, and 750 (maximum).  Randomization will follow a 2:1 
(treatment:control) allocation ratio and be stratified by site, using a blocked 
randomization scheme with blocks of randomly varying sizes.  Further details on the 
randomization process are provided in Section 5.2. 
In addition to the planned interim analyses that will determine the sample size, there will 
be several interim analyses conducted for the purpose of possibly declaring an early win.  
The first of these will occur when 300 subjects have completed 2 years of follow-up.  If 
the trial does not stop for success at that analysis, a second analysis will occur when 450 
have completed 2 years of follow-up.  If the trial does not stop for success at that analysis, 
a final analysis will occur when the entire enrolled cohort has completed 2 years.  It is not 
necessary for the trial to have stopped enrollment in order for the interim “Early Win” 
analyses to occur.  For example, the first Early Win analysis (when 300 have completed 2 
years) will occur even if the trial is still enrolling (i.e., the sample size determination 
algorithm has not determined the final sample size).  Of course, if the final sample size is 
300, there can be only 1 Win analysis (when the full cohort has reached 2 years); if the 
final sample size is 450, there can be only 2 Win analyses (when 300 have reached 2 
years and when the full cohort has reached 2 years). 
The sample size determination analyses and the “Early Win” interim analyses are 
triggered by different circumstances (number enrolled versus number completing 2 years) 
and are expected to follow different analysis schedules (i.e., although it is possible, a 
sample size analysis and an early win analysis are unlikely to occur simultaneously). 
Further details on this analysis plan are given below. 

 
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Determination of Non-Inferiority and Superiority (“Win” Analyses) 
 
Interim “Win” analyses are scheduled to occur when 300 and 450 subjects have 
completed 2 years of follow-up.  A final analysis will occur when the entire enrolled 
cohort has completed 2 years of follow-up.  At each of these analyses, the probability of 
non-inferiority Pr( Hδ=0.15 | data) will be calculated, based on all observed data, including 
predicted 2-year outcomes for those subjects who have not reached 2 years.  The prior 
distributions for pt and pc in this calculation are Beta (1,1).  Details on the prediction are 
given below under the heading “Predictions.”  Decisions will be based on the following: 
• If, at an interim “win” analysis, Pr( Hδ=0.15 | Data) ≤ Ψ, subjects will continue to be 
followed until the next scheduled “win” analysis (interim or final). 
• If, at an interim “win” analysis, Pr( Hδ=0.15 | Data) > Ψ, non-inferiority will be claimed 
and an early submission will follow.  In addition, if Pr(Hδ=0 | data) > Ψ, superiority 
will also be claimed at the same time.  However, if Pr(Hδ=0 | data) ≤ Ψ, subjects will 
continue to be followed and analyzed according to the same analysis plan.  At a 
subsequent “win” analysis, if Pr( Hδ=0 | data) > Ψ, a delayed determination of 
superiority will be claimed. 
 
The threshold Ψ is chosen to be Ψ = 0.980.  This value is selected by trial-and-error to 
achieve a type 1 error rate (under simulation) of 0.05.   
 
Determination of Sample Size 
 
The sample size is guided by a standard frequentist non-inferiority power analysis.  Under 
the assumptions of pt = 0.70, pc = 0.70, δ=0.15, 2:1 randomization, α= 0.05, and power = 
80%, the method of Farrington and Manning1 as implemented in PASS 20052 indicates 
that the required sample size for a single-look analysis is 242. The estimated success rate 
of 70% utilized for sample size calculation was selected based on a review of available 
literature for the control procedure. These references report patient success to be between 
67% and 87% depending on the outcome measure 19-24. To allow for up to 15% dropout, 
285 must be enrolled.  Furthermore, to compensate for power lost in a 3-look sequential 
analysis plan, 15 additional subjects need to be enrolled, for a total of 300.  Fifteen of 285 
is approximately 5%.  It is well known that inserting two interim analyses can require a 
sample size increase of anywhere from 3% (O’Brien-Fleming bounds) to 18% (Pocock 
bounds)3.  
 
                                            
1  Farrington, C. P. and Manning, G. 1990. 'Test Statistics and Sample Size Formulae for Comparative Binomial Trials with Null 
Hypothesis of Non-Zero Risk Difference or Non-Unity Relative Risk.' Statistics in Medicine, Vol. 9, pages 1447-1454. 
2  Hintze, J. (2004).  NCSS and PASS, Number Cruncher Statistical Systems.  Kaysville UT.  www.ncss.com. 
3  Jennison C and Turnbull BW, Group Sequential Methods with Applications to Clinical Trials.  Boca Raton:  Chapman & Hall, 
2000, p 27, 30. 

 
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The trial’s sponsor maintains that using δ=0.15 is appropriate as a margin of non-
inferiority, while regulatory authorities (FDA) have indicated that, while they may be 
persuaded to use this margin, they would prefer and may even require the use of a margin 
of δ=0.10.  Following a calculation similar to the one above, a margin of δ=0.10 would 
require approximately 750 enrolled subjects. 
 
Given the uncertainty in the ultimate δ-margin that will be used, the sponsor wishes to 
employ an adaptive trial design where sample size will be determined on the basis of 
δ=0.10, but the standard for declaring non-inferiority (“winning”) is based on a margin of 
δ=0.15.  In other words, although the “win” analyses will be based on the margin of 
δ=0.15, the sponsor does not wish to shut down enrollment unless there is a reasonably 
high probability of trial success using a margin of δ=0.10.   
 
The sample size determination algorithm is thus defined as follows.  When N = Ni 
subjects are enrolled (Ni = 300, 450, 600), two predictive probabilities are calculated:   
 
• PPwin = Pr(Eventual Win | Data, δ=0.10, N=Ni is the final sample size) 
• PPfut = Pr(Eventual Win | Data, δ=0.15, N=750 is the final sample size) 
 
If PPwin exceeds a suitably high threshold Wi, subject accrual will stop because final 
success looks probable even using δ=0.10.  On the other hand, if PPfut is less than a 
suitably low threshold Fi, subject accrual will stop and futility will be declared.  If neither 
of these conditions obtains, enrollment will continue to the next larger sample size (450, 
600, 750).  Thresholds Wi and Fi are listed in Table 8.3.1.  Further detail on the 
calculations of the predictive probabilities is given below under the heading 
“Predictions.” 
 
Table 8.3.1  Thresholds for stopping enrollment for reasons of futility or probable 
eventual success, for each of the 3 interim sample size determination analyses.   
*The trial will not be stopped for futility at N=300. 
Sample Size 
Determination 
Analysis 
(i) 
Enrollment Size 
(Ni) 
Threshold for  
Stopping for 
Futility 
(Fi) 
Threshold for 
Stopping for 
Likely Future 
Win 
(Wi) 
1 
300 
0.00* 
0.80 
2 
450 
0.05 
0.80 
3 
650 
0.10 
0.80 
 
 

 
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8.4 
Predictions 
Predicted values of 2-year outcomes for those subjects who have not reached 2 years will 
be based on the intermediate outcomes measured at 6 months and 12 months. 3 month 
data will not be used in any of the predictive modeling.  During this time, patients are 
continuing the post-operative healing process and may not be appropriate for this 
purpose. 
 
At the time point of an interim analysis, there will be 4 types of subjects:  subjects with 
complete 2-year data; subjects with 1-year data but no 2-year data; subjects with 6-month 
data but no 1-year or 2-year data, and subjects who are have begun the study but do not 
yet have 6-month or 1-year data.  For those with 6-month or 1-year interim data but no 2-
year data, subjects will be considered to be one of the following: 
 
a) successes (i.e., meet all the criteria to be treatment successes, except that this is 
measured at 6 months or 1 year rather than 2 years) 
b) recoverable non-successes (i.e., do not meet the criteria to be successes, but it is 
still possible that they might become successes at 2 years) 
c) failures (i.e., subjects who cannot meet the definition of success at 2 years because 
of an event such as a device removal or re-operation.)  
 
Subjects without 2-year follow-up data will thus be considered to be in one of 14 states (7 
for each treatment group).  The 7 states are: 
• no interim data 
• success at 6 months 
• recoverable non-success at 6 months 
• failure at 6 months 
• success at 1 year 
• recoverable non-success at 1 year 
• failure at 1 year 
 
Interim failures can be imputed to be failures at 2 years, with certainty.  For each of the 
remaining 10 states (5 for each treatment group), the probability of becoming a success at 
2 years is modeled via a Beta (a,b) prior distribution which is updated to a Beta(a+S, 
b+F) distribution, based on the number S and F of subjects who went on from that state to 
become 2-year successes and failures, respectively.  For example, if, in the treatment 
group at an interim analysis time point, 70 of 100 subjects with 2-year data are successes, 
and if 50 of the 70 two-year successes also met the definition of success at 1 year, then 
the transition probability from the 1-year success state to the 2-year success state will be 
modeled as Beta (a+50, b+20).  At an interim analysis time point, any treatment-group 
subjects residing in the success-at-1-year-but-without-2-year-data state will have their 2-
year outcome predicted on the basis of this Beta(a+50, b+20) distribution.  Figure 8.4.1 
graphically depicts the various transitions for a generic treatment group (treatment or 
control).  The numerical example above would apply to transition #2 in the figure. 

 
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S
R
S
R
S
No data
#1
#2
#5
#4
#3
6 Months
24 Months
12 Months
 
Figure 8.4.1. Graphical depiction of transitions from interim states (S = Success, R 
= Recoverable Non-Success, No Data) to 2-year Success.  Each transition is assigned 
a Beta (a,b) prior distribution which is updated as data are gathered. 
 
By predicting 2-year outcomes for each of these states, and combining with the data from 
subjects with known 2-year outcomes, a posterior probability of non-inferiority is 
calculated; it is based on observed 2-year data and also a predictive model that employs 
interim outcomes and the relationship between those interim outcomes and their 
corresponding final outcomes that is learned during the current trial.  This is 
accomplished in Monte Carlo fashion.  With any one imputation of incomplete data, we 
calculate the posterior probability Pr(Hδ=δ* | Observed 2-year Data, Imputed 2-year Data), 
and store it.  By iterating this process and averaging these posterior probabilities, we are 
essentially integrating them over the predictive distribution of imputed data.  This 
resulting quantity we have denoted as Pr(Hδ=δ* | Data).  The model is very similar to that 
employed in Lipscomb et al.4  The chief differences are that this model incorporates 6-
month and 1-year interim outcomes (rather than just 1-year interim outcomes) and the 
model also separates interim non-successes into recoverable non-successes and 
permanent failures. 
 
In addition, the predictive probability of eventual trial success can be calculated in a 
similar manner.  With any one imputation of incomplete data, we calculate the posterior 
probability Pr(Hδ=δ* | Observed 2-year Data, Imputed 2-year Data) and record whether this 
value exceeds the threshold Ψ.  By iterating this processing and reporting the proportion 
of times that Ψ is exceeded, we obtain an estimate of the predictive probability of 
eventual trial success (meaning a trial that results in a declaration of non-inferiority).  
 
                                            
4  Lipscomb B, Ma G, Berry D, “Bayesian predictions of final outcomes: regulatory approval of a spinal implant,”  
Clinical Trials, Vol. 2, No. 4, 325-333 (2005) 

 
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0.0
0.2
0.4
0.6
0.8
1.0
Transition 1: 12m
 Beta( 411.97 , 64
0.0
0.2
0.4
0.6
0.8
1.0
Transition 2: 12m
 Beta( 386.55 , 29
0.0
0.2
0.4
0.6
0.8
1.0
Transition 3: 6m
 Beta( 229.8 , 153
0.0
0.2
0.4
0.6
0.8
1.0
Transition 4: 6m
 Beta( 204 , 51 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 5: No
 Beta( 234.5 , 100
In this trial, predictive probabilities of eventual success are used in the determination of 
sample size (i.e., analyses in the adaptive portion of the trial, or “sample size looks”).  
Posterior probabilities are used for the determination of non-inferiority (i.e., analyses in 
the evaluation portion of the trial, or “win looks”). 
 
Prior Distributions for Transition Probabilities 
 
The transitions of Figure 8.4.1 are all assigned Beta(a,b) prior distributions.  For “sample 
size looks,” the values of a and b are tabulated in Table 8.4.2 and graphically depicted in 
Figure 8.4.2.  These values represent the trial sponsor’s knowledge and belief about the 
relationship of the various interim states to the final state.  At the times when sample size 
decisions must be made, the number of subjects who have completed 2 years (and thus 
provide information on the transition probabilities) will generally be insufficient to make 
good sample size decisions without including some additional information.  Therefore, in 
all sample size determination analyses, the transitions are given informative priors, as 
tabulated in Table 8.4.2.  However, for all “win looks,” only flat priors (a = b = 1) for the 
transitions will be used.   
 
Table 8.4.2  Parameters for Prior Distributions of the Transition Probabilities used in the 
determination of sample size.  For all "win" analyses, a and b are set to 1. 
 
Transition # 
1 
2 
3 
4 
5 
Parameter 
a 
411.97 
386.55 
229.80 
204.00 
234.50 
b 
644.36 
29.09 
153.20 
51.00 
100.50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 8.4.2  Prior Distributions of the Transition Probabilities used in the determination 
of sample size.  For all "win" analyses, a and b are set to 1 for all transitions. 

 
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8.5 
Operating Characteristics 
The design described above has been subjected to intensive simulations in order to 
evaluate its anticipated performance in practice.  In the simulation, the proportion of 
simulated trials that result in a declaration of non-inferiority is the estimated power when 
Pt > Pc and the estimated type I error when Pt ≤ Pc.     The estimated operating 
characteristics are based on 10000 simulated trials per scenario, with predictions (in each 
of the 10000 trials) based on 5000 draws from each of the transition probability 
distributions.  In order to generate data for this simulation, several assumptions about 
enrollment rates and correlations had to be made.  These are described (and varied) in 
Appendix 6. 
 
Table 8.5.1 displays the operating characteristics and summarizes the performance of the 
adaptive sample size determination algorithm under various assumed values of Pt and Pc.  
The column “Overall Power” is the proportion of trials that resulted in a declaration of 
non-inferiority (NI).  The column “Avg Sample Size” shows the average sample size 
attained for that row.  The probability of attaining any of the allowed sample sizes (300, 
450, 600, 750) is then displayed, followed by the probability that futility is declared at 
450 or at 600.  (Futility cannot be declared at 300 or at 750, by definition.)  Finally, the 
probability of NI (i.e., a “win”) at the 3 “Win” looks (300 at 2 years, 450 at 2 years, full 
cohort at 2 years) is displayed.  These probabilities sum to the value shown in the 
“Overall Power” column (subject to rounding error). 
 
In Table 8.5.1, the type I error rate (when Pt = 0.55 = Pc – 0.15) is 0.043, and the chance 
of declaring futility when 450 or 600 are enrolled is 0.289 or 0.358, respectively.  When 
Pt = Pc = 0.70, the overall power is 0.962;  the chance of finding this at the first “win” 
look (when 300 have finished 2 years) is 0.882.  The average sample size is 638.8.  In the 
event that Pt = 0.80 and Pc = 0.70, enrollment will stop at 300 with probability 0.274 and 
at 450 with probability 0.641;  the chance of declaring NI at the first “win” look is 
essentially 1.0. 
 
Table 8.5.1 Operating characteristics of the design, from a simulation of 10000 simulated 
trials per line.  Interpretations of column headings are given in the narrative. 
Pt 
Pc 
Overall 
Power 
Avg 
Sample 
Size 
Sample Size Determination Analyses 
"Win" Analyses 
Pr(Size 
= 300) 
Pr(Size 
= 450) 
Pr(Size 
= 600) 
Pr(Size 
= 750) 
Futile 
at 
450? 
Futile 
at 
600? 
Pr(NI 
@ Look 
#1) 
Pr(NI 
@ Look 
#2) 
Pr(NI 
@ Look 
#3) 
0.550 0.700 
0.043 
609.4 
0.000 
0.289 
0.358 
0.352 
0.289 
0.358 
0.031 
0.008 
0.004 
0.600 0.700 
0.289 
673.6 
0.000 
0.146 
0.218 
0.636 
0.141 
0.211 
0.184 
0.063 
0.042 
0.650 0.700 
0.733 
699.2 
0.001 
0.100 
0.134 
0.764 
0.057 
0.065 
0.542 
0.121 
0.070 
0.700 0.700 
0.962 
638.8 
0.012 
0.223 
0.259 
0.506 
0.016 
0.011 
0.884 
0.060 
0.018 
0.725 0.700 
0.988 
576.1 
0.034 
0.371 
0.316 
0.280 
0.008 
0.003 
0.957 
0.026 
0.004 
0.750 0.700 
0.995 
515.6 
0.077 
0.525 
0.281 
0.116 
0.004 
0.001 
0.986 
0.008 
0.001 
0.800 0.700 
1.000 
422.7 
0.274 
0.641 
0.079 
0.007 
0.000 
0.000 
1.000 
0.000 
0.000 

 
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8.6 
Missing Data and Sensitivity Analyses (Primary Objective) 
By design, the analysis of the primary objective (at both the interim and final time points) 
will predict 2-year outcomes for any subjects without measured 2-year outcomes, based 
on transitions from interim states and the experience of those who went on from those 
states to provide complete 2-year data.  This is true whether the missing 2-year outcomes 
are due to being enrolled later in the trial (as happens for many subjects at the interim 
analysis) or some other cause, such as loss to follow-up (which will likely apply at both 
the interim and final analyses).  Several additional analyses are planned which will 
explore the sensitivity of the main conclusions to this prediction for subjects whose 
missing 2-year outcomes cannot be explained by simply being enrolled late (i.e., subjects 
who are known to be lost to follow-up or whose 2-year visit window has closed without a 
measured outcome).  In these analyses and for such subjects, 2-year outcomes will be 
imputed according to the model described below.  
 
As with the primary analysis, any such subject will be viewed as belonging to one of 
several states.  These are the same states used in the primary analysis: 
• no interim data 
• success at 6 months 
• recoverable non-success at 6 months 
• failure at 6 months 
• success at 1 year 
• recoverable non-success at 1 year 
• failure at 1 year 
 
Interim failures can be imputed to be failures at 2 years, with certainty.  For each of the 
remaining states, the probability of becoming a responder at 2 years will be modeled via a 
logistic formulation.  Based on the number S and F of subjects who went on from that 
state to become 2-year successes and failures, respectively, a logistic regression of the 
following form will be fit: 
 
logit( p ) = β0  
 
where the parameter β0 will be assigned a vague N(0,102) distribution.  The posterior 
distribution for β0 will then be shifted by a biasing constant γ and will be back-
transformed to the probability scale as: 
 
p* = logit–1(β0+ γ) 
 
The 2-year outcome for any subject belonging to this state but lost thereafter will be 
imputed based on this distribution of p*.  The case γ = 0 contains no bias and corresponds 
essentially to the primary analysis.   
 

 
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By varying γ, we can examine the impact of a biasing influence on the study results.  The 
values γ = –∞ and γ = +∞ correspond to setting all such observations to be failures or 
successes, respectively.  The impact of various values of γ will examined and presented in 
a sensitivity analysis, representing both positive and negative biases for the two groups.   
 
Further analyses will explore the sensitivity of efficacy to the imputation model.  
Specifically, one analysis will present posterior probabilities of non-inferiority/superiority 
without the use of prediction (i.e., completers only).  Another will present  posterior 
probabilities while predicting 24-month outcomes from 12-month outcomes (but not from 
patients without 12-month outcomes). 
 
In addition to the above specified sensitivity analyses of the primary endpoint, several 
additional sensitivity analysis are planned. A secondary analysis that evaluates the 
sensitivity of the conclusions based on the inclusion of a radiographic success component 
as part of the primary endpoint will be performed.  For this analysis, subjects who have 
not achieved radiographic success, as defined in section 5.6.1, will be considered failures 
for the primary endpoint. The analysis will look at each Investigational group 
radiographic success criteria independently. A second sensitivity analysis that evaluates 
the sensitivity of the conclusions to inclusion of subjects who require pain management 
procedures such as injections, nerve root blocks, denervation procedures, etc at the 
operative level as possible subject successes will also be undertaken.   
 
In addition, analyses that evaluate the correlation between pain medication usage and 
effectiveness outcomes will be performed. 
 
8.7 
Secondary Objectives  
General Considerations for Secondary Objectives 
While there are many pre-specified secondary objectives, only the first five are designated 
as objectives for which FDA-approved labeling claims may be sought, and only for the 
results measured at the 24-month time point.  The rest of the secondary objectives have 
been pre-specified but are intended to be explanatory and supportive in nature, and not 
the basis of specific labeling claims. 
 
As indicated in “Analysis Methods for Secondary Objectives,” below, flat or diffuse prior 
distributions have been identified for all secondary objective analyses.  For any 
hypothesis test, a posterior probability greater than 95% for any hypothesis will be 
considered to constitute evidence in favor of the hypothesis, in the same sense that a 
frequentist analysis would reject a null hypothesis when p < 0.05 and call it “statistically 
significant.”  However, for the subset of secondary objectives on which labeling claims 
may be sought, the posterior probability threshold for making the claim is somewhat more 
stringent.  See the section entitled “Multiplicity Considerations,” below. 

 
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Zurich Claudication Questionnaire (ZCQ) – Physical Function Domain (PF) 
The ZCQ PF domain scores for subjects in each treatment group will be summarized at 
the 3-, 6-, 12-, and 24-month time points.  For the 24-month time point, a statistical test 
will be conducted.  The relevant hypothesis is 
 
H:  μt – μc < δ 
 
where μt and μc are the average PF scores in the treatment and control groups, 
respectively, and δ is the margin of non-inferiority.  For this objective we take δ = 0.5, a 
value that is thought to represent a clinically meaningful difference and is consistent with 
the definition of Success on this component of the primary objective. The posterior 
probability of non-inferiority Pr(Hδ=0.5 | data) will be reported.  In addition, the posterior 
probability of superiority Pr(Hδ=0 | data) will be reported.  The statistical method will be 
the Bayesian version of a t-test (with predictions), described below. 
 
Also presented will be a supportive analysis that summarizes the proportion of subjects 
with meaningful improvement (defined as ZCQ PF improvement ≥ 0.5), meaningful 
worsening (defined as ZCQ PF worsening ≥ 0.5), and no change (defined as either 
improvement or worsening by less than 0.5). 
 
Zurich Claudication Questionnaire (ZCQ) – Symptom Severity Domain (SS) 
The ZCQ SS domain scores for subjects in each treatment group will be summarized at 
the 3-, 6-, 12-, and 24-month time points.  For the 24-month time point, a statistical test 
will be conducted.  The relevant hypothesis is 
 
H:  μt – μc < δ, 
 
where μt and μc are the average SS scores in the treatment and control groups, 
respectively, and δ is the margin of non-inferiority.  For this objective we take δ = 0.5, a 
value that is thought to represent a clinically meaningful difference and is consistent with 
the definition of Success on this component of the primary objective.  The posterior 
probability of non-inferiority Pr(Hδ=0.5 | data) will be reported.  In addition, the posterior 
probability of superiority Pr(Hδ=0 | data) will be reported.  The statistical method will be 
the Bayesian version of a t-test (with predictions), described below. 
 
Also presented will be a supportive analysis that summarizes the proportion of subjects 
with meaningful improvement (defined as ZCQ SS improvement ≥ 0.5), meaningful 
worsening (defined as ZCQ SS worsening ≥ 0.5), and no change (defined as either 
improvement or worsening by less than 0.5.  

 
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Back Pain on Visual Analog Scale (VAS) 
The back pain VAS scores for subjects in each treatment group will be summarized at the 
3-, 6-, 12-, and 24-month time points.  For inference, the relevant hypothesis is  
H:  μt – μc < 0, 
where μt and μc are the average back pain VAS scores for subjects in the treatment and 
control groups, respectively. The statistical technique will be the Bayesian version of a t-
test (with predictions), described below. 
In addition, a comparison of proportion of subjects with meaningful improvement in back 
pain VAS score, defined as ≥ 20mm improvement, will be presented. 
 
Also presented will be a supportive analysis that summarizes the proportion of subjects 
with meaningful improvement (defined as improvement ≥ 20mm), meaningful worsening 
(defined as worsening ≥ 20mm), and no change (defined as either improvement or 
worsening by less than 20mm.  
SF-36 Physical Composite Score (PCS) 
The SF-36 PCS scores for subjects in each treatment group will be summarized at the 3-, 
6-, 12-, and 24-month time points.  For the 24-month time point, a statistical test will be 
conducted.  The relevant hypothesis is 
 
H:  pt – pc > – δ, 
where pt and pc are the proportions of subjects in the treatment and control groups, 
respectively, who improve by at least 15% relative to baseline.  The posterior probability 
of non-inferiority Pr(Hδ=0.15 | data) will be reported.  The value δ=0.15 for the non-
inferiority margin is thought to represent a clinically meaningful difference and is 
consistent with the non-inferiority margin specified in the primary objective.   
In addition, the posterior probability of superiority Pr(Hδ=0 | data) will be reported.  The 
statistical method will be the Bayesian version of a comparison of proportions (with 
predictions), described below. 
 
SF-36 Mental Composite Score (MCS) 
The SF-36 MCS scores for subjects in each treatment group will be summarized at the 3-, 
6-, 12-, and 24-month time points.  For the 24-month time point, a statistical test will be 
conducted.  The relevant hypothesis is 
H:  pt – pc > – δ, 

 
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where pt and pc are the proportions of subjects in the treatment and control groups, 
respectively, who improve by at least 15% relative to baseline.  The posterior probability 
of non-inferiority Pr(Hδ=0.15 | data) will be reported.  The value δ=0.15 for the non-
inferiority margin is thought to represent a clinically meaningful difference and is 
consistent with the non-inferiority margin specified in the primary objective.  In addition, 
the posterior probability of superiority Pr(Hδ=0 | data) will be reported.  The statistical 
method will be the Bayesian version of a comparison of proportions (with predictions), 
described below. 
Radiographic Assessment of Flexion-Extension Range of Motion 
Assessment of Flexion-Extension Range of Motion for subjects in each treatment group 
will be summarized at baseline and at each of the 3-, 6-, 12-, and 24-month time points.  
At 24 months, a statistical test will be conducted.  For inference, the relevant hypothesis 
is  
H:  μT(24) – μT(B) > 0, 
where μT(24)  and μT(B)  are the average flexion-extension range of motion scores for 
subjects in the treatment group at 24 months and baseline, respectively. The statistical 
technique will be the Bayesian version of a paired t-test (with predictions), described 
below. 
Also presented will be a supportive analysis that summarizes the proportion of subjects 
with meaningful improvement, meaningful worsening, and no change.  Meaningful 
improvement will be evaluated using both the ≥ 5 +/-1 º criterion and the ≥ 3 +/-1 º 
criterion included as part of the radiographic success assessment. 
Radiographic Success 
Radiographic Success rate will be summarized for each treatment group at the 3-, 6-, 12-, 
and 24-month time points.  For the 24-month time point, a statistical test will be 
conducted.  The relevant hypothesis is 
H:  pt – pc > – δ, 
 
where pt and pc are the proportions of subjects in the treatment and control groups, 
respectively, who achieve radiographic success.  The posterior probability of non-
inferiority Pr(Hδ=0.15 | data) will be reported.  The value δ=0.15 for the non-inferiority 
margin is thought to represent a clinically meaningful difference and is consistent with 
the non-inferiority margin specified in the primary objective.  In addition, the posterior 
probability of superiority Pr(Hδ=0 | data) will be reported.  The statistical method will be 
the Bayesian version of a comparison of proportions (with predictions), described below. 

 
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Neurological Assessment 
A neurological assessment will be conducted at 3-, 6-, 12-, and 24-months, and 
summarized.  For the 24-month time point, a statistical test will be conducted.  The 
relevant hypothesis is 
 
H:  pt – pc > – δ, 
 
where pt and pc are the proportions of subjects in the treatment and control groups, 
respectively, whose neurological assessment status relative to baseline is maintained or 
improved.  The posterior probability of non-inferiority Pr(Hδ=0.15 | data) will be reported.  
In addition, the posterior probability of superiority Pr(Hδ=0 | data) will be reported.  The 
statistical method will be the Bayesian version of a comparison of proportions (with 
predictions), described below. 
Leg Pain on Visual Analog Scale (VAS) 
The leg pain VAS scores for subjects in each treatment group will be summarized 
separately by the more symptomatic and less symptomatic legs of each subject, as 
measured at baseline.  For inference, the relevant hypothesis is  
 
H:  μt – μc < 0 
 
where μt and μc are the average VAS scores for the more symptomatic legs (or less 
symptomatic legs, as appropriate) in the treatment and control groups, respectively.  The 
posterior probability P(H | data) will be reported.  The results will be summarized at the 
3-, 6-, 12-, and 24-month time points.  The statistical technique will be the Bayesian 
version of a t-test (with predictions), described below. 
 
In addition, leg pain VAS scores at the 3-, 6-, 12-, and 24-month time points will be 
summarized for all legs according to whether they are symptomatic or asymptomatic at 
baseline.  For this analysis, a leg will be considered to be symptomatic if the baseline 
VAS score is at least 5 on a 10-point scale.   
 
A comparison of proportion of subjects with meaningful improvement in leg pain VAS 
score, defined as ≥ 20mm improvement in at least one leg, will also be presented. 
 
Also presented will be a supportive analysis that summarizes the proportion of subjects 
with meaningful improvement (defined as improvement ≥ 20mm), meaningful worsening 
(defined as worsening ≥ 20mm), and no change (defined as either improvement or 
worsening by less than 20mm.  

 
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Oswestry Disability Index (ODI) 
The ODI scores for subjects in each treatment group will be summarized at the 3-, 6-, 12-, 
and 24-month time points.  For the 24-month time point, a statistical test will be 
conducted.  The relevant hypothesis is 
 
H:  μt – μc < δ 
 
where μt and μc are the average ODI scores in the treatment and control groups, 
respectively.   The posterior probability of non-inferiority Pr(Hδ=0.15 | data) will be 
presented.  In addition, the posterior probability of superiority Pr(Hδ=0 | data) will be 
presented.   The statistical method will be the Bayesian version of a t-test (with 
predictions), described below. 
 
Also presented will be a supportive analysis that summarizes the proportion of subjects 
with meaningful improvement (defined as improvement ≥ 15 points), meaningful 
worsening (defined as worsening ≥ 15 points), and no change (defined as either 
improvement or worsening by less than 15 points.  
Adverse Events 
All Adverse Events (AEs) will be tabulated and summarized as counts and percentages by 
treatment group.  AEs will also be cross-tabulated separately according to treatment 
group and: 
 
• 
Severity (Mild, Moderate, Severe) 
• 
Seriousness (Serious, Non-serious) 
• 
Device-Relatedness (Related, Not Related) 
• 
Surgery-Relatedness (Related, Not Related) 
 
In addition, the occurrence of any Unanticipated Adverse Device Effects (UADE) will be 
listed.  The classification of severity, relatedness, and anticipated nature of AEs will be 
made by the Clinical Events Committee (CEC). 
 
Summaries will include counts, percentages, and 95% Bayesian credible intervals for the 
difference in proportions between treatment groups.  An analysis of safety outcomes 
which combines all AFRS treated patients (randomized and non-randomized) compared 
to control patients will also be performed.  The statistical method for dichotomous 
outcomes (e.g., device-relatedness, surgery-relatedness) will be the Bayesian version of a 
comparison of proportions, described below.  The statistical method for trichotomous 
outcomes (e.g., Severity) will be the Bayesian version of a comparison of polytomous 
outcomes, described below. 

 
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Surgical Revisions, Reoperations, Removals, and Supplemental Fixation 
The incidence of a composite of surgical revisions, reoperations, removals, and 
supplemental fixation at the index level for subjects in each treatment group will be 
summarized at the 3-, 6-, 12-, and 24-month time points.  For the 24-month time point, a 
statistical test will be conducted.  The relevant hypothesis is 
 
H:  pt – pc < 0 
 
where pt and pc are the proportions of subjects in the treatment and control groups, 
respectively, who experience one or more of the defining surgical events.  The statistical 
method will be the Bayesian version of a comparison of proportions (with predictions), 
described below. 
Radiographic Measurements 
Radiographic measurements in each treatment group will be summarized at the 3-, 6-, 12-
, and 24-month time points.  Continuous radiographic endpoints are disc height, vertebral 
range of motion, and translation.  For these, statistical summaries will include means, 
medians, standards of deviation, and 95% central Bayesian credible intervals for the 
means and mean differences over time between treatment groups, where appropriate.  
Dichotomous radiographic endpoints are fusion, device migration, and the presence of 
radiolucencies around the hardware and screws.  For these, statistical summaries will 
include proportions and 95% Bayesian credible intervals for the proportions and, where 
appropriate, the difference in proportions between treatment groups. 
Return to Normal Activities of Daily Life 
The proportion of subjects able to return to “Most” or “All” of the activities of daily life 
will be summarized at the 3-, 6-, 12-, and 24-month time points.  Statistical summaries 
will include proportions and 95% Bayesian credible intervals for the proportions and the 
difference in proportions between treatment groups.  The statistical method will be the 
Bayesian version of a comparison of proportions, described below. 
Return to Work 
 
For subjects in each treatment group, the time from date of surgery to date of return to 
work will be computed and summarized with descriptive statistics.  It is possible that 
some subjects will never return to work and be censored in this analysis, either at the end 
of the study or at the point of death or loss to follow-up, so the statistical technique will 
be the Bayesian Survival Analysis, described below.  The proportion who have returned 
to work at t0 = 3-, 6-, 12-, and 24-months will be computed as 1 – S(t0), where S(t) is the 
survivor function for the event of returning to work.  (i.e., S(t) is the function of time that 
represents the probability of a patient not experiencing the event of going back to work by 

 
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time t.)   Both point estimates and 95% BCIs at times t0 will be presented.  In addition, a 
test for superiority over all time will be conducted.  The relevant hypothesis is: 
 
H:   θ > 1 
 
where θ is the hazard ratio of returning to work in the treatment group relative to the 
control.  The posterior probability P(H | data) will be reported.   
 
Any subjects not intending to return to work for reasons unrelated to problems of the 
lumbar spine (e.g, retired, not working prior to diagnosis) will be excluded from this 
analysis.  
  
ZCQ Patient Satisfaction Domain Score 
The ZCQ Patient Satisfaction domain scores will be summarized for subjects in each 
treatment group at the 3-, 6-, 12-, and 24-month time points.  For the 24-month time 
point, a statistical test will be conducted.  The relevant hypothesis is 
H:  μt – μc > 0 
 
where μt and μc are the average satisfaction scores in the treatment and control groups, 
respectively.   The posterior probability of superiority Pr(H | data) at 24 months will be 
presented, along with 95% BCIs for the means and differences in means at each of the 
time points (3, 6, 12, and 24 months).  The statistical method will be the Bayesian version 
of a t-test (with predictions), described below. 
Also presented will be a supportive analysis that summarizes the proportion of subjects 
with meaningful satisfaction (defined as satisfaction scores < 2.5 points). 
Narcotic Medication Usage 
 
The proportions of subjects in each treatment group who are not on narcotic pain 
relieving medications and in whom an epidural injection, denervation procedure or other 
procedure for pain management has not been performed at the index level will be 
summarized at the 3-, 6-, 12-, and 24-month time points.  For the 24-month time point, a 
statistical test will be conducted.  The relevant hypothesis is 
 
H:  pt – pc > 0, 
 
where pt and pc are the proportions of subjects in the treatment and control groups, 
respectively, who are not taking narcotic medications and have not had pain management 
procedures at the index level. The posterior probability of superiority Pr(H | data) will be 
reported.  The statistical method will be the Bayesian version of a comparison of 
proportions (with predictions), described below. 

 
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Length of Hospital Stay 
 
The length of hospital stay will be calculated for each subject (with the day of surgery = 
Day 0) and summarized by treatment group.  A statistical test of the difference in length 
of stay between treatment groups will be conducted.  The relevant hypothesis is  
 
H:  μt – μc < 0 
 
where μt and μc are the average stays in the treatment and control groups, respectively.  It 
is anticipated that the distribution of hospital stays will be somewhat skewed, so the data 
will be ranked and the statistical method will be the Bayesian version of the Wilcoxon 
Rank-Sum test, described below.  If a subject should die in hospital before being 
discharged, that subject will be assigned a length of stay that is 1 day greater than the 
maximum observed length of stay for any patient.  
 
Duration of Procedure 
 
The duration of the procedure will be summarized for the treatment and control groups.  
Statistical summaries will include means, medians, and standards of deviation, as well as 
95% credible intervals for μt, μc, and (μt – μc).  A statistical test will be conducted on the 
hypothesis 
H:  μt – μc < 0 
 
where μt and μc are the average procedure durations in the treatment and control groups, 
respectively.  The statistical method will be the Bayesian version of a t-test, described 
below.   
 
 
Instrumentation Time 
 
The portion of the procedure time that is due to Instrumentation Time will be summarized 
for the treatment and control groups.  Statistical summaries will include means, medians, 
and standards of deviation, as well as 95% credible intervals for μt,, μc, and (μt – μc).   A 
statistical test will be conducted on the hypothesis 
 
H:  μt – μc < 0, 
 
where μt and μc are the average instrumentation times in the treatment and control groups, 
respectively.  The statistical method will be the Bayesian version of a t-test, described 
below.   
 
 
 

 
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Procedural Blood Loss 
 
The blood lost by subjects during the implant procedure will be summarized for the 
treatment and control groups.  Statistical summaries will include means, medians, and 
standards of deviation, as well as 95% credible intervals for μt,, μc, and (μt – μc).   A 
statistical test will be conducted on the hypothesis 
 
H:  μt – μc < 0 
 
where μt and μc are the average blood loss in the treatment and control groups, 
respectively.  The statistical method will be the Bayesian version of a t-test, described 
below. 
 
Rehabilitation Utilization 
 
The proportions of subjects in each treatment group who utilize rehabilitation therapy will 
be summarized at the 3-, 6-, 12-, and 24-month time points.  A subject will be considered 
to have used rehabilitation therapy at 6 months if he/she has used rehabilitation therapy at 
any time between the 3-month and the 6-month visits, and similar for each of the other 
time points.  A statistical test will be conducted for each time point.  The relevant 
hypothesis is 
 
H:  pt – pc < 0, 
 
where pt and pc are the proportions of subjects in the treatment and control groups, 
respectively, who have utilized rehabilitation therapy since the last (surgery to 3 months, 
3 months to 6 months, 6 months to 12 months, 12 months to 24 months) follow-up visit.   
The posterior probability of superiority Pr(H | data) will be reported.  The statistical 
method will be the Bayesian version of a comparison of proportions, described below. 
 
8.8 
Analysis Methods for Secondary Objectives 
As indicated below, flat or diffuse prior distributions have been identified for all 
secondary objective analyses.   
 
Discrete (Dichotomous) Data:  Bayesian Version of a Comparison of Proportions 
 
Given proportions pt and pc for a dichotomous outcome, let each be assigned a flat 
Beta(1, 1) prior.  Then the posterior distributions for pt and pc follow Beta(1+Yt,1+Nt–Yt) 
and Beta(1+Yc,1+Nc–Yc) distributions, respectively, where Yt and Yc represent the number 
of “successes” and Nt and Nc represent the number of “tries” (e.g., subjects) in their 
respective treatment groups.  The distribution of the difference pt – pc can be easily 
estimated by drawing a large number of observations (e.g., 25000) from each Beta 
posterior, and subtracting.  The posterior probability P(pt – pc > δ | data) is estimated as 

 
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the proportion of these observations where the difference exceeds δ.  A 95% equal-tail 
Bayesian credible interval can be calculated from the 2.5th and 97.5th percentiles of the 
sampled distribution of pt – pc. 
 
Discrete (Polytomous) Data:  Bayesian Version of a Comparison of Proportions 
 
Given the vectors pt and pc of k-variate proportions for a polytomous outcome, let each be 
assigned a flat Dirichlet(1) prior.  The Dirichlet distribution is the multidimensional 
analog of the Beta distribution.  After observing multinomial count data Yt and Yc, the 
posterior distributions of pt and pc follow Dirichlet(1+Yt) and Dirichlet(1+Yc) 
distributions, respectively.  The distribution of the difference pt – pc can be easily 
estimated by drawing a large number of observations (e.g., 25000) from each Dirichlet 
posterior, and subtracting.  The marginal posterior probability Pr(pt(i) – pc(i) >  δ | data) for 
the ith  component of (pt – pc) is estimated as the proportion of these observations where 
the difference exceeds δ.  A 95% Bayesian equal-tail credible interval can be calculated 
from the 2.5th and 97.5th percentiles of the sampled distribution of pt(i) – pc(i). 
 
Continuous Data:  Bayesian version of a t-test. 
 
Assuming that the quantity of interest Y follows a N(μ,σ2) distribution, and placing a 
uniform prior distribution on (μ, log(σ)), the posterior distribution of μ has the form27  
 
1
~
−










−
nt
Y
n
s
y
µ
 
 
Employing this for both μt and μc, the distribution of (μt - μc) can be estimated in Monte 
Carlo fashion by drawing a large number of observations (e.g., 25000) from a tn-1 
distribution for n = nt and n = nc, back-transforming these observations to the μt- and μc-
scales, and subtracting.  The posterior probability P(μt – μc > δ | data) is estimated as the 
proportion of observed values of (μt – μc) that exceed δ.  A 95% equal-tail Bayesian 
credible interval can be calculated from the 2.5th and 97.5th percentiles of the sampled 
distribution of μt – μc.    
 
Continuous Data:  Bayesian version of a paired t-test. 
 
Assuming that the quantity of interest Y follows a N(μ,σ2) distribution, and placing a 
uniform prior distribution on (μ, log(σ)), the posterior distribution of μ has the form27  
 
1
~
−










−
nt
Y
n
s
y
µ
 

 
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The distribution of μ can be estimated in Monte Carlo fashion by drawing a large number 
of observations (e.g., 25000) from a tn-1 distribution and back-transforming these 
observations to the μ-scale.  The posterior probability P(μ > 0 | data) is estimated as the 
proportion of observed values of μ that exceed 0.  A 95% equal-tail Bayesian credible 
interval can be calculated from the 2.5th and 97.5th percentiles of the sampled distribution 
of μ.    
 
Continuous Data (Distribution-free, Superiority):  Bayesian Version of a Wilcoxon 
Rank-Sum Test 
 
For this test, analogous to the Wilcoxon Rank-Sum test, data in each group are ranked.  
Let Rt = the sum of the ranks in the treatment group.  When nt and nc are greater than 10, 
the following quantity Z is approximately distributed as standard normal28: 
)1
(
12
1
)1
(
2
1
2
1
+
+
+
+
−
+
≡
c
t
c
t
c
t
t
t
n
n
n
n
n
n
n
R
Z
 
 
A flat prior (equal to 1 on the whole real line) is placed on Z, and the posterior 
distribution of Z is thus approximately N(0,1).  Superiority will be assessed by the 
calculation of P(Z < 0 | data) or P(Z > 0 | data), as appropriate, which is easy to obtain 
directly from the cumulative distribution function of the standard normal distribution. 
 
Continuous Data (Time-to-Event Analysis):  Bayesian Survival Analysis 
 
A semiparametric survival analysis can be achieved by means of a piecewise exponential 
hazard model29, 30.  Let the hazard function h0(t) be defined to be piecewise constant such 
that 






∈
∈
∈
=
−
]
,
(
,
]
,
(
,
]
,0
(
,
)
(
1
2
1
2
1
1
0
K
K
K
T
T
t
T
T
t
T
t
t
h
λ
λ
λ

 
Then the survivor function S(t) is represented by  




∫
−
=
t
d
h
t
S
0
0
0
)
(
exp
)
(
τ
τ
 
A proportional hazard model can be fit by specifying that h(t) = h0(t)exp(θ).  For this 
analysis we specify vague but proper priors for each λi  (i = 1, …, K) by declaring that  
)
001
.0
,
001
.0
(
~ Gamma
iid
iλ
 

 
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In addition, we specify a vague but proper prior for θ by declaring that 
)
10
,0
(
~
2
N
θ
.  
The parameterization of the Gamma(a,b) distribution is such that the mean is a/b, while 
the parameterization  of the Normal distribution is such that the variance is 102.  
Furthermore, we take K = 10 and partition the time axis into intervals (Ti–1,Ti] such that 
there is an equal number of events in each interval when the data from the two treatment 
groups are combined.  (Exact equality of events in each interval may or may not be 
possible, depending on the extent of ties in the data). While the endpoints of the intervals 
are not pre-specified, the method by which they will be determined is pre-specified.  
Sensitivity of conclusions to the specification of intervals will be evaluated. 
This model can easily be fit using Markov chain Monte Carlo techniques in the 
WinBUGS31 software package.  95% equal-tail Bayesian credible intervals for the 
posterior probability of any quantity of interest (e.g., S(t0), θ) can be easily obtained from 
the 2.5th and 97.5th percentiles of the Monte Carlo samples, and the probability of 
superiority in the hazard ratio is easily estimated by the proportion of MCMC samples of 
θ that exceed 0. 
 
Multiplicity Considerations 
 
It is recognized that with a multiplicity of tests comes an inflation in the chance of a false 
finding of superiority or non-inferiority.  Therefore, for the purposes of seeking FDA-
approved claims on designated secondary objectives, the following standard will be used. 
 
If the primary objective demonstrates non-inferiority, claims will only be sought for the 
subset of non-inferiority objectives constituted by: 
 
1. ZCQ Physical Function (24-month time point) 
2. ZCQ Symptom Severity (24-month time point) 
3. Back Pain on Visual Analog Scale (24-month time point) 
4. SF-36 Physical Composite Score (24-month time point) 
5. SF-36 Mental Composite Score (24-month time point) 
6. Radiographic Assessment of Flexion-Extension Range of Motion for the  
investigational device group (24-mo time point) 
 
For the purposes of seeking claims, these objectives will only be evaluated once, as 
follows: 
• If the primary objective does not demonstrate non-inferiority until the final analysis 
(when all subjects have reached 2 years), these secondary objectives will be tested at 
that time point. 
• If the primary objective demonstrates both non-inferiority and superiority at any 
“Win” analysis, these secondary objectives will be tested at that same time point. 
• If the primary objective demonstrates non-inferiority but not superiority at a “Win” 
analysis, an early submission to FDA will be made, seeking approval on the basis of 
non-inferiority for the primary objective.  However, since follow-up will continue and 

 
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superiority of the primary metric might yet be achieved at the final analysis, claims 
will not be sought for these secondary objectives until the final analysis.  Under this 
scenario, analysis of any secondary objectives contained in the early submission and 
conducted at the interim “Win” time point should be viewed as explanatory and 
supportive, with all “alpha” reserved for the final analysis time point.  
 
The remaining secondary objectives may be of interest for scientific or financial reasons 
but will not be the basis for seeking any FDA-approved labeling claims. 
 
Among the 5 objectives and for the purposes of seeking claims, the posterior probability 
threshold for concluding non-inferiority will be raised to a level ≥ 0.95.  The approach is 
fashioned as a Bayesian analog to Holm’s sequentially rejective method for controlling 
type-1 errors among N tests in the frequentist setting32.  In Holm’s method, p-values are 
ranked in increasing order.  For k = 1,2,…,N, the kth p-value is compared to α/(N – k + 1).  
Let k0 represent the first such value of k where pk ≥ α/(N–k+1).  Then all the hypotheses 
for k = 1, 2, …, k0 –1 are rejected, and hypotheses for k ≥ k0 are not rejected.  If p1 > α/N, 
no hypotheses are rejected. 
 
This trial will implement the following analogous procedure:  Among these N = 5 
objectives, the posterior probabilities P(Hk | data), k = 1, …,5, will be listed in decreasing 
order.  P(Hk | data) will be compared to the threshold value 1 – 0.05/(N – k + 1).  Let k0 
represent the first such value of k where P(Hk | data) < 1 – 0.05/(N – k + 1).  Then all the 
hypotheses for k = 1, 2, …, k0–1, will be considered to have met the threshold for 
claiming non-inferiority.  
 
If the threshold for claiming non-inferiority is met for certain objectives, then superiority 
will also be examined for these objectives.  The threshold for claiming superiority for 
each objective will be the same as the non-inferiority threshold.  Specifically, if 
hypotheses Hk, k = 1, 2, …, k0–1, demonstrate non-inferiority (using the values of δ 
specified for each objective) because P(Hk | data) > 1 – 0.05/(N – k + 1), then P(Hk | data) 
(using δ = 0,  k = 1, 2, …, k0–1) will be compared against a threshold value of 1 – 0.05/(N 
– k + 1).  Any superiority hypothesis resulting in P(Hk | data) > 1 – 0.05/(N – k + 1) will 
be deemed to have demonstrated superiority. 
 
Missing Data In Secondary Objectives 
 
For the secondary objectives identified as those for which labeling claims may be sought, 
sensitivity to missing data will be assessed in a manner similar to the primary objective. 
Where predictions are included in the secondary objective analyses, an analysis involving 
completers only will also be presented as an ancillary analysis.  
 
For those objectives with dichotomous 24-month outcomes (e.g., SF-36 PCS or MCS 
responder), subjects will be dichotomously classified as “Successes” or “Recoverable 
Non-Successes” (no non-recoverable Failures) at the 6- and 12-month intermediate time 

 
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points, and a model analogous to that used in the primary objective analysis will be 
employed to predict the final outcomes for those subjects missing the 24-month measure, 
based on their last known interim measure.  Specifically, the probability of becoming a 
Success at 2 years will be modeled via a logistic formulation.  Based on the number S and 
F of subjects who went on from an interim state (Success, Recoverable Non-Success) to 
become 2-year successes and failures, respectively, a logistic regression of the following 
form will be fit: 
logit( p ) = β0  
 
where the parameter β0 will be assigned a vague N(0,102) distribution.  The posterior 
distribution for β0 will then be shifted by a biasing constant γ and will be back-
transformed to the probability scale as: 
 
p* = logit–1(β0+ γ) 
 
The 2-year outcome for any subject belonging to this state but lost thereafter will be 
imputed based on this distribution of p*.   
 
The case γ = 0 corresponds to the assumption of no bias and missingness completely at 
random. 
 
By varying γ, we can examine the impact of a biasing influence on the study results.  The 
values γ = –∞ and γ = +∞ correspond to setting all such observations to be failures or 
successes, respectively.  The impact of various values of γ will examined and presented in 
a sensitivity analysis, representing both positive and negative biases for the two groups.   
 
For those objectives that are based on continuous measures (e.g., ZCQ, VAS), the 24-
month score will similarly be imputed via a model, based on the last known interim 
measure.  For example, if a subject is missing the 24-month measure but has a 12-month 
measure, that subject’s 24-month measure will be modeled as 
 
N( β0 + β1Z12, τ2 ) 
 
where the parameters βi (i=0,1) and τ2 are assigned vague N(0,102) and Inverse 
Gamma(0.001,0.001) prior distributions, respectively; these distributions are then updated 
to posterior distributions via data from subjects with both 12- and 24-month measures.  
Subjects missing both 12- and 24-month measures can have their 12-month measure 
imputed first by modeling Z12 as N(α,ν2) (with similarly vague priors assigned to the 
hyperparameters α and ν2) and generating the missing Z12 values via the posterior 
distributions of α and ν2 that arise from the observed 12-month data. The 2-year outcome 
for subjects missing their 24-month measures will then be imputed based on the resulting 
posterior distributions of all parameters, with a bias term (γ) added: 
E(Z24) = β0 + β1Z12 + γ 

 
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When γ  = 0, the subject is assumed to be missing at random and there is no bias.  By 
varying γ, we can examine the impact of a biasing influence on the study results.  The 
impact of various values of γ will be examined and presented in a sensitivity analysis, 
representing both positive and negative biases for the two groups.   
8.9 
Poolability Analyses 
To evaluate differences among sites in the study, summary tables by site will be presented 
and compared for important baseline variables, including demographics and medical 
history, baseline clinical variables, and procedure variables, as well as for the primary and 
secondary endpoint variables.  Centers with fewer than seven participants will be pooled.  
Continuous variables will be presented by site in terms of percentiles (e.g., median, 25th 
and 75th percentile).  For categorical parameters, data will be summarized by site using 
relative frequencies. 
 
Comparisons will be made across sites for selected baseline variables.  Continuous data 
will be compared across sites using a one-way analysis of variance, with a term for site.  
A two-factor ANOVA with treatment group and site as factors will be used to assess 
differences among sites and site by treatment interactions.  Dichotomous data will be 
similarly analyzed via logistic regression analysis.   If variables are observed to differ by 
study site, that variable and/or study site may be identified for special consideration in 
subsequent analyses.   
 
The site effect will be further examined in a multivariable analysis to determine if site is 
independently associated with outcome.   Tests for differences in rates of the primary 
outcome between treatment groups across sites will be performed using a logistic 
regression model with terms for sites, treatment assignment, and site-by-treatment 
interaction.  If an association between center and treatment effect is identified, center 
differences will be further evaluated by assessing the endpoint with and without the 
center(s) for which the differences are observed, so that the impact of the center(s) can be 
assessed. 
 
A similar evaluation of poolability will be undertaken for the following subgroups: 1) 
anatomical stenosis location (lateral, lateral recess or central), 2) number of levels 
requiring decompression, 3) presence or absence of spondylolisthesis at either the 
treatment or adjacent level, 4) smoking status during the study.. 

 
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9.0 
RISK/BENEFIT ANALYSIS 
There are certain risks associated with the use of the AFRS device, including risks that 
are associated with any surgical procedure, risks that are generally associated with spinal 
intervention procedures and risks that are unique to the use of a Facet Arthroplasty 
Implant. Below is a detailed explanation of these potential risks and the means by which 
they may be minimized, as well as a justification for conducting the study.  
9.1  
Surgical Risks 
There are risks related to any surgical procedure as well as procedures specific to spinal 
intervention. Surgical risks associated with this procedure include: vessel 
damage/bleeding; superficial infection; deep wound infection; hematoma at surgical site; 
incisional pain; pulmonary embolism; stroke; myocardial infarction; coronary episode; 
pneumonia; kidney failure; bowel obstruction; dural tear; thrombosis; nerve injury; cauda 
equina syndrome; transverse process fracture; pseudomeningocele; paralysis; spinal fluid 
leakage; spinal cord damage; bone fracture; spinous process fracture; spondylosis; 
heterotopic bone formation; scoliosis; kyphosis; segmental instability; decrease in 
neurological function; worsening back pain; worsening pain associated with stenosis; 
respiratory distress; wound dehiscence; wound swelling.  
 
It is expected that the risks and complication rates strictly associated with the procedure 
would be similar to those associated with other posterior fixation procedures.   
 
9.2  
Implant Risks 
In addition to the risks listed above, the AFRS implant may be associated with unique 
risks associated with its instrumentation, implant design and the use of cobalt chrome and 
Hydroxyapatite materials in the implant. These risks include implant breakage; 
component disarticulation; component degradation; implant displacement; pedicle 
disruption/failure; allergic reaction to implant materials; and reaction to implant wear 
debris. 
 
The AFRS implant consists of inferior and superior cobalt chrome implants articulating 
with each other to preserve motion. The implants are secured with pedicle screw fixation 
with locking nuts. In addition, there is a cross member securing the inferior implants. The 
risks of this design include disarticulation, dislocation of the implants, generation of wear 
debris from articulation, increased metal ion concentration from the implants, loosening 
of the implants, fracture or failure of the implants, degeneration at adjacent levels and 
fracture or damage to the pedicle or spinous process.  
 
The cobalt chrome and hydroxyapatite materials used in the implant also have risks 
associated with their use. These can include allergic reaction to the materials, adverse 
reaction of the surrounding tissue and bone, failure of the bone to heal around the implant 
and bone resorption due to the materials. 
 

 
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9.3 
Minimizing Study Risks 
The following steps have been taken to minimize risks associated with the procedure and 
the use of the AFRS implant: 
• The instrumentation used to create the surgical site and place the AFRS has been 
designed with positive stops to prevent contact with the spinal nerves or 
associated vessels.  
• The AFRS has been designed to work based upon existing pedicle screw fixation 
methods. This allows the implant to be secured in a location known to support 
current accepted fixation methods. There is a long positive history associated with 
the use of pedicle screw fixation in similar spine applications.  
• In the event that the AFRS procedure cannot be completed, the surgeon has the 
ability to complete a posterior fusion per his/her standard procedure.  
• The cobalt chrome and Hydroxyapatite material used in the AFRS has been 
selected based on its successful past use in bone fixation medical devices such as 
total knee and hip replacements.   
• A broad spectrum of biomechanical testing including mechanical strength, wear, 
fatigue and kinematic testing of the AFRS implant has verified its biomechanical 
properties. Its mechanical properties meet or exceed those of similar devices used 
for spine procedures. 
• Testing of the cobalt chrome and hydroxyapatite materials to accepted 
biocompatibility standards has demonstrated its acceptable properties. 
• Testing of wear debris in excess of that expected to be generated in during clinical 
use was tested in a rabbit model. The results demonstrate the absence of tissue 
reactions to the tissues associated with the spinal canal.  
• All investigators receive detailed training in the use of the ACADIA® Facet 
Replacement System.  The training includes hands-on use of the instruments and 
implants in a lab setting. 
 
9.4 
Justification for Investigation 
Although there are risks associated with the AFRS, many of these risks are similar to 
those seen with other spinal devices that are implanted through a posterior approach. 
From a procedural standpoint, these devices have shown a satisfactory history of clinical 
use. In addition, appropriate steps have been taken to minimize the risks associated with 
the device design and materials.  A successful Facet Arthroplasty procedure can enable 
patients to avoid fusion of the facets which is currently the typical treatment for stenosis 
of this nature. This procedure and device potentially allows patients to resume near-
normal level activity, whereas allowing further disease progression can result in 
worsening disability.   
 
Furthermore, the Facet Arthroplasty Implant offers the patient the potential ability to 
maintain motion and stability at the facet joint that otherwise would be lost as a result of a 
posterior fusion procedure and is an advantage over existing spinal treatments.   
 

 
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As noted above, there are substantial potential benefits associated with the AFRS and the 
risks associated with the procedure have been identified and minimized where possible. 
Thus, the balance of potential risks and benefits associated with the Facet Arthroplasty 
Implant warrants further clinical research and justifies this investigation. 
 
 

 
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10.0 ADMINISTRATIVE RESPONSIBILITIES 
This Clinical Study will be performed in accordance with the Code of Federal 
Regulations 21 CFR Part 812, 50, 56, 54, the tripartite harmonised ICH guidelines and 
the World Medical Association Declaration of Helsinki.  
 
10.1  IRB Committee Information 
The investigation must be reviewed and approved by the appropriate IRBs before subject 
enrollment may begin.  All proposed changes to the investigational plan must be 
reviewed and approved by Globus Medical.  Globus will also obtain any necessary FDA 
approval in accordance with 21 CRF § 812.35, and IRB approvals consistent with 21 
CRF Part 56 and individual IRB policies.   
10.1.1 IRB Committee Approval 
IRB Committee approval or its designee is required for each institution participating in 
this clinical investigation.  Prior to shipment of investigational devices, a signed copy of 
the IRB Committee approval letter identifying the clinical study must be submitted to 
Globus Medical, Inc. signifying study approval.  Investigators are responsible for 
obtaining and maintaining approval of the study by the IRB. 
10.1.2  Informed Consent (ICF) 
Written informed consent is mandatory and must be obtained from all subjects prior to 
performing any study procedures in this clinical study.  Globus Medical, Inc will provide 
each investigator site with a Sponsor-approved ICF template. Each site is expected to 
modify the template, if necessary, to meet their facilities requirements. Modified ICF 
templates must be reviewed by the Sponsor prior to submission to their IRB.  
 
Informed consent must be obtained and shall inform the subject as to the objective and 
procedures of the study and possible risks involved.  The subjects must be informed about 
their right to withdraw from the study at any time and for any reason without sanction, 
penalty, or loss of benefits to which the subject is otherwise entitled and that withdrawal 
from the study will not jeopardize their future medical care.  The clinical study informed 
consent must be used in addition to the institution’s standard consent form for spine 
surgery.  The institutional standard subject consent form does not replace the study 
consent form.   
Additionally, authorization to access patient health information (PHI) as part of the 
approved ICF or as a stand alone site specific consent form is required for patient 
participation in the study. It is the responsibility of the investigator to obtain both an 
authorization for patient health information and study consent. 
The IRB Committee approved Informed Consent Forms must be retained at the 
investigational site along with the other investigational case report forms.  A signed copy 
of the consent form must be given to each subject enrolled in the study. 
Applicable laws, institutional requirements (including the IRB/IEC), or other 
considerations (such as federal funding mandates) may require the disclosure of 

 
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additional information to the patient and/or inclusion of additional information in an 
informed consent document. 
Modifications to the Clinical Study Informed Consent and any written subject 
information must be approved by Globus Medical and as necessary, the IRB as 
appropriate.  
 
10.2  Confidentiality 
All information and data sent to Globus Medical or their authorized representatives, 
concerning subjects or their participation in this study will be considered confidential. All 
data used in the analysis and reporting of this evaluation will be used in a manner without 
identifiable reference to the subject. The patient will be informed that the information 
obtained during the study will be used to evaluate the safety and effectiveness of the 
investigational product. The patient will be informed that every effort will be made to 
maintain their confidentiality, but that his/her medical records are subject to review by the 
Sponsor, representatives of the Sponsor, the IRB/IEC, and regulatory authorities as 
required by law. 
10.3 Data Monitoring and Quality Control 
10.3.1 Training 
The training of investigational site personnel will be the responsibility of Globus 
Medical.  To ensure uniform data collection and protocol compliance, Globus-appointed 
clinical staff will review the clinical protocol, techniques for the identification of eligible 
subjects, instructions on in-hospital/office visit data collection with the research 
coordinators. 
10.3.2 Case Report Forms 
Case Report Forms (CRFs) will be used to collect patient data during the study.  CRFs 
must be completed fully for each study patient and faxed or copies sent to Globus 
Medical within 10 business days of the study visit or adverse event.  Adverse event and 
neurologic status CRFs are signed by the Investigator. 
CRF’s must be available for review and source document verification by Globus Medical 
(or designees) at the institution, during monitoring visits or as requested outside of 
monitoring visits.  
10.3.3 Data Reporting 
The investigator, or an individual designated by him/her, is responsible for recording all 
study data on the CRFs supplied by Globus Medical.  The data on each CRF must be 
legibly handwritten. 
The Investigator is required to sign the CRF on the appropriate page(s) to verify that 
he/she has reviewed the recorded data. 

 
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Completed CRFs will be verified by a Globus-appointed monitor at the site at regular 
intervals throughout the study.  To this end, the Investigator must permit inspection of the 
study files, patient CRF’s, and subject medical records by Globus-appointed monitors and 
authorized government agencies, as indicated.  
10.3.4 Investigational Site Monitoring  
Globus Medical, Inc. is the Sponsor of this study. The study will be monitored according 
to applicable provisions of Globus Medical Monitoring Procedures, and in conformance 
with 21 CFR Part 812. Monitoring functions will be performed in compliance with 
recognized Good Clinical Practices.  
The major function of the clinical monitor is to observe and assess the quality of the 
clinical study. In addition, the study will be monitored to ensure that potential adverse 
trends are quickly identified allowing immediate corrective action.  The monitor’s duties 
include: on-site visits, observation of treatment with the AFRS, and review of study 
documents and verification of protocol compliance, and source verification of submitted 
study data.   
 
 
10.4 Record Maintenance 
 
10.4.1 Records 
Investigators must keep accurate, secured, separate records (other than the CRFs) of all 
patient data, including all pertinent related information. Any and all AEs must be 
thoroughly documented. The investigator agrees that Globus Medical, its employees or 
agents, and regulatory and/or local health authorities will have the right from time to 
time, both during and after this study, to inspect facilities, and to audit and review 
pertinent medical records related to the clinical study. Patients will not be identified by 
name, and confidentiality of information in medical records will be preserved.  
Globus Medical, Inc. (or its representatives) or the investigative site must notify the other 
within two weeks of notification by regulatory authorities of a potential audit. 
As a minimum, the following records must be maintained at the clinical site in designated 
Globus Medical Clinical Study administrative files: 
 
• Clinical Protocol and all amendments 
• Signed Clinical Trial Agreement 
• Signed Investigator Agreement(s) 
• IRB approval letter(s) and approved Informed Consent(s) (including any 
revisions) 
• Correspondence relating to this study (with Sponsor, Clinical Monitors, other 
Investigators, etc.) 
• Correspondence with the IRB Committee 
• Instructions for Use 

 
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• Current Medical License for all Investigators 
• Curriculum Vitae for all Investigators 
• Investigational device log  
• Investigational device related paperwork (including shipping documents, invoices, 
device return log, etc.) 
• Monitor sign-in log 
• Site authorized personnel signature list 
• Blank set of CRFs and instructions for completion 
• CRF monitoring forms  
• Reports (including Adverse Event reports, annual reports and final reports from 
Investigator and Sponsor) 
• Protocol Deviation Log 
 
The following records must be maintained for each patient enrolled in the study: 
 
• Signed patient Informed Consent Form 
• All completed CRFs 
• Record of any side effects/adverse events, device malfunctions, and treatment 
failures (with supporting documentation) 
• Procedure reports, physician dictations, nursing notes, and patient medical records 
• Copies of all patient radiographs 
• Records of any interventions (procedure reports, physician dictations, nursing 
notes, etc.) 
• Records related to patient deaths during the investigation (including death records, 
death certificate and autopsy report, if performed) 
 
 
10.4.2 Reports 
Investigators are required to prepare and submit the following complete, accurate, and 
timely reports as outlined in the following table: 
 
Responsibilities for Preparing & Submitting Data and Reports 
 
Type of Report 
Notify or Submit to 
Time of Notification or Action 
Case Report Forms 
Globus Medical 
Within 10 working days of visit 
(preoperative forms at least 2 
working days before surgery) 
Copies of Radiographs   Globus Medical 
Within 30 working days of visit 
(preoperative films at least 2 
working days before surgery) 
Serious Adverse Event 
(device related or not) 
Globus Medical  
(and IRB as required) 
Within 24 hours of knowledge 
Device malfunction 
Globus Medical 
Within 24 hours of knowledge 

 
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Type of Report 
Notify or Submit to 
Time of Notification or Action 
Subject death during the 
investigation 
Globus Medical  
(and IRB as required) 
Within 24 hours of knowledge 
Unanticipated adverse 
events 
Globus Medical  
(and IRB as required) 
Within 24 hours of knowledge 
Subject withdrawal 
Globus Medical 
Within 24 hours of knowledge 
Withdrawal of IRB 
approval 
Globus Medical 
Within 24 hours of knowledge 
Deviations from 
investigational protocol 
Globus Medical 
(and IRB as required) 
Within 24 hours of knowledge 
Informed consent not 
obtained from subject 
Globus Medical, IRB 
Within 24 hours of knowledge 
Annual Progress Report Globus Medical and 
IRB, if required 
Within 1 month of annual IRB 
approval date 
Final Summary Report 
Globus Medical and 
IRB, if required 
Within 3 months of study 
completion 
Other information as 
requested by Globus 
Medical or IRB 
Globus Medical, IRB 
As requested 
 
Investigator files containing all records and reports of the investigation should be retained 
for a minimum of 2 years after the completion or termination of the investigational study 
or until two years after they are no longer needed to support FDA approval.  They may be 
discarded upon notification by Globus Medical.  To avoid any error, the Investigator 
should contact Globus Medical before destroying any records and reports pertaining to 
the study to ensure they no longer need to be retained. 
 
In addition, in accordance with the Clinical Study Agreement, Globus Medical should be 
contacted if the investigator plans to leave the investigational site so that appropriate 
arrangements can be made. 
 
10.4.3 Investigator’s Annual and Final Reports 
Each year a summary report may be prepared by the investigator providing a synopsis of 
the subjects treated to date as well as other pertinent clinical information associated with 
the device usage, if requested.  The report may be provided to the IRB and Globus 
Medical.  The Sponsor may provide an Annual Report on the overall study to the IRB, in 
lieu of an annual Investigator report. 
 
Upon completion or termination of the study, a final report may be prepared.  This report 
will contain a critical evaluation of all data collected during the course of the 
investigation at each institution.  The report may be provided to the IRB and Globus 
Medical.  Any modifications to this final report must be reviewed and approved by 

 
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Globus Medical.  The Sponsor may provide a Final Annual Report on the overall study to 
the IRB, in lieu of a final Investigator report. 
 
10.5 Device Accountability 
All investigational devices received and used by the investigator will be inventoried and 
accounted for by the sponsor throughout the study.  The investigational devices will be 
supplied by representatives of Globus Medical.  A set of investigational implants (and 
instruments) will be provided by a Globus representative for use in surgery for enrolled 
patients, and will be returned to Globus after each surgery.  All unused devices will be 
returned to Globus Medical, as will any explanted devices.  No devices will be used 
except by authorized investigators, in accordance with the protocol. 
 
10.6 Protocol Deviations & Medical Emergencies 
The Investigator will not deviate from the protocol without the prior written approval of 
Globus Medical except in medical emergencies or in unforeseen, isolated instances where 
minor changes are made that will not increase the subject’s risk or affect the validity of 
the study.  In medical emergencies, prior approval for protocol deviations will not be 
required, but Globus Medical must be notified within 24 hours of occurrence. 
 
10.7 Investigational Site Termination 
Globus Medical, Inc. reserves the right to terminate an investigational site for any of the 
following reasons: 
• Repeated failure to complete Case Report Forms 
• Failure to obtain Informed Consent  
• Failure to report Serious Adverse Events within 24 hours of knowledge 
• Loss of or unaccounted for investigational device inventory 
• Repeated protocol violations 
• Failure to enroll an adequate number of patients 
 

 
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11. 
REFERENCES 
 
1 Newest knowledge of lower back pain: a critical look. Nachemson AL. Clin Orthop 1992:8-20. 
2 Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United 
States. Lawrence RC, Helmick CG, Arnett FC. Arthritis Rhuem 1998;41:778-99 
3 Occupational injury and illness in the United States: estimates of costs, morbidity and mortality. 
Leigh JP, Markowitz SB, Fahs M, et al. Arch Inter Med 1997;157:1557-68 
4 Indications and outcomes of reconstructive surgery in chronic pain of spinal origin. Slosar PJ. 
Spine 2002;27(22): 2552-62 
5 Discs degenerate before facets. Butler D, Trafimow JH, Andersson GB, et al. Spine 1990;15(2): 
111-13 
6 Spinal joint changes and dental infections. Ingelmark BE. Acta Anat 1959:38 (suppl 36) 
7 Cervical, dorsal and lumbar spine syndromes. Hult L. Acta Orthop Scand 1954; suppl 17: 65-73 
8 Osteoarthritis and disc degeneration in an urban population. Kellgren JH, Lawrence JS. Ann 
Rhuem Dis 1958; 17: 388-397 
9 Lumbar disc degeneration: correlation with age sex and spine level in 600 autopsy specimens. 
Miller JA, Schmatz C, Shultz AB. Spine 1988; 13: 173-178 
10 The facet syndrome. Mooney V, Robertson J. Clin Ortho Rel Res 1976; 115: 149-156 
11 Clinical anatomy of the lumbar spine and sacrum. Bognuk N. 3rd edition 1997:15 Churchill 
Livingstone 
12 Clinical features of patients with pain stemming from the lumbar zygapophyseal joints. 
Schwartzer AC, Aprill CN, Derby R, et al. Spine 1994; 19(10): 1132-1137 
13 Relation between laminectomy and development of adjacent segment instability after lumbar 
fusion with pedicle fixation. Lai PL, Chen LH, Nui CC, et al. Spine 2004; 29(22): 2527-32 
14 Adjacent segment degeneration and adjacent segment disease: the consequences of spinal 
fusion? Hilibrand AS, Robbins M. Spine 2004; 4(6 suppl): S190-4 
15 Lee SS, Bono CM. Physical Examination of the Spine. In: Bono CM, Garfin SR, eds. Spine 
Orthopedic Surgery Essentials. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:1-13   
16 Greiner-Perth R, Boehm H, Allam Y, Elsaghir H, Franke J. Reoperation rate after instrumented 
posterior lumbar interbody fusion: a report on 1680 cases. Spine. 2004 Nov 15;29(22):2516-20. 
17 Farrington C. P. and Manning, G. 1990. 'Test Statistics and Sample Size Formulae for 
Comparative Binomial Trials with Null Hypothesis of Non-Zero Risk Difference or Non-Unity 
Relative Risk.' Statistics in Medicine, Vol. 9, pages 1447-1454. 
18Hintze J. (2004).  NCSS and PASS, Number Cruncher Statistical Systems.  Kaysville UT.  
www.ncss.com. 
19 Molinari RW, Gerlinger T. Functional outcomes of instrumented posterior lumbar interbody 
fusion in active-duty US servicemen: a comparison with nonoperative management. Spine J. 
2001 May-Jun;1(3):215-24. 

 
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20 Freeman BJ, Licina P, Mehdian SH. Posterior lumbar interbody fusion combined with 
instrumented posterolateral fusion: 5-year results in 60 patients. Eur Spine J. 2000 Feb;9(1):42-
6. 
21Agazzi S, Reverdin A, May D.  Posterior lumbar interbody fusion with cages: an independent 
review of 71 cases. J Neurosurg. 1999 Oct;91(2 Suppl):186-92. 
22Barnes B, Rodts GE, McLaughlin MR, Haid RW Jr. Threaded cortical bone dowels for lumbar 
interbody fusion: over 1-year mean follow up in 28 patients. J Neurosurg. 2001 Jul;95(1 
Suppl):1-4. 
23Potter BK, Freedman BA, Verwiebe EG, Hall JM, Polly DW Jr, Kuklo TR. Transforaminal 
lumbar interbody fusion: clinical and radiographic results and complications in 100 consecutive 
patients. J Spinal Disord Tech. 2005 Aug;18(4):337-46 
24Rivet DJ, Jeck D, Brennan J, Epstein A, Lauryssen C. Clinical outcomes and complications 
associated with pedicle screw fixation-augmented lumbar interbody fusion. J Neurosurg Spine. 
2004 Oct;1(3):261-6. 
25Jennison C and Turnbull BW, Group Sequential Methods with Applications to Clinical Trials.  
Boca Raton:  Chapman & Hall, 2000, p 27, 30. 
26Lipscomb B, Ma G, Berry D, “Bayesian predictions of final outcomes: regulatory approval of a 
spinal implant,”  Clinical Trials, Vol. 2, No. 4, 325-333 (2005) 
27Gelman A, Carlin JB, Stern HS, Rubin DB.  Bayesian Data Analysis, Chapman & Hall, 
London, 1995, p 69 
28Berry DA, Lindgren BW, Statistics: Theory and Methods (2nd ed), Belmont, CA, Duxbury 
Press, 1996, p 504). 
29Ibrahim J, Chen M-H, and Sinha D (2001), Bayesian Survival Analysis, Springer:    New York, 
p. 106. 
30Congdon P (2006), Bayesian Statistical Modeling, 2 ed, Wiley: Chichester, Sec 13.5, 13.5.1 
31Lunn D.J., Thomas A., Best N., and Spiegelhalter D. (2000) WinBUGS -- a Bayesian 
modelling framework: concepts, structure, and extensibility. Statistics and Computing, 10:325-
337.  
32Holm S. (1979).  A simple sequentially rejective multiple test procedure, Scandinavian Journal 
of Statistics, 6, 65-70. 

 
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APPENDIX 1: STUDY SUMMARY 
 
 

 
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Evaluation 
Screening/ 
Enrollment 
Procedure/ 
Discharge 
6 weeks 
(±2 weeks) 
postop 
3 months 
(±2 weeks) 
postop 
6 months 
(±1 month) 
postop 
12 months  
(±2 months) 
postop 
24 months  
(±2 months) 
postop & 
annually 
Informed Consent 
 
√ 
 
 
 
 
 
 
Medical History  
 
√ 
 
 
 
 
 
 
Physical Exam 
√ 
 
√ 
√ 
√ 
√ 
√ 
Medication use 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
CT, MRI, Myelography 
√ 
 
 
 
 
 
 
DEXA Scan (patients 
with SCORE >6) 
√ 
 
 
 
 
 
 
Disc Height 
Measurement 
√ 
 
 
 
 
 
 
Static lateral, A/P 
standing Radiographs 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Standing 
Flexion/Extension 
Radiographs 
√ 
 
 
√ 
√ 
√ 
√ 
Standing Lateral 
Bending Radiographs 
√ 
 
 
√ 
√ 
√ 
√ 
ODI and ZCQ 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
SF-36 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
Neurological 
Exam 
√ 
 
√ 
√ 
√ 
√ 
√ 
VAS 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
Patient Satisfaction 
 
 
 
√ 
√ 
√ 
√ 
√ 
Adverse Events 
 
 
√ 
√ 
√ 
√ 
√ 
√ 

 
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APPENDIX 2: RADIOGRAPHIC PROTOCOL 

 
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RADIOGRAPHIC PROTOCOL 
INVESTIGATIONAL DEVICE: AFRS 
CONTROL: POSTERIOR FUSION 
 
Introduction 
This radiographic evaluation is designed to compare the performance of Anatomic Facet 
Replacement System (AFRS) and posterior fusion at the operative and adjacent levels of the 
lumbar spine.  The evaluation will be made from plain film radiographs and will include the 
assessment of segmental range of motion, intervertebral translation, disc height, implant 
displacement (migration), radiolucency and fusion.  All analyses will be conducted by an 
independent radiology laboratory.  All data and materials shall be considered confidential and 
will remain the exclusive property of Globus Medical.   
 
Study Population 
The study population is as outlined in protocol 1020-9052. The study is open to all patients 
that meet the inclusion criteria.  The study groups will include the investigational AFRS 
device and the control procedure. 
 
Radiographic Protocol 
The radiographic protocol calls for assessments to be done from lateral view flexion-
extension films and anterior view lateral bending films. Suggested radiographic techniques 
for proper completion of the films are included with this protocol.  Flexion-extension films 
will be used to assess range of motion and intervertebral translation.  Lateral-bending films 
will be used to assess range of motion.  Lateral and AP views will be used to assess disc 
height.  All films will be considered in assessing device displacement, radiolucency and the 
growth of bridging bone.  The following table summarizes the number of films by visit. 
 
View 
Position 
Pre-Op 
6wk 
3mo 
6mo 
12mo 
24mo 
Lateral 
Neutral 
1 
1 
1 
1 
1 
1 
Lateral Flexion - Extension 
2 
0 
2* 
2 
2 
2 
AP 
Neutral 
1 
1 
1 
1 
1 
1 
AP 
Lateral Bending 
2 
0 
2* 
2 
2 
2 
Total 
 
6 
2 
6* 
6 
6 
6 
*Flexion-extension and lateral bending films depend on patient ability and physician approval.   
 
Assessment Methods 
Radiographic assessments will be managed and performed by the independent laboratory, in 
accordance with documented Standard Operating Procedures and documented Assessment 
Protocols.  All quantitative assessments associated with the radiographs will be completed 
and reviewed by board certified radiologists with a musculoskeletal background, previous to 
reporting of results. All qualitative assessments are completed by board certified radiologists 
with a musculoskeletal background.  
 

 
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Data Collection 
The investigational sites will produce the films identified in the radiographic protocol above.  
The films will be collected by the Sponsor and coded with the investigation site number, 
patient number and follow up period. The evaluator will be blinded to the investigational site, 
patient identification and follow-up period. The films (or copies of the films) will be 
provided to the independent laboratory.  The films will be digitized and imported into a 
database for analysis.  All results will be forwarded to the Sponsor for inclusion into the 
database. 
 
Quantitative Radiographic Measurements 
Quantitative radiographic measurements (range of motion, translation and disc height) will be 
calculated.  Range of motion will be reported in degrees.  Translation and disc height will be 
reported in mm.  Conversion from image pixels to mm will be done by calibrating the 
images.  Image calibration will be performed by inserting a calibration ring in the field of 
view during X-ray imaging. 
 
Range of Motion 
Range of motion will be calculated from 
flexion-extension and lateral bending 
radiographs.  Range of motion will be 
calculated in accordance with Figure 1.  
Landmarks drawn on the edges of the 
superior and inferior vertebral endplates are 
used to define a line along the endplate.  The 
change in the angle of that line from flexion 
to extension determines the range of motion.  This methodology represents the 
difference between the angle measurements taken at flexion and extension. 
This same technique will be applied to left/right 
lateral bending images. 
 
Intervertebral Translation 
Intervertebral translation will be calculated from flexion-extension radiographs in 
accordance with Figure 2.  Intervertebral translation is defined as displacement of the 
posterior-inferior corner of the superior vertebra in a direction defined by the superior 
endplate of the inferior vertebra. 
 
 
 
 
Figure 1 
Figure 2 
[Grab your reader’s attention 
with a great quote from the 
document or use this space to 
emphasize a key point. To 
place this text box anywhere 
on the page, just drag it.] 

 
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Disc Height 
Anterior, posterior and average disc height will 
be calculated from lateral and AP radiographs in 
accordance with Figure 3.  Anterior (posterior) 
disc height is defined as the distance between 
the anterior (posterior) edge of the inferior 
endplate 
of the superior vertebra, and the corresponding 
edge of the inferior vertebra.  The average disc 
height is a simple average of the anterior and 
posterior disc height.  This distance is measured 
perpendicular to the superior endplate of the 
inferior vertebra. 
 
Qualitative Radiographic Assessments 
Qualitative radiographic assessments (device displacement, radiolucency and bridging bone) 
will be performed by a board-certified radiologist with extensive training and/or experience 
in musculoskeletal imaging and spine imaging in particular.  
 
Device Displacement 
Device displacement will be assessed for migration and graded as YES or NO, where 
YES is defined as ≥ 3 mm displacement from the initial operative placement.  If the 
migration is graded as YES, the radiologist will state the direction of the migration.  
 
Radiolucency 
Radiolucency will be assessed by a radiologist along the superior and, if applicable, 
inferior components of the device.  The assessment will be graded as NONE, MILD 
(<25%), MODERATE (25-50%) or SEVERE (>50%), where the % indicates amount 
of radiolucency along the device. 
 
Bridging Bone 
Bridging bone will be assessed by a radiologist and graded as YES or NO in 
accordance with the following definition: 
 
Bridging Bone – continuous connection of bone from the superior vertebral body 
to the inferior vertebral body 
 
Fusion 

 
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Fusion will be assessed and graded as YES or NO according to the following criteria: 
 
Bridging Bone – continuous connection of bone from the superior vertebral body 
to the inferior vertebral body 
Radiolucency - Absence of >50% radiolucencies around the control device and 
bone. 
 
Translation, Angular Motion: <3mm translation and < 5o angular motion as 
measured on flexion/extension films. 
 
Clinically Significant Stability without Fusion 
Clinically Significant Stability without Fusion is based on the point where clinically 
relevant instability occurs as defined by the AMA Guide to the Evaluation of 
Permanent Impairment.  It is defined as meeting both of the following criteria:  
 
Range of Motion less than 20o and 
Translation less than 4.5mm 
 
 
 

 
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APPENDIX 3: DERMATOME LOCATIONS 

 
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APPENDIX 4: PATIENT DISCHARGE 
INSTRUCTIONS 
 

 
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AFR System Study Discharge Instructions 
 
The following instructions are provided by the investigator to the patient upon 
discharge 
 
Please follow these instructions closely to prevent complications and to 
increase the probability of acceptable surgical results.  
 
1. Restrict your sitting to a minimum until you are seen in your physician’s 
office. You may sit briefly for meals and for bathroom use. When you do 
sit, be sure to use a chair with good back support. 
2. Avoid driving for 2 weeks. However, you may ride as a passenger on short 
trips 
3. Do not stoop, bend or twist your back. Do not lift or participate in sports 
activities. Use your discomfort as a guide for most activities. Further 
instructions on activities and work limitations will be provided when you 
are seen for follow up in your physician’s office. 
4. Avoid back exercises for one month.  
5. You may shower after your physician has given permission to do so.  
6. Please discuss your return to work status with your physician or his/her 
office assistant. 
7. Many people have some increase in pain a week or so after surgery. This is 
normal as there is swelling when healing takes place. The pain usually 
resolves in a few days. 
8. Please call the physician’s office if there are any signs of infection (i.e. 
fever, chills, redness, wound problems and increased pain). 
9. If you have significantly increased pain that is not relieved by your pain 
medication, difficulty walking, difficulty passing your urine or moving 
your bowels, call your physician’s office or go to the emergency room.  
10. If you have any other questions or concerns or believe that you have any 
other difficulties, please call your physician’s office.   
 

 
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APPENDIX 5: RETRIEVAL PROTOCOL 
 
 

 
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AFRS IMPLANT RETRIEVAL PROTOCOL 
 
1. Introduction 
The purpose of this protocol is to define a standard retrieval and analysis procedure 
for implants that may be removed from the patient during execution of the clinical 
trial per protocol 1020-9052. Providing clear instructions on device retrieval and 
analysis will provide an opportunity to understand potential device failure modes and 
to examine the effects of the implant and its wear products on the surrounding tissues. 
 
This protocol defines a suggested procedure to be followed by investigators and the 
Sponsor, Flobus Medical, in the event an implant is removed for any reason during 
the course of the investigation including events both directly related to the implant, as 
well as those apparently unrelated to the AFRS procedure are included in this 
protocol. The actual procedure followed during retrieval will be based on the medical 
judgment of the investigator. As required, all retrievals will be documented per the 
Adverse Events section of the protocol. 
 
2. References 
The methods outlined in this protocol are in compliance with the following reference 
standards: 
 
 
ISO 12891-1 
Retrieval and analysis of surgical implants 
 
 
 
 
 
Part 1: Retrieval and handling 
 
 
ISO 12891-2 
Retrieval and analysis of surgical implants 
 
 
 
 
 
Part 2:  Analysis of retrieved metallic surgical implants 
 
In addition, the methods of analysis outlined below have been standard practice 
within the Implant Retrieval Lab in their analysis of retrieved metal-on-metal hip 
replacements. 
 
3.  Procedure  
 
3.1 In situ evaluation 
Prior to implant removal, lateral and AP X-rays will be taken to document the status 
and location of the device. Upon surgical access, digital photographs will be taken of 
the device in situ before implant retrieval is started. Observations will be documented 
regarding device marking or discoloration, fractures, tissue metallosis, and 
periprosthetic tissue appearance. or other features that might help in the investigation. 
Details will be noted regarding the visual appearance of the surrounding bone and the 
degree of fixation of the implants. Where possible, device articulation will be 
attempted and the results on the device and surrounding tissues will be documented. 
 
3.2 Periprosthetic Tissue Sampling 

 
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Where the surgeon determines that patient safety is not compromised, periprosthetic 
tissue samples will be retrieved from the implant site. Tissue that is in direct contact 
with the device, preferably in the area of device failure (if applicable or known) and 
the articulating surfaces will be taken. Tissue between a loose device and the bone 
will be sampled, along with any reamings of the site as it is prepared for a revision 
component. All samples will be placed immediately into containers of 10% formalin 
and labeled with the patient study identification, tissue site and retrieval date. 
 
The removed samples will be forwarded to the designated contract lab. Analysis will 
include histological evaluation of the tissues utilizing differential staining techniques 
as required to ascertain any immunological reaction to the implant material or debris 
associated with the implant. If wear or failure debris is present in the sample, analysis 
on debris size, structure composition and origin will be undertaken and reported. 
 
3.3 Implant Removal 
Implant removal will be completed based on the best potential outcome for the 
patient. Where possible, the implant will be removed in a manner that best preserves 
its integrity and preserves the bone interfaces.  As components are removed, any 
observations related to the device status or potential cause of failure will be recorded. 
Digital photographs will be taken to support observations. The implants will be 
placed in separate containers of 10% formalin to prevent post-retrieval damage to the 
articulating surfaces.  The specimen containers will be labeled with the patient study 
identification, retrieval date and specimen site and forwarded to the contract lab for 
evaluation. 
 
3.4 Implant Evaluation 
All removed implants will be systematically evaluated whether they are associated 
with a failure or not. The evaluation form attached to this protocol will be used to 
outline potential evaluations and to document initial results. Initial evaluation consists 
of non-destructive methods. An inventory of returned components and any legible 
device identification markings will be recorded. The articulating surfaces will be 
carefully cleaned with a laboratory grade detergent applied with a Q-tip to remove 
adhered blood so that they surfaces can be inspected.  A stereo light microscope will 
be used to perform a gross visual evaluation on each component to document signs of 
fracture, wear or other notable surface features such as corrosion, discoloration or 
alteration of original form. Attention will be paid to the fixation surfaces; the amount 
and nature of attached tissue will be documented. In cases with no tissue attachment, 
the appearance of the HA coating will be noted, with specific attention to 
delaminating or fracturing of the coating. Damage to the articulating surfaces such as 
scratching or pitting, or signs of wear such as polishing or burnishing will be noted. 
  
Articulating Surfaces 
A non-contact laser profilometer will be used to measure surface roughness of 5 
representative site of wear or damage to provide an average Ra and Rmax of the 

 
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articulating surfaces.  Wear depth will be measured by coordinate measuring machine  
which is accurate to 2 microns. 
 
Fixation Surfaces 
Implants that are retrieved with attached bone will be processed for ground 
histological analysis of the bone/implant interface. This will involve embedding all or 
part of the component in polymethylmethacrylate to form a hard block. The block 
with then be sectioned to provide a 1mm thick slice through the porous coating. This 
will be attached to a plastic slide and thinned with petrographic grinding equipment 
until it is thin enough to allow the bone/implant interface to be viewed with a light 
microscope. The amount of bone on and within the porous coating will be measured 
with a computerized image analysis system.  
 
Fractured Specimens 
Where device fracture is evident, non-destructive fractographic evaluation will be 
conducted to ascertain the mode of fracture. This will be done by inspecting the 
fracture surfaces with a scanning electron microscope and noting the fracture pattern 
and any nearby features that may have contributed to the fracture (for example, 
corrosion or bending) 
 
Histological Analysis 
The periprosthetic tissues will be processed into paraffin and sectioned at 5 microns, 
then stained with haematoxylin and eosin for routine light microscopic analysis. The 
sections will be examined for the nature of the tissues (viable or necrotic, fibrous, 
granulation tissue etc), the predominant cell types that are present (including acute 
and chronic inflammatory cells, histiocytes and foreign body giant cells) and the 
presence and extent of wear debris. For the detection of wear debris, transmitted and 
polarized light will be used; metal particulate produces a yellow margin when 
polarized while hydroxyapatite is only weakly birefringent but appears as a crystalline 
particle at high magnification). In the event that chronic inflammatory cells are 
present, identification of cell types may be done with immunohistochemical staining 
(see below).   If excessive wear debris is present (that is, where there is gross 
discoloration of the tissues and abundant visible debris in the tissues) identification of 
the debris may be done using SEM EDAX (energy dispersive analysis of X-rays, see 
below) or with atomic absorption spectroscopy of acid digested tissue samples. 
 
Additional Testing  
As appropriate, destructive testing of the implant may be undertaken as required to 
complete the investigation, but should be completed to a detailed plan to allow the 
best use of limited material based on the results of the previously completed analysis 
in this protocol. Additional implant testing may include some or all of the following: 
 
• Verification of material identification via scanning electron microscopy  or 
atomic absorption spectroscopy 

 
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• Verification of material microstructure including grain size, inclusion content, 
material condition (soft, work-strengthened, hot-forged etc)  
• Evidence and nature of corrosion device fracture, fretting or other features 
based on scanning electron microscopy and macroscopic evaluation  
• Mechanical properties such as hardness, tensile strength, elongation or other 
tests needed to verify material properties. 
 
Immunohistochemistry 
Paraffin sections will be stained to highlight the presence of T and B lymphocytes. 
 
 
4. Report 
The implant retrieval lab will provide the results of the above analyses to the Sponsor, 
who, in turn will compile a final report. This report will detail the methods used for 
the evaluation, facilities and experts contracted to complete the testing, raw data, 
summary of findings, discussion of findings and conclusions that may be drawn based 
on the evaluation. Results will be shared with study investigators and appropriate 
actions taken as dictated by the Clinical Events Committee.  

 
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APPENDIX 6: CASE REPORT FORMS 
 

 
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APPENDIX 6: CASE REPORT FORMS 
 
The following Case Report Forms are used for reporting in the IDE study and are 
provided in this appendix: 
 
 
SA1 
Patient Qualification Form - Inclusion 
SA2 
Patient Qualification Form - Exclusion 
SA3 
Patient Enrollment Form 
SA4 
Physical Examination Form 
SA5 
Neurological Assessment Form 
SA6 
Preop Radiographic Assessment Form 
SA7 
Patient Questionnaires 
SA8 
Operative & Discharge Form 
SA9 
Radiograph Capture Form 
SA10 
Adverse Event Form 
SA11 
Surgical Intervention Form 
SA12 
Patient Disposition Form 
SA13 
Rehabilitation Utilization Form 
SA14 
Protocol Deviation Form 
 

 
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APPENDIX 7: BAYESIAN SIMULATION DETAILS 
 
 

 
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APPENDIX 7: 
BAYESIAN SIMULATION DETAILS 
In order to conduct a simulation for the study of operating characteristics, simulated data must be 
generated.  In order to generate such data, some additional assumptions must be made.  This set 
of assumptions is the subject of this section.  These assumptions apply only to the generation of 
the simulated data and the timing of the interim analysis, not to the analysis method.  The 
analysis method applied to the data in the simulation is exactly the one described above in the 
statistical analysis portion of the protocol, without additional assumptions; it is the same as the 
analysis that will be applied to the real data collected in the prospective trial.    
 
The first assumption pertains to the correlation of interim (6-month, 1-year) outcomes with 2-
year outcomes.  In order to create a correlated data set, it is helpful first to envision all possible 
transitions a subject may make, as in Figure 7.1.  All subjects begin the trial in the “Start (no 
data)” state and, barring loss to follow-up, will follow one and only one of the paths through the 
transition tree.  To generate reasonable correlated data for the simulation, we must specify 
reasonable probabilities for each transition, in such a way that the final value P24S is equal to a 
value that we wish to study in the operating characteristics (e.g., by forcing Pt or Pc = P24S when 
P24S = 0.60, 0.70, or 0.75).   
 
Figure 7.1 Directed graph 
showing possible 
transitions for subjects 
through the study. 
 
 
 
In order to create such 
correlated data, it is helpful 
to construct a reasonable 
“base case” and alter it as 
needed.  The “base case” makes the following assumptions: 
 
P6S ≡ probability of a subject being a Success (Responder) at 6 months = 0.50 
P6R ≡ probability of a subject being a Recoverable Non-Success at 6 months = 0.47 
P12S|6S ≡ probability of a subject being a Success at 12 months given that the subject was a 
Success at 6 months = 0.85 
P12R|6S ≡ probability of a subject being a Recoverable Non-Success at 12 months given that 
the subject was a Success at 6 months = 0.12 
P12S|6R ≡ probability of a subject being a Success at 12 months given that the subject was a 
Recoverable Non-Success at 6 months = 0.40 
P12R|6R ≡ probability of a subject being a Recoverable Non-Success at 12 months given that 
the subject was a Recoverable Non-Success at 6 months = 0.57 
P24S|12S ≡ probability of a subject being a Success at 24 months given that the subject was a 
Success at 12 months = 0.93 
P24S|12R ≡ probability of a subject being a Success at 24 months given that the subject was a 
Recoverable Non-Success at 12 months = 0.39 
 
These assumptions uniquely determine all transition probabilities and imply that P12S ≡ 
probability of a subject being a Success at 12 months is 0.613 (since P12S = 
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with a great quote from the 
document or use this space to 
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place this text box anywhere 
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P12S|6S*P6S+P12S|6R*P6R) and that P24S ≡ probability of a subject being a Success at the final time 
point is 0.698 (since P24S = P24S|12S*P12S+P24S|12R*P12R, where P12R = P12R|6S*P6S+P12R|6R*P6R).  
We note that, under these assumptions, the marginal probability of being a success increases with 
time (from 0.5 to 0.613 to 0.698 for 6 months, 12 months, and 24 months, respectively.   
 
In order to adjust the base case so that different target values of P24S (e.g., 0.60, 0.70, 0.75) are 
achieved, we take a logistic approach and alter the probabilities of several of the above 
quantities, based on a common value of ε on the logit scale.  We thus obtain new values for the 
probabilities specified above, by adding or subtracting a single value ε , chosen to result in a 
specific target value of P24S: 
logit(P6S*) ≡ logit(P6S + ε) 
logit(P6R*) ≡ logit(P6R – ε) 
logit(P12S|6S*) ≡ logit(P12S|6S  + ε) 
logit(P12R|6S*) ≡ logit(P12R|6S – ε) 
logit(P24S|12S*) ≡ logit(P24S|12S + ε) 
 
Table 7.1 displays the values of ε and the resulting transition and marginal probabilities. The 
column representing ε=0 results in the base case. Note that the values of the 5 transitions 
depicted in Figures S-1 and S-2 are generally consistent with the values displayed in Table 6.1, 
where the 5 transitions are in the rows corresponding to P24S|12R, P24S|12S,  P24S|6R,  P24S|6S, and  
P24S.  For example, when 0.65 ≤ P24S ≤ 0.75 (the most plausible range of values), P24S|12S in Table 
Y.1 ranges from  0.9034 to 0.9506, values which are consistent with the distribution of Transition 
2 in Figure S-2. 
 
Sensitivity of the operating characteristics to these assumptions is examined in Appendix 8. 

 
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Table 7.1  Transition Probabilities and Induced Marginal Probabilities for various desired values of P24S.  Setting ε = 0 results in the 
“base case.”  By altering ε, different target values of P24S are achieved. 
   
  
  
  
Epsilon (ε) 
0 
-1.1975 
-0.9644 
-0.7470 
-0.5434 
-0.3506 
-0.1656 
0.0145 
0.1924 
0.3709 
0.5529 
0.7416 
Initial 
Probabilities 
P6S 
0.5000 
0.2319 
0.2760 
0.3215 
0.3674 
0.4132 
0.4587 
0.5036 
0.5480 
0.5917 
0.6348 
0.6773 
P6R 
0.4700 
0.7460 
0.6994 
0.6518 
0.6043 
0.5574 
0.5114 
0.4664 
0.4225 
0.3796 
0.3378 
0.2970 
P6F 
0.0300 
0.0221 
0.0246 
0.0267 
0.0283 
0.0294 
0.0299 
0.0300 
0.0296 
0.0287 
0.0274 
0.0257 
Transition 
(Conditional) 
Probabilities 
P12S|6S 
0.8500 
0.6311 
0.6836 
0.7286 
0.7670 
0.7996 
0.8276 
0.8518 
0.8729 
0.8914 
0.9078 
0.9225 
P12R|6S 
0.1200 
0.3111 
0.2635 
0.2235 
0.1901 
0.1622 
0.1386 
0.1185 
0.1011 
0.0860 
0.0727 
0.0610 
P12F|6S 
0.0300 
0.0578 
0.0530 
0.0479 
0.0429 
0.0382 
0.0337 
0.0297 
0.0260 
0.0226 
0.0194 
0.0165 
P12S|6R 
0.4000 
0.4000 
0.4000 
0.4000 
0.4000 
0.4000 
0.4000 
0.4000 
0.4000 
0.4000 
0.4000 
0.4000 
P12R|6R 
0.5700 
0.5700 
0.5700 
0.5700 
0.5700 
0.5700 
0.5700 
0.5700 
0.5700 
0.5700 
0.5700 
0.5700 
P12F|6R 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
P24S|12S 
0.9300 
0.8005 
0.8351 
0.8629 
0.8853 
0.9034 
0.9184 
0.9309 
0.9415 
0.9506 
0.9585 
0.9654 
P24S|12R 
0.3900 
0.3900 
0.3900 
0.3900 
0.3900 
0.3900 
0.3900 
0.3900 
0.3900 
0.3900 
0.3900 
0.3900 
Induced 
Transition 
Probabilities 
P24S|6S 
0.8373 
0.6265 
0.6736 
0.7159 
0.7531 
0.7857 
0.8142 
0.8392 
0.8613 
0.8810 
0.8985 
0.9143 
P24S|6R 
 0.5943 
 0.5425 
  0.5563 
  0.5675 
  0.5764 
  0.5837 
 0.5897 
0.5947 
0.5989 
0.6025 
 0.6057 
 0.6085 
Induced 
Marginal 
Probabilities 
P6S 
0.5000 
0.2319 
0.2760 
0.3215 
0.3674 
0.4132 
0.4587 
0.5036 
0.5480 
0.5917 
0.6348 
0.6773 
P6R 
0.4700 
0.7460 
0.6994 
0.6518 
0.6043 
0.5574 
0.5114 
0.4664 
0.4225 
0.3796 
0.3378 
0.2970 
P6F 
0.0300 
0.0221 
0.0246 
0.0267 
0.0283 
0.0294 
0.0299 
0.0300 
0.0296 
0.0287 
0.0274 
0.0257 
P12S 
0.6130 
0.4448 
0.4684 
0.4949 
0.5235 
0.5534 
0.5842 
0.6156 
0.6473 
0.6793 
0.7114 
0.7436 
P12R 
0.3279 
0.4974 
0.4713 
0.4434 
0.4143 
0.3847 
0.3551 
0.3255 
0.2962 
0.2673 
0.2387 
0.2106 
P12F 
0.0591 
0.0579 
0.0602 
0.0617 
0.0622 
0.0619 
0.0608 
0.0589 
0.0565 
0.0534 
0.0498 
0.0458 
P24S 
0.6980 
0.5500 
0.5750 
0.6000 
0.6250 
0.6500 
0.6750 
0.7000 
0.7250 
0.7500 
0.7750 
0.8000 

 
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The second assumption pertains to the responder rate Pc in the control group.  Section 8.3 
presents the justification for assuming that Pc = 0.70.  It is possible that Pc is somewhat less or 
greater than this value.  Sensitivity to this assumption is also examined in Appendix 8. 
 
The third assumption pertains to the enrollment rate.  In this simulation, it is assumed that 
subjects are enrolled at a rate of 15 per month, after an initial ramp-up period.  Specifically, the 
numbers of subjects enrolled per month in the first 12 months are 3, 3, 3, 6, 6, 6, 12, 12, 12, 12, 
15, 15, and thereafter 15 per month until enrollment is completed. Sensitivity to this assumption 
is examined in Appendix 8. 
 
The fourth assumption pertains to subject loss to follow-up.  It is assumed that there is a 15% rate 
of dropout.  This was implemented in the simulation by allowing each subject to drop out with 
probability 0.15.  Therefore, in successive simulated trials, it is possible that a different number 
of subjects is lost to follow-up, though it would be approximately 15%.  Furthermore, for those 
subjects who drop out, it is assumed that they drop out at random times, uniformly distributed 
over the 2-year follow-up period.  In the simulation, subjects do not miss a visit and then return 
for a subsequent visit; only subjects that are that are lost to follow-up miss any visits, and once 
subjects are lost, they never return. 
 
The final assumption pertains to the timing of the interim “Win” and “Sample Size” analyses.  
The pre-specified time points are when a set number K of subjects have achieved some milestone 
(e.g., when K=450 subjects are enrolled, or when K=300 have completed 2 years).  This was 
implemented in the simulation code by assuming that an analysis can only occur at the end of a 
month.  Therefore, the interim analysis occurred at the end of the month in which the defining 
event happened (e.g., 450 subjects were enrolled).  At the end of that month, the exact number of 
subjects who had achieved the milestone could be greater than K and could vary from simulated 
trial to simulated trial, depending on the enrollment rate and simulated dropout mechanism. 
 
Sensitivity of the Operating Characteristics to several of these assumptions is explored in 
Appendix 8. 

 
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Appendix 8:  Sensitivity of Operating Characteristics 
 
In this appendix, sensitivity of the design’s operating characteristics to a number of key 
assumptions employed in the generation of simulated data is explored.  As in the principal 
operating characteristics (Table 8.5.1 in Section 8.5), operating characteristics for each of the 
tables below are estimated based on 10,000 simulated trials per row, with the predictions for 
unobserved 2-year outcomes  calculated on the basis of 5000 draws from each of the transition 
probability distributions. 
 
 
Varying the enrollment rate (30/month) 
 
Tables 8.1 and 8.2 show the operating characteristics when the enrollment rate is either faster or 
slower than the rate of 15/month that was assumed in the principal operating characteristics 
(Table S.3 in Section 8.3).  Table 8.1 displays the results when enrollment for the first 12 months 
is 6, 6, 12, 12, 18, 18, 18, 18, 24, 24, 24, 30 subjects/month, and thereafter 30/month until 
enrollment is complete.   Table 8.2 displays the results when the enrollment for the first 12 
months is 3, 3, 3, 3, 3, 6, 6, 6, 6, 9, 9, 9 subjects/month, and thereafter 9/month until complete.   
 
Table 8.1  Operating Characteristics when the enrollment rate is 30/mo.  Interpretations of 
column headings are given in the narrative just above Table 8.5.1 in the section “Statistical 
Analysis Plan.” 
Pt 
Pc 
Overall 
Power 
Avg 
Sample 
Size 
Sample Size Determination Analyses 
"Win" Analyses 
Pr(Size 
= 300) 
Pr(Size 
= 450) 
Pr(Size 
= 600) 
Pr(Size 
= 750) 
Futile 
at 
450? 
Futile 
at 
600? 
Pr(NI @ 
Look #1) 
Pr(NI @ 
Look #2) 
Pr(NI @ 
Look #3) 
0.550 
0.700 
0.041 
734.4 
0.000 
0.000 
0.104 
0.896 
0.000 
0.104 
0.024 
0.009 
0.007 
0.600 
0.700 
0.292 
739.2 
0.000 
0.000 
0.072 
0.928 
0.000 
0.068 
0.169 
0.068 
0.054 
0.650 
0.700 
0.747 
736.0 
0.000 
0.004 
0.085 
0.911 
0.000 
0.049 
0.534 
0.131 
0.083 
0.700 
0.700 
0.960 
703.5 
0.000 
0.032 
0.246 
0.722 
0.000 
0.023 
0.878 
0.062 
0.021 
0.725 
0.700 
0.982 
666.7 
0.000 
0.084 
0.388 
0.528 
0.000 
0.015 
0.956 
0.022 
0.005 
0.750 
0.700 
0.992 
620.2 
0.000 
0.171 
0.523 
0.306 
0.000 
0.008 
0.986 
0.005 
0.000 
0.800 
0.700 
0.998 
530.1 
0.003 
0.506 
0.445 
0.046 
0.000 
0.002 
0.998 
0.000 
0.000 
 
Table 8.2  Operating Characteristics when the enrollment rate is 9/mo 
Pt 
Pc 
Overall 
Power 
Avg 
Sample 
Size 
Sample Size Determination Analyses 
"Win" Analyses 
Pr(Size 
= 300) 
Pr(Size 
= 450) 
Pr(Size 
= 600) 
Pr(Size 
= 750) 
Futile 
at 
450? 
Futile 
at 
600? 
Pr(NI @ 
Look #1) 
Pr(NI @ 
Look #2) 
Pr(NI @ 
Look #3) 
0.550 
0.700 
0.045 
565.7 
0.000 
0.466 
0.296 
0.238 
0.466 
0.296 
0.026 
0.012 
0.006 
0.600 
0.700 
0.302 
657.3 
0.002 
0.205 
0.203 
0.590 
0.199 
0.197 
0.169 
0.080 
0.053 
0.650 
0.700 
0.769 
691.2 
0.017 
0.110 
0.121 
0.752 
0.052 
0.057 
0.510 
0.171 
0.088 
0.700 
0.700 
0.975 
602.5 
0.096 
0.243 
0.210 
0.451 
0.009 
0.005 
0.857 
0.094 
0.023 
0.725 
0.700 
0.995 
521.4 
0.196 
0.356 
0.222 
0.225 
0.002 
0.001 
0.946 
0.043 
0.006 
0.750 
0.700 
0.999 
450.0 
0.335 
0.416 
0.163 
0.086 
0.000 
0.000 
0.985 
0.013 
0.001 
0.800 
0.700 
1.000 
350.9 
0.694 
0.276 
0.027 
0.003 
0.000 
0.000 
1.000 
0.000 
0.000 

 
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Varying the responder rate in the control group (Pc) 
 
The responder rate Pc was varied between 0.65 and 0.75 (compared to 0.70 for Table 8.5.1 in 
Section 8.5).  The operating characteristics resulting from Pc = 0.75 are shown in Table 8.3.  The 
operating characteristics resulting from Pc = 0.65 are shown in Table 8.4.  (Here the enrollment 
rate is again 15/month, as assumed in the principal operating characteristics.) 
 
Table 8.3 Operating Characteristics when Pc = 0.75 
Pt 
Pc 
Overall 
Power 
Avg 
Sample 
Size 
Sample Size Determination Analyses 
"Win" Analyses 
Pr(Size 
= 300) 
Pr(Size 
= 450) 
Pr(Size 
= 600) 
Pr(Size 
= 750) 
Futile 
at 
450? 
Futile 
at 
600? 
Pr( NI 
@ Look 
#1) 
Pr( NI 
@ Look 
#2) 
Pr( NI 
@ Look 
#3) 
0.600 
0.750 
0.043 
610.3 
0.000 
0.282 
0.367 
0.351 
0.282 
0.367 
0.030 
0.007 
0.006 
0.650 
0.750 
0.321 
680.7 
0.000 
0.132 
0.199 
0.670 
0.128 
0.191 
0.206 
0.068 
0.047 
0.700 
0.750 
0.780 
699.8 
0.001 
0.093 
0.144 
0.761 
0.050 
0.059 
0.594 
0.123 
0.063 
0.750 
0.750 
0.980 
624.9 
0.015 
0.247 
0.297 
0.442 
0.009 
0.007 
0.919 
0.048 
0.012 
0.775 
0.750 
0.992 
556.7 
0.039 
0.427 
0.317 
0.217 
0.006 
0.002 
0.979 
0.011 
0.002 
0.800 
0.750 
0.998 
495.8 
0.087 
0.594 
0.247 
0.073 
0.002 
0.000 
0.995 
0.003 
0.000 
 
Table 8.4 Operating Characteristics when Pc = 0.65 
Pt 
Pc 
Overall 
Power 
Avg 
Sample 
Size 
Sample Size Determination Analyses 
"Win" Analyses 
Pr(Size 
= 300) 
Pr(Size 
= 450) 
Pr(Size 
= 600) 
Pr(Size 
= 750) 
Futile 
at 
450? 
Futile 
at 
600? 
Pr( NI 
@ Look 
#1) 
Pr( NI 
@ Look 
#2) 
Pr( NI 
@ Look 
#3) 
0.500 
0.650 
0.044 
610.2 
0.000 
0.288 
0.356 
0.356 
0.288 
0.356 
0.031 
0.008 
0.005 
0.550 
0.650 
0.282 
671.6 
0.000 
0.158 
0.207 
0.635 
0.153 
0.197 
0.180 
0.060 
0.042 
0.600 
0.650 
0.709 
698.2 
0.001 
0.102 
0.138 
0.759 
0.064 
0.075 
0.510 
0.124 
0.075 
0.650 
0.650 
0.948 
649.5 
0.010 
0.200 
0.239 
0.550 
0.021 
0.014 
0.842 
0.082 
0.024 
0.675 
0.650 
0.980 
595.4 
0.027 
0.323 
0.304 
0.346 
0.011 
0.005 
0.932 
0.041 
0.007 
0.700 
0.650 
0.993 
535.4 
0.056 
0.480 
0.302 
0.162 
0.005 
0.001 
0.977 
0.015 
0.001 
0.750 
0.650 
0.999 
439.9 
0.220 
0.642 
0.123 
0.014 
0.001 
0.000 
0.998 
0.000 
0.000 
 
 
Varying the correlation between interim (6-month, 1-year) outcomes and 2-year outcomes 
 
We approach the examination of correlation by simulating the extreme cases where (a) the 2-year 
outcomes are completely correlated with the 6-month and 1-year outcomes, and (b) the 2-year 
outcomes are completely independent of the 6-month and 1-year outcomes.   
 
Table 8.5 displays operating characteristics for a case where the 6-month outcomes are totally 
correlated with the 2-year outcomes.  This was implemented by making the following 
assignments:  
P6S = Pt or Pc, as appropriate 
P6R = 0 
P12S|6S  = 1 
P12S|6R  = 0 
P12R|6S  = 0 

 
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P12R|6R  = 1 
P24S|12S  = 1 
P24S|12R  = 0 
 
Here, there are no Recoverables—only Successes (who remain Successes) and (non-recoverable) 
Failures, who remain Failures by definition.  Knowing the 6-month outcomes is as good as 
knowing the 2-year outcomes. 
 
Table 8.5 Operating Characteristics when interim outcomes are totally correlated with 2-
year outcomes (Version 1) 
Pt 
Pc 
Overall 
Power 
Avg 
Sample 
Size 
Sample Size Determination Analyses 
"Win" Analyses 
Pr(Size 
= 300) 
Pr(Size 
= 450) 
Pr(Size 
= 600) 
Pr(Size 
= 750) 
Futile 
at 
450? 
Futile 
at 
600? 
Pr( NI 
@ Look 
#1) 
Pr( NI 
@ Look 
#2) 
Pr( NI 
@ Look 
#3) 
0.550 
0.700 
0.032 
599.4 
0.000 
0.272 
0.459 
0.269 
0.272 
0.459 
0.024 
0.007 
0.000 
0.600 
0.700 
0.281 
680.7 
0.003 
0.105 
0.243 
0.649 
0.098 
0.235 
0.217 
0.062 
0.002 
0.650 
0.700 
0.785 
697.0 
0.019 
0.086 
0.122 
0.772 
0.026 
0.046 
0.701 
0.083 
0.001 
0.700 
0.700 
0.984 
606.0 
0.088 
0.229 
0.239 
0.445 
0.003 
0.004 
0.962 
0.021 
0.000 
0.725 
0.700 
0.997 
537.8 
0.153 
0.350 
0.256 
0.241 
0.001 
0.001 
0.993 
0.004 
0.000 
0.750 
0.700 
1.000 
471.1 
0.262 
0.432 
0.208 
0.098 
0.000 
0.000 
0.999 
0.001 
0.000 
0.800 
0.700 
1.000 
376.2 
0.552 
0.393 
0.051 
0.004 
0.000 
0.000 
1.000 
0.000 
0.000 
 
There is more than one way to specify total correlation of interim outcomes and final outcomes.  
One can also specify: 
P6S = Pt or Pc, as appropriate 
P6R = 1 – PS1 – 0.01 
P12S|6S1  = 1 
P12S|6R  = 0 
P12R|6S  = 0 
P12R|6R  = 1 
P24S|12S  = 1 
P24S|12R  = 0 
 
Here, almost all of the non-successes at 6 months are of the Recoverable type.  Only a small 
fraction (0.01) are non-recoverable (i.e., Failures).  A Success stays a Success, a Recoverable 
stays a Recoverable, and a Failure stays a Failure (by definition).  Once again, knowing the 6-
month outcomes is as good as knowing the 2-year outcomes.  Table 8.6 displays operating 
characteristics for this instance. 
 

 
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Table 8.6 Operating Characteristics when interim outcomes are totally correlated with 2-
year outcomes (Version 2) 
Pt 
Pc 
Overall 
Power 
Avg 
Sample 
Size 
Sample Size Determination Analyses 
"Win" Analyses 
Pr(Size 
= 300) 
Pr(Size 
= 450) 
Pr(Size 
= 600) 
Pr(Size 
= 750) 
Futile 
at 
450? 
Futile 
at 
600? 
Pr( NI 
@ Look 
#1) 
Pr( NI 
@ Look 
#2) 
Pr( NI 
@ Look 
#3) 
0.550 
0.700 
0.025 
597.6 
0.000 
0.282 
0.453 
0.266 
0.281 
0.452 
0.018 
0.006 
0.001 
0.600 
0.700 
0.264 
674.7 
0.000 
0.125 
0.252 
0.623 
0.117 
0.244 
0.198 
0.060 
0.006 
0.650 
0.700 
0.777 
701.5 
0.001 
0.093 
0.133 
0.772 
0.029 
0.050 
0.672 
0.097 
0.007 
0.700 
0.700 
0.981 
630.1 
0.008 
0.254 
0.267 
0.471 
0.007 
0.003 
0.957 
0.024 
0.001 
0.725 
0.700 
0.997 
572.9 
0.018 
0.408 
0.312 
0.262 
0.002 
0.001 
0.992 
0.005 
0.000 
0.750 
0.700 
0.999 
517.6 
0.046 
0.567 
0.279 
0.109 
0.001 
0.000 
0.999 
0.000 
0.000 
0.800 
0.700 
1.000 
445.2 
0.137 
0.764 
0.092 
0.007 
0.000 
0.000 
1.000 
0.000 
0.000 
 
Table 8.7 displays operating characteristics for a case where the interim outcomes are 
independent of the final outcomes.  This was implemented by forcing that there be no interim 
(non-recoverable) Failures, since their final outcomes would be correlated to the interim 
outcomes, by definition, and also by forcing everyone else to be a Success at both of the interim 
time points: 
P6S = 1 
P6R = 0 
P12S|6S  = 1 
P12S|6R  = 0 
P12R|6S  = 0 
P12R|6R  = 1 
P24S|12S  = Pt or Pc, as appropriate 
P24S|12R  = 0 
 
Table 8.7 Operating Characteristics when interim outcomes are independent of the 2-year 
outcomes (Version 1)  
Pt 
Pc 
Overall 
Power 
Avg 
Sample 
Size 
Sample Size Determination Analyses 
"Win" Analyses 
Pr(Size 
= 300) 
Pr(Size 
= 450) 
Pr(Size 
= 600) 
Pr(Size 
= 750) 
Futile 
at 
450? 
Futile 
at 
600? 
Pr( NI 
@ Look 
#1) 
Pr( NI 
@ Look 
#2) 
Pr( NI 
@ Look 
#3) 
0.550 
0.700 
0.050 
606.5 
0.000 
0.313 
0.331 
0.356 
0.295 
0.329 
0.036 
0.008 
0.006 
0.600 
0.700 
0.280 
650.3 
0.000 
0.229 
0.206 
0.565 
0.168 
0.187 
0.173 
0.061 
0.045 
0.650 
0.700 
0.696 
663.0 
0.000 
0.212 
0.155 
0.632 
0.075 
0.072 
0.479 
0.128 
0.089 
0.700 
0.700 
0.940 
618.7 
0.000 
0.323 
0.229 
0.448 
0.025 
0.012 
0.821 
0.089 
0.030 
0.725 
0.700 
0.977 
587.8 
0.000 
0.402 
0.277 
0.321 
0.013 
0.006 
0.921 
0.046 
0.010 
0.750 
0.700 
0.989 
552.8 
0.000 
0.510 
0.294 
0.196 
0.008 
0.002 
0.970 
0.019 
0.001 
0.800 
0.700 
0.999 
496.9 
0.000 
0.724 
0.241 
0.036 
0.001 
0.000 
0.998 
0.001 
0.000 
 
There is more than one way to specify independence of interim outcomes and final outcomes.  In 
any specification, it must be true that there be no interim (non-recoverable) Failures, else the 2-
year outcomes would be completely correlated with the interim outcomes for those subjects.  
After that stipulation, one can assign status (Success, Recoverable Non-Responder) to the 6-

 
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month, 1-year, and 2-year outcomes independently, each using probability of Success equal to Pc 
or Pc, as appropriate: 
P6S = Pt or Pc, as appropriate 
P6R = 1 – P6S 
P12S  = Pt or Pc, as appropriate 
P12R  = 1 – P12S 
P24S  = Pt or Pc, as appropriate 
P24F  = 1 – P24S 
 
Note that, in the above specification, the probabilities are marginal probabilities (i.e., at the time 
points), and not conditional (transition) probabilities.  The results of implementing this approach 
to independence are shown in Table 8.8. 
 
Table 8.8 Operating Characteristics when interim outcomes are independent of the 2-year 
outcomes (Version 2)  
Pt 
Pc 
Overall 
Power 
Avg 
Sample 
Size 
Sample Size Determination Analyses 
"Win" Analyses 
Pr(Size 
= 300) 
Pr(Size 
= 450) 
Pr(Size 
= 600) 
Pr(Size 
= 750) 
Futile 
at 
450? 
Futile 
at 
600? 
Pr( NI 
@ Look 
#1) 
Pr( NI 
@ Look 
#2) 
Pr( NI 
@ Look 
#3) 
0.550 
0.700 
0.048 
614.9 
0.000 
0.281 
0.338 
0.380 
0.281 
0.338 
0.032 
0.010 
0.007 
0.600 
0.700 
0.289 
671.4 
0.000 
0.161 
0.203 
0.637 
0.154 
0.194 
0.177 
0.059 
0.052 
0.650 
0.700 
0.711 
691.3 
0.001 
0.117 
0.155 
0.727 
0.071 
0.071 
0.494 
0.128 
0.089 
0.700 
0.700 
0.946 
640.8 
0.005 
0.224 
0.265 
0.506 
0.024 
0.013 
0.830 
0.089 
0.027 
0.725 
0.700 
0.977 
588.6 
0.015 
0.354 
0.323 
0.308 
0.012 
0.004 
0.925 
0.043 
0.009 
0.750 
0.700 
0.991 
536.2 
0.032 
0.508 
0.314 
0.146 
0.006 
0.001 
0.972 
0.017 
0.001 
0.800 
0.700 
0.998 
453.8 
0.124 
0.736 
0.130 
0.010 
0.001 
0.000 
0.998 
0.000 
0.000 
 
 
Varying the “base case” of correlation between interim (6-month, 1-year)  
 
Appendix 7 describes a “base case” correlation from which all the other correlations of the 
simulation are derived.  Table 7.1 lists the “base case” as the “θ” column. 
 
The sample size adaptation algorithm depends in part on informative prior distributions about the 
various transition probabilities.  The sponsor believes these priors to be reasonable and useful for 
predicting future outcomes.  But it is sensible to explore whether the sample size determination 
algorithm could be “fooled” into selecting an inappropriate sample size by correlated data that 
follow a very different “base case.” For example, consider a case where the treatment and control 
response rates are equal at 24 months but very unequal in the early outcomes (6 months, 12 
months).   Does the adaptation algorithm choose the wrong sample size based on early promise, 
and in so doing dramatically alter either the type 1 error or power? 
 
To investigate this possibly, we define a new “Base Case 2” and compare its results to those of 
the previous base case (now designated “Base Case 1”).  Table 8.9 displays the base cases.  The 
most dramatic differences are in the “Induced marginal Probabilities” section, where it is seen 

 
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that Base Case 2 tends have a higher success rate at 6 and 12 months (see P6S and P12S values) 
but actually finishes lower (see P24S column).  
 
Table 8.9 Comparison of Base Case 1 and Base Case 2 
 
Base 
Case 1 
Base 
Case 2 
Initial 
Probabilities 
P6S 
0.5000 
0.7500 
P6R 
0.4700 
0.2000 
P6F 
0.0300 
0.0500 
Transition 
(Conditional) 
Probabilities 
P12S|6S 
0.8500 
0.8500 
P12R|6S 
0.1200 
0.1200 
P12F|6S 
0.0300 
0.0300 
P12S|6R 
0.4000 
0.2200 
P12R|6R 
0.5700 
0.7500 
P12F|6R 
0.0300 
0.0300 
P24S|12S 
0.9300 
0.9000 
P24S|12R 
0.3900 
0.1000 
Induced 
Transition 
Probabilities 
P24S|6S 
0.8373 
0.7770 
P24S|6R 
 0.5943 
0.2730 
Induced 
Marginal 
Probabilities 
P6S 
0.5000 
0.7500 
P6R 
0.4700 
0.2000 
P6F 
0.0300 
0.0500 
P12S 
0.6130 
0.6815 
P12R 
0.3279 
0.2400 
P12F 
0.0591 
0.0785 
P24S 
0.6980 
0.6374 
 
Table 8.10 is analogous to Table 7.1 and displays all transition and marginal probabilities for 
various target values of P24S, using Base Case 2. 

 
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Table 8.10  Transition Probabilities and Induced Marginal Probabilities for various desired values of P24S, based on Base 
Case 2.  Setting ε = 0 results in “base case 2.”  By altering ε, different target values of P24S are achieved. 
   
  
  
  
Epsilon (ε) 
Base 
Case 2 
(ε=0) 
-0.3476 
-0.2503 
-0.1516 
-0.0507 
0.0528 
0.1600 
0.2717 
0.3892 
0.5137 
0.6473 
0.7922 
Initial 
Probabilities 
P6S 
0.7500 
0.6794 
0.7002 
0.7205 
0.7404 
0.7598 
0.7788 
0.7974 
0.8157 
0.8337 
0.8514 
0.8689 
P6R 
0.2000 
0.2614 
0.2431 
0.2254 
0.2082 
0.1917 
0.1756 
0.1600 
0.1449 
0.1301 
0.1157 
0.1017 
P6F 
0.0500 
0.0592 
0.0567 
0.0541 
0.0514 
0.0485 
0.0456 
0.0425 
0.0394 
0.0362 
0.0328 
0.0295 
Transition 
(Conditional) 
Probabilities 
P12S|6S 
0.8500 
0.8001 
0.8152 
0.8296 
0.8434 
0.8566 
0.8693 
0.8815 
0.8932 
0.9045 
0.9154 
0.9260 
P12R|6S 
0.1200 
0.1618 
0.1490 
0.1370 
0.1255 
0.1145 
0.1041 
0.0941 
0.0846 
0.0754 
0.0666 
0.0582 
P12F|6S 
0.0300 
0.0381 
0.0357 
0.0334 
0.0311 
0.0289 
0.0266 
0.0244 
0.0222 
0.0201 
0.0179 
0.0158 
P12S|6R 
0.2200 
0.2200 
0.2200 
0.2200 
0.2200 
0.2200 
0.2200 
0.2200 
0.2200 
0.2200 
0.2200 
0.2200 
P12R|6R 
0.7500 
0.7500 
0.7500 
0.7500 
0.7500 
0.7500 
0.7500 
0.7500 
0.7500 
0.7500 
0.7500 
0.7500 
P12F|6R 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
0.0300 
P24S|12S 
0.9000 
0.8641 
0.8751 
0.8855 
0.8953 
0.9047 
0.9135 
0.9219 
0.9300 
0.9377 
0.9450 
0.9521 
P24S|12R 
0.1000 
0.1000 
0.1000 
0.1000 
0.1000 
0.1000 
0.1000 
0.1000 
0.1000 
0.1000 
0.1000 
0.1000 
Induced 
Transition 
Probabilities 
P24S|6S 
0.7770 
0.7075 
0.7283 
0.7483 
0.7677 
0.7864 
0.8045 
0.8221 
0.8391 
0.8557 
0.8718 
0.8875 
P24S|6R 
0.2730 
0.2651 
0.2675 
0.2698 
0.2720 
0.2740 
0.2760 
0.2778 
0.2796 
0.2813 
0.2829 
0.2845 
Induced 
Marginal 
Probabilities 
P6S 
0.7500 
0.6794 
0.7002 
0.7205 
0.7404 
0.7598 
0.7788 
0.7974 
0.8157 
0.8337 
0.8514 
0.8689 
P6R 
0.2000 
0.2614 
0.2431 
0.2254 
0.2082 
0.1917 
0.1756 
0.1600 
0.1449 
0.1301 
0.1157 
0.1017 
P6F 
0.0500 
0.0592 
0.0567 
0.0541 
0.0514 
0.0485 
0.0456 
0.0425 
0.0394 
0.0362 
0.0328 
0.0295 
P12S 
0.6815 
0.6011 
0.6243 
0.6473 
0.6702 
0.6930 
0.7156 
0.7381 
0.7605 
0.7827 
0.8049 
0.8269 
P12R 
0.2400 
0.3060 
0.2867 
0.2677 
0.2491 
0.2308 
0.2128 
0.1951 
0.1777 
0.1605 
0.1435 
0.1268 
P12F 
0.0785 
0.0929 
0.0890 
0.0850 
0.0807 
0.0762 
0.0716 
0.0668 
0.0619 
0.0568 
0.0516 
0.0463 
P24S 
0.6374 
0.5500 
0.5750 
0.6000 
0.6250 
0.6500 
0.6750 
0.7000 
0.7250 
0.7500 
0.7750 
0.8000 
 

 
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Protocol Number: 1020-9052 
Revision K: 14 February 2013 
When simulated data for both groups follow Base Case 2  
 
Table 8.11 displays the operating characteristics that result when the simulated data follow the 
probabilities of Table 8.10 (i.e., based on Base Case 2).  The power remains acceptably high, the 
type 1 error is acceptably low, and the average sample size is similar to the main operating 
characteristics (Table 8.5.1 in Section 8.5). 
 
Table 8.11 Operating Characteristics when the Control Group is favored early 
Pt 
Pc 
Overall 
Power 
Avg 
Sample 
Size 
Sample Size Determination Analyses 
"Win" Analyses 
Pr(Size 
= 300) 
Pr(Size 
= 450) 
Pr(Size 
= 600) 
Pr(Size 
= 750) 
Futile 
at 
450? 
Futile 
at 
600? 
Pr(NI @ 
Look #1) 
Pr(NI @ 
Look #2) 
Pr(NI @ 
Look #3) 
0.550 
0.700 
0.039 
603.0 
0.000 
0.294 
0.391 
0.315 
0.293 
0.390 
0.025 
0.009 
0.005 
0.600 
0.700 
0.291 
669.7 
0.001 
0.156 
0.220 
0.623 
0.146 
0.209 
0.192 
0.062 
0.037 
0.650 
0.700 
0.750 
689.2 
0.007 
0.116 
0.154 
0.724 
0.051 
0.066 
0.568 
0.125 
0.056 
0.700 
0.700 
0.968 
625.9 
0.024 
0.252 
0.249 
0.474 
0.014 
0.008 
0.908 
0.051 
0.009 
0.725 
0.700 
0.991 
570.7 
0.042 
0.388 
0.294 
0.276 
0.005 
0.002 
0.970 
0.018 
0.003 
0.750 
0.700 
0.997 
516.1 
0.081 
0.523 
0.271 
0.125 
0.002 
0.000 
0.991 
0.005 
0.001 
0.800 
0.700 
1.000 
438.6 
0.207 
0.672 
0.112 
0.009 
0.000 
0.000 
1.000 
0.000 
0.000 
 
 
When the treatment group is favored early  
 
Table 8.12 displays the operating characteristics when the simulated treatment group data are 
generated from base case 2 and the simulated control group data are generated from base case 1.  
In the Pt = 0.70, Pc = 0.70 row, the 24-month responder rates are equal, and yet in following the 
correlations from base case 2, the treatment group has more responders at the 6- and 12-month 
time points.  Sample size tends to be smaller—inappropriately—than the main scenario (Table 
8.5.1 in Section 8.5).  Power is slightly reduced, but the type 1 error rate remains controlled.  
 
Table 8.12 Operating Characteristics when the Control Group is favored early 
Pt 
Pc 
Overall 
Power 
Avg 
Sample 
Size 
Sample Size Determination Analyses 
"Win" Analyses 
Pr(Size 
= 300) 
Pr(Size 
= 450) 
Pr(Size 
= 600) 
Pr(Size 
= 750) 
Futile 
at 
450? 
Futile 
at 
600? 
Pr(NI @ 
Look #1) 
Pr(NI @ 
Look #2) 
Pr(NI @ 
Look #3) 
0.550 
0.700 
0.046 
604.0 
0.010 
0.285 
0.375 
0.331 
0.268 
0.370 
0.032 
0.009 
0.005 
0.600 
0.700 
0.279 
630.5 
0.042 
0.214 
0.243 
0.501 
0.133 
0.206 
0.189 
0.059 
0.030 
0.650 
0.700 
0.701 
578.8 
0.121 
0.303 
0.173 
0.404 
0.049 
0.058 
0.550 
0.109 
0.042 
0.700 
0.700 
0.930 
473.6 
0.276 
0.434 
0.148 
0.143 
0.012 
0.009 
0.867 
0.053 
0.011 
0.725 
0.700 
0.967 
430.1 
0.369 
0.456 
0.113 
0.062 
0.007 
0.002 
0.944 
0.020 
0.003 
0.750 
0.700 
0.988 
391.6 
0.493 
0.423 
0.066 
0.019 
0.002 
0.001 
0.982 
0.005 
0.000 
0.800 
0.700 
0.998 
339.7 
0.743 
0.249 
0.008 
0.000 
0.000 
0.000 
0.998 
0.000 
0.000 
 
 
 
 
 

 
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Revision K: 14 February 2013 
When the control group is favored early  
 
Table 8.13 displays the operating characteristics when the simulated treatment group data are 
generated from base case 1 and the simulated control group data are generated from base case 1.  
In the Pt = 0.70, Pc = 0.70 row, the 24-month responder rates are equal, and yet in following the 
correlations from base case 1, the treatment group has fewer responders at the 6- and 12-month 
time points.  Sample size tends to be larger than the main scenario (Table 8.5.1 in Section 8.5).  
Power is similar to the main scenario, and the type 1 error rate remains controlled.  
 
Table 8.13 Operating Characteristics when the Control Group is favored early 
Pt 
Pc 
Overall 
Power 
Avg 
Sample 
Size 
Sample Size Determination Analyses 
"Win" Analyses 
Pr(Size 
= 300) 
Pr(Size 
= 450) 
Pr(Size 
= 600) 
Pr(Size 
= 750) 
Futile 
at 
450? 
Futile 
at 
600? 
Pr(NI @ 
Look #1) 
Pr(NI @ 
Look #2) 
Pr(NI @ 
Look #3) 
0.550 
0.700 
0.045 
602.6 
0.000 
0.308 
0.366 
0.326 
0.308 
0.366 
0.031 
0.009 
0.005 
0.600 
0.700 
0.289 
672.6 
0.000 
0.152 
0.211 
0.636 
0.152 
0.211 
0.179 
0.065 
0.045 
0.650 
0.700 
0.742 
718.4 
0.000 
0.064 
0.083 
0.853 
0.061 
0.066 
0.549 
0.130 
0.064 
0.700 
0.700 
0.963 
712.2 
0.000 
0.050 
0.152 
0.799 
0.017 
0.011 
0.889 
0.059 
0.015 
0.725 
0.700 
0.989 
678.9 
0.001 
0.095 
0.280 
0.624 
0.007 
0.003 
0.960 
0.025 
0.004 
0.750 
0.700 
0.997 
627.4 
0.002 
0.203 
0.407 
0.389 
0.003 
0.000 
0.990 
0.006 
0.001 
0.800 
0.700 
1.000 
515.3 
0.025 
0.572 
0.345 
0.057 
0.000 
0.000 
1.000 
0.000 
0.000