Cellentra Viable Cell Bone Matrix (VCBM) Anterior Cervical Discectomy and Fusion Outcomes Study (VCBM/MaxAn)
Phase: NA
Conditions: Cervical Disc Degenerative Disorder
Sponsor: Zimmer Biomet

 
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Cellentra™ Viable Cell Bone Matrix (VCBM) Anterior 
Cervical Discectomy and Fusion Outcomes Study  
(VCBM/MaxAn®) 
 
Protocol Number CS-092-03 
 
 
 
 
 
 
 
 
August 15, 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPONSOR 
Biomet Spine 
310 Interlocken Parkway, Suite 120 
Broomfield, CO 80021 
 
Telephone: 
1-866-378-4195 
1-303-443-7500 
Facsimile: 
1-720-249-0230 
 
 
 
 
 

 
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SIGNATURE PAGE 
 
TITLE: Cellentra™ Viable Cell Bone Matrix (VCBM) Anterior Cervical Discectomy and Fusion 
Outcomes Study (VCBM/MaxAn) 
 
 
 
PROTOCOL NUMBER: CP-092-03 
DATE: 15-August-2014 
 
 
 
 
The signatures of the investigator and representative of the sponsor below constitute their 
approval of this protocol and provide the necessary assurances that this Post Market Surveillance 
Validation will be conducted according to Good Clinical Practices and to all stipulations, clinically 
and administratively, as stated in the protocol, including all statements as to confidentiality. 
It is agreed that the protocol contains all necessary information required to conduct the Post 
Market Surveillance Validation as outlined in the protocol.  
It is agreed that all participants in this post market surveillance will provide written informed 
consent and/or a HIPAA Authorization (addendum to be provided by sponsor) and agree to the 
Post Market Surveillance Validation procedures as agreed by the Institutional Review Board or 
Independent Ethics Committee, if applicable. 
 
 
 
 
SPONSOR: 
 
__________________________________ 
Print Name 
 
__________________________________ 
 
______________________ 
Signature 
 
 
 
 
 
Date 
 
PRINCIPAL INVESTIGATOR: 
 
__________________________________ 
Print Name 
 
__________________________________ 
 
______________________ 
Signature 
 
 
 
 
 
Date 

 
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TABLE OF CONTENTS 
1 
Investigational Plan .................................................................................................. 5 
1.1 
Purpose .................................................................................................................... 5 
2 
Introduction ............................................................................................................... 5 
2.1 
Background ............................................................................................................. 5 
2.2 
Device Description.................................................................................................. 6 
3 
Study Design .............................................................................................................. 8 
3.1  
Design ..................................................................................................................... 8 
3.2  
Inclusion Criteria .................................................................................................... 8 
3.3  
Exclusion Criteria ................................................................................................... 9 
3.4 
Subject Screening Exceptions ............................................................................... 10 
4 
Study Procedure ...................................................................................................... 10 
4.1  
Screening Assessments ......................................................................................... 10 
4.1.1 Informed Consent.......................................................................................... 10 
4.1.2 Medical History and Demographic Data ...................................................... 10 
4.1.3 Pregnancy Screening ..................................................................................... 11 
4.1.4 Clinical Assessment ...................................................................................... 11 
4.2 
Perioperative and Postoperative Management ...................................................... 12 
4.3 
Investigator Training ............................................................................................. 12 
4.4 
Follow-Up Assessments........................................................................................ 13 
4.5 
Independent Radiographic Assessment ................................................................ 14 
4.6 
Success Criteria ..................................................................................................... 14 
4.6.1 Primary Measure of Effectiveness ................................................................ 14 
4.6.2 Primary Measure of Safety ........................................................................... 15 
4.6.3 Secondary Measure of Effectiveness ............................................................ 15 
4.7 
Subject Withdrawal ............................................................................................... 15 
5 
Complications .......................................................................................................... 15 
6 
Statistical Analysis Plan ......................................................................................... 16 
6.1 
Primary Objective and Sample Size Justification ................................................. 16 
6.2 
Inferential Methods ............................................................................................... 18 
6.2.1 Significance Levels ....................................................................................... 18 
6.2.2 Models for Continuous Measures ................................................................. 18 
6.2.3 Categorical Data Analyses ............................................................................ 18 
7 
Ethical and Regulatory Requirements .................................................................. 18 
7.1 
Code of Conduct ................................................................................................... 18 
7.2  
Reports .................................................................................................................. 18 
7.3 
Institutional Review Boards (IRB) ....................................................................... 19 
7.4 
Informed Consent.................................................................................................. 19 
7.5  
Source Documentation Requirements................................................................... 20 
7.6 
Subject Confidentiality ......................................................................................... 21 
7.7 
Retention of Records by the Investigator.............................................................. 21 
7.8 
Data Reporting ...................................................................................................... 22 
7.8.1 Case Report Forms ........................................................................................ 22 
7.8.2 Final Report .................................................................................................. 22 
7.9 
Monitoring ............................................................................................................ 22 
7.9.1 Data Quality Assurance ................................................................................ 23 

 
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7.9.2 Screened Subjects who are not enrolled ....................................................... 23 
8 
References ................................................................................................................ 24 
APPENDIX 1 ................................................................................................................... 26 
Case Report Forms (CRFs) ............................................................................................... 26 
CLINICAL PROTOCOL CHANGE HISTORY ......................................................... 27 
 

 
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1 
Investigational Plan 
 
1.1 
Purpose 
The purpose of this study is to assess the clinical, radiographic, functional 
and economic outcomes in patients who undergo ACDF procedures using 
Cellentra™ Viable Cell Bone Matrix (VCBM), cortical allograft spacers, 
and the MaxAn® Anterior Cervical Plate System. 
 
2 
Introduction 
 
2.1 
Background 
Cervical degenerative disc disease (DDD) causing axial neck pain and/or 
radicular arm pain is a frequently diagnosed condition. When conservative 
therapies fail, operative intervention is often recommended. One such 
surgical procedure is the anterior cervical discectomy and fusion (ACDF). 
This 
procedure 
involves 
discectomy 
(removal 
of 
the 
damaged 
intervertebral disc) with fusion of the adjacent vertebral bodies, and can 
involve one or more spinal levels. It has a history of clinical success based 
upon relief of symptoms and favorable outcomes.1,2 Autologous iliac crest 
bone grafts are frequently used for creating bony fusion of two vertebrae; 
however, bone harvesting is associated with short- and long-term 
morbidity and increased operative time.3,4 Alternative grafts and 
instrumentation techniques have thus been utilized. The use of allograft 
eliminates the need for donor graft harvesting and its associated 
complications.  Interbody cages/spacers provide initial stability, and by 
filling the disc space, require less structural bone graft. The spacers are 
manufactured from different materials such as titanium alloy, and PEEK; 
however, these can only be marketed for use with autograft as 
supplemental bone graft material, as per current US regulatory 
requirements. Machined allograft bone spacers are also available and can 
be used with allograft for supplemental fusion, thereby eliminating the 
need for donor site autograft material. Anterior cervical plating can provide 
immediate stability, maintain spinal alignment, prevent graft dislodgement 
and collapse, enhance fusion rates, and eliminate the need for external 
immobilization.  
 
This study will assess outcomes in subjects who undergo ACDF 
procedures using the Cellentra™ Viable Cell Bone Matrix (VCBM) graft, 

 
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machined allograft interbody spacer, and the MaxAn® Anterior Cervical 
Plate System. 
 
2.2 
Device Description 
Use of any other devices and/or graft materials for ACDF procedures in 
subjects enrolled in this study will be considered a protocol deviation.  
 
Cellentra™ Viable Cell Bone Matrix (VCBM) 
 
Cellentra™ VCBM is a human tissue allograft consisting of cryopreserved 
cancellous bone that contains naturally occurring viable cells within the 
cancellous bone matrix, combined with demineralized cortical bone matrix.   
 
Indications for Use: Cellentra™ VCBM is an allogeneic bone graft 
containing naturally occurring viable donor cells intended for homologous 
use in the repair, replacement, reconstruction or supplementation of the 
recipient’s tissue in musculoskeletal defects.  These defects may be 
surgically created or from traumatic injury to bone. 
 
Contraindications:  Cellentra™ VCBM is contraindicated in patients with 
a sensitivity or allergies to any of the processing agents: Cryopreservation 
solution – Aqueous serum-free and protein-free electrolyte/mineral 
solution, Dimethyl sulfoxide (DMSO), Antibiotic Solution – Gentamicin 
Sulfate, Vancomycin, Amphotericin B, Dulbecco’s Modified Eagle’s 
Medium (DMEM). Processing Solution – Hydrochloric Acid, Acetic Acid, 
Phosphate Buffered Saline (PBS), water; use in immune compromised 
patients; or use as a standalone in load bearing applications.  
 
Machined Allograft Interbody Spacers  
  
Cellentra™ VCBM will be utilized in conjunction with LifeLink® cortical 
allograft spacers, available from Biomet under the catalog numbers of: 
LGAP915, 
LGAP916, 
LGAP917, 
LGAP918, 
LGAP919, 
LGAL915, 
LGAL916, LGAL917, LGAL918 and LGAP919.  All allograft spacers are 
processed in accordance to AATB standards. 
 
For the purposes of this study, Cellentra™ VCBM will be packed within the 
cavity of the allograft spacer.   
 
 

 
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MaxAn® Anterior Cervical Plate System 
 
The MaxAn® Anterior Cervical Plate System provides a simple, efficient 
and innovative approach to anterior cervical plating.  The system offers a 
decompression-based technique for cervical spine stabilization and 
introduces an innovative one-level plate technique that provides a direct 
relationship between the bone graft/spacer size and the position of the 
plate holes.  The unique ability to obtain maximum screw angulation and 
place a fixed screw at any angle up to 30° cephalad on the superior end of 
the plate and up to 30°caudal on the inferior end of the plate allows for 
versatile screw placement close to the endplates.  Note that the screws 
converge at 10° in the transverse plane and are not intended to have 
additional variability in that plane.  The significant cephalad-caudal 
angulation affords the surgeon the opportunity to choose a smaller plate to 
help minimize the potential for adjacent level ossification. 
 
The plate is low profile and allows for excellent intra-operative 
visualization of the vertebral end plate and graft.  The system also 
provides a choice of fixed and variable self-drilling screws to provide the 
surgeon with multiple options. 
 
 
The MaxAn® Anterior Cervical Plate System is an anterior cervical spinal 
fixation device made from titanium alloy (Ti-6Al-4VELI).  Pre-contoured 
plates that conform to the natural lordotic curvature of the spine are 
available in one, two, or three level configurations.  These offerings also 
range from 8.0mm to 72mm in length when measured from screw hole to 
screw hole.  The system includes variable and fixed bone screws, which 
are available in 4.0mm and 4.5mm diameters in various lengths.  The 
MaxAn® Anterior Cervical Plate System is cleared under premarket 
notification [510(K)] K080646.  
 
Indications for Use: The MaxAn® Anterior Cervical Plate System is 
intended for anterior interbody screw fixation of the cervical spine. The 
system is indicated for use in the temporary stabilization of the anterior 
spine during the development of cervical spinal fusions in patients with 
degenerative disc disease (as defined by neck pain of discogenic origin 
confirmed by patient history and radiographic studies), trauma (including 
fractures), tumors, deformity (defined as 'kyphosis, lordosis, or scoliosis), 
pseudarthrosis, and/or failed previous fusions. The intended levels for 
treatment range from C2 -T1. 

 
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Contraindications for Use:  The MaxAn® Anterior Cervical Plate System 
is contraindicated in patients with spinal infection or inflammation; morbid 
obesity; mental illness, alcoholism or drug abuse; pregnancy; metal 
sensitivity/foreign body sensitivity; inadequate tissue coverage over the 
operative site, open wounds local to the operative area, or rapid joint 
disease, bone absorption, osteopenia and/or osteoporosis.  Osteoporosis 
is a relative contraindication since the condition may limit the degree of 
obtainable correction, the amount of mechanical fixation and/or 
intolerance. 
 
3 
Study Design 
 
3.1  Design 
This is a prospective single-arm multi-center study of  Cellentra™ Viable 
Cell Bone Matrix (VCBM), cortical allograft spacers, and the MaxAn® 
Anterior Cervical Plate System when used in anterior cervical discectomy 
and fusion procedures. This study will enroll up to eighty (80) subjects 
across up to eight (8) clinical sites. Subjects will be recruited from a pool 
of patients presenting to investigators for an anterior cervical discectomy 
and fusion procedure.  
 
3.2  Inclusion Criteria 
Subjects will be considered for inclusion in this study if they satisfy all of 
the following criteria. 
 
1. The subject is scheduled to undergo a two or three level primary spinal 
fusion surgery between the levels of C2-T1 (Cervical 2 to Thoracic 1) 
using Cellentra™ VCBM, allograft spacers, and the MaxAn® Anterior 
Cervical Plate System. 
2. The subject is 18 years of age or older. 
3. The subject was unresponsive to conservative treatment for at least 6 
weeks unless clinically indicated sooner. 
4. The subject has persistent neck, shoulder, or arm pain consistent with 
cervical degenerative disc disease confirmed by patient history and 
radiographic studies. 
5. The subject must in the investigator’s opinion, be psychosocially, 
mentally, and physically able to fully comply with this protocol including 

 
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the required follow-up visits, the filling out of required forms, and have 
the ability to understand and give written informed consent. 
 
3.3  Exclusion Criteria 
Subjects will be excluded from this trial if they satisfy any of the following 
criteria (Exclusion criteria 1, 2, 3, 4, 5, 10, and 13 are specific to the 
MaxAn® Anterior Cervical Plate). 
 
1. Subject has an active local or systemic infection.  
2. Subject is morbidly obese, defined as a BMI greater than 40. 
3. Subject has a history (present or past) of substance abuse (recreational 
drugs, prescription drugs or alcohol) that in the investigator’s opinion 
may interfere with protocol assessments and/or with the subject’s 
ability to complete the protocol required follow-up.  
4. Subject has inadequate tissue coverage over the operative site. 
5. Subject has an open wound local to the operative area, or rapid joint 
disease, 
bone 
absorption, 
osteopenia, 
osteomalacia 
and/or 
osteoporosis.  
6. Any previous cervical spinal surgery. 
7. Subject has a condition requiring medications that may interfere with 
bone or soft tissue healing (i.e., oral or parenteral glucocorticoids, 
immunosuppressives, methotrexate, etc.) or immunocompromised. 
8. Subject has any medical condition or extenuating circumstance that, in 
the opinion of the investigator, would preclude participation in the 
study.  
9. Subject who does not meet the specific indications for use of the 
Cellentra™ VCBM or MaxAn® Anterior Cervical Plate System. 
10. Subject is pregnant, lactating or interested in becoming pregnant 
during the duration of the study. 
11. Subject is currently involved in another investigational drug or device 
study that could confound study data. 
12. Subject is a prisoner. 
13. Subject has a metal sensitivity/foreign body sensitivity. 

 
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14. Subject is involved in or planning to engage in litigation or receiving 
Worker’s Compensation related to neck or back pain. 
15. Subject has sensitivity or allergies to any of the processing agents. 
(See package insert for Cellentra™ VCBM). 
 
3.4 
Subject Screening Exceptions 
No subject screening exceptions for inclusion or exclusion criteria will be 
granted for this study. 
 
4 
Study Procedure 
4.1  Screening Assessments 
4.1.1 Informed Consent 
Subjects will be provided with an informed consent and will be given 
ample opportunity to review the consent and ask questions. The signed 
informed consent will be obtained before any study specific procedures, 
that are not part of the investigator’s standard of care begin. A copy of the 
informed consent will be given to the subject. All subjects who meet all of 
the entry criteria will be considered for inclusion in this trial. Any subject 
meeting any of the exclusion criteria will be excluded from the trial. 
All subjects who have agreed to participate in this study, and have signed 
informed consent and who meet the inclusion/exclusion criteria will be 
considered enrolled and assigned a subject ID number. Once a Subject ID 
number has been issued, it cannot be reassigned or used for another 
subject. 
4.1.2 Medical History and Demographic Data 
Within 60 days prior to the surgery date, the following information will be 
collected according to the parameters described by VCBM/MaxAn CRFs: 
 Demographic data (including date of birth, employment status, 
smoking status and history of substance abuse) 
 Medical history, including a complete history of spinal disorder(s) 
(non-operative or operative treatments performed) 
 Physical examination (including height, weight, blood pressure and 
pulse) 

 
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 Neurological Assessment (motor, sensory & reflex assessments) 
 Standard radiographs and/or  CT scans 
 Current pain medications and other drug therapies. 
4.1.3 Pregnancy Screening 
A pregnancy test will be performed and negative results will be on file for 
all female subjects unless sterilized or post-menopausal to ensure 
pregnant subjects are not enrolled into the study. 
4.1.4 Clinical Assessment 
The subject will undergo the following pain and function assessments 
within 60 days prior to the surgery date: 
Pain/Function Disability Assessment:  Pre-operatively the subject will 
complete 
the 
Neck 
Disability 
Index 
(NDI) 
Questionnaire. 
The 
questionnaire is a combined pain and function index. It will be used to 
assess the subject’s neck pain and how that pain affects the subject’s 
ability to manage in everyday life. 
The questionnaire is divided into ten sections designed to assess 
limitations of various activities of daily living. Each section contains six 
statements and each statement describes a greater degree of difficulty in 
that activity than the preceding statement. The subject marks the one 
statement in each section, which describes his/her limitations most 
accurately. Each section is scored on a 0-5 scale, 5 representing the 
greatest disability. The scores for all sections are added together, giving a 
possible score of 50.  If a subject marks two statements, the highest 
scoring statement is recorded as a true indication of his disability. If a 
section is not completed because it is inapplicable, the final score will be 
adjusted. 
Neck and Shoulder/Arm Pain:  Preoperatively all subjects will assess 
their neck and/or radicular shoulder/Arm pain in one or both arms using a 
visual analogue scale (VAS) from 0-10 cm with 10 being considered most 
painful.  
Hip Pain:  Preoperatively all subjects will assess their hip pain in both hips 
using a visual analogue scale (VAS) from 0-10 cm with 10 being 
considered most painful.  Hip pain is being measured as some of the 
subjects will undergo bone harvesting for autograft from the iliac crest. 
 

 
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SF-36v2™ Health Survey:  Preoperatively all subjects will complete a 
SF-36v2™ Health Survey as an outcome measure to assess quality of life. 
 
Subject completed self-assessments will be collected preoperatively and 
postoperatively.  
 
4.2 
Perioperative and Postoperative Management 
 
Surgeons will perform a 2 or 3 level anterior cervical discectomy and 
fusion per their customary care utilizing Cellentra™ VCBM, cortical 
allograft spacers and the MaxAn® Cervical Plate.  Surgeons will perform 
the discectomy and endplate preparations and will insert the allograft 
spacer with Cellentra™ VCBM per their preferred insertion method.  
Screws will be tightened and locked per the MaxAn® system ring locking 
mechanism instructions for use and the closure performed per the 
surgeon's normal ACDF customary care.  Data will be collected during and 
immediately after the surgery according to the parameters described by 
the VCBM/MaxAn CRFs.  This includes: duration of surgery, blood loss, 
OR time, length of hospital stay, instrumentation used, type of procedure, 
surgical level, biological augmentation, size of interbody spacer used and 
amount of Cellentra™ VCBM used. In addition, all intra-operative 
complications (e.g. excessive blood loss, hematoma, vascular injury, etc.) 
will be reported and recorded as a complication on the CRF. 
Intra-operative (after hardware is completed) or immediate post-operative, 
x-rays will be obtained.  These images will be transferred electronically via 
an internet connection to the independent imaging vendor and may be 
reviewed by Biomet Spine and an independent radiologist. Postoperative 
care will follow the standard of care at each institution for subjects who 
undergo anterior cervical fusion procedures. 
 
4.3 
Investigator Training 
All investigators participating in this study will have adequate training and 
familiarity with surgical technique for ACDF procedures, cortical allograft 
spacers, Cellentra™ VCBM and the MaxAn® Anterior Cervical Plate 
System.  
 

 
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4.4 
Follow-Up Assessments 
Subjects will be asked to return postoperatively at 3 (± 2 weeks), 6 (± 2 
weeks), 12 (± 1 month) and 24 (± 1 month) months for a clinical and 
radiographic exam.  The following data will be recorded on the Case 
Report Forms (CRFs) and in addition, electronic data entry will be 
employed via an Internet connection when using the Electronic Data 
Capture (EDC) program, OpenClinica. 
Clinical assessment: The investigator will carry out a clinical examination 
at the 3, 6, 12 and 24 month visit to assess: 
 subject compliance with postoperative care instructions, 
 Neurological Assessment (motor, sensory & reflex 
assessments) 
 ability to return to work and normal activity, and 
 any procedure related or device related complications since 
discharge from the hospital  
Subject self-assessment: 
 Each subject will be asked to complete a follow-up Neck 
Disability Index (NDI) form, SF-36 form and a Neck and 
Shoulder/Arm Pain VAS and Hip Pain VAS form at each follow-
up visit. 
Radiographic assessment: Each subject will undergo AP and lateral x-rays 
at the 3, 6, 12 and 24 month visits and flexion and extension x-rays at the 
6, 12, and 24 visits as well as a CT scan at the 12 month visit to assess: 
 Evidence of progression towards fusion 
 Presence / absence of heterotopic bone at the fusion site or at 
the adjacent vertebral levels 
 Evidence of plate and/or spacer migration or subsidence  
 Evidence of adjacent level ossification 
All x-ray and CT images collected during the follow-up visits will be 
transferred electronically via an internet connection to the independent 
imaging vendor.  
 
 

 
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4.5 
Independent Radiographic Assessment 
An independent radiographic analysis will be performed to evaluate all 
images and assess subjects’ radiographic status. The following 
quantitative and qualitative assessments will be performed.  
Fusion Determination 
Fusion will be assessed by an independent radiologist using the subjects’ 
12 month visit x-ray and CT images.  All x-ray and CT images will be 
transferred electronically via an internet connection to the independent 
imaging vendor. The subjects’ 12 month CT images will be evaluated by 
an independent radiologist to determine fusion. In addition, the subjects’ 
12 month x-rays will be evaluated for fusion determination using the 
Bridwell anterior fusion grading system5,6.  The Bridwell grading system is 
as follows:   
 Grade I (definite) – Fused with remodeling and trabeculae 
 Grade II (probable) – Graft intact, not fully remodeled and 
incorporated through, no lucencies 
 Grade III (probably not) – Graft intact, but a definite lucency at the 
top or bottom of the graft 
 Grade IV (no) – Definitely not fused, with resorption of bone graft or 
collapse 
 
Radiographic Success: Radiographic success is defined as Grades I or II. 
Radiographic Failure: Radiographic failure is defined as Grades III or IV. 
 
The subjects’ x-ray images from the 3, 6, and 24 month follow-up visits 
may also be assessed for fusion by an independent radiologist using the 
Bridwell grading system. 
 
4.6 
Success Criteria 
4.6.1 Primary Measure of Effectiveness  
The primary measure of effectiveness will be assessed by the 
improvement in the Neck Disability Index (NDI) score at 12 months. 
Subjects treated with Cellentra will be considered a success if they show a 
clinically meaningful improvement in NDI score (from baseline to 12 
months) of 8 or more NDI points. 

 
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 BIOMET                                                                                          Page 15 of 27 
 
4.6.2 Primary Measure of Safety 
The primary measure of safety will be determined by the percentage of 
adverse events as compared to published literature for cervical plate 
systems and allograft spacers with autograft or allograft. 
4.6.3 Secondary Measure of Effectiveness 
The secondary measure of effectiveness will be determined by fusion. A 
subject will be considered a success if fusion as assessed by an 
independent radiologist is a Grade I or Grade II at 12 months. 
 
4.7 
Subject Withdrawal 
It is recognized that the subject’s participation in this trial is entirely 
voluntary, and that she/he may refuse to participate and may withdraw 
from participation at any time without jeopardy to any future medical care.  
It is also recognized that the surgeon, at his/her discretion, may withdraw 
a subject from this study based upon his/her professional judgment.  If the 
subject is withdrawn for any reason at any time a final evaluation form will 
be completed. 
 
Other Conditions for Withdrawal: 
 
Any subject who develops a severe concurrent medical illness during the 
study should be withdrawn.  This type of illness is defined as any illness 
that would hinder the subject’s ability to return for scheduled follow-up 
appointments.  Such a withdrawal will not be counted for the purposes of 
determining success or failure. 
 
5 
Complications 
 
In addition to the standard operating procedures for reporting 
complications per hospital/physician protocol, all clinical events, including 
both observed or volunteered problems, complaints, symptoms, physical 
signs or disease which either occur during the study, having been absent 
at baseline, or, if present at baseline, appear to worsen during the clinical 
outcomes collection study are to be recorded as complications in the 
subject’s medical record and on the appropriate case report form.  In 
addition for any cleared device, or tissue product a Product Experience 

 
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 BIOMET                                                                                          Page 16 of 27 
 
Report (PER) must be completed per the manufacturer’s customary 
complaint procedure (SOP 114.0.1 – Product Complaint Procedure). 
 
Complications reported in the literature as most commonly associated with 
ACDF procedures include, but are not limited to, dysphagia, soft tissue or 
wound  hematoma, recurrent laryngeal nerve palsy, cerebrospinal fluid 
leakage secondary to dural tear, esophageal or pharyngeal perforation,  
Horner’s syndrome, vascular injury, mechanical failure of cervical 
instrumentation, and extrusion of bone graft material.7   
 
 
Definition 
 
A complication is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, 
safety, effectiveness, performance, or any indication of the failure of a 
device or tissue product to meet a user or customer’s expectations. The 
complaint may be the possible failure of a device, labeling, or packaging to 
meet any of its specifications after it is released for distribution. 
 
6 
Statistical Analysis Plan  
 
6.1 
Primary Objective and Sample Size Justification 
The primary objective of this study is to show subjects who are treated 
with Cellentra have a clinically meaningful NDI improvement (from 
baseline to 12 months) of 8 or more NDI points. The secondary objective 
is to compare the results to published NDI changes in similar populations 
treated with standard of care bone grafts (autograft and allograft).  
 
For subjects who have undergone an ACDF procedure, the minimal 
clinically important difference (MCID) in the change of NDI was 
determined to be 8 points8,9. In published literature, the reported 
improvement in NDI from baseline to 12 months was found to be similar 
between subjects who had an ACDF procedure performed with autograft 
and allograft. The average improvement in NDI ranged from 7 to 20 points 
(on an NDI scale from 0-50 points) 8, 10-14. For the purposes of this sample 
size calculation an average 12 month NDI improvement of 14 points (SD: 
12) was chosen, as Cellentra is expected to perform similarly to the 
standard of care.  
 

 
CONFIDENTIAL  
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Sample sizes were calculated to determine if subjects treated with 
Cellentra have clinically relevant improvements of at least 8 NDI points, 
and to compare Cellentra to published NDI changes under the standard of 
care (ACDF with allograft or autograft).  As published studies have 
typically shown that subjects have an average of 14 points NDI 
improvement, we have assumed a non-inferiority margin of 6 NDI points 
such that changes in NDI score using Cellentra are no more than 6 NDI 
points smaller than the typical change of 14 using standard of care.  Note 
that this margin is smaller than the MCID of 8 points. 
 
Sample sizes were calculated assuming a 5% two-sided type 1 error rate 
and 97.5% power for a 1 sample t test. The Cellentra group will result in 
clinically relevant improvements in NDI if the lower bound of the 95% 
confidence interval does not overlap 8.  Assuming a standard deviation of 
12, this will be achieved if the mean NDI improvement is 11 points.  
Secondarily, this would provide some evidence that Cellentra results in 
NDI changes no less than 6 NDI points lower than the standard of care 
treatments, which result in an average change of 14 points.  However, this 
claim must be made carefully, as different populations may experience 
different changes in NDI.  Again, assuming a standard deviation of 12, if 
the lower bound of the 95% confidence interval overlaps 8, NDI changes 
of 14 or greater with Cellentra can be ruled out, suggesting that the 
standard of care may outperform Cellentra.   
 
Definitions: 
 
μ1: the mean value of the ΔNDI12 in the study group (Cellentra) 
μ0:  Clinically relevant change in NDI.  The lower 95% confidence bound 
for ΔNDI of subjects at 12 months must be greater than μ0. 
 
The primary hypothesis is given by: 
 
H0: μ1 ≤ μ0   versus   H1: μ1 > μ0  
 
Assumptions: 
α = 0.05 
 
Probability of Type I error 
β = 0.025 
 
Probability of Type II error:  power = 1 – β 
μ1 = 14 
 
Estimated ΔNDI from baseline to 12 months 
μ0 = 8   
 
Clinically Relevant Improvement 
 

 
CONFIDENTIAL  
 BIOMET                                                                                          Page 18 of 27 
 
Sample sizes were calculated in R version 3.1.0.    
 
In order to rule out NDI changes of less than 8 points, 64 subjects are 
required (5% type I error rate, 97.5% power).  The sample size was 
increased by 25% to allow for possible attrition.  This gives a sample size 
of 80 total Cellentra study subjects.   
 
6.2 
Inferential Methods 
6.2.1 Significance Levels 
Statistical tests will be performed using a 2-sided α = 0.05 to compare 
changes in NDI.   
6.2.2 Models for Continuous Measures 
Continuous measures will be summarized using standard summary 
statistics (mean, standard deviation, and range).  Changes in NDI will be 
evaluated using a 1 sample t-test.  Secondary analyses may include 
multiple linear regression models in order to adjust for important 
covariates (such as age, sex, BMI, tobacco use, etc.).   
6.2.3 Categorical Data Analyses 
Categorical measures will be summarized using standard summary 
statistics (frequency and percentage of total).  
 
7 
Ethical and Regulatory Requirements 
 
7.1 
Code of Conduct 
The Investigator will ensure that the clinical study is conducted in 
accordance with good clinical practice (GCP) and all regulatory and 
institutional requirements, including those for subject privacy, informed 
consent, Independent Ethics Committee (IEC)/Institutional Review Board 
(IRB) approval and record retention, the Food and Drug Administration 
(FDA) 
Guidelines 
for 
the 
conduct 
of 
clinical 
trials, 
and 
the 
CPMP/ICH/135/95. 
 
7.2  Reports 
Clinical investigators must make the following required reports: 

 
CONFIDENTIAL  
 BIOMET                                                                                          Page 19 of 27 
 
 Unanticipated Adverse Device Effects   
 Withdrawal of IRB Approval  
 Yearly report to Sponsor/IRB 
 Other reports requested by a reviewing IRB or FDA  
 
7.3 
Institutional Review Boards (IRB) 
The Investigator must obtain appropriate Institutional Review Board (IRB) 
or Independent Ethics Committee (IEC) approval before the study can be 
initiated. A copy of the written approval from the IEC/IRB and a copy of the 
approved informed consent form should be sent to the Sponsor. A list of 
the IEC/IRB members (including their Institution affiliations, gender 
makeup, and occupations); or a statement from the IEC/IRB specifying 
that the membership comply with applicable regulations is to be provided 
to the sponsor. 
 
If the Investigator advertises for subjects, whether in a professional or 
consumer publication, radio, television or community notices, all 
advertising must receive prior approval by the Sponsor and the IEC/IRB. 
 
Any changes to the protocol must be discussed and approved by the 
Sponsor in writing unless the change is made to assure the safety of the 
subject.  In the non-emergent setting, after agreement on the changes has 
been reached, an amendment to the protocol will be provided by the 
Sponsor for submission to the IEC/IRB for review and approval prior to 
initiation of the change.  Any change made emergently must be 
documented in the subject's medical record. 
 
The Investigator must immediately forward to the IEC/IRB any written 
safety reports or updates from the Sponsor. 
 
The Investigator must keep the IEC/IRB informed of the progress of the 
study at least annually. 
 
7.4 
Informed Consent 
The Investigator must observe the requirements of the appropriate 
regulatory body by obtaining written informed consent. The Sponsor will 
supply a sample informed consent form.  Whether or not the sample 

 
CONFIDENTIAL  
 BIOMET                                                                                          Page 20 of 27 
 
informed consent form is used or adapted, the site will submit the 
proposed informed consent form to the Sponsor for review PRIOR to 
submission to the IEC/IRB. The informed consent form must be approved 
by the institution’s designated IEC/IRB. Copies of the informed consent 
form used in the study must contain the IEC/IRB-approval stamp (if 
applicable) and version date.  
 
Subjects will be informed of new information learned during the study, 
which may affect the subject’s decision to continue participation in the 
study. 
 
The study informed consent form must be obtained prior to the initiation of 
any study procedures. The subject (or the subject's legally authorized 
representative) must be allowed sufficient time to thoroughly read (or have 
explained to them), the informed consent form.  The Investigator should 
answer any questions that the subject/representative might have. If the 
subject agrees to participate in the study, the subject must sign the 
informed consent form. The Investigator or a representative for the 
investigator, who is obtaining informed consent, must also sign the 
informed consent form. A copy of the signed consent form will be given to 
the subject and the original signed form will be retained in the patient’s 
subject binder. The study staff should adequately and accurately 
document the sequence of actions in the consenting process as well as 
the date of the subject’s signature on the informed consent form in the 
subject’s medical chart to document that informed consent was obtained 
prior to initiating any study procedures. 
 
Signed informed consent forms (or copies) are to be maintained in the 
study file and must be available for verification by monitors or inspectors. 
 
7.5  Source Documentation Requirements 
Source documentation for this study will be maintained to document the 
treatment and study course of a subject and to substantiate the integrity of 
the trial data submitted for review and analysis. Source documentation will 
include, but not be limited to, signed and dated consent form, worksheets, 
hospital and/or clinic or office records documenting subject visits including 
study and other treatments or procedures, medical history and physical 
examination information, laboratory and special assessments results, 
pharmacy records, device accountability records, pregnancy tests and 
medical consultations (as applicable). 

 
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 BIOMET                                                                                          Page 21 of 27 
 
 
7.6 
Subject Confidentiality 
The Sponsor will maintain the confidentiality of the identity of all subjects 
enrolled in the study and the information contained in their records.  The 
Sponsor will also instruct the study investigators in the importance of 
maintaining the confidentiality of study records.  The subject records will 
be made available as required for review by governing regulatory 
agencies such as FDA and a reviewing IEC/IRB, however to every extent 
possible; the subject’s identities will not be disclosed. 
 
Compliance with the Health Insurance Portability and Accountability Act of 
1996 (HIPAA) is required and data collection must comply with the 
Standards for Privacy of Individually Identifiable Health Information, 45 
CFR Part 160 and Part 164, as amended from time to time (the “Privacy 
Rule”), under HIPAA. 
The case report forms do not include any subject identifying information in 
accordance with HIPAA.  Therefore, once the data is entered in the online 
database a subject can no longer be identified.  It is the responsibility of 
the investigator to maintain a list of subject identification and study ID 
numbers. 
By assigning subjects a unique study ID number, their identity is protected 
in OpenClinica, an online database.  The database is restricted, allowing a 
physician and his/her research associate to view and enter data from their 
enrolled subjects.  User authentication is required to view research data.  
The data is transmitted to a centralized database through a secured (SSL) 
channel on the Internet.  Data in transit is in 128-bit encryption.  The 
access to the centralized database is limited to those who are responsible 
for maintaining the database.   
7.7 
Retention of Records by the Investigator 
The Investigator will retain records for a period of 2 years following the 
date of study conclusion. 
 

 
CONFIDENTIAL  
 BIOMET                                                                                          Page 22 of 27 
 
7.8 
Data Reporting 
7.8.1 Case Report Forms 
Data for this clinical trial will be collected and documented on the patient 
Case Report Forms (CRFs) provided which may be in paper form or in an 
electronic form. Authorized study site personnel will complete CRFs only.  
 
Since there is a potential for errors, inaccuracies, and misinterpretation in 
transcribing data onto the CRFs, originals or photocopies of all relevant 
records and reports, and copies of test results must be available at all 
times for inspection and comparison to the CRFs by the study monitor. 
7.8.2 Final Report 
Following completion of this trial, final reports will be issued as required. 
 
7.9 
Monitoring  
The Investigator must allow regular inspection of all study records 
including CRFs, source documents and regulatory documents during the 
study by the monitor or a representative of the Sponsor.  This measure is 
to ensure that the study is carried out and documented in accordance with 
the terms of this protocol, GCPs, ICH, IRB and if applicable federal 
regulations.  The Investigator also agrees to allow inspections by 
members of any regulatory agencies at any point, if such inspections are 
requested. 
 
In cooperation with the on-site staff, monitors will: 
 Review all study documentation to ensure compliance with the 
protocol. 
 Review data recording for each visit to verify the accuracy and 
completeness of the information on the CRFs against appropriate 
source documents. 
 Review adequacy of enrollment rate. 
 Review required regulatory documentation. 
 
Biomet will monitor at least 20% of the sites during the course of the 
study.  If inconsistencies in the data are found, an increased percent of 
monitoring will be performed. 

 
CONFIDENTIAL  
 BIOMET                                                                                          Page 23 of 27 
 
7.9.1 Data Quality Assurance 
Standardized subject case report forms will be provided for use at all 
Investigational Sites.  The Investigator is responsible for completion and 
timely submission of the forms to the study Sponsor for data processing. 
Data will be collected on all subjects pre-operatively, intra-operatively and 
postoperatively at 3, 6, 12 and 24 months. Electronic data entry will be 
employed via an Internet connection when possible, using our Electronic 
Data Capture (EDC) system OpenClinica.  Access to the EDC program is 
limited to the physician or research associate.  All users will be given a 
unique user name and password and will be assigned a specific role.  The 
role determines the level of access granted to each user.  Study monitors 
will have access to subject numbers only; any subject identifying 
information will be blocked.  In the event the site does not have Internet 
access, data will be recorded on paper Case Report Forms (CRFs).   
Incoming data are reviewed to identify inconsistent or missing data and 
complications.  Data inconsistencies will be addressed through telephone 
calls, faxes, or emails to the Investigational Sites and during site visits.  All 
hard copy forms and data files will be secured to ensure confidentiality. 
7.9.2 Screened Subjects who are not enrolled 
Only data for enrolled subjects will be monitored and entered into the 
database.  Subjects who are screened for the study but are not enrolled 
for any reason will not be followed and the Sponsor will not evaluate their 
data.  The sites may retain the screening case report forms for these 
subjects, at their discretion. 

 
CONFIDENTIAL  
 BIOMET                                                                                          Page 24 of 27 
 
8 
References 
 
1. Gore DR, Sepic SB. Anterior cervical fusion for degenerated or protruded 
discs. A review of one hundred forty-six patients. Spine 1984 Oct; 9 (7): 
667 – 71. 
 
2. Palit M, Schofferman J, Goldthwaite N , et al. Anterior discectomy and 
fusion for the management of neck pain . Spine 1999 Nov 1; 24 (21): 2224 
– 8. 
 
3. McConnell JR, Freeman BJ, Debnath UK, et al. A prospective randomized 
comparison of coralline hydroxyapatite with autograft in cervical interbody 
fusion. Spine 2003 Feb 15; 28 (4): 317 – 23. 
 
4. Samartzis D, Shen FH, Goldberg EJ, et al. Is autograft the gold standard 
in achieving radiographic fusion in one-level anterior cervical discectomy 
and fusion with rigid anterior plate fixation? Spine 2005 Aug 1; 30 (15): 
1756 – 61. 
5. Bridwell KH, Lenke LG, McEnery KW, et al. Anterior fresh frozen structural 
allografts in the thoracic and lumbar spine. Do they work if combined with 
posterior fusion and instrumentation in adult patients with kyphosis or 
anterior column defects? Spine 1995; 20(12): 1410–1418. 
6. Söderlund CH1, Pointillart V, Pedram M et al.: Radiolucent cage for 
cervical vertebral reconstruction: a prospective study of 17 cases with 2-
year minimum follow-up. European Spine Journal 2004; 13(8): 685-690. 
7. Fountas KN, Kapsalaki EZ, Nikolakakos LG, Smisson HF, Johnston KW, 
Grigorian AA, Lee GP, Robinson JS Jr. Anterior cervical discectomy and 
fusion associated complications. Spine 2007 Oct 1; 32 (21):2310-7. 
Review.  
 
8. Carreon LY, Glassman SD, Campbell MJ, Anderson PA, Neck Disability 
Index, short form-36 physical component summary, and pain scales for 
neck and arm pain: the minimum clinically important difference and 
substantial clinical benefit after cervical spine fusion. Spine 2010 June; 10 
(6): 469-474 
 

 
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9. Young BA, Walker MJ, Strunce JB, Boyles RE, Whitman JM, Childs JD, 
Responsiveness of the Neck Disability Index in patients with mechanical 
neck disorders. The Spine Journal 2009 Oct; 9 (10): 802-808 
 
10. Coric D, Nunley PD, Guyer RD, Musante D, Carmody CN, Gordon CR, 
Lauryssen C, Ohnmeiss DD, Boltes MO, Prospective, randomized, 
multicenter study of cervical arthroplasty: 269 patients from the Kineflex|C 
artificial disc investigational device exemption study with a minimum 2-
year follow-up: clinical article. Journal of Neurosurgery: Spine 2011 Oct; 
15 (4): 348-358. 
 
11. Davis RJ, Kim KD, Hisey MS, Hoffman GA, Bae HW, Gaede SE, 
Rashbaum RF, Nunley PD, Peterson DL, Stokes JK, Cervical total disc 
replacement with the Mobi-C cervical artificial disc compared with anterior 
discectomy and fusion for treatment of 2-level symptomatic degenerative 
disc disease: a prospective, randomized, controlled multicenter clinical 
trial: clinical article. Journal of Neurosurgery: Spine 2013 Nov; 19 (5): 532-
545. 
 
12. Löfgren H, Engquist M, Hoffmann P, Sigstedt B, Vavruch L, Clinical and 
radiological evaluation of Trabecular Metal and the Smith-Robinson 
technique in anterior cervical fusion for degenerative disease: a 
prospective, randomized, controlled study with 2-year follow-up. European 
Spine Journal 2010 Mar; 19 (3): 464-473. 
 
13. Miller LE, Block JE, Safety and effectiveness of bone allografts in anterior 
cervical discectomy and fusion surgery. Spine 2011 Nov. 15; 36 (24): 
2045-2050. 
 
14. Mummaneni PV, Burkus JK, Haid RW, Traynelis VC, Zdeblick TA, Clinical 
and radiographic analysis of cervical disc arthroplasty compared with 
allograft fusion: a randomized controlled clinical trial. Journal of 
Neurosurgery: Spine 2007 Mar; 6 (3): 198-209. 
 
 
 
 

 
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APPENDIX 1 
 
 
 
Case Report Forms (CRFs) 

 
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CLINICAL PROTOCOL CHANGE HISTORY 
From 
Version 
To 
Version 
New Version 
Date 
Change 
Page 
No. 
Description of Changes 
CS-092-
01 
CS-092-
02 
5-15-2014 
1-3, 5, 
11-25 
Updated randomization process. Amended radiographic assessments 
to be performed by physicians and the independent radiologist. Added 
requirement for sites to send radiographic images to an independent 
imaging vendor instead of Biomet. Updated EDC system to 
OpenClinica. Aligned protocol to match updated CRF requirements. 
Corrected grammatical errors and adjusted formatting.  
CS-092-
02 
CS-092-
03 
8-15-2014 
All 
Revised study design to a prospective single-arm multi-center study of 
Cellentra and MaxAn in ACDF procedures.