A Multicenter, Prospective, Randomized, Subject and Evaluator Blinded Comparative Study of Nerve Cuffs and Avance® Nerve Graft Evaluating Recovery Outcomes for the Repair of Nerve Discontinuities
Phase: PHASE3
Conditions: Peripheral Nerve Discontinuities
Sponsor: Axogen Corporation



Protocol No. ANG-CP-007 
 
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Table of Contents 
 
1 
Introduction ............................................................................................................................. 7 
1.1 
Background ...................................................................................................................... 8 
1.2 
Product Description ........................................................................................................ 11 
1.3 
Comparator Product Description .................................................................................... 11 
1.4 
Risk Analysis .................................................................................................................. 12 
2 
Study Objectives .................................................................................................................... 15 
2.1 
Primary Objective .......................................................................................................... 15 
2.2 
Secondary Objectives ..................................................................................................... 15 
3 
Study Design.......................................................................................................................... 15 
3.1 
Description of Design ..................................................................................................... 15 
3.2 
Study Treatment ............................................................................................................. 16 
3.3 
Study Population ............................................................................................................ 16 
3.4 
Eligibility Criteria .......................................................................................................... 17 
3.5 
Endpoints ........................................................................................................................ 19 
3.6 
Measures to Minimize/Avoid Bias ................................................................................. 22 
3.7 
Randomization ............................................................................................................... 23 
3.8 
Study Procedures ............................................................................................................ 25 
3.9 
 
3.10 
Sensory Re-education ................................................................................................. 27 
3.11 
Subject/Study Discontinuation ................................................................................... 28 
4 
Adverse Events ...................................................................................................................... 29 
4.1 
Procedures for Eliciting Reports and Reporting of Adverse Events .............................. 29 
4.2 
Adverse Event Specific Definitions ............................................................................... 30 
4.3 
Review of safety information ......................................................................................... 30 
4.4 
Adverse Event ................................................................................................................ 31 
4.5 
Serious Adverse Event ................................................................................................... 33 
4.6 
IND Safety Reports ........................................................................................................ 34 
5 
Statistical Considerations ...................................................................................................... 35 
5.1 
Data Collection Methods ................................................................................................ 36 
5.2 
Statistical Analysis Plans ............................................................................................... 36 
5.3 
Hypotheses Tested .......................................................................................................... 36 
5.4 
Sample Size Estimates ................................................................................................... 36 

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5.5 
Analysis Populations ...................................................................................................... 37 
5.6 
Planned Analyses ........................................................................................................... 37 
5.7 
General Issues for Statistical Analysis ........................................................................... 37 
5.8 
Efficacy Analyses ........................................................................................................... 39 
5.9 
Safety Analyses .............................................................................................................. 40 
5.10 
Study Success ............................................................................................................. 40 
6 
Study Product Management................................................................................................... 41 
6.1 
Packaging and Labeling ................................................................................................. 41 
6.2 
Handling, Storage, and Disposal .................................................................................... 41 
7 
Records Management ............................................................................................................ 41 
7.1 
Data Collection ............................................................................................................... 41 
7.2 
Source Documents.......................................................................................................... 41 
7.3 
File Management at the Study Site ................................................................................ 42 
7.4 
Records Retention at the Study Site ............................................................................... 42 
8 
Quality Control and Quality Assurance................................................................................. 42 
8.1 
Data Management Considerations ................................................................................. 42 
8.2 
Monitoring ...................................................................................................................... 42 
8.3 
Auditing .......................................................................................................................... 42 
9 
Ethics and Responsibility ...................................................................................................... 43 
10 
Clinical Study Report ......................................................................................................... 43 
11 
Confidentiality ................................................................................................................... 43 
12 
Regulatory Considerations ................................................................................................. 44 
12.1 
Amendments ............................................................................................................... 44 
12.2 
Protocol Deviations .................................................................................................... 44 
12.3 
Sponsor and Investigator Responsibilities .................................................................. 44 
13 
References .......................................................................................................................... 45 
14 
Appendix 1 – Investigator Agreement ............................................................................... 48 
15 
Appendix 2 : Schedule of Assessments ............................................................................. 49 
16 
Appendix 3 - Instructions for Use: Avance® Nerve Graft ................................................ 50 
17 
Appendix 4-  Example 
 
 (Type I Bovine Collagen Nerve Cuff) . 57 
 
 
 

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1 
 Introduction 
 
Avance® Nerve Graft is a decellularized, predegenerated and sterilized extracellular matrix (ECM) 
processed from donated human peripheral nerve tissue (see Figure 1-1). The structure is the ECM of 
native peripheral nerve and is comprised of bundles of small diameter endoneurial tubes (as shown in 
Figure 1-2).  The tissue is processed to remove cellular and non-cellular factors such as Schwann cells, 
fat, blood, axonal debris and chondroitin sulfate proteoglycans (CSPG), while preserving the three-
dimensional scaffold, vascular structure, basal lamina laminin, fibronectin, and glycosmainoglycans. 
 
 
 
Figure 1-1 
Avance® Nerve Graft 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1-2 
Scanning Electron Micrographs (SEMs) of the Avance® Nerve Graft showing the general overall tubular 
structure (scale bar=429um) and a close up view of the multiple empty tubes within the structure (scale 
bar=20um). 
 
 
Avance® Nerve Graft is intended to reconstruct and repair peripheral nerve discontinues; and support 
axonal regeneration of peripheral nerves following transection injury.  Processing results in a flexible, 
pliable, open multi-tubular ECM structure that can be sutured in place and allows for a tension free 
approximation of the proximal and distal nerve stumps (see Figure 1-2).  The graft revascularizes and 
remodels into the patients’ own tissue while supporting axonal growth across the nerve discontinuity.  
The resulting axonal growth can lead to functional recovery of the target organ.  Furthermore, because 
Avance® Nerve Graft is decellularized, it does not require immunosuppressive therapy, which had 
previously limited the clinical use of cellular nerve allografts [1-4]. 
 

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Currently, repair options for peripheral nerve discontinuities, when direct tension-free gap closure is not 
possible, include the nerve autograft and nerve cuff.  While the use of the nerve autograft is considered 
the historical standard for gap repair, it in itself presents challenges to the surgeon and patient including: 
additional surgery and the risks associated with it, donor site morbidity and limited tissue availability (e.g. 
during a large traumatic nerve injury), as well as, increased operative time and cost associated with tissue 
harvest.  The nerve cuff (Medical Device Product Code JXI) was made available in the 1990’s as an 
alternative to sacrificing healthy nerve.  While the nerve cuff has been used as an alternative nerve repair 
option, its mono-tubular structure and rigidity limit its use for repairs with branching nerves or across 
joints in the digits where early mobilization was prescribed due to concomitant tendon repairs.  The 
flexible, pliable, multi-tubular structure of the Avance® Nerve Graft overcomes these limitations to 
provide the surgeon with an additional treatment option. 
 
This study will evaluate the difference in functional recovery outcomes between the study groups to 
assess the non-inferiority and superiority of the Avance® Nerve Graft to nerve cuffs 
 
 a Type I Bovine Collagen nerve cuff). 
 
1.1 
Background 
 
Peripheral Nerve Discontinuities 
 
In normal nerve anatomy, nerve cell bodies are located in or near the spinal cord.  The nerve 
processes or fibers (called axons) extend from the cell bodies and travel down little tubes (endoneurial 
tubes or basal lamina) in the nerve trunks and in the peripheral nerves, until they make contact with 
the appropriate end organ, such as muscle or skin.  A signal generated in the brain travels down the 
spinal cord, into the axons, then to the muscle where it is converted into a muscle contraction, which 
results in arm motion.  After a nerve is transected, many of the nerve cell bodies in and around the 
spinal column die just from the devastating shock of the injury.  All nerve fibers in the distal (or 
downstream) nerve stump, that are now separated from their cell bodies, die and are quickly broken 
down by the body in a process called Wallerian Degeneration.  Almost immediately after a nerve 
transection, all sensory and motor function directed by that injured nerve is lost.  These types of 
injuries can severely impact patients in many different ways.  For example, a nerve laceration in the 
hand may result in loss of movement or sensation in the fingers.  In prostate cancer, the necessary 
removal of the prostate and associated cavernous nerves can result in erectile dysfunction and/or 
incontinence and injuries to the facial nerve can result in the patient losing the ability to smile. 
 
 
Transected axons almost immediately start the regeneration process by sending out exploratory 
branches, however, these branches can only find their way into the distal nerve stump if an adequate 
surgical repair has been performed.  Many nerve lacerations can be primarily repaired by suturing the 
cut ends together.  Other times, either due to nerve tissue loss or nerve end retraction, a bridging 
material is required to connect the two ends [1].  This bridging material must be able to support 
regenerating axons.  Recovery is not possible if the nerve is left unrepaired or if the method or 
material used to reconstruct the nerve discontinuities fails to support axonal regeneration across the 
nerve discontinuity [1,5,6].  
 
Adequate repair of the nerve discontinuity is not the sole factor in ensuring the return of function.  
Patient demographics, general health of the patient, age of injury, location of injury, mechanism of 
injury, extent of trauma to surrounding and target tissue, patient compliance with rehabilitation 
regimen, and brain plasticity, all play a role in the clinical outcome. 

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Current Treatment Options 
 
As stated previously, when possible, a direct tension free nerve repair is the ideal repair method.  
When an insurmountable gap exists, the separated nerve ends must be bridged using a biological or 
artificial material [1, 2, 7].  Currently, there are several “bridging” options including autograft nerve, 
Avance® Nerve Graft, and nerve cuffs (tubes).  Unfortunately, use of autograft nerve tissue requires a 
secondary surgical procedure, which increases anesthesia time and facility cost, and sacrifices a 
healthy functioning nerve.  This not only leads to functional (usually sensory) loss and scarring, but 
can also result in painful neuroma formation or other complications such as infection [1, 2, 5, 8-10].  The 
paucity of “expendable” nerves within the human body results in a limited supply of autograft and 
may necessitate size mismatching between donor and native nerve. 
 
Spurred by many of the disadvantages of nerve autograft, nerve cuffs, first introduced in the 1990’s, 
have seen a steady increase in popularity and, currently, multiple nerve cuffs are available for 
commercial use. Hollow tubes made from collagen or synthetic materials are designed to entubulate 
the proximal and distal ends of the transected nerve.  A fibrin clot forms between the two nerve ends 
and is contained within the nerve tube.  Axons can regenerate within this fibrin clot and cross the gap 
to the distal nerve stump.  Single lumen nerve cuffs, however, have a limited effective length and 
undesirable handling characteristics, which limits their clinical application and acceptance. 
 
Modern usage of viable, cellular nerve allograft was developed by Susan Mackinnon, M.D., in the 
1990s.  The results of her work were published in 2001 and detailed the outcomes of seven patients 
[4].  While the results of this study showed promise, cellular nerve allografting as a strategy for nerve 
reconstruction is hampered by the need for donor matched tissue and prolonged immunosuppression.  
Cellular nerve allograft remains commercially unavailable. 
 
A more recent addition to the armamentarium of the nerve surgeon, processed acellular nerve 
allograft, does not require the immunosuppressive therapies associated with cellular nerve allografts.  
Avance® Nerve Graft was introduced as a 361 Tissue for Transplantation in 2007 and was the first 
commercially available decellularized nerve allograft product.  Since that release date, Axogen has 
distributed over 7,000 grafts.  Avance® Nerve Graft has been utilized in the reconstruction of 
traumatic and iatrogenic peripheral nerve transection injuries in the upper and lower extremities, head 
and neck, chest and pelvis.  Mechanisms of injury have included, but are not limited to, laceration, 
blunt trauma, amputation, avulsion, gunshot wound, shrapnel, improvised explosive product (IED) 
blast trauma, neuroma resection, chemical burns, and oncologic resection. 
 
Clinical Outcomes with Nerve Cuffs 
 
Currently, there are very few controlled outcomes studies that compare the different peripheral nerve 
repair options [11].  Inherent challenges associated with this type of data collection include the 
heterogeneous nature of traumatic injuries, of which include varying degrees of nerve damage and 
concomitant injuries [12].  Conclusive comparative clinical efficacy evaluations require standardized, 
homogeneous samples [13].  
 
Nerve cuffs, are regulated as class II medical devices under 510(k) exemption and are defined in the 
code of federal regulations (CFR) at 21 §CFR 882.5275 as “a tubular silicone rubber sheath used to 
encase a nerve for aid in repairing the nerve (e.g., to prevent in growth of scar tissue) and for capping 
the end of the nerve to prevent the formation of neuroma (tumors)”.  Since they are regulated as 

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segmental defects, in that in order for function recovery to occur, the repair treatment must allow for 
regenerating axons to cross the discontinuity and enter the distal nerve sheath.  The endpoint 
measures are well defined and can consistently be measured from subject to subject. Also, the 
endpoints allow for treatment efficacy to be reviewed within 12 months from repair, given that nerves 
regenerate at a rate of 1-2 mm per day. Additionally, the frequency of digital nerve injuries is such 
that it allows for enrollment of comparable injuries within a reasonable time period. Other repair 
models may report varying degrees of function recovery while utilizing different outcome 
assessments, as not all nerve types have homogenous outcomes, for instance, the repair of a mixed 
nerve will yield both sensory and motor outcomes. 
 
1.2 
Product Description 
 
Avance® Nerve Graft is a decellularized, cleansed, and sterilized extracellular matrix from donated 
human peripheral nerve.  The cleansing process preserves the inherent and relevant structural 
characteristics of the tissue. 
 
Avance® Nerve Graft is intended to be used to repair nerve discontinuities anywhere in the body at 
lengths of up to 70mm.  It has a flexible, pliable, multi-tubular ECM structure (See Figures 1-1, and 
1-2) and handles similarly to nerve autograft allowing for versatile utilization including repairs across 
joints and shallow would beds; a limitation seen with the use of nerve cuffs[14, 15, 18].  These 
advantages provide the surgeon with a clinically beneficial off-the-shelf nerve graft option that avoids 
the disadvantages of autograft harvest or nerve cuff limitations. 
 
 
Avance® Nerve Graft is provided frozen and sterile.  After thawing the graft, implantation should be 
completed using the same tensionless surgical technique used when implanting a nerve autograft. The 
graft is positioned within the nerve gap and coapted to the proximal and distal stumps of the host 
nerve.  See Figure 1.2-1. 
 
 
Images Courtesy of Mayo Clinic Foundation 
 
Figure 1.2-1 
In-situ placement of the Avance® Nerve Graft.  A. Surgeon will trim the graft to length dependent 
upon discontinuity.  B. Avance® Nerve Graft after implantation for two individual nerve injuries. 
 
1.3 
Comparator Product Description 
 
Regulated as Class II medical devices via FDA 510k clearance, absorbable nerve cuffs are marketed 
under numerous brand names (NeuroTube®, NeuroLac®, NeuraGen®, NeuroMatrix™, NeuroFlex™).  
Nerve cuffs, which are constructed from absorbable or non-absorbable polymers or processed 

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collagen, are molded or extruded to form a hollow tube structure that encases the proximal and distal 
ends of the injured nerve.  For the purpose of this clinical study, 
 
 a Type I 
bovine collagen nerve cuff, will be utilized as the control treatment.  Implantation is to be done 
according to the manufacturer’s instructions (Appendix 4.0).   
1.4 
Risk Analysis 
 
Inherent risks of any surgical procedure include: infection, blood loss, and anesthesia-associated 
complications.  Complications specific to nerve reconstruction include pain, decreased or increased 
sensitivity, and impaired motor or sensory function.  As with all peripheral nerve surgeries, there is a 
risk that the nerve may fail to regenerate.   
 
Hypersensitivity, allergic reactions, or other adverse immune responses have not been seen in 
preclinical studies or reported clinically with the use of Avance® Nerve Graft.  Because Avance® 
Nerve Graft is composed of proteins such as collagen and laminin; the potential may exist for such 
reactions.  All adverse outcomes potentially attributed to Avance® Nerve Graft are to be promptly 
reported to Axogen, Inc, in accordance with state and federal regulations. 
 
Avance® Nerve Graft is processed human nerve tissue.  As with all donated human tissue products the 
risk for transmission of communicable disease does exist.  Robust donor screening and selection is 
completed as required by FDA and is in accordance with American Association of Tissue Banks 
(AATB), state, and federal guidelines. Processing controls and terminal sterilization with gamma 
irradiation greatly reduce but cannot totally eliminate the risk of disease transmission.  As disease-
screening methods are limited, there is the potential for certain diseases to not be detected.  The 
following complications of tissue transplantation may occur: 
 
– Transmission of diseases of unknown etiology; 
 
– Transmission of known infectious agents including, but not limited to viruses, bacteria, and 
fungi. 
 
The processing of Avance® Nerve Graft was developed with a robust safety and efficacy profile to 
include extensive preclinical testing, established manufacturing controls, and documented previous 
human clinical experience. 
 
Risks associated with the use of 
 
 include adverse events related to the 
implantation of a foreign body and reactions associated with the xenogeneic protein that is used to 
construct the nerve cuff.  The implantation of a foreign body (such as a nerve cuff) in a non-sterile 
environment may increase the risk of infection.  Inflammation or surgical site reaction has been 
observed with the use of nerve cuffs and can occasionally be severe enough to cause extrusion of the 
cuff through the skin.  Additionally, use of 
 is contraindicated in individuals at risk of 
localized reaction or anaphylaxis due to known or suspected sensitivity to bovine proteins. 
 
1.4.1 Preclinical Testing for Avance® Nerve Graft 
Comprehensive in vitro and in vivo biocompatibility evaluations provide support that Avance® Nerve 
Graft is safe for use in humans.  Additionally, in vivo testing utilizing well established and validated 
animal models has demonstrated efficacy in its intended use to reconstruct and repair peripheral nerve 
discontinues; and support axonal regeneration of peripheral nerves following transection injury.  

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Effective regeneration in this model has been well characterized by both Susan Mackinnon, MD at 
Washington University, St. Louis, MO and David Muir, PhD at the University Of Florida Department 
Of Neuroscience, Gainesville, FL.  Both designed and conducted preclinical efficacy studies and are 
recognized as leaders in peripheral nerve research (summarized in Table 1.4.1-1). 
 
Avance® Nerve Graft has been subjected to well established and accepted test panels for preclinical 
product safety evaluation and has been found to be a non-toxic, non-reactive, non-sensitizing, non-
pyrogenic, non-mutagenic, and non-irritant. 
 
Table 1.4.1-1: In vivo Preclinical Efficacy Study Summary 
Study Description 
Results 
Reconstruction of Rat Sciatic 
Nerve Discontinuity with 
Avance® Processed Allografts 
or Nerve Grafts[19] 
Avance® processed allografts effectively supported regeneration of 
axons across the 10 mm nerve discontinuity and compared favorably 
to isograft.  Functional recovery results correlated with histological 
results.  Processed allografts supported robust axon regeneration 
across the injury that was not statistically different from isograft.  
Nerve regeneration after reconstruction of a 10 mm sciatic nerve 
injury with Avance® processed grafts is comparable to that after 
standard nerve graft repair in its intended use and function as a 
conduit for axon regeneration across a gap.  
Reconstruction of Rat Sciatic 
Nerve Discontinuity by 
Avance® Processed 
Allografts, Collagen Nerve 
Cuffs, or Nerve Grafts[20] 
Avance® processed allografts effectively supported regeneration 
across the nerve injury in both 14 and 28 mm long defects.  Based on 
total fiber counts at midgraft and distal to 14 mm grafts taken 6 
weeks after repair, isograft performed better than processed 
allografts, which performed better than collagen nerve cuffs.  At 12 
weeks after repair, there were no measurable differences in fiber 
count or wet muscle mass ratios between groups.  Fiber counts, fiber 
quality and electrical stimulation data following repair with 28 mm 
grafts demonstrated that isograft performed better than processed 
allografts, which performed better than collagen nerve cuffs.  Wet 
muscle mass, extensor postural thrust testing, and walking track 
analysis demonstrated that nerves repaired with processed allografts 
functioned as well as and were not statistically different than those 
repaired with the NeuraGen® Nerve Guide.  
Evaluation of the Effect of 
Nerve Graft Tissue Source on 
Graft Effectiveness in a Rat 
Tibial Nerve Injury Model[21] 
Regardless of nerve type source (i.e. motor, sensory or mixed nerve), 
Avance processed allografts effectively supported regeneration of 
axons across a 5 mm tibial nerve discontinuity in a rat.  Processed 
allografts support reproducible axon regeneration across the graft 
into the distal nerve based on both total and myelinated axon counts.  
 
 
1.4.2 Manufacturing Controls 
 
Axogen has established procedures for tissue recovery, relevant donor medical record review and 
release to processing criteria that meet FDA requirements as defined in 21 CFR §1271, state 
regulations, and AATB standards.  Furthermore, Axogen utilizes validated processes for the 
handling of raw material components, environmental control, decellularization, and terminal 

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sterilization of the peripheral nerve allograft.  In addition to ongoing monitoring activities for 
product conformity to specifications and sterility, product storage, shelf life and stability have 
been validated in accordance with applicable industry standards. 
 
1.4.3 Previous Clinical Experience 
 
1.4.3.1   General Use 
 
Avance® Nerve Graft is a commercially available product that has been and continues to be 
marketed as a HCT/P tissue product in accordance with 21 CFR §1271 regulations since July 
2007.  Since that release date, Axogen has distributed over 7,000 grafts.  Utilization of Avance® 
Nerve Graft has allowed for the reconstruction of traumatic and iatrogenic peripheral nerve 
transection injuries in the upper and lower extremities, head and neck, chest and pelvis.  Injuries 
have included, but are not limited to, laceration, blunt trauma, amputation, avulsion, gunshot 
wound, shrapnel, improvised explosive product (IED) blast trauma, neuroma resection, chemical 
burns, oncologic resection such as facial nerve reconstruction following resection of parotid gland 
tumor, reconstruction of neurovascular bundle following radical prostatectomy, and reinnervation 
of breast reconstructions following mastectomy. 
 
1.4.3.2  Published Clinical Studies 
 
In 2009, Mayo Clinic published their results regarding the performance of Avance® Nerve Graft [3]. This 
investigator initiated study reported on segmental nerve defects in the hand and digits. Functional 
recovery was evaluated by blinded hand therapist using moving (m2PD) and static (s2PD) two point 
discrimination tests. All subjects recovered near normal two-point discrimination. Avance® Nerve Graft 
was demonstrated to be safe and effective with no reported signs of infection, rejection, or graft extrusion. 
 
Ducic et al reported on outcomes from 54 discreet nerve repairs that were treated with various repair 
techniques [22] .The authors found that Avance® Nerve Graft returned functional improvements similar to 
those of other test groups. No safety concerns were discussed. 
 
 
 
Shanti and Ziccardi reported on a single uncontrolled case of Avance® Nerve Graft for reconstruction of 
the Inferior Alveolar Nerve in the face [23]. Recovery of function was documented. No safety concerns 
were discussed. 
 
The investigators from the Axogen sponsored RANGER® registry have independently reported on their 
experiences with the Avance® Nerve Graft in two separate peer-reviewed publications. 
Brooks et al reported on 132 individual nerve injuries [24]. Twelve sites with 25 surgeons contributed data 
to this registry database. Data was analyzed to determine the safety and functional outcomes from the use 
of Avance® Nerve Graft. Sufficient data for efficacy analysis was reported in 76 injuries (49 sensory, 18 
mixed, and 9 motor nerves). Subgroup analysis demonstrated consistency, with no significant differences 
with regard to recovery outcomes between the groups (P>0.05 Fisher’s Exact Test). No implant related 
adverse experiences were reported. These outcomes were found to compare favorably to the established 
historical controls from the literature for nerve autograft and nerve cuffs. This work was expanded by Cho 
et al who reported on their finding from a subgroup analysis on outcomes, specifically for upper extremity 
nerve repairs with outcomes data from the RANGER® registry database [25]. In this analysis an upper 
extremity specific population was identified within the RANGER® database presenting with 71 nerves 

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Graft or 
 
.  Subjects requiring more than one repair should have all qualifying 
repairs made with the assigned treatment for the subject. 
 
This study will consist of a screening visit, an operative visit, and 5 post-operative follow-up visits at 
1, 3, 6, 9, and 12 months.  This study will be conducted in accordance with the FDA, ICH/GCP 
requirements and regional IRB Regulations (21 CFR Parts 50 and 56, respectively). 
3.2 
Study Treatment 
 
3.2.1   Identification of Products 
 
3.2.1.1 Study Product 
 
Description: Avance® Nerve Graft is processed allograft tissue intended for bridging nerve 
discontinuities.  Avance® Nerve Graft is a decellularized and cleansed extracellular matrix 
from donated human peripheral nerve.  The cleaning process preserves the inherent and 
relevant structural characteristics of the tissue.  It is supplied sterile, in a variety of lengths 
and diameters.  It is for single patient use only.  Approximate graft lengths and diameters are 
listed on the package label.  Avance® nerve Graft is coapted between the proximal and distal 
ends of a transected nerve.  Regenerating axons can grow through the allograft scaffold, into 
the patient’s distal nerve tissue and on toward the target muscle or skin. 
 
Regulatory Classification: Avance® Nerve Graft is a human tissue for transplantation.  It is 
processed and distributed in accordance with FDA requirements for Human Cellular and 
Tissue-based Products (HCT/P) (21 CFR Part 1271), State regulations and the guidelines of 
the AATB.  This graft is to be dispensed only by or on the order of a licensed physician.  See 
Appendix 3 for Instructions for Use. 
3.2.1.2 Control Product 
 
Description: 
 
, a Type I bovine collagen nerve cuff, will serve as the 
control in this study.  These nerve cuffs are composed of purified bovine Type I collagen, 
sourced from bovine tendon.  It is supplied sterile, in a variety of lengths and diameters.  It is 
for single patient use only.  Tube lengths and internal diameters are listed on the package 
label.  The transected nerve ends are placed inside the internal diameter of the tube 
(entubulation) and serve as a containment area for the milieu of fluids that seep from the 
severed ends. 
 
Regulatory Classification: Regulated as Class II medical devices via FDA 510(k) clearance.  
Nerve cuffs are manufactured to form a hollow tube construct to entubulate the injured nerve 
stumps.  See Appendix 4 for Instructions for Use. 
 
3.3 
Study Population 
 
Adult male and female subjects that have sustained an injury to at least one nerve, distal to the 
superficial palmar arch and proximal to the distal interphalangeal joint, which after resection results 
in a nerve gap between 5 mm and 25 mm, inclusive. 

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3.4 
Eligibility Criteria 
3.4.1 Informed Consent 
 
Written informed consent will be obtained from all subjects before any study related procedures 
are performed.  Investigators may discuss the availability of the study and the possibility for entry 
with a potential subject without first obtaining consent.  However, informed consent must be 
obtained and documented prior to initiation of any procedures that are performed solely for the 
purpose of determining eligibility for research.  The investigator(s) has both ethical and legal 
responsibility to ensure that each subject under consideration for enrollment is given a full 
explanation of the study.  This shall be documented on a written Informed Consent Form (ICF), 
which shall be approved by the same Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) responsible for approval of this protocol.  Each ICF shall include the elements 
required by Food and Drug Administration (FDA) regulations in 21 (CFR) Part 50 and 
International Committee on Harmonization (ICH) Good Clinical Practice (GCP) and must adhere 
to the ethical principles that have their origin in the Declaration of Helsinki.  The investigator 
agrees to obtain approval from the sponsor of any written ICF used in the study, preferably prior 
to submission to the IRB/IEC. 
 
Once the appropriate, essential study information has been provided to the subject, fully 
explained by the investigator (or qualified designee) and it is agreed that the subject understands 
the implications of participating, the IRB/IEC –approved written informed consent form shall be 
signed and dated by all applicable parties in accordance to what is required by the IRB/IEC.  The 
subject will be given a copy of the signed informed consent form and the original will be kept on 
file by the investigator.  Explanation of study and the signing of the informed consent shall occur 
prior to the subject’s participation in the trial. 
 
3.4.2   Inclusion Criteria 
To be considered for enrollment, subjects must meet the following inclusion criteria: 
 
Table 3.4.2-1: Inclusion Criteria  
1. Subjects 18 to 65 years of age, inclusive; 
2. Require primary or secondary nerve injury repair with 
 
, a bovine Type 1 
collagen nerve cuff or Avance® Nerve Graft in at least 1 digital nerve; 
3. Zone of injury to nerve must be resectable; 
4. Nerve gaps following resection, between 5 and 25 mm, inclusive; 
5. Undergo tension free end to end nerve to nerve graft coaptation on both the proximal and distal 
portion of the nerve gap in the Avance® Nerve Graft Group or nerve entubulation in the Nerve Cuff 
group; 
6. Have an uninjured contralateral or adjacent digit that is suitable to serve as a referenced digit for 
baseline functional assessments; 
7. Be willing and able to comply with all aspects of the treatment and evaluation schedule over a 12 
month duration; and 
8. Sign and date an IRB-approved written informed consent prior to initiation of any study 
procedures. 
 

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3.4.3   Exclusion Criteria 
To be included in the study, the following criteria must not occur: 
 
Table 3.4.3-1 Exclusion Criteria 
1. Estimated distance of regeneration of >150 mm (distance from proximal injury site to tip of target 
digit); 
2. Injuries distal to the distal interphalangeal joint; 
3. Extensive soft tissue injury which will impair recovery assessment; 
4. Incomplete nerve transections; 
5. Injury requiring replantation of target digit 
6. Injuries to the affected nerve proximal to the superficial palmar arch; 
7. Nerve injuries >24 weeks post initial injury; 
8. End to side nerve repair; 
9. Injuries with vascular damage resulting in inadequate perfusion despite repair; 
10. Subjects with Type 1 Diabetes Mellitus or Type 2 Diabetes Mellitus requiring regular insulin 
therapy; 
11. Subjects who are undergoing or expected to undergo treatment with chemotherapy, radiation 
therapy, or other known treatment affects the growth of neural and/or vascular system; 
12. Use of bovine collagen based nerve conduit in a subject with known or suspected bovine sensitivity; 
13. History of neuropathy, diabetic or any other known neuropathy; 
14. Currently enrolled in another investigational interventional study; 
15. Expected use of medication during the study that is known to impact nerve regeneration or to cause 
peripheral neuropathy; 
16. History of chronic ischemic condition of the upper extremity; and 
17. Any subject who at the discretion of the Investigator is not suitable for inclusion in the study. 
 
3.4.4   Enrollment in Study 
3.4.4.1 Subject Screening and Numbering 
 
After the subject has signed an IRB-approved informed consent form, they will be assigned a 
unique screening number.  At each site, the screening numbers will start with S001.  Subjects 
who meet the inclusion and exclusion criteria will be eligible for the study.  Randomization 
will occur intra-operatively.  A randomization number will be assigned to identify the 
enrolled subject. 
3.4.4.2 Subject Withdrawal or Discontinuation 
 
If a subject discontinues from the study, the reason given must be recorded in source 
documentation and the eCRF.  If the subject is withdrawn due to an adverse event, the 
adverse event must be indicated as the reason for withdrawal.  All subjects have the right to 
withdraw at any point during the treatment without prejudice.  The investigator can also 
discontinue a subject’s participation at any time if medically necessary. 
 
The sponsor should be notified promptly when a subject is withdrawn or if the trial is stopped 
at a clinical site. For subjects that withdraw early (Early Termination), all efforts should be 
made to collect End of Study data points prior to final withdraw. 

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 
Decision by the sponsor to suspend or discontinue testing, evaluation, or 
development of the study product. 
 
Conditions that may warrant termination of the clinical study at a particular investigative site 
include, but are not limited to, the following: 
 
 
The investigative site fails to comply with all applicable regulations; 
 
 
Deliberate submission of false information from the site to Axogen, Corporation., 
their designee, or regulatory authorities; 
 
 
Inadequate adherence to protocol requirements; or 
 
 
Inadequate enrollment. 
 
In the event of a discontinuation of the study at an investigative site, the principal investigator 
will return all study materials including study documentation and CRFs to the sponsor, provide a 
written statement explaining the reason for termination, and notify the appropriate Institutional 
Review Board/Ethics Committee. 
4 
Adverse Events 
4.1 
Procedures for Eliciting Reports and Reporting of Adverse Events 
 
The primary safety endpoint is intended to evaluate adverse events associated with the surgical repair 
of the injured nerve and is not intended to evaluate the adverse events of the trauma that precipitated 
the injury.  Both the Avance® Nerve Graft and the 
 
 are commercially 
available products and are restricted to the implantation at the nerve injury site. The effect of each 
product is localized to the area of the nerve discontinuity only. Therefore, the intent is not to capture 
all adverse events that may occur in a subject throughout the follow-up period but only events directly 
relating to the study product and/or surgical intervention.  Given the nature of traumatic hand injuries, 
in-depth medical management approach will be required for a majority of the subjects enrolled in the 
clinical study.  Assessment of adverse events may be limited, to some degree, to those adverse events 
that are related directly to the injured hand, however, to prevent under reporting of potentially 
associated adverse events, the following may be collected: 
 
Adverse events associated with the affected hand, may include but is not limited to: 
 
bleeding; 
 
infection in the affected hand; 
 
painful scar at the nerve reconstruction site; 
 
extrusion on nerve repair product; 
 
delayed wound healing; 
 
allergic reaction; 
 
hypersensitivity at or distal to the repair site; 
 
anaphylaxis; 
 
communicable diseases; 
 
any change in medical or overall health condition that results in the withdrawal 
of the subject from the study; 

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 
any adverse event meeting the criteria for Serious Adverse Event; and/or any 
other event that in the opinion of an investigator warrants collection. 
 
 
Concurrent illnesses that are present at or before study product implantation, which manifest with 
the same severity, frequency, or duration, subsequent to study product implantation, need not be 
recorded as AEs.  Similarly, signs or symptoms related to a pre-existing disease need not be 
recorded as AEs.  However, incidents where there is an increase in severity or duration of the 
concurrent illness or pre-existing disease that meet the above criteria must be reported.  
 
Adverse events should be reported by the investigator or qualified designee in accordance with 
21CRF part 312.32 and Guidance for Industry and Investigators:  Safety Reporting Requirements 
for INDs and BA/BE Studies.  
 
4.2 
Adverse Event Specific Definitions 
 
Associated with the use of the drug. There is a reasonable possibility that the experience may have 
been caused by the drug.  
 
Disability. A substantial disruption of a person’s ability to conduct normal life functions. 
 
Life-threatening adverse drug experience. Any adverse drug experience occurring at any dose that 
results in any of the following outcomes: Death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect.  Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered a serious adverse 
drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 
Unexpected adverse drug experience:  Any adverse drug experience, the specificity or severity of 
which is not consistent with the current investigator brochure; or, if an investigator brochure is not 
required or available, the specificity or severity of which is not consistent with risk information 
described in the general investigational plan or elsewhere in the current application, as amended.  For 
example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if 
the investigator brochure only referred to elevated hepatic enzymes or hepatitis.  Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the 
investigator brochure only listed cerebral vascular accidents.  “Unexpected,” as used in this 
definition, refers to an adverse drug experience that has not been previously observed (e.g., included 
in the investigator brochure) rather than from the perspective of such experience not being anticipated 
from the pharmacological properties of the pharmaceutical product.  
4.3 
Review of safety information 
 
The sponsor shall promptly review all information relevant to the safety of the drug obtained or 
otherwise received by the sponsor from any source, foreign or domestic, including information 
derived from any clinical or epidemiological investigations, animal investigations, commercial 
marketing experience, reports in the scientific literature, and unpublished scientific papers, as well as 
reports from foreign regulatory authorities that have not already been previously reported to the 
agency by the sponsor.  

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4.4 
Adverse Event 
 
 An AE is any untoward event experienced by a subject (whether or not considered product-related by 
the principal investigator or sponsor), or any event that has changed adversely in nature, severity, or 
frequency.  An untoward AE or any event that has changed adversely in nature, severity, or frequency 
during the course of study product administration is considered to be a treatment-emergent adverse 
event. 
 
An AE can be, but is not limited to, subjective symptoms experienced by a subject, or objective 
findings that may or may not include subjective symptoms.  Examples of objective findings are 
clinically significant laboratory abnormalities.  All AEs that occur during or after study product 
implantation/device insertion must be recorded in the subject’s medical record (progress notes) and 
then transcribed onto the CRF.  The investigator’s assessment of the AE’s relationship to the study 
product is unrelated to its characterization as an AE.  For example, an anomaly that the investigator 
judges to be unrelated to the investigational/control product may nonetheless be identified as an AE.  
A serious adverse event (SAE) is an AE that causes death, is life threatening, is permanently 
disabling, or requires (or prolongs) hospitalization or interventional surgery.  
 
4.4.1 List of Anticipated Adverse Event 
 
Consistent with the subject’s informed consent form and the risk analysis section of this protocol, 
the following adverse events are anticipated and may potentially occur during the subject’s 
participation in this investigation: 
 
mild incisional redness; 
 
tenderness of surgical area; 
 
mild edema of surgical area; 
 
decreased pain at surgical area; 
 
numbness 
These adverse events are considered expected and are not required to be recorded on the Adverse 
Events eCRF unless they increase in severity. 
 
4.4.2 Severity of Adverse Events 
 
Adverse events will be graded for severity and noted in the description of the event.  The NCI 
(NIH)-developed Common Terminology Criteria for Adverse Events (NCI_CTCAE), Version 
4.0, will be used.  In addition, any AE associated with subject termination from the study must be 
reported to the sponsor or sponsor-approved designee within 7 days of knowledge.  If the AE is a 
SAE, then the reporting requirements listed in section 4.5.2 will apply.  
 
4.4.3 Relationship to Study Product 
 
The principal investigator or designee will document his/her opinion on the relationship of the 
adverse event to the study product or control product for all adverse events, using the criteria 
outlined in Table 4.4.3-1. 
 
 

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Table 4.4.3-1 Relationship of Adverse Events to Study Product 
 
 
Relationship 
 
Description 
 
 
Unrelated 
An AE that is clearly and uncontrovertibly due to extraneous causes (disease, environment, etc.)  
 
 
                and does not meet the criteria for study product relationship listed under possible or   probable. 
 
 
Possible  
An AE may be considered as possibly related if: 
 
 
 
 
 
 
1) it cannot be reasonably explained by the subject’s clinical state by environmental or toxic  
 
 
 
factors; or 
 
 
 
2) it follows a reasonable temporal sequence from administration of study product; or, 
 
 
 
3) it follows a known pattern of response to the study product. 
 
 
Probable  
An AE considered, with a high degree of certainty, to be related to the study product. An AE may  
 
 
                be considered probably related to study product if: 
 
 
 
1) it cannot be reasonably explained by the known characteristics of the subject’s clinical state or  
 
 
 
by environmental or toxic factors; 
 
 
 
2) it follows a reasonable temporal sequence from administration of study product; 
 
 
 
3) it follows a known pattern of response to study product; 
 
 
 
4) it disappears or decreases upon removal. 
 
 
Definitely  
An AE that is clearly and uncontrovertibly due to study product. 
 
 
Related 
 
 
4.4.4 Follow-up of Adverse Events 
 
Subjects who present with unresolved or new adverse events at the final scheduled visit will be 
followed by the principal investigator: 
 
 
until the adverse event has resolved; or 
 
 
until the subject is lost to follow-up; or 
 
 
until the adverse event is stabilized or deemed a permanent disease or condition. 
 

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“Resolution” of an AE occurs when the subject has returned to his/her baseline state of health or 
when the principal investigator does not expect any further improvement or worsening of the AE.  
On the last clinical study day, the principal investigator will instruct the subject to report any 
subsequent adverse event that the subject or the subject’s physician believes might reasonably be 
caused by, or probably caused by, the study product.  The principal investigator will continue to 
report any significant follow-up information to the sponsor or authorized designee.  All SAEs that 
occur up to 30 days following the subject’s last study assessment must be reported immediately to 
the medical monitor.  
 
4.5 
Serious Adverse Event 
 
4.5.1  Definition of Serious Adverse Event 
 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
 
 
Results in death; 
 
 
Is life threatening – a “life-threatening” event is present when the subject is, in the opinion of 
the principal investigator, at immediate risk of death from the event as it occurs.  Note that 
this definition does not include an event that, had it occurred in a more serious form, might 
have caused death; 
 
 
Requires in-patient hospitalization or prolongation of existing hospitalization – 
hospitalization for elective treatment of pre-existing condition that did not worsen during the 
clinical investigation is not considered an adverse event.  Hospitalization or nursing home 
admission for the purpose of caregiver respite is not considered an adverse event.  
Complications that occur during hospitalization are adverse events, and if a complication 
prolongs hospitalization, the event is considered serious; 
 
 
Results in a persistent or significant disability/incapacity (i.e., a substantial disruption of a 
person’s ability to conduct normal life functions); or 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious events when, based upon medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above.  
 
4.5.2 Reporting Serious Adverse Events 
 
This protocol will follow the standard level of SAE reporting.  Thus, it is necessary to report all 
SAEs following any exposure to study that: 
 
 
Result in death, regardless of  relationship to study product; 
 
 
Result in persistent or significant disabilities or incapacities, regardless of relationship to 
study product; 
 

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 
Are an adverse reaction, definitely, probably, or possibly related to study product, that 
requires or prolongs existing hospitalization, or requires intervention to prevent 
significant/permanent disability or death; or 
 
 
Are life threatening, including all Grade 4 adverse reactions that are definitely, probably, or 
possibly related to study product. 
 
All SAEs must be reported immediately to sponsor or approved sponsor designee, followed by 
the completion of the SAE CRF.  The sponsor or authorized designee, in turn, will promptly 
notify the medical monitor.  The SAE report and CRF should contain all adverse event 
information available at time of event onset. As updates become available, the SAE report and 
CRF should be updated appropriately until event is resolved. 
 
The sites will relay all SAE information to the sponsor or authorized designee within 24 hours of 
receipt.  The SAE form will collect data surrounding the event, e.g., the nature of the symptom(s), 
time of onset in relation to placement of study product, and whether or not treatment with study 
product was interrupted or discontinued.  The principal investigator’s assessment on the probable 
cause of the event will also be included. 
 
Subjects experiencing a SAE or emergency situation should be examined by a physician as soon 
as possible.  The physician in attendance should do whatever is medically necessary for the safety 
and well-being of the subject.  The subject will remain under observation for as long as medically 
indicated in the opinion of the principal investigator and/or attending physician.  The SAE will be 
followed until resolved or until medically stabilized.  The principal investigator or designee will 
notify the sponsor (and the IRB/Ethics Committee and appropriate regulatory body, if necessary) 
within 24 hours of event onset.   
 
4.5.3   Relationship to Product and Study Procedure 
 
The principal investigator will document his/her opinion on the relationship of the adverse event 
to the study product or control product and to the study procedure for all SAEs.  The investigator 
should follow the same criteria outlined above when determining product- or procedure-
relatedness. 
 
4.6 
IND Safety Reports 
 
4.6.1   Written reports 
 
The sponsor shall notify FDA and all participating investigators in a written IND safety report of: 
 
 
Any adverse experience associated with the use of the drug that is both serious and 
unexpected; or 
 
 
Any findings from tests in laboratory animals that suggest a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.  Each 
notification shall be made as soon as possible and in no event later than 15 calendar days 
after the sponsor’s initial receipt of the information.  Each written notification may be 

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submitted either on an FDA Form 3500A or in a narrative format (foreign events may be 
submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I form; reports 
from animal or epidemiological studies shall be submitted in a narrative format) and shall 
bear prominent identification of its contents, i.e., “IND Safety Report.”  Each written 
notification to FDA shall be transmitted to the FDA product review division in the Center 
for Biologics Evaluation and Research that has responsibility for review of the IND.  If 
FDA determines that additional data is needed, the agency may require further data to be 
submitted. 
 
In each written IND safety report, the sponsor shall identify all safety reports previously filed 
with the IND concerning a similar adverse experience, and shall analyze the significance of the 
adverse experience in light of the previous, similar reports. 
 
4.6.2   Telephone and facsimile transmission safety reports 
 
The sponsor shall also notify FDA by telephone, by facsimile transmission, or by electronic 
Common Technical Document (eCTD) transmission of any unexpected fatal or life-threatening 
experience associated with the use of the product as soon as possible but in no event later than 7 
calendar days after the sponsor’s initial receipt of the information.  Each telephone call or 
facsimile transmission to FDA shall be transmitted to the FDA to the product review division in 
the Center for Biologics Evaluation and Research that has responsibility for review of the IND. 
 
4.6.3   Follow up 
 
Follow up information to a safety report shall be submitted as soon as the relevant information is 
available.  If the results of a sponsor’s investigation show that an adverse experience was initially 
determined to be not reportable  according to the applicable regulations, but is later deemed 
reportable, the sponsor shall report such experience in a written safety report as soon as possible, 
but in no event later than 15 calendar days after the determination is made.  Results of a sponsor’s 
investigation of other safety information shall be submitted, as appropriate, in an information 
amendment or annual report. 
5 
Statistical Considerations 
 
Descriptive statistical methods will be used to summarize the data from this study,  
with hypothesis testing performed for the primary and other selected efficacy endpoints.  Unless stated 
otherwise, the term “descriptive statistics” refers to number of events (n), mean, median, standard 
deviation (SD), standard error, minimum, maximum, and coefficient of variation (CV) for continuous 
data and frequencies and percentages for categorical data.  The term “repair type” refers to randomized 
treatment assignment of either 
 
 or Avance® Nerve Graft.  All data collected 
during the study will be included in data listings.  Unless otherwise noted, the data will be sorted first by 
repair type, subject number, and then by date within each subject number. 
 
Unless specified otherwise, all statistical testing will be two-sided and will be performed using an overall 
significance (alpha) level of 0.05. 
 
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher. 

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6 
Study Product Management 
6.1 
Packaging and Labeling 
 
Commercially available product will be used for both treatment groups, however each site will be 
provided quality controlled serialized investigational product and control product labeling. Once 
subject has been randomized the appropriate investigational product labeling will be affixed to 
product packaging and returned to CRO for documentation and label accountability.  Refer to the 
Study Operations Manual for labeling procedures.  
6.2 
Handling, Storage, and Disposal 
 
Per product specifications as defined in the Instructions for Use. 
7 
Records Management 
 
Questions or interpretations of the protocol or CRFs must be referred to the sponsor or its 
representatives.  
 
7.1 
Data Collection 
 
During each subject’s visit, the investigator or designee should document all significant observations.  
Information from the source documents will be promptly transcribed to into the electronic data 
capture system (EDC) via electronic case report forms.  
 
Any changes in information in the study progress notes or other source documents will be initialed 
and dated on the day the change is made, by a site study staff member authorized to make the change.  
Changes will be made by striking a single line through erroneous data, and clearly entering the correct 
data.  If the reason for the change is not apparent, a brief explanation for the change will be written 
adjacent to the change on the source document and updated accordingly in the EDC system.  
7.2 
Source Documents 
 
Source documents are defined as the result of original observations and activities of a clinical 
investigation.  Source documents will include, but are not limited to, progress notes, electronic data, 
screening logs, and recorded data from automated instruments.  All source documents pertaining to 
this study will be maintained by the investigators and made available for direct inspection by 
authorized persons.  
 
All source documents from this study will be maintained by the study center and made available for 
inspection by authorized persons.  The original signed Informed Consent Form for each subject shall 
be filed with a patient’s clinical record at the site and a copy shall be given to the subject and/or 
legally authorized representative.  
 
 
 

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7.3 
File Management at the Study Site 
 
It is the responsibility of the investigator to ensure that the site files are maintained in accordance with 
Section 8 of the International Conference on Harmonization (ICH) Guideline for Good Clinical 
Practice (GCP) and FDA regulations.  
7.4 
Records Retention at the Study Site 
 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application or until at least 2 years have elapsed since the formal discontinuation of the clinical 
development of the investigational product.  However, essential documents may be retained for a 
longer period if required by the applicable regulatory requirements or by agreement with the sponsor.  
It’s the responsibility of the sponsor to inform the principal investigator that the essential documents 
no longer need to be retained.  
8 
Quality Control and Quality Assurance 
 
8.1 
Data Management Considerations 
 
Data Management will be overseen by an independent CRO contracted and qualified by the sponsor.  
All data points in the study will be held to a global Data Management Plan.  Original study logs will 
remain secured at the clinical site and a copy will be transmitted to the data manager.  Paper copies 
received by the data manager will be scanned and electronically saved as a Portable Document 
Format (pdf).  The scanned copy will be compared to the paper copy to assure all pages are accounted 
for and quality meets expectations.  
  
Data will be entered in to the EDC by the site coordinator or other qualified site personnel.  Quality 
control checks will be established for each data management procedure in order to ensure accuracy 
and to preserve the integrity of the data.  Onsite data monitoring visits will be conducted by certified 
Clinical Research Associates (CRA) employed by the study’s CRO.  Visits will be conducted 
according to an established procedure and occur according to a predetermined schedule for the entire 
length of the study. 
8.2 
Monitoring 
 
The sponsor or their authorized designee will conduct routine monitoring visits to ensure the safe and 
ethical conduct of the study.  This will include routine data monitoring of the study’s critical variables 
that are defined in the data management plan and clinical monitoring plan.  As part of a concerted 
effort to fulfill the requirements of the protocol, the sponsor or designee may visit the center during 
the study in addition to maintaining frequent telephone and written communication.  
8.3 
Auditing 
 
The sponsor’s Quality Assurance Unit or authorized designee may conduct audits at the study site(s).  
Audits will include, but are not limited to, product supply, presence of required documents, the 
informed consent process, and comparison of case report forms with source documents.  The 
investigator agrees to participate with audits conducted at a reasonable time and in a reasonable 
manner.  

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Regulatory authorities may also audit the investigator during or after the study.  The investigator 
should contact the sponsor immediately if this occurs, and must fully cooperate with the regulatory 
bodies during the conduct of the study audit. 
9 
Ethics and Responsibility 
 
This study must be conducted in compliance with the protocol, FDA regulations, the ICH GCP 
Guidelines, and all other applicable regulatory requirements.  
 
The study protocol and the written informed consent form must be submitted to the IRB/IEC identified 
with the responsibility to approve research for the study site.  Written approval must come from the 
IRB/IEC Chairman or Secretary, either as a letter or as a copy of the appropriate sections of the IRB/IEC 
meeting minutes where the review of the study protocol and associated informed consent form were 
discussed and approved.  The investigator will not participate in the decision.  If the investigator is an 
IRB/IEC member, the written approval must indicate such non-participation. 
 
The investigator will submit study status reports to the IRB/IEC no less frequently than annually (when 
applicable).  The investigator must notify the IRB/IEC in writing of the interruption and/or completion of 
the study.  The investigator must promptly report to the IRB/IEC all changes in research (protocol 
amendments), and will not make such changes without IRB/IEC approval except when necessary to 
eliminate apparent immediate hazards to human subjects.  In these cases, the IRB/IEC must be notified 
with 5 working days of the change.  The investigator will promptly report to the IRB/IEC all 
unanticipated problems involving risks to subjects or others.  The investigator must maintain accurate and 
complete records of all correspondence written to and received from the IRB/IEC and must agree to share 
all such documents and reports with the sponsor.  
10 Clinical Study Report 
 
Upon completion of the study, the data management group biostatisticians will generate the Tables, 
Forms, and Listings for the Lead Investigators and sponsor to review.  Once verified and approved, the 
Tables, Forms, and Listings will be finalized.  Based on this study data, a study report will be drafted.  
This report will be provided to the collaborative investigators for review and comment.  The sponsor will 
then finalize and distribute the study report to the appropriate parties.  
11 Confidentiality 
 
All information generated in this study must be considered highly confidential and must not be disclosed 
to any persons not directly concerned with the study without first written permission from Axogen.  
However, authorized regulatory officials and Axogen personnel (or their representatives) will be allowed 
full access to inspect and copy study records.  All study materials collected shall be used solely in 
accordance with this protocol, unless first agreed to in writing by Axogen.  
 
Subjects will be identified only by initials and unique subject numbers in CRFs.  Their full names may, 
however, be made known to a regulatory agency or other authorized officials if necessary.  

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12 Regulatory Considerations 
12.1 Amendments 
 
The investigator will not make any changes to this protocol without prior written consent from the 
sponsor and subsequent approval by the IRB/IEC.  Any permanent change to the protocol, whether an 
overall change or a change for specific study center(s), must be handled as a protocol amendment.  
Any amendment to the protocol identified as necessary and occurring during active study conduct, 
will be fully discussed by the investigator(s) and the sponsor prior to any protocol updates.  If 
agreement is reached regarding the need for an amendment, the sponsor will be responsible for 
updating the protocol.  The written amendment must be submitted to the chairman of the IRB/IEC 
designated with this responsibility.  Except for ‘administrative amendments’ investigators must await 
IRB/IEC approval of protocol amendments before implementing the changes(s).  Administrative 
amendments are defined as having no effect on the safety of the research subjects, scope of the 
investigation, or quality of the trial.  However, a protocol change intended to eliminate an apparent 
immediate hazard to subjects should be implemented immediately, and the IRB/IEC notified within 
five working days.  Axogen will submit all official protocol amendments to the FDA or other 
regulatory agencies.  
 
When, in the judgment of the chairman of the IRB/IEC, the investigators and/or the sponsor, the 
amendment to the protocol substantially alters the study design and/or increases the potential risk to 
the subject, the currently approved written informed consent form will require similar modification.  
In such cases, repeat informed consent will be obtained from all subjects enrolled in the study before 
continued participation.  
12.2 Protocol Deviations 
 
This study is intended to be conducted as described in this protocol.  In the event of a significant 
deviation from the protocol due to an emergency, accident, or mistake, the investigator or designee 
must contact the sponsor at the earliest possible time by telephone.  This will allow for an early, joint 
decision regarding the subject’s continuation in the study.  This decision will be documented by the 
investigator and the sponsor, and reviewed by the monitor.  
12.3 Sponsor and Investigator Responsibilities 
 
The sponsor and participating investigators shall be responsible for the conduct of this clinical study 
as specified in 21CRF part 312 Subpart D.  This clinical investigation will be performed in 
compliance with the protocol, Clinical Study Agreement, the FDA Good Clinical Practices including 
21CRF part 312, 601, 50, 56, ICH E6, and local applicable regulatory requirements.  
 
 

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13 References 
 
1. Lundborg, G., A 25-yr perspective of peripheral nerve surgery: evolving neuroscientific concepts and 
clinical significance.  Journal of Hand Surgery [Am], 2000. 25: p. 391-414. 
 
2. Dvali, L. and S. Mackinnon, Nerve repair, grafting, and nerve transfers. Clinics in Plastic Surgery, 
2003. 30: p. 203-221. 
 
3. Karabekmez, F.E., A. Duymaz, and S.L. Moran, Early Clinical Outcomes with the use of 
Decellularized Nerve Allograft for Repair of Sensory Defects Within the Hand. Hand (NY), 2009. 
4(3): p. 245-9  
 
4. Mackinnon, S.E., et al., Clinical outcomes following nerve allograft transplantation. Plastic and 
Reconstructive Surgery, 2001. 107: p. 1419-1429. 
 
5. Mackinnon, S.E. and A.L. Dellon, Results of Nerve Repair and Grafting, in Surgery of Peripheral 
Nerve. 1988, Thieme Medical: New York. 
 
6. Millesi, H., Nerve Grafting.Clin Plast Surg, 1984. 11: p. 105-113. 
 
7. Noble, J., et al., Analysis of Upper and Lower Extremity Peripheral Nerve Injuries in a Population of 
Recipients with Multiple Injuries. The Journal of Trauma, 1998. 45: p. 116-122. 
 
8. FF, I.J., J.P. Nicolai, and M.F. Meek, Sural nerve donor-site morbidity: thirty-four years of follow-up. 
Ann Plast Surg, 2006. 57(4): p. 391-5. 
 
9. Frykman, G. and K. Gramyk, Results of nerve grafting, in Operative nerve repair and reconstruction, 
R. Gelberman, Editor. 1991, JB Lippincott: Philadelphia.  
 
10. Meek, M.F., J.H Coert, and P.H. Robinson, Poor results after nerve grafting in the upper extremity: 
Quo vadis? Microsurgery, 2005. 25(5): p. 396-402. 
 
11. Campbell, W.W., Evaluation and management of peripheral nerve injury. Clinical Neurophysiology, 
2008. 119 p. 1951-1965. 
 
12. Birch, R., G. Bonney, and C.B. Wynn Parry, Surgical disorders of the peripheral nerves. 1998, 
Churchill Livingstone, Edinburgh.  
 
13. Friedman, L., C. Furberg, and D. DeMets, Fundamentals of clinical trials. 3rd ed. 1999.  
 
14. Weber, R.A., et al., A Randomized Prospective Study of PGA Conduits for Digital Nerve 
Reconstruction in Humans. Plast Recon Surgery, 2000. 106: p. 1036-1045. 
 
15. Mackinnon, S.E.a.D., A.L., Clinical nerve reconstruction with a bioabsorbablepolyglycolic acid 
tube.Plast Recon Surgery, 1990. 85(3): p. 419-424. 
 

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16. Bertleff, M.J., M.F. Meek, and J.P. Nicolai, A prospective clinical evaluation of 
bioabsorbableneurolac nerve guides for sensory nerve repair in the hand. J Hand Surg Am, 2005. 
30(3): p. 513-8. 
 
17. Bushnell, B.D., et al., Early clinical experience with collagen nerve tubes in digital nerve repair. J 
Hand Surg Am, 2008. Sep. 33(7): p. 1081-7. 
 
18. Lohmeyer, J.A., et al., The clinical use of artificial nerve conduits for digital nerve repair: a 
perspective cohort study and literature review. J Reconstr Microsurg, 2009. Jan. 25(1): p. 55-61. 
 
 
19. Graham, J.B., et al., A chrondroitinase-treated, decellularized nerve allograft compares favorably to 
the cellular isograft in rat peripheral nerve repair. Journal of Neurodegeneration and Regeneration, 
2009. 2(1): p. 19-29. 
 
20. Whitlock, E.L., et al., Processed allografts and type I collagen conduits for repair of peripheral nerve 
gaps. Muscle Nerve, 2009. 39(6): p. 787-99. 
 
21. Neubauer, D., J.B. Graham, and D. Muir, Nerve grafts with various sensory and motor fiber 
compositions are equally effective for the repair of a mixed nerve defect. Experimental Neurology, 
2010. 223: p. 203-206. 
 
22. Ducic, Ivica, Rose Fu, and Matthew L Iorio. Innovative Treatment of Peripheral Nerve Injuries: 
Combined Reconstructive Concepts. Ann Plast Surg 68.2 (February, 2012): 180-7. 
23. Shanti RM, Ziccardi VB. Use of decellularized nerve allograft for inferior alveolar nerve 
reconstruction: a case report. J Oral Maxillofac Surg. 2011 Feb;69(2):550-3. 
24. Brooks D, Weber RV, Chao JD, et al.  Processed nerve allografts for peripheral nerve 
reconstruction: a multicenter study of utilization and outcomes in sensory, mixed, and motor nerve 
reconstructions.  Microsurgery, 2012;32:1-14. 
25. Cho, M. S., B. D. Rinker, R. V. Weber, J. D. Chao, J. V. Ingari, D. Brooks and G. M. Buncke, 
Functional outcome following nerve repair in the upper extremity using processed nerve allograft.  J 
Hand Surg Am (2012). 37(11): 2340-2349. 
26. Aberg, M., et al., Considerations in evaluating new treatment alternatives following peripheral nerve 
injuries: a perspective clinical study of methods used to investigate sensory, motor and functional 
recovery. Plast Reconstr Aesthet Surg, 2007. 60(2): p. 103-13. 
 
27. Mackinnon, S.E. and A.L. Dellon, Surgery of the Peripheral Nerve. 1st ed. 1988, New York: Thieme 
Medical.  
 
 
28. Dellon, A.L., et al., Reliability of two-point discrimination measurements. J Hand Surg Am, 1987 
Sep. 12(5.1): p. 693-6. 
 
29. Crosby, P.M., et al., Comparison of two-point discrimination testing devices. Micro Surg., 1989. 10: 
p. 134-137. 
 

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30. Stone, J.H., Sensibility, In Clinical Assessment Recommendations, 2nd ed. 1992, Chicago: American 
Association of Hand Therapists. 
 
31. Aitken, R.C.B. Measurement of feelings using visual analogue scales. In Proceedings of the Royal 
society of Medicine. 1969: Visual Analogue Scales (VAS). 
 
32. Beaton, D.E., W.J., Katz, J.N., Development of the QuickDASH: Comparison of three item-reduction 
approaches. Journal of Bone & Joint Surgery, 2005. 87(5): p. 1038-1046. 
 
33. Aleid C.J. Ruijs, J.-B.J., H.A.M. Daanen, S.E.R. Hovius, Cold Intolerance of the Hand Measured By 
the CISS Questionnaire in a Normative Study Population. J Hand Surg Eur 2006. 31(5): p. 533-536. 
 
34. Oud, T., et al., Sensory re-education after nerve injury of the upper limb: a systematic review. Clin 
Rehabil, 2007. 21(6): p. 483-94. 
 
35. Daniele, H.R. and L. Agued, Early compensatory sensory re-education. J Reconstr Microsurg, 2003. 
19(2): p. 107-10; discussion 11-2.  
 
36. Rinker, B. and J.Y. Liau, A prospective randomized study comparing woven polyglycolic acid and 
autogenous vein conduits for reconstruction of digital nerve gaps. J Hand Surg Am. 36(5): p. 546-7. 
 
37. Altissimi, M., G.B. Mancini, and A. Azzara, Results of primary digital nerve repair. J Hand Surg Br, 
1994. 19(2): p. 255-7.  
 
38. Al-Ghazal, S.K., et al., Results of clinical assessment after primary digital nerve repair. J Hand Surg 
Br, 1994. 19(2): p. 255-7. 

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14 Appendix 1 – Investigator Agreement 
 
 
Agreement Signatures 
 
 
I have read and understand the protocol (including the Investigator’s Brochure) and agree that it contains 
all the ethical, legal, and scientific information necessary to conduct this study.  I will personally conduct 
this study as described herein and in Axogen’s Clinical Trial Agreement.  
 
I will provide copies of the protocol to all study staff who will participate in the study as part of my study 
team.  I will discuss the protocol with them to ensure that they are sufficiently informed regarding the 
conduct and requirements of the study.  I am aware that this protocol must be approved by the IRB 
governing the research conducted at my Institution.  I agree to adhere strictly to the protocol (unless 
amended, at which time I agree to adhere strictly to the protocol as amended).  I understand that this IRB-
approved protocol will be submitted to the Food and Drug Administration by Axogen.  I agree that 
clinical data entered on case report forms by me and my staff will be utilized by Axogen in various ways, 
including but not limited to, submission of data to governmental regulatory authorities and/or in 
combination with clinical data gathered from other research sites, whenever applicable.  I agree to allow 
Axogen monitors and auditors (or their designees) full access to all medical records at the research facility 
for subjects screened or enrolled in the study. 
 
I agree to provide all subjects with informed consent forms, as required by local and federal regulatory 
bodies as well as in accordance with ICH regulations.  I agree to report to Axogen any adverse 
experiences in accordance with the terms of Axogen (or designee’s) Clinical Trial Agreement and FDA 
regulations, 21 CFP 312.64.  I further agree to provide all required information regarding financial 
certification or disclosure to Axogen for all investigators and sub-investigators in accordance with the 
terms of FDA regulation 21 CFR 54.  
 
I assure that my participation in this clinical study will be conducted according to all requirements of this 
protocol, the FDA Good Clinical Practices including the Investigational New Drug regulation (IND) and 
other GCP regulations, and local regulatory requirements.  
 
 
 
_________________________________ 
 
_________________________________ 
 
Printed Name  
 
Date 
 
 
Signature 
 
 
 
Principal Investigator   
 
 
 
Principal Investigator 
 
 
 
 
 
 

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16 Appendix 3 - Instructions for Use: Avance® Nerve Graft (LB-211) 
 
 
 
 

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