A Multicenter, Prospective, Randomized and Subject Blinded Comparative Study of AxoGuard® Nerve Cap and Neurectomy for the Treatment of Symptomatic Neuroma and Prevention of Recurrent End-Neuroma Pain
Phase: NA
Conditions: Symptomatic Neuroma, Morton's Neuroma, Chronic Nerve Pain
Sponsor: Axogen Corporation



Protocol No. CAP-CP-001 
Page 1 of 50 
Final Version 3.0 
THIS DOCUMENT CONTAINS PROPRIETARY INFORMATION AND MAY NOT BE REPRODUCED, PUBLISHED, OR DISTRIBUTED IN ANY FORM, IN WHOLE OR IN PART, WITHOUT 
WRITTEN AUTHORIZATION FROM AXOGEN  
 
 
 
 
 
 
Title of Study: A Multicenter, Prospective, Randomized, Subject Blinded Comparative Study of 
Axoguard® Nerve Cap and Neurectomy for the Treatment of Symptomatic Neuroma and Prevention of 
Recurrent End-Neuroma Pain 
Estimated Number of Study Centers and Countries: Up to 20 Centers in the US 
Study Type: Pilot to Comparative Parallel Group 
Study Design: Randomized, controlled, prospective, subject blinded, multi-center, pilot to comparative 
parallel group study  
Objective: The primary objective of the pilot phase of this study is to evaluate the difference in pain 
scores from baseline at 12 weeks; The primary objective of the comparative phase is the differences in 
pain assessments between the study groups at 12 months.  The secondary objectives of this study are to 
compare degree of recovery over time (reduction in pain); quality of life and economic data for each 
treatment group over a 12-month period. 
Study Population: Adult male and female subjects with symptomatic neuroma in the foot or ankle to 
at least one nerve where the nerve cannot be repaired to a distal nerve end 
Test Product: Axoguard® Nerve Cap 
Control: Neurectomy 
Number of Subjects per Treatment Group: Enroll approximately 15 evaluable subjects in the pilot 
study. Enroll approximately 86 additional subjects for the randomized comparative study.   
Duration of Study: Up to 13 months including screening period.  
Inclusion Criteria: 
Potential Subjects must:  
1. Be able and willing to provide documented informed consent prior to the conduct of any study 
procedures; 
2. Be an adult male or non-pregnant female ≥ 18 years of age;  
3. Report baseline pain scores of >65mm on a 100mm Visual Analog Scale (VAS) at screening;   
4. Have a documented diagnosis of symptomatic neuroma of at least one interdigital nerve in the 
foot which cannot be repaired to a distal nerve end; 
5. Must have the of the following: 
x 
Pain with at least 3 of the following characteristics: burning, sharp, shooting, electric, 
parasthesias, numbness, cold intolerance; 
x 
Symptoms in a defined neural anatomic distribution 
x 
History of nerve injury or suspected nerve injury 
Must have at least 1: 
x 
Positive response to local anesthetic injection 
x 
US or MRI confirmation of neuroma 
6. Be candidates indicated for surgery to address a symptomatic neuroma;  
7. Have sufficient healthy soft tissue available to adequately cover the Axoguard® Nerve Cap; 

Protocol No. CAP-CP-001 
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WRITTEN AUTHORIZATION FROM AXOGEN  
- CONFIDENTIAL- 
 
 
8. In the surgeon’s opinion, be likely to achieve complete resection of the symptomatic neuroma  
and be able to undergo implantation with the Axoguard® Nerve Cap or complete the 
neurotomy procedure in the control group; 
9. Be willing and able to comply with all aspects of the treatment and evaluation schedule over a 
12-month duration. 
 
 Exclusion Criteria: 
 
Potential subjects must not:  
1. Have undergone surgical treatment of pain from symptomatic neuroma in the target nerve(s)on 
three or more occasions; 
2. Have biomechanical pathology and associated pain (such as plantar fasciitis, bursitis, sesamoid 
bone pain, tendinitis, etc); 
3. Have a life expectancy of less than 12 months; 
4. Have a history of or planned radiotherapy in the area of the end-neuroma; 
5. be contraindicated for soft tissue implants.; this includes but is not limited to any pathology 
that would limit the blood supply; compromise healing or indicate the presence of a local 
infection; 
6. Have a history of chronic ischemic conditions of the extremity; 
7. Have a diagnosis of type 1 Diabetes Mellitus; or uncontrolled Type 2 Diabetes Mellitus (at the 
discretion of the investigator); 
8. Have a history of diabetic neuropathy; 
9. Be undergoing or expected to undergo treatment with chemotherapy, radiation therapy, or other 
known treatment which affects the growth of neural and/or vascular system; 
10. Be immunosuppressed, immunocompromised or have planned immunosuppressive therapy 
within 12 months following the study procedure; 
11. Have a History of congenital neuropathy or compressive neuropathy affecting the target limb; 
12. Have a history of prior surgical management of more proximal compressive neuropathies or 
spinal conditions (e.g. spinal stenosis) not related to the symptomatic neuroma that affect the 
target limb; 
13. Currently use or likely need to use medication during the study known to impact nerve 
regeneration or to cause peripheral neuropathy; 
14. be pregnant or plan to become pregnant during the duration of the study; 
15. Be or have been enrolled in another interventional study within 30 days prior to consenting; 
16. Have a known allergy to anesthetic agents; 
17. Have a known sensitivity to porcine derived materials; or 
18. Be, in the opinion of the Investigator, unsuitable for inclusion in the study. 
 
Conduct of Study: Randomized, controlled, prospective, subject blinded, multi-center comparative 
parallel group study. The study will be composed of eight (8) scheduled visits. See Appendix B: 
Schedule of Assessments for details. 
Criteria for Evaluation: 
 
Safety Endpoints 
Primary Safety Endpoints: 
1. 
Serious Adverse Events (SAEs) at 3 months            
2. 
Adverse Events (AEs) or Unanticipated Adverse Device Effects (UADEs) at 3 months 
 

Protocol No. CAP-CP-001 
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Final Version 3.0 
THIS DOCUMENT CONTAINS PROPRIETARY INFORMATION AND MAY NOT BE REPRODUCED, PUBLISHED, OR DISTRIBUTED IN ANY FORM, IN WHOLE OR IN PART, WITHOUT 
WRITTEN AUTHORIZATION FROM AXOGEN  
 
 
 
 
Table of Contents 
 
1. INTRODUCTION ............................................................................................................................................................... 5
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1.3.1 Preclinical Testing for Axoguard® Nerve Cap ................................................................................................................. 8
1.3.2 Manufacturing Controls ............................................................................................................................................................ 9
1.3.3 Previous Clinical Experience ................................................................................................................................................. 10
1.3.4 Published Clinical Studies ....................................................................................................................................................... 10
2. STUDY OBJECTIVES ...................................................................................................................................................... 10
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3. STUDY DESIGN ................................................................................................................................................................ 11
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3.2.1 Study Product ............................................................................................................................................................................... 12
3.2.2 Control ............................................................................................................................................................................................. 12
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3.4.1  Informed Consent ...................................................................................................................................................................... 12
3.4.2  Inclusion Criteria ....................................................................................................................................................................... 13
3.4.3  Exclusion Criteria ...................................................................................................................................................................... 14
3.4.4  Enrollment in Study .................................................................................................................................................................. 15
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3.5.1 Safety Endpoints ......................................................................................................................................................................... 15
3.5.2 Efficacy Endpoints ...................................................................................................................................................................... 16
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3.6.1  Pain Assessments – VAS and PROMIS® ............................................................................................................................ 16
3.6.2  Quality of Life Questionnaires (FHSQ and WPAI) ...................................................................................................... 17
3.6.3  Nerve Cap Utilization Form and Surgeon Experience Survey .............................................................................. 17
3.6.4  Economic Questionnaire ........................................................................................................................................................ 17
3.6.5  Concomitant Medication Log and Daily Pain Medication Diary (Quantity and Class) ............................ 17
3.6.7  Subject Satisfaction Survey ................................................................................................................................................... 18
3.6.8 Daily Pain Diary .......................................................................................................................................................................... 18
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3.7.1  Blinding .......................................................................................................................................................................................... 18
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3.9.1  Visit 1: Pre-Operative Screening, (-6 weeks, Day -42) .............................................................................................. 19
3.9.2  Visit 2: Operative Day, Day 0*.............................................................................................................................................. 19
3.9.3 Visit 3: Post Operative Visit, Day 14/Week 2 (± 7 days) ........................................................................................... 21
3.9.4 Visits 4: Months 1 (±7 days) ................................................................................................................................................... 21
3.9.5 Visits 5-7: Months 3, 6, 9 (±14 days) .................................................................................................................................. 21
3.9.6 Visit 8: End of Study/Early Termination Visit, Month 12 (± 14 days) ............................................................... 21

Protocol No. CAP-CP-001 
Page 2 of 50 
Final Version 3.0 
THIS DOCUMENT CONTAINS PROPRIETARY INFORMATION AND MAY NOT BE REPRODUCED, PUBLISHED, OR DISTRIBUTED IN ANY FORM, IN WHOLE OR IN PART, WITHOUT 
WRITTEN AUTHORIZATION FROM AXOGEN  
 
 
 
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3.10.1  Screen Failures ......................................................................................................................................................................... 22
3.10.2  Subject Discontinuation ....................................................................................................................................................... 22
3.10.3  Discontinuation of the Study ............................................................................................................................................. 22
4. ADVERSE EVENTS .......................................................................................................................................................... 23
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ͶǤ͵
 	  ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹ͵
ͶǤͶ
      ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹͶ
ͶǤͷ
  
 ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹͶ
ͶǤ͸
   ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹͷ
4.6.1 Reporting Serious Adverse Events ...................................................................................................................................... 26
ͶǤ͹
   		 ȋȌ ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹ͸
4.7.1  Reporting of Unanticipated Adverse Device Effects (UADE) ................................................................................. 27
ͶǤͺ
	Ǧ 	   ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹ͹
ͶǤͻ
 	 	 	ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹ͹
5. STATISTICAL CONSIDERATIONS .............................................................................................................................. 27
ͷǤͳ
   ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹͺ
ͷǤʹ
   ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹͺ
ͷǤ͵
 ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹͺ
ͷǤͶ
  ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹͻ
ͷǤͷ
 ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹͻ
ͷǤ͸
 ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵Ͳ
ͷǤ͹

  	  ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵Ͳ
5.7.1  Multiple Comparisons and Multiplicity ........................................................................................................................... 30
5.7.2  Covariates ..................................................................................................................................................................................... 30
5.7.3  Planned Subgroups ................................................................................................................................................................... 30
5.7.4  Missing Data ................................................................................................................................................................................ 31
5.7.5 Demographic and Baseline Characteristics ................................................................................................................... 31
ͷǤͺ
		 ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵ͳ
5.8.1  Primary Efficacy Endpoint .................................................................................................................................................... 31
5.8.2  Secondary Efficacy Endpoints ............................................................................................................................................. 31
5.8.3  Other Endpoints ......................................................................................................................................................................... 32
ͷǤͻ
	 ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵ʹ
ͷǤͳͲ
 ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵͵
6. STUDY PRODUCT MANAGEMENT ............................................................................................................................ 33
͸Ǥͳ 

  
ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵͵
͸Ǥʹ

ǡ 
ǡ   ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵͵
7. RECORDS MANAGEMENT ............................................................................................................................................ 33
͹Ǥͳ  ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵͵
͹Ǥʹ
 ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵͵
͹Ǥ͵
	 
    ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵͵
͹ǤͶ
     ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵Ͷ
8. QUALITY CONTROL AND QUALITY ASSURANCES .............................................................................................. 34
ͺǤͳ
 
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Protocol No. CAP-CP-001 
Page 3 of 50 
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WRITTEN AUTHORIZATION FROM AXOGEN  
 
 
 
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ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵Ͷ
9. ETHICS AND RESPONSIBILITY .................................................................................................................................. 34
10. CLINICAL STUDY REPORT ........................................................................................................................................ 35
11. CONFIDENTIALITY ..................................................................................................................................................... 35
12. REGULATORY CONSIDERATIONS .......................................................................................................................... 35
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13. REFERENCES ................................................................................................................................................................. 37
APPENDIX A: INVESTIGATOR AGREEMENT .............................................................................................................. 41
APPENDIX B: SCHEDULE OF ASSESSMENTS .............................................................................................................. 42
APPENDIX C: INSTRUCTIONS FOR USE AXOGUARD® NERVE CAP (LB-580 R04)  ........................................ 43
 
 
 

Protocol No. CAP-CP-001 
Page 4 of 50 
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WRITTEN AUTHORIZATION FROM AXOGEN  
 
 
 
 
ACRONYMS: 
 
 
AE: 
 
Adverse Effects / Events 
 
CRA:   
Clinical Research Associate 
 
CRF(S):  
Case Report Forms 
 
CTA:   
Clinical Trial Agreement 
 
ICH:  
International Conference on Harmonization  
 
IRB:   
Institutional Review Board 
 
EOS:   
End of Study 
 
EOT:   
End of Treatment 
 
EU: 
 
European Union 
 
FDA:   
Food and Drug Administration 
 
FHSQ:  
Foot Health Status Questionnaire 
 
GCPs:   
Good Clinical Practices 
 
IDE: 
 
Investigational Device Exemption 
 
ISO:   
International Standards Organization 
 
PROMIS®:  
Patient Reported Outcome Measurement Information System 
 
SAE:   
Serious Adverse Event 
 
UADE: 
Unanticipated Adverse Device Effect  
 
VAS:   
Visual Analogue Scale 
 
WIRB:  
Western Institutional Review Board (central IRB) 
 
 
 

Protocol No. CAP-CP-001 
Page 6 of 50 
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WRITTEN AUTHORIZATION FROM AXOGEN  
 
 
 
Pharmacological methods may employ antidepressants, anticonvulsants, agonists, opioids, and lidocaine. 
Unfortunately, although pharmacological therapy may lead to transient relief, amputees often experience 
considerable side effects and reduced benefit over time, not to mention the possibility of abuse and 
dependency.13 Multiple clinical and non-clinical studies have demonstrated that neuroma pain is best 
controlled by the use of opioid medications, as it is refractory to other first-line neuropathic pain 
medications.14,15  For some amputees suffering from neuroma pain, the improvement in function offered 
by effective pain control is worth the trade-off of moderate to severe side effects including the risk of 
hyperalgesia.14 However, chronic use of opioid analgesics is associated with an increased risk of 
dependence and abuse.16 Local treatment options, such as cauterization and steroid, phenol, and alcohol 
injections are merely a temporary solution as repeated injections are required.6 Thus, a better approach to 
long-term relief may be surgical methods designed to prevent neuromas and eliminate or reduce 
symptomatic neuroma pain. 
 
This study is to evaluate the safety and performance of the Axoguard Nerve Cap for surgical nerve 
amputation in the treatment of symptomatic neuroma compared to neurectomy. By providing a new 
treatment option to surgeons, the vision is for patients to benefit from reduced pain, improved 
rehabilitation outcomes, reduced dependence on opioids, and overall better quality of life.  We predict that 
the partition design of the Axoguard Nerve Cap will cushion the axons within the nerve end and protect 
them from external stimulation and prevent painful neuroma formation post implant.  
 
1.2     Product Description 
Axoguard® Nerve Cap is a surgical implant that is a tubular device with one open end, one sealed end 
(cap) and internal channels designed to provide protection for a peripheral nerve end or stump where 
repair is unattainable or not desired. The device isolates the nerve stump from the surrounding soft tissue 
bed by pulling the nerve into the tube and suturing the nerve within the cap. The end of cap has a 
suturable tab to allow the surgeon to suture the device to surrounding tissue.  See Figure 1.2-1 for Image 
of Axoguard® Nerve Cap, and figure 1.2-2 for Image of placement of Axoguard® Nerve Cap. 
 
Axoguard® Nerve Cap is an extracellular matrix (ECM) that is fully remodeled during the healing 
process. When hydrated, Axoguard® Nerve Cap is easy to handle, soft, pliable, nonfriable and porous. 
Axoguard® Nerve Cap is flexible and pliable to accommodate movement of the joints and surrounding 
soft tissues and has sufficient mechanical strength to hold appropriately sized non-absorbable suture.  
 
Processed porcine ECM is readily and available proven to be safe and effective in a wide range of 
clinical applications.17, 18   
 
Axoguard® Nerve Cap is provided sterile, for single use only, and in a variety of sizes to meet clinical 
needs.  The device is supplied in a plastic tray within a sterile pouch. The pouch is heat-sealed to 
provide a sterile barrier and has a chevron seal.  Contents of the package are guaranteed sterile unless 
the package is opened or damaged. Axoguard® Nerve Cap and packaging does not contain natural 
rubber latex.19  To assure patient safety, the small intestine submucosa (SIS) material undergoes a 
thorough disinfection, decellularization, and viral inactivation process. As a final step in the process, all 
SIS products are sterilized by validated sterilization methods.20 
 

Protocol No. CAP-CP-001 
Page 7 of 50 
Final Version 3.0 
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WRITTEN AUTHORIZATION FROM AXOGEN  
 
 
 
Porcine ECM processed by Cook Biotech is decelluarized and elicits an immune response that is 
predominately Th-2-like, promoting remodeling of soft tissues rather than eliciting an acute rejection 
response.21  
 
Axoguard® Nerve Cap should be stored in a clean, dry location between 10 – 30°C/50 – 86°F. The 
device should be used prior to the “Use By” date specified on the package. The “Use By” date is in the 
form Year-Month-Day.19  
 
Regulatory Classification: Axoguard® Nerve Cap is a class II device which obtained 510(k) clearance 
(K163446).24  
 
 
 
Figure 1.2-1: Image of Axoguard® Nerve Cap 
 
  
 
 
Figure 1.2-2: Diagram placement of the Axoguard® Nerve Cap 
 

Protocol No. CAP-CP-001 
Page 8 of 50 
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WRITTEN AUTHORIZATION FROM AXOGEN  
 
 
 
 
1.3     Risk Analysis 
Axoguard® Nerve Cap is contraindicated for use in any patient for whom soft tissue implants are 
contraindicated; this includes any pathology that would limit the blood supply and compromise healing 
or evidence of a current infection. Axoguard® Nerve Cap is derived from a porcine small intestinal 
submucosa (also called SIS) and should not be used for patients with known sensitivity to porcine 
derived materials.19 
 
If any of the following conditions occur and cannot be resolved, careful removal of the device should be 
considered: 
x Infection; 
x Allergic reaction; and/or 
x Acute or chronic inflammation (initial application of surgical graft materials may be associated 
with transient, mild, localized inflammation). 
 
As with any surgical procedure, complications can occur such as pain, infection, decreased or increased 
nerve sensitivity, and complications associated with the use of anesthesia. 
 
Additional complications that may be associated with these types of procedures may potentially occur 
after implantation.  These complications may be expected and are not required to be recorded unless 
they increase in severity: 
x mild incisional redness 
x tenderness of surgical area 
x mild edema of surgical area  
x controllable pain at surgical area 
x decreased sensation; and/or  
x numbness 
 
The following precautions should be taken into consideration prior to implanting the Axoguard® Nerve 
Cap:19 
 
Adverse events associated with the use of Axoguard® Nerve Cap may include but are not limited to: 
x Failure to reduce symptomatic neuroma pain 
x Transitory local irritation 
x Infection 
x Allergy 
x Delayed wound healing; and/or 
x Protrusion 
 
1.3.1 Preclinical Testing for Axoguard® Nerve Cap 
Comprehensive in vitro and in vivo biocompatibility evaluations provide support that Axoguard® Nerve 
Cap 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 

Protocol No. CAP-CP-001 
Page 12 of 50 
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WRITTEN AUTHORIZATION FROM AXOGEN  
 
 
 
 
3.2.1 Study Product 
Description: Axoguard® Nerve Cap is a surgical implant that is a tubular device with one open end, one 
sealed end (cap) and internal channels designed to provide protection for a peripheral nerve end or 
stump where repair is unattainable or not desired. The device isolates the nerve stump from the 
surrounding soft tissue bed by pulling the nerve into the tube and suturing the nerve within the cap. The 
end of cap has a suturable tab to allow the surgeon to suture the device to surrounding tissue.  
 
Axoguard® Nerve Cap is provided sterile, for single use only, and offered in a variety of sizes to allow 
the surgeon to choose the appropriate size to address the injured tissue.  Multiple patient labels with 
product code, lot number and expiration date are provided for subject records.   
 
Federal (U.S.A.) law only allows Axoguard® Nerve Cap to only be sold under or by the order of a 
physician.  This product is intended for use by trained medical professionals only.  
 
3.2.2 Control 
Description: Standard surgical treatment with neurectomy. 
 
Neurectomy is a surgical treatment for symptomatic neuroma.  It entails neuroma excision with high 
transection of the nerve. The goal is to relocate the nerve stump proximally into an area more protected 
by muscle and soft tissue, where it is less likely to become irritated and symptomatic.33 
 
3.3     Study Population 
Adult male and female subjects (age ≥ 18 years old) with symptomatic neuroma in the foot or ankle to at 
least one nerve where the nerve cannot be repaired to a distal nerve end. 
 
3.4     Eligibility Criteria 
 
3.4.1  Informed Consent 
Authorized written informed consent (witnessed, where required by law or regulation) 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 prior to obtaining consent.  
However, informed consent must be obtained and documented on a written IRB approved consent form 
prior to initiation of any procedures that are performed solely for the purpose of determining eligibility 
for research.  The site 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 current Good Clinical Practices (GCP) as described in the ISO 14155:2011 standard; 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, prior to submission to 
the IRB/IEC. 
 

Protocol No. CAP-CP-001 
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WRITTEN AUTHORIZATION FROM AXOGEN  
 
 
 
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 all associated risks with 
participating on the study, 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 site 
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  
Potential Subjects must: 
1. Be able and willing to provide documented informed consent prior to the conduct of any study 
procedures; 
2. Be an adult male or non-pregnant female ≥ 18 years of age;  
3. Report baseline pain scores of >65mm on a 100mm Visual Analog Scale (VAS) at screening;   
4. Have a documented diagnosis of symptomatic neuroma of at least one interdigital nerve in the foot 
which cannot be repaired to a distal nerve end; 
5. Must have the following: 
x 
Pain with at least 3 of the following characteristics: burning, sharp, shooting, electric, 
parasthesias, numbness, cold intolerance; 
x 
Symptoms in a defined neural anatomic distribution 
x 
History of nerve injury or suspected nerve injury 
Must have at least 1: 
x 
Positive response to local anesthetic injection 
x 
US or MRI confirmation of neuroma 
6. Be candidates indicated for surgery to address a symptomatic neuroma;  
7. Have sufficient healthy soft tissue available to adequately cover the Axoguard® Nerve Cap; 
8. In the surgeon’s opinion, be likely to achieve complete resection of the symptomatic neuroma and 
be able to undergo implantation with the Axoguard® Nerve Cap or complete the neurotomy 
procedure in the control group; 
9. Be willing and able to comply with all aspects of the treatment and evaluation schedule over a 12-
month duration.  
 
 
 
 
 
 

Protocol No. CAP-CP-001 
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WRITTEN AUTHORIZATION FROM AXOGEN  
 
 
 
 
 
3.4.3  Exclusion Criteria 
To be included in the study, the following criteria must not occur: 
 
Table 3.4.3-1 Exclusion Criteria 
Potential subjects must not: 
1. Have undergone surgical treatment of pain from symptomatic neuroma in the target nerve(s)on 
three or more occasions; 
2. Have biomechanical pathology and associated pain (such as plantar fasciitis, bursitis, sesamoid 
bone pain, tendinitis, etc); 
3. Have a life expectancy of less than 12 months; 
4. Have a history of or planned radiotherapy in the area of the end-neuroma; 
5. be contraindicated for soft tissue implants.; this includes but is not limited to any pathology that 
would limit the blood supply; compromise healing or indicate the presence of a local infection; 
6. Have a history of chronic ischemic conditions of the extremity; 
7. Have a diagnosis of type 1 Diabetes Mellitus; or uncontrolled Type 2 Diabetes Mellitus (at the 
discretion of the investigator); 
8. Have a history of diabetic neuropathy; 
9. Be undergoing or expected to undergo treatment with chemotherapy, radiation therapy, or other 
known treatment which affects the growth of neural and/or vascular system; 
10. Be immunosuppressed, immunocompromised or have planned immunosuppressive therapy within 
12 months following the study procedure; 
11. Have a History of congenital neuropathy or compressive neuropathy affecting the target limb; 
12. Have a history of prior surgical management of more proximal compressive neuropathies or spinal 
conditions (e.g. spinal stenosis) not related to the symptomatic neuroma that affect the target limb; 
13. Currently use or likely need to use medication during the study known to impact nerve regeneration 
or to cause peripheral neuropathy; 
14. be pregnant or plan to become pregnant during the duration of the study; 
15. Be or have been enrolled in another interventional study within 30 days prior to consenting; 
16. Have a known allergy to anesthetic agents; 
17. Have a known sensitivity to porcine derived materials; or 
18. Be, in the opinion of the Investigator, unsuitable for inclusion in the study. 
 
 
 
 
 
 

Protocol No. CAP-CP-001 
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-
- 
 
 
3.4.4  Enrollment in Study 
3.4.4.1  Treatment of Multiple Neuromas 
In instances where subjects have multiple neuromas in the foot/ankle, the surgeon must identify the 
target nerve for inclusion in this study, and agree to treat all additional neuromas as per the 
randomization assignment. Additionally, if subjects are diagnosed with bilateral neuromas (whether 
interdigital or elsewhere in the foot/ankle) each limb and all affected nerves must follow the same 
randomization assignment. Please note, for instances of bilateral neuromas, surgical treatment for each 
foot may be completed at the same time, but no later than 270 days after subject randomization.  
 
For instances when surgical intervention cannot be completed for the contralateral foot by day 270, 
further surgical intervention is to occur after the subject has completed the study, or study participation 
must discontinue. 
3.4.4.2  Subject Screening and Numbering 
After the subject has signed an IRB-approved informed consent form, he/she 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. In the comparative phase, randomization 
will occur intra-operatively, and a randomization number will be assigned to identify the enrolled 
subject. 
3.4.4.3  Subject Withdrawal or Discontinuation 
If a subject discontinues early from the study, the reason should be recorded in source documentation 
and the CRF.  If the subject is withdrawn due to an adverse event, the adverse event should be indicated 
as the reason for withdrawal.  All subjects have the right to withdraw at any point during the study 
without prejudice.  The Investigator (in consultation with the sponsor) can discontinue a subject’s 
participation at their discretion at any time if medically necessary or in the case of non-compliance with 
the study protocol at. 
 
The investigator shall promptly notify the sponsor 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 discontinuation. 
3.4.4.4  Subject Replacement 
Once a subject is randomized, they may not be replaced.  
 
3.5     Study Endpoints 
 
3.5.1 Safety Endpoints   
Primary Safety Endpoint 
1. The rate of occurrence of Serious Adverse Events (SAEs) at 3 months 
2. The rate of occurrence of Adverse Experiences (AEs) or Unanticipated Adverse Device Effects 
at 3 months 
 
Secondary Safety Endpoints 

Protocol No. CAP-CP-001 
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and mobilization of the nerve stump will be per performed in accordance with the 
Investigator’s/Institution’s standards-of-care.  After interoperative confirmation of eligibility is 
determined, randomization will occur.  For patients randomized to receive Axoguard® Nerve Cap, the 
investigator will determine nerve diameter and select an appropriately sized Axoguard® Nerve Cap to fit 
the nerve stump, accounting for post-operative swelling and sufficient to allow easy insertion of the 
nerve stump into the device.  Entubulation should be conducted in accordance with the product 
instructions for use (see IFU appendix C).  Photographs of the surgical site, neuroma prior to resection 
and post-treatment (i.e. surgical implant or resected end) should be taken, if possible.  Wound closure 
and immobilization will occur based on the institution’s standard of care.  Subjects will be followed for 
a total of 12 months post-operatively.  Standardized assessments will occur at each visit.  Study 
assessment time points are summarized below and in the Schedule of Assessments (see Appendix B).   
3.9.1  Visit 1: Pre-Operative Screening  
 
Once informed consent has been obtained, the subject will be assigned a screening number and the 
following pre-operative assessments will be performed at the Pre-Operative Screening visit  
1. Assess Inclusion/Exclusion criteria  
2. Obtain relevant vital signs (height / weight) 
3. Identify relevant medical history 
4. Demographics 
5. Assess for Neuroma  
6. Pain Assessments (VAS, PROMIS®) prior to nerve block  
7. Pain Assessment (VAS) post nerve block (if applicable) 
8. Quality of Life Questionnaires (FHSQ 
 
 
9. Concomitant Medication review and Daily Pain Medication Diary issuance (treatments 
including quantity and class of pain medications, dispense and review with subject)  
10. Dispense Daily Pain Diary (review instructions with subject)  
11. For subjects with multiple neuromas, additional Neuroma Information must be captured for 
each neuroma treated. 
 
 
3.9.2  Visit 2: Operative Day, Day 0  
The following will be collected during the Operative Day: 
1. Verify Inclusion/Exclusion criteria 
2. Obtain Vital signs 
3. Document Operative Information: description of nerve injury presentation and location, and 
implantation information – see sequence below19 
4. Randomization (comparative study only) 
5. Pain Assessments (VAS, PROMIS®) prior to nerve block, if not performed during screening 
6. Pain Assessment (VAS) post nerve block, if not performed during screening 
  
8. Concomitant Medication review and Daily Pain Medication Diary review (treatments 
including quantity, quality and class of pain medications, review with subject and re-educate 
if needed) 
9. Daily Pain Dairy (review with subject prior to Pain Assessments, re-educate if needed) 
10. Adverse Events review 

Protocol No. CAP-CP-001 
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-
- 
 
 
  
 
The following sequence of steps will take place intraoperatively for the Nerve Cap group:19 
1. After debridement and mobilization of the nerve stump, determine the nerve diameter in 
millimeters (mm).   
2. Select an Axoguard® Nerve Cap to fit the nerve stump, accounting for post-operative 
swelling and to allow easy insertion of the nerve stump into the device.  If there is no 
Axoguard® Nerve Cap that matches the diameter of the nerve stump, select the device that is 
one size larger. 
3. Hemostasis of the proximal nerve stump must be achieved prior to beginning the 
entubulation procedure. If a tourniquet is used, release the tourniquet and achieve hemostasis 
before entubulating.  
4. Open the outer carton and remove the chevron pouch. Using standard aseptic technique, open 
the pouch and pass the inner tray into the sterile field for further handling.  
5. Open the tray and fill the pre-molded reservoir with room temperature sterile saline or sterile 
Lactated Ringer’s solution. Allow the Axoguard® Nerve Cap to hydrate for at least 10 
seconds or until the desired handling characteristics are achieved, but not more than 20 
minutes. NOTE: Small diameter Axoguard® Nerve Caps may need to be hydrated by flushing 
the lumen of the cap with solution. Care should be taken to avoid puncturing the Axoguard® 
Nerve Cap during this process.  
6. Transfer the Axoguard® Nerve Cap from the reservoir and entubulate approximately 3-5 mm 
of the nerve stump into the Nerve Cap. Entubulate the stump by passing the suture (non-
absorbable) through the wall of the tube from outside to inside at least 2 mm from the edge. 
Then pass the suture transversely through the epineurium of the nerve stump at a distance of 
at least 1 mm from the cut nerve face. Reverse the suture and pass it through the wall of the 
Axoguard® Nerve Cap by pulling the suture so that the nerve stump is drawn into the cap. 
Ensure that the nerve stump face is linearly aligned within the cap. To reduce the potential 
risk for misalignment, avoid abutting the nerve stump up to or inserting past the internal 
partition.   
7. Tie suture securely being careful not to generate excess tension at the suture site.  If desired, 
add sutures to secure the device to the nerve stump. 
8. The lumen of the Axoguard® Nerve Cap may be gently filled/flushed with sterile saline or 
Lactated Ringer’s solution. Ensure the nerve stump is not expelled from the tube while 
irrigating the lumen.  
9. Once the Axoguard® Nerve Cap is securely sutured onto the nerve stump, the distal tab of the 
Nerve Cap may be sutured to a plane of surrounding soft tissue if desired (e.g., muscle or 
fascia). Tie the suture so that it is secure but avoid generating tension on the nerve when 
securing.   
10. Prior to surgical site closure, visually confirm final alignment of the nerve within the cap.  
11. Close the surgical site as required by your institutional practices or professional judgement 
concerning patient care.  
12. Discard any unused portions of the Axoguard® Nerve Cap according to institutional 
guidelines for biological waste.  
 

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recorded using standard medical terminology in order to avoid the use of vague, ambiguous, or 
colloquial expressions.  
 
Concurrent illnesses that are present at or before study device administration, which manifest with the 
same severity, frequency, or duration subsequent to study device administration, need not be recorded as 
AEs. Similarly, signs or symptoms related to a pre-existing disease (prior to patient consenting) need not 
be recorded as AEs and will be recorded in the medical history CRF.  However, medical history events 
that increase in severity or duration must be reported on the AE CRF.   
 
Each AE must be promptly recorded and sufficiently documented by the Investigator or a qualified 
designee, even if the AE is assessed by the Investigator as unrelated to therapy with study device. The 
Investigator or qualified designee should attempt, if possible, to establish a diagnosis based on the 
presenting signs and symptoms. Each AE must also be described by date and time of onset, date and 
time of cessation, frequency (intermittent or continuous), the action taken (change in study device, 
concomitant medication, etc.), and outcome. In addition, the site Investigator must evaluate all AEs with 
respect to their severity and relationship to the study device according to the definitions given in the 
above tables 4-1 and 4-2. 
 
 
4.6     Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that occurs per the following 
definition:39 
    
x Results in death; 
x Is immediately life threatening – In the opinion of the site Investigator, the participant was at 
substantial risk of dying at the time of the event, or use or continued use of the device might have 
resulted in the death of the subject; 
x Requires in-patient hospitalization or prolongation of existing hospitalization.Complications that 
occur during hospitalization are adverse events, and if a complication prolongs hospitalization, 
the event is considered serious.  Emergency room visits that do not result in overnight hospital 
admissions should be evaluated for one of the other serious outcomes (e.g., life-threatening; 
required intervention to prevent permanent impairment or damage);  
x Results in disability or Permanent Damage - substantial disruption of a person's ability to 
conduct normal life functions, i.e., resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in body function/structure, physical activities and/or quality of 
life; 
x Results in a Congenital Anomaly/Birth Defect - suspect that exposure to the device prior to 
conception or during pregnancy may have resulted in an adverse outcome in the child; or 
x Requires Intervention to Prevent Permanent Impairment or Damage – medical or surgical 
intervention was necessary to preclude permanent impairment of a body function, or prevent 
permanent damage to a body structure, either situation suspected to be due to the use of the 
device. 
x Other Serious (Important Medical Events) - when the event does not fit the other outcomes, but 
the event may jeopardize the subject and may require medical or surgical intervention 

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4.7.1  Reporting of Unanticipated Adverse Device Effects (UADE) 
The Investigator should report any unanticipated adverse device effects to the Sponsor and the IRB as 
soon as possible, but no less than 10 working days after the site Investigator first learns of the UADE. 
The Sponsor must immediately conduct an evaluation of the UADE and determine whether the UADE 
presents an unreasonable risk to the subject. If an unreasonable risk is concluded, the Sponsor shall 
terminate all or part of the investigation as soon as possible but no later that 5 working days after the 
Sponsor make the determination and no later than 15 working days after the Sponsor first learns of the 
effect.  
 
4.8     Follow-up of Adverse Events 
All adverse events ongoing at the final study visit will be followed by the site Investigator: 
 
x until the adverse event has resolved; or 
x until the subject is lost to follow-up; or 
x until the adverse event is stabilized or deemed a permanent disease or condition. 
 
“Resolution” of an AE occurs when the subject has returned to his/her baseline state of health or when 
the site Investigator does not expect any further improvement or worsening of the AE.  On the last 
clinical study day, the 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 site Investigator will continue to report any significant follow-up information to the 
Sponsor or designee. 
 
All SAEs that occur up to 30 days following the subject’s last study assessment must be reported 
immediately to the medical monitor.  
 
4.9     Review of Safety Information 
The Sponsor shall promptly review all information relevant to the safety of the study device 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.  
 
5. STATISTICAL CONSIDERATIONS 
Descriptive statistical methods will be used to summarize the data from this study. 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.  All data collected during the study will be 
included in data listings.  Unless otherwise noted, the data will be sorted by subject number, and then by 
date within each subject number. 
 

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5.10     Study Success 
Study success is defined as demonstrating the reduction in pain by VAS score with the treatment of 
Axoguard® Nerve Cap is superior to the reduction in VAS score for neurectomy group 
 
  In addition, there should be no clinically significant difference of product 
related adverse events rates following implantation of Axoguard® Nerve Cap compared to neurectomy.  
 
6. STUDY PRODUCT MANAGEMENT 
6.1    Packaging and Labeling 
Commercially available product will be used. 
 
6.2     Handling, Storage, and Disposal 
Per product specifications as defined in the Instructions for Use (see Appendix C). 
 
7. RECORDS MANAGEMENT 
7.1    Data Collection 
During each subject’s visit, the Investigator or designee shall document all significant observations.  
Information from the source documents will be promptly transcribed to either a paper case report form 
(CRF) document or an electronic data capture system (EDC) via electronic CRFs. 
 
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 study personnel 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 site 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 subject’s clinical record at the site and a copy shall be given to the subject and/or legally 
authorized representative.  All Daily Pain Diaries and Concomitant and Pain Medication Diaries will be 
collected from the site by the sponsor representative or designee and may be included in the final data 
analysis. 
 
7.3     File Management at the Study Site 

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It is the responsibility of the site Investigator to ensure that the site files are adequately and accurately 
maintained in accordance with Section 8 of the International Conference on Harmonization (ICH) 
Guideline for Good Clinical Practice (GCP) FDA regulations and ISO 14155:2011.  
 
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.  Study 
sites must obtain approval from the study sponsor prior to discarding any study records. 
8. QUALITY CONTROL AND QUALITY ASSURANCES 
8.1     Data Management Considerations 
Data analysis will be overseen by the Sponsor’s Data Management Team. All data associated with this 
study will be held to a 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 Management 
Team 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 is maintained.   
 
Quality control checks will be established for each data procedure to ensure accuracy and to preserve the 
integrity of the data.  Onsite interim monitoring visits will be conducted by the Sponsor’s Clinical 
Research Associate (CRA).   
 
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 a contact log to include telephone and written communications. 
  
8.3     Auditing 
The Sponsor or Regulatory representatives 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, logs/forms, 
training and qualifications.  The site Investigator agrees to participate with audits conducted.  
 
Regulatory authorities may audit the site Investigator or clinical site.  The site Investigator should 
contact the Sponsor of any such audits, whether the audit is related to the study, immediately upon 
notification 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, ICH and GCP 
Guidelines, ISO 14155:2011 and all other applicable regulatory requirements.  

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The study protocol and the written informed consent form must receive a favorable review and/or 
approval from the governing IRB/IEC with the responsibility to approve research for the study site.  The 
site Investigator will not participate in the approval process of a clinical study he/she is conducting.  If 
the site Investigator is an IRB/IEC member, the written approval must indicate such non-participation. 
 
The site Investigator will submit study status reports to the IRB/IEC in accordance with local IRB/IEC 
requirements. The site Investigator must notify the IRB/IEC in writing of the interruption and/or 
completion of the study.  The site 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 site Investigator will promptly report 
to the IRB/IEC all unanticipated problems involving risks to subjects or others.  The site 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 
a final clinical study report will be prepared at the completion of the study.  This report will be provided 
to the collaborative site Investigators.  
 
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 written permission from Axogen, Corp.  
However, authorized regulatory officials and Axogen, Corp. 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, Corp.  
 
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 required.   Under the 
Health Insurance Portability and Accountability Act (HIPAA), Axogen, Corp. is committed to 
upholding the security and privacy provisions for protected health information (PHI) of the Act (1996) 
and the additional obligations introduced by the HIPAA Omnibus Final Rule (2013).    
 
12. REGULATORY CONSIDERATIONS 
12.1     Amendments 
The site Investigator will not make any changes to this protocol without prior written consent from the 
Sponsor and subsequent approval by the IRB/IEC.  Any 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 site 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 

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responsibility.  Except for ‘administrative amendments’ site 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.   
 
When, in the judgment of the chairman of the IRB/IEC, the site 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, re-consenting will be obtained from each enrolled subject at the onset of their next scheduled 
study visit.  
 
 
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 site Investigator or designee 
must notify the sponsor as soon as possible.  This will allow for an early, joint decision regarding the 
subject’s continuation in the study.  This decision will be documented by the site Investigator and the 
Sponsor and be reviewed by the study monitor.  
 
12.3     Sponsor and Site Investigator Responsibilities 
The Sponsor and participating site Investigators shall be responsible for the conduct of this clinical study 
in compliance with the study protocol, FDA 21 CFR parts 50, and 56, ICH/GCP guidelines (ICH E6), 
ISO 14155:2011, and applicable local regulatory requirements and study specific trial agreements. All 
site Investigators will agree to comply with the protocol and these responsibilities by signing the 
Investigator Agreement in Appendix A. 
 
 

Protocol No. CAP-CP-001 
 
 
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APPENDIX A: INVESTIGATOR AGREEMENT 
 
Agreement Signatures 
 
I have read and understand the protocol 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 Corporation’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 agree to allow Axogen, 
Corp. 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, Corp. any adverse 
events in accordance with the terms of Axogen, Corp. (or designee’s) Clinical Trial Agreement (CTA).  
I further agree to provide all required information regarding financial certification or disclosure to 
Axogen, Corp. for all site Investigators and site 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 (GCPs) and other GCP regulations (including ISO 
14155:2011), and local regulatory requirements.  
 
 
 
_________________________________ 
 
_________________________________ 
 
Printed Name  
 
Date 
 
 
Signature 
 
 
Date 
Principal Investigator   
 
 
 
Principal Investigator  
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol No. CAP-CP-001 
 
 
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APPENDIX C: INSTRUCTIONS FOR USE Axoguard® Nerve Cap (LB-580 R04) 

Protocol No. CAP-CP-001 
 
 
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