Effects of Postoperative Percutaneous Peripheral Nerve Stimulation on Acute and Chronic Amputation Pain
Phase: NA
Conditions: Phantom Limb Pain, Postoperative Pain, Neuroma, Acute Pain, Chronic Pain, Residual Limbs, Amputation
Sponsor: Hunter Holmes Mcguire Veteran Affairs Medical Center

 
1 
 
 
2 
EFFECT OF POSTOPERATIVE 
PERCUTANEOUS PERIPHERAL 
NERVE STIMULATION ON 
ACUTE AND CHRONIC 
AMPUTATION PAIN 
Hunter Holmes McGuire VA Medical Center 
Richmond, VA 
Protocol version 1.2 – June 11, 2018 
      
Denise Lester, M.D., Brooke Trainer, M.D., Robert Trainer, D.O.  
Douglas Murphy, M.D., Michael Amendola, M.D., Erik Baker, D.O.  
Thomas Phan, M.D., Claudia Kem-Bumbala, R.N. 
Christina Johnson, P.A., Kenneth Stutz, P.A. 

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Protocol Version 1.2 –  June 11, 2018  
 
Table of Contents 
 
 
 
 
 
 
 
Page 
 
1. Purpose and Objectives 
 
 
 
 
 
2 
2. Background and Significance 
 
 
 
 
2 
3. Scientific Rationale and Study Design  
 
 
4 
4. Study Outcomes and Exploratory Measures  
 
5 
5. Study Protocol  
 
 
 
 
 
 
6 
6. Data Management 
 
 
 
 
 
 
15 
7. Risks and Benefits 
 
 
 
 
 
 
17 
8. Data and Safety Monitoring 
 
 
 
 
20 
9. Consultants 
 
 
 
 
 
 
 
21 
10. Appendix  
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 Purpose and Objectives 
3 
1.1 
Purpose  
4 
This prospective randomized controlled trial evaluates the feasibility of using percutaneous peripheral nerve 
5 
stimulation (PNS) to reduce acute post-surgical pain in nontraumatic lower extremity amputation and 
6 
decrease the incidence and/or severity of chronic phantom limb pain (PLP) or residual limb pain (RLP).  
7 
The use of a novel, intentionally reversible, single-lead, PNS system has demonstrated promising results in 
8 
the management of chronic pain syndromes including PLP and RLP (7).  This study will apply the same 
9 
PNS system to nontraumatic transfemoral or transtibial amputees (TFA or TTA, respectively) in the post-
10 
operative setting within 5-7 days after surgery to evaluate the feasibility and efficacy of peripheral nerve 
11 
stimulation in the management of acute and chronic PLP and RLP. 
12 
1.2 
Objectives  
13 
The goal of this study is to demonstrate that PNS is a safe, effective method of reducing acute and chronic 
14 
pain in the nontraumatic lower extremity amputee, and can lessen the use of opioid pain medications.  This 
15 
pilot study will evaluate the feasibility of recruitment, randomization, retention, assessment procedures, 
16 
and implementation of PNS in the acute post-operative period to develop a larger, multicenter, blinded, 
17 
placebo-controlled, randomized clinical trial to evaluate efficacy in reducing acute and chronic PLP and 
18 
RLP.  Upon completion, we will assess the reliability and validity of the proposed study design.  In 
19 
conducting this investigation, we hope to answer the following questions: 
20 
- 
What is the feasibility of placing a PNS system in a transfemoral or transtibial amputee in the acute 
21 
post-operative period?   
22 
- 
Does PNS produce clinically significant reductions in acute PLP or RLP? 
23 
- 
Does the application of PNS in the acute post-operative period reduce the incidence and severity 
24 
of chronic PLP and RLP?  
25 
- 
Can PNS lessen the use of opioid and non-opioid pain medications? 
26 
- 
Does PNS affect time to prosthesis fitting, function outcomes (Functional Independence Measure 
27 
[FIM] scores), wound healing, incidence of neuromas, time to hospital discharge, 30-day 
28 
readmission rate, and hospital discharge survey answers? 
29 
1.3 
Study Hypothesis  
30 
Percutaneous peripheral nerve stimulation may provide clinically significant relief of acute post-surgical 
31 
pain in nontraumatic lower extremity amputation and decreases the incidence and/or severity of chronic 
32 
PLP and RLP when applied in the acute post-operative setting.   
33 
2.0 Background and Significance  
34 
2.1 
Background 
35 
Amputees commonly experience acute and chronic post-amputation pain.  Amputation leads to persistent 
36 
pain in up to 70-90% of patients, resulting in decreased quality of life, increased risk of depression, and 
37 
negative impacts on interpersonal relationships and ability to work (10).  The prevalence of persistent PLP 
38 
or RLP in amputees is estimated to range from 45 to 74% for RLP and 51 to 85% for PLP (11, 12).  Pain 
39 
secondary to loss of limb, rather than the loss of limb itself, has a larger effect on ability to perform activities 
40 
of daily living, complete simple tasks, and shows a negative correlation with return to work (13).  Post-
41 
amputation pain can also impact the ability to use a prosthesis. 
42 
When present, post-amputation pain is difficult to manage. More than 50 different treatments have been 
43 
developed for PLP, yet most have been unsuccessful (1).  In many studies, acute PLP intensity was the only 
44 

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Protocol Version 1.2 –  June 11, 2018  
 
significant independent predictor of chronic PLP intensity at 6 and 12 months after amputation (2).  Liu et 
45 
al have demonstrated the most significant risk factor for post-procedure pain (PPP) for total knee and total 
46 
hip arthroplasties to be acute postoperative pain (3).  Increased postoperative Visual Analog Scale (VAS) 
47 
scores on days 1 to 5 has correlated with PPP at 3 months (4). 
48 
Perioperative pain management in lower extremity amputations commonly involves a multimodal approach 
49 
utilizing pharmacologic and interventional therapies (8).  Both acute and persistent post-amputation pain is 
50 
commonly managed with opioids which are associated with undesirable adverse effects such as nausea, 
51 
vomiting, sedation, and respiratory depression.  Further, they often result in unsatisfactory reductions in 
52 
post-amputation pain and have the potential for addiction and misuse (14).  Several interventional therapies 
53 
are available for use in the perioperative setting, however there is no consistent therapy that has been shown 
54 
to prevent the development of persistent post-amputation RLP or PLP (8).  Karanikolas et al demonstrated 
55 
that optimized epidural analgesia and/or intravenous patient-controlled analgesia (PCA) in the perioperative 
56 
setting decreases PLP intensity, prevalence, and frequency at 6 months after amputation (23).  This study 
57 
did not assess sustained pain relief beyond 6 months, and RLP was not significant in the study population.   
58 
Peripheral nerve catheter based pre-emptive analgesia has become an essential component of Standard 
59 
Medical Therapy (SMT) at the Hunter Holmes McGuire VA Medical Center (VA) in lower extremity 
60 
amputations to prevent onset of chronic pain, decrease opioid use, and decrease health care utilization (both 
61 
inpatient and outpatient).  The efficacy of peripheral nerve catheter-based regional analgesia for pain relief 
62 
in the immediate postoperative period is well documented.  However, associated motor, sensory, and 
63 
proprioceptive deficits can increase the risk of falling (15) and duration of use is limited due to risk of 
64 
infection (16).  This intervention is limited by the fact that peripheral infusion catheters (typically femoral 
65 
and sciatic nerve catheters) must be removed by postoperative day 5 to reduce the risk of infection.  
66 
Furthermore, Apfelbaum demonstrated in a large study that many patient’s worst incidence of postoperative 
67 
pain occurs after discharge (5).  Given this safety limitation and the need for continued pain control in the 
68 
entire perioperative period, this study seeks to augment this therapy with a percutaneously placed PNS 
69 
system.  This is expected to extend the period of perioperative pain control to greater than 30 days and 
70 
beyond. There is convincing evidence in studies thus far showing that when a PNS system is applied to 
71 
chronic pain sufferers, it can extend the treatment effect well beyond the time in which it is implanted.  To 
72 
date, the system studied is the only intentionally reversible, percutaneously placed PNS system.  More 
73 
comprehensive and earlier treatment of acute pain is believed by many in the field to be even more effective 
74 
(6,7). 
75 
2.2 
Literature Review  
76 
PNS has been studied for the treatment of some chronic pain syndromes (7, 17-19), including persistent 
77 
post-amputation pain.  The mechanism of action of peripheral nerve stimulation in pain relief is commonly 
78 
explained using the “gate control theory” of Melzack and Wall (20).  This theory explains that electrical 
79 
current-induced activation of large-diameter myelinated afferent peripheral nerve fibers inhibits the 
80 
transmission of pain signals from small-diameter pain fibers to the central nervous system at the level of 
81 
the spinal cord (15).  Rauck et al (7) showed that 9 of 14 subjects who completed two-weeks of PNS therapy 
82 
reported reductions in mean daily worst post-amputation pain, average RLP and PLP, and interference from 
83 
RLP and PLP at least one month after the end of treatment.  Interference from RLP or PLP refers to how 
84 
pain has interfered with general activity, mood, walking ability, work, relations with others, sleep, and 
85 
enjoyment of life.  PNS was shown to be effective in reducing post-amputation pain when most pain is 
86 
confined to one or two nerve distributions (7, 21-22).  Results showed that 14 of 16 subjects reported ≥75% 
87 
paresthesia coverage from PNS, obtained clinically significant pain relief, and proceeded to a 2-week home 
88 
trial with this system.  9 subjects completed the 2-week trial and 5 subjects did not complete the trial because 
89 

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Protocol Version 1.2 –  June 11, 2018  
 
of accidental dislodgement (N=2), temporary discomfort near the lead (N=2), and return of post-amputation 
90 
pain despite stimulation (N=1). The 9 responders who completed the home trial reported reductions in their 
91 
mean daily worst post-amputation pain (56 ± 26%, 56 ± 26%, N = 9), average residual limb pain (72 ± 
92 
28%, 42 ± 27%, N = 7), average phantom limb pain (81 ± 28%, 47 ± 48%, N = 7), interference from residual 
93 
limb pain (81 ± 27%, 53 ± 17%, N = 6), interference from phantom limb pain (83 ± 31%, 56 ± 46%, N = 
94 
7), and Pain Disability Index (PDI) (70 ± 38%, 55 ± 32%, N = 9) during the 2nd week of stimulation and 4 
95 
weeks after the end of stimulation, respectively. All 9 responders rated their change in quality of life as 
96 
improved at the end of stimulation and at the end of the 4-week follow-up period. 
97 
3.0 Scientific Rationale and Study Design 
98 
3.1 
Scientific Rationale  
99 
The feasibility of using PNS to reduce acute postoperative pain is not currently well documented in medical 
100 
literature.  A preliminary report demonstrated the use of PNS to treat pain after total knee arthroplasty in 
101 
10 subjects who experienced postoperative knee pain difficult to control with oral analgesics between 6 and 
102 
97 days after surgery.  Nine out of 10 subjects experienced at least 57% decrease in pain, and half had 
103 
complete resolution of pain at rest (9).  The application of PNS in the treatment of acute postoperative 
104 
amputation pain and the efficacy of using PNS to prevent or reduce the severity of persistent PLP or RLP 
105 
has not been documented. 
106 
Currently, literature documenting the use of PNS in postoperative amputation pain is limited.  The PNS 
107 
system in this study has been used previously to evaluate the reduction in chronic post RLP or PLP (7).  
108 
There is an ongoing multi-site investigation evaluating the use of PNS in chronic pain after traumatic lower 
109 
extremity amputation.  To date, there is no study that documents the use of PNS therapy in the acute 
110 
postoperative period after TFA or TTA.   This study aims to report on the feasibility and efficacy of using 
111 
PNS in this clinical setting to evaluate reductions in acute post-amputation pain, incidence or severity of 
112 
chronic post-amputation pain, and reliance on opioid medications amongst other outcome measures as 
113 
described in Section 4.0: Study Outcomes and Exploratory Measures. 
114 
3.2 
Study Design  
115 
This prospective randomized controlled trial aims to assess the feasibility of using a novel percutaneous 
116 
peripheral nerve stimulator system to produce clinically significant reductions in acute post-surgical pain 
117 
after nontraumatic lower extremity amputation, and evaluate reductions in the incidence and/or severity of 
118 
chronic PLP or RLP.  Subjects who have moderate pain 2 to 7 days after transfemoral or transtibial 
119 
amputation surgery will be enrolled and randomized to Group 1 (“Treatment Group”) or Group 2 (“Control 
120 
Group”).  Subjects in Group 1 will be treated with 30 to 60 days of PNS in addition to SMT.  Subjects in 
121 
Group 2 will be treated with the SMT alone.  SMT is defined as the same routine medical care given to all 
122 
patients, regardless of whether they are enrolled in the study.  This may include, but is not limited to non-
123 
opioid and opioid pain medications, regional anesthesia peripheral nerve blockade, daily postoperative 
124 
visits by the Acute Pain Service, and follow-up appointments in the Interventional Pain Clinic.   
125 
• 
Group 1: 30 to 60 days of peripheral nerve stimulation starting within 7 days after surgery and 
126 
Standard Medical Therapy 
127 
• 
Group 2: Standard Medical Therapy only 
128 
Subjects are evaluated daily by study investigators from the time of study enrollment to hospital discharge.  
129 
Subsequent telephone or outpatient clinic evaluations occur at intervals which are detailed in the Schedule 
130 
of Study Procedures (Appendix). 
131 

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Protocol Version 1.2 –  June 11, 2018  
 
4.0 Study Outcomes and Exploratory Measures 
132 
4.1  
Primary Outcomes 
133 
4.1.1 Effect of PNS on acute pain after lower extremity amputation 
134 
The Brief Pain Inventory Short Form (BPI) is a 9-item questionnaire used to evaluate the severity of a 
135 
patient's pain and the impact of this pain on the patient's daily functioning.  The patient is asked to rate their 
136 
worst, least, average pain, and rate the degree that pain interferes with general activity, mood, walking 
137 
ability, normal work, relations with other persons, sleep, and enjoyment of life on a 10-point scale.  Levels 
138 
of PLP and RLP are re-assessed at follow-up Visits according to the Schedule of Study Procedures.  
139 
Questions used to assess pain or sensation are listed below.  For BPI #3, #4, and #5, responses are recorded 
140 
on an 11-point scale from “0” to “10” with “0” defined as “No Pain” and “10” defined as “Pain as Bad as 
141 
You Can Imagine.”   
142 
• 
Check yes or no if you experienced any (phantom limb or residual limb) sensation in the last 
143 
24 hours. 
144 
• 
BPI #3: “Please rate your (phantom limb or residual limb) pain by marking the box beside the 
145 
number that best describes your pain at its worst over the last 24 hours.” 
146 
• 
BPI #4: “Please rate your (phantom limb or residual limb) pain by marking the box beside the 
147 
number that best describes your pain at its least over the last 24 hours.” 
148 
• 
BPI #5: “Please rate your (phantom limb or residual limb) pain by marking the box beside the 
149 
number that best describes your pain on the average over the last week.” 
150 
4.1.2 Effect of PNS on the incidence and severity of chronic pain after lower 
151 
extremity amputation 
152 
Chronic pain (i.e. pain persisting for more than 2 to 3 months after TFA or TTA surgery will be evaluated 
153 
using BPI questions #3, #4, and #5 as above at follow-up Visits according to the Schedule of Study 
154 
Procedures.  Data will be compared between groups to assess for differences in the incidence and severity 
155 
of chronic pain.   
156 
4.2 
Secondary Outcomes 
157 
4.2.1 Interference due to Pain  
158 
BPI #9 will be assessed at intervals defined in the Schedule of Study Procedures.  This question asks 
159 
subjects to rate how pain has interfered with various aspects of life: “Mark the box beside the number that 
160 
describes how, during the past 24 hours, pain has interfered with your: (a) General activity (b) Mood (c) 
161 
Walking ability (d) Sleep (e) Enjoyment of life.”  Responses are recorded on an 11-point scale from “0” to 
162 
“10” with “0” defined as “Does Not Interfere” and “10” defined as “Completely Interferes.”   
163 
4.2.2 Patient Global Impression of Change (PGIC) Scale 
164 
Participant ratings of global improvement are one of the core outcome domains in chronic pain studies 
165 
(Dworkin et al. 2005).  Patient Global Impression of Change (PGIC) Scale is assessed at intervals defined 
166 
in the Schedule of Study Procedures, which rates perception of change in activity limitations, symptoms, 
167 
emotions, and overall quality of life in relation to pain since beginning treatment.  The scale ranges from 0 
168 
defined as “No change” to 7 defined as “A great deal better, and a considerable improvement that has made 
169 
all the difference.”  Responses are collected by telephone or outpatient office evaluations in the 
170 
Interventional Pain Clinic.    
171 

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4.2.3 Pain Disability Index (PDI) 
172 
The Pain Disability Index (PDI) a simple and rapid instrument for measuring the impact that pain has on 
173 
the ability of a person to participate in essential life activities. This can be used to evaluate patients initially 
174 
to monitor them over time and to judge the effectiveness of interventions. The index was developed at St. 
175 
Louis University Medical Center.  PDI) is assessed at intervals defined in the Schedule of Study Procedures, 
176 
which measures subjects’ disruption in various aspects of life secondary to chronic pain, including 
177 
family/home responsibilities, recreation, social activity, occupation, sexual behavior, self-care, and life-
178 
support activities.  Each category is rated on an 11-point scale from “0” to “10” with “0” defined as “No 
179 
Disability” and “10” defined as “Worst Disability.”  Responses are collected by telephone or outpatient 
180 
office evaluations in the Interventional Pain Clinic.  
181 
4.2.4 Pain Catastrophizing Scale (PCS) 
182 
The PCS is a widely-used, validated and reliable 13-question instrument to assess rumination (4 
183 
questions), magnification (3 questions), and helplessness (6 questions) (Sullivan, 2009.; Osman et al. 
184 
1997). The survey asks participants to think back on painful experiences in the past and reflect on how 
185 
often they had specific thoughts or feelings. Each question is scored on a 0-4 scale with 0 = “not at all” 
186 
and 4 = “all the time”. Higher scores indicate a greater tendency towards catastrophizing pain, which has 
187 
been correlated with worse postoperative pain and response to pain therapies (Riddle et al 2010; Pavlin et 
188 
al 2005; Forsythe et al 2008).  
189 
4.2.5 Analgesic use and Opioid-related Side Effects 
190 
All opioid and nonopioid pain medication use will be assessed at intervals according to the Schedule of 
191 
Study Procedures.  The Virginia Prescription Monitoring Program Database will be queried.  Subjects will 
192 
be asked if they are taking any medications for pain.  Subjects will be asked to count their remaining number 
193 
of pills of narcotic pain medication at each follow-up encounter. 
194 
4.2.6 Functional Independence Measure (FIM) 
195 
The FIM provides a uniform system of measurement for disability based on the International 
196 
Classification of Impairment, Disabilities and Handicaps.  The FIM instrument measures the level of a 
197 
patient's disability and indicates how much assistance is required for the individual to carry out activities 
198 
of daily living.  A baseline mobility FIM will be recorded with the assistance of the Department of 
199 
Physical Therapy shortly after amputation but before stimulator placement (Group A) and follow-up FIM 
200 
will be recorded at the 4 and 8-week outpatient clinic visits. Improvement in FIM will be evaluated and 
201 
compared between groups.    
202 
4.2.7 Patient Outcomes and Hospital Discharge Survey 
203 
Other secondary outcomes including time to prosthesis fitting, wound healing, incidence of neuromas, time 
204 
to hospital discharge 30-day readmission rate, and hospital discharge survey will be documented from the 
205 
electronic medical record and compared between groups.  
206 
5.0 Study Protocol 
207 
5.1 
Study Materials  
208 
The SPRINT™ Peripheral Nerve Stimulator (PNS) System will be used by subjects in Group 1.  Up to two 
209 
SPRINT Systems (i.e. 1 lead per stimulator) will be used by each subject.  
210 

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Protocol Version 1.2 –  June 11, 2018  
 
5.2 
Concurrent Medications and Non-Drug Therapies  
211 
Subjects in both groups will receive SMT, which may include medication and/or non-drug therapies.  
212 
However, subjects in both groups should not perform any rehabilitation activities that may conflict with the 
213 
device Instructions for Use (such as water therapy) during the study. 
214 
5.3 
Patient Recruitment 
215 
Patients planned for nontraumatic TFA or TTA will be screened at the Vascular Clinic.  A Waiver of 
216 
Informed Consent for Recruitment Purposes and a Waiver of Authorization for Recruitment Purposes will 
217 
be submitted to the Institutional Review Board (IRB). Protected Health Information (PHI) will be used to 
218 
locate and review appropriate medical records (CPRS, and paper medical records) to determine study 
219 
eligibility.  If a patient appears to meet all eligibility criteria (see Eligibility, Section 5.4), then he/she will 
220 
be contacted by study investigators and given information detailing study objectives, procedures, follow-
221 
up encounters, assessments, and potential risks and benefits.  If the patient agrees to participate, he/she will 
222 
be asked to sign the Consent Form.  Study staff will explain the process randomization, lead placement, 
223 
data collection, and follow-up encounters.  All baseline information and outcome measurements will be 
224 
collected and recorded on the appropriate Case Report Forms. 
225 
5.4 
Eligibility 
226 
5.4.1 Inclusion Criteria 
227 
Inclusion criteria are nontraumatic transfemoral or transtibial amputation (TFA or TTA, respectively) and 
228 
age over 18..   
229 
5.4.2 Exclusion Criteria 
230 
Exclusion criteria are systemic infection, immunosuppressive disorder, implanted electronic devices, 
231 
pregnancy, previous allergy to skin contact materials and/or anesthetic agent altered mental status, inability 
232 
to provide consent, greater than 180 morphine equivalents (MED) per day. 
233 
5.5 
Study Plan  
234 
The study includes 13 Visits.  Please refer to the Appendix for a schedule of study procedures for both 
235 
groups as well as outcomes measured at each visit.   
236 
Patients planned for nontraumatic TFA or TTA will be screened by the study investigators who are working 
237 
on the Acute Pain Service (APS).  APS is usually consulted for all transfemoral and transtibial amputations 
238 
to provide perioperative anesthesia, which typically includes placement of a peripheral nerve catheter for 
239 
local anesthetic blockade.  When a potential subject is identified, study investigators will begin a chart 
240 
review for screening purposes.  The investigators will review the medical record of potential subjects and 
241 
complete Form 00 (Screening and Demographic Information).  Chart review will include the collection of 
242 
name, social security number and date of birth from CPRS, the ORC, and the Vascular Clinic.  Protected 
243 
Health Information (PHI) will be used to locate and review appropriate medical records (CPRS and paper 
244 
medical records) to determine study eligibility.  If a subject appears to meet all eligibility criteria (see 
245 
Section 5.4. Eligibility), then he/she will be contacted by study investigators and given recruitment 
246 
materials detailing study objectives, randomization, procedures, follow-up encounters, assessments, and 
247 
potential risks and benefits.  The subject will be provided with patient information pertaining to the 
248 
peripheral nerve stimulator system under investigation.  If permitted by the subject, a sponsor representative 
249 
or their designee may be present at any of the study visits to advise on material handling and answer 
250 
questions as needed. 
251 

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Protocol Version 1.2 –  June 11, 2018  
 
Patients who are interested in participation will be asked to complete a Beck Depression Inventory (see 
252 
Form BDI) to be screened for depression (must score 20 or less) prior to enrollment.  Veteran participants 
253 
who are evaluated by study staff and suspected to be depressed will be further evaluated by a psychiatrist 
254 
or psychologist utilizing the Mental Health Consultation and Liaison Service at McGuire VAMC. Research 
255 
study staff will page the C&L service at 351-1067 (Use *601 pager# 9198 after 4pm and on weekends) and 
256 
then walk the participant to the C&L provider to facilitate the evaluation on the day that the participant 
257 

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Protocol Version 1.2 –  June 11, 2018  
 
presents as depressed.  If non-veterans participants are enrolled, arrangements made for him/her to be 
258 
evaluated at a non-VA facility.   
259 
 
260 
Figure 1 Subject flowchart. 
261 

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Patients who agree to participate in the study will be asked to sign the Consent Form.  Ideally, patients 
262 
should provide informed consent and be enrolled in the study prior to surgery.  Typically, the local 
263 
anesthetic peripheral nerve block catheters (or single shock femoral or sciatic nerve blockade) are placed 
264 
on the day prior to surgery or day of surgery.  Subjects will be given the opportunity to enroll in the study 
265 
when the catheter is placed, however, those who wish to decide on enrollment after their surgery may be 
266 
enrolled up until the time in which their peripheral nerve block catheter is removed, which is usually by 
267 
post-op day 5.  Upon enrollment, subjects will be evaluated by APS daily.   
268 
The Consent Form will be scanned into the electronic medical record.  Consent for photographic and video 
269 
recordings will be requested.  If collected, photographs and videos are intended for potential use in 
270 
publications, future grant applications, and educational purposes.  Subjects will receive a copy of their 
271 
consent forms if requested.  HIPPA Forms will be signed.  The Schedule of Study Procedures outlines the 
272 
baseline information and outcome measures recorded at each “Visit” on Case Report Forms (CRFs).  All 
273 
completed paper documents will be securely stored in a locked box placed in a fixed, locked file cabinet in 
274 
the Interventional Pain Clinic on 2C.  Only authorized study personnel will have the keys to access study 
275 
materials containing protected patient information.  A note may be documented in the patient’s electronic 
276 
medical record to indicate participation in the study.  Subjects will be randomized to Group 1 (“Treatment 
277 
Group”) or Group 2 (“Control Group”) (see Section 6.2. Sampling and Randomization Procedures). 
278 
5.5.1 Visit 1: 24-48 hours after removal of peripheral nerve block catheter  
279 
Subjects will be assessed at least 24-48 hours after removal of the peripheral nerve catheter (or after the 
280 
effects of a single shot femoral and/or sciatic nerve block have worn off).  They will be evaluated for post-
281 
surgical complications, and for the presence of phantom limb sensation or pain and RLP.  Average pain 
282 
severity and anatomic distribution will be reported by answering BPI-SF #2 and #5.   
283 
Subjects in Group 1 will proceed to Visit 2 and undergo placement of the peripheral nerve stimulator lead(s) 
284 
by post-op day 7, in addition to receiving SMT.  Subjects in Group 2 will skip to Visit 3.  They will be 
285 
treated with SMT and followed up by study investigators daily until discharged.  They will subsequently 
286 
be followed up by telephone according to the Schedule of Study Procedures.   
287 
5.5.2 Visit 2A: Placement of percutaneous peripheral stimulator leads (Group 1 
288 
only) 
289 
Subjects randomized to Group 1 proceed to placement of the stimulator leads by post-op day 7 to begin 
290 
peripheral nerve stimulation therapy with the SPRINTTM PNS System (Figure 2.1).  The procedure for 
291 
placement of the peripheral nerve stimulator lead (Figure 2.2) is similar to placement of a peripheral nerve 
292 
catheter for local anesthetic blockade.  The main difference is that instead of delivering medications, 
293 
electrical stimulation is applied to the peripheral nerve over a wide range of parameters.  Also, the stimulator 
294 
lead does not need to be placed as close to the nerve as a local anesthetic peripheral nerve catheter.  This 
295 
study will evaluate the application of one or two leads per subject: one for the femoral nerve and/or one for 
296 
the sciatic nerve.   Lead placement is expected to take up to 2 hours.   
297 
Before placement of the lead, test stimulation with a needle electrode is performed to determine an 
298 
appropriate location for stimulator wire lead placement, assess for nerve function, and to confirm that the 
299 
subject’s pain is responsive to stimulation.  The relevant section of the leg will be cleansed and a test 
300 
stimulation needle electrode will be percutaneously inserted within 0.5-3 cm of the femoral nerve under 
301 
mandatory ultrasound-guidance.  For comfort, local anesthesia may be administered at the insertion site.  
302 
The needle electrode is connected to the battery-powered electrical stimulator device, which is used to 
303 
deliver electrical stimulation to confirm electrode placement distance from the nerve trunk.  If the patient 
304 
feels subcutaneous sensations proximal to the test needle, which indicates stimulation of afferent nerve 
305 

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Protocol Version 1.2 –  June 11, 2018  
 
fibers in the local region superficial to 
306 
the electrode, then the needle is 
307 
advanced slightly (0.2-0.5 cm) and test 
308 
stimulation is delivered again.  The 
309 
process of advancing the needle 
310 
electrode 
and 
adjusting 
stimulus 
311 
intensity 
is 
repeated 
in 
small 
312 
increments 
until 
comfortable 
313 
paresthesia as are evoked in the distal 
314 
regions of postoperative amputation 
315 
pain without causing uncomfortable 
316 
sensations 
or 
unwanted 
motor 
317 
contractions.  If this is not achieved, 
318 
the needle electrode is withdrawn, and 
319 
the test stimulation procedure is 
320 
repeated until a satisfactory location is 
321 
determined.  Once a suitable entry site is determined, the fine-wire stimulator lead will be placed. Each 
322 
subject in Group 1 may undergo placement of one to two leads in relation to the femoral and/or sciatic 
323 
nerves.  The techniques and procedures described below may be adapted as needed on a case-by-case basis. 
324 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lead placement near the femoral nerve uses an anterior approach guided by anatomic landmarks including 
325 
the inguinal ligament, inguinal crease, and femoral artery.  The subject will be in supine position with 
326 
ipsilateral extremity slightly (approximately 10-20o) abducted.  The lead introducer is inserted near but 
327 
below the inguinal crease and approximately 1 cm lateral to the pulse of the femoral artery.   
328 

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Protocol Version 1.2 –  June 11, 2018  
 
 
 
 
 
 
Lead placement near the sciatic nerve uses the posterior transgluteal or subgluteal approaches that are 
329 
commonly practiced in regional anesthesiology.  Landmarks for the transgluteal approach include the 
330 
greater trochanter and the posterior superior iliac spine.  The subject is placed in lateral decubitus position, 
331 
and the lead introducer is aimed approximately 4 cm distal to the midpoint between the greater trochanter 
332 
and the posterior iliac spine to target the sciatic nerve.  Landmarks for the subgluteal region include the 
333 
Figure 3. Example of a percutaneous anterior 
approach that may be used to access the femoral 
nerve. The inguinal crease (noted with dotted 
line), femoral artery (noted with an “A”), and 
needle insertion site (noted with a circled “X”) are 
shown on the right leg. 
Figure 4. Cross section shows the femoral nerve 
(FN), femoral artery (FA), and femoral vein (FV) 
relative to surrounding structures of adipose tissue 
and muscle (e.g. sartorius muscle, iliopsoas 
muscle, and pectineus muscle; and the white 
dashed-line box indicates the area scanned in the 
ultrasound image in Figure 6.  
 
Figure 5. Needle insertion using out of plane 
ultrasound guidance (ultrasound transducer is 
perpendicular to the needle) is shown but in plane 
ultrasound guidance may also be used.  
 
Figure 6. Ultrasound image shows the FN (at the 
bottom right tip of the white line) relative to the 
FA, FV, and the iliopsoas muscle (IPM) (adapted 
from Ultrasound for Regional Anesthesia). 
Adapted from SPR TherapeuticsTM 

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Protocol Version 1.2 –  June 11, 2018  
 
greater trochanter and the ischial tuberosity, and the lead introducer is aimed approximately 4 cm distal to 
334 
the midpoint between the greater trochanter and the ischial tuberosity.   
335 
 
336 
Alternate anatomic approaches for lead placement (e.g. popliteal approach for sciatic nerve) may be utilized 
337 
to optimize safety and improve patient response.  Once a lead has been placed, stimulus parameters will be 
338 
adjusted to determine the settings necessary to evoke comfortable sensations that overlap with the regions 
339 
of pain associated with TFA or TTA surgery.  Parameters which can be adjusted include amplitude (mA), 
340 
duration (μs), and frequency (Hz).  Study staff will attempt to determine the parameters which produce the 
341 
most comfort as endorsed by the subject.  These parameters will vary from subject to subject and may be 
342 
adjusted as needed throughout the study.   
343 
Once satisfactory lead placement and stimulus parameters have been achieved, subjects will begin the 30 
344 
to 60-day treatment phase.  Subjects will be provided with a manual and educated on the use and care of 
345 
the device.  Stimulation may be delivered continuously up to 24 hours per day until the end of therapy.  
346 
Figure 7. Example of a percutaneous posterior 
approach that may be used to access the sciatic 
nerve. The dashed line bisecting the line between 
the greater trochanter (GT) and ischial tuberosity 
(IT) indicates the sciatic nerve and the midpoint 
(“x”) marks the needle insertion location 
 
 
Figure 8. Cross section shows the sciatic nerve 
(arrowhead) surrounded by the gluteus maximus 
muscle (GMM), quadratus femoris muscle 
(QFM), adipose tissue, IT, and GT. 
 
Figure 9. The ultrasound probe is placed 
perpendicular to the sciatic nerve to provide a 
transverse image as the needle is inserted.  
 
Figure 10. Ultrasound image shows the sciatic 
nerve (arrowhead) relative to surrounding 
structures (adapted from Ultrasound for Regional 
Anesthesia). 
 
Adapted from SPR TherapeuticsTM 

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Protocol Version 1.2 –  June 11, 2018  
 
Leads will be indwelling no more than a total of 60 days.  If a lead is dislodged or broken prior to the end 
347 
of therapy, the subject may be offered the opportunity for a lead replacement depending on their willingness 
348 
to undergo the lead replacement procedure and time remaining in the treatment period.  
349 
If the subject provides media consent, photographs and video of the lead placement procedure may be 
350 
recorded and are intended for potential use in publications, future grant applications, and educational 
351 
purposes. Media may be stored on VA CAC access computers on a HIPAA-compliant share drive. 
352 
5.5.3 Visit 2B: Daily hospital evaluations until discharge 
353 
Subjects in both groups will be evaluated by study investigators daily until they are discharged.  The length 
354 
of stay is approximately 14 days for TFA per VASQIP 2016 quarter 4 data (Veterans Affairs Surgical 
355 
Quality Improvement Program).  Based on this data, subjects in Group 1 will likely be discharged 7 to 14 
356 
days after starting peripheral nerve stimulation.  Group 1 subjects will be asked questions to re-assess the 
357 
stimulation-evoked paresthesia coverage of the leg.  Stimulator devices will be inspected to ensure 
358 
appropriate function.  Lead exit sites are inspected for skin irritation, infection, and inflammation.  These 
359 
risks will be minimized by using sterile leads and sterile technique.  Maintenance, care of the leads and lead 
360 
exit sites, and bandage changes will be performed as needed.  Subjects in both groups will be evaluated for 
361 
the presence of phantom sensations, as well as least, worst, and average PLP or RLP according to the 
362 
Schedule of Study Procedures.    
363 
. 
364 
5.5.4 Visits 3, 4 and 5: Weekly telephone follow-up evaluations 
365 
Visits 3, 4 and 5 consist of weekly telephone evaluations at 1, 2 and 3 weeks after starting peripheral nerve 
366 
stimulation (Group 1) or discontinuation of peripheral nerve block (Group 2).  If issues related to the 
367 
peripheral nerve stimulator device or leads occur and cannot be resolved by telephone, subjects may be 
368 
evaluated in the Interventional Pain Clinic as needed.   
369 
Subjects are asked to rate their worst, least, and average PLP and RLP (BPI #3, #4, and #5).  A medical 
370 
reconciliation will be completed during each phone evaluation by asking the subject how many pills of 
371 
narcotic pain medications they have left and querying the Virginia Prescription Monitoring Program 
372 
Database.   
373 
5.5.5 Visit 6: First outpatient clinic evaluation / 30 days after start of PNS 
374 
All subjects are asked to return to the Interventional Pain Clinic at 4 weeks after the start of peripheral nerve 
375 
stimulation.  Stimulator devices (Group 1) will be inspected to ensure appropriate function.  Lead exit sites 
376 
are inspected for skin irritation, infection, and inflammation.  Maintenance, care of the leads and lead exit 
377 
sites, and bandage changes will be performed as needed.   
378 
All subjects are asked to rate their worst, least, and average PLP and RLP (BPI #3, #4, and #5).  Subjects 
379 
will rate the degree with which pain has interfered with general activity, mood, walking ability, sleep, and 
380 
enjoyment of life (BPI #9).  Pain Disability Index (PDI) and Patient Global Impression of Change (PGIC) 
381 
will be assessed.  A medical reconciliation will be completed during each phone evaluation by asking the 
382 
subject how many pills of narcotic pain medications they have left and querying the Virginia Prescription 
383 
Monitoring Program Database.   
384 
5.5.6 Visit 7, 8, and 9: Weekly follow-up telephone evaluations  
385 
Visits 7, 8, and 9 consist of weekly telephone evaluations at 5, 6, 7 weeks after starting peripheral nerve 
386 
stimulation (Group 1) or discontinuation of peripheral nerve block (Group 2).  If issues related to the 
387 

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Protocol Version 1.2 –  June 11, 2018  
 
peripheral nerve stimulator device or leads occur that cannot be resolved by telephone, subjects may be 
388 
evaluated in the Interventional Pain Clinic if needed.   
389 
Subjects are asked to rate their worst, least, and average PLP and RLP (BPI #3, #4, and #5).  A medical 
390 
reconciliation will be completed during each phone evaluation by asking the subject how many pills of 
391 
narcotic pain medications they have left and querying the Virginia Prescription Monitoring Program 
392 
Database.   
393 
5.5.7 Visit 10: Second outpatient clinic evaluation / up to 60 days after start of PNS 
394 
All subjects are asked to return to the Interventional Pain Clinic at approximately 60 days after starting 
395 
peripheral nerve stimulation (Group 1) or discontinuation of peripheral nerve block (Group 2).  Stimulator 
396 
leads will be removed by gentle traction.  The lead will be visually inspected by study staff to evaluate for 
397 
lead fracture   In the case of a retained lead fragment, study staff will determine the most appropriate medical 
398 
plan to further evaluate and treat the subject.  In most instances, retained lead fragments do not need to be 
399 
removed and are rarely associated with further complications.  Lead exit sites are inspected for skin 
400 
irritation, infection, and inflammation.  Both groups will continue to be treated with SMT as needed until 
401 
the end of participation in the study.  Subjects in Group 1 are encouraged to complete the entire 60-days of 
402 
peripheral nerve stimulation, however are free to discontinue treatment at any time during the treatment 
403 
phase.   
404 
5.5.8 Visits 11, 12, and 13: Phone evaluations at 3, 6, and 12 months after study 
405 
enrollment 
406 
Telephone evaluations for both groups occur at approximately 3, 6, and 12 months after study enrollment.  
407 
Outcome measures to be assessed are listed in the Schedule of Study Procedures.  
408 
5.5.9 Unscheduled Visits/Lead Replacements 
409 
Unanticipated complications related to the PNS system may occur, including technical issues with the 
410 
device, assistance with bandage change or lead exit site care, or adverse events requiring further evaluation 
411 
by study staff.  Most issues may be addressed by telephone.  Subjects may return to clinic for further 
412 
evaluation if necessary.  Based on the discretion of the subject and study investigators, a decision may be 
413 
made to allow the subject to continue in the study or be discharged.   
414 
5.6 
Facilities and Resources 
415 
Subjects will be screened at the Vascular Clinic.  Lead placement will take place in the Interventional Pain 
416 
Clinic (IPC) or at the subject’s bedside.  Study data, recruitment materials, and sensitive patient information 
417 
will be stored in a fixed, locked file cabinet in the IPC in 2C-117.  Peripheral nerve stimulators and all 
418 
related materials will be stored in a locked cabinet in the IPC.  Devices will be labeled and designated 
419 
specifically for research purposes.  Only these labeled devices may be used in the study.   
420 
Study investigators who have received necessary training on the study procedures will be performing the 
421 
placement of the peripheral nerve stimulator lead wire.  Procedures include but are not limited to: (1) 
422 
placement of stimulator lead under ultrasound guidance, (2) removal of stimulator lead at the end of the 30 
423 
to 60-day treatment period (3) replacement of stimulator lead (if applicable). 
424 
5.7 
Study Staff  
425 
Denise Lester, M.D. (Principle Investigator (PI), Assistant Professor, Anesthesiologist and Algologist) 
426 
oversees all research related activities and leads the research team in developing the experimental protocol, 
427 
conducting data analysis, writing and editing literature for publication, placing the stimulators, and may 
428 
assist with following up with subjects. 
429 

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Protocol Version 1.2 –  June 11, 2018  
 
Douglas Murphy, M.D. (Project Mentor, Regional Amputee Center Medical Director, Polytrauma and 
430 
Amputee Musculoskeletal/Ultrasound Fellowship Director) provides expertise in the care of amputees and 
431 
assists with protocol development.   
432 
Brooke Trainer, M.D. (Co-Investigator, Assistant Professor, Staff Anesthesiologist, and Acute Pain 
433 
Physician) will assist with development of the protocol, screening of subjects, data analysis, placement of 
434 
the stimulators, and following up with subjects. 
435 
Robert Trainer, D.O. (Co-Investigator, Director of Interventional Pain Services, Anesthesiologist and 
436 
Pain Physician) will participate in placement of the stimulators, follow up with subjects, and assist with 
437 
protocol development and data analysis. 
438 
Erik Baker, D.O. (Co-Investigator, Staff Anesthesiologist, Acute Pain Physician) will participate in 
439 
placement of the devices and follow up with subjects.  
440 
Michael Amendola, M.D. (Co-Investigator, Chief of Vascular Surgery) will assist with development of 
441 
the protocol and follow-up with subjects in the Vascular Clinic.  
442 
Thomas Phan, M.D. (Co-Investigator, Physical Medicine and Rehabilitation PGY-3 resident) will assist 
443 
with developing the research protocol, create the Case Report Forms and patient diary document, follow up 
444 
with subjects, collect data, conducting data analysis, and write and edit literature for publication.   
445 
Claudia Kem-Bumbala, R.N. (Co-Investigator, Registered Nurse, Board certified by the American Nurses 
446 
Credentialing Center for Pain Management) follow up with subjects and assist with clinical activities and 
447 
procedures. 
448 
Christina Johnson, P.A. (Co-Investigator, Anesthesia Physician Assistant) will assist with screening and 
449 
follow-up with subjects.   
450 
Kenneth Stutz, P.A. (Co-Investigator, Anesthesia Physician Assistant) will assist with screening and 
451 
follow-up with subjects.   
452 
5.8 
Study Duration 
453 
The duration of this investigation is expected to be 18-24 months.  We anticipate enrolling 2-4 patients per 
454 
month.  Each patient’s participation will last approximately 12 months. 
455 
6.0 Data Management 
456 
6.1 
Sample Size 
457 
The investigation seeks to broaden the knowledge of the effects of neuromodulation on acute post-operative 
458 
pain in nontraumatic lower extremity amputation.  The aim is to evaluate the feasibility of implementing 
459 
PNS in TFA or TTA in the acute post-operative period. 16 subjects will be randomized into two groups 
460 
with 8 each.  Sampling will not be restricted by race or gender.  The sample size of 16 is expected to allow 
461 
the investigators to conduct a cost-effective yet informative pilot study to assess the logistics of placing the 
462 
device as described in this protocol, evaluate safety, and report any clinically significant differences in 
463 
primary and secondary outcomes between Treatment and Control Groups.  The study outcomes will be 
464 
reported in nontraumatic TFA or TTA, many of which are secondary to dysvascular disease.  Although this 
465 
is a specific subset of all amputations that are performed, dysvascular disease accounts for a sizeable 
466 
proportion of limb loss in the US with an estimated prevalence of 38-82% (24, 25).  The results of this 
467 
investigation will be used to refine the study design, recruitment, randomization, retention, and assessment 
468 
procedures, and ultimately develop a larger, multicenter, randomized controlled trial to further evaluate 
469 

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Protocol Version 1.2 –  June 11, 2018  
 
treatment efficacy, adverse effects, and cost efficiency.  To improve generalizability, subsequent 
470 
investigations will seek to include a wider subset of amputations which may be accomplished with the 
471 
addition of more study sites. 
472 
6.2 
Sampling and Randomization Procedures 
473 
Based upon historical data on amputations at the HHM-VAMC, there are estimated to be one to two 
474 
amputations per week that would qualify for enrollment in this study.  Subjects will be screened for 
475 
enrollment through the vascular surgery clinic.  A considerable proportion of vascular clinic patients will 
476 
require lower extremity amputation and are usually scheduled for next day surgery due to the urgency of 
477 
presentation.  Study investigators will conduct a chart review of potential subjects and complete Form 01-
478 
A (screening and demographic information).  Based on the chart review, if a patient appears to meet all 
479 
eligibility criteria, then they will be contacted by study investigators for potential enrollment.  If the patient 
480 
agrees to participate, they will be consented and randomized to Group 1 or Group 2.   
481 
Prior to the start of this study, a member of the study staff that is not involved with recruitment or data 
482 
evaluation will be responsible for generating a random string of group assignments long enough to fill all 
483 
anticipated spots in this study.  The numbers will be placed in secure envelopes by blocks of two.  A block 
484 
of two will contain one assignment to the Treatment Group and one assignment to the Control Group.  As 
485 
subjects are consented and enrolled in the study, they will be assigned an envelope which randomizes them 
486 
to a group.  Subjects are not blinded to their group assignments.  Subjects in the Treatment Group will 
487 
receive the investigational treatment (30 to 60-days of peripheral nerve stimulation) in addition to SMT.  
488 
Subjects in the Control Group will be treated with the SMT alone. 
489 
6.3 
Data Analysis 
490 
A table of outcome measures recorded during the study can be found in Appendix.  Scores rating daily 
491 
average, worst, and least pain will be compared between groups.  Changes in pain will be evaluated for 
492 
individual subjects and compared between groups.  For each subject, mean pain scores over the first and 
493 
second months following TFA or TTA surgery will be calculated.  An overall mean across all subjects will 
494 
be calculated.  Additionally, sub-analyses will be performed to determine if there is a difference in these 
495 
outcomes between groups over different post-operative phases (such as acute (e.g. days 1-30) or subacute 
496 
(e.g., 1-3 months), or chronic (e.g. >3 months)).  Statistical analysis will be performed with two-sample t-
497 
test, and p-values will be reported without adjustment, consistent with feasibility study design and the 
498 
number of subjects.   
499 
Pain medication usage will be recorded in subject diaries and obtained during follow up encounters. Opioid 
500 
medication use will be analyzed by averaging 24-hour morphine equivalent dosing (MED) over each 
501 
follow-up interval and comparing groups.  Changes in opioid medication use will be reported for individual 
502 
subjects by calculating morphine equivalent dosing (MED).  Average MED will be calculated and 
503 
compared between groups.  The time to cessation of opioid use will be reported.  Side effects associated 
504 
with opioid use will be assessed at each visit and the number of side effects occurring over various intervals 
505 
will be recorded.  Analgesic-related outcomes will be compared between the Groups. 
506 
Patient Global Impression of Change (PGIC), Pain Catastrophizing Scale (PCS), and Pain Disability Index 
507 
(PDI) scores will be averaged for each group and compared.  Data regarding functional outcomes 
508 
(Functional Independence Measure [FIM] score), time to wound healing, incidence of neuromas, prosthesis 
509 
fitting, time to hospital discharge, 30-day readmission rate, and hospital discharge survey will be compared 
510 
between groups.   
511 

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Protocol Version 1.2 –  June 11, 2018  
 
7.0 Risks and Benefits 
512 
7.1 
Potential Benefits 
513 
It is possible that subjects in this study may not receive any direct benefit from their participation in this 
514 
study.  If the investigational treatment is successful, subjects in the Treatment Group may have a reduction 
515 
in acute post-amputation pain, decreased probability of developing chronic post-amputation pain, less 
516 
interference due to pain, decreased opioid medication use, increased tolerance for rehabilitation and 
517 
accelerated functional improvement.  This research may benefit future patients with post-operative pain 
518 
following TFA or TTA.   
519 
7.2 
Potential Risks 
520 
The devices used in this study have been cleared by the United States Food and Drug Administration to 
521 
provide postoperative analgesia.  Potential risks include infection, lead fracture, lead migration and/or 
522 
dislodgement, nerve injury, bleeding, skin irritation, increased pain, and discomfort on insertion, during use 
523 
or with withdrawal.  However, there may be other risks that are currently unknown.  The incidences 
524 
provided are all estimated except for lead fracture. The risks listed below are described as either common 
525 
(occurring more than 10% of the time), uncommon (occurring about 2-10% of the time), or rare (occurring 
526 
less than 1% of the time).  
527 
7.2.1 Infection 
528 
Based on previous studies using this PNS system, the risk of infection is rare.  When compared to 
529 
continuous femoral nerve block and/or continuous sciatic nerve blocks, the risk of infection from a 
530 
percutaneously placed lead near these nerves is expected to be lower.  The risk is thought to be mitigated 
531 
by the inherent structure and design of the lead.  Unlike nerve block catheters, PNS leads do not have an 
532 
internal conduit through which bacteria can enter the body.  The coiled structure of the fine wire lead allows 
533 
it to stretch when pulled, rather than move into or out of the insertion site.  This is thought to minimize the 
534 
potential of introducing bacteria into the body. Lastly, the electrode is designed to have a tight electrode-
535 
skin barrier to help prevent bacterial inoculation.  Infection risk will be minimized by using sterile leads 
536 
and thoroughly cleansing the insertion site with antibacterial solution at the time of insertion.  The insertion 
537 
site will be covered with a dressing to keep it clean and dry, and the subjects will be instructed to inspect 
538 
the site for signs of infection or irritation regularly and to inform the investigator if they occur.  If infection 
539 
occurs, the investigator may administer an antibiotic and/or remove the lead. 
540 
7.2.2 Lead fracture 
541 
Lead fracturing beneath the skin is a common risk, with most or all fractures occurring during the procedure 
542 
to remove the lead.  When this occurs, one or more lead fragments may remain in the body.  Granuloma 
543 
(mild tissue inflammation) is directly related to the risk of retained electrode fragments.  The investigators 
544 
will inspect the lead after removal to determine if any fragments were retained in the body.  If there is 
545 
suspicion of a retained fragment, the investigator will determine if removal of the lead is medically 
546 
necessary.   In most cases, removal is not necessary unless there are further sequalae associated with the 
547 
fragment, such as infection or granuloma.  Retained fragments may also be removed if the subject desires.  
548 
The impact of retained fragments in situ is minimal and in most cases, retained fragments do not need to be 
549 
removed.  
550 
7.2.3 Lead migration and/or dislodgement 
551 
It is possible for a lead to migrate from its original position or become dislodged (i.e. entirely removed from 
552 
the insertion site) during the 30-day treatment period.  This is a common risk.  If migration occurs, the 
553 
subject may experience discomfort during stimulation.  Stimulation near the skin surface may be perceived 
554 

P a g e  19 | 25 
Protocol Version 1.2 –  June 11, 2018  
 
as “pins and needles” which may be uncomfortable to the subject.  Please see below for the steps taken 
555 
cases of discomfort associated with the PNS system.  In cases of significant migration or complete 
556 
dislodgement, a replacement lead may be inserted depending on the desires of the patient and time 
557 
remaining in the treatment period.   
558 
The risk of lead migration or dislodgement is reduced by providing instructions to the subject and their 
559 
caregiver, as appropriate, to ensure careful handling of the lead and lead connector during bandage changes.  
560 
Discomfort or pain due to stimulation may occur if the lead migrates from its original location.  Stimulation 
561 
near the skin surface may be perceived as a “pins and needles” sensation and may be uncomfortable.  
562 
Stimulation parameters or a new lead may be placed if necessary for additional comfort.  A tingling 
563 
sensation may be felt under the pad but this sensation is not expected to be uncomfortable. 
564 
7.2.4 Nerve injury 
565 
The risk of mechanically damaging a nerve with the introducer is rare and will be mitigated by using 
566 
ultrasound to visualize the nerves, surrounding landmarks, and relative position of the introducer. Though 
567 
the lead placement procedure is like the procedure used for regional anesthesia nerve blocks, the lead can 
568 
be placed further away from the nerve when compared to placement of nerve block catheters. The risk of 
569 
nerve injury may be further reduced by proper subject positioning and slow advancement of the 
570 
introducer, stopping approximately 0.5 – 3 cm proximal to the nerve. 
571 
7.2.5 Bleeding 
572 
The risk of bleeding from lead placement is rare and is expected to be no greater than the risk of bleeding 
573 
related to peripheral nerve block catheters.  INR for anticoagulated patients will be available for review as 
574 
patients undergoing surgery will have this checked as a part of routine pre-operative assessment.    
575 
7.2.6 Skin irritation 
576 
It is a common risk for skin to become irritated at the lead exit site, under the stimulator pad (a modified 
577 
surface electrode that is positioned between the skin and the stimulator device), in the area surrounding the 
578 
lead insertion site, and at the site where an adhesive bandage and lead connecter are taped to the skin.  Skin 
579 
irritation is reduced by excluding patients with known sensitivity to skin-contact materials (stickers, 
580 
bandages, tape etc.).  Subjects and their caregivers will be advised to examine the electrode exit site at 
581 
regular intervals to look for any signs of irritation.  To avoid irritation under the pad and lead connector 
582 
tape, subjects will be advised that the stimulator and pad may be moved to various locations near the lead 
583 
insertion site throughout the study.  To avoid irritation under the belt, subjects will be instructed to move 
584 
the belt as needed.  In addition, subjects will be instructed to avoid placing the pad, belt, lead connector 
585 
tapes, or bandages on unhealthy skin.   
586 
7.2.7 Discomfort or increased pain on insertion, during use or with withdrawal 
587 
Like procedures involving percutaneously inserted needles (e.g., injections, needle electromyography, 
588 
acupuncture), discomfort associated with test stimulation/placement of the stimulator lead is possible.  
589 
Usually the discomfort is transient and improves shortly after needle insertion.  Subjects are asked to 
590 
provide feedback on pain or discomfort experienced during the procedure.  Symptomatic relief with local 
591 
anesthesia may be used to reduce discomfort.   
592 
Electrical stimulation is perceived by the subject as tingling or vibratory sensations.  These sensations are 
593 
expected to be comfortable, however it is possible that they can cause discomfort or pain.  Uncomfortable 
594 
sensations are likely directly related to stimulus intensity, which is adjusted on the PNS stimulator.  Pain is 
595 
typically associated with higher intensity levels.  During the lead placement procedure, stimulus intensity 
596 
is adjusted to the determine the minimum and maximum range of intensities that produce comfortable 
597 

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Protocol Version 1.2 –  June 11, 2018  
 
sensations without discomfort or pain.  Prior to completion of the lead placement procedure, an appropriate 
598 
stimulation intensity is set.  Further, the subject can select from a range of intensities determined by the 
599 
investigators as safe and unlikely to cause discomfort.  If a subject ever feels pain related to stimulation, 
600 
they can turn down the intensity or turn the stimulator off.   
601 
Subjects may experience worsening of pain symptoms or may not obtain any therapeutic benefit from the 
602 
system.  Worsening pain could be caused by natural changes in pain during post-operative recovery and 
603 
rehabilitation, or may be caused by electrical stimulation, or the presence of the lead.  This is a common 
604 
risk, but worsening pain is expected to be transient, resolving without additional treatment.  Subjects can 
605 
have their stimulation parameters adjusted throughout the study for optimal comfort, or treatment may be 
606 
discontinued.  These risks are mitigated by clinical training on the safe limits of stimulation and the proper 
607 
placement of the leads. 
608 
7.3 
Risk-Benefit Analysis 
609 
All efforts will be made to reduce the incidence of the potential risks described above.  Despite taking all 
610 
necessary precautions, these events, as well as unanticipated events may still occur.  All procedures will be 
611 
performed by trained attending physicians working within their scope of practice.  Practices will be 
612 
maintained to mitigate the potential risks discussed above.  If an event occurs, the potential for significant 
613 
harm is low because the risks presented have non-serious consequences.  Further, the subjects in the 
614 
Treatment Group may gain no direct benefit from electrical stimulation.  This investigation has inherent 
615 
risks to Treatment Group subjects which are justifiable based on the following rationale: 
616 
The insertion of needles targeting the femoral or sciatic nerves carries the risk of damaging unintending 
617 
structures including nerves, blood vessels, organs, and joint spaces.  The risk of damage to these structures 
618 
is reduced by utilization of ultrasound guidance, knowledge of anatomic landmarks, and awareness of 
619 
needle position and depth.  The physicians performing placement of the PNS system are trained in regional 
620 
anesthesiology with experience in the placement of peripheral nerve block catheters or will receive the 
621 
appropriate training necessary to safely conduct the procedure.  Lead placement for the peripheral nerve 
622 
stimulator requires a needle distance that is further from the target nerve than does placement of a peripheral 
623 
nerve block catheter (5 – 30 mm and 2 mm, respectively).  The increased distance between target nerve and 
624 
needle should lower the risk of injury to unintended structures.  Further, evoked responses to electrical 
625 
stimulation are used to guide lead placement (i.e. the needle is advanced slightly; once stopped, stimulation 
626 
is applied and the subject is evaluated for responses; process is repeated as needed).  If damage to a nerve 
627 
occurs from direct mechanical injury or nerve compression secondary to hematoma, symptoms are expected 
628 
to occur within 24-48 hours.  Subjects are instructed to contact study personnel if any changes in medical 
629 
status occurs. 
630 
The risk of irritation or infection from needle insertion is reduced by cleaning the lead insertion site using 
631 
aseptic technique, sterile test needles, and lead introducer needles.  Needles are not reused.  Subjects with 
632 
systemic infection and/or immunosuppressive disorders will be excluded.  Subjects are instructed to contact 
633 
study personnel in case of any change in medical status. 
634 
The risk of discomfort associated with needle insertion or electrical stimulation are possible.  Discomfort 
635 
arising from needle insertion is usually transient and resolves shortly after needle insertion.  Subjects are 
636 
asked to provide feedback regarding sensations, pain, or discomfort experienced during the lead placement 
637 
procedure and throughout the study.  The test needle and lead introducer needle can be repositioned as 
638 
necessary to obtain the most comfort.  Local anesthetic will be used as needed to reduce discomfort during 
639 
the procedure.  Stimulation parameters can be adjusted throughout the study to obtain the most comfort. 
640 

P a g e  21 | 25 
Protocol Version 1.2 –  June 11, 2018  
 
Lead fracture and subsequent retention of lead fragments is possible.  Study personnel will inspect the lead 
641 
upon removal to look for signs of fracture.  Usually, no treatment is required for retained fragments unless 
642 
an infection or granuloma occurs.  The study investigators will determine the most appropriate course of 
643 
treatment.   
644 
The potential benefits expected from successful treatment include reduction in pain intensity after TFA or 
645 
TTA surgery in the acute post-operative setting, decrease in the incidence and/or severity of chronic post-
646 
amputation PLP or RLP, reduction in opioid medication use, increased tolerance for rehabilitation and faster 
647 
functional recovery.  This research may benefit future patients with post-operative pain following TFA or 
648 
TTA.  Additionally, the PNS system used in this study has not been formally investigated to be used in the 
649 
acute post-operative setting after TFA or TTA.  Information regarding its efficacy and utility in this setting 
650 
may be useful in determining the most appropriate applications for this system in the future.  The potential 
651 
risks associated with the use of this PNS system have non-serious consequences and are expected to be 
652 
uncomplicated to manage.  The risks are justifiable by the potential benefits.  The information to be gained 
653 
in this study may be used to refine further research within the area of peripheral nerve stimulation for the 
654 
management of post-operative pain. 
655 
8.0 Data and Safety Monitoring 
656 
Primary and secondary outcomes will be recorded at each follow-up visit.  Study investigators will retain 
657 
study-related documents in double-locked filed cabinet in 2C-117.  The PI or an investigator will conduct 
658 
a data and safety monitoring review once every 8 weeks in which Case Report Forms and any AE forms 
659 
are evaluated.  Safety information is also assessed at outpatient study visits and by telephone calls.  If study 
660 
investigators determine that the PNS treatment is unsafe to continue (i.e. systemic infection, increased pain 
661 
that is intolerable to the subject, need for implantable electronic device that requires discontinuation of the 
662 
PNS), then PNS will be discontinued as appropriate. 
663 
8.1 
Serious Adverse Events 
664 
Serious Adverse Events (SAE) will be recorded on Form AE and the IRB will be notified within 5 days of 
665 
occurrence.  Monitoring for SAEs will occur at each follow-up encounter.  Subjects will be asked if they 
666 
are experiencing any increased discomfort, pain, skin irritation, or bleeding.  At the outpatient follow-up 
667 
visits, the PNS lead exit site will be examined and the stimulator device will be interrogated to ensure proper 
668 
functioning.  Any adverse event will be investigated and managed as appropriate.   Subjects are instructed 
669 
to notify study personnel by telephone (804-675-5188) in case of any changes in medical status as soon as 
670 
possible.  If investigators need to be reached after normal business hours, subjects will be given instructions 
671 
on how to page study staff who call the subject as soon as possible.   
672 
Details regarding any observed adverse event and its relation to the PNS system will be collected on Form 
673 
AE.  The severity of the AE will be classified as mild (event that causes mild discomfort or inconvenience 
674 
and resolves without treatment), moderate (event that requires medical intervention or medication to treat), 
675 
or severe (event that requires intervention to prevent permanent impairment or damage, an event that 
676 
requires or prolongs hospitalization, or an event that is disabling, causing permanent damage, life 
677 
threatening, or causing death).  Any treatment necessary related to the AE will be documented.  AEs will 
678 
be followed to resolution, even if a subject is discharged from the study early.  Adverse events will be 
679 
documented and reported so that the safety profile of this system may be further understood.   
680 
8.2 
Confidentiality 
681 
All subjects who sign a Consent Form will be asked to provide name, social security number, and date of 
682 
birth.  We will use this information to create a “unique identifier” to protect patient confidentiality.  The 
683 

P a g e  22 | 25 
Protocol Version 1.2 –  June 11, 2018  
 
unique identifier will be used in place of the subjects’ names for all data collection forms and study 
684 
databases.  A master list linking the subjects to the unique identifier will be maintained by study 
685 
investigators in 2C-117.  The number of subjects to be enrolled does not include screen failures.  A record 
686 
will be maintained of all subjects that are screened at the Vascular Clinic.  A Subject Identification log will 
687 
be completed for all subjects enrolled in the study.  Information pertaining to subjects are accessible by 
688 
study personnel in the electronic medical record.  Information to be collected includes age, race, gender, 
689 
height, weight, past medical and surgical history, and eligibility criteria will be assessed as outlined in Form 
690 
00.  Preliminary screening will be used to determine a subject’s eligibility for study participation.  All 
691 
patient sensitive information, study related documents and materials will be stored in a secured, locked 
692 
cabinet in 2C-117.   
693 
The protection of patient confidentiality is of utmost importance.  Subject names and personal identifiers 
694 
will not appear in any publications resulting from this research.  Subjects will be informed that the IRB and 
695 
regulatory authorities will have access to records that identify them as individuals.  All applicable HIPAA 
696 
regulations will be followed. 
697 
9.0 Consultants 
698 
Non-sensitive data resulting from this study will be made available to Robert Litwack, M.D. for assistance 
699 
with data analysis.  Outcome measures (e.g. pain scores and patient survey scores) without sensitive 
700 
identifying information will be communicated to Dr. Litwack via VA regulated email and Safe Access File 
701 
Exchange (SAFE) to ensure secure transmission of study information.  Data will be transmitted at various 
702 
periods during the study and a final data set will be created at the end of the study duration. 
703 
 
704 
Nate Crosby, Ph.D. of SPR Therapeutics has assisted with protocol development. His research background 
705 
as well as knowledge of the SPRINT PNS System and ongoing studies with the device in chronic post-
706 
amputation pain and total knee arthroplasties has been important to the development of this protocol.  He 
707 
will assist in training the study investigators in placement of the device.  He will continue to provide advice 
708 
during the study as needed.  
709 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.0 Appendix 
Schedule of Study Procedures 
 

P a g e  23 | 25 
Protocol Version 1.2 –  June 11, 2018  
 
 
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
Screen 
and 
Consent
Baselin
e
Lead 
placement 
(Group 1 
only)
1 week 
PNS
2 weeks 
PNS
3 weeks 
PNS 
4 weeks 
PNS/1st IPC 
evaluation
5 weeks 
PNS
6 weeks 
PNS
7 weeks 
PNS 
8 weeks 
PNS/2nd IPC 
evaluation
3 month 
phone
6 month 
phone
12 month 
phone
Chart Review/Screening
x
Informed Consent
x
Remove PNB catheter
x
Beck Depression Inventory
x
Randomize
x
Lead Placement
x
Start Stimulation
x
Inspect bandages and 
Lead exit site
x
x
x
Remove Lead
x
Assess AEs
x
x
x
x
x
x
x
x
x
x
x
BPI-2 (pain distribution)
x
BPI-3 (worst pain)
x
x
x
x
x
x
x
x
x
x
x
x
BPI-4 (least pain)
x
x
x
x
x
x
x
x
x
x
x
x
BPI-5 (average pain)
x
x
x
x
x
x
x
x
x
x
x
x
Phantom sensation
x
x
x
x
x
x
x
x
x
x
x
x
Opioid-related side 
effects
x
x
x
x
x
x
x
x
x
x
x
x
Pain medications
x
x
x
x
x
x
x
x
x
x
x
x
BPI-9 (interference)
x
x
x
x
x
x
PGIC
x
x
x
x
x
PCS
x
x
x
x
x
x
PDI
x
x
x
x
x
x
FIM
x
x
x
Time to prosthesis fitting
Time to hospital 
discharge
Hospital discharge survey
30-day readmission rate
Incidence of neuromas
Study Procedure
Pain/Sense
Data collected from medical record
Data collected from medical record
Data collected from medical record
Data collected from medical record
Data collected from medical record
Meds/SE

P a g e  24 | 25 
Protocol Version 1.2 –  June 11, 2018  
 
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