Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation: A Non-Pharmacologic Alternative for the Treatment of Postoperative Pain
Phase: NA
Conditions: Rotator Cuff Repair, Anterior Cruciate Ligament Reconstruction, Ankle Arthrodesis or Arthroplasty, Hallux Valgus Correction
Sponsor: University of California, San Diego

Title:  Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation:  A Non-Pharmacologic 
Alternative for the Treatment of Postoperative Pain 
 
 
NCT Number:  NCT03481725 
 
 
Document Date:  October 12, 2020 
 
 
 
 
 

 
 
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UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN 
Instructions for completing the Research Plan are available on the HRPP website. 
The headings on this set of instructions correspond to the headings of the Research Plan. 
General Instructions: Enter a response for all topic headings.  
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project. 
Version date: 9/30/2013 
1. 
PROJECT TITLE 
Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation:  A Non-Pharmacologic 
Alternative for the Treatment of Postoperative Pain 
 
2. 
PRINCIPAL INVESTIGATOR  
Brian M. Ilfeld, MD, MS 
 
3. 
FACILITIES 
UCSD hospitals and the UCSD CTRI 
 
4. 
ESTIMATED DURATION OF THE STUDY 
Six years (1 year regulatory and preparation, 3.5 years enrollment, 1 year follow-up, 0.5 year analysis 
and publication) 
 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
Postoperative pain is usually treated with opioids that have undesirable and sometimes dangerous 
side effects (e.g., vomiting and respiratory depression)—and yet over 80% of patients still experience 
inadequate pain relief.  A novel, non-pharmacologic analgesic technique—percutaneous peripheral 
nerve stimulation (PNS)— holds extraordinary potential to greatly reduce or obviate opioid 
requirements and concurrently improve analgesia following painful surgery.  This technique involves 
inserting an insulated electric lead adjacent to a target nerve through a needle prior to surgery using 
ultrasound guidance.  Following surgery, a tiny electric current is delivered to the nerve resulting in 
potent pain control without any cognitive or adverse systemic side effects whatsoever.  The electrical 
pulse generator (stimulator) is so small it is simply affixed to the patient’s skin.  The leads are already 
cleared by the US Food and Drug Administration to treat acute (postoperative) pain for up to 60 days; 
and, since percutaneous PNS may be provided on an outpatient basis, the technique holds the 
promise of providing potent analgesia outlasting the pain of surgery—in other words, the possibility of 
a painless, opioid-free recovery following surgery.  We propose a multicenter, randomized, double-
masked, placebo-controlled, parallel-arm clinical trial to determine the effect of percutaneous PNS on 
postoperative analgesia and opioid requirements, as well as physical and emotional functioning, the 
development of chronic pain, and ongoing quality of life.  This investigation has a strong potential to 
dramatically reduce or obviate postoperative opioid requirements and their resultant negative effects 
on both individuals and society; while concurrently improving analgesia, increasing the ability to 
function in daily life, decreasing the risk of transition from acute to chronic pain, and improving quality 
of life. 
 
 
 
 
 

 
 
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6. 
SPECIFIC AIMS 
 
UG3 Planning Phase 
 
The initial UG3 feasibility study will be a randomized, double-masked, placebo-controlled, parallel-arm, 
human subjects pilot study with two Specific Aims: 
 
Specific Aim 1 (UG3):  To determine the feasibility and optimize the protocol of the Implementation 
Phase (UH3) multicenter clinical trial that will compare percutaneous PNS with usual and 
customary opioid-based analgesia following moderate-to-severely painful ambulatory surgery. 
 
Specific Aim 2 (UG3):  To estimate the treatment effect of percutaneous PNS on pain and opioid 
consumption following moderate-to-severely painful ambulatory surgery compared with usual and 
customary opioid-based analgesia.  This will allow determination of the required sample size of 
the definitive multicenter clinical trial of the Implementation Phase (UH3). 
 
UH3 Implementation Phase 
The primary Specific Aim of the trial is to determine the effect of percutaneous PNS on postoperative 
opioid requirements and analgesia following moderate-to-severely-painful ambulatory surgery 
(under the usual conditions in which PNS will be applied, making this a “pragmatic trial”).  
Secondary Specific Aims are to determine the effect of percutaneous PNS on physical and 
emotional functioning, chronic pain, and quality of life following moderate-to-severely-painful 
ambulatory surgery. 
 
Hypothesis 1 (UH3):  Opioid consumption will be significantly decreased within the first 7 days 
following surgery with percutaneous PNS compared with usual and customary analgesia. 
 
Hypothesis 2 (UH3):  Surgical pain will be decreased within the first 7 days following surgery with 
percutaneous PNS compared with usual and customary analgesia (measured with a Numeric 
Rating Scale). 
 
Hypothesis 3 (UH3):   Physical and emotional functioning will be significantly improved in the 12 
months following ambulatory surgery with percutaneous PNS as compared with usual and 
customary analgesia (measured with the Brief Pain Inventory). 
 
Hypothesis 4 (UH3):  The incidence and intensity of chronic pain will be significantly decreased 6 and 12 
months following surgery with percutaneous PNS compared with usual and customary analgesia 
(measured with a Numeric Rating Scale). 
 
Hypothesis 5 (UH3):  Quality of life will be significantly increased in the 12 months following surgery 
with percutaneous PNS as compared with usual and customary analgesia (measured with the 
World Health Organization Quality of Life-BREF Instrument). 
 
7. 
BACKGROUND AND SIGNIFICANCE 
 
Background.  There are tens-of-millions of ambulatory surgical procedures performed in the United 
States annually.  Over 80% of patients experience inadequate pain relief following surgery with 
consequences for both individuals and society.  For patients, inadequate postoperative analgesia 

 
 
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results not only in suffering, but also an increased risk of comorbidity (e.g., perioperative myocardial 
infarction), inferior rehabilitation, and the transition from acute pain to persistent (“chronic”) post-
surgical pain [incidence: 10-50%].  Persistent post-surgical pain frequently results in decreased 
productivity and a strain on personal relationships, as well as an increased risk of depression, chronic 
low-back and joint pain, obesity, and accelerated onset of cardiovascular disease.  For society as a 
whole, inadequately-treated acute pain is a burden to the healthcare system, requiring increased 
healthcare provider time and the costs of readmission for ambulatory patients.  Furthermore, 
persistent post-surgical pain not only increases medical care costs, but decreases overall economic 
output:  the economic toll for chronic nonmalignant pain is over $100-billion annually within the United 
States. 
 
Clearly, inadequately-controlled post-surgical pain is a substantial problem, which is intimately 
related to a reliance on perioperative opioids use—the foundation of postoperative analgesia for over 
a century.  Unfortunately, opioids have significant undesirable consequences for both individuals and 
society.  Frequent systemic side effects such as nausea, vomiting, and pruritus are irritants; but some 
effects may be fatal, such as cognitive impairment13 and respiratory depression (with life-threatening 
hypoventilation requiring naloxone administration occurring in 1 of 333 patients).  And, even minor 
ambulatory surgical procedures can lead to chronic opioid use, with significant negative 
consequences such as hyperalgesia, dependence and decreased quality of life. 
 
The toll of opioids on society cannot 
be overemphasized.  In the last 20 
years the rate of prescription opioid 
diversion, abuse, addiction, and 
overdose has multiplied 
dramatically (Figure 1), with the 
overall economic cost of opioid 
abuse within the United States in 
excess of $70-billion annually.  
Over 5-million people within the 
United States use prescription 
analgesics without medical need 
or prescription, and this rate has 
more than doubled in the last 20 
years.  In excess of 28,000 
deaths due to overdose occurred 
within the United States in 2010, 
a 700% increase in less than 2 
decades.  Shockingly, 65-80% of 
current heroin-dependent users 
began their addiction by abusing 
prescription opioids. 
 
Considering 4-20% of all opioid pills prescribed within the United States are diverted and 
abused—almost 500-million doses annually—the supply of oral opioids is of great concern.  
Nearly 80% of abused oral opioids were originally intended for someone else, with most obtained 
from a friend or relative.  Unused prescription opioids are so ubiquitous that “young recreational 
users do not have to venture outside their immediate social networks to find those who will sell or 
 Figure 1.  Rates of opioid analgesic sales, unintentional 
overdose deaths, and addiction treatment admissions.1 

 
 
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share pills.”  Indeed, it has been conclusively demonstrated that both the abuse of opioids and extent 
of diversion are relative to their prescriptive availability. 
 
Wounded service members and Veterans have been disproportionately affected, given that 
addiction is especially common in populations with co-existing psychopathology (e.g., 
depression, post-traumatic stress disorder).  Evidence of the latter may be found in the most-recent 
(2009) Department of Defense Survey of Health Related Behaviors Among Active Duty Military 
Personnel Report.  Within the U.S. Armed Services, the most-commonly abused class of prescription 
drugs is opioids, with the incidence of prescription drug misuse increasing from 2% to 11% 
between 2002 and 2008.  This alarming trend has not abated, and the Army has recently instituted a 
policy to limit opioid prescription use due to the rising rates of abuse to what most now describe as 
an epidemic.  The Department of Defense has prioritized non-addictive analgesic modalities for pain 
states that are currently treated primarily with opioids.  Thus, inadequately-controlled postoperative 
pain and opioid diversion/abuse are significant challenges for Armed Services members, Veterans 
and their families.  A new treatment for postoperative pain is desperately needed to both improve 
analgesia and concurrently decrease dependence on opioids. 
 
 
One analgesic alternative—percutaneous peripheral nerve stimulation (PNS)—holds 
extraordinary promise to improve post-surgical analgesia while concurrently decreasing 
or obviating opioid requirements; and, all without any adverse systemic side effects. 
 
 
Many hypotheses have been proposed to explain the analgesic effects of stimulation—also termed 
“neuromodulation”, but Melzack and Wall’s “gate control theory” is the most common and accepted 
theory:  electric current stimulates large-diameter afferent peripheral nerves that subsequently 
interrupt communication (the “gate”) from small-diameter pain fibers to the central nervous system at 
the level of the spinal cord.  Neuromodulation has a long history—and demonstrated efficacy—in the 
management of chronic pain using surgically implanted spinal cord and peripheral nerve stimulators. 
 
However, the application of neurostimulation to postoperative pain states has been limited by the 
invasive nature of the available electrical leads:  conventional units typically require multiple 
electrodes in close proximity to the peripheral nerve that require invasive and time consuming 
surgery to place and subsequently remove.  Stimulation with electrodes placed on the skin 
(transcutaneous electrical nerve stimulation, “TENS”) has been investigated previously to determine 
if it has the potential to avoid these limitations.  However, activation of pain fibers in the skin greatly 
limit the degree of tolerated current that can be delivered by TENS and creates an undesirable 
analgesic ‘ceiling’. 
 
To apply neurostimulation to treatment postoperative pain, optimally this modality should be 
administered without an open surgical incision.  Extremely small, insulated electrical leads have 
now been developed that permit relatively rapid percutaneous insertion through a needle, 
obviating the need for a surgical incision (Figure 2, following page; MicroLead, SPR Therapeutics, 
Cleveland, OH).1 
 

 
 
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Figure 2.  A 12 cm, 20 g needle with a pre-loaded helically-coiled insulated electrical lead (inset: a 
magnified lead).
Using ultrasound to guide placement, a lead may be reliably inserted 
0.5-3.0 cm from a peripheral nerve using similar landmarks and 
accepted approaches as for peripheral nerve block or 
perineural catheter administration (Figure 3). 
 
An external stimulator—so small that it may be directly adhered 
to the skin (Figure 4)—subsequently delivers a small electric 
current through the insulated lead to the target nerve. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preliminary studies and pilot data.  We recently published 2 series of cases describing the first 
uses of percutaneous PNS to treat postoperative pain [funded, in part, by NIH 1R44AG052196].1,2  
We used the novel leads described previously that were recently cleared by the US Food and Drug 
Administration (FDA) to treat acute pain within the peripheral nervous system.  A total of 10 
Figure 3.  Ultrasound-
guided lead insertion 
Figure 4.  A stimulator (inset) and setup for 
percutaneous peripheral nerve stimulation 

 
 
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individuals were included who experienced pain difficult to control with oral analgesics between 6 and 
97 days following total knee arthroplasty.  Using ultrasound guidance, a femoral and/or sciatic nerve 
electrical lead was inserted, depending on where the majority of pain originated (anterior vs. posterior 
knee, respectively).  Pain scores were recorded before and after the stimulator was activated.  Of 
these 10 subjects, 5 had complete resolution of their pain, 4 experienced a 57-67% decrease, 
and 1 a 14% reduction (Figure 5).1,2 
 
   The significant analgesia demonstrated in these 10 subjects led 
our group to investigate the possibility of using PNS immediately 
following surgery.  Seven patients had femoral and sciatic nerve 
leads inserted using ultrasound guidance prior to undergoing 
total knee arthroplasty.3  A single-injection adductor canal nerve 
block was administered using a long-acting local anesthetic, and 
surgical anesthesia provided with a spinal or general.  The 
following morning stimulators were reconnected to the leads and 
current delivered continuously for up to 6 weeks.  Patients were 
discharged home with their leads in situ.  In 6 of 7 subjects 
(86%), the average of daily pain scores across the first 2 weeks 
was well controlled and mild (<4 on the 0-10 Numeric Rating 
Scale for pain).  Of the 5 subjects with data on opioid use, the 
median time to complete opioid cessation was only 8 days, 
with 100% of subjects opioid-free 1 month following surgery.  
This is a dramatic improvement compared with the typical median time to cessation of nearly 2 
months (vs. 8 days), with a 1-month opioid-independence rate of 11-33% (vs. 100%) for patients 
having the same surgical procedure within the United States. 
 
The opioid-sparing potential of PNS for painful ambulatory surgery is illustrated by one subject who, 
following a hallux valgus repair (“bunionectomy”)—one of the most painful orthopedic procedures 
performed—reported only mild pain and required no opioids from the recovery room through her 
entire period of convalescence with two weeks of sciatic nerve stimulation (unpublished data).  Due 
to the ability to provide PNS in ambulatory patients and a treatment duration of up to 30 days, the 
PNS system outlasted the pain of surgery.  These remarkable results led our team to submit an 
application to the Department of Defense (FY16 Peer Reviewed Orthopaedic Research Program) to 
support a clinical trial investigating the use of percutaneous PNS to improve function and 
rehabilitation following orthopedic trauma of the lower extremity using knee arthroplasty as a model. 
 
Significance.  In contrast to that submission and our previous work involving inpatient knee 
arthroplasty, the present application proposes applying percutaneous PNS to the most painful 
ambulatory surgical procedures to improve postoperative analgesia and dramatically reduce opioid 
requirements.  If successful, benefits of decreasing pain in the immediate postoperative period 
may lead to a plethora of patient benefits beyond simply decreasing suffering and opioid 
requirements, including decreasing pain-related interference in activities of daily living and greatly 
improving physical rehabilitation—in and of itself critical in maximizing long-term outcomes.  In 
addition, persistent post-surgical pain is correlated with increased perioperative pain; and, therefore, 
maximizing postoperative analgesia may decrease the incidence of transition from acute to chronic 
pain [incidence:  10-50%], reduce pain-related interference in activities of daily living, and improve 
quality of life. 
 
Figure 5.  Pilot data 

 
 
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Moreover, greatly reducing opioid requirements will not only reduce irritating systemic side effects 
such as nausea, vomiting, and pruritus; but diminish the incidence and severity of cognitive 
impairment and respiratory depression (with its associated mortality).  Crucially, if opioid 
requirements can be dramatically reduced—or even eliminated—for the most painful ambulatory 
surgery, then opioid prescriptions may be drastically reduced or even eliminated for all related 
surgical procedures associated with a lower degree of pain.  It is imperative that novel, non-opioid 
postoperative analgesic modalities are developed and disseminated considering: 
 
• Tens-of-millions of ambulatory procedures are performed annually 
• The number of surgical procedures is expected to grow exponentially in the coming decades 
• Up to 20% of prescribed opioids—almost 500-million doses annually—are diverted and 
abused 
• The abuse of opioids and extent of diversion are relative to their prescriptive availability 
• Illicit opioid use has grown to epidemic proportions 
• U.S. military personnel, Veterans and their families are disproportionately affected by these 
catastrophic trends with the incidence of prescription drug misuse increasing from 2% to 11% 
in the six years leading to 2008, and this trend continues unabated. 
 
Ultrasound-guided percutaneous PNS has been used to treat chronic pain (e.g., phantom limb pain),4 
has demonstrated extraordinary potential to provide potent postoperative analgesia and concurrently 
reduce opioid requirements in our pilot studies, and is already cleared by the US FDA for use in 
treating post-surgical pain.  Most importantly—and in contrast to opioids—it has no abuse/addiction 
potential, produces no adverse systemic side effects, and does not influence cognitive 
functioning whatsoever.4  Consequently, we propose an initial pilot study phase (UG3) followed by 
a definitive randomized, triple-masked, placebo-controlled, parallel design, human subjects pragmatic 
clinical trial to determine the effect(s) of ultrasound-guided, percutaneous PNS on postoperative 
pain, opioid requirements, and functioning/quality of life following painful ambulatory surgical 
procedures. 
 
8. 
PROGRESS REPORT 
None. 
 
9. 
RESEARCH DESIGN AND METHODS 
 
We propose a feasibility study during the initial 2-year Planning Phase [UG3] and multicenter, 
randomized, triple-masked (investigators, subjects, statisticians), placebo-controlled, parallel arm, 
human-subjects pragmatic clinical trial period during the subsequent 4-year Implementation Phase 
[UH3] to determine if ultrasound-guided percutaneous peripheral nerve stimulation (PNS) greatly 
reduces or obviates postoperative opioid requirements without a concurrent increase in surgical pain.  
For the entire duration of the funding period we will comply with policies and practices developed by 
the Work Groups of the NIH-DoD-VA Pain Management Collaboratory, and we will work with the 
Coordinating Center in providing relevant information and material.  We have included a diverse 
group of recruitment sites that will provide a broad, representative patient sample of active duty 
military members, Veterans and their families.  Study participants will be recruited from 7 centers, 
including both U.S. military and Veterans Affairs medical centers within a wide geographic range, 
providing a study sample with ethnic, racial, and socioeconomic diversity. 
 
 

 
 
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U.S. military medical centers: 
• 
Brooke Army Medical Center [San Antonio, Texas] 
• 
Fort Bragg [Fayetteville, North Carolina] 
• 
Naval Medical Center San Diego [San Diego, California] 
• 
Walter Reed National Military Medical Center [Bethesda, Maryland] 
 
Veterans Affairs medical centers: 
• 
Palo Alto Veterans Affairs Medical Center [Palo Alto, California] 
 
Civilian university medical centers: 
• 
The Cleveland Clinic [Cleveland, Ohio] 
• 
University California San Diego [San Diego, California] 
 
The study protocol and materials will be approved by each center’s Institutional Review Board; and, 
the investigation will be prospectively registered on the clinicaltrial.gov website.  The study will be 
overseen by a Data Safety Monitoring Board comprised of two physicians familiar with the ethical 
conduct of clinical research and one biostatistician.  The DSMB will review enrollment, study data, 
protocol violations, adverse events, and oversee all aspects of the clinical trial.  
 
 
UG3 Planning Phase 
 
The initial UG3 feasibility study will be a randomized, double-masked, placebo-controlled, parallel-
arm, human subjects pilot study with two Specific Aims: 
 
Specific Aim 1 (UG3):  To determine the feasibility and optimize the protocol of the 
Implementation Phase (UH3) multicenter clinical trial that will compare percutaneous PNS with 
usual and customary opioid-based analgesia following moderate-to-severely painful ambulatory 
surgery. 
 
Specific Aim 2 (UG3):  To estimate the treatment effect of percutaneous PNS on pain and 
opioid consumption following moderate-to-severely painful ambulatory surgery compared with 
usual and customary opioid-based analgesia.  This will allow determination of the required 
sample size of the definitive multicenter clinical trial of the Implementation Phase (UH3). 
 
Therefore, the protocol for the UG3 Planning Phase feasibility study and the UH3 Implementation 
Phase pragmatic trial will be identical, with the exception of any improvements determined by the 
UG3 study. 
 
Enrollment.  Surgeons at each enrolling center will identify potential study subjects at preoperative 
patient visits.  Surgeons will be seeing patients as part of regular medical care, and therefore this 
protocol will adhere to Health Insurance Portability and Accountability Act (HIPAA) regulations.  
Patients meeting inclusion and exclusion criteria will be presented with the study, and prospective 
study subjects desiring additional information will be required to give permission for a research 
coordinator to contact them to adhere to HIPAA requirements.  Research coordinators will review the 
study protocol in detail with interested prospective subjects; and, for subjects desiring participation, 
written, informed consent will be obtained prior to any measurements, data collection, and/or 

 
 
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interventions.  The method of documenting consent will be using written informed consent forms 
approved by the local Institutional Review Board. 
 
For women of childbearing age with the possibility of pregnancy, a sample of urine will be collected 
before any study interventions to confirm a non-pregnant state [this is standard for the surgery 
regardless of study participation].  Study participation will require that women of childbearing age with 
the possibility of pregnancy use a birth control method, such as abstinence, diaphragm, condom or 
intrauterine device to prevent pregnancy until lead removal.  Anthropomorphic and demographic 
characteristics as well as baseline end points will be recorded/measured, including a pain score at 
the surgical site using the Numeric Rating Scale (NRS, 0-10), sensory deficits (measured with von 
Frey filaments within the cutaneous distribution of the target nerve), and muscle strength (measured 
with a pressure transducer; Table 1). 
 
Table 1.  Anatomic locations for electrical leads and peripheral nerve blocks. 
Surgical 
Location 
Surgical Procedures 
Lead Location 
Peripheral Nerve 
Block Location 
Muscle Motion/ 
Strength Tested 
Shoulder 
• Rotator cuff repair 
Brachial plexus 
trunks 
Brachial plexus 
trunks 
Grip strength 
Knee 
• Anterior cruciate 
ligament repair with a 
patellar autograph 
Femoral 
Adductor canal 
---- 
Foot or 
ankle 
• Hallux valgus correction 
• Ankle arthrodesis/ 
arthroplasty 
Subgluteal 
sciatic 
Popliteal sciatic 
Plantar flexion 
 

 
 
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Figure 8.  Study protocol 
Time Point 
Event 
Years 2 (UG3) and 
3-5 (UH3) of the 
award period 
Potential subject identification 
Postoperative Day 0 
[day of surgery] 
Baseline 
Lead insertion(s) 
Randomization 
Stimulation 
Subject consent & enrollment 
Measurements 
Demographics 
Postoperative 
end point 
measurements 
Surgical procedure 
Postoperative Days 
1-14 
Recovery room 
end point 
measurements 
Follow-up 
end point 
measurements 
Lead removal 
Postoperative Months 
1, 3, 6, 9, 12 
NO stimulation 
 Or 

 
 
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Lead insertion.  Insulated leads 
will be inserted prior to peripheral 
nerve block administration.  The 
lead insertion sites will be 
cleansed with chlorhexidine 
gluconate and isopropyl alcohol, 
and a sterile, fenestrated drape 
applied.  A portable ultrasound 
paired with either a linear or 
curved array transducer within a 
sterile sleeve will be used for 
lead insertion (Figure 9).  The 
target nerve will be imaged in a 
transverse cross-sectional (short 
axis) view and a local anesthetic 
skin wheal raised lateral to the 
ultrasound transducer. 
 
A needle and a pre-loaded, 
monopolar, helically-coiled, insulated 
lead (SPR Therapeutics, Cleveland, OH) will be inserted.  Using an in-plane ultrasound approach, the 
needle tip will be advanced to approximately 1-2 cm from the target nerve.  The lead will be subsequently 
attached to an external stimulator (SPR Therapeutics), and a surface return electrode applied.  Accurate 
lead placement will be confirmed with subject reports of comfortable sensations over the surgical site 
without eliciting muscle contractions. 
 
Frequency will be set to 100 Hz, which is known to generate 
comfortable sensations and reduce pain compared to lower 
frequencies (2-50 Hz).  Stimulus amplitude and pulse 
duration will be increased until the subject reports that 
comfortable sensations cover the surgical site (region in 
which pain is anticipated following surgery).  Stimulation 
parameters will be adjusted to improve stimulation coverage 
and comfort.  Once optimum parameters have been 
determined, the needle will be withdrawn over the lead.  The 
lead will be affixed to the skin with a sterile occlusive 
dressing (Figures 4 and 10).  The stimulator will be set to 
deliver a range of currents.  During their treatment, subjects 
can control these levels.  Muscle strength will again be tested 
with the stimulator set for the optimal setting.  The stimulator will 
be removed until after surgery. 
 
Preoperatively, day of surgery.  Subjects will continue to receive usual and customary local 
anesthetic-based analgesia.  Because percutaneous PNS does not induce a sensory block and 
therefore does not provide anesthesia for the surgical procedure itself, we will continue to provide 
subjects with a preoperative single-injection local anesthetic-based peripheral nerve block (Table 1; 
30 mL of ropivacaine 0.5% with epinephrine 1:400,000).  In addition, surgeons will be permitted to 
infiltrate the surgical area with local anesthetic (bupivacaine HCl). 
 
Figure 10.  Inserted electrical 
lead secured under gauze and 
a dressing 
Figure 9.  Ultrasound-guided sciatic nerve lead insertion 

 
 
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Treatment group assignment (randomization).  Subjects will be allocated to a treatment only after 
confirmation of successfully-inserted electrical leads and surgical procedure initiation; and will be 
randomized to one of two possible treatment groups (Figure 11): 
 
(1)  Current delivered via the electrical lead(s) [Experimental group] 
(2)  No current delivered via the electrical lead(s) [Control group] 
 
Figure 11.  Treatment groups. 
Postoperative Day 
0  [day of surgery] 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Experimental 
Electric current 
Control 
No electric current 
 
Randomization will be stratified by institution and anatomic lead location (Table 4) in a 1:1 ratio and 
in randomly chosen block sizes.  Randomization lists for each enrolling center will be created by the 
Cleveland Clinic.  Treatment group assignment will be conveyed to the enrolling sites via the same 
secure web-based system (RedCap) used to collect and collate all post-intervention endpoints (see 
“Data Collection” paragraph below).  Stimulators are capable of programming to either (1) pass 
electrical current; or, (2) not pass electrical current.  Importantly, these 2 modes (active and sham) 
are indistinguishable in appearance, and therefore investigators, subjects, and all clinical staff will be 
masked to treatment group assignment, with the only exception being the unmasked individual who 
programs the stimulator (and will not have direct contact with the subject).  The unmasked personnel 
will have access to the randomization list on RedCap, program the stimulator appropriately (sham vs. 
active), and provide the individual interacting with the study subject with the device without indicating 
the treatment group. 
 
Subjects will be informed that often during postoperative active treatment with electrical current 
patients do not always have the sensations experienced during preoperative lead placement and 
once proper placement is confirmed with comfortable sensations, therapeutic levels of stimulation 
may be delivered sub-threshold (below the intensity required for sensation and still provide relief, 
which is factual/accurate).  This protocol will ensure a randomized, double/triple-masked, 
sham/placebo-controlled trial.  For the feasibility study (UG3), unmasking will occur 2 weeks 
following surgery to allow for protocol revisions, as necessary (“double masked” during data 
collection).  In contrast, for the definitive pragmatic clinical trial (UH3) unmasking will not occur until 
statistical analysis for the entire investigation is complete (termed “triple masked”). 
 
Intraoperative course.  The primary surgical anesthetic will be a general anesthetic, spinal 
anesthetic (bupivacaine) or exclusively the preoperative single-injection peripheral nerve block.  
Anesthetics that are also analgesics such as ketamine will not be used:  the only permitted analgesic 
will be intravenous fentanyl, which will be minimal since all subjects will receive a single-injection 
peripheral nerve block immediately prior to surgery. 
 
Postoperative course.  Within the recovery room following surgery, the stimulators will be attached 
to the leads and activated, followed by end point assessment.  Subjects who had a spinal anesthetic 
will have end points recorded following spinal resolution.  Operating and recovery room 
pharmacologic analgesic requirements will be recorded. 
 

 
 
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Post-hospital course.  Prior to discharge, subjects and their caretakers will be provided with verbal 
and written stimulator/lead instructions and the telephone and pager numbers of a local investigator 
available at all times.  Subjects will be discharged home with their leads in situ, and contacted every-
other day by a healthcare provider until lead removal.  Subjects will be also be discharged with a 
prescription for immediate-release oral oxycodone (5 mg tablets taken for breakthrough pain).  
Therefore, all patients of this study—regardless of the treatment arm they are randomized to—will 
continue to receive current usual and customary analgesia.  Subjects will be contacted by telephone 
for end point collection.  Lead removal will occur on postoperative day 14 (+/- 2 days) by healthcare 
providers.  If the lead is removed following Day 14, the stimulator will be turned off on Day 14 and 
removed subsequently.  Similar to perineural catheters,135 this procedure encompasses simply 
removing the occlusive dressing and gently pulling on the lead.  Following study completion, the 
results will be mailed electronically or by the United States Postal Service to all enrolled subjects in 
written form using non-technical language. 
 
Outcome measurements (end points).  We have selected outcome measures that have 
established reliability and validity, with minimal inter-rater discordance, and are recommended for 
pain-related clinical trials by the World Health Organization and the Initiative on Methods, 
Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus statement.136  
Importantly, nearly all outcome measures are common data elements from the National 
Institute of Neurological Disorders and Stroke (NINDS).137  End points (Table 2) will be evaluated 
at baseline (prior to surgery on postoperative day 0), during the treatment period (postoperative days 
1-14); and the follow-up period (postoperative day 15 and months 1, 4, and 12). 
 
Table 2.  Summary of post-enrollment assessments (color added for clarity) 
Time Point: 
Postoperative Days 
Postoperative 
Months 
0 1 2 3 4 7 
11 
15 
1 
4 
12 
Opioid consumption previous 24 h 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Average Pain [NRS] 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Worst Pain [NRS] 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Brief Pain Inventory, Short Form 
• 
 
 
• 
 
• 
 
• 
• 
• 
• 
Defense and Veterans Pain 
Rating Scale 
• 
 
 
• 
 
• 
 
• 
• 
• 
• 
World Health Organization Quality 
of Life Instrument 
• 
 
 
 
 
 
 
 
• 
• 
• 
Post-Traumatic Stress Disorder 
Checklist (C) 
• 
 
 
 
 
 
 
 
 
 
 
Masking Assessment 
 
• 
 
 
 
 
 
 
 
 
 
 

 
 
Biomedical IRB Application Instructions 
Page 14 
Demographic and medical history.  Subjects will have demographic and anthropomorphic data 
collected based on NINDS case report form General Core and Demographics Modules and 
Guidelines, including age, sex, height, weight, educational level, employment status, marital status, 
and U.S. military service (e.g., none, discharged, active).  In addition, the medical history based on 
the common data elements of the NINDS Medical, Family, Behavioral History, History of 
Disease/Injury Event, and Prior and Concomitant Medications Sub-Domains will be collected, and 
include the mechanism of original injury, medications (including analgesics), previous surgical 
procedures, comorbidities, existing sensory deficits of the target nerve distribution, preoperative pain 
levels measured on a Numeric Rating Scale for pain (including daily least, average, worst and 
current), and muscle strength if applicable (measured with a pressure transducer; Table 1).  In 
addition, since post-traumatic stress disorder (PTSD) may be associated with the severity of pain,138 
at baseline we will apply the PTSD Checklist (PCL-C), a 20-item self-report measure reflecting 
symptoms of PTSD validated in military,139 Veteran,140-142 and civilian populations.143 
 
Postoperatively, surgical endpoints will be recorded such as surgical duration, tourniquet duration (if 
applicable), analgesic administration, anesthetic administered, and any sedative agents provided.  In 
addition, subjects will have baseline end points measured including a pain score at the surgical site 
using the Numeric Rating Scale (NRS, 0-10).  The remaining end points of Table 2 are described 
in detail under each Hypothesis in the UH3 Implementation Phase section description below. 
 
Data collection.  Much of the surgical data from the day of surgery will be extracted from electronic 
health records to leverage data collection that occurs in health care delivery rather than requiring 
independent research data collection.  Subject demographic, surgical and percutaneous PNS 
administration data will be uploaded from each enrolling center via the Internet to a secure,144 
password-protected, encrypted central server (RedCap, Department of Outcomes Research, 
Cleveland Clinic, Cleveland, Ohio).145  All data collection following the day of enrollment (postoperative 
day 0)—regardless of enrolling center—will be collected by telephone from the University of California 
San Diego. Staff masked to treatment group assignment will perform all assessments. 
 
UG3 Milestones.  The 2-year UG3 feasibility period has explicit milestones (Table 3, following page) 
that are feasible, quantifiable, and scientifically justified to allow an assessment of progress.  Each of 
the items listed in Table 3 and the following outline is considered a milestone and must be 
completed in order to proceed to the 4-year UH3 definitive, pragmatic clinical trial. 
 
Study Preparation.  Finalize protocol with the Steering Committee, Site Directors, Significant 
Contributors, and NIH-DoD-VA Pain Management Collaboratory. Finalize common and individual site 
case report forms (each enrolling site will require forms that conform to its own specific 
requirements).  In concert with the Principal Investigator, the Department of Outcomes Research 
(Cleveland Clinic, Cleveland, OH) will create the data-entry platform (database) used to store all 
study-related information.  Equipment (e.g., electrical leads and stimulators) will be ordered for each 
enrolling center.  Research Coordinators will be hired and trained at all enrolling centers.  The 
Primary Investigator will visit each of the enrolling centers to train both Site Directors and Research 
Coordinators in all aspects of the study.  In addition, a trained representative from the developer and 
manufacturer of the percutaneous PNS system (SPR Therapeutics) will travel to each enrolling 
center to train Site Directors and Research Coordinators on how to insert and manage the leads and 
stimulators.  This will be done at the company’s expense, and conform to all HIPAA requirements.  
Training will continue with successive subjects until both the representative and study personnel feel 
comfortable with the site’s future enrollment without further training. 

 
 
Biomedical IRB Application Instructions 
Page 15 
 
Table 3.  Two-year UG3 Planning Phase feasibility study Timeline (color added for clarity) 
Funding Year: 
1 
2 
Months (within year): 1-4 
5-8 
9-
12 
1-6 
6-
12 
Identify staff who will participate in NIH-DoD-VA Pain Management 
Collaboratory Work Groups 
• 
 
 
 
 
Work with NIH-DoD-VA Pain Management Collaboratory to comply 
with approved policies and practices 
• 
• 
• 
• 
• 
Initiate DSMB and develop DSMB charter 
• 
 
 
 
 
Report to medical monitor (monthly) and DSMB as charter specifies 
• 
• 
• 
• 
• 
Initiate and complete CRADAs at military treatment facilities 
• 
• 
• 
 
 
Finalize preparation for UG3 feasibility study (details below) 
• 
 
 
 
 
Hire/train research coordinators 
• 
 
 
 
 
Prepare training/implementation documents and videos 
• 
 
 
 
 
Prepare data-entry platform at the Cleveland Clinic 
• 
• 
 
 
 
Enrollment site IRB submissions, reviews and revisions 
• 
• 
• 
 
 
NIH-DoD-VA oversight body submission 
• 
• 
• 
 
 
Site visits and training by Principal Investigator 
 
 
• 
 
 
Educate clinic contacts (e.g., surgeons) for referrals 
 
 
• 
 
 
Order and prepare equipment 
 
 
• 
• 
 
Lead/stimulator training for all Site Directors by SPR Therapeutics  
 
 
• 
• 
 
Register study and update on clinicaltrials.gov 
 
 
 
• 
• 
Subject enrollment (following IRB approval) 
 
 
 
• 
 
Data collection, University California San Diego (Day 1 to Month 3) 
 
 
 
• 
• 
Quality assurance 
 
 
 
• 
• 
Address any ethical, human subject safety and oversight issues 
 
 
 
• 
• 
Assess adequacy of protocol, data-entry platform, and study sites 
 
 
 
• 
• 
Replace any study sites, if necessary 
 
 
 
 
• 
Data cleaning and statistical analysis 
 
 
 
 
• 
Revise pragmatic clinical trial (UH3) statistical section, as necessary 
 
 
 
 
• 
Revise protocol for pragmatic clinical trial (UH3), as necessary 
 
 
 
 
• 
If necessary, revise budget for pragmatic clinical trial 
 
 
 
 
• 
IRB revisions at enrolling centers and oversight agencies, if needed 
 
 
 
 
• 
Manuscript preparation:  protocol description 
 
 
 
 
• 
Upload results to ClinicalTrials.gov 
 
 
 
 
• 
Final UG3 report to funding and oversight agencies 
 
 
 
 
• 
CRADA:  Cooperative Research and Development Agreement 
 
Regulatory Review and Approval Process.  Of note, the entire first year of the funding period is 
currently designated for this purpose due to the often-prolonged period of time required for regulatory 

 
 
Biomedical IRB Application Instructions 
Page 16 
review and approval.  However, enrollment may commence sooner if the regulatory process requires 
less than 1 year.  This is probable since the stimulation system used in the proposed investigation is 
already cleared for use in treating acute pain, and therefore US FDA investigational device 
exemption approval is not needed and the proposed use in this study is on label.  The final protocol 
will be formatted and then submitted to all enrolling site IRBs and the funding agency’s oversight 
committee (e.g., U.S. Army Medical Research and Materiel Command Human Research Protection 
Office).  The DSMB will be initiated which will design the DSMB charter describing role, reporting 
procedures, and meeting protocol.  A Medical Monitor (DSMB Chair, “subject advocate”) will receive 
monthly reports prepared by the Principal Investigator (reviews project accomplishments, issues, 
problems, upcoming goals, adverse events, protocol deviations, etc.).  DSMB will occur at a minimum 
of very 6 months, or more often if specified by the DSMB charter.  The DSMB will review progress 
and recommends modification, continuation, or termination: 
 
• Approval of the trial protocol before enrollment 
• Review data in order to determine efficacy, futility, and safety, and to determine 
continuation 
• Review data quality and data integrity 
• Evaluate risk versus benefit by thorough examination of the data accumulated 
• Determine whether the trial is proceeding as planned, the protocol is being followed, the 
recruitment of patients is on schedule, and data are being collected with the proper 
accuracy 
• Review patient dropouts, if any, and make appropriate recommendations 
• Determine whether safety concerns have been raised by the experimental or control 
treatments 
• Modifications of the study protocol based upon the review of the safety data 
• Suspension or early termination of the study or of one or more study arms because of 
serious concerns about patients' safety, inadequate performance, or rate of 
enrollment 
• Suspension or early termination of the study or of one or more study arms because study 
objectives have been obtained according to pre-established statistical guidelines 
• Optional approaches for executive committee and investigators to consider when the 
DSMB determines that the incidence of the primary study outcomes is substantially 
less than expected, such as recommendations to increase the number of trial 
centers or extend the recruitment period 
• Corrective actions regarding a study center whose performance appears unsatisfactory or 
suspicious 
 
Study Implementation.  The study will be registered on clinicaltrials.gov prior to enrollment of the 
first subject, and be kept updated.  Research Coordinators will re-educate clinical contacts on ethical 
referral process and initiate the referral period.  For the initial subject at each enrolling center, a 
trained representative from the developer and manufacturer of the percutaneous PNS system (SPR 
Therapeutics) will travel to each enrolling center to train both Site Directors and Research 
Coordinators in how to insert and manage leads and stimulators.  For quality assurance, the Principal 
Investigator will review with the study team the entire first subject’s course, from referral to enrollment 
to lead insertion to medical follow-up and adverse event or protocol deviation reporting. 
 
Enrollment.  The Research Coordinator or Site Director at each site will schedule lead insertions for 
that specific site.  Baseline and day-of-surgery (postoperative day 0) data collection will occur at each 

 
 
Biomedical IRB Application Instructions 
Page 17 
enrolling site, with the case report forms faxed to the Principal Investigator at the University California 
San Diego using a secure fax machine in a locked office to protect personal health information.  All 
data collection following the day of surgery will occur by telephone from the University of California 
San Diego, which will then enter all data to the database.  For the UG3 feasibility study, the final data 
collection point for each subject will be at 4 months following surgery (the 12-month time point will be 
used for the definitive UH3 pragmatic clinical trial).  Quality assurance will be ongoing by the 
University of California San Diego, which will monitor data for sources of error and report to the 
Medical Monitor (DSMB Chair) with written monthly reports.  Each enrolling center will be expected to 
enroll at least 1 subject for each of the 3 possible lead locations (e.g., brachial plexus trunks) in each 
of the first two quarters of the 2nd year of the funding period.  Combined, the 7 centers will enroll a 
total of 64 subjects as part of the feasibility study. 
 
Preparation for the UH3 Clinical Trial.  If one or more centers fails to enroll their designated 
subjects—for whatever reason(s)—other centers will make up this enrollment with coordination by 
the Principal Investigator.  The 64-subject feasibility study will enable evaluation of the study 
intervention, protocol, case report forms, outcome measures, data-entry platform, Research 
Coordinators, Site Directors, and study oversight.  Any changes deemed necessary by the Principal 
Investigator in concert with the DSMB, funding agency, Steering Committee, Site Directors and NIH-
DoD-VA Pain Management Collaboratory Coordinating Center will be made to any aspect of the 
study design (such as the outcome measures or informed consent forms), including replacing any 
enrolling center that fails to demonstrate the ability to adequately enroll and execute the protocol.  
The data from the first 64 subjects will be cleaned by University of California San Diego and a 
statistical analysis performed by the study statistician (Edward Mascha, PhD) at the Department of 
Outcomes Research (Cleveland Clinic). 
 
In concert with the NIH-DoD-VA Pain Management Collaboratory Coordinating Center, the statistical 
section for the subsequent UH3 pragmatic clinical trial will be revised to reflect the estimated 
treatment effect and treatment group means.  For the initial submission, we have estimated the 
probable maximum sample size for budgeting and planning purposes; but, the results of the initial 
feasibility study will most-likely decrease the definitive UH3 pragmatic trial required sample size.  The 
statistical section and budget will be revised to reflect any changes.  Any revisions to the protocol or 
informed consent forms will be submitted to the DSMB, individual center IRBs and funding center’s 
oversight body.  A manuscript with the results of the pilot study will be prepared and submitted with 
the results concurrently uploaded to ClinicalTrials.gov.  Lastly, a final UG3 period report will be 
prepared for the funding and oversight agencies. 
 
UG3 Planning Phase Specific Aims.  The investigation described above will accomplish the two 
Specific Aims of the UG3 Planning Phase: 
 
Specific Aim 1 (UG3):  To determine the feasibility and optimize the protocol of the 
Implementation Phase (UH3) multicenter clinical trial that will compare percutaneous PNS with 
usual and customary opioid-based analgesia following moderate-to-severely painful ambulatory 
surgery. 
 
Specific Aim 2 (UG3):  To estimate the treatment effect of percutaneous PNS on pain and 
opioid consumption following moderate-to-severely painful ambulatory surgery compared with 
usual and customary opioid-based analgesia.  This will allow determination of the required 
sample size of the definitive multicenter clinical trial of the Implementation Phase (UH3). 

 
 
Biomedical IRB Application Instructions 
Page 18 
 
UH3 Implementation Phase 
 
The 4-year UH3 Implementation Phase will include a multicenter, randomized, triple-masked, 
placebo-controlled, parallel-arm, human subjects pragmatic clinical trial.  The primary Specific Aim 
of the trial is to determine the effect of percutaneous PNS on postoperative opioid requirements 
and analgesia following moderate-to-severely-painful ambulatory surgery (under the usual 
conditions in which PNS will be applied, making this a “pragmatic trial”).  Secondary Specific Aims 
are to determine the effect of percutaneous PNS on physical and emotional functioning, chronic 
pain, and quality of life following moderate-to-severely-painful ambulatory surgery.  The definitive 
UH3 pragmatic clinic trial will use the same protocol as the UG3 Planning Phase feasibility study 
described above, with the addition of any revisions determined necessary following that initial 
investigation.  We will work closely with the NIH-DoD-VA Pain Management Collaboratory 
Coordinating Center at all phases of the definitive pragmatic clinical trial, from preparation through 
data analysis and manuscript preparation. 
 
The primary end points will be cumulative opioid consumption and average surgical pain 
(measured with a Numeric Rating Scale) within the first 7 days following surgery.  The 
primary analyses will compare the two treatment groups, one of which will receive active stimulation 
while the other will receive no stimulation. 
 
 
Hypothesis 1 (UH3): Opioid consumption will be significantly decreased within the first 7 days 
following surgery with percutaneous PNS compared with usual and customary 
analgesia. 
 
 
Opioid analgesic consumption [oxycodone 5 mg tablets] will be recorded at all time points (Table 2), 
with the primary end point being the cumulative opioid dose for postoperative days 0-7 (see 
statistical section for further details). 
 
 
Hypothesis 2 (UH3):    Surgical pain will be decreased within the first 7 days following surgery with 
percutaneous PNS compared with usual and customary analgesia 
(measured with a Numeric Rating Scale). 
 
 
Current/present, worst, least, and average pain at the surgical site will be assessed using a Numeric 
Rating Scale (NRS) as part of the Brief Pain Inventory (short form).  The Brief Pain Inventory is an 
approved NINDS common data elements Scale.  The use of single items (e.g., average pain) in 
addition to the composite score is supported by the IMMPACT recommendations for assessing pain 
in clinical trials.  The NRS will be recorded at all time points (Table 2), with the primary end point 
being the mean value of the “average” pain scores for postoperative days 0-7 (see statistical 
section for further details).  The NRS is a highly-sensitive measure of pain intensity with numbers 

 
 
Biomedical IRB Application Instructions 
Page 19 
ranging from 0 to 10, zero equivalent to no pain and 10 equivalent to the worst imaginable pain.  The 
NRS has been demonstrated to be a valid and reliable measure following analgesic interventions.  In 
addition, NRS scores correlate well with other measures of pain intensity, and demonstrate high test-
retest reliability.   These NRS characteristics led to recent IMMPACT consensus recommendations 
for use of the 10-point NRS of pain intensity for pain trials. 
 
An additional instrument, the Defense and Veterans Pain Rating Scale (DVPRS), will be utilized at 
various time points following surgery.  The DVPRS was developed specifically for—and subsequently 
validated in—active duty military and Veteran patient populations.   Unfortunately, this new instrument 
has not been validated for repeated measures, and therefore will not be used as a primary end point 
for the current investigation.   However, future pain-related investigations involving military personnel 
and Veterans will undoubtedly use the DVPRS, and we want the results of the current study to be 
comparable.  Therefore, we will use the DVPRS as a secondary end point at various time points (not 
all to lessen the questionnaire burden on subjects). 
 
Primary end point:  In order to claim that percutaneous PNS is superior to usual and customary 
analgesia, at least one of Hypotheses 1 and 2 above must be superior while the other either superior 
or at least noninferior. 
 
 
Hypothesis 3 (UH3):   Physical and emotional functioning will be significantly improved in the 12 
months following ambulatory surgery with percutaneous PNS as compared 
with usual and customary analgesia (measured with the Brief Pain Inventory). 
 
 
The Brief Pain Inventory (short form) is an instrument specifically designed to assess pain and its 
impact on physical and emotional functioning.  It has established reliability and validity, with minimal 
inter-rater discordance, is recommended by the Initiative on Methods, Measurement, and Pain 
Assessment in Clinical Trials (IMMPACT) consensus statement, and is an approved NINDS common 
data elements Scale.  The Brief Pain Inventory is comprised of three domains:  (1) pain, with four 
questions involving “worst”, “average”, “least”, and “current” pain levels using a 0-10 NRS; (2) 
percentage of relief provided by pain treatments with one question [reported score is the percentage 
divided by 10 and then subtracted from 10:  0 = complete relief, 10 = no relief]; and, (3) interference 
with 7 questions involving physical and emotional functioning using a 0-10 Likert scale [0 = no 
interference; 10 = complete interference]:  general activity, mood, walking ability, normal work, 
relations with other people, sleep, and enjoyment of life.  The use of both single items (e.g., average 
pain) and the composite score (0 = optimal; 120 = worst possible) is supported by the IMMPACT 
recommendations for assessing pain in clinical trials.   The Brief Pain Inventory has been used in 
countless clinical studies of chronic pain.   This instrument is associated with minimal subject burden 
and is easily interpreted by patients of all ages and education levels.160  It has high test-retest 
reliability and correlates well with much longer questionnaires, including the McGill measures and 
EuroQol. 

 
 
Biomedical IRB Application Instructions 
Page 20 
 
 
Hypothesis 4 (UH3):  The incidence and intensity of chronic pain will be significantly decreased 6 
and 12 months following surgery with percutaneous PNS compared with usual 
and customary analgesia (measured with a Numeric Rating Scale). 
 
 
Current/present, worst, least, and average pain at the surgical site will be assessed using a 
Numeric Rating Scale (NRS) as part of the Brief Pain Inventory (short form).151  The use of single 
items (e.g., average pain) in addition to the composite score is supported by the IMMPACT 
recommendations for assessing pain in clinical trials and is an approved NINDS common data 
elements Sub-Scale.  As described previously, the NRS is a highly-sensitive measure of pain 
intensity with numbers ranging from 0 to 10, zero equivalent to no pain and 10 equivalent to the 
worst imaginable pain.  The NRS has been demonstrated to be a valid and reliable measure 
following analgesic interventions. 
 
 
 
Hypothesis 5 (UH3):  Quality of life will be significantly increased in the 12 months following 
surgery with percutaneous PNS as compared with usual and customary 
analgesia (measured with the World Health Organization Quality of Life-BREF 
Instrument). 
 
 
While the primary goal of postoperative analgesics is in providing pain control, the most important 
outcomes for post-surgical patients are measures of well-being.  These measures reflect the 
dimensions of health as they are conceptualized and valued by patients themselves.  While health-
related quality of life is a subjective concept, various instruments are available that convert health 
status into quantifiable values.  The World Health Organization Quality of Life (WHOQoL) Instrument 
is specifically designed to evaluate clinically important, patient-relevant changes in health-related 
quality of life. The WHOQoL-BREF was developed by the World Health Organization to focus on 
those aspects of life most important to patients and is composed of 24 questions assessing 4 
dimensions:  (1) physical health, (2) psychological health, (3) social relationships, and (4) 
environment (e.g., participation in and opportunities for recreation).  In addition, two items are 
examined separately and involve individuals’ overall perception of both their quality of life and health.  
Each of the 26 questions is rated on a 0-5 scale, and then summed to produce both a total score as 
well as domain-specific scores for more in depth analysis.  Domain scores are scaled in a positive 
direction (i.e. higher scores denote higher quality of life).  The mean score of items within each 
domain is used to calculate the domain score.  Mean scores are then converted to range between 0-
100 to enable comparisons to be made between domains comprised of unequal numbers of 
questions. 
 
This quality of life instrument has been used in countless clinical investigations of pain, is validated 
specifically in postoperative populations following orthopedic surgery, and will increase the yield of 
this trial by improving comparisons with other investigations.  This instrument has good clinical 
acceptability with minimal subject burden and is available in both self- and interviewer-administered 
formats.  It has exceptional internal consistency, intra-rater (test-retest) reliability, construct validity, 
and discriminant validity. 

 
 
Biomedical IRB Application Instructions 
Page 21 
 
UH3 Milestones.  The 4-year UH3 implementation period has explicit milestones that are feasible, 
quantifiable, and scientifically justified to allow an assessment of progress.  Annual milestones are 
listed below following the timeline (Table 4).  All milestones must be completed in order to 
consider the UH3 definitive, pragmatic clinical trial successfully concluded. 
 
Table 4.  Four-year UH3 Implementation Phase pragmatic clinical trial Timeline (color added for 
clarity) 
 
Any revisions made to the feasibility study protocol and informed consent form (or any other aspect 
of the project) will have been completed during the last 2 quarters of the previous funding year (and 
submitted/approved by the appropriate regulatory bodies).  Therefore, study staff already well versed 
in the logistics of the project will implement the protocol.  As with the feasibility study, the Principal 
Investigator will review with the study team the entire first subject’s course, from referral to enrollment 
to lead insertion to medical follow-up and adverse event or protocol deviation reporting for quality 
assurance.  As with the feasibility study, prospective subjects will be identified in surgical clinics, 
referred to study personnel (adhering to HIPAA guidelines), offered enrollment by Research 
Coordinators, enrolled with written, informed consent, undergo the intervention and randomization, 
Funding Year: 
3 
4 
5 
6 
Months (within year): 
1-3 
4-12 
 
1-8 
8-12 
1-8 
9-12 
Complete any revisions remaining from UG3 
feasibility study 
• 
 
 
 
 
 
 
Re-initiate subject enrollment 
• 
 
 
 
 
 
 
Continue subject enrollment 
• 
• 
• 
• 
 
 
 
Data collection phone calls and database entry 
• 
• 
• 
• 
• 
• 
 
Medical Monitor reports (monthly) 
• 
• 
• 
• 
• 
• 
• 
DSMB reports and meetings (every 6 months) 
• 
• 
• 
• 
• 
• 
• 
Funding agency / oversight body reports (annually) 
 
• 
• 
 
• 
 
• 
Enrolling center IRB Continuing Reviews 
 
• 
• 
• 
• 
• 
 
Data entry and quality assurance 
 
• 
• 
• 
• 
• 
 
Interim analyses (25%, 50%, 75% enrollment) 
 
• 
• 
• 
 
 
 
Keep clinicaltrials.gov registry up-to-date 
 
• 
• 
• 
• 
• 
• 
Data cleaning and analysis 
 
 
 
 
 
 
• 
Final data analysis 
 
 
 
 
 
 
• 
Results to coinvestigators and interpretation 
 
 
 
 
 
 
• 
Results sent to all study participants 
 
 
 
 
 
 
• 
Results sent to funding agency 
 
 
 
 
 
 
• 
Manuscript preparation and submission 
 
 
 
 
 
 
• 
Final results uploaded to clinicaltrials.gov 
 
 
 
 
 
 
• 
Study closure by all regulatory bodies 
 
 
 
 
 
 
• 
Conclude DSMB with final report 
 
 
 
 
 
 
• 
Final report to funding agency 
 
 
 
 
 
 
• 

 
 
Biomedical IRB Application Instructions 
Page 22 
medical follow-up by the local Site Director, and data collection by the University of California San 
Diego. 
 
Definitive information about the execution of the intervention will be collected by the Primary 
Investigator and provided to the funding agency (any deficiencies will be corrected with the Site 
Directors).  As with the feasibility study, monitoring of all Sites will continue by the Primary 
Investigator, with monthly reports provided to the Medical Monitor (DSMB Chair), reports provided to 
the DSBM every 6 months (unless the DSMB charter specifies a different duration), and to the 
funding agency / oversight body annually.  The IRB continuing reviews will occur annually at the 
enrolling centers.  Clinicaltrials.gov registry will remain up-to-date.  We will continue to work closely 
with the NIH-DoD-VA Pain Management Collaboratory Coordinating Center regarding all aspects of 
the project. 
 
Year 3 Milestones [Implementation Phase Year 1]: 
o Re-initiate enrollment with revised protocol 
o Successfully enroll a total of 48 subjects during each quarter, for a total of 192 
subjects over the course of the year, divided approximately by anatomic lead 
location (e.g., 33% sciatic lead subjects) 
o Successfully upload to the data-collection platform (database) all data from UH3 
clinical trial subjects 
o First interim analysis after 25% of subjects enrolled 
o Approval by all regulatory bodies (DSMB, local IRBs, funding agency’s 
regulatory body) 
 
Year 4 Milestones: 
o Successfully enroll a total of 48 subjects during each quarter, for a total of 192 
subjects over the course of the year 
o Successfully upload to the data-collection platform (database) all data from UH3 
clinical trial subjects 
o Second interim analysis after 50% of subjects enrolled 
o Approval by all regulatory bodies (DSMB, local IRBs, funding agency’s 
regulatory body) 
 
Year 5 Milestones: 
o Successfully enroll a total of 48 subjects during each of the first 3 quarters, for a 
total of 144 subjects over the course of the year (Principal Investigator to work 
with all centers to ensure an equal number of total subjects with each anatomic 
lead location) 
o Successfully upload to the data-collection platform (database) all data from UH3 
clinical trial subjects 
o Third interim analysis after 75% of subjects enrolled 
o Conclusion of enrollment anticipated in the third quarter 
o Approval by all regulatory bodies (DSMB, local IRBs, funding agency) 
o Clinicaltrials.gov updated 
 
Year 6 Milestones: 
o Complete data collection 1 year following enrollment of the final subject 
(anticipated 3rd quarter) 

 
 
Biomedical IRB Application Instructions 
Page 23 
o Successfully upload to the data-collection platform (database) final data 
o Data cleaning and final analysis 
o Results dissemination to coinvestigators and interpretation 
o Results sent to funding agency and all study participants (by email or U.S. mail) 
o Manuscript preparation and submission 
o Clinicaltrials.gov updated with final results 
o Study closure by all regulatory bodies (DSMB, local IRBs, funding agency’s 
regulatory body) 
o Conclude DSMB with final report 
o Final report to funding agency 
 
 
Medical Monitor.  The study will have a designated medical monitor, Steven Shafer, MD, 
who will remain completely independent of the investigative team and will be a strong 
subject advocate.  The Medical monitor will oversee volunteer recruitment, volunteer 
enrollment, data collection, data storage, data analysis, and will report any discrepancies or 
problems to the Institutional Review Boards of both the enrolling center and lead center 
(University of California San Diego), as well as the Army Human Research Protections 
Office.  The Medical monitor will have the authority to stop the clinical trial at any time, and 
take any actions necessary to protect the safety and well-being of research volunteers until 
the Institutional Review Boards can assess the situation(s).  In addition, the Medical monitor 
will review all adverse events and provide a written opinion regarding the relationship and 
outcome of any unanticipated problems related to participation, serious adverse events, and 
subject deaths. 
 
 
 
 
Figure 12.  Institutional projected quarterly enrollment, with the first year dedicated to 
regulatory approval, the second year for feasibility study enrollment and protocol revisions, 
11 quarters of enrollment for the pragmatic clinical trial, a year for subject follow-up, and the 
final quarter for data analysis and manuscript preparation. 
 
 
 
 

 
 
Biomedical IRB Application Instructions 
Page 24 
 
The Study Team (Figure 13).  The study team consists of the Principal Investigator, 7 additional 
members of the Steering Committee, 7 Site Directors, 1 research coordinator for each of the 7 
enrolling centers, and 2 Significant Contributors from the company that developed the electrical 
leads and stimulator. 
 
  
 
 
 
Steven Cohen, MD
Co-Investigator
Uniformed Services University,
Walter Reed, and Johns Hopkins
Steering Committee
Harold Gelfand, MD
Site Director
Walter Reed
James Eisenach, MD
Co-Investigator
Wake Forest Medical Center
Edward Mascha, PhD
Co-Investigator & Statistician
Cleveland Clinic
Scott Griffith, MD
Co-Investigator
Walter Reed
Edward Mariano, MD
Site Director
Palo Alto VA
Enrolling Centers
Brian Ilfeld, MD, MS
P.I. & Steering Committee Chair
University California San Diego
Anthony Plunkett, MD
Site Director
Fort Bragg (WAMC)
Alparslan Turan, MD
Site Director
Cleveland Clinic
WRNMMC
Research
Coordinator
Palo Alto VA
Research
Coordinator
Fort Bragg
Research
Coordinator
Cleveland
Research
Coordinator
Steven Hanling, MD
Co-Investigator
Augusta University
Ian Fowler, MD
Site Director
Naval Medical Center
San Diego
NMCSD
Research
Coordinator
Paul Pasquina, MD
Co-Investigator
Uniformed Services University and
Walter Reed
Sandeep Dhanjal, MD
Site Director
Brooke Army Medical Center
BAMC
Research
Coordinator
Daniel Sessler, MD
Co-Investigator
Cleveland Clinic
Joseph Boggs, PhD
Significant Contributor
SPR Therapeutics
Amorn Wongsarnpigoon, PhD
Significant Contributor
SPR Therapeutics
Matthew Swisher, MD
Site Director
UC San Diego
UCSD
Research
Coordinator

 
 
Biomedical IRB Application Instructions 
Page 25 
Statistical Plan and Data Analysis 
 
Randomized groups will be compared for balance on baseline characteristics using descriptive 
statistics and the standardized difference (i.e., difference in means or proportions divided by pooled 
standard deviation).    Absolute standardized differences larger than 0.10 will be considered 
imbalanced and the corresponding variables considered for adjustment in all analyses.  Primary 
analyses will be modified intent-to-treat, such that all randomized patients who receive at least some 
of the study intervention will be included in the analyses.  All patients will be analyzed in the group to 
which they were randomized. 
 
Statistical methods will largely be the same for the Planning Phase and the Implementation Phase.  
As explained below, one difference is that in the planning phase focus we will be on the estimated 
confidence interval for the treatment effects and the variability of the outcomes, as these will be used 
in designing the full trial. Another is that interim analyses and more thorough subgroup analyses will 
be done in the Implementation Phase.  Details are given below. 
 
UG3 Planning Phase.  For Specific Aim 2 we will estimate the treatment effect of PNS versus usual 
and customary care on pain and opioid consumption using a joint hypothesis testing framework.  
Specifically, we will conclude PNS is superior to usual and customary analgesia, at least one of 
Hypotheses 1 and 2 must be superior while the other either superior or at least noninferior.   
 
We will first test for noninferiority of PNS to usual care on each of the two outcomes using 1-tailed 
noninferiority tests.  The noninferiority deltas will be 1 point (worse) in pain score and 20% higher in 
opioid consumption.  Noninferiority will be assessed at the overall 0.05 significance level with no 
adjustment to the significance criterion for testing two outcomes since noninferiority is required on 
both outcomes – i.e., an intersection union test.  A noninferiority delta of 1 point in pain score is 
conservative since receiver operating characteristic curve analysis has demonstrated that changes 
from baseline of at least 1.7 along a 10-point NRS accurately identified patients who rated 
improvements as “much improved” or more, compared with those who perceived no change or 
worsening following analgesic interventions.153,156,177-179 
 
We will assess noninferiority on pain score using a one tailed t-test which incorporates the 
noninferiority delta of 1 point. The estimated treatment effect for pain score will be derived from a 
linear mixed effects model with the outcome of patient’s “average” pain score for each day, with fixed 
effects for intervention (PNS vs usual care) and time (days 1 through 7), and assuming an 
autoregressive correlation structure among and measurements on the same patient overtime. We will 
then test for noninferiority with a one tailed t-test in which the numerator is the estimated treatment 
effect from the model minus the noninferiority delta (1), and the denominator is the standard error of 
the estimated treatment effect.  This method will yield results similar to comparing groups on the 
patient mean of these seven days, but is more flexible since it allows for missing data and also 
directly accounts for the correlation within patient.  The model also allows assessing the treatment by 
time interaction, but this will most likely not be of interest.180,181 
 
Cumulative opioid consumption is not typically normally distributed, but usually approximates a log-
normal distribution.  We therefore plan to assess the treatment effect of PNS versus usual care on 
the log transformed cumulative consumption through POD 7 using a simple linear regression model 
(equivalent to a t-test).  The estimated treatment effect (i.e., difference between groups) will then be 
used in a noninferiority test with null and alternative hypotheses as:     H0:   µ1 – µ2  ≥  log(1.2) = 

 
 
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0.263 versus   HA:    µ1 – µ2  <   log(1.2) = 0.263, where µ1 and  µ2  are the means of log-
transformed opioid consumption for PNS and usual care, respectively, and µ1 – µ2  is estimated by 
the coefficient (i.e., beta) for PNS versus usual care in the regression model.  The estimated 
treatment effect beta will also be an estimate of the ratio of geometric means for the two groups, 
assuming data for each group is log-normal with similar coefficient of variation between groups. 
 
In the planning phase, focus will be on the estimated confidence interval for the treatment effects and 
the variability of the outcomes.  
 
Secondary outcomes will be assessed using appropriate statistical methods.  We will use the t-test or 
Wilcoxon rank sum test for physical and functioning as measured by the Brief Pain Inventory 
(Hypothesis 3), chi-square analyses and t-test of Wilcoxon rank sum test for incidence and intensity 
of chronic pain, respectively (Hypothesis 4), and Wilcoxon rank sum for quality of life measure by the 
World Health Organization Quality of Life-BREF Instrument. 
 
Subgroup analysis for gender and ethnicity.  There is little relevant prior experience with the study 
intervention in the patient population of the proposed investigation, so it is not known whether either 
gender or ethnicity would interact with the treatment effect.  Therefore, in accord with the Human 
Subjects recommendations, we will assess the treatment effect of PNS on each outcome of interest 
within gender and ethnicity subgroups.  In addition, we will analyze each anatomic location to detect 
variations in treatment effect among the various lead insertion sites and types of surgical procedures.  
We will not require a significant interaction between treatment effect and these factors, but will rather 
conduct the subgroup analyses for each level of sufficient size (n=30).  The subgroup analyses will 
be the same as those conducted on the entire sample, and so would be just as valid and unbiased. 
 
Planning Phase sample size considerations.  The sample size for the planning phase of 64 
patients will be sufficient to estimate the treatment effects of interest with moderate precision, i.e., a 
confidence interval width of roughly 1.1 standard deviations for each outcome measure.  Confidence 
interval width for a standard deviation estimate will be 0.70 standard deviations.  The planning phase 
will be sufficient to use in estimating the expected treatment effect and standard deviation for each 
outcome for the larger trial. 
 
UH3 Implementation Phase.  Statistical methods for the UH3 Implementation Phase will follow very 
closely the methods described for the UG3 Planning Phase.  The main difference is that UH3 
Implementation Phase will have sufficient data to conduct the subgroup analyses and also 
considerably more power to assess the treatment effects of interest.    
 
Another substantive difference from the planning phase is that in the full trial we will conduct interim 
analyses at each 25% of the planned enrollment using a group sequential method with gamma 
spending function and gamma parameter of -4 (quite conservative) for efficacy and 0 (moderately 
aggressive) for futility (Figure 14).  The probability of crossing a boundary for either efficacy (mainly) 
or futility at the first through fourth looks would be 0.10, 0.42, 0.80 and 1.0, respectively, assuming 
the alternative hypotheses were true. 
 
 

 
 
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Figure 14.  Stopping 
boundaries for 1-tailed 
tests for superiority for 
either pain score or opioid 
consumption. Blue region 
indicates superiority 
(reduced opioid 
consumption or pain score) 
and pink region indicates 
futility (lack of superiority).  
Z-statistic represents 
strength of evidence 
against the null hypothesis, 
either ratio of means or 
difference in means divided 
by standard error.   
  
 
 
Missing outcomes data will 
be summarized along with 
the etiology of the absence.  
While very little outcomes 
data is expected to be missing, 
all 
analyses will be intention to treat, and imputation of missing data using methods such an multiple 
imputation and last observation carried forward will therefore be utilized, based on the situation.  In a 
conservative analysis imputation will involve the conservative approach of assigning the worst 
observed outcome to patients in intervention groups and best observed outcomes to those in control. 
 
Throughout, the significance level will be 0.05 for each hypothesis.  SAS statistical software (Cary, 
NC) will be used for all analyses, and East 6.0 (Cytel, Inc. Cambridge, MA) for interim monitoring and 
sample size calculations. 
 
UH3 Implementation Phase sample size considerations.  Sample size parameters for the 
implementation phase will be derived from estimates in the planning phase.  The sample size 
calculations below are conservative in that we observed a coefficient of variation for opioid 
consumption observed in our preliminary data of 0.48, substantially better than the assumed 0.65. It 
is thus quite possible that the actual sample size for the implementation phase will be smaller. 
 
Sample size for the full trial will be chosen to allow an overall 90% power at the 0.025 significance 
level (since 1-tailed tests) to claim the intervention more effective than the control on postoperative 
opioid requirements and pain as measured by NRS pain score.  In our joint hypothesis testing on 
these two outcomes, we power the study to have overall 90% power to detect superiority on either 

 
 
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outcome and at least noninferiority on both.  We assume a coefficient of variation of 1.0 for opioid 
consumption and a standard deviation of 2 for pain score. 
 
Power for the joint hypothesis testing will be driven by superiority tests since superiority is needed for 
at least 1 of the 2 outcomes.  For cumulative opioid consumption through POD 3 our previous data 
had a coefficient of variation (CV) of 46% (mean (SD) of 28 (13) mg).  Conservatively assuming a 
coefficient of variation of 75% through 7 days,183 with a total N=528 we would have 90% power to 
detect a relative reduction of 20% in mean opioid consumption at the overall 0.025 significance level 
(0.0125 for each of the two 1-tailed tests for superiority), adjusting for interim analyses (N=448 before 
adjustment for interim analyses). 
 
This sample size will yield high power (>0.95%) to detect superiority based on the intervention group 
having 1 point or more better than the control group on NRS pain score within the first 7 days, 
assuming a standard deviation of 2 points for mean of the “average” pain score for each patient. 
 
10. 
HUMAN SUBJECTS 
 
Inclusion criteria:  (1) Adult patients of at least 18 years of age; (2) with a planned single-injection 
peripheral nerve block for postoperative analgesia; and (3) undergoing one of the following surgical 
procedures: 
a.  rotator cuff repair (shoulder) 
b.  anterior cruciate ligament repair with a patellar autograph (knee) 
c.  ankle arthrodesis or arthroplasty (ankle) 
d.  hallux valgus correction (“bunionectomy” of the foot) 
 
These procedures are the most painful surgeries commonly performed on an outpatient (ambulatory) 
basis for each of the anatomic locations (shoulder, knee, ankle, and foot), with postoperative pain 
requiring opioid consumption usually lasting 2 weeks. 
 
Exclusion criteria:  (1) chronic analgesic use including opioids (daily use within the 2 weeks prior to 
surgery and duration of use > 4 weeks); (2) neuro-muscular deficit of the target nerve(s); (3) 
compromised immune system based on medical history (e.g., immunosuppressive therapies such as 
chemotherapy, radiation, sepsis, infection), or other conditions that places the subject at increased risk; 
(4) implanted spinal cord stimulator, cardiac pacemaker/defibrillator, deep brain stimulator, or other 
implantable neurostimulator whose stimulus current pathway may overlap; (5) history of bleeding 
disorder; (6) antiplatelet or anticoagulation therapies other than aspirin due to the risk of bleeding with a 
20-gauge insertion needle; (7) allergy to skin-contact materials (occlusive dressings, bandages, tape 
etc.); (8) incarceration; (9) pregnancy; (10) chronic pain of greater than 3 months of any severity in an 
anatomic location other than the surgical site; (11) anxiety disorder; (12) history of substance abuse; or 
(13) inability to contact the investigators during the treatment period, and vice versa (e.g., lack of 
telephone access). 
 
Anticipated enrollment at UCSD will be 100 subjects and anticipated enrollment at all other centers will be 
600 subjects, for a total of 700 subjects. 
 
11. 
RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH 
Enrollment.  Surgeons, anesthesiologists or their counterparts (e.g., CRNAs, PAs) at each enrolling 
center will identify potential study subjects at preoperative patient visits prior to a planned 
amputation.  Surgeons will be seeing patients as part of regular medical care, and therefore this 
protocol will adhere to Health Insurance Portability and Accountability Act (HIPAA) regulations.  

 
 
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Alternatively, the investigators may need to contact potential subjects prior to their pre-surgery visit 
and therefore request a waiver of consent for recruitment purposes.  We would scan the upcoming 
ambulatory surgery schedule (which we have access to being anesthesiologists—we use this 
schedule daily for medical purposes), identify patients having the types of surgical procedures 
specified for this study, look in their electronic records to determine eligibility, and if eligible either call 
the potential subjects ourselves or provide the name and contact information to a research 
coordinator to contact the potential subjects. 
 
1.  These procedures are minimal risk to the potential subjects as we are anesthesiologists who will 
be viewing these records even without study participation in preparation for surgery and 
postoperative analgesia planning.  There is no information that an anesthesiologist would not view 
regardless of the existence of the study. 
 
2.  A waiver of consent would not adversely affect the rights and welfare of the potential subjects as 
we are anesthesiologists who will be viewing these records even without study participation in 
preparation for surgery and postoperative analgesia planning.  There is no information that an 
anesthesiologist would not view regardless of the existence of the study. 
 
3.  This clinical trial could not be practicably carried out without the waiver because many relatively 
healthy ambulatory patients are not seen in preop clinic; or, they are seen just 1-2 days prior to their 
date of surgery.  We need to bring subjects into clinic within the 7 days prior to their surgery to have 
their leads inserted.  We do not have enough time to do this the morning of surgery. 
 
4.  After subjects are contacted, if they would like to participate they will receive written, informed 
consent using an IRB-approved informed consent form. 
 
These procedures would also include access to PHI, so we request a partial waiver of HIPAA 
authorization to be granted: 
 
1.  Identifiers will include the potential subject’s date of surgery, surgeon, name, phone number, and 
email address (to send ICF if patient is interested in participation).  This information will be recorded 
in hard-copy format and destroyed using a paper shredder (or in the locked UCSD PHI disposal 
stations) following contact with the patient.  If the patient does not participate, then there will be no 
record of PHI whatsoever.  If the patient does participate, then PHI will be protected as described in 
#16 below. 
 
2.  This clinical trial could not be practicably carried out without the waiver because many relatively 
healthy ambulatory patients are not seen in preop clinic; or, they are seen just 1-2 days prior to their 
date of surgery.  We need to bring subjects into clinic within the 7 days prior to their surgery to have 
their leads inserted.  We do not have enough time to do this the morning of surgery. 
 
3.  The privacy risk to individuals whose PHI will be used is minimal since, as anesthesiologists at 
UCSD caring for ambulatory surgery patients, we use the surgery schedule daily in the normal 
course of our work caring for patients; and, we will not record any PHI other than date of surgery, 
surgeon, name, contact phone numbers, and email address—and, these will be destroyed following 
use.  The anticipated benefit to subjects is a chance of improving their postoperative pain control if 
they are randomized to active stimulation. 
 

 
 
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4.  PHI that will be used includes date of surgery, surgeon, name, contact phone numbers, email 
address, basic anthropomorphic data such as height and weight, past medical and surgical history, 
and the surgical schedule itself.  Only coinvestigators will access this PHI, and the only people they 
might share it with are research coordinators actively participating in this research who understand 
PHI procedures and to appropriately destroy the hard copy of date/surgeon/name/contact 
numbers/email address after use. 
 
 
Patients meeting inclusion and exclusion criteria will be presented with the study, and prospective 
study subjects desiring additional information will be required to give permission for a research 
coordinator to contact them to adhere to HIPAA requirements.  The study protocol will be reviewed 
with interested prospective subjects in detail; and, for subjects desiring participation, written, informed 
consent will be obtained prior to any measurements, data collection, and/or interventions.  The 
method of documenting consent will be using written informed consent forms approved by the local 
Institutional Review Board. 
  
12. 
INFORMED CONSENT 
Once a prospective subject contacts (or gives permission to be contacted by) an investigator or 
research coordinator by telephone or email, they will be provided information on the study purpose 
and protocol, as well as have any questions answered.  Candidates who meet inclusion and 
exclusion criteria and desire study enrollment will be scheduled to arrive the day of surgery earlier 
than normal to allow for written informed consent and baseline instruments to be applied.  Written 
informed consent will be attained prior to any measurements or procedures prior to surgery.  Each 
site director is responsible for ensuring that written, informed consent is obtained from every subject 
at their respective enrolling center.  Clinical research coordinators—also one for each enrolling site—
will be specifically trained by the site directors to provide informed consent followed by 
documentation of informed consent using an Institutional Review Board-approved informed consent 
form.  When subjects present for surgery, research coordinators will provide and attain written 
informed consent.  This will occur in private patient care areas, so that subjects may feel comfortable 
asking questions of the research coordinator.  If a subject desires—or if there is a question that a 
research coordinator cannot answer—the site director will be called in by the research coordinator to 
discuss the study directly with the subject. 
We do not foresee any issues relevant to the mental capacity of the potential human subjects.  
Written, informed consent will be attained prior to any study procedures or measurements; and, 
subjects will not receive procedure-related sedation until following the written, informed consent 
process is completed.  Subjects will be provided privacy and time for decision making both in the 
study description/explanation telephone call to the site director or research coordinator, as described 
above; and also the morning of the initial treatment using a private patient care area to again review 
the study, informed consent form, and answer any remaining questions.  As noted previously, 
subjects may speak with the site director by telephone from initial contact through the morning of 
treatment; and, will have access during and following the treatment(s) with cellular phone and pager 
numbers provided upon discharge. 
This study protocol has follow-up data-collection telephone calls a maximum of 1 year following the 
initial study treatment, so repeated informed consent following the initial consent is unnecessary, as 
opposed to multi-year, longer-term clinical trials.  Surrogate consent will not be accepted; therefore, if 

 
 
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human subjects cannot provide consent on their own, they will not be offered study enrollment.  
Consent by an individual’s Legally Authorized Representative is unacceptable for study enrollment. 
 
13. 
ALTERNATIVES TO STUDY PARTICIPATION 
Patients can decline enrollment.  If they do so, they will still receive the standard-of-care 
postoperative analgesia. 
 
14. 
POTENTIAL RISKS 
The procedures and devices used in this study are already 510k cleared by the United States Food 
and Drug Administration to provide postoperative analgesia. However, there may be risks that are not 
yet known, and the incidences provided are all estimated with the exception of lead fracture.  
Potential risks include infection (<0.01% for up to 60 days of infusion),5 lead fracture (7.5%), lead 
dislodgement (<1%), nerve injury (<0.001%), bleeding (<0.01%), skin irritation (1-5%), lead migration 
(<0.1%), increased surgical pain, and discomfort/pain on insertion and/or during stimulation (10%). 
In addition, there is the risk of loss of confidentiality.  The following study procedures will be done to 
maintain confidentiality of this study:  hard copies will be kept in locked medical offices and the 
locked Investigational Drug Service’s files.  Any digitized records containing personal health 
information will be stored as password-protected and encrypted files. 
 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
The principle protection for participants and the true foundation for conducting a safe and effective 
clinical study is a well-trained and caring research staff.  The principle investigator of this proposal, 
Dr. Brian Ilfeld, is an experienced multicenter clinical trial Principal Investigator with a Master’s of 
Science Degree in Clinical Investigation that included multiple classes specifically addressing the 
ethical conduct of human subjects research.  Dr. Ilfeld has published special articles within peer-
reviewed journals specifically addressing this issue (Ilfeld BM: Informed consent for medical 
research: an ethical imperative. Reg Anesth Pain Med 2006; 31: 353-7.  PMID: 16857555).  All study 
personnel will receive training in human subjects protection and compliance with the HIPAA 
regulations. 
 
Subjects will be given clear instructions to call an investigator with any questions or concerns 
regarding their study participation.  If a patient experiences an injury that is directly caused by this 
study, only professional medical care that they receive at the medical center.  No other compensation 
is offered.  Any adverse events will be reported to the IRB using the standard adverse events 
reporting and upon continuing review (depending on severity, as defined by the IRB).  During 
stimulation, subjects will be contacted daily by an investigator, and subjects will have a physicians’ 
pager and cellular phone numbers available to respond 24 hours/day and 7 days/week until the day 
following lead removal.  This procedure has proven effective for ambulatory surgical patients with 
perineural local anesthetic infusions (continuous peripheral nerve blocks). 
 
Precautions and responses to possible specific adverse events: 
 
Infection:  Leads will be placed under sterile conditions as is standard-of-care for any percutaneous 
device insertion.  In addition, all patients having orthopedic surgical procedures receive perioperative 
antibiotics, which will further decrease any risk of infection.  Subjects will be called daily and asked 

 
 
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about signs and symptoms of lead infection.  Should a lead become infected, it will be removed and 
oral antibiotics prescribed. 
 
Lead fracture:  It remains unknown what leads to lead fracture in a small percentage of patients, and 
therefore we cannot take specific steps to minimize its occurrence other than removing the leads with 
continuous, gentle traction. 
 
Lead dislodgement and migration:  Leads include a small “anchor” at the distal end to help keep 
the lead from withdrawing.  In addition, the leads are shaped as a helical coil, which means they 
“unravel” if pulled on outside of the skin—the tip of the lead is withdrawn only after the entire lead has 
uncoiled with traction.  Therefore, inadvertent dislodgement and migration are extremely unlikely.  An 
occlusive dressing is used to affix the lead to the skin. 
 
Nerve injury:  Leads never intentionally come into contact with the nerve—they are inserted 0.5-2.0 
cm distant from the target nerve.  Therefore, a nerve injury should—theoretically—only occur with 
accidental contact with the target nerve.  The investigators are all specifically trained and have 
experience inserting perineural catheters using ultrasound guidance, which permits real-time 
visualization of the insertion needle and target nerve.  
 
Bleeding:  Exclusion criteria include ongoing active anticoagulation and/or bleeding disorders to 
decrease the risk of bleeding.  During insertion, vessels are avoided with the use of real-time 
ultrasound guidance.  The investigators are all specifically trained and have experience inserting 
perineural catheters using ultrasound guidance. 
 
Discomfort:  Subjects will have a single-injection peripheral nerve block with long-acting local 
anesthetic prior to surgery and be provided with a prescription for an oral opioid.  Therefore, if the 
electrical leads provide an inadequate degree of analgesia, subjects will take their oral opioids. 
 
Confidentiality:  The risks to confidentiality are the release of names/ telephone numbers/ 
demographic data (e.g. weight, age, height), which will be minimized by the use of password-
protected computers and case report forms that will be stored in locked offices. 
 
The study will have a designated medical monitor, Steven Shafer, MD, who will remain completely 
independent of the investigative team and will be a strong subject advocate.  The Medical monitor will 
oversee volunteer recruitment, volunteer enrollment, data collection, data storage, data analysis, and 
will report any discrepancies or problems to the Institutional Review Boards of both the enrolling 
center and lead center (University of California San Diego), as well as the Army Human Research 
Protections Office.  The Medical monitor will have the authority to stop the clinical trial at any time, 
and take any actions necessary to protect the safety and well-being of research volunteers until the 
Institutional Review Boards can assess the situation(s).  In addition, the Medical monitor will review 
all adverse events and provide a written opinion regarding the relationship and outcome of any 
unanticipated problems related to participation, serious adverse events, and subject deaths. 
 
The study Data Safety Monitoring Board (DSMB) will be comprised of the Medical Monitor, a 
physician experienced in both clinical trial management and the ethical conduct of research (Pamela 
Flood, MD), and a statistician, also well-experienced in multicenter trials (Jarrod Dalton, PhD).  All 
three of these individuals will be completely independent of the investigative team.  No member of 
the DSMB will have any financial, proprietary, professional, or other interests that may affect 

 
 
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impartial, independent decision-making by the DSMB.  The board will comprise individuals with no 
vested interest in the outcome of the research study.  The members will also sign a confidentiality 
statement.  The DSMB will operate from a charter describing its role, membership, reporting 
procedures, and meeting protocol. The DSMB will decide on its own protocols, set triggers for data 
review or analyses, and establish guidelines for monitoring the study, stopping the study for safety 
concerns, and for efficacy based on plans specified in the protocol.  Confidentiality will be maintained 
during all phases of DSMB review and deliberations.  DSMB members will maintain strict 
confidentiality concerning all privileged trial results provided to them. The board will perform the 
following functions: 
 
• Approval of the trial protocol before enrollment of patients 
• Review the data in order to determine efficacy, futility, and safety, and to determine whether the 
study should continue 
• Review data quality and data integrity 
• Evaluate risk versus benefit by thorough examination of the data accumulated 
• Determine whether the trial is proceeding as planned, the protocol is being followed, the recruitment 
of patients is on schedule, and data are being collected with the proper accuracy 
• Review patient dropouts, if any, and make appropriate recommendations 
• Determine whether safety concerns have been raised by the experimental or control treatments 
 
Review Items.  Items to be reviewed by the DSMB include: 
• Interim/cumulative data for evidence of study-related adverse events 
• Interim/cumulative data for evidence of efficacy according to pre-established statistical guidelines in 
the study protocol 
• Data quality, completeness, and timeliness 
• Performance of individual centers 
• Adequacy of compliance with goals for recruitment and retention, including those related to 
participation of women and minorities 
• Adherence to the protocol 
• Factors that might affect the study outcome or compromise the confidentiality of the trial data (such 
as protocol violations etc.) 
• Factors external to the study such as scientific or therapeutic developments that may impact 
participant safety or the ethics of the study 
 
Recommendations.  The DSMB will conclude each review with their recommendations to the 
principal investigator and primary site Institutional Review Board (at the University of California San 
Diego) as to whether the study should continue without change, be modified, or terminated. 
Recommendations regarding modification of the design and conduct of the study may include: 
• Modifications of the study protocol based upon the review of the safety data 
• Suspension or early termination of the study or of one or more study arms because of serious 
concerns about patients' safety, inadequate performance, or rate of enrollment 
• Suspension or early termination of the study or of one or more study arms because study objectives 
have been obtained according to pre-established statistical guidelines 
• Optional approaches for executive committee and investigators to consider when the DSMB 
determines that the incidence of the primary study outcomes is substantially less than expected, 
such as recommendations to increase the number of trial centers or extend the recruitment period 
• Corrective actions regarding a study center whose performance appears unsatisfactory or 
suspicious 

 
 
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Appropriate reports will be made to the Institutional Review Boards at all enrolling centers and the 
executive committee, comprised of all co-investigators and site directors 
 
Patient Serious Adverse Event Reporting.  All unanticipated events and adverse events will be 
reported to the specific center’s Institutional Review Board (IRB), the primary supervising IRB 
(University of California San Diego), the study Data and Safety Monitoring Board (DSMB), and the 
Army Human Research Protections Office.  The adverse event and unanticipated event profile will be 
discussed at monthly executive committee video-conference meetings. 
 
Management of adverse events.  Adverse events for study-related injuries will be managed by the 
site director of each center.  For a medical emergency that is potentially life-threatening, subjects will 
be instructed to dial 911 for emergency services to go directly to their location, and the site director 
will meet the subject at the site’s emergency department. 
 
In the event of a study-related injury, the treatment institutions will provide medical care needed to 
treat those injuries without cost to study subjects.  The institutions will not provide any other form of 
compensation for study-related injuries.  This information is specified within the informed consent 
forms.  The forms also instruct subjects to contact the local Institutional Review Board, the enrolling 
investigator, or the principal investigator of the study for further information (phone numbers provided 
for all entities).  In addition, active duty United States Armed Forces service members who enrolled at 
a civilian institution who sustain a research-related injury may receive medical care at a military 
hospital or clinic free of charge.  The informed consent form instruct active duty service members to 
contact the United States Army Medical Research and Materiel Command (USAMRMC) Office of the 
Staff Judge Advocate (legal office) for issues that are inadequately resolved (with phone number). 
 
 
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT 
Pre-ICF information.  The only information that will be recorded on hard-copy format before a 
subject provides written, informed consent is date of surgery, surgeon, name, contact phone 
numbers, and email address.  This information will be destroyed using a paper shredder (or in the 
locked UCSD PHI disposal stations) following contact with the patient.  If the patient does not 
participate, then there will be no record of PHI whatsoever. 
Disposition of data.  The original, hard-copy signed informed consent forms and case report forms 
will be stored within the local site director’s locked office, where they will remain for at least 7 years.  
These hard copies will not be mailed or otherwise transferred.  Data will be uploaded and stored in 
one location: the central servers of Department of Outcomes Research at the Cleveland Clinic, a 
department dedicated completely to clinical research. This department has a full-time Research 
Electronic Data Capture (REDCap) programmer dedicated to developing REDCap databases and 
providing support for clinical trials. REDCap is a relational database for data entry and auditing. This 
is a web-based application designed exclusively to support data capture for research studies.  The 
Department of Outcomes Research at the Cleveland Clinic web servers are encrypted and 
password-protected with multiple firewalls to the standards of the National Institutes of Health. Of 
note, the servers are backed up every night. In the case of a disk failure, only data written to the files 
since the last backup will be subject to loss and can be easily restored. Databases are protected 
through electronic measures using a multi-layered, but simple approach: all study related files will 
reside on the database server rather than on individual hard disk drives and the files will be protected 
by the operating systems features against general access. User names will be password protected.  
The electronic data will remain within the Department of Outcomes Research for 7 years following 

 
 
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study completion.  The UCSD research coordinator may receive training at the UCSD CTRI in 
REDCap use. With such training, up to six hours of user support is provided without recharge. 
However, technical and most user support will be provided by the Cleveland Clinic. 
Each local site will transfer certain PHI to the UCSD research coordinator who will make all data 
collection phone calls for all subjects. PHI transferred will include the subject’s name, phone 
numbers, and study ID. This information will be transferred via a secure online system known as the 
Army Missile and Research, Development and Engineering Command Safe Access File Exchange 
System (AMRDEC SAFE). AMRDEC SAFE is a secure, password-protected, system that the military 
has approved, and requires, for the transfer of such data. Civilian centers may use this system if 
access is granted, or fax to a locked office with access restricted only to the UCSD study coordinator 
and the PI. 
Sharing study results. Following study completion, all subjects will be provided with the study 
results in written form and in language appropriate for non-medical individuals. In addition, the master 
dataset will be de-identified. 
 
17. POTENTIAL BENEFITS 
Subjects might experience less postoperative pain than they otherwise would have without 
participation.  If so, they might require fewer opioid analgesics and have a lower risk of experiencing 
opioid-related side effects such as nausea, vomiting, and pruritus.  They might have a lower risk of 
chronic pain, opioid dependence, and mental/physical disability. 
 
18. RISK/BENEFIT RATIO 
While there are risks involved in the insertion, use, and removal of percutaneous leads, they are 
relatively rare and not catastrophic when they do occur.  With its ease of insertion, prolonged 
duration of action, presumably lower risk of complications or side effects, and simple removal, 
neuromodulation has the very real possibility of replacing local anesthetic administration—the 
standard of care for the past 100 years—that would completely revolutionize postoperative analgesia, 
as we know it. 
 
19. EXPENSE TO PARTICIPANT 
There will be no additional costs to subjects as a result of being in this study, other than any 
transportation costs and parking charges for their return trip for lead removal.  If a subject is injured as 
a direct result of participation in this research, the University of California will provide any medical care 
they need to treat those injuries. The University will not provide any other form of compensation for an 
injury. 
 
20. COMPENSATION FOR PARTICIPATION 
There is no compensation for participation. 
 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
Principal Investigator, Brian M. Ilfeld, MD, MS, is a board-certified anesthesiologist with fellowship 
training in and 17 post-training years experience with regional anesthesia and acute pain medicine.  
Dr. Ilfeld holds a license to practice medicine in California.  Dr. Ilfeld has medical privileges at the UC 
Medical Centers.  Dr. Ilfeld, or another investigator, will follow all subjects following their treatment.  

 
 
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Dr. Ilfeld will be responsible for the overall management of this study, as well as for the well-being of 
study subjects. 
 
Co-investigators, Rodney Gabriel, MD, MAS; Matthew Swisher, MD; are board-certified 
anesthesiologists with fellowship training in and extensive experience with regional anesthesia and 
acute pain medicine.  All hold a license to practice medicine in California and have medical privileges 
at the UC Medical Centers.  All will help consent subjects, perform a history and physical exam, 
perform the treatment on subjects, and will follow subjects following their treatment. 
 
The study will be overseen a medical monitor, Steven Shafer, MD, of Stanford University, Stanford, 
California—in essence a study subject advocate.  As the former Editor-in-Chief of one of 
anesthesiology’s two highest-impact medical journals, a clinician, and a Federally-funded research 
himself, Dr. Shafer is thoroughly experienced in management of clinical trials, the ethical conduct of 
clinical research, the patient population under investigation, and Acute Pain Medicine interventions 
for postoperative analgesia.  As such, Dr. Shafer is a strong study subject advocate.  Dr. Shafer has 
extensive experience working on committees and authoring/editing peer-reviewed evidence-based 
publications, and will be an active member of the DSMB.  He has been, and will continue to be, 
completely independent of the investigative team.  In addition, Dr. Shafer has no financial, 
proprietary, professional, or other interests that may affect impartial, independent decision-making by 
the DSMB. Lastly, he has no vested interest in the outcome of the research study.  Dr. Shafer will 
remain completely independent of the investigative team and will be a strong subject advocate.  The 
Medical monitor will oversee volunteer recruitment, volunteer enrollment, data collection, data 
storage, data analysis, and will report any discrepancies or problems to the Institutional Review 
Boards of both the enrolling center and lead center (University of California San Diego), as well as 
the Army Human Research Protections Office.  The Medical monitor will have the authority to stop 
the clinical trial at any time, and take any actions necessary to protect the safety and well-being of 
research volunteers until the Institutional Review Boards can assess the situation(s).  In addition, the 
Medical monitor will review all adverse events and provide a written opinion regarding the 
relationship and outcome of any unanticipated problems related to participation, serious adverse 
events, and subject deaths. 
 
 
DSMB members Pamela Flood, MD, and Jarrod Dalton, PhD, are from Stanford University and the 
Cleveland Clinic.  Dr. Flood is a board-certified anesthesiologist and clinical researcher in the with 
extensive experience involving the ethics of human subjects research.  Dr. Dalton is a statistician 
with over two decades of experience involving clinical research. 
 
Baharin Abdullah is a research coordinator with the UCSD CTRI, with the required training—
including up-to-date CITI training—for her position. 
 
 
22. BIBLIOGRAPHY 
 
1. Ilfeld BM, Grant SA: Ultrasound-guided percutaneous peripheral nerve stimulation for 
postoperative analgesia: Could neurostimulation replace continuous peripheral nerve blocks? 
Reg Anesth Pain Med 2016; 41: 720-722 

 
 
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2. Ilfeld BM, Gilmore CA, Grant SA, Bolognesi MP, Del Gaizo DJ, Wongsarnpigoon A, Boggs 
JW: Ultrasound-guided percutaneous peripheral nerve stimulation for analgesia following total 
knee arthroplasty: a prospective feasibility study. J Orthop Surg Res 2017; 12: 4 
3. Ilfeld BM, Grant SA, Gilmore CA, Chae J, Wilson RD, Wongsarnpigoon A, Boggs JW: 
Neurostimulation for Postsurgical Analgesia: A Novel System Enabling Ultrasound-Guided 
Percutaneous Peripheral Nerve Stimulation. Pain Pract 2017; 17: 892-901 
4. Ilfeld BM, Ball ST, Gabriel RA, Sztain JF, Monahan AM, Abramson WB, Khatibi B, Said ET, 
Parekh J, Grant SA, Wongsarnpigoon A, Boggs JW: Perioperative percutaneous peripheral 
nerve stimulation utilizing preoperative lead placement for the treatment of postoperative pain 
[abstracted]. Reg Anesth Pain Med 2017: 3603 
5. Ilfeld BM, Gabriel RA, Saulino MF, Chae J, Peckham PH, Grant SA, Gilmore CA, Donohue 
MC, deBock MG, Wongsarnpigoon A, Boggs JW: Infection Rates of Electrical Leads Used for 
Percutaneous Neurostimulation of the Peripheral Nervous System. Pain Pract 2017; 17: 753-
762 
 
23. FUNDING SUPPORT FOR THIS STUDY 
Drs. Ilfeld, Swisher and Gabriel will be supported by a Department of Defense grant award 
(NH170005) which will help to support his nonclinical time and the product used in this investigation.  
Start date for this grant will be determined soon and will terminate after 6 years.  Please contact 
Yolanda Boyd, grants specialist, at (619) 471-3320 for information regarding this DoD grant. All 
funding for this investigation is provided by the Department of Defense. 
 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
Not applicable. 
 
 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
Not applicable. 
 
26. IMPACT ON STAFF 
None.  All study procedures will be executed by investigators and research coordinators without the 
assistance of non-investigator staff members. 
 
27. CONFLICT OF INTEREST 
The Department of Defense is funding this study in its entirety. There is no financial or otherwise 
conflict of interest for any of the investigators. 
 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
Not applicable. 
 
29. OTHER APPROVALS/REGULATED MATERIALS 
None. 
 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT 

 
 
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Not applicable:  surrogate consent will not be accepted.