A Randomized, Single-Blinded, Sham-Controlled Study Evaluating the Efficacy and Safety of RELAY, a Device Enabling Both Local Anesthetic Delivery and Neuromodulation Following Shoulder or Foot Surgery: Single Arm Training Run-In Phase
Phase: NA
Conditions: Rotator Cuff Injuries, Shoulder Disease, Hallux Valgus, Ankle Arthropathy
Sponsor: University of California, San Diego

Official Title:  A Device Enabling Both Local Anesthetic Delivery 
and Neuromodulation for Postoperative Analgesia:  A Feasibility 
and Randomized Pilot Study 
 
 
 
NCT:  06818708 
 
 
 
Document date:  January 22, 2025 
 

 
 
Office of IRB Administration (OIA) 
Biomedical Protocol for  
Interventional Research 
Version Date 12.08.21 
 
*= Required 
      Edited version of NIH-FDA Clinical Trial Template v1.07 
A Randomized, Single-Blinded, Sham-Controlled Study Evaluating the Efficacy 
and Safety of RELAY, a Device Enabling Both Local Anesthetic Delivery and 
Neuromodulation for Postoperative Analgesia, in Participants Having Shoulder 
or Foot Surgery Following a Single Arm Training Run-In 
                                   Protocol Number:  810455 
 
National Clinical Trial (NCT) Identified Number:  pending 
Principal Investigator: Brian M. Ilfeld, MD, MS 
Funded by: Gate Science, the study sponsor is paying UC San Diego to conduct 
this research study. 
 
Protocol: Version 1.5 
22 January 2025 
 
 
 
Summary of Changes from Previous Version: 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
Cover page, funding information. 
Funding information is revised to 
“Gate Science, the study sponsor is 
paying UC San Diego to conduct this 
research study.” 
 
  
To clarify funding information. 

 
 
  
 
ii 
Table of Contents 
1 
PROTOCOL SUMMARY ....................................................................................................................................... 1 
1.1 
Synopsis .................................................................................................................................................. 1 
1.2 
Schema .................................................................................................................................................... 6 
1.3 
Schedule of Activities (SoA) .................................................................................................................... 7 
2 
INTRODUCTION ................................................................................................................................................. 7 
2.1 
Study Rationale ....................................................................................................................................... 7 
2.2 
Background ............................................................................................................................................. 7 
2.3 
Risk/Benefit Assessment....................................................................................................................... 12 
2.3.1 
Known Potential Risks ....................................................................................................... 12 
2.3.2 
Known Potential Benefits ................................................................................................. 13 
2.3.3 
Assessment of Potential Risks and Benefits ..................................................................... 13 
3 
OBJECTIVES AND ENDPOINTS .......................................................................................................................... 14 
4 
STUDY DESIGN ................................................................................................................................................. 15 
4.1 
Overall Design ....................................................................................................................................... 15 
4.2 
Scientific Rationale for Study Design .................................................................................................... 16 
4.3 
Justification for Dose ............................................................................................................................ 16 
4.4 
End of Study Definition ......................................................................................................................... 16 
5 
STUDY POPULATION ........................................................................................................................................ 17 
5.1 
Inclusion Criteria ................................................................................................................................... 17 
5.2 
Exclusion Criteria .................................................................................................................................. 17 
5.3 
Lifestyle Considerations ........................................................................................................................ 17 
5.4 
Screen Failures ...................................................................................................................................... 17 
6 
STUDY INTERVENTION ..................................................................................................................................... 17 
6.1 
Study Intervention(s) Administration ................................................................................................... 18 
6.1.1 
Study Intervention Description ......................................................................................... 18 
6.1.2 
Dosing and Administration ............................................................................................... 20 
6.2 
Preparation/Handling/Storage/Accountability .................................................................................... 20 
6.2.1 
Acquisition and accountability .......................................................................................... 20 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ......................................................... 20 
6.2.3 
Product Storage and Stability ........................................................................................... 20 
6.2.4 
Preparation ....................................................................................................................... 20 
6.3 
Measures to Minimize Bias: Randomization and Blinding ................................................................... 20 
6.4 
Study Intervention Compliance ............................................................................................................ 20 
6.5 
Concomitant Therapy ........................................................................................................................... 20 
6.5.1 
Rescue Medicine ............................................................................................................... 20 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL ............. 21 
7.1 
Discontinuation of Study Intervention ................................................................................................. 21 
7.2 
Participant Discontinuation/Withdrawal from the Study .................................................................... 21 
7.2.1 
Discontinuation Criteria .................................................................................................... 21 
7.3 
Lost to Follow-Up .................................................................................................................................. 21 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................................................................... 21 
8.1 
Efficacy Assessments ............................................................................................................................ 22 
8.2 
Safety and Other Assessments ............................................................................................................. 23 
8.3 
Adverse Events and Serious Adverse Events ........................................................................................ 24 
8.3.1 
Definition of Adverse Events (AE) ..................................................................................... 24 
8.3.2 
Definition of Serious Adverse Events (SAE) ...................................................................... 24 
8.3.3 
Classification of an Adverse Event .................................................................................... 24 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up .................................. 25 
8.3.5 
Adverse Event Reporting .................................................................................................. 26 
8.3.6 
SERIOUS ADVERSE EVENT REPORTING .................................................................... 26 
8.3.7 
Reporting Events to Participants ...................................................................................... 26 

 
 
  
 
iii 
8.3.8 
Events of Special Interest .................................................................................................. 27 
8.3.9 
Reporting of Pregnancy .................................................................................................... 27 
8.4 
Unanticipated Problems ....................................................................................................................... 27 
8.4.1 
Definition of Unanticipated Problems (UP) ...................................................................... 27 
8.4.2 
Unanticipated Problem Reporting .................................................................................... 27 
8.4.3 
Reporting Unanticipated Problems to Participants .......................................................... 28 
9 
STATISTICAL CONSIDERATIONS ....................................................................................................................... 28 
9.1 
Statistical Hypotheses ........................................................................................................................... 28 
9.2 
Sample Size Determination .................................................................................................................. 28 
9.3 
Populations for Analyses ...................................................................................................................... 28 
9.4 
Statistical Analyses................................................................................................................................ 28 
9.4.1 
General Approach ............................................................................................................. 28 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) .................................................................... 29 
9.4.3 
Analysis of the Secondary Endpoint(s) ............................................................................. 29 
9.4.4 
Safety Analyses ................................................................................................................. 30 
9.4.5 
Baseline Descriptive Statistics........................................................................................... 30 
9.4.6 
Planned Interim Analyses ................................................................................................. 30 
9.4.7 
Sub-Group Analyses .......................................................................................................... 30 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................................................... 30 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .................................................................... 31 
10.1.1 
INFORMED CONSENT PROCESS ................................................................................. 31 
10.1.2 
Study Discontinuation and Closure ................................................................................... 32 
10.1.3 
Confidentiality and Privacy ............................................................................................... 32 
10.1.4 
Future Use of Stored Specimens and Data ....................................................................... 33 
10.1.5 
Key Roles and Study Governance ..................................................................................... 33 
10.1.6 
Safety Oversight ................................................................................................................ 33 
10.1.7 
Clinical Monitoring ............................................................................................................ 33 
10.1.8 
Data Handling and Record Keeping .................................................................................. 34 
10.1.9 
Protocol Deviations ........................................................................................................... 34 
10.2 
Additional Considerations .................................................................................................................... 35 
10.2.1 
ALTERNATIVES TO STUDY PARTICIPATION ....................................................................... 35 
10.2.2 
EXPENSE TO PARTICIPANT ................................................................................................ 35 
10.2.3 
COMPENSATION FOR PARTICIPATION .............................................................................. 35 
10.2.4 
Management of adverse events ....................................................................................... 35 
10.2.5 
PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES ......... 35 
10.2.6 
FUNDING SUPPORT FOR THIS STUDY ............................................................................... 35 
10.3 
Abbreviations ........................................................................................................................................ 36 
10.4 
Protocol Amendment History ............................................................................................................... 36 
11 
REFERENCES ..................................................................................................................................................... 37 
12 
Appendix .......................................................................................................................................................... 39 
 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
1 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
A Randomized, Single-Blinded, Sham-Controlled Study Evaluating the Efficacy and 
Safety of RELAY, a Device Enabling Both Local Anesthetic Delivery and 
Neuromodulation for Postoperative Analgesia, in Participants Having Shoulder or Foot 
Surgery Following a Single-Arm Training Run-In. 
 
Study 
Description: 
This is a single-center, sham-controlled study to investigate the efficacy and safety of 
RELAY, a device that enables the delivery of both local anesthetic and 
neuromodulation (peripheral nerve stimulation) to treat postoperative pain.  
RELAY is comprised of a basic catheter-over-needle device to allow administration of a 
single-injection of local anesthetic via the needle (or catheter) followed by a 
perineural local anesthetic infusion via the remaining catheter (when desired).  
Subsequent to the local anesthetic administration, instead of removing the catheter 
as with all previous continuous peripheral nerve block equipment, electric current 
may be delivered via the same catheter for up to a total of 28 days.  This is potentially 
paradigm shifting because it would allow an anesthesiologist to deliver (1) a single-
injection peripheral nerve block; (2) a continuous peripheral nerve block; and (3) 
neuromodulation using a single device that can theoretically be placed in the same 
amount of time required for a single-injection peripheral nerve block.  Instead of 
providing fewer than 24 hours of postoperative analgesia, up to 28 days of pain 
control could be delivered without disruption of the existing practice patterns. 
Following a training run-in period, the randomized single blind sham-controlled part 
of the study will commence.  The purpose of the training run-in period is to ensure 
that RELAY can be safely placed next to a target nerve, successfully programmed and 
induce peripheral nerve block and neuromodulation based on the instructions for use. 
This will ensure familiarity with the device prior to the randomized portion of the 
study.  The training period will consist of up to 20 participants (~ 5 to 10 catheter lead 
insertions per anesthesiologist) across at least two different surgical procedures.  
It is anticipated that during the training run-in phase, the successful deployment of 
the RELAY system will be achieved 80% or more of the time. If less than 80% is 
achieved, the study will not proceed to the randomized portion. A brief study report 
will be submitted to the FDA prior to initiating the randomized portion. 
RELAY deployment success will be defined as a successfully placed catheter/lead as 
evidenced by sensory changes in the distribution of the target nerve with (1) electrical 
stimulation eliciting paresthesia and (2) inducing a conduction nerve block with 
injection of local anesthetic injection leading to either decreased or absent sensation 
to cold with alcohol swab.  
The randomized portion will include 40 participants (with up to 10 additional 
participants to account for drop-outs) randomized (1:1) to the experimental and sham 
arms, respectively.  A futility analysis will be performed once 20 participants have 
been randomized and data through post-operative Day 7 are available.  The following 
two criteria must be achieved to move forward: 1) RELAY deployment success in the 
lead/catheter insertion of ≥ 85% in RELAY participants, and 2) a conditional power 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
2 
(Cp) of ≥30% for the primary efficacy endpoint. Of note, a standardized effect size of 
0.49 would not meet criteria to continue.  There will be no stopping for early efficacy.  
 
Objectives/ 
Endpoints 
The primary objective of the proposed research study is to assess postoperative 
analgesia that extends beyond the duration of the local anesthetic interventions to 
prepare for a subsequent pivotal definitive clinical trial with the RELAY device 
compared to sham control. 
Primary endpoint: Difference in the average daily pain intensity for Days 1-7 as 
measured with the Numeric Rating Scale (NRS) within the Brief Pain Inventory (BPI) 
via the RELAY device compared to sham control. 
• 
Hypothesis 1:  Neuromodulation with the RELAY device will decrease average 
pain intensity for Days 1-7 following foot and shoulder surgery currently 
treated with a single-injection peripheral nerve block (as measured with the 
NRS within the BPI). 
The key secondary objectives are: 
1) To estimate the effect on opioid consumption of neuromodulation via the RELAY 
device as compared to sham control  
Key secondary endpoint 1 (hierarchical: tested for significance only if the primary 
endpoint achieves significance at alpha 1-sided <0.025): Difference in the 
cumulative opioid use (oxycodone equivalents) for Days 1-7 via the RELAY device 
compared to sham control. 
• 
Hypothesis 2:  Neuromodulation with the RELAY device will decrease opioid 
consumption within the week following foot and shoulder surgery currently 
treated with a single-injection peripheral nerve block (measured in oxycodone 
equivalents), as measured both with daily and cumulative opioid consumption 
within the first postoperative week). 
2) To estimate the effect on physical and emotional functioning of 
neuromodulation via the RELAY device as compared to sham control  
Key secondary endpoint 2 (hierarchical: tested for significance only if the primary 
endpoint and key secondary endpoint 1 both achieve significance at alpha 1-sided 
<0.025): Difference in BPI interference subscale on Day 3 as measured with the 
NRS within the BPI Inventory via the RELAY device compared to sham control. 
• 
Hypothesis 3:  Neuromodulation with the RELAY device will decrease pain’s 
interference in physical and emotional functioning within the week following 
foot and shoulder surgery currently treated with a single-injection peripheral 
nerve block (as measured with the Interference Subscale of the BPI). 
Other Secondary Endpoints to include:  
• 
Interference in physical and emotional functioning (as measured with the 
Interference Subscale of the BPI) on Post-op Day 7 
• 
Opioid use (oxycodone equivalents) on Post-op Days 1, 2, 3, 4, 7, 8 and 14 
• 
Awakenings due to pain on Post-op Days 1, 2, 3, 4, 7, 8 and 14 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
3 
• 
Daily Pain intensity (“average” and “worst” NRS) on Post-op Days 1, 2, 3, 4, 7, 
8, 14 
• 
Daily Pain intensity (“current” and “least” NRS) on Post-op Days 3 and 7 
• 
Frequency, pulse duration, amplitude, and anode (proximal vs distal) will be 
recorded at baseline; amplitude during postoperative Days 1, 2, 3, 4, and 7 
• 
Masking assessment on Post-op Day 1 (randomized period only) 
Post-
Enrollment 
Assessments 
 
 
Study 
Population 
There will be approximately 70 participants. 
Inclusion criteria: 
1. Adult participants of at least 18 years of age 
2. Undergoing a rotator cuff repair, total shoulder arthroplasty, hallux valgus 
correction or ankle arthroplasty/arthrodesis 
3. Planned single-injection peripheral nerve block(s) 
4. An Android or Apple smartphone able to download the Gate Keeper controller 
app 
Exclusion criteria: 
1. Chronic opioid or tramadol use (daily within prior 2 weeks and duration > 4 
weeks) 
2. Neuro-muscular deficit of the surgical limb 
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 of 
infection 
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 
7. Allergy to skin-contact materials (occlusive dressings, bandages, tape etc.) 
8. Incarceration 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
4 
9. Pregnancy 
10. Moderate pain (NRS > 3) in an anatomic location other than the surgical site 
11. Anxiety disorder 
12. History of substance misuse 
13. Inability to communicate with the investigators 
14. Inability to contact the investigators during the treatment period, and vice 
versa (e.g., lack of telephone access) 
15. Allergy to amide local anesthetics 
16. Morbid obesity (body mass index > 40 kg/m2) 
Phase: 
Not applicable to this investigation involving a medical device (as opposed to a 
medication) 
Description of 
Sites/Facilities 
Enrolling 
Participants 
U.C. San Diego Clinical and Translational Research Institute and hospitals (including 
the ambulatory surgical centers) 
Description of 
Study 
Intervention 
The RELAY system combines a catheter-over-needle to permit ultrasound-guided 
percutaneous insertion with the tip adjacent to a peripheral nerve or plexus, followed 
by needle removal which leaves the catheter in situ to deliver a bolus of local 
anesthetic (if desired) and subsequent perineural local anesthetic infusion (if desired).  
The catheter also has 3 integrated electrodes to enable neuromodulation using the 
integrated pulse generator and battery (figure below). 
 
Participants will have standard external monitors placed and oxygen delivered by 
facemask or nasal cannula.  The peripheral nerve block site(s) will be cleansed with 
chlorhexidine gluconate and isopropyl alcohol.  Intravenous sedation/analgesia with 
midazolam and/or fentanyl will be titrated for patient comfort as is standard for 
peripheral nerve block administration.  The nerves treated will include the sciatic 
proximal to the popliteal crease for foot surgery and the brachial plexus for shoulder 
surgery.  The target nerve(s) will be visualized with ultrasound using a transverse 
cross-sectional (short axis) view and a skin wheal of local anesthetic will be raised 
inferior to the transducer to anesthetize the skin and then the track towards the 
target. 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
5 
Treatment group allocation (randomization). Participants in the training run-in 
period will all receive active neuromodulation.  Participants in the randomized portion 
will be randomized (1:1) to one of two possible treatments groups: 
o Neuromodulation (Active) 
o Sham (Control) 
Randomization will be stratified by anatomic location (shoulder and foot/ankle 
surgery) in a 1:1 ratio and in blocks of 2.  Computer-generated randomization lists will 
be created by the UC San Diego Investigational Drug Service and the allocation 
provided to the investigators via sequential, opaque envelopes.   
Pulse generators are available that are capable of either (1) passing electrical current; 
or (2) not passing electrical current.  Importantly, these 2 modes (active and sham) 
are indistinguishable in appearance, and therefore investigators, participants, and all 
clinical staff will be masked to treatment group assignment, with the only exception 
being the unmasked individuals who insert the RELAY and program the stimulator. 
The RELAY system with the integrated needle will be inserted adjacent to the target 
nerve with an in-plane approach.  Dextrose 5% in water (1-20 mL) will be injected via 
the needle to open a space around the target nerve(s), the catheter advanced, and 
the needle subsequently withdrawn. 
Active (neuromodulation) group.  For participants receiving active (neuromodulation) 
treatment, electrical current will be introduced with increasing intensity via each of 
the anode electrodes to optimize participant’s perceived stimulation (control 
provided by the Gate Keeper app from an investigator’s phone or tablet).  Accurate 
lead placement will be confirmed with subject reports of comfortable sensations over 
the surgical site without eliciting muscle contractions.  The minimum threshold and 
maximum comfortable amplitudes will be determined along with the optimal 
frequency, pulse duration, and anode/cathode.  Starting from the lowest possible 
current the current will be increased until a participant states that they feel a 
“buzzing” sensation (some describe it as a “comfortable massage”).  That is the 
minimal sensed current.  The current will then continue to be increased with 
instruction to the participant to let the investigator know when it starts to be less 
comfortable—and to stop the investigator before it hurts.  That is the maximum 
comfortable current.  The stimulator will then be set to deliver the minimum 
threshold amplitude and turned off for surgery.   
Sham (control) group.  For participants receiving sham treatment, electric current will 
not reach the anodes, but the investigators will connect the RELAY to the Gate Keeper 
app just as with the active group and set the parameters as follows:  anode (distal), 
cathode (proximal), frequency (100 Hz), pulse duration (100 µs), and amplitude (5 
mA). 
Local anesthetic for active and sham groups.  Local anesthetic (10 mL of lidocaine 2% 
with epinephrine) will be injected with negative aspiration every 3 mL and resulting 
sensory block confirmed to ensure accurate catheter tip placement.  Following block 
confirmation (sensory deficits in the expected nerve distributions), the RELAY system 
will be affixed with both surgical adhesive (2-Octyl 2-cyanoacrylate) at the entry site 
and a chlorohexidine-impregnated occlusive dressing.  Subsequently, 10 mL of 
bupivacaine 0.5% with epinephrine will be injected negative aspiration every 3 mL 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
6 
along with a supplemental single-injection saphenous nerve block for foot/ankle 
surgery. 
Intraoperatively, surgeons will be permitted to infiltrate the surgical area with long-
acting local anesthetic as their common practice dictates. 
Postoperatively, the stimulators will be connected to participants’ phones and turned 
on. 
For the training run-in period, if a patient’s surgeon requests a postoperative 
continuous peripheral nerve block, a ropivacaine 0.2% infusion will be provided per 
standard UC San Diego protocol.   
After 7 days, participants in both the active and sham groups, themselves or their 
caretaker will remove the occlusive dressing and withdraw the catheter (and 
integrated electrodes) with gentle traction and rotation at home.  The devices are 
single-use and disposable. 
Study 
Duration: 
Approximately 12 months 
 
Participant 
Duration: 
Approximately 2 weeks 
 
1.2 
SCHEMA 
 
 
 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
7 
 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
  
 
2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
Postoperative pain remains undertreated with inadequate analgesic options.  Opioids have well-known 
limitations for both individuals and society; single-injection and continuous peripheral nerve blocks 
provide intense analgesia but are limited in duration to 24-72 hours; and current neuromodulation 
options—with a duration measured in weeks and not hours—are prohibitively expensive and require an 
additional procedure.  One possible solution is a device currently under investigation to treat 
postoperative pain.  The RELAY system (Gate Science, Moultonborough, New Hampshire) is comprised 
of a basic catheter-over-needle device to allow administration of a single-injection of local anesthetic via 
the needle (or catheter) followed by a perineural local anesthetic infusion via the remaining catheter 
(when desired).  Subsequent to the local anesthetic administration, instead of removing the catheter as 
with all previous continuous peripheral nerve block equipment, electric current may be delivered via the 
same catheter for up to a total of 28 days.  This is potentially revolutionary because it would allow an 
anesthesiologist to deliver (1) a single-injection peripheral nerve block; (2) a continuous peripheral 
nerve block; and (3) neuromodulation using a single device that can theoretically be placed in the same 
amount of time required for a single-injection peripheral nerve block.  Instead of providing fewer than 
24 hours of postoperative analgesia, up to 28 days of pain control could be delivered without disruption 
of existing practice patterns.  The ultimate objective of the proposed research study is to prepare for a 
large, multicenter clinical trial investigating the use of the RELAY device to provide postoperative 
analgesia. 
 
2.2 
BACKGROUND  

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
8 
There are tens-of-millions of 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 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, misuse, 
addiction, and overdose has multiplied 
dramatically (Figure 1), with the 
overall economic cost of opioid misuse 
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 misused—almost 
500-million doses annually—the supply 
of oral opioids is of great concern.  Nearly 80% of misused 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 
 Figure 1.  Rates of opioid analgesic sales, unintentional 
overdose deaths, and addiction treatment admissions 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
9 
networks to find those who will sell or share pills.” [Daniulaityte R, Falck R, Carlson RG: Sources of 
pharmaceutical opioids for non-medical use among young adults. J Psychoactive Drugs 2014; 46: 198-
207] Indeed, it has been conclusively demonstrated that both the misuse of opioids and extent of 
diversion are relative to their prescriptive availability. 
Single-injection peripheral nerve blocks have been used for decades to treat postoperative pain but 
have a duration of action of less than 24 hours.  The analgesia may be prolonged with the use of 
liposomal bupivacaine or a perineural local anesthetic infusion (continuous peripheral nerve block), but 
these are similarly limited in duration to approximately 72 hours.  For many surgical procedures, the 
duration of pain is measured in weeks and not hours or days.  One analgesic alternative—percutaneous 
peripheral nerve stimulation (PNS)—can improve post-surgical analgesia while concurrently decreasing 
or obviating opioid requirements without any adverse systemic side effects.  However, the only available 
lead/electrode available to date cleared for treating acute pain within the United States (SPRINT, SPR 
Therapeutics, Cleveland, Ohio) was developed for chronic pain states and costs over $4,000.  Therefore, 
while this device is being used within clinical research, it is not anticipated to gain widespread use 
clinically.  In addition, this device does not provide the potent analgesia required by patients in the 
immediate postoperative period, and therefore a single-injection local anesthetic peripheral nerve block 
is added, requiring two separate procedures and associated equipment. 
However, a new device has been developed and is under investigation with an FDA IDE:  the RELAY 
system by Gate Science (Moultonborough, New Hampshire).  This device differs from all previous 
equipment in that it enables a single-injection peripheral nerve block, postoperative perineural local 
anesthetic infusion, and subsequent neuromodulation, all with a single apparatus.  Percutaneous 
perineural insertion is achieved using standard ultrasound-guidance which places the needle tip 
adjacent to a peripheral nerve, through which local anesthetic may be injected to induce the peripheral 
nerve block (duration 8-24 hours).  When the needle is withdrawn a perineural catheter remains in situ 
through which a perineural local anesthetic infusion may be delivered (duration up to approximately 72 
hours).  The device also has an integrated battery, pulse generator, and 3 leads/electrodes that can be 
activated to provide peripheral nerve stimulation (the device may remain implanted for up to 28 days).  
Using this combination, optimal postoperative analgesia may be theoretically achieved using 3 different 
modes of analgesia and all with a single preoperative procedure requiring the skills every anesthesia 
resident is currently taught (ultrasound-guided regional anesthesia).  
 
 
 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
10 
Preliminary studies and pilot data.   
Gate Science conducted a prospective, open-label, dual-center, randomized, controlled pilot study, to 
assess preliminary safety, performance, and effectiveness of the RELAY System in participants requiring 
ankle surgery (bunionectomy, ankle fusion, ankle fracture), knee surgery (total knee replacement), and 
shoulder surgery (rotator cuff repair, labral repair and capsulorraphy).   
A total of 29 participants were enrolled out of the 63 planned.  Based on an interim analysis of the study 
data, it was determined that demonstration of efficacy in this study was unlikely and refinement to the 
study design and conduct would potentiate the demonstration of clinically relevant efficacy 
Overall RELAY was safe and well tolerated (summary table provided in Table 3). Twelve of 19 
participants (63.2%) who received RELAY reported at least one adverse event as compared to one of 9 
participants (11.1%) in the SOC arm.  The disparity in adverse events between RELAY and SOC is largely 
attributable to placement of the catheter, detailed below.  The majority of participants in the RELAY arm 
experienced mild AEs (9 of 12 participants, 47.4%) with only 2 participants reporting moderate AEs (pain 
at insertion site) and 1 patient with a severe AE (implant breakage).   
The severe AE was coded to implant breakage. As the catheter was being pulled out on Day 28 by the 
patient per protocol, the catheter broke and the sheared fragment was left embedded in the thigh near 
the adductor canal insertion site. An ultrasound scan confirmed a portion of catheter remained in 
sartorius muscle in the leg. This event resulted in a secondary surgical intervention (SSI). The catheter 
fragment was removed by a surgeon under sedation and local anesthesia.   
A second subject reported pain at the thigh area which resulted in routine removal of the RELAY device 
early on Day 13. This event was classified by the Investigator as an SSI, although it does not meet clearly 
meet the definition of an SSI. 
Table 3: Safety Summary 
RELAY 
(n=19) 
SOC 
(n=9) 
Total 
(n=28) 
At least one Adverse Event  
12 (63.2) 
1 (11.1) 
13 (4.8) 
Severity 
Mild 
Moderate 
Severe 
 
9 (47.4) 
2 (10.5) 
1 (5.3) 
 
0 
1 (11.1) 
0 
 
9 (32.1) 
3 (10.7) 
1 (3.6) 
Serious Adverse Event 
0 
0 
0 
Unexpected Adverse Device Effect 
0 
0 
0 
Resulted in SSI 
2 (10.5) 
0 
2 (7.1) 
The most common AEs reported by patient who received the RELAY device, regardless of causality are as 
follows: 
• 
Pain: 6 participants/9 events (6 mild, 3 moderate) 
• 
Weakness: 6 participants/6 events (6 mild) 
• 
Redness/itching/irritation: 4 participants/4 events (4 mild) 
• 
Numbness/tingling: 3 participants/3 events (3 mild) 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
11 
The disparity in adverse events between RELAY and SOC is largely attributable to placement of the 
catheter. The adverse events of redness and pain (tenderness) observed at the insertion site are 
consistent with local inflammatory response to percutaneous devices and are frequently seen with 
other similar devices such as perineural catheters, and percutaneous intravenous central lines (Jeng et 
al. Complications of peripheral nerve block. Br J Anaesth, December 2010; 105(1): I97-I1071).  The 
dressing (Tegaderm impregnated with chlorohexidine), applied to the skin to cover and secure the 
catheter insertion site can also cause redness and irritation. These resolve once the dressings are 
removed (dos Santos et al. Local Cutaneous Effects Associated with Chlorhexidine Impregnated Gel 
Dressing in Hematopoietic Stem Cell Transplantation Patients. Open Journal of Nursing, 2018; 8: 115-
129.). 
These findings are consistent with reports for the approved Sprint device (SPR Therapeutics) which are 
percutaneously implanted and left in place up to 60 days “the most common adverse event reported in 
clinical studies was skin irritation due to components being adhered to the skin (which may include 
inflammation, mild blistering, and/or redness). The majority of the adverse events in clinical studies 
were resolved with little to no intervention within a few days, and none were classified as serious 
(www.sprtherapeutics.com/patients/faq/#:~:text=The%20most%20common%20adverse%20event,after
%20lead%20placement%20and%20infection). These reactions resolved spontaneously with removal of 
the device. None of the patients in these studies developed infection.  
While there was a modest trend favouring RELAY in the primary efficacy measure (AUE, Days 1-7, NRS), 
the expected efficacy (utilizing the NRS scale) was not achieved. An approximately 50% reduction in 
opioid use was observed in the RELAY arm. 
Significance.  The present application proposes applying percutaneous PNS to the most painful 
ambulatory surgical procedures to improve postoperative analgesia and dramatically reduce opioid 
requirements following local anesthetic resolution.  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. 
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 surgical procedures, 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 surgical 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 misused 
• 
The misuse of opioids and extent of diversion are relative to their prescriptive availability 
• 
Illicit opioid use has grown to epidemic proportions 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
12 
Ultrasound-guided percutaneous PNS has demonstrated extraordinary potential to provide potent 
postoperative analgesia and concurrently reduce opioid requirements, and is already cleared by the US 
FDA for use in treating post-surgical pain using a different delivery device.  Most importantly—and in 
contrast to opioids—neuromodulation has no abuse/addiction potential, produces no adverse 
systemic side effects, and does not influence cognitive functioning whatsoever.   
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
The techniques used in this study have been used to treat pain for decades.  However, the specific 
device we will be using is currently investigational and we will therefore be working under an FDA IDE.  
The risks listed here are drawn from experience with FDA-cleared devices; and there may be risks that 
are not yet known (the incidences provided are all estimated for the device under investigation). 
1. Infection (low risk).  The perineural catheters will be inserted under sterile conditions and 
affixed using liquid adhesive and a sterile occlusive chlorohexidine-impregnated dressing.  
Phone calls to participants will include questions regarding signs and symptoms of catheter site 
infection.  Should a catheter site become suspicious for infection, the site will be evaluated by a 
physician investigator.  If indicated, the catheter will be removed, the catheter tip cultured, and 
the subject placed on the appropriate antibiotics.  Of note, there are no reported permanent 
sequelae from a perineural catheter infection in the published literature. 
2. Bleeding (very low risk).  There is the risk of bleeding since the needle and catheter will be 
inserted through the skin into muscle.  If this was to happen, we would hold pressure until the 
bleeding stopped. 
3. Catheter dislodgement (low risk).  There is a risk of the catheter being accidentally and 
prematurely dislodged.  The RELAY system has small integrated anchors that theoretically 
decrease dislodgement (removal of the catheter is achieved by simply rotating the catheter 
which releases the anchors); liquid adhesive will be applied along with a sterile occlusive 
dressing covering the catheter entry site.  Should a catheter be accidentally dislodged, 
participants have the option of returning to the center to have the catheter replaced as soon as 
possible.  Of note, accidental catheter dislodgement has never been reported to cause injury—
just a cessation of the perineural local anesthetic infusion.  If it occurs and a participant elects to 
have the catheter replaced, there may be the inconvenience and same risks as listed above as 
for the initial catheter insertion. 
4. Pain during catheter and lead implantation (low risk).  Although we use local anesthetic to 
anesthetize the skin and muscle through which the implanting needle travels, participants may 
experience discomfort or pain during catheter and lead implantation as well as postoperative 
neurostimulation.  If this occurs, we will administer intravenous fentanyl as is standard practice 
when administering peripheral nerve blocks.   
5. Pain post-operative (medium risk).  If the pain occurs postoperatively, participants will attempt 
to achieve pain relief by increasing amplitude of stimulation with the Gate Keeper app. 
Participants in the training run-in period with a continuous peripheral nerve block, will use their 
pump’s integrated bolus button to administer additional local anesthetic, when needed if pain 
persists.  If pain relief is not achieved and pain remains (NRS ≥4), participants are instructed to 
take prescribed opioids q4h. Note: Not all surgeons at UC San Diego use continuous peripheral 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
13 
nerve blocks; and those who do use them do so for some patients, but not others (depending on 
various surgical factors or simply their opinion of the technique). 
6. Nerve injury (very low risk).  The risk of a nerve injury with a local anesthetic-based peripheral 
nerve block is approximately 1 out of 10,000.  No known nerve injuries have occurred with 
ultrasound-guided percutaneous neuromodulation, although it is theoretically possible. 
7. Lead migration (very low risk).  The lead tip could migrate while the catheter/lead itself remains 
in situ.  This could result in a decrease in analgesia. 
8. There is the risk of loss of confidentiality (low risk).  The following procedures will be done to 
maintain confidentiality:  written, paper forms will be kept in a locked medical office and the 
locked Investigational Pharmacy’s files.  Computerized records containing personal health 
information will be stored on password-protected and encrypted computers. 
2.3.2 KNOWN POTENTIAL BENEFITS  
For participants who receive sham neuromodulation:  There will be no difference between being in this 
study and deciding against participation.  Therefore, there is no potential for direct benefits from this 
sham “treatment”. 
For participants who receive active neuromodulation:  Participants 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 constipation.  They might also have a lower risk of sleep disturbances, chronic pain, opioid 
dependence, and mental/physical disability. 
Participants 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 constipation.  They might also have a lower risk 
of sleep disturbances, chronic pain, opioid dependence, and mental/physical disability. 
Possible benefits to others:  Future patients may benefit if it is determined that the RELAY device is 
feasible and decreases pain, opioid requirements, sleep disturbances, and the incidence of chronic pain.  
With the opioid epidemic, any decrease in opioid requirements would be a welcome development and 
could benefit society greatly. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
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 opioids—the standard of care for the past 100 years—that 
would completely revolutionize postoperative analgesia, as we know it. 
The risks of percutaneous neuromodulation are minimal compared with opioids.  There have no 
previous cases of permanent negative sequelae reported in the literature, and we therefore believe that 
the potential risks of percutaneous neuromodulation are minimal compared to the potential benefits. 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
14 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS  
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To assess postoperative analgesia 
that extends beyond the duration 
of the local anesthetic 
interventions to prepare for a 
subsequent pivotal definitive 
clinical trial with the RELAY device 
as compared to sham control. 
Difference in the average daily pain 
intensity for Days 1-7 as measured 
with the NRS within the BPI between 
the RELAY device and sham control 
arms. 
 
Pain negatively 
influences physical and 
emotional functioning. 
Key Secondary 
 
 
To estimate the effect on opioid 
consumption of neuromodulation 
via the RELAY device as compared 
to sham control 
Neuromodulation with the RELAY 
device will decrease cumulative 
opioid consumption during the first 
postoperative week following foot 
and shoulder surgery currently 
treated with a single-injection 
peripheral nerve block (measured in 
oxycodone equivalents). 
Opioid use has negative 
individual and society 
consequences 
To estimate the effect on physical 
and emotional functioning of 
neuromodulation via the RELAY 
device as compared to sham 
control 
The physical and emotional 
functioning of participants will be 
improved on postoperative Day 3 
following foot and shoulder surgery 
currently treated with a single-
injection peripheral nerve block (as 
measured with the BPI Interference 
Subscale) 
Pain negatively 
influences physical and 
emotional functioning. 
Other Secondary 
 
 
To estimate the effect on physical 
and emotional functioning of 
neuromodulation via the RELAY 
device as compared to sham 
control 
The physical and emotional 
functioning of participants will be 
improved on postoperative Day 7 
following foot and shoulder surgery 
currently treated with a single-
injection peripheral nerve block (as 
measured with the BPI Interference 
Subscale) 
Pain negatively 
influences physical and 
emotional functioning. 
To estimate the analgesic effect of 
neuromodulation via the RELAY 
device as compared to 
sham/placebo for the RELAY device 
following foot and shoulder 
surgical procedures at various time 
points post-treatment  
Neuromodulation with the RELAY 
device will decrease pain intensity 
(as measured by the “average” and 
“worst” (maximum) daily NRS within 
the BPI) on Days 1, 2, 3, 4, 7, 8, and 
14 following foot and shoulder 
surgery currently treated with a 
single-injection peripheral nerve 
block. 
Pain negatively 
influences physical and 
emotional functioning. 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
15 
OBJECTIVES 
ENDPOINTS  
JUSTIFICATION FOR 
ENDPOINTS 
To estimate the analgesic effect of 
neuromodulation via the RELAY 
device as compared to 
sham/placebo for the RELAY device 
following foot and shoulder 
surgical procedures at various time 
points post-treatment  
Neuromodulation with the RELAY 
device will decrease pain intensity 
(as measured by “current” and 
“least” daily NRS within the BPI) on 
Days 3 and 7 following foot and 
shoulder surgery currently treated 
with a single-injection peripheral 
nerve block.  
Pain negatively 
influences physical and 
emotional functioning. 
To estimate the effect on opioid 
consumption of neuromodulation 
via the RELAY device as compared 
to sham/placebo for the RELAY 
device following foot and shoulder 
surgical procedures at various time 
points post-treatment 
Neuromodulation with the RELAY 
device will decrease daily opioid 
consumption following foot and 
shoulder surgery currently treated 
with a single-injection peripheral 
nerve block (measured in oxycodone 
equivalents on Days 1, 2, 3, 4, 7, 8 
and 14). 
Opioid use has negative 
individual and society 
consequences 
To estimate the effect on sleep 
disturbances of neuromodulation 
via the RELAY device as compared 
to sham/placebo for the RELAY 
device following foot and shoulder 
surgical procedures at various time 
points post-treatment  
Neuromodulation with the RELAY 
device will decrease cumulative 
awakenings due to pain following 
foot and shoulder surgery currently 
treated with a single-injection 
peripheral nerve block (evenings of 
postoperative Days 1, 2, 3, 4, 7, 8 and 
14) 
Poor sleep quality is 
correlated with inferior 
analgesia and 
functioning 
To evaluate the masking quality of 
the study protocol 
The masking assessment on Post-op 
Day 1 
Successful masking 
reduces bias 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This is a single-center, sham-controlled study to investigate the efficacy and safety of RELAY use of a 
device that enables the delivery of both local anesthetic and neuromodulation (peripheral nerve 
stimulation) to treat postoperative pain.   
Following a training run-in period, the randomized single blind sham-controlled part of the study will 
commence.  The purpose of the training run-in period is to ensure that RELAY can be safely placed next 
to a target nerve, successfully programmed and induce peripheral nerve block and neuromodulation 
based on the instructions for use. This will ensure familiarity with the device prior to the randomized 
portion of the study.  The training period will consist of up to 20 participants (~ 5 to 10 catheter lead 
insertions per anesthesiologist) across at least two different surgical procedures.  
It is anticipated that during the training run-in phase, the successful deployment of the RELAY system 
will be achieved 80% or more of the time. If less than 80% is achieved, the study will not proceed to the 
randomized portion. A brief study report will be submitted to the FDA prior to initiating the randomized 
portion. 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
16 
RELAY deployment success will be defined as a successfully placed catheter/lead as evidenced by 
sensory changes in the distribution of the target nerve with (1) electrical stimulation eliciting paresthesia 
and (2) inducing a conduction nerve block with injection of local anesthetic injection leading to either 
decreased or absent sensation to cold with alcohol swab.  
The randomized portion will include 40 participants (with up to 10 additional participants to account for 
drop-outs) randomized (1:1) to the experimental and sham arms, respectively.  A futility analysis will be 
performed once 20 participants have been randomized and data through post-operative Day 7 are 
available.  The following two criteria must be achieved to move forward: 1) RELAY deployment success 
in the lead/catheter insertion of ≥ 85% in RELAY participants, and 2) a conditional power (Cp) of ≥30% 
for the primary efficacy endpoint. Of note, a standardized effect size of 0.49 would not meet criteria to 
continue.  There will be no stopping for early efficacy.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Postoperative pain remains undertreated with inadequate analgesic options.  Opioids have well-known 
limitations for both individuals and society; single-injection and continuous peripheral nerve blocks 
provide intense analgesia but are limited in duration to 24-72 hours; and current neuromodulation 
options—with a duration measured in weeks and not hours—are prohibitively expensive and require an 
additional procedure.  One possible solution is a device currently under investigation to treat 
postoperative pain.  The RELAY system (Gate Science, Moultonborough, New Hampshire) is comprised 
of a basic catheter-over-needle device to allow administration of a single-injection of local anesthetic via 
the needle (or catheter) followed by a perineural local anesthetic infusion via the remaining catheter 
(when desired).  Subsequent to the local anesthetic administration, instead of removing the catheter as 
with all previous continuous peripheral nerve block equipment, electric current may be delivered via the 
same catheter for up to a total of 28 days.  This is potentially revolutionary because it would allow an 
anesthesiologist to deliver (1) a single-injection peripheral nerve block; (2) a continuous peripheral 
nerve block; and (3) neuromodulation using a single device that can theoretically be placed in the same 
amount of time required for a single-injection peripheral nerve block.  Instead of providing fewer than 
24 hours of postoperative analgesia, up to 28 days of pain control could be delivered without disruption 
of existing practice patterns.  The ultimate objective of the proposed research study is to prepare for a 
large, multicenter clinical trial investigating the use of the RELAY device to provide postoperative 
analgesia. 
4.3 
JUSTIFICATION FOR DOSE 
Regarding the local anesthetics, we are using standard volumes and concentration of local anesthetics 
currently used at our institution.  We do not want to change our standard of care for the local 
anesthetic-based peripheral nerve blocks. 
Regarding the electrical stimulation, the pulse generator of the RELAY has a frequency between 1-250 
Hz, a pulse duration of 1-200 µs, and a current of 0.001-10 mA (1-10,000 µA).  If the same pattern holds 
for the RELAY device as for previously tested peripheral nerve stimulators, we will maximize frequency, 
minimize pulse duration, and have participants adjust the amplitude, as needed.  Participants will use 
their smartphone to download an app that allows them to increase or decrease the amplitude using a 
Bluetooth connection with the pulse generator.  Participants can only adjust the amplitude and not the 
other parameters. 
4.4 
END OF STUDY DEFINITION 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
17 
The end of the study is defined as completion of the last follow up data collection time point (14 days) of 
the final enrolled participant. 
5 
STUDY POPULATION 
We will be enrolling adult participants (at least 18 years of age) undergoing a rotator cuff repair, total 
shoulder arthroplasty, hallux valgus correction, or ankle arthroplasty/arthrodesis.  Up to 20 participants 
will be enrolled to the training run-in period.  An additional 40 participants are anticipated for the 
randomized portion of this study.  However, to account for dropouts, will are requesting an additional 
10 participants.  This will total up to 70 participants overall. 
 
5.1 
INCLUSION CRITERIA 
1. Adult participants of at least 18 years of age 
2. Undergoing a rotator cuff repair, total shoulder arthroplasty, hallux valgus correction or ankle 
arthroplasty/arthrodesis 
3. Planned single-injection peripheral nerve block(s) 
4. An Android or Apple smartphone able to download the Gate Keeper controller app 
 
5.2 
EXCLUSION CRITERIA 
1. Chronic opioid or tramadol use (daily within prior 2 weeks and duration > 4 weeks) 
2. Neuro-muscular deficit of the surgical limb 
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 of infection 
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 
7. Allergy to skin-contact materials (occlusive dressings, bandages, tape etc.) 
8. Incarceration 
9. Pregnancy 
10. Moderate pain (NRS > 3) in an anatomic location other than the surgical site 
11. Anxiety disorder 
12. History of substance misuse 
13. Inability to communicate with the investigators 
14. Inability to contact the investigators during the treatment period, and vice versa (e.g., lack of 
telephone access) 
15. Allergy to amide local anesthetics 
16. Morbid obesity (body mass index > 40 kg/m2) 
5.3 
LIFESTYLE CONSIDERATIONS 
Not Applicable. 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. 
 
6 
STUDY INTERVENTION 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
18 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
For individuals of childbearing potential, a sample of urine will be collected before any study 
interventions to confirm a non-pregnant state (this is standard procedure for all surgical patients) 
[standard of care]. 
The RELAY device combines a catheter-over-needle to permit ultrasound-guided percutaneous insertion 
with the tip adjacent to a peripheral nerve or plexus, followed by needle removal which leaves the 
catheter in situ to deliver a bolus of local anesthetic (if desired) and subsequent perineural local 
anesthetic infusion (if desired).  The catheter also has 3 integrated electrodes to enable 
neuromodulation using the integrated pulse generator and battery (figure below). 
 
Participants will have standard external monitors placed and oxygen delivered by facemask or nasal 
cannula [standard of care].  The peripheral nerve block site(s) will be cleansed with chlorhexidine 
gluconate and isopropyl alcohol [standard of care].  Intravenous sedation/analgesia with midazolam 
and/or fentanyl will be titrated for patient comfort as is standard for peripheral nerve block 
administration [standard of care].  The nerves treated will include the sciatic proximal to the popliteal 
crease for foot surgery and the brachial plexus for shoulder surgery [standard of care].  The target 
nerve(s) will be visualized with ultrasound using a transverse cross-sectional (short axis) view and a skin 
wheal of local anesthetic will be raised inferior to the transducer to anesthetize the skin and then the 
track towards the target [standard of care]. 
Treatment group allocation (randomization).   
All participants in the training run-in period will receive active neuromodulation [research specific].   
Participants in the randomized portion of the study will be randomized and allocated to one of two 
possible treatments groups [research specific]: 
• 
Neuromodulation 
• 
Sham (Control) 
Postoperative Day 
0 [Day of surgery] 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Neuromodulation 
Electric current 
 
Control 
No electric current 
 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
19 
Randomization [all research specific] will be stratified by anatomic location (shoulder and foot/ankle 
surgery) in a 1:1 ratio and in blocks of 2.  Computer-generated randomization lists will be created by the 
UC San Diego Investigational Drug Service and the allocation provided to the investigators via 
sequential, opaque envelopes.  Pulse generators are available that are capable of either (1) passing 
electrical current; or (2) not passing electrical current.  Importantly, these 2 modes (active and sham) are 
indistinguishable in appearance, and therefore investigators, participants, and all clinical staff will be 
masked to treatment group assignment, with the only exception being the unmasked individuals who 
insert the RELAY and program the stimulator. 
The RELAY system with the integrated needle will be inserted adjacent to the target nerve with an in-
plane approach [same as standard-of-care].  Dextrose 5% in water (1-20 mL) will be injected via the 
needle to open a space around the target nerve(s) [research specific], the catheter advanced [same as 
standard-of-care], and the needle subsequently withdrawn [same as standard-of-care]. 
Electrical current will be introduced with increasing intensity via each of the anode electrodes to 
optimize participant’s perceived stimulation (control provided by the Gate Keeper app from an 
investigator’s phone or tablet).  Accurate lead placement will be confirmed with subject reports of 
comfortable sensations over the surgical site without eliciting muscle contractions.  The minimum 
threshold and maximum comfortable amplitudes will be determined along with the optimal frequency, 
pulse duration, and anode/cathode.  Starting from the lowest possible current we increase the current 
until the participant states that they feel a “buzzing” sensation (some describe it as a “comfortable 
massage”).  That is the minimal sensed current.  We then continue increasing with the instructions to let 
us know when it starts to be less comfortable—and to stop us before it hurts.  That is the maximum 
comfortable current.  The stimulator will be then set to deliver the minimum threshold amplitude and 
turned off for surgery.  Sham treatment group [all research specific].  For participants receiving sham 
treatment, electric current will not reach the anodes, but the investigators will connect to the RELAY to 
the mobile phone or tablet just as with the active group and set the parameters as follows:  anode 
(distal), cathode (proximal), frequency (100 Hz), pulse duration (100 µs), and amplitude (5 mA). 
Local anesthetic for active and sham groups.  Local anesthetic (10 mL of lidocaine 2% with epinephrine) 
will be injected with negative aspiration every 3 mL and resulting sensory block confirmed to ensure 
accurate catheter tip placement [research specific].  Following block confirmation (sensory deficits in 
the expected nerve distributions), the RELAY will be affixed with both surgical adhesive (2-Octyl 2-
cyanoacrylate) at the entry site and a chlorohexidine-impregnated occlusive dressing [research specific].  
Subsequently, 10 mL of bupivacaine 0.5% with epinephrine will be injected negative aspiration every 3 
mL along with a supplemental single-injection saphenous nerve block for foot/ankle surgery [standard 
of care]. 
Intraoperatively, surgeons will be permitted to infiltrate the surgical area with long-acting local 
anesthetic as their common practice dictates [standard of care]. 
Postoperatively, the stimulators will be connected to participants’ phones and turned on [research 
specific]. 
For the training run-in period, if a patient’s surgeon requests a postoperative continuous peripheral 
nerve block, a ropivacaine 0.2% infusion will be provided per standard UC San Diego protocol [standard 
of care].   
After 7 days, participants in both the active and sham groups, themselves or their caretaker will remove 
the occlusive dressing and withdraw the catheter (and integrated electrodes) with gentle traction and 
rotation at home [research specific].  The devices are single-use and disposable [research specific]. 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
20 
Following study completion, the results will be mailed electronically or by the United States Postal Service 
to all enrolled participants in written form using non-technical (e.g., “layperson”) language [research 
specific]. 
6.1.2 DOSING AND ADMINISTRATION 
The pulse generator of the RELAY has a frequency between 1-250 Hz, a pulse duration of 1-200 µs, and a 
current of 0.001-10 mA (1-10,000 µA).  We will maximize frequency, minimize pulse duration, and have 
participants adjust the amplitude, as needed.  Administration is described above in 6.1.1. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
The RELAY device will be shipped to the clinical trial site by Gate Science.  Accountability records will be 
maintained at the site. 
Any investigational medical device that is defective will be sent back to Gate Science, and the 
investigational medical device will be resupplied to replace the defective.  When the device is explanted, 
it will be discarded. Any remaining device at the site at the end of the study will be returned to Gate 
Science. 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Not applicable to this trial involving the investigation of a medical device, as opposed to a medication. 
6.2.3 PRODUCT STORAGE AND STABILITY 
The RELAY system will be stored in the Principal Investigator’s or Program Manager’s locked office or the 
locked anesthesia workroom. 
The expiration of RELAY is based on date of manufacture and is provided to the clinical trial site and will 
be monitored accordingly by the Sponsor. 
6.2.4 PREPARATION 
The RELAY devices do not need “preparation”.  
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
The randomized portion of the study will utilize a randomized, observer- and participant-masked, 
sham/placebo-controlled protocol.  Randomization will be stratified by surgical procedure (shoulder and 
foot/ankle surgery) in a 1:1 ratio and in blocks of 2.  Computer-generated randomization lists will be 
created by the UC San Diego Investigational Drug Service and the allocation provided to the 
investigators in sequential, opaque envelopes.  A masking assessment question will be queried on 
postoperative Day 1.   
6.4 
STUDY INTERVENTION COMPLIANCE 
Not applicable. 
6.5 
CONCOMITANT THERAPY 
6.5.1 RESCUE MEDICINE 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
21 
As inpatients, our current standard analgesic protocol will be followed:  acetaminophen 975-1000 mg po 
QID, oxycodone 5-10 mg po q4 h prn moderate pain (NRS 4-7), and morphine 1-2 mg IV prn severe pain 
(NRS>7).  Prior to discharge, participants will all be provided with a prescription for oxycodone (5 mg 
tablets) by their surgeon, as dictated by our current standard of care. If pain occurs postoperatively, 
participants will attempt to achieve pain relief by increasing amplitude of stimulation with the Gate 
Keeper app. Participants in the training run-in period with a continuous peripheral nerve block, will use 
their pump’s integrated bolus button to administer additional local anesthetic, when needed if pain 
persists.  If pain relief is not achieved and pain remains (NRS ≥4), participants are instructed to take 
prescribed opioids q4h. 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Catheter/lead implantation will be discontinued if the participant requests during the procedure.  The 
catheter/lead may be removed at any time of the participant’s choosing within the first week after 
surgery. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
7.2.1 DISCONTINUATION CRITERIA 
1. Participants may withdraw voluntarily from participation in the study at any time and for any 
reason.  
2. Participants may be withdrawn on the basis of the Investigator’s clinical judgment, protocol 
deviation or loss to follow-up. 
3. This study may be terminated at the discretion of any regulatory agency for reasons including 
safety and/or efficacy.  
4. The Primary Investigator may elect to discontinue or stop the study for any reason including 
safety. 
5. When a participant withdraws or is withdrawn before completing the study, the date and reason 
for withdrawal are to be documented in the CRF.   
6. In the event that a patient is withdrawn prematurely due to an AE or serious AE, the AE or 
serious AE will be followed until it resolves or stabilizes, or until it is judged by the Principal 
Investigator to be no longer clinically significant. 
7.3 
LOST TO FOLLOW-UP 
Study participants may miss data collection phone calls—it is common even though the investigators 
attempt multiple contacts with participants at specified times—but this study will not consider any 
patient “lost to follow-up”.  We may not be able to collect all data for all participants at all study time 
points; but we will continue to attempt to contact participants until 14 days have passed for that 
participant (the duration of study participation) or the participant requests study withdrawal (in which 
case it is a withdrawal and not “lost to follow-up”). 
8 
STUDY ASSESSMENTS AND PROCEDURES 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
22 
 
8.1 
EFFICACY ASSESSMENTS  
 
Outcome measurements.  We have selected outcome measures that have established reliability and 
validity, with minimal inter-rater discordance, and are recommended for pain clinical trials by the 
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus 
statement. The primary outcome measure will be the median “average” daily pain intensity for Days 1-7 
as measured with the NRS within the BPI.  The primary analysis will compare the two treatments (inter-
subject comparisons) in which half of the participants will receive active neuromodulation and the other 
half a sham/placebo neuromodulation.  Endpoints will be evaluated on postoperative Days 1, 2, 3, 4, 7, 
8, and 14.  In addition, participants will receive a phone call the evening of postoperative Day 0 (the day 
of surgery) to answer any questions they may have about the stimulator or study protocol. 
Each time the questionnaire is applied, participants will be instructed to respond for the previous 24 
hours.  The exception will be on Day 1 because at these time points, the interest is in participants’ 
experiences subsequent to discharge from the recovery room.  During this day only, participants will be 
instructed to respond for the period of time since they were discharged from the recovery room. 
We will record basic anthropomorphic characteristics (e.g., age, physiological sex, height, and weight), 
intervention characteristics (e.g., pulse generator parameters, catheter insertion duration, 
minimum/maximum comfortable amplitude), surgical characteristics (e.g., surgical duration) and 
protocol deviations / adverse events. 
All data collection following the day of the intervention (Day 0) will be collected by telephone from the 
University of California San Diego by the investigators, Program Manager, and/or research coordinators 
specifically trained in these instruments’ application, minimizing inter-rater discordance and 
standardizing responses across all enrolling centers.  Observers masked to treatment group assignment 
will perform all postoperative assessments.  Each data collection phone call will require approximately 5 
minutes. 
In addition to the outcomes described below, we will record awakenings due to pain at each data 
collection phone call, as well as any sensory deficits for participants with continuous peripheral nerve 
blocks, and patient-controlled changes to the neuromodulation amplitude.  On postoperative day 1 we 
will query participants on whether they believe they are receiving active or sham stimulation (a masking 
assessment). 
Hypothesis 1:  Neuromodulation with the RELAY device will decrease pain intensity for Days 1-7 
following foot and shoulder surgery currently treated with a single-injection peripheral 
nerve block (as measured with the NRS within the BPI). 
Current/present, worst, least, and average `surgical pain will be assessed using the NRS as part of the 
BPI (short form), with the “average” pain scores collected on postoperative days 1, 2, 3, 4 and 7 
designated as the primary endpoint.  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 in multiple pain states and 
following analgesic interventions.  In addition, NRS scores correlate well with other measures of pain 
intensity, and demonstrate high test-retest reliability in chronic nociceptive and neuropathic pain states.  
These NRS characteristics led to recent IMMPACT consensus recommendations for use of the 10-point 
NRS of pain intensity for pain trials.  

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
23 
Hypothesis 2:  Neuromodulation with the RELAY device will decrease opioid consumption within 
the week following foot and shoulder surgery currently treated with a single-injection 
peripheral nerve block (measured in oxycodone equivalents), as measured both with daily 
and cumulative opioid consumption within the first postoperative week). 
Opioid analgesic consumption will be recorded at all time points (Table 2), with the secondary outcome 
measure of greatest importance being the cumulative opioid dose in oral oxycodone equivalents for the 
first 7 postoperative days following recovery room discharge.  The two treatment groups’ daily opioid 
consumption will also be compared at all timepoints, including Day 14. 
 
Hypothesis 3:  Physical and emotional functioning as measured with the Interference Subscale of 
the BPI.  Neuromodulation with the RELAY device will decrease pain’s interference in 
physical and emotional functioning within the week following foot and shoulder surgery 
currently treated with a single-injection peripheral nerve block. 
 
It is well-recognized that, “pain is a complex, multidimensional, sensory, and emotional experience that 
is individually perceived and described in many different ways.”  This observation has led to consensus 
recommendations that “multiple core domains and related measures be considered in pain treatment 
trials,” that “tap into a wider experience of pain over time and its impact on functioning and quality of 
life.”  Therefore, the proposed trial will include the BPI, an instrument that includes—in addition to pain 
intensity scales—seven measures evaluating the pain’s interference with physical and emotional 
functioning, such as sleep, relations with others, and enjoyment of life.  It is this 7-question Interference 
Scale that will be used specifically for Hypothesis 3.  The BPI has been used and validated in countless 
clinical pain-related studies.  This instrument is associated with minimal subject burden and is easily 
interpreted by participants of all ages and education levels.  It has high test-retest reliability and 
correlates well with much longer questionnaires, including the McGill measures and EuroQol.  The 
secondary outcome measures of greatest interest after the cumulative opioid consumption will be the 
Interference Scale (0-70) recorded on Day 3. 
8.2 
SAFETY AND OTHER ASSESSMENTS 
Prospective participants will be provided with informed consent and then screened for inclusion and 
exclusion criteria. The following safety and eligibility procedures will occur during that time: 
• 
Study Eligibility – A study investigator will review all medical history, medications and the 
inclusion/exclusion criteria with the participants. 
• 
Informed Consent - Participants will provide written informed consent prior to any other study 
procedures. 
• 
Vital Signs – These include blood pressure, heart rate, temperature and respiratory rate as well 
as pulse oximetry and continuous 5-lead ECG. 
• 
Adverse Event Collection – Participants’ progress notes will be followed during days of 
hospitalization and any adverse events recorded.  Following discharge, investigators will inquire 
about any adverse or unexpected events that have occurred since the previous contact.  All 
events will be evaluated by a study investigator and will be followed until resolution. 
Any of the safety assessment results will be made available to participants should they request them. 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
24 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
The FDA definition of an Adverse event is any untoward medical occurrence associated with the use of 
an intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).  An AE 
can be either (a) a new occurrence or (b) an existing process (including the disease under study) that 
increases significantly in intensity or frequency. The medical product may be a drug or a device, being 
used either prior to or after regulatory approval. 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An AE is serious when the patient outcome is one or more of the following: 
• 
Death. Applies to the event that is the primary cause of death 
• 
Life-threatening, meaning that the patient was at immediate or substantial risk of death from the 
event at the time that the event occurred. It does not include an event which hypothetically might 
have caused death if it occurred in a more severe form.  
• 
Hospitalization, initial or prolonged, meaning that a hospital admission and/or prolongation of a 
hospital stay was required for the treatment of the AE, or occurred as a consequence of the event. 
It does not include a pre-planned elective hospital admission for treatment or diagnostic 
procedures, or, in general, a hospital admission of less than 24 hours duration.  
• 
Disability or incapacity that substantially disrupts the patient’s ability to carry out normal life 
functions and is persistent or significant.  
• 
Congenital anomaly or birth defect.  
• 
Important medical event that, although not immediately life-threatening, requires intervention 
in order to prevent one of the other serious outcomes listed above. Examples of such events are 
allergic bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in hospitalization; or the development of drug 
dependency or drug misuse. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
25 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
8.3.3.3 EXPECTEDNESS  
Brian Ilfeld, MD, study Principal Investigator (PI) will be responsible for determining whether an adverse 
event (AE) is expected or unexpected.  An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described in the risk section 
for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during hospitalization or post-discharge follow-up data-collection phone calls. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
A study coordinator will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit.  Events will be followed for outcome information until resolution or stabilization.  
Precautions and responses to possible specific adverse events: 
Infection:  The perineural catheters will be inserted under sterile conditions and affixed using liquid 
adhesive and a sterile occlusive chlorohexidine-impregnated dressing.  Phone calls to participants will 
include questions regarding signs and symptoms of catheter site infection.  Should a catheter site 
become suspicious for infection, the site will be evaluated by a physician investigator.  If indicated, the 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
26 
catheter will be removed, the catheter tip cultured, and the subject placed on the appropriate 
antibiotics. 
Bleeding:  There is the risk of bleeding since the needle and catheter will be inserted through the skin 
into muscle.  If this was to happen, we would hold pressure until the bleeding stopped. 
Catheter dislodgement.  There is a risk of the catheter being accidentally and prematurely dislodged.  
The RELAY has small integrated anchors that theoretically decrease dislodgement (removal of the 
catheter is achieved by simply rotating the catheter which releases the anchors); liquid adhesive will be 
applied; a sterile occlusive dressing will cover the catheter entry site.  Should a catheter be accidentally 
dislodged, participants have the option of returning to the center to have the catheter replaced as soon 
as possible.  Of note, accidental catheter dislodgement has never been reported to cause injury—just a 
cessation of the perineural local anesthetic infusion. 
Lead migration.  The lead tip could migrate while the catheter/lead itself remains in situ.  This could 
result in a decrease in analgesia.  Should a catheter/lead migrate, participants have the option of 
returning to the center to have the catheter replaced as soon as possible. 
Pain.  Although we use local anesthetic to anesthetize the skin and muscle through which the implanting 
needle travels, participants may experience discomfort or pain during catheter and lead implantation as 
well as postoperative neurostimulation.  If this occurs, we will administer intravenous fentanyl as is 
standard practice when administering peripheral nerve blocks.  If the pain occurs postoperatively, 
participants will attempt to achieve pain relief by increasing amplitude of stimulation with the Gate 
Keeper app.   participants in the training run-in period with a continuous peripheral nerve block, will use 
their pump’s integrated bolus button to administer additional local anesthetic when needed if pain 
persists. If pain relief is not achieved and pain remains (NRS ≥4), participants are instructed to take 
prescribed opioids q4h.  Note: Not all surgeons at UC San Diego use continuous peripheral nerve blocks; 
and those who do use them do so for some participants, but not others (depending on various surgical 
factors or simply their opinion of the technique). 
Nerve injury (very low risk).  The risk of a nerve injury with a local anesthetic-based peripheral nerve 
block is approximately 1 out of 10,000.  No known nerve injuries have occurred with ultrasound-guided 
percutaneous neuromodulation, although it is theoretically possible.  If a nerve injury was to occur, the 
participant would be referred to neurology for evaluation and management.  The investigators would 
follow. 
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. 
8.3.5 ADVERSE EVENT REPORTING  
A member of the study staff shall complete a summary report or log of all AEs and submit to the UCSD 
Office of IRB Administration at the time of study annual renewal or closeout. 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
SAEs must be reported within 24 hours of discovery to Gate Science via a completed SAE form. The 
study investigator shall submit all SAEs to the UCSD Office of IRB Administration as soon as possible, but 
no later than 10 working days after the investigator first learns of the effect.  
8.3.7 REPORTING EVENTS TO PARTICIPANTS  

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
27 
In the event of an SAE determined to be related to study procedure, participants will be informed after 
IRB review of the event.  Upon IRB acknowledgement and study team fulfillment of any protocol 
changes, participants will be informed via a consent form addendum or a new version of the consent 
form.  Participants will be given the choice to withdraw from the study or sign the new consent and 
continue. 
8.3.8 EVENTS OF SPECIAL INTEREST  
Not applicable.  
8.3.9 REPORTING OF PREGNANCY  
Conception following the surgical procedure is not considered an AE for this study:  there is no 
prohibition against pregnancy with peripheral nerve stimulation (it is far preferred over systemic opioid 
consumption). 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems (UP) involving 
risks to participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report UPs to Gate Science and to UCSD Office of IRB Administration.  The UP 
report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB within 10 days of the 
investigator becoming aware of the event.  

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
28 
• 
Any other UP will be reported to the IRB within 30 days of the investigator becoming aware of 
the problem.  
• 
All unanticipated events and adverse events will be reported to the supervising IRB (University 
of California San Diego). 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
In the event of a UP determined to be related to study procedure, participants will be informed after IRB 
review of the event.  Upon IRB acknowledgement and study team fulfillment of any protocol changes, 
participants will be informed via a consent form addendum or a new version of the consent form.  
Participants will be given the choice to withdraw from the study or sign the new consent and continue. 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
Hypothesis 1:  Neuromodulation with the RELAY device will decrease average pain intensity for 
Days 1-7 following foot and shoulder surgery currently treated with a single-injection peripheral 
nerve block (as measured with the NRS within the BPI).  
Hypothesis 2:  Neuromodulation with the RELAY device will decrease opioid consumption within 
the week following foot and shoulder surgery currently treated with a single-injection 
peripheral nerve block (measured in oxycodone equivalents), as measured both with daily and 
cumulative opioid consumption within the first postoperative week). 
Hypothesis 3:  Physical and emotional functioning as measured with the Interference Subscale of 
the BPI.  Neuromodulation with the RELAY device will decrease pain’s interference in physical 
and emotional functioning within the week following foot and shoulder surgery currently 
treated with a single-injection peripheral nerve block. 
9.2 
SAMPLE SIZE DETERMINATION 
The sample size estimation is centered around the hypothesis that neuromodulation lowers the severity 
of pain the week after surgery.  To this end, the primary outcome measure is the median “average” daily 
pain intensity for Days 1-7 as measured with the NRS within the BPI.  This outcome measure was used 
by the authors previously for a similar study treating the same patient population with a different 
percutaneous peripheral nerve stimulation pulse generator and lead, and we therefore will use the 
resulting mean (SD) from each treatment group to power the present pilot study [Ilfeld et al. 
Anesthesiology 2021; 135: 95-110].  Specifically, the treated and sham groups reported a mean (SD) of 
1.1 (1.1) and 3.1 (1.7), respectively.  Assuming a standard deviation of 2.05, a sample size of 20 
participants per group provides 85.2% power to detect a group difference of 2 points. With an additional 
10 participants allowed to replace drop-outs in the randomized portion, a total of up to 70 participants 
may be enrolled in this study combining the run-in and randomized stages. 
9.3 
POPULATIONS FOR ANALYSES 
A total of 40 individuals are anticipated for the randomized portion of the trial; however, an additional 
10 may be enrolled to account for dropouts.   
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
29 
Baseline characteristics of the randomized groups will be summarized with means, standard deviations, 
and quartiles. Balance between groups will be assessed following the approach described by Schober 
(2018). Specifically, standardized differences will be calculated using Cohen’s d whereby the difference 
in means or proportions is divided by the pooled standard deviation estimates. Any key variables (age, 
sex, height, weight, BMI, and surgical procedure) with an absolute standardized difference greater than 
1.96× √2/𝑛 = 0.716, where 𝑛= 15 is the target sample size per group (Austin (2009)), will be noted 
and included in a sensitivity analysis with a generalized linear model (e.g. linear regression for pain 
severity NRS or logistic regression for incidence rates) to obtain an estimate of the treatment effect 
adjusted for the imbalanced covariate(s). If key model assumptions are violated (i.e. homoscedasticity or 
Gaussian distribution for linear models), data transformations and/or alternative generalized linear 
models will be applied as appropriate. Missing data is expected to be negligible. In the event of 
unexpected missing data, multiple imputation by chained equations (Stef van Buuren, Karin Groothuis-
Oudshoorn (2011). mice: Multivariate   Imputation by Chained Equations in R. Journal of Statistical 
Software, 45(3), 1-67) will be applied to obtain estimates of treatment effects under the assumption of 
missing at random. The imputation model will exhaustively consider all measured baseline covariates 
and longitudinal observations to maximize the likelihood that the missing at random assumption is met. 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
The primary analytic approach will be an unadjusted two-sample Mann-Whitney U test of the median 
value of each participant’s average daily NRS for Days 1, 2, 3, 4, and 7 (data is not collected on Days 5 
and 6). If any key variables are imbalanced at baseline, a linear regression model, or appropriate 
generalized linear model, adjusting for those variables will be applied.  The p-value and 95% confidence 
interval associated with the estimated group difference in average daily NRS will be provided.  P<0.05 
will be considered statistically significant for the primary outcomes. 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Continuous endpoints will be analyzed with the same approach as the primary endpoint. Binary 
endpoints will be analyzed with Fisher’s Exact test for two proportions, or logistic regression in the event 
of imbalance on key baseline variables. Ordinal endpoints will be analyzed with the Armitage trend test, 
or cumulative link regression model as warranted. We will test key secondary outcomes using a serial 
gatekeeping procedure.  Nominal 95% confidence intervals will be provided for secondary analyses. 
Study-wide Type I error control.  We will use a serial gatekeeping procedure to control the study-wide 
type I error at 0.05 [Mascha EJ, Turan A: Joint hypothesis testing and gatekeeping procedures for studies 
with multiple endpoints. Anesth Analg 2012; 114: 1304-17].  For this procedure we therefore have 
prioritized (a priori) the study outcomes (Table below).  Analysis will proceed in that order, and testing 
will proceed through each “gate” to the next set if and only if the outcome in the current set reaches 
significance. The significance level for each set will be 0.05 times a cumulative penalty for non-significant 
results in previous sets (i.e., a “rejection gain factor” equal to the cumulative product of the proportion 
of significant tests across the preceding sets). We will use the corresponding 2-tailed alpha level of 0.05 
for the gatekeeping, as all sets involve 2-tailed tests.  Treatment effects will also be assessed at 
individual time points regardless of preceding gatekeeping results, and no other adjustments will be 
made for testing multiplicity. 
 
 
Serial gatekeeping procedure 
Sets 
Time frame 
Required to pass to next set 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
30 
1:  Pain intensity (median of 5 daily “average” 
NRS) 
1st week 
Significance on this outcome 
2:  Cumulative opioid use (oxycodone 
equivalents) 
1st week 
Significance on this outcome 
3:  BPI interference subscale 
Postop Day 3 
Significance on this outcome 
4:  Pain intensity (median of 5 daily “worst” NRS) 
1st week 
Significance on this outcome 
5:  BPI interference subscale 
Postop Day 7 
Significance on this outcome 
6:  Cumulative awakenings due to pain 
1st week 
Significance on this outcome 
7:  Pain intensity (“average” NRS) 
Postop Day 7 
Significance on this outcome 
8:  Pain intensity (“worst” NRS) 
Postop Day 7 
Significance on this outcome 
9:  Opioid use (oxycodone equivalents) 
Postop Day 7 
Significance on this outcome 
10:  Awakenings due to pain 
Postop Day 7 
Significance on this outcome 
11:  Opioid use (oxycodone equivalents each day) 
Postop Days 1, 
2, 3, 4, 8, 14 
Significance on this outcome 
12:  Pain intensity (each daily “average” NRS) 
Postop Days 1, 
2, 3, 4, 8, 14 
Significance on this outcome 
13:  Pain intensity (each daily “worst” NRS) 
Postop Days 1, 
2, 3, 4, 8, 14 
Not applicable 
 
9.4.4 SAFETY ANALYSES 
Device-related Adverse Events.  The investigators will record all device-related adverse events. These 
complications cannot be “ranked”, but rather the two groups will be compared descriptively on each of 
these possible complications. 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
As described above, balance on baseline covariates will be assessed using absolute standardized 
difference (ASD).  Variables considered imbalanced will be adjusted for in the statistical analyses.  
Analyses will be carried out using modified intention-to-treat i.e., participants who received any study 
treatment will be analyzed according to the group to which they were randomized. 
9.4.6 PLANNED INTERIM ANALYSES  
A futility analysis will be performed once 20 participants have been randomized and data through post-
operative Day 7 are available.  The following two criteria must be achieved to move forward: 1) RELAY 
deployment success in the lead/catheter insertion of ≥ 85% in RELAY participants, and 2) a conditional 
power (Cp) of ≥30% for the primary efficacy endpoint. Of note, a standardized effect size of 0.49 would 
not meet criteria to continue.  There will be no stopping for early efficacy. 
9.4.7 SUB-GROUP ANALYSES 
Descriptive analyses will be performed by surgery type (shoulder or ankle). 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
31 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
Enrollment.  Potential study participants will be identified from the surgical schedule: 
Candidates who meet inclusion and exclusion criteria and desire study enrollment will be scheduled to 
arrive the day of surgery 30 to 60 minutes earlier than normal to allow for written informed consent, 
baseline information collection, and additional time for study procedures.  Written informed consent 
will be attained prior to any measurements or procedures prior to surgery.  When participants present 
for surgery, an investigator, Program Manager, or research coordinator will provide and attain written 
informed consent.  This will occur in private patient care areas, so that participants may feel 
comfortable asking questions. 
We do not foresee any issues relevant to the mental capacity of the potential human participants.  
Written, informed consent will be attained prior to any study procedures or measurements; and 
participants will not receive procedure-related sedation until following the written, informed consent 
process is completed.  Participants will be provided privacy and time for decision making both in the 
study description/explanation telephone call by an investigator as well as the morning of surgery using a 
private patient care area to again review the study, informed consent form, and answer any remaining 
questions.  As noted previously, participants may speak with an investigator 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 14 days 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 
human participants 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. 
Following informed consent and the signing of the UCSD IRB-approved ICF and HIPAA documents, these 
documents will be copied, and the copy placed in the patient’s medical record.  The participant will be 
provided a copy along with the Participants’ Bill of Rights. 
We are requesting a partial waiver of HIPAA authorization for recruitment as protected health 
information will be reviewed to ascertain appropriate inclusion/exclusion criteria: 
The investigators will need to know in advance which participants would like to participate in order to 
have an investigator and research coordinator present on the day of surgery.  The investigators 
therefore need to contact potential participants prior to their day of surgery and request a waiver of 
consent for recruitment purposes.  We will scan the upcoming surgery schedule (which we have access 
to being anesthesiologists—we use this schedule daily for medical purposes), identify participants 
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 participants ourselves or provide the name 
and contact information to a research coordinator to contact the potential participants. 
1.  These procedures are minimal risk to the potential participants 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. 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
32 
2.  A waiver of consent would not adversely affect the rights and welfare of the potential participants 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 surgical patients are not seen in preop clinic; or they are seen just 1-2 days prior to their date of 
surgery.  The investigators will need to know in advance which patients would like to participate in order 
to have an investigator and research coordinator present on the day of surgery.  In addition, we need to 
bring participants to the surgical center 30 minutes earlier than regularly scheduled in order to provide 
written, informed consent, record baseline measurements, and leave extra time for the study 
intervention. 
4.  After participants are contacted, if they would like to participate, they will receive written, informed 
consent using an IRB-approved informed consent form. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause by either the Principal Investigator, Gate Science or the IRB.  Written notification, documenting 
the reason for study suspension or termination, will be provided by the suspending or terminating party 
to study participants, investigator, funding agency, and regulatory authorities.  If the study is 
prematurely suspended or terminated, the Principal Investigator will promptly inform the Institutional 
Review Board and will provide the reason(s) for the termination or suspension. Study participants will be 
contacted, as applicable, and be informed of any changes to the data collection schedule. 
 Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy or futility that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the PI, Gate Science and the IRB. 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators and their 
staff. This confidentiality is extended to cover testing of biological samples in addition to the clinical 
information relating to participants. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the study or the data 
will be released to any unauthorized third party without prior written approval of the Principal 
Investigator. 
All research activities will be conducted in as private a setting as possible. 
Representatives of Gate Science, Institutional Review Board (IRB) and/or regulatory agencies may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
33 
The study participant’s contact information will be securely stored at the clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB and/or Institutional policy requirements.  
All case report forms (data capture forms, or “CRFs”) will be identified by only the randomization 
number and first and last initials of the participants’ names (as a check for the randomization numbers).  
Therefore, any protected health information will be separated from identifiers.  The connection 
between participant identifiers and the randomization numbers will be accessible solely by the Principal 
Investigator and Program Manager (for follow-up data collection purposes).  Therefore, no case report 
form will be tied to an identifiable individual on the forms themselves, ensuring patient confidentiality 
should a form be inappropriately accessed.  All case report forms will be retained in the locked offices of 
the Principal Investigator and/or Program Manager.  These hard copies will not be mailed or otherwise 
transferred and will remain available to audit for a minimum of 7 years. Data will be entered into an 
Excel spreadsheet kept on a password-protected and encrypted computer and retained by the Principal 
Investigator for at least 7 years. The IRB is eligible to review study records at any time. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
The original, hard copy signed informed consent forms and case report forms will be stored within the 
Principal Investigator and/or Program Manager’s locked office; and they will remain with the Principal 
Investigator for at least 7 years.  Data will be entered into an Excel spreadsheet kept on a password-
protected and encrypted computer and retained by the Principal Investigator for at least 7 years. 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Brian M. Ilfeld, MD,MS 
University of California, San Diego 
9452 Medical Center Drive 
La Jolla, CA  92037 
(858) 444-5949 
bilfeld@health.ucsd.edu 
 
10.1.6 SAFETY OVERSIGHT 
Safety oversight at the site level will be the purview of the Principal Investigator; but all investigators, 
the Program Manager, and research coordinators have the obligation to report any safety 
issues/violation to the Principal Investigator. 
In addition, Gate Science will appoint a qualified physician as the Independent Medical Monitor (IMM) 
to oversee all medical monitoring issues and provide safety oversight. The IMM will evaluate the 
available information during the course of the trial and advise about the continuing safety of the trial to 
ensure the wellbeing of the study participants 
10.1.7 CLINICAL MONITORING 
This study will be monitored in accordance with the Clinical Monitoring Plan.  The purpose of monitoring 
is to ensure that: 
• 
The rights and well-being of human subjects are protected; 
• 
The data is accurate, complete and verified from source documents; and 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
34 
• 
The conduct of the study is in compliance with the currently approved protocol/amendment(s), 
with International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s). 
The Site Monitor is the liaison between Gate Science and the site and will conduct on-site and remote 
site visits. The Site Monitor will ensure: 
• 
Investigator has sufficient staff and facilities to conduct the study safely and effectively; 
• 
Investigator has adequate qualifications and resources throughout the study 
• 
Investigator and staff are appropriately trained to properly conduct the study.  
10.1.8 DATA HANDLING AND RECORD KEEPING  
 
10.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
The investigators will create a hard-copy case report form for each study participant enrolled, which will 
include only the randomization number and first/last name initials (as a check), anthropometric (e.g., 
age, height, weight), and demographic information.  All case report forms will be identified by only the 
randomization number and first and last initial of the participants’ names (as a check for the 
randomization numbers).  Therefore, any protected health information will be separated from 
identifiers.  The connection between participant identifiers and the randomization numbers will be 
accessible solely by the Principal Investigator and Program Manager (for follow-up data collection 
purposes).  Therefore, no case report form will be tied to an identifiable individual on the forms 
themselves, ensuring patient confidentiality should a form be inappropriately accessed.  All enrollment 
and case report forms will be retained in the locked offices of the Principal Investigator and/or Program 
Manager.  The data from each enrollment form will be entered to the project database.  These hard 
copies will not be mailed or otherwise transferred and will remain available to audit for a minimum of 7 
years. 
10.1.8.2 STUDY RECORDS RETENTION  
The data from each enrollment form will be uploaded to the project database.  These hard copies will 
not be mailed or otherwise transferred and will remain available to audit for a minimum of 7 years.  
10.1.9  PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol or International Conference on 
Harmonisation Good Clinical Practice (ICH GCP). The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions will be 
implemented promptly.  
These practices are consistent with ICH GCP:  
• 
Section 4.5: Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
Section 5.1: Quality Assurance and Quality Control, section 5.1.1  
• 
Section 5.20: Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the study investigator to use continuous vigilance to identify all deviations and 
report appropriate deviations (such as those related to an SAE) within 10 working days.  All deviations 
must be addressed in study source documents and ultimately reported to the UCSD Office of IRB 
Administration. 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
35 
10.2 ADDITIONAL CONSIDERATIONS 
10.2.1 ALTERNATIVES TO STUDY PARTICIPATION 
Potential study participants may simply decline enrollment. 
10.2.2 EXPENSE TO PARTICIPANT 
There will be no additional costs to participants as a result of being in this study. 
10.2.3 COMPENSATION FOR PARTICIPATION 
There is no financial compensation for participation. 
10.2.4 MANAGEMENT OF ADVERSE EVENTS 
Adverse events for study-related injuries will be managed by the Principal Investigator.  For a medical 
emergency that is potentially life-threatening, participants will be instructed to dial 911 for emergency 
services to go directly to their location. In the event of a study-related injury, UC San Diego will provide 
medical care needed to treat those injuries without cost to study participants.  UC San Diego 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 participants to contact the UC San Diego 
Institutional Review Board or the Principal Investigator for further information (phone numbers 
provided for all entities). 
10.2.5 PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
Principal Investigator, Brian M. Ilfeld, MD, MS, is a board-certified anesthesiologist with fellowship 
training in and 23 post-training years’ experience with regional anesthesia, acute pain medicine, and 
clinical investigation.  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 participants 
following their treatment.  Dr. Ilfeld will be responsible for the overall management of this study. 
Co-investigators John Finneran, MD, and Engy Said, MD, are board-certified anesthesiologists with 
experience with regional anesthesia and acute pain medicine.  All hold a license to practice medicine in 
California and medical privileges at the UC Medical Centers.  All will help consent participants, perform a 
history and physical exam, perform the treatment on participants, and will follow participants following 
their treatment. 
Baharin Abdullah is a Program Manager with the Department of Anesthesiology with the required 
experience and training—including up-to-date CITI training—for her position. 
10.2.6 FUNDING SUPPORT FOR THIS STUDY 
There is no extramural funding available for this trial, although the investigators will pursue such 
funding.  However, the manufacturer will be donating the RELAY devices.  Department funding will be 
used in the interim or if no extramural funding is awarded.  Please contact Kimberly Giles, grants 
specialist, at kgiles@health.ucsd.edu for information regarding Departmental funding. 
 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
36 
10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
ACTRI 
Altman Clinical & Translational Research Institute 
BPI 
Brief Pain Inventory 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA Health Insurance Portability and Accountability Act  
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
NRS 
Numeric Ratings Scale  
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
UCSD 
University of California, San Diego 
WHO 
World Health Organization 
 
10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1.5 
22 Jan 2025 
Funding information is revised to 
“Gate Science, the study sponsor is 
paying UC San Diego to conduct this 
research study.” 
To clarify funding information. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
37 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 REFERENCES  
1. 
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 
2. 
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 
3. 
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 
4. 
Shellock FG, Zare A, Ilfeld BM, Chae J, Strother RB: In Vitro Magnetic Resonance Imaging Evaluation 
of Fragmented, Open-Coil, Percutaneous Peripheral Nerve Stimulation Leads. Neuromodulation 
2018; 21: 276-283 
5. 
Ilfeld BM, Said ET, Finneran JJt, Sztain JF, Abramson WB, Gabriel RA, Khatibi B, Swisher MW, Jaeger 
P, Covey DC, Robertson CM: Ultrasound-guided percutaneous peripheral nerve stimulation: 
Neuromodulation of the femoral nerve for postoperative analgesia following ambulatory anterior 
cruciate ligament reconstruction, a proof of concept study. Neuromodulation 2018; 22: 621-629 
6. 
Ilfeld BM, Gabriel RA, Said ET, Monahan AM, Sztain JF, Abramson WB, Khatibi B, Finneran JJt, 
Jaeger PT, Schwartz AK, Ahmed SS: Ultrasound-guided percutaneous peripheral nerve stimulation: 
Neuromodulation of the sciatic nerve for postoperative analgesia following ambulatory foot 
surgery, a proof-of-concept study. Reg Anesth Pain Med 2018; 43: 580-589 
7. 
Gabriel RA, Ilfeld BM: Novel Methodologies in Regional Anesthesia for Knee Arthroplasty. 
Anesthesiol Clin 2018; 36: 387-401 
8. 
Ilfeld BM, Finneran JJt, Gabriel RA, Said ET, Nguyen PL, Abramson WB, Khatibi B, Sztain JF, Swisher 
MW, Jaeger P, Covey DC, Meunier MJ, Hentzen ER, Robertson CM: Ultrasound-guided 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
38 
percutaneous peripheral nerve stimulation: Neuromodulation of the suprascapular nerve and 
brachial plexus for postoperative analgesia following ambulatory rotator cuff repair. A proof-of-
concept study. Reg Anesth Pain Med 2019; 44: 310-18 
9. 
Ilfeld BM, Ball ST, Gabriel RA, Sztain JF, Monahan AM, Abramson WB, Khatibi B, Said ET, Parekh J, 
Grant SA, Wongsarnpigoon A, Boggs JW: A Feasibility Study of Percutaneous Peripheral Nerve 
Stimulation for the Treatment of Postoperative Pain Following Total Knee Arthroplasty. 
Neuromodulation 2019; 22: 653-660 
10. Ilfeld BM, Gelfand H, Dhanjal S, Hackworth R, Plunkett A, Turan A, Vijjeswarapu AM, Cohen SP, 
Eisenach JC, Griffith S, Hanling S, Mascha EJ, Sessler DI: Ultrasound-Guided Percutaneous Peripheral 
Nerve Stimulation: A Pragmatic Effectiveness Trial of a Nonpharmacologic Alternative for the 
Treatment of Postoperative Pain. Pain Med 2020; 21: S53-S61 
11. Ilfeld BM, Plunkett A, Vijjeswarapu AM, Hackworth R, Dhanjal S, Turan A, Cohen SP, Eisenach JC, 
Griffith S, Hanling S, Sessler DI, Mascha EJ, Yang D, Boggs JW, Wongsarnpigoon A, Gelfand H, 
Investigators PA: Percutaneous Peripheral Nerve Stimulation (Neuromodulation) for Postoperative 
Pain: A Randomized, Sham-controlled Pilot Study. Anesthesiology 2021; 135: 95-110 
12. Ilfeld BM, Finneran JJt, Said ET, Cidambi KR, Ball ST: Percutaneous Auricular Nerve Stimulation 
(Neuromodulation) for the Treatment of Pain: A Proof-of-Concept Case Report using Total Joint 
Arthroplasty as a Surrogate for Battlefield Trauma. J Trauma Acute Care Surg 2022 
13. Ilfeld BM, Finneran Iv JJ, Dalstrom D, Wallace AM, Abdullah B, Said ET: Percutaneous auricular 
nerve stimulation (neuromodulation) for the treatment of pain following outpatient surgery: a 
proof-of-concept case series. Reg Anesth Pain Med 2022 
14. Gabriel RA, Ilfeld BM: Extending Perioperative Analgesia with Ultrasound-Guided, Percutaneous 
Cryoneurolysis, and Peripheral Nerve Stimulation (Neuromodulation). Anesthesiol Clin 2022; 40: 
469-479 
15. Finneran JJt, Said ET, Ball ST, Cidambi KR, Abdullah B, Ilfeld BM: Percutaneous Auricular Nerve 
Stimulation (Neuromodulation) for Analgesia and Opioid-Sparing Following Knee and Hip 
Arthroplasty: A Proof-of-Concept Case Series. A A Pract 2022; 16: e01621 
16. Ilfeld BM, Plunkett A, Vijjeswarapu AM, Hackworth R, Dhanjal S, Turan A, Cohen SP, Eisenach JC, 
Griffith S, Hanling S, Sessler DI, Mascha EJ, Han Y, Boggs JW, Wongsarnpigoon A, Gelfand H, 
Investigators PA: Percutaneous Neuromodulation of the Brachial Plexus and Sciatic Nerve for the 
Treatment of Acute Pain Following Surgery: Secondary Outcomes From a Multicenter, Randomized, 
Controlled Pilot Study. Neuromodulation 2023; 26: 638-649 
 
 

Neuromodulation & Local Anesthetic 
Version 1.5 
Protocol: The RELAY device 
22 January 2025 
Biomedical Protocol – Interventional Research 
 
39 
 
12 APPENDIX