Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation: A Department of Defense Funded Multicenter Pilot Study

This is a pilot or feasibility study (designated as UG3 by the Department of Defense) which will be a randomized, double-masked, placebo-controlled, parallel-arm, human subjects pilot study with two Specific Aims:

Specific Aim 1 (UG3): To determine the feasibility and optimize the protocol of the Implementation Phase (UH3) multicenter clinical trial that will compare percutaneous PNS with usual and customary opioid-based analgesia following moderate-to-severely painful ambulatory surgery.

Specific Aim 2 (UG3): To estimate the treatment effect of percutaneous PNS on pain and opioid consumption following moderate-to-severely painful ambulatory surgery compared with usual and customary opioid-based analgesia. This will allow determination of the required sample size of the definitive multicenter clinical trial of the Implementation Phase (UH3).

Anthropomorphic and demographic characteristics as well as baseline end points will be recorded/measured, including a pain score at the surgical site using the Numeric Rating Scale (NRS, 0-10), sensory deficits (measured with von Frey filaments within the cutaneous distribution of the target nerve), and muscle strength (measured with a pressure transducer).

Shoulder • Rotator cuff repair Brachial plexus trunks (lead \& interscalene nerve block)

Knee • Anterior cruciate ligament repair with a patellar autograph Femoral lead \& Adductor canal nerve block

Foot or ankle • Hallux valgus correction or Ankle arthrodesis/ arthroplasty Subgluteal sciatic lead and Popliteal sciatic nerve block

Insulated leads will be inserted prior to peripheral nerve block administration. The lead insertion sites will be cleansed with chlorhexidine gluconate and isopropyl alcohol, and a sterile, fenestrated drape applied. A portable ultrasound paired with either a linear or curved array transducer within a sterile sleeve will be used for lead insertion. The target nerve will be imaged in a transverse cross-sectional (short axis) view and a local anesthetic skin wheal raised lateral to the ultrasound transducer.

A needle and a pre-loaded, monopolar, helically-coiled, insulated lead (SPR Therapeutics, Cleveland, OH) will be inserted. Using an in-plane ultrasound approach, the needle tip will be advanced to the target nerve. The lead will be subsequently attached to an external stimulator (SPR Therapeutics). Accurate lead placement will be confirmed with subject reports of comfortable sensations over the surgical site without eliciting muscle contractions.

Stimulation parameters will be adjusted to improve stimulation coverage and comfort. Once optimum parameters have been determined, the needle will be withdrawn over the lead. The lead will be affixed to the skin with a sterile occlusive dressing. The stimulator will be set to deliver a range of currents. During their treatment, subjects can control these levels. Muscle strength will again be tested with the stimulator set for the optimal setting. The stimulator will be removed until after surgery.

Preoperatively, day of surgery. Subjects will continue to receive usual and customary local anesthetic-based analgesia. Because percutaneous PNS does not induce a sensory block and therefore does not provide anesthesia for the surgical procedure itself, we will continue to provide subjects with a preoperative single-injection local anesthetic-based peripheral nerve block (20 mL of ropivacaine 0.5% with epinephrine 1:400,000). In addition, surgeons will be permitted to infiltrate the surgical area with local anesthetic.

Treatment group assignment (randomization). Subjects will be allocated to a treatment only after confirmation of successfully-inserted electrical leads and surgical procedure initiation; and will be randomized to one of two possible treatment groups:

1. Current delivered via the electrical lead(s) [Experimental group]
2. No current delivered via the electrical lead(s) [Control group]

Randomization will be stratified by institution and anatomic lead location in a 1:1 ratio and in randomly chosen block sizes. Treatment group assignment will be conveyed to the enrolling sites via the same secure web-based system (RedCap) used to collect and collate all post-intervention endpoints. Stimulators are capable of programming to either (1) pass electrical current; or, (2) not pass electrical current. Importantly, these 2 modes (active and sham) are indistinguishable in appearance, and therefore investigators, subjects, and all clinical staff will be masked to treatment group assignment, with the only exception being the unmasked individual who programs the stimulator who will not have contact with the subject following randomization.

Subjects will be informed that often during postoperative active treatment with electrical current patients do not always have the sensations experienced during preoperative lead placement and once proper placement is confirmed with comfortable sensations, therapeutic levels of stimulation may be delivered sub-threshold (below the intensity required for sensation and still provide relief, which is factual/accurate). This protocol will ensure a randomized, double/triple-masked, sham/placebo-controlled trial. For the feasibility study (UG3), unmasking will occur 2 weeks following surgery to allow for protocol revisions, as necessary ("double masked" during initial data collection). In contrast, for the definitive pragmatic clinical trial (UH3) unmasking will not occur until statistical analysis for the entire investigation is complete (termed "triple masked").

Intraoperative course. The primary surgical anesthetic will be a general anesthetic, spinal anesthetic (bupivacaine) or exclusively the preoperative single-injection peripheral nerve block. Anesthetics that are also analgesics such as ketamine will not be used: the only permitted analgesic will be intravenous fentanyl, which will be minimal since all subjects will receive a single-injection peripheral nerve block immediately prior to surgery.

Postoperative course. Within the recovery room following surgery, the stimulators will be attached to the leads and activated, followed by end point assessment. Subjects who had a spinal anesthetic will have end points recorded following spinal resolution. Operating and recovery room pharmacologic analgesic requirements will be recorded.

Prior to discharge, subjects and their caretakers will be provided with verbal and written stimulator/lead instructions and the telephone and pager numbers of a local investigator available at all times. Subjects will be discharged home with their leads in situ. Subjects will be also be discharged with a prescription for an immediate-release oral opioid. Subjects will be contacted by telephone for end point collection (pain and analgesic consumption will be reported by phone on postoperative days 1, 2, 3, 4, 7, 11, and 15 as well as months 1 and 4). Lead removal will occur on postoperative day 14 (+/- 2 days) by healthcare providers. If the lead is removed following Day 14, the stimulator will be turned off on Day 14, and removed subsequently. Following study completion, the results will be mailed electronically or by the United States Postal Service to all enrolled subjects in written form using non-technical language.

Outcome measurements (end points). We have selected outcome measures that have established reliability and validity, with minimal inter-rater discordance, and are recommended for pain-related clinical trials by the World Health Organization and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus statement. Importantly, nearly all outcome measures are common data elements from the National Institute of Neurological Disorders and Stroke (NINDS). End points will be evaluated on postoperative days 0 (baseline), 1, 2, 3, 4, 7, 11, and 15 as well as months 1 and 4).

Demographic and medical history. Subjects will have demographic and anthropomorphic data collected based on NINDS case report form General Core and Demographics Modules and Guidelines, including age, sex, height, weight, educational level, employment status, marital status, and U.S. military service (e.g., none, discharged, active). In addition, the medical history based on the common data elements of the NINDS Medical, Family, Behavioral History, History of Disease/Injury Event, and Prior and Concomitant Medications Sub-Domains will be collected, and include the mechanism of original injury, medications (including analgesics), previous surgical procedures, comorbidities, existing sensory deficits of the target nerve distribution, preoperative pain levels measured on a Numeric Rating Scale for pain (including daily least, average, worst and current), and muscle strength if applicable (measured with a pressure transducer). In addition, since post-traumatic stress disorder (PTSD) may be associated with the severity of pain, at baseline we will apply the PTSD Checklist (PCL-C), a 20-item self-report measure reflecting symptoms of PTSD validated in military, Veteran, and civilian populations.

Data collection. Much of the surgical data from the day of surgery will be extracted from electronic health records to leverage data collection that occurs in health care delivery rather than requiring independent research data collection. Subject demographic, surgical and percutaneous PNS administration data will be uploaded from each enrolling center via the Internet to a secure, password-protected, encrypted central server (RedCap, Department of Outcomes Research, Cleveland Clinic, Cleveland, Ohio). All data collection following the day of enrollment (postoperative day 0)-regardless of enrolling center-will be collected by telephone from the University of California San Diego. Staff masked to treatment group assignment will perform all assessments.

UG3 Planning Phase Specific Aims. The investigation described above will accomplish the two Specific Aims of the UG3 Planning Phase:

Specific Aim 1 (UG3): To determine the feasibility and optimize the protocol of the Implementation Phase (UH3) multicenter clinical trial that will compare percutaneous PNS with usual and customary opioid-based analgesia following moderate-to-severely painful ambulatory surgery.

Specific Aim 2 (UG3): To estimate the treatment effect of percutaneous PNS on pain and opioid consumption following moderate-to-severely painful ambulatory surgery compared with usual and customary opioid-based analgesia. This will allow determination of the required sample size of the definitive multicenter clinical trial of the Implementation Phase (UH3).

** The primary end points will be cumulative opioid consumption and the mean value of the "average" daily surgical pain scores (measured with a Numeric Rating Scale) within the first 7 days following surgery (data collected Days 1, 2, 3, 4, and 7). In order to claim that percutaneous PNS is superior to usual and customary analgesia, at least one of Hypotheses 1 and 2 above must be superior while the other either superior or at least noninferior.