Multicenter Prospective Trial of Office-based Carpal Tunnel Release With Ultrasound Guidance (ROBUST)
Phase: NA
Conditions: Carpal Tunnel Syndrome, CTS
Sponsor: Sonex Health, Inc.

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No. 90098-TP, Rev.01 
Multicenter prospective trial of office-based carpal 
tunnel release with ultrasound guidance (ROBUST)  
 
 
 
 
CLINICAL STUDY PROTOCOL: 
 
No. 90098-TP Revision 01 
Dated December 19, 2022 
 
 
 
SPONSOR: 
 
Sonex Health, Inc. 
950 Blue Gentian Road, Suite 200 
Eagan, MN 55121 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study will be conducted in compliance with the protocol and applicable regulatory requirements. 
 
Confidential Information 
No use or disclosure of this document outside The Institute of Advanced Ultrasound Guided Procedures 
(The Institute) is permitted without prior written authorization from The Institute. 
 
 
 

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No. 90098-TP, Rev.01 
Multicenter prospective trial of office-based carpal 
tunnel release with ultrasound guidance (ROBUST)  
 
Protocol Signature Page 
 
No. 90098-TP Revision 01 
Dated December 19, 2022 
 
 
 
 
I have read this protocol and agree to adhere to the requirements.  I will provide copies of 
this protocol and all pertinent information to the study personnel under me.  I will discuss 
the material with them and ensure they are fully informed regarding the conduct of the 
study according to this protocol, applicable regulatory requirements, and IRB 
requirements. 
 
I agree to and understand the material presented in this protocol and must not publicly 
disclose in any manner the design, results, or conclusions of this investigation without 
prior written consent of Sonex Health. 
 
 
 
 
___________________________________ 
Clinical Site Name 
 
 
 
___________________________________  
 
_____________________ 
Site Principal Investigator  
 
 
 
 
Date 
Signature 
 
 
 
 
 
 
__________________________________ 
Site Principal Investigator  
Printed Name 

 
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TABLE OF CONTENTS 
1. PROTOCOL SYNOPSIS ....................................................................... 5 
2. LIST OF ABBREVIATIONS ................................................................ 7 
3. BACKGROUND AND OBJECTIVE ................................................... 8 
4. DEVICE DESCRIPTION ...................................................................... 9 
5. SUMMARY OF PRIOR CLINICAL EXPERIENCE ......................10 
6. STUDY PROCEDURES ......................................................................13 
6.1 Investigational Site Selection .............................................................................. 13 
6.2 Subject Selection .................................................................................................. 13 
6.2.1 
Inclusion Criteria ........................................................................................ 13 
6.2.2 
Exclusion Criteria ....................................................................................... 13 
6.2.3 
Screen Failures ........................................................................................... 14 
6.2.4 
Timing of Patient Screening........................................................................ 14 
7. SUBJECT ENROLLMENT ................................................................15 
7.1 Procedure .............................................................................................................. 15 
7.2 Procedure LOCATION ....................................................................................... 15 
7.2.1 
Post-treatment Assessments ........................................................................ 15 
7.2.2 
Follow-up Assessments ............................................................................... 16 
7.2.3 
Unscheduled Follow-up Visits .................................................................... 17 
7.2.4 
Loss to Follow-up ....................................................................................... 17 
7.3 Subject Withdrawal from Study......................................................................... 17 
7.3.1 
Voluntary Withdrawal ................................................................................. 17 
7.3.2 
Involuntary Withdrawal .............................................................................. 17 
7.3.3 
End of Study ................................................................................................ 18 
8. OUTCOMES .........................................................................................18 
8.1 Primary Endpoint ................................................................................................ 18 
8.2 Secondary Endpoints ........................................................................................... 18 
8.2.1 
Time to Return to Normal Daily Activities ................................................. 18 
8.2.2 
Time to Return to Work Among Employed Subjects ................................... 18 
8.2.3 
BCTQ-FSS Change at 3 Months ................................................................. 19 
8.2.4 
MHQ Change at 3 Months .......................................................................... 19 
8.2.5 
Numeric Pain Scale Change at 3 Months ................................................... 19 
8.2.6 
EQ-5D-5L Change at 3 Months .................................................................. 19 
8.2.7 
Device- or Procedure-related Adverse Events at 3 Months ....................... 19 
8.2.8 
Global Satisfaction...................................................................................... 20 
8.2.9 
Additional Outcomes ................................................................................... 20 
9. ADVERSE EVENTS ............................................................................20 
9.1 Serious Adverse Event ......................................................................................... 20 
9.2 Unanticipated Adverse Device Effect ................................................................. 21 
9.3 RelationShip of Adverse Events to the DEVICE OR Procedure .................... 21 

 
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9.4 Device Failures, Malfunctions and Near Incidents ........................................... 22 
9.5 Reporting of Adverse Events .............................................................................. 22 
9.6 Independent Medical Reviewer .......................................................................... 22 
9.7 Data Safety Monitoring Board ........................................................................... 23 
9.8 RISK-BENEFIT ANALYSIS .............................................................................. 23 
9.8.1 
Risk Analysis ............................................................................................... 23 
9.8.2 
Potential Benefits ........................................................................................ 23 
10. DATA ANALYSIS ................................................................................24 
10.1 
Sample Size Justification.............................................................................. 24 
10.2 
Analysis Populations..................................................................................... 24 
10.2.1 Duration Variables ..................................................................................... 24 
10.2.2 Analysis Windows ....................................................................................... 25 
10.2.3 Data Analysis Methods ............................................................................... 25 
11. STUDY RESPONSIBILITIES AND MANAGEMENT ...................26 
11.1 
Investigator Responsibilities ........................................................................ 26 
11.2 
Subject Enrollment Process ......................................................................... 26 
11.3 
Institutional Review Board .......................................................................... 27 
11.4 
Informed Consent Form .............................................................................. 27 
11.5 
Case Report Form ........................................................................................ 27 
11.6 
Central Database .......................................................................................... 27 
11.7 
Records .......................................................................................................... 28 
11.8 
Reports ........................................................................................................... 28 
11.9 
Sponsor Responsibilities............................................................................... 29 
11.9.1 Confidentiality............................................................................................. 30 
11.9.2 Amending the Investigational Study Protocol............................................. 30 
11.9.3 Protocol Deviations .................................................................................... 30 
11.9.4 Site Noncompliance and Nonperformance ................................................. 30 
11.9.5 Device Accountability ................................................................................. 30 
12. STUDY MONITORING ......................................................................31 
13. REFERENCES ......................................................................................32 
 
 

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1. PROTOCOL SYNOPSIS 
Title 
Multicenter prospective trial of office-based carpal tunnel release with 
ultrasound guidance (ROBUST) 
Purpose 
To report the safety and effectiveness of office-based carpal tunnel release with 
ultrasound guidance (CTR-US) in patients with symptomatic carpal tunnel 
syndrome (CTS) 
Study Design 
Multicenter prospective single-arm trial of subjects with symptomatic CTS 
treated with CTR-US in an office-based setting 
Enrollment 
A minimum of 140 subjects will be enrolled in the study and treated with CTR-
US 
Procedure 
Unilateral or simultaneous bilateral CTR-US 
Visit 
Schedule 
Post-procedure remote subject-reported outcomes evisits:  
1-14 days; 1, 3, 6, 12, and 24 months 
Clinical Sites 
Up to 12 investigational sites located within the United States 
Inclusion 
Criteria 
1. ≥18 years of age 
2. Clinical diagnosis of unilateral or bilateral idiopathic CTS  
3. CTS-6 score >12 in target hand* 
4. Median nerve cross-sectional area ≥10 mm2 in the proximal carpal tunnel 
region of the target hand measured by diagnostic ultrasound* 
5. Prior failure of one or more nonsurgical treatment options (e.g., physical 
activity modification, bracing, splinting, corticosteroid injection)* 
6. Subject agrees to complete follow-up questionnaires over a 24-month period  
7. Subject has a valid smart phone number and/or email address to receive and 
answer follow-up questionnaires 
Exclusion 
Criteria 
1. Prior surgery on the target wrist or hand with the exception of (a) trigger 
finger release or similar minor finger procedure (e.g., digital ganglion cyst 
removal, foreign body removal) that has clinically recovered, or 
release for DeQuervain’s syndrome (1st dorsal compartment) that has 
clinically recovered* 
2. History of prior surgical CTR in the target hand* 
3. History of infection in the target hand* 
4. History of prior surgery in the non-target hand, including CTR, within 3 
months of enrollment or with persistent symptoms that interfere with normal 
daily activities or work at the time of consent 
5. Planned surgical or interventional procedure on the contralateral hand within 
3 months of the target hand procedure date* 
6. Corticosteroid injection in the target hand within 6 weeks of study procedure 
date* 
7. Presence of additional process in the target hand requiring additional 
intervention beyond carpal tunnel release (e.g. neurolysis, mass removal, 
tenosynovectomy)* 
8. Clinically significant degenerative arthritis of the upper limb (shoulder to 
hand) on the target side* 
9. Clinically significant inflammatory disease (including tenosynovitis) of the 
upper limb (shoulder to hand) on the target side* 

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10. Clinically significant trauma or deformity of the upper limb (shoulder to 
hand) on the target side* 
11. Clinically significant vascular disease (including Raynaud’s phenomenon) of 
the upper limb (shoulder to hand) on the target side* 
12. Clinically significant neurological disorder (including complex regional pain 
syndrome) of the upper limb (shoulder to hand) on the target side* 
13. Systemic inflammatory disease (e.g., rheumatoid arthritis, lupus) 
14. Amyloidosis  
15. Chronic renal insufficiency requiring dialysis  
16. Diabetes not controlled by a stable dose of medication  
17. Uncontrolled thyroid disease 
18. Pregnant or planning pregnancy in the next 24 months 
19. Workers’ compensation subjects 
20. Inability to provide a legally acceptable Informed Consent Form and/or 
comply with all follow-up requirements 
21. Subject has other medical, social, or psychological conditions that, in the 
opinion of the investigator, preclude them from receiving the pre-treatment, 
required treatment, and post-treatment procedures and evaluations 
 
Note: An asterisk (*) denotes that this criterion must be applied to the target hand 
for unilateral CTR-US procedures, or to both hands for simultaneous bilateral 
CTR-US procedures. 
 
Clinically significant is defined as likely to interfere with the performance of the 
procedure in a safe and/or effective manner. 
Primary 
Endpoint 
Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ-SSS) 
change at 3 months 
Secondary 
Endpoints 
• Time to Return to normal daily activities 
• Time to Return to work among employed subjects 
• Boston Carpal Tunnel Questionnaire Functional Status Scale (BCTQ-FSS) 
change at 3 months 
• Michigan Hand Questionnaire (MHQ) 
• Numeric Pain Scale change at 3 months 
• EuroQol 5-Dimension 5-Level (EQ-5D-5L) change at 3 months 
• Device- or procedure-related adverse events at 3 months 
• Global Satisfaction at 3 months 
Principal 
Investigator: 
Ashley L. Pistorio, MD, MS, FACS 
University of Nevada, Las Vegas 
1707 W. Charleston Boulevard, Suite 190 
Las Vegas, NV 89102 
Study 
Sponsor  
and Data 
Management: 
Sonex Health 
950 Blue Gentian Road, Suite 200 
Eagan, MN 55121 
Tel: 888-518-8780 
Email: robust-study@sonexhealth.com 
 

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2. LIST OF ABBREVIATIONS  
AAOS 
American Academy of Orthopedic Surgery 
AE 
Adverse event 
BCTQ 
Boston Carpal Tunnel Questionnaire 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
CMS 
Centers for Medicare and Medicaid Services 
CTR 
Carpal tunnel release  
CTR-US 
Carpal tunnel release with ultrasound guidance 
CTS 
Carpal tunnel syndrome  
DSMB 
Data Safety Monitoring Board 
ECTR 
Endoscopic carpal tunnel release 
EQ-5D-5L 
EuroQol 5-Dimension 5-Level 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act  
ICF 
Informed Consent Form 
IFU 
Instructions for Use 
IQR 
Interquartile range 
IRB 
Institutional Review Board  
MCID 
Minimal Clinically Important Difference 
MHQ 
Michigan Hand Questionnaire 
mOCTR 
Mini-open carpal tunnel release 
OCTR 
Open carpal tunnel release 
PI 
Principal Investigator 
QDASH 
Quick form of the Disabilities of the Arm Shoulder and Hand 
SAE 
Serious adverse event 
SOP 
Standard Operating Procedure 
TCL 
Transverse carpal ligament 
UADE 
Unanticipated Adverse Device Effect  
 
 

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3. BACKGROUND AND OBJECTIVE 
Carpal tunnel syndrome (CTS) is the most common peripheral neuropathy, affecting 
approximately 5% of the population 1.  A multitude of treatments are available to treat CTS, 
including activity modification, bracing/splinting, hand therapy, modalities (e.g., therapeutic 
lasers or ultrasound, iontophoresis), acupuncture, corticosteroid injections, and carpal tunnel 
release (CTR) surgery performed using traditional open or endoscopic approaches 2-7.  Currently, 
there is no universally accepted algorithm to guide treatment for patients suffering with CTS.  
The American Academy of Orthopedic Surgery (AAOS) CTS Clinical Practice Guidelines 
reported that only three treatments are strongly supported in the literature: splinting, 
corticosteroid injections, and CTR 4.  Although some patients with mild-moderate symptoms are 
successfully treated with splinting and/or corticosteroid injections, those with progressive, 
refractory, or severe symptoms generally proceed to CTR for definitive management 2,3,5-9. 
 
The goal of CTR is to reduce median nerve pressure by dividing the transverse carpal ligament 
(TCL) while avoiding iatrogenic injury to surrounding neurovascular structures.  Among the 
~600,000 CTR procedures performed in the United States annually 1,10, most (70-80%) use a 
traditional open technique (OCTR) during which a palmar incision is made to dissect down to 
the TCL and transect it using a scalpel, scissors, or a similar cutting device 11-13.  The OCTR 
technique requires a relatively large (3-5 cm) incision and may be associated with a prolonged 
recovery period due to palmar pain and the need to protect the wound 12,14-17 .   
 
Over time, there has been a trend to use smaller incisions (1-3 cm) to reduce surgical morbidity 
using mini-OCTR (mOCTR) or endoscopic CTR 11,16-18 .  Because long-term outcomes and 
complication profiles are generally equivalent among these CTR procedures 19, factors related to 
patient recovery time such as time to return to normal activities and work absenteeism are 
important considerations that may assist in shared decision-making between physicians and 
patients. 
 
In recent years, multiple studies have demonstrated the feasibility of using ultrasound to perform 
CTR through even smaller incisions while maintaining or even improving visualization of the 
carpal tunnel region, including its at-risk neurovascular structures.  During CTR with ultrasound 
guidance (CTR-US), the carpal tunnel is typically accessed through a single small wrist or 
palmar incision <5 mm length and the TCL is transected using a small knife or similar cutting 
instrument while the carpal tunnel structures are continuously monitored visually using US.  To 
date, a total of 22 clinical studies have been published reporting results on over 2,100 hands in 
over 1,650 patients at up to 2 years post-treatment comparing recovery time, effectiveness, and 
safety in subjects with CTS treated with CTR-US or mOCTR with US guidance 20-32.  Among 
these over 2,100 hands, there were no major neurovascular complications, and the clinical 
success rate was >95%.   
 
Historically, CTR procedures were performed in a hospital or an ambulatory surgery center 
(ASC).  However, due to advancements in technology, greater patient demand, and concerns 
about growing healthcare costs, there is a distinct trend from performing CTR procedures in a 
hospital or ASC to an office-based setting.  A recently published prospective single-center study 
demonstrated the feasibility of CTR-US when performed in an office-based setting 33.  The 

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improvement in CTS symptoms following office-based CTR-US was statistically significant and 
clinically important over 1 year of follow-up and no intraoperative complications or reoperations 
were reported. However, it remains unclear whether these results are reproducible across 
multiple practices treating patients with office-based CTR-US in real-world practice.  Thus, the 
objective of this prospective multicenter trial is to evaluate the safety and effectiveness of office-
based CTR-US in a large cohort of patients (n=140) with symptomatic CTS followed for 2 years 
post-treatment. 
 
4. DEVICE DESCRIPTION  
The UltraGuideCTR (Sonex Health, Inc., Eagan, MN) is a commercially available medical 
device specifically developed to facilitate CTR-US.  The device is a single-use, hand-held device 
that is inserted into the carpal tunnel through a small (typically < 5 mm) wrist incision using 
continuous US guidance.  The working tip of the UltraGuideCTR consists of two inflatable 
balloons that border a centrally located, retractable retrograde cutting knife.  When inflated with 
sterile saline, the balloons increase the diameter of the tip from 4 mm to 8 mm.  After the tip is 
positioned within the transverse safe zone of the carpal tunnel, the balloons are inflated to create 
space in the carpal tunnel, the blade is activated, and the TCL is transected in a retrograde 
manner.  Following TCL transection, the blade is recessed, the balloons deflated, and the device 
is removed.  The TCL is probed to ensure a complete release.  The entire procedure is performed 
using US guidance.  The first commercial CTR-US procedure with the device was performed in 
February 2017.  Since then, over 100 different physicians have been trained to use the 
UltraGuideCTR, who collectively have performed over 15,000 procedures.  Labeled images of 
the device are provided below. 
 
  
 
 
 
 

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5. SUMMARY OF PRIOR CLINICAL EXPERIENCE 
Representative prior experience with CTR-US using the UltraGuideCTR device is derived from 
the APEX-CTR post market registry 32.  This multicenter, observational post-market registry 
enrolled patients treated with CTR-US in routine clinical practice in the United States.  Data 
collection in this registry began after FDA clearance to collect post-market safety and 
effectiveness information about the device and patient outcomes.  The research methods adhered 
to the guidelines set forth in the Declaration of Helsinki.  This study was granted a waiver of 
consent exemption from WCG IRB (Puyallup, WA). 
 
The eligibility criteria were purposely broad to reflect a heterogenous sample of CTS patients 
treated in routine clinical practice.  Patient diagnosis was determined according to the practice 
patterns of each participating physician, all of whom were experienced in the diagnosis and 
management of CTS.  CTS was diagnosed primarily on clinical grounds, with ancillary testing 
such as electrodiagnostic studies ordered at the discretion of the physician.  Eligible patients 
were adults (age ≥18 years) who were treated with CTR-US and demonstrated a willingness to 
participate in the registry and participate in specified follow-up activities.  No limitations were 
imposed on maximum patient age, medical or surgical history, or clinical presentation. 
 
All patients were treated with CTR-US using the UltraGuideCTR device, which was inserted 
into the carpal tunnel through a small (typically <5 mm) wrist incision using real-time ultrasound 
guidance.  The physicians in this study represented a variety of specialties and procedural 
experience and all completed a formal cadaver-based training program prior to performing CTR-
US in clinical practice.  Factors such as patient selection, anesthesia, and postoperative care were 
determined by practice-specific preferences.  Face-to-face follow-up visits varied according to 
the usual practice patterns of each participating physician and were not dictated by the study.  
There was no requirement for return follow-up visits as all data were collected via text message, 
e-mail, or chart review. 
 
Patients completed a preoperative questionnaire, daily post-operative text message questions for 
up to 14 days post procedure, and emailed questionnaires at 2 weeks, 1 month, 3 months, and 6 
months postoperatively.  Pre-treatment patient assessments included demographic data, medical 
and surgical history, work status, and patient-reported outcomes including the Quick form of the 
Disabilities of the Arm, Shoulder, and Hand Questionnaire (QDASH) and Boston Carpal Tunnel 
Symptom Severity and Functional Status Scores (BCTQ-SSS and BCTQ-FSS).  Return to 
normal activities and return to work were collected via daily text messages for the first 14 days.  
Thereafter, postoperative outcomes were collected via e-mail or text message and included 
QDASH, BCTQ-SSS, BCTQ-FSS, return to normal activities, return to work, and patient 
satisfaction. 
 
Co-primary endpoints of this study were QDASH, BCTQ-SSS, and BCTQ-FSS.  The QDASH is 
an 11-item patient-reported questionnaire that has been validated for CTS, where the total score 
ranges from 0 (indicating no disability) to 100 (indicating most severe disability) 34.  The BCTQ 
is a CTS specific questionnaire consisting of 11 symptom severity questions (BCTQ-SSS) and 8 
functional status questions (BCTQ-FSS).  Scoring for the BCTQ- SSS and BCTQ-FSS ranges 
from 1 to 5, with higher scores indicating more severe symptoms and more severe disability, 

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respectively 35.  Minimal clinically important differences (MCIDs) for the postoperative change 
in patient-reported outcomes were 15 points for QDASH 36, 1.14 points for BCTQ-SSS 37, and 
0.74 points for BCTQ-FSS 37.  Return to normal activities was ascertained by asking patients 
when they had returned to normal daily activities outside of work.  Return to work was 
ascertained by asking employed patients when they had returned to work in any capacity, a 
definition that is commonly used among CTS studies 38,39.  Patient satisfaction with the 
procedure was reported on a 5-point Likert scale ranging from 1 (very dissatisfied) to 5 (very 
satisfied); a score of 4 or 5 indicated that a patient was satisfied with the procedure.  
Postoperative complications were recorded via chart review performed by the treating physician.  
 
Among 535 patients who enrolled in the registry and provided postoperative follow-up, data 
were available on 499 (93%) patients at 2 weeks, 475 (89%) at 1 month, 446 (83%) at 3 months, 
and 373 (70%) at 6 months.  The cohort of 373 patients with 6-month follow-up formed the basis 
for the report.  Between November 2019 and July 2021, 373 patients (427 hands, mean age 55 
years, 71% female, 62% employed) underwent CTR-US at 24 sites in the United States.  A total 
of 329 (88.2%) procedures were performed using local anesthesia, 44 (11.8%) were performed 
using monitored anesthesia care, and no procedures were performed using general anesthesia.  
There were 217 unilateral CTR-US procedures, 51 staged bilateral CTR-US procedures, and 54 
simultaneous bilateral CTR-US procedures.  Simultaneous procedures consisted of 14.5% of 
cases and 25.3% of treated hands.   
 
Patient-reported measures of symptom severity and physical function demonstrated rapid 
improvement following CTR-US.  Mean QDASH scores were 41.7±20.1 at baseline, 21.4±15.9 
at 2 weeks, 17.7±15.1 at 1 month, 13.3±15.0 at 3 months, and 11.0±15.2 at 6 months.  QDASH 
scores decreased by 20.3 (95% CI: 17.5 to 23.0) points at 2 weeks and 30.8 (95% CI: 28.1 to 
33.4) points at 6 months (p<0.001 at each follow-up interval).  Mean BCTQ-SSS scores were 
3.0±0.7 at baseline, 1.7±0.6 at 2 weeks, 1.7±0.6 at 1 month, 1.5±0.6 at 3 months, and 1.4±0.6 at 
6 months.  BCTQ-SSS scores decreased by 1.3 (95% CI: 1.2-1.4) points at 2 weeks and 1.6 (95% 
CI: 1.5-1.7) points at 6 months (p<0.001 at each follow-up interval).  Mean BCTQ-FSS scores 
were 2.4±0.8 at baseline, 1.7±0.6 at 2 weeks, 1.6±0.5 at 1 month, 1.4±0.5 at 3 months, and 
1.3±0.5 at 6 months.  BCTQ-FSS scores decreased by 0.7 (95% CI: 0.5-0.8) points and 1.0 (95% 
CI: 0.9-1.1) points at 2 weeks and 6 months, respectively (p<0.001 at each follow-up interval).   
 
The median time to return to normal activities following CTR-US was 3 days (interquartile range 
[IQR]: 2-5 days), with 96.5% of patients reporting returning to normal activities within 2 weeks 
of the procedure.  Among employed patients, the median time to return to work following CTR-
US was 5 days (IQR: 3-9 days), with 92.3% of patients reporting returning to work within 2 
weeks of the procedure.  The median time to return to work based on employment type was 4 
days (IQR: 3-6 days) for desk-based occupations, 6 days (IQR: 4-11 days) for light manual 
occupations, and 5 days (IQR: 3-14 days) for heavy manual occupations.  The percentage of 
patients who were satisfied or very satisfied with the procedure was 91.6% at 2 weeks, 88.2% at 
1 month, 88.0% at 3 months, and 89.8% at 6 months.   
 
Among 346 (93%) patients with available complication data, no major neurovascular 
complications were reported.  Specifically, there was 1 (0.3%) incomplete release confirmed 

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during reoperation and no reports of superficial infection, deep infection, arterial laceration, or 
permanent nerve injury. 
 
A recent study by Bergum and Ciota 33 demonstrated the feasibility of CTR-US when performed 
in an office-based setting.  This was a prospective single-center study that evaluated 1-year 
outcomes in patients treated with office-based CTR-US.  Among 88 patients (123 hands) with 1-
year follow-up data, 29 patients (57 hands) were treated with simultaneous bilateral procedures, 
18 patients (25 hands) were treated with staged bilateral procedures, and 41 were treated with a 
unilateral procedure.  All office-based procedures were successfully completed with local 
anesthesia and no intraoperative complications occurred.   
 
Mean BCTQ-SSS scores decreased by 1.2 (SE 0.07) points at 2 weeks, 1.3 (SE 0.07) points at 1 
month, 1.6 (SE 0.09) points at 3 months, and 1.7 (SE 0.08) points at 1 year (p<0.001 at each 
follow-up interval).  Mean BCTQ-FSS scores decreased by 0.6 (SE 0.06) points at 2 weeks, 0.9 
(SE 0.07) points at 1 month, 1.1 (SE 0.07) points at 3 months, and 1.2 (SE 0.07) points at 1 year 
(p<0.001 at each follow-up interval).  Mean QDASH scores decreased by 14 (SE 2) points at 2 
weeks, 23 (SE 2) points at 1 month, 27 (SE 2) points at 3 months, and 32 (SE 2) points at 1 year 
(p<0.001 at each follow-up interval).  No neurovascular injuries, tendon injuries, infections or 
significant post-surgical wound complications occurred, and there were no recurrences or 
reoperations reported in the study.  One patient developed complex regional pain syndrome 
without evidence of nerve injury, which was promptly recognized and successfully treated.  This 
patient ultimately had CTR-US performed on the contralateral hand.  
 
The purpose of this prospective multicenter study is to determine the safety and effectiveness of 
CTR-US when performed in an office setting. 
 
 
 
 
 
 
 

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6. STUDY PROCEDURES 
6.1 INVESTIGATIONAL SITE SELECTION 
Investigational sites will be selected based on the availability of the subject pool to be included 
in the study, the ability of the study site to perform the research in compliance with the 
investigational plan, and agreement to comply with the institutional review board (IRB) 
requirements.  All investigators will be board certified physicians experienced in the diagnosis 
and treatment of CTS, including CTR-US.  Each investigator will complete a structured training 
program in musculoskeletal ultrasound including ultrasound machine controls, sonographic 
anatomy of the carpal tunnel region, identification and cross-sectional measurement of the 
median nerve, and CTR-US using the UltraGuideCTR device.  In addition, all investigators must 
have conducted a minimum of 10 procedures using CTR-US prior to treating subjects in the 
clinical trial. 
 
6.2 SUBJECT SELECTION 
Patients with suspected CTS in one or both hands will be consecutively evaluated for study 
eligibility at each site.  Patients must meet all inclusion criteria and no exclusion criteria to be 
enrolled in the trial.   
6.2.1 Inclusion Criteria 
1. ≥18 years of age 
2. Clinical diagnosis of unilateral or bilateral idiopathic CTS  
3. CTS-6 score >12 in target hand* 
4. Median nerve cross-sectional area ≥10 mm2 in the proximal carpal tunnel region of the 
target hand measured by diagnostic ultrasound* 
5. Prior failure of one or more nonsurgical treatment options (e.g., physical activity 
modification, bracing, splinting, corticosteroid injection)* 
6. Subject agrees to complete follow-up questionnaires over a 24-month period  
7. Subject has a valid smart phone number and/or email address to receive and answer 
follow-up questionnaires 
6.2.2  Exclusion Criteria 
1. Prior surgery on the target wrist or hand with the exception of (a) trigger finger release or 
similar minor finger procedure (e.g., digital ganglion cyst removal, foreign body 
removal) that has clinically recovered, or release for DeQuervain’s syndrome (1st dorsal 
compartment) that has clinically recovered* 
2. History of prior surgical CTR in the target hand* 
3. History of infection in the target hand* 
4. History of prior surgery in the non-target hand, including CTR, within 3 months of 
enrollment or with persistent symptoms that interfere with normal daily activities or work 
at the time of consent 
5. Planned surgical or interventional procedure on the contralateral hand within 3 months of 
the target hand procedure date* 
6. Corticosteroid injection in the target hand within 6 weeks of study procedure date* 

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7. Presence of additional process in the target hand requiring additional intervention beyond 
carpal tunnel release (e.g. neurolysis, mass removal, tenosynovectomy)* 
8. Clinically significant degenerative arthritis of the upper limb (shoulder to hand) on the 
target side* 
9. Clinically significant inflammatory disease (including tenosynovitis) of the upper limb 
(shoulder to hand) on the target side 
10. Clinically significant trauma or deformity of the upper limb (shoulder to hand) on the 
target side* 
11. Clinically significant vascular disease (including Raynaud’s phenomenon) of the upper 
limb (shoulder to hand) on the target side* 
12. Clinically significant neurological disorder (including complex regional pain syndrome) 
of the upper limb (shoulder to hand) on the target side* 
13. Systemic inflammatory disease (e.g., rheumatoid arthritis, lupus) 
14. Amyloidosis  
15. Chronic renal insufficiency requiring dialysis  
16. Diabetes not controlled by a stable dose of medication  
17. Uncontrolled thyroid disease 
18. Pregnant or planning pregnancy in the next 24 months 
19. Workers’ compensation subjects 
20. Inability to provide a legally acceptable Informed Consent Form and/or comply with all 
follow-up requirements 
21. Subject has other medical, social, or psychological conditions that, in the opinion of the 
investigator, preclude them from receiving the pre-treatment, required treatment, and 
post-treatment procedures and evaluations 
 
Note: An asterisk (*) denotes that this criterion must be applied to the target hand for unilateral 
CTR-US procedures, or to both hands for simultaneous bilateral CTR-US procedures. 
 
Clinically significant is defined as likely to interfere with the performance of the procedure in a 
safe and/or effective manner. 
6.2.3 Screen Failures 
Participants who are consented to participate in the clinical trial, but who do not meet one or 
more criteria required for participation in the trial during the screening procedures, are 
considered screen failures.  Screen failures will be immediately discontinued from the trial and 
will not receive CTR-US within the trial.  Participants who are discontinued from the study due 
to screen failure may not be reconsidered for study enrollment at a later date.  Study sites will 
document screen failures by recording the date of screening, an anonymized patient identifier, 
and the primary inclusion and/or exclusion criterion failure that resulted in the decision to 
discontinue the patient from the study.   
6.2.4 Timing of Patient Screening 
All baseline testing and evaluations should be performed as close to the time of the procedure as 
possible.  If the subject’s procedure date is more than 30 days from the baseline electronic 
patient reported outcomes completion, validated questionnaires must be repeated to ensure 
accuracy of baseline condition at the time of procedure.   

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7. SUBJECT ENROLLMENT  
Subjects meeting all study inclusion/exclusion criteria after their screening evaluation will 
receive CTR-US.  Only subjects who receive CTR-US will be considered enrolled in the study.  
If a subject has a CTR with a method other than CTR-US they will not be considered enrolled in 
the study.  Eligible patients who do not receive treatment will be discontinued from the trial. 
 
 
7.1 PROCEDURE 
The key procedural steps involved in CTR-US are listed below.   
1. Using real-time US visualization, identify relevant anatomical structures within the carpal 
tunnel. 
2. Dissect synovial tissue from the undersurface of the TCL.  
3. Insert the device through a small wrist incision and advance into the carpal tunnel. 
4. Position the tip of the device distal to the distal TCL so that the TCL Blade will engage 
the distal TCL. 
5. Confirm the position of the device under ultrasound, including the safety of surrounding 
structures. 
6. Activate the Stealth MicroGuard balloons to create space within the carpal tunnel. 
7. Deploy the TCL Blade by moving the slide button proximally to transect the TCL from 
distal to proximal until the TCL Blade passes into its proximal recessed position. 
8. With the device or an elevator, probe the TCL to ensure a complete release. 
 
Complete procedural details are provided in the Instructions for Use 
(https://sonexhealth.com/physicians/ultraguidectr/instructions-for-use). 
 
Patients may undergo unilateral or simultaneous bilateral CTR-US procedures in this trial.  The 
decision of which procedure to undergo will be made based on the clinical diagnosis and by 
shared decision-making between the patient and physician.   
 
7.2 PROCEDURE LOCATION 
All CTR-US procedures will be performed in-office.  Per the Place of Service Codes set forth by 
the Centers for Medicare & Medicaid Services (CMS), in-office is defined as a location, other 
than a hospital, skilled nursing facility (SNF), military treatment facility, community health 
center, State or local public health clinic, or intermediate care facility (ICF), where the health 
professional routinely provides health examinations, diagnosis, and treatment of illness or injury 
on an ambulatory basis 40. 
 
7.2.1 Post-treatment Assessments 
Postoperative patient care instructions will be standardized among all participating sites to 
minimize bias. Investigators will instruct subjects to “participate in activities and return to work, 
as tolerated, based on pain, function, and wound healing status”. 
 

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7.2.2 Follow-up Assessments 
A list of the study assessments performed by the investigational site at each study interval is 
provided in the table below.  
 
 
1Required for all treated hands.  
2Measured on both hands 
 
A list of the patient reported outcomes provided by the patient at each study interval is provided 
in the table below. 
 
Assessment 
Baseline 
Screening 
Procedure 
 
Post-Op 
Daily 
1-14 
1 
month 
3 
months 
6 
months 
12 
months 
24 
months 
Demographics 
√ 
 
 
 
 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
BCTQ-SSS 1 
√ 
 
 
√ 2 
√ 
√ 
√ 
√ 
√ 
BCTQ-FSS  
√ 
 
 
√2 
√ 
√ 
√ 
√ 
√ 
MHQ 
√ 
 
 
√2 
√ 
√ 
√ 
√ 
√ 
EQ-5D-5L 
√ 
 
 
√2 
√ 
√ 
√ 
√ 
√ 
Numeric Pain 
Scale 1 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Procedure 
 
√ 1 
 
 
 
 
 
 
 
Return To 
Activities 
 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
Return To Work3  
 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
Pain Medication 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
1Measured on all treated hands. 
2Collected only at 14-day evaluation 
3Employed subjects only 
 
Assessment 
Baseline 
Screening 
Procedure 
Post-
Op 
Day 
7 
Day 
14 
1 
month 
3 
months 
6 
months 
12 
months 
24 
months 
Demographics 
√ 
 
 
 
 
 
 
 
 
 
Ultrasound 
median nerve 
cross-sectional 
measurement 1 
√ 
 
 
 
 
 
 
 
 
 
CTS-62  
√ 
 
 
 
 
 
 
 
 
 
Procedure 
 
√ 
 
 
 
 
 
 
 
 
Adverse events 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 

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7.2.3 Unscheduled Follow-up Visits 
If subjects are seen for unscheduled visits because of an AE or additional hand surgery, 
appropriate Case Report Form(s)will be completed, if applicable. 
 
7.2.4 Loss to Follow-up 
If a subject fails to comply with follow-up evaluations, the investigational site must make at least 
two repeated attempts to contact the subject.  Each attempt to contact the subject and the method 
used (e.g., telephone contact, registered letter) must be documented in the subject’s records.   
 
7.3 SUBJECT WITHDRAWAL FROM STUDY 
7.3.1 Voluntary Withdrawal 
A subject may voluntarily withdraw from the study at any time.  If a subject officially withdraws 
from the study, the investigator must ensure that the reason for the withdrawal is documented.  If 
the subject had an AE, the subject should be followed until the resolution of the AE, if possible.  
Data from these subjects will be included in the analysis up to the point of each subject’s 
withdrawal. 
7.3.2 Involuntary Withdrawal 
A subject also may be withdrawn by the investigator if the investigator determines that continued 
subject participation in the study will have a negative effect on the safety of the subject.  Data 
obtained up to the date of subject withdrawal will be included in the study.   
7.3.2.1 Prior to 3 months eVisit following ROBUST Surgery  
• 
Subjects who have any subsequent surgery on either hand during the first 3 months 
following their procedure will be withdrawn from the study. 
7.3.2.2 After 3 months eVisit : 
• 
Subjects Treated with Unilateral CTR-US in ROBUST  
o Surgery in the Contralateral Hand - Subjects who have subsequent surgery on the 
contralateral hand (i.e., non-study hand), including CTR, will not be involuntarily 
withdrawn from the study.  Note that a subsequent CTR-US in the contralateral 
hand is still not eligible for enrollment in ROBUST. 
o Surgery in the Study Target Hand –  
• 
Subjects who have subsequent surgery on the ROBUST hand that includes 
the wrist or carpal tunnel region, metacarpals, or thumb (with the 
exception of trigger thumb release) will be withdrawn from the study.   
• 
Subjects who have subsequent finger surgery (including trigger finger 
release) or trigger thumb release that does not affect the wrist or carpal 
tunnel region will not be withdrawn from the study 

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• 
Subjects Treated with Simultaneous Bilateral CTR-US in ROBUST - Subjects who have 
subsequent surgery on either hand that includes the wrist or carpal tunnel region, 
metacarpals, or thumb (with the exception of trigger thumb release) will be withdrawn 
from the study.    
7.3.3 End of Study 
Subjects may exit the study at the end of the study (i.e., the study is discontinued by the Sponsor) 
or when the subject has completed the 24-month follow-up visit, whichever comes first, unless 
the subject opted to find an alternative treatment.   
 
An End of Study CRF will be completed at the time the study is completed, discontinued, or lost 
to follow-up for each subject. 
 
 
8. OUTCOMES 
8.1 PRIMARY ENDPOINT 
The primary endpoint of the study is BCTQ-SSS change at 3 months.  The BCTQ is a CTS 
specific questionnaire that has been shown to be highly reproducible, internally consistent, valid, 
and responsive to clinical change in CTS and subject status post-CTR. The BCTQ includes a 
symptom severity score (BCTQ-SSS) and a functional status score (BCTQ-FSS).  The BCTQ-
SSS consists of 11 symptom severity questions.  Scoring for the BCTQ- SSS ranges from 1 to 5, 
with higher scores indicating more severe symptoms, and is calculated as the mean of each 
response.  The change in BCTQ-SSS score at the 3-month follow-up relative to baseline will 
represent the primary endpoint of the study. 
 
8.2 SECONDARY ENDPOINTS 
8.2.1 Time to Return to Normal Daily Activities  
Time to return to normal daily activities will be ascertained through the ViedocMe ePRO module 
which asks whether the subject has returned to normal daily activities outside of work.  
Reminders will be sent to the subjects either by email or text messaging to minimize the risk of 
missing data.  Time to return to normal daily activities postoperatively will represent a secondary 
endpoint of the study.  The time to return to normal daily activities will be defined as the number 
of days between treatment and the time the subject reports returning to normal daily activities, 
irrespective of work status.   
8.2.2 Time to Return to Work Among Employed Subjects 
Among study subjects who report full-time or part-time employment, time to return to work will 
be ascertained through the ViedocMe ePRO module by asking whether the subject has returned 
to work in any capacity (full or limited).  Reminders will be sent to the subjects either by email 
or text messaging to minimize the risk of missing data.  Time to return to work postoperatively 
will represent a secondary endpoint of the study.  The time to return to work will be defined as 
the number of days between treatment and the time the subject reports returning to work in any 
capacity. 

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8.2.3 BCTQ-FSS Change at 3 Months  
The BCTQ-FSS additionally consists of 8 functional status questions (BCTQ-FSS).  Scoring for 
the BCTQ-FSS ranges from 1 to 5, with higher scores indicating more functional limitation, and 
is calculated as the mean of each response.  The change in BCTQ-FSS score at the 3-month 
follow-up relative to baseline will represent a secondary endpoint of the study. 
 
8.2.4 MHQ Change at 3 Months  
The Michigan Hand Questionnaire (MHQ) is a validated, hand-specific questionnaire consisting 
of 37 questions in 6 domains:  
• overall hand function 
• activities of daily living 
• work performance 
• pain 
• aesthetics 
• satisfaction 
 
The raw score for each of the six domains is converted to a score ranging from 0-100, with 100 
being the best score for each domain with the exception of the pain domain for which 100 = 
maximal pain.  An overall MHQ score can be obtained by reversing the pain domain score (pain 
= 100 minus pain score), summing the scores for all six domains, then dividing by six.  MHQ 
scores may be reported as overall scores or scores by each domain. For example, previous 
studies have documented a minimally clinically important difference of 13 for the overall 
function, 23 for the pain, and 8 for work domains.  The MHQ has also been validated to use in 
patients with bilateral hand symptoms, such as bilateral CTS.  The change in the total MHQ 
score as well as each of its 6 domains score at the 3-month follow-up relative to baseline will 
represent secondary endpoints of the study. 
8.2.5 Numeric Pain Scale Change at 3 Months 
Subjects will be asked to rate their wrist pain severity on a scale of 0 to 10, where 0 represents 
“no pain” and 10 represents “worst possible pain”.  The change in Numeric Pain Scale score at 
the 3-month follow-up relative to baseline will represent a secondary endpoint of the study. 
8.2.6 EQ-5D-5L Change at 3 Months 
The EuroQol 5-Dimension 5-Level (EQ-5D-5L) is a generic preference-based questionnaire 
developed by the EuroQol Group to measure health-related quality of life.  The EQ-5D-5L 
measures quality of life across 5 domains: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression.  Each dimension is scored on a 5-level severity ranking consisting of: no 
problems, slight problems, moderate problems, severe problems, unable to/extreme problems.  
The change in EQ-5D-5L score at the 3-month follow-up relative to baseline will represent a 
secondary endpoint of the study. 
8.2.7 Device- or Procedure-related Adverse Events at 3 Months 
Adverse events (AEs) occurring within 90 days of treatment and that are adjudicated as 
definitely related or probably related to the device, or definitely related or probably related to the 

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procedure will be included in this endpoint.  The incidence of device- or procedure-related AEs 
within 90 days of treatment will represent a secondary endpoint of the study. 
8.2.8 Global Satisfaction  
Subjects will be asked to rate their satisfaction with the carpal tunnel release procedure and how 
likely they are to recommend their carpal tunnel release procedure to a friend or colleague.   
8.2.9 Additional Outcomes 
Additional outcomes of the study will include: 
• BCTQ-SSS change at 2 weeks, 1 month, 6 months, 12 months, and 24 months 
• BCTQ-FSS change at 2 weeks, 1 month, 6 months, 12 months, and 24 months 
• MHQ change at 2 weeks, 1 month, 6 months, 12 months, and 24 months 
• Numeric Pain Scale change at 2 weeks, 1 month, 6 months, 12 months, and 24 months 
• EQ-5D-5L change at 2 weeks, 1 month, 6 months, 12 months, and 24 months 
• Device- or procedure-related AEs at 2 weeks, 1 month, 6 months, 12 months, and 24 
months 
• Serious device- or procedure-related AEs at 2 weeks, 1 month, 3 months, 6 months, 12 
months, and 24 months 
 
9. ADVERSE EVENTS 
An Adverse Event (AE) is defined as any adverse change (i.e., de novo or preexisting condition) 
from the subject’s baseline medical condition occurring after the initial procedural incision has 
been initiated.  Any AE which resolved and then recurred will be reported as a separate AE.  A 
pre-specified listing of AEs will be documented on the Adverse Event eCRF. 
 
9.1 SERIOUS ADVERSE EVENT 
A serious adverse event (SAE) is defined as one that suggests a significant hazard or side effect, 
regardless of the relationship to the device or procedure.  This includes, but may not be limited 
to, any event that: 
• Results in death  
• Is life threatening, or places the participant at immediate risk of death from the event as it 
occurred 
• Requires or prolongs hospitalization  
• Causes persistent or significant disability or incapacity  
• Results in congenital anomalies or birth defects  
• Is another condition which investigators judge to represent significant hazards 
 
Important medical events may be considered serious by the investigator although they may not 
be immediately life threatening or result in death or prolong hospitalization.  Such important 
medical events are those that may jeopardize the subject, require intervention to prevent one of 
the outcomes listed above, or result in urgent investigation.  
  

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SAEs should be reported to the study Sponsor as soon as possible (24 hours recommended), but 
no more than 10 working days after the date the site becomes aware of the event. 
 
Sites are also required to adhere to the reviewing IRB requirements for reporting of SAEs. 
 
9.2 UNANTICIPATED ADVERSE DEVICE EFFECT 
An unanticipated adverse device effect (UADE) is any serious adverse effect on the health or 
safety of a subject, any life-threatening problem or death caused by, or associated with a device, 
if such effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan (e.g., ICF, Study Protocol, Instructions for Use (IFU), 
publications, etc.), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects. 
 
If an unanticipated adverse effect associated with the device occurs, the investigator shall notify 
the Sponsor and the IRB as soon as possible.   
 
The Sponsor will investigate the event and notify the FDA and all other participating IRBs and 
investigators.  Should the Sponsor determine that an unanticipated adverse effect presents an 
unreasonable risk to all participating subjects, the Sponsor will suspend the clinical investigation 
and notify all participating investigators, IRBs, country regulatory bodies and FDA.  
 
9.3 RELATIONSHIP OF ADVERSE EVENTS TO THE DEVICE OR 
PROCEDURE 
A description of how an AE relates to the study device or procedure will be reported on the 
Adverse Event CRF. 
 
A device-related AE is directly attributable to the device or to improper use of the device.   
A procedure-related AE is directly attributable to the procedure, irrespective of the device, 
including complications from anesthesia or other procedures incidental to the main procedure. 
 
The relationship of the AE to the device or procedure will be determined by the Investigator 
using the following definitions: 
 
- 
Definite:  The AE follows a reasonable temporal sequence from the time of the index 
procedure, which includes AEs that occur during the index procedure or during the 
follow-up period. 
- 
Probable:  The AE follows a reasonable temporal sequence from the time of the index 
procedure, and the possibility can be excluded that factors other than the index procedure, 
such as underlying disease, concomitant drugs, or concurrent treatment caused the AE. 
- 
Possible:  The AE follows a reasonable temporal sequence from the time of the index 
procedure and the possibility of index procedure involvement cannot be excluded.  
However, other factors such as underlying disease, concomitant medications, or 
concurrent treatment are presumable. 

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- 
Unlikely:  The AE has an improbable temporal sequence from the time of the index 
procedure, or such AE can be reasonably explained by other factors, including underlying 
disease, concomitant medication, or concurrent treatment. 
- 
Not related: The AE has no temporal sequence from the time of the index procedure, or it 
can be explained by other factors, including underlying disease, concomitant medication, 
or concurrent treatment. 
 
9.4 DEVICE FAILURES, MALFUNCTIONS AND NEAR INCIDENTS 
Device failures or malfunctions will be reported to Sonex Health by the clinical sites.  If the 
failure or malfunction results in an AE, the event shall be reported to the Sponsor within two (2) 
working days after the Investigator becomes aware of the event and reported to the IRB (if 
required) within the IRB required timeframe.  The device involved in the incident should be 
returned to the Sponsor for evaluation.   
 
9.5 REPORTING OF ADVERSE EVENTS 
AEs will be recorded on the Adverse Event CRF and described by (a) duration (onset and 
resolution dates); (b) relationship to the study device or procedure; (c) action taken to resolve the 
event; (d) outcome of the event; and (e) whether or not such event is considered to have been 
serious.  Additional information, such as procedural notes, treatment notes, or a signed clinical 
summary may be required as supporting documentation for the reported AE. 
 
During the study, all deaths must be reported to the Sponsor within 48 hours and should also be 
reported on the End of Study CRF.  A copy of the subject’s death records, medical records for 
the events that led to the subject’s death, and a death certificate (if available) should be provided. 
 
Determination of whether a subject experienced an AE can be made in three different ways.  
First, an AE can be documented by the site during the study procedure.  Second, a subject may 
report an AE directly via phone call to the investigative site.  Third, an AE can be identified by 
the site during the review of the subject-uploaded wound healing images. If the site identifies a 
potential AE based on image review or is notified of a potential AE by the subject, confirmation 
of the AE will occur by a phone call with the subject or, if necessary, by asking the subject to 
return for a follow-up clinical evaluation.   
 
9.6 INDEPENDENT MEDICAL REVIEWER 
Evaluation and adjudication of all AEs will be performed on an ongoing basis by an independent 
medical reviewer.  The independent medical reviewer will review AEs for AE classification, 
seriousness, and relationship to the device or procedure.  Discrepancies between the 
investigational site and the independent medical reviewer will be handled by discussion, with the 
determination by independent medical reviewer serving as the final classification. 
 
 
 
 

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9.7 DATA SAFETY MONITORING BOARD 
A Data Safety Monitoring Board (DSMB) will oversee enrollment and safety of the subjects for 
the study.  Members of DSMB will be independent of the sponsor and investigational sites.  The 
DSMB for the study will consist of three (3) clinicians with expertise in orthopedic or plastic 
surgery, and with experience and expertise in clinical trials.  The DSMB will convene at least 
once during the subject enrollment period and will review, at a minimum, subject enrollment 
status and incidence of AEs.  Based on a review of these data, the DSMB will advise the Sponsor 
to continue the trial with no modification, or to modify the trial as appropriate if enrollment or 
safety concerns are identified. 
 
 
9.8 RISK-BENEFIT ANALYSIS 
9.8.1 Risk Analysis 
Complications and risks that exist for other CTR treatments may also exist for carpal tunnel 
release using UltraGuideCTR and real-time ultrasound guidance.   UltraGuideCTR has 
undergone extensive risk analysis testing and is designed with safeguards built into the device to 
mitigate the serious risks.  The full list of anticipated adverse events is provided on the Adverse 
Event CRF.  
 
9.8.2 Potential Benefits 
The data obtained from this study will be used to document the safety and effectiveness of 
UltraGuideCTR when performed in an office-based setting.  The data derived from this study 
may benefit individuals with CTS in the context of a shared decision-making process when 
contemplating CTR. In addition, subjects potentially could directly benefit from participation in 
this study.  Treatment with UltraGuideCTR and real-time ultrasound guidance in an in-office 
setting may potentially allow for rapid return to work and normal daily activities, as well as 
avoidance of general anesthesia and the costs associated with treatment in a hospital or 
ambulatory surgery center. 
 
 

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10. DATA ANALYSIS 
This is a prospective, multicenter, single-arm trial designed to evaluate the safety and 
effectiveness of office-based CTR-US in treating subjects with symptomatic CTS.   
 
10.1 SAMPLE SIZE JUSTIFICATION 
This study will enroll a minimum of 140 subjects who will receive office-based CTR-US.  This 
sample size provides adequate statistical power for the evaluation of the primary endpoint given 
the assumptions below: 
 
- 
Primary endpoint: BCTQ-SSS change at 3 months 
- 
Statistical test: Linear mixed model 
- 
Two-tailed alpha: 0.05 
- 
Standard deviation change in BCTQ-SSS at 3 months: 0.75 points 
- 
Subject attrition: 15% 
 
The results of this power analysis show that a sample size of 100 evaluable subjects provides 
90% statistical power to detect a mean change of 0.2 points on the BCTQ-SSS at 3 months.  To 
account for reasonable subject attrition, a minimum of 140 subjects will be enrolled in the trial.   
 
10.2 ANALYSIS POPULATIONS  
The primary statistical analyses will be performed on subjects who meet all study eligibility 
criteria and receive treatment with CTR-US.  Subjects who withdraw from the study prior to 
treatment will not be included in the analysis. 
 
10.2.1 Duration Variables 
Study day 0 is the day the subject receives office-based CTR-US.  Postoperative study day will 
be calculated relative to day 0 as follows: 
 
Study Day = (Date of Event – Date of Treatment) 
 
 
 

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10.2.2 Analysis Windows 
Study data will be categorized into discrete, contiguous reporting windows to ensure that all 
available data are included in the analyses.  The analysis windows for this study are defined 
below: 
 
Study Visit 
Target Days 
Analysis Window 
Treatment 
0 
0 
2 weeks 
14 
7-22 
1 month 
30 
23-60 
3 months 
90 
61-135 
6 months 
180 
136-270 
12 months 
365 
271-547 
24 months 
730 
548-912 
 
10.2.3 Data Analysis Methods 
Baseline data will be analyzed using descriptive statistics.  Continuous data will be summarized 
using mean and standard deviation for normally distributed data, median and interquartile range 
for non-normally distributed data, and counts and percentages for categorical data.  For 
categorical variables, percentages will be calculated based on non-missing data. 
 
The primary endpoint will be reported as the mean change in BCTQ-SSS at 3 months relative to 
baseline.  Data will be reported as the mean change and 95% confidence interval.  A linear 
mixed model will be the statistical test used to assess the primary endpoint, which accounts for 
the correlation inherent with bilateral procedures 41.  The study will be deemed successful if the 
mean BCTQ-SSS score at 3 months is statistically significantly lower than at baseline, as 
determined by a p-value less than 0.05 using the linear mixed model.   
 
Time to return to normal daily activities and time to return to work among employed individuals 
will be reported as the median and interquartile range in each treatment group.   
 
Longitudinally measured continuous outcomes (i.e., BCTQ-SSS, BCTQ-FSS, MHQ, Numeric 
Pain Scale, EQ-5D-5L) will be analyzed using a linear mixed model.   
 
Adverse events will be reported using counts, percentages and exact 95% confidence intervals 
using Clopper-Pearson’s method.  Calculation of AE incidence will be performed on a per-
subject basis. 
 
Statistical analyses will be performed using a two-sided hypothesis test at a 5% level of 
significance.  No adjustments for multiplicity are planned.  Missing data imputation will not be 
performed.  Subgroup analyses will be performed for subjects undergoing a unilateral or bilateral 
simultaneous procedure. 
 
 
 

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11. STUDY RESPONSIBILITIES AND MANAGEMENT 
This study will be performed in accordance with all requirements set forth in the U.S. 
regulations, 21 Code of Federal Regulations (CFR) Parts 812, 50, 54, and 56, the Declaration of 
Helsinki, and any other applicable local laws, regulations, or guidelines.  
 
11.1 INVESTIGATOR RESPONSIBILITIES  
Each investigator will be responsible for ensuring the investigation is conducted according to all 
signed agreements, the study protocol, IRB requirements, and applicable laws and regulations.  
Investigators may not begin enrollment until the Sponsor, or its designee, receives and approves 
(when necessary) the following documents: 
 
· 
Signed Investigator Agreement 
· 
Financial disclosure forms for all participating investigators 
· 
IRB roster (or IRB registration number from the Office of Human Research Protection) 
· 
IRB protocol and ICF approvals 
· 
Investigators’ current curricula vitae and medical license 
· 
Signed Site Delegation Log 
 
It is acceptable for Investigators to delegate one or more of the above functions to a Co- or Sub-
Investigator, or a trained Research Coordinator; however, the Investigator remains responsible 
for the proper conduct of the clinical investigation, including obtaining and documenting proper 
study informed consent, collecting all required data, submitting accurate and complete CRFs, etc. 
 
At each study site, appropriate procedures must be followed to maintain subject confidentiality 
according to appropriate local regulations (e.g., Health Insurance Portability and Accountability 
Act (HIPAA) in the U.S.).  Each site may have its own internal procedures or requirements for 
use and release of subject medical information in research studies.  Each Investigator is 
responsible for obtaining appropriate approvals, consents, or releases of medical information as 
dictated by their relevant subject privacy laws. 
 
The study is not transferable to other sites attended by the Investigator unless prior approval is 
obtained from the appropriate IRB and the Sponsor. 
 
11.2 SUBJECT ENROLLMENT PROCESS 
All study candidates must appropriately consent to participate in the study, as administrated by 
qualified study site personnel using an IRB and Sponsor-approved informed consent form (ICF) 
prior to beginning any aspect of the study procedure or tests that are not standard of care for the 
site.  Investigational sites will be required to document the consent process within each enrolled 
subject’s medical record.   
 
 
 
 

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11.3 INSTITUTIONAL REVIEW BOARD 
Investigators must submit the study protocol to the Institutional Review Board (IRB) and obtain 
the IRB’s written approval before being allowed to conduct and participate in the study.  Each 
Investigator is responsible for fulfilling any conditions of approval imposed by the IRB, such as 
regular reporting, study timing, etc.  Investigators will provide the Sponsor with copies of such 
approvals and reports. 
 
11.4 INFORMED CONSENT FORM 
The Sponsor will provide a template informed consent form (ICF) to each study site for IRB 
submission.  The template may be modified to suit the requirements of the individual study site, 
but the Sponsor must pre-approve all changes to the ICF prior to initial submission to the IRB.   
 
Each Investigator or assigned designee must administer this approved ICF to each prospective 
study subject and obtain the subject's signature or a legally approved designee’s signature along 
with the date of consent prior to enrollment in the study.  The ICF must be obtained in 
accordance with the applicable guidelines on 21 CFR 50, 52 and 56, the Declaration of Helsinki, 
ISO 14155 or local regulations and laws, whichever represents the greater protection of the 
individual.  Subjects must be informed about their right to withdraw from the study at any time 
and for any reason without sanction, penalty, or loss of benefits to which the subject is otherwise 
entitled and be informed that withdrawal from the study will not jeopardize their future medical 
care.  A copy of their signed ICF must be given to each subject enrolled in the study.  The 
institutional standard subject consent form does not replace the study ICF. 
 
11.5 CASE REPORT FORM 
The Sponsor will provide standardized case report forms (CRFs) for each individual subject.  
The CRFs will be electronic (EDC, 21 CRF Part 11 compliant), and will be used to record study 
data, and are an integral part of the study and subsequent reports.   
 
The electronic CRFs for individual subjects will be provided by the Sponsor via a web portal.  
After the data has been submitted, reviewed, and centrally monitored, corrections will be 
initiated via automatic data queries and/or manual data queries answered by appropriate study 
site personnel.  The Investigator will provide his/her electronic signature on the appropriate 
eCRFs in compliance with local regulations. 
 
11.6 CENTRAL DATABASE 
All subject data will be collected and compiled in a limited access secure electronic data capture 
system (EDC).  Appropriate quality control measures will be established to ensure accurate and 
complete transfer of information from the study documentation to the central database. 
 
 

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11.7 RECORDS 
Each Investigator must maintain the following accurate, complete, and current records relating to 
the conduct of the study investigation.  The final responsibility for maintaining such records 
remains with the Investigator.  These records include, but not limited to: 
 
- 
All signed agreements 
- 
IRB approval letter(s) 
- 
Approved ICF template 
- 
Records of AEs, including supporting documents 
- 
Records of protocol deviations, including supporting documents 
- 
Records of each subject’s case history, including study required CRFs, signed ICF, all 
relevant observations of AEs, the condition of each subject upon entering and during the 
investigation, relevant medical history, the results of all diagnostic testing, etc. 
- 
Signature authorization and delegation log 
- 
Any other records that applicable regulation requires to be maintained 
 
11.8 REPORTS  
The table below lists those reports that are the investigator's responsibility to deliver to the 
Sponsor.  Each study investigator must follow the IRB reporting requirements for their 
respective site.  If applicable regulations or IRB requirements mandate stricter reporting 
requirements than those listed, the stricter requirements must be followed. 
 
 
 
 

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Type of Report 
Prepared by PI for 
Notification Time Frame 
UADE 
 
Sponsor, IRB 
 
Within 10 working days of knowledge 
Death 
Sponsor, IRB 
Written reports (e.g., via e-mail) 
within 48 hours 
SAE 
Sponsor 
 
IRB, if required 
Within 10 working days of knowledge 
 
Per IRB requirement 
Device malfunction 
with clinical sequelae 
Sponsor 
 
IRB, if required 
Within 48 hours via written 
communication.  Return the device to 
sponsor within 48 hours. 
Serious protocol 
deviations (e.g., ICF 
not obtained, to 
protect the life or 
physical well-being of 
a subject in an 
emergency) 
Sponsor 
 
IRB, if required 
Within 5 working days of knowledge 
 
Per IRB requirement 
Withdrawal of IRB 
approval 
Sponsor 
 
Within 5 working days of knowledge 
Annual progress 
report 
Sponsor, IRB 
Annually 
Final report 
Sponsor, IRB 
Within 6 months of study completion 
or termination 
Note: Institutional IRBs may require more stringent reporting requirements that those listed in 
this table. 
 
11.9 SPONSOR RESPONSIBILITIES  
Sonex Health is the Sponsor of this study.  The Sponsor’s responsibilities in the study include: 
- 
Selecting the Principal Investigator(s), all clinical investigators and study sites, and other 
consultants (e.g., monitors) who participate in the study. 
- 
Provide study protocol, device, and GCP training to participating study sites, in quantities 
sufficient to support study activities, per agreements executed with the study sites. 
- 
Provide financial support to each study site. 
- 
Follow/promote all regulatory standards per appropriate regulations for study sites, and 
other participants, and ensure compliance through central monitoring. 
- 
Retain ownership of all clinical data generated in this study and control the use of the 
data for appropriate purposes only.   
- 
Review and approve publication of study results in the literature. 
 
 

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11.9.1 Confidentiality 
All information and data sent to the Sponsor concerning subjects or their participation in this 
study will be considered confidential according to HIPAA regulations.  Data used in the analysis 
and reporting of this evaluation will be used in a manner without identifiable reference to the 
subject.     
11.9.2 Amending the Investigational Study Protocol 
Only the study Sponsor can amend the Investigational Protocol.  All changes to the 
Investigational Protocol must be submitted to the IRB for review and approval.  Any change that 
would require alteration to the ICF must receive approval from the applicable IRB prior to 
implementation.  Following approval, any Investigational Protocol amendment must be 
distributed to all protocol recipients at the site. 
11.9.3 Protocol Deviations 
A protocol deviation is an unplanned excursion from the protocol that is not implemented or 
intended as a systematic change.  An Investigator who fails to perform tests or examinations as 
required by the protocol or failures on the part of study subjects to complete scheduled visits as 
required by the protocol, would be considered protocol deviations.  These types of deviations are 
reported to the Sponsor and in accordance with the IRB policy. 
A Protocol Deviation CRF must be completed by the site for each study protocol deviation (e.g., 
failure to obtain informed consent, enrolling a subject who does not meet inclusion / exclusion 
criteria, not performing required testing, missed follow-up window, etc.).  An Investigator must 
notify the Sponsor and the reviewing IRB of any deviation from the study protocol that was done 
to protect the life or physical well-being of a subject.  Such notice should be given as soon as 
possible, but no later than five (5) working days after the emergency occurred. 
11.9.4 Site Noncompliance and Nonperformance 
Repeat protocol deviations will be closely monitored.  If excessive deviations or a failure to 
reduce deviations are noted, the Sponsor reserves the right to suspend study enrollment at that 
site until a sufficient system is in place at the site to reduce further deviations.  
 
After a site completes all required approvals and training, a site initiation visit will be conducted 
as a final check of the site readiness.  If a site is not able to enroll its first subject 3 months after 
“Ready to Enroll” status, the Sponsor may elect to terminate the investigational site and allocate 
the slot to another candidate site.   
11.9.5 Device Accountability 
The UltraGuideCTR is an FDA 510k cleared device, will be purchased by the investigational 
sites for use in the study, and does not require device accountability tracking within the study. 
 
 

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12. STUDY MONITORING 
The study sponsor is responsible to ensure that proper monitoring of this investigation is 
conducted.  Appropriately trained personnel, appointed by the study sponsor, will perform 
monitoring.  Monitors will ensure that the investigation is conducted in accordance with:  
- 
The signed Investigator’s Agreement 
- 
The Investigational Plan  
- 
Appropriate laws and regulations  
- 
Any conditions of approval imposed by the reviewing IRB and/or other regulatory 
agencies 
 
The clinical study will be monitored using electronic central monitoring processes.  On-site 
monitoring may occur as needed.  The Sponsor may choose to perform random inspections 
throughout the study as an element of quality assurance.  Investigators shall allow auditing of 
their clinical investigation procedures, if necessary. 
 
A study specific Monitoring Plan will be created and implemented to standardize monitoring 
activities across centers and to ensure human subject protection and verify data integrity.  The 
monitors shall receive study specific and SOP training prior to conducting any monitoring visits.  
Study monitors are selected based on their training, qualifications, and experience to monitor the 
progress of an investigation.  Study monitors may be Sponsor’s employees or representatives.  
All study monitors will be required to follow the Sponsor’s monitoring plan and monitoring 
standard operating procedures (SOPs).  
Study closure is defined as a specific date that is determined by study completion and/or 
regulatory requirements that have been satisfied per the study protocol and/or by decision of the 
Sponsor.  Study closure visits will be conducted via telephone call for all enrolling clinical sites 
to review record retention requirements with site personnel.   
 
 
 

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