Sustained Acoustic Medicine (SAM) Combined With a Diclofenac Ultrasound Coupling Patch for Knee Osteoarthritis
Phase: PHASE1
Conditions: Osteo Arthritis Knee, Arthritis
Sponsor: ZetrOZ, Inc.

Version 1 - July 2019 
 
1
 
 
 
 
 
 
 
UPLOAD  5/11/2021  
 
 
PROTOCOL & SAP 
 
 
Medical Pain Consultants 

Version 1 - July 2019 
 
2
Study Protocol 
 
HF-01 
 
NCT04391842 
 
 
Sustained Acoustic Medicine (SAM) Combined 
with a Diclofenac Ultrasound Coupling Patch for 
Knee Osteoarthritis 
 
 
July 1st 2019

Version 1 - July 2019 
 
3
 
1.0 Background and Scientific Rationale  
1.1 Background Information 
Approximately 50 million people in the United States suffer from some form 
of arthritis pain, and Osteoarthritis is the most common form of the disease. 
The prevalence of osteoarthritis is greater among women than men, 
increases with age, and affects all race/ethnicity groups.  
 
Osteoarthritis affects articular cartilage, the smooth fibrous connective 
tissue essential for smooth movement and cushioning of the joint. As the 
disease progresses, the cartilage becomes thinner and may completely 
wear away. Inflammation of the synovial membrane, the lining that 
surrounds the knee joint and contains the synovial fluid, is often a result of 
these changes. Osteoarthritis can form in any joint but is more common in 
weight bearing joints such as the knee and hip, and results in joint space 
narrowing, severe pain and loss of mobility. 
 
Ultrasound therapy for the treatment of Osteoarthritis may be used as 
conservative care (see reference: cochrane review).  
 
 
1.2 Investigational Product Description 
Low intensity therapeutic ultrasound (LITUS) will be delivered in this study 
using ZetrOZ’s Ultrasonic Diathermy Device called sam®. The device 
package consists of a Power Controller, 2 Applicators (ultrasound 
generators), Ultrasound Coupling Bandages 1% Diclofenac, Ultrasound 
Gel, Y-Adapter, Charger and User Manual.  
 
1.3 Hypotheses 
It is hypothesized that users of the LITUS device (sam®) device will be able 
to successfully apply and remove the device daily to the knee. It is 
hypothesized that treatment with the LITUS device (sam®) will yield 
improvements in pain and stiffness in subjects with knee Osteoarthritis.   
 
1.4 Potential Risks to Subjects 
The risks of using ultrasound devices to administer physical therapy are 
well established and include: burn, itching and/or pain. These risks 
decrease when using lower intensity ultrasound, as in this study. The 
Ultrasound Diathermy Device uses existing technology to deliver ultrasound 
therapy in a portable and convenient fashion. The subjects will be given the 
chance to ask any questions regarding the trial procedures, requirements, 
and purposes. Once the subjects are fully informed of the possible risks 
and benefits of participation in the study and all of their questions have 
been satisfactorily answered, they will be required to sign the informed 
consent form in order to participate in the study. All subjects must give 
consent themselves and no legally authorized representatives will be 
accepted on their behalf. 
 
 

Version 1 - July 2019 
 
4
2.0 Study Objectives and Design  
2.1 Objectives 
Evaluate the usability of the device for proper design.   
 
Evaluate the ability of LITUS to reduce  pain, stiffness as measured by NRS 
scale and the Western Ontario and McMaster Universities Arthritis Index 
(WOMAC) 
 
2.2 Study Design 
2.2.1 General Study Design 
This study is designed as a single cohort case series. After 
screening and enrollment, subjects will self-administer LITUS daily 
for 7 consecutive days. 
 
2.2.2 Study Design Schematic 
 
 
3.0 Study Population 
3.1 General Characteristics of the Proposed Subject Population(s) 
This study will enroll subjects with physician confirmed knee Osteoarthritis 
pain. The long duration wearable therapeutic ultrasound treatment has 
multiple benefits likely to aid the patients enrolled in this study with knee 
Osteoarthritis pain. Acoustic waves mechanically stimulate tissue, triggering 
biological effects including the down regulation of inflammatory cytokines, 
increased transport kinetics, protein synthesis, and extracellular matrix 
deposition. It is therefore hypothesized that the wearable device has the 
potential to provide sustained OA symptom management.  
 
3.2 Anticipated Number of Research Subjects 
 
Enrollment will be monitored at the assumed rates of Screen Failures and 
Discontinuation may be found to differ in this study from historical controls. 
The objective is to screen and enroll towards a target of 30 completed 
subjects. 

Version 1 - July 2019 
 
5
 
Subjects to be Screened 
50 
Assumed Screen Fail Rate 
30% 
Subjects to be Enrolled (sign ICF) 
35 
Assumed Discontinuation Rate 
10% 
Total Number Completers (complete 24-wk treatment phase) 
30 
 
3.3 Inclusion Criteria 
Subjects to be enrolled in the trial will: 
• 
Have physician-diagnosed mild to moderate knee OA (OARSI atlas grades 
1-2)  
• 
Fulfill the American College of Rheumatology clinical and radiological 
diagnostic criteria for knee OA 
• 
Are between 35-80 years of age 
• 
Report a frequent pain score between 3-7 (range: 0-10) during the week 
preceding enrollment 
• 
Report that knee pain negatively affects quality of life 
• 
Are willing not to use any cream, gel, or topical solution during the 
administration of treatment other than the approved ultrasound gel 
provided to the subject at the initiation of the study 
• 
Are deemed appropriate by their physician or by the study site physician to 
participate.  
• 
Be willing and able to self-administer treatment daily within their place of 
residence or during normal daily activity, excluding bathing, showering, or 
other water activities which may result in submersion of the study device. 
• 
Not use or initiate opioid and/or non-opioid analgesic medications. 
• 
Be willing to discontinue any other interventional treatment modalities on 
the knee during the study period (e.g., transcutaneous electrical nerve 
stimulation, electronic muscle stimulation, traditional ultrasound). 
 
3.4 Exclusion Criteria 
A potential subject will be excluded from participation in this study if he or she: 
• 
Cannot successfully demonstrate the ability to put on and take off the 
device. 
• 
Displays any condition which, in the judgment of the investigator, would 
make participation in the study unacceptable including, but not limited to, 
the subject’s ability to understand and follow instructions. 
• 
Participated in a clinical trial for an investigational drug and/or agent 
within 30 days prior to screening. 
• 
Is pregnant. 
• 
Is a prisoner. 
• 
Is non-ambulatory (unable to walk). 
• 
Has a pacemaker. 
• 
Has a malignancy in the treatment area. 
• 
Has an active infection, open sores, or wounds in the treatment area. 
• 
Has impaired sensation in the treatment area, such as caused by 
chemotherapy or anesthesia. 
• 
Has a known neuropathy (disease of the brain or spinal nerves). 

Version 1 - July 2019 
 
6
• 
Has a hereditary disposition (tendency) for excessive bleeding 
(hemorrhage). 
• 
Have knee replacement, other surgical intervention, or hyaluronidase 
injection in the affected knee in the past 6 months 
• 
Are currently taking steroids 
• 
Have any contraindication to radiograph 
• 
Have a secondary cause of arthritis (metabolic or inflammatory) 
 
4.0 Study Procedures 
4.1 Subject Recruitment  
It is planned at one site to enroll subjects into this trial. Therefore, based on 
the assumptions presented in Section 3.2, we will need to screen 
approximately 50 subjects to meet the target enrollment number of 30 
subjects, and support a target completion number of 30. The target 
enrollment period for this study is 2 months.  
 
4.1.1 Subject Compensation 
Subjects will be compensated up to $50 for participation in the study. 
Subjects will not be compensated for the initial screening/enrollment visit, 
but will $50 for completed Visit 2. 
 
4.2 Screening Procedures 
Subjects will come to the clinic to be screened for inclusion in the study. 
The investigator or a sub-investigator will review the Eligibility Screening 
Checklist with the subject. All subjects must have physician-diagnosed mild 
to moderate knee OA (OARSI atlas grades 1-2). 
 
4.3 Study Treatment 
4.3.1 Treatment Groups 
Subjects will participate in one treatment arm. All devices are manufactured 
by ZetrOZ Systems (Trumbull, CT) and are all identical. The 3 MHz device 
was FDA cleared in November 2013, and is marketed in the United States 
under the brand name sam®.  All study subjects will apply 2 applicators 
affixed to the coupling bandages to their knee on the medial and lateral 
sides as shown in the figure below. The applicators are connected via a Y-
adapter to a single power controller. The subjects will set the power 
controller to a 4-hour treatment duration for each daily treatment.  
 

Version 1 - July 2019 
 
7
 
 
 
 
 
 
 
This device delivers continuous 
ultrasound with a maximum acoustic 
power output of 1.3 W/cm2 ±20% 
when 2 applicators are used. The 
frequency is 3 MHz ± 20%. The 
maximum treatment duration 
permitted is 4 hours per day. 
 
Treatment protocol: subjects will self-administer the LITUS therapy for 4 
hours per day at least 5 days (and up to 7 days) for the 1-week study. 
 
4.3.2 Randomization   
Not Applicable.  
 
4.3.3 Breaking the Blind 
Not Applicable 
 
4.3.4 Treatment Adherence/ Study Compliance 
Treatment compliance will be assessed by review of daily diaries and 
count of remaining bandages at the end of the study. The Research 
Coordinator will remind the subjects of the treatment protocol and retrain 
them on use of the device if necessary. Study visits should be completed 
within 3 days of the specified time in the Schedule of Assessments 
(Section 4.6). 
 
 
4.4 Follow-Up Procedures 
4.4.1 Procedures to Assess Usability and Efficacy  
Usability and Efficacy will be assessed at the end of the study. 
Subjects will maintain a Daily Diary at home, which will be a 
printed booklet that they will complete manually daily throughout 
the study period.  
 
Daily Diary 
Subjects will complete a Daily Diary throughout the 1-week 
treatment period to collect usability and pain ratings before, during 
and after treatment. 
 
Numeric Rating Scale (NRS) 
Subject-reported rating of pain severity, 0 = no pain, 10 = worst 
pain imaginable  
 
Sample  
Applicator Placement 

Version 1 - July 2019 
 
8
Western Ontario and McMaster Universities Arthritis 
Index (WOMAC) 
Subject reported rating of pain, stiffness and function validated for 
knee Osteoarthritis. 
 
Exit Assessment 
At the conclusion of the trial, each subject will be asked to 
complete an exit assessment form which solicits the subject’s 
feedback on their use of the device, and satisfaction with therapy. 
 
4.4.2 Procedures to Assess Safety  
Adverse events will be recorded at each study visit. 
 
4.5 Use of Non-Study Drugs and Procedures 
Not Applicable. Not Allowed. 

Version 1 - July 2019 
 
9
4.6 Schedule of Assessments 
 
 
1 - Visit window: ±3 days 
2 - Research coordinator should review subject diaries to ensure completeness, and evidence that subject is using the device per 
protocol.  
5.0 Data Management and Analysis 
5.1 Outcome Measures and Data Analysis Plan 
5.2 Change in NRS pain score from baseline will be analyzed for pre and post-
treatment each treatment day throughout the study, and WOMAC (pain, 
stiffness, and functional change) will be evaluated on day 1 and day 7. Data 
will be analyzed using t-tests and repeated measure ANOVAs. 
 
6.0 Risk Analysis 
6.1 Adverse Event Recording and Reporting  
6.1.1 Adverse Event Definitions 
Adverse effect. Any untoward medical occurrence in a clinical study of an 
investigational device; regardless of the causal relationship of the 
problem with the device or, if applicable, other study treatment or 
diagnostic product(s). 
 
Associated with the investigational device or, if applicable, other study 
treatment or diagnostic product(s).  There is a reasonable possibility that 
the adverse effect may have been caused by the investigational device 
or, if applicable, the other study treatment or diagnostic product(s). 
 
Disability.  A substantial disruption of a person’s ability to conduct normal 
life functions. 
 
Life-threatening adverse effect.  Any adverse effect that places the 
subject, in the view of the investigator-sponsor, at immediate risk of death 
from the effect as it occurred (i.e., does not include an adverse effect that, 
had it actually occurred in a more severe form, might have caused death). 
Visit Number
V1
V1
V2
Visit Type
Screening
Start 
Treatment
End of 
Treatment
/Early 
Terminati
on (3)
Visit Day (1)
0
0
7
Inclusion/Exclusion 
Criteria
x
Informed Consent
x
Medical history
x
Treatment history
x
Device Assignment Form
x
Physical Examination
x
Confirm baseline pain >4 
week preceding 
x
Train Subject on sam 
Device
x
Confirm subject and put 
on and take off device
x
WOMAC Scale
x
x
Adverse Events
x
x
Protocol Deviations
x
Distribute Daily Diary
x
Review/Collect Daily Diary
x
Assess Compliance (2)
x
Distribute sam Device 
with patches
x
Distribute Patches
x
Issue Subject 
Compensation and Signed 
Receipt
x
Collect sam Device and 
Unused Patches
x
Exit Assessment 
Questionnaire 
x

Version 1 - July 2019 
 
10
 
Serious adverse effect. Any adverse effect that results in any of the 
following outcomes: death, a life-threatening adverse effect, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or 
significant disability/incapacity, or a congenital anomaly/birth defect. 
 
 
Unexpected adverse effect.  Any adverse effect, the frequency, specificity 
or severity of which is not consistent with the risk information described in 
the clinical study protocol(s)  
 
Unanticipated adverse device effect.  Any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the 
investigational plan or IDE application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
 
6.1.2 Eliciting Adverse Effect Information 
Clinical study subjects will be routinely questioned about adverse 
effects at study visits. 
 
6.1.3 Recording and Assessment of Adverse Effects 
All observed or volunteered adverse effects (serious or non-
serious) and abnormal test findings, regardless of treatment 
group, if applicable, or suspected causal relationship to the 
investigational device or, if applicable, other study treatment or 
diagnostic product(s) will be recorded in the subjects’ case 
histories.  For all adverse effects, sufficient information will be 
pursued and/or obtained so as to permit 1) an adequate 
determination of the outcome of the effect (i.e., whether the effect 
should be classified as a serious adverse effect) and; 2) an 
assessment of the casual relationship between the adverse effect 
and the investigational device or, if applicable, the other study 
treatment or diagnostic product(s).    
 
Adverse effects or abnormal test findings felt to be associated with 
the investigational device or, if applicable, other study treatment or 
diagnostic product(s) will be followed until the effect (or its 
sequelae) or the abnormal test finding resolves or stabilizes at a 
level acceptable to the investigator-sponsor. 
 
6.1.3.1 
Causality and Severity Assessment 
The investigator-sponsor will promptly review documented 
adverse effects and abnormal test findings to determine 1) 
if the abnormal test finding should be classified as an 
adverse effect; 2) if there is a reasonable possibility that 
the adverse effect was caused by the investigational 
device or, if applicable, other study treatment or diagnostic 

Version 1 - July 2019 
 
11
product(s); and 3) if the adverse effect meets the criteria 
for a serious adverse effect. 
 
If the investigator-sponsor’s final determination of causality 
is “unknown and of questionable relationship to the 
investigational device or, if applicable, other study 
treatment or diagnostic product(s)”, the adverse effect will 
be classified as associated with the use of the 
investigational device or study treatment or diagnostic drug 
product(s) for reporting purposes.  If the investigator-
sponsor’s final determination of causality is “unknown but 
not related to the investigational device or, if applicable, 
other study treatment or diagnostic product(s)”, this 
determination and the rationale for the determination will 
be documented in the respective subject’s case history. 
6.1.4 Reporting of Adverse Effects to the FDA   
The investigator-sponsor will submit a completed Form FDA 3500 
A to the FDA’s Center for Devices and Radiological Health for any 
observed or volunteered adverse effect that is determined to be 
an unanticipated adverse device effect.  A copy of this completed 
form will be provided to all participating sub-investigators.   
 
The completed Form FDA 3500 A will be submitted to the FDA as 
soon as possible and, in no event, later than 10 working days after 
the investigator-sponsor first receives notice of the adverse effect. 
 
If the results of the sponsor-investigator’s follow-up evaluation 
show that an adverse effect that was initially determined to not 
constitute an unanticipated adverse device effect does, in fact, 
meet the requirements for reporting; the investigator-sponsor will 
submit a completed Form FDA 3500 A as soon as possible, but in 
no event later than 10 working days, after the determination was 
made. 
 
For each submitted Form FDA 3500 A, the sponsor-investigator 
will identify all previously submitted reports that that addressed a 
similar adverse effect experience and will provide an analysis of 
the significance of newly reported adverse effect in light of the 
previous, similar report(s). 
 
Subsequent to the initial submission of a completed Form FDA 
3500 A, the investigator-sponsor will submit additional information 
concerning the reported adverse effect as requested by the FDA. 
 
6.1.5 Reporting of Adverse Effects to the Responsible IRB 
In accordance with applicable policies of the Institutional Review 
Board (IRB), the investigator-sponsor will report, to the IRB, any 
observed or volunteered adverse effect that is determined to meet 
all of the following criteria: 1) associated with the investigational 
device or, if applicable, other study treatment or diagnostic 

Version 1 - July 2019 
 
12
product(s); 2) a serious adverse effect; and 3) an unexpected 
adverse effect.  Adverse event reports will be submitted to the IRB 
in accordance with the respective IRB procedures.  
 
Applicable adverse effects will be reported to the IRB as soon as 
possible and, in no event, later than 10 calendar days following 
the investigator-sponsor’s receipt of the respective information.  
Adverse effects which are 1) associated with the investigational 
drug or, if applicable, other study treatment or diagnostic 
product(s); 2) fatal or life-threatening; and 3) unexpected will be 
reported to the IRB within 24 hours of the investigator-sponsor’s 
receipt of the respective information.  
 
Follow-up information to reported adverse effects will be submitted 
to the IRB as soon as the relevant information is available.  If the 
results of the sponsor-investigator’s follow-up investigation show 
that an adverse effect that was initially determined to not require 
reporting to the IRB does, in fact, meet the requirements for 
reporting; the investigator-sponsor will report the adverse effect to 
the IRB as soon as possible, but in no event later than 10 
calendar days, after the determination was made. 
 
7.0 Monitoring Procedures 
Monitoring of the clinical study for clinical protocol compliance will be conducted 
periodically (i.e., at a minimum of annually) by the clinical team. The sponsor-
investigator will permit direct access to the study monitors and appropriate regulatory 
authorities to the study data and to the corresponding source data and documents to 
verify the accuracy of these data. 
 
8.0 Additional Records and Reports   
8.1 Data Handling and Record-keeping 
A Case Report Form (will be completed at each study visit for each subject 
enrolled into the clinical study.  The investigator-sponsor will review, 
approve and sign/date each completed CRF; the investigator-sponsor’s 
signature serving as attestation of the investigator-sponsor’s responsibility 
for ensuring that all clinical and laboratory data entered on the CRF are 
complete, accurate and authentic.   
 
The clinical research team will work with each site to ensure accurate 
completion of CRFs reconciling illegible entries, missing data, and 
conflicting data entries.  
 
Source Data are the clinical findings and observations, laboratory and test 
data, and other information contained in Source Documents.  Source 
Documents are the original records (and certified copies of original 
records); including, but not limited to, hospital medical records, physician or 
office charts, physician or nursing notes, subject diaries or evaluation 

Version 1 - July 2019 
 
13
checklists, pharmacy dispensing records, recorded data from automated 
instruments, x-rays, etc.  When applicable, information recorded on the 
CRF shall match the Source Data recorded on the Source Documents.   
 
 
8.2 Record Maintenance and Retention 
The investigator-sponsor will maintain records in accordance with Good 
Clinical Practice guidelines; to include: 
 
• 
IRB correspondence (including approval notifications) related to the 
clinical protocol; including copies of adverse event reports and annual or 
interim reports; 
• 
Current and past versions of the IRB-approved clinical protocol and 
corresponding IRB-approved consent form(s) and, if applicable, subject 
recruitment advertisements. 
• 
Signed Investigator’s Agreements and Certifications of Financial Interests 
of Clinical Investigators; 
• 
Curriculum vitae (investigator-sponsor and clinical protocol sub-
investigators); 
• 
Certificates of required training (e.g., human subject protections, Good 
Clinical Practice, etc.) for investigator-sponsor and listed sub-
investigators; 
• 
Instructions for on-site preparation and handling of the investigational 
device and/or study treatment or diagnostic product(s), and other study-
related materials (i.e., if not addressed in the clinical protocol); 
• 
Decoding procedures for blinded trials; 
• 
Master device list; 
• 
Signed informed consent forms; 
• 
Completed Case Report Forms; signed and dated by investigator-
sponsor; 
• 
Source Documents or certified copies of Source Documents; 
• 
Monitoring visit reports; 
• 
Copies of investigator-sponsor correspondence to sub-investigators, 
including notifications of adverse effect information; 
• 
Subject screening and enrollment logs; 
• 
Subject identification code list; 
• 
Device accountability records, including documentation of device disposal 
and returns to sponsor; 
• 
Final clinical study report. 
 
Site-subject identification numbers will be assigned to all subjects to de-
identify the associated clinical data. A master subject ID log will be 
maintained by research coordinator separately from clinical trial data. The 
master log will contain the assigned site-subject identification number 
matched to each subject’s full name, gender, and date-of-birth. The site-
subject ID will be generated by a two-digit site ID separated by a dash from 
the subject number at that site. Subjects’ names or other directly identifiable 
information will not be used in any reports, publication or other disclosures 
of clinical study outcomes. 

Version 1 - July 2019 
 
14
 
The investigator-sponsor will retain the specified records and reports for up 
to 2 years after the marketing application is approved for the investigational 
device; or, if a marketing application is not submitted or approved for the 
investigational drug, until 2 years after investigations under the IDE have 
been discontinued and the FDA so notified. 
9.0 References 
 
Therapeutic ultrasound for osteoarthritis, Cochrane Review, 20 January 2010. 
http://www.cochrane.org/CD003132/MUSKEL_therapeutic-ultrasound-for-osteoarthritis  

Version 1 - July 2019 
 
15