Treatment of Sinus Headache Using a Novel Device That Combines Acoustic Vibration With Oscillating Expiratory Pressure: Randomized Controlled Trial
Phase: NA
Conditions: Facial Pain
Sponsor: Mayo Clinic

 
 
 
 
 
COVER PAGE FOR PROTOCOL AND STATISITICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
Official Study Title: Treatment of Sinus Headache Using a Novel Device That Combines 
Acoustic Vibration with Oscillating Expiratory Pressure: Randomized Controlled Trial 
 
NCT Number: NCT05479604 
IRB Approval Date: April 8, 2024 (04/09/2024) 
Unique Protocol ID: 22-001904 (Mayo Clinic), CAH-003 (Sponsor) 

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Title Page 
Principal Investigator: Amar Miglani, M.D. 
Protocol Title: Treatment of sinus headache using a novel device that combines acoustic vibration with 
oscillating expiratory pressure: Randomized Controlled Trial 
Protocol Number: CAH-003 
Amendment Number: Not applicable 
Brief Title: Novel device for treatment of sinus headache 
Study Phase: Phase 3 
SONIC 
Sponsor Name:  Healthy Humming LLC 
Legal Registered Address: 1320 Veterans Rd. Suite D Columbia SC 29209 US 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
 
 
ClinicalTrials.gov 
NCT03906968 
 
Approval Date:  
 
Sponsor Signatory: 
 
David Lewis, MD 
Owner and Operator 
 
Date 
 
 
 
 

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Table of Contents 
1. 
Protocol Summary ..........................................................................................................5 
1.1. 
Synopsis ............................................................................................................................5 
1.2. 
Schema ..............................................................................................................................7 
1.3. 
Schedule of Activities (SoA) ............................................................................................8 
2. 
Introduction ...................................................................................................................11 
2.1. 
Study Rationale ...............................................................................................................12 
2.2. 
Background .....................................................................................................................12 
2.3. 
Benefit/Risk Assessment ................................................................................................12 
2.3.1. 
Risk Assessment .............................................................................................................13 
2.3.2. 
Benefit Assessment .........................................................................................................13 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................13 
3. 
Objectives, Endpoints, and Estimands .......................................................................14 
4. 
Study Design ..................................................................................................................16 
4.1. 
Overall Design ................................................................................................................16 
4.2. 
Scientific Rationale for Study Design ............................................................................16 
4.3. 
Justification for Dose ......................................................................................................16 
4.4. 
End-of-Study Definition .................................................................................................17 
5. 
Study Population ...........................................................................................................18 
5.1. 
Inclusion Criteria ............................................................................................................18 
5.2. 
Exclusion Criteria ...........................................................................................................18 
5.3. 
Screen Failures ................................................................................................................18 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................19 
6.1. 
Study Intervention(s) Administered................................................................................19 
6.1.1. 
Medical Devices..............................................................................................................20 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................20 
6.3. 
Assignment to Study Intervention ..................................................................................20 
6.4. 
Blinding, Masking ..........................................................................................................20 
6.5. 
Study Intervention Compliance ......................................................................................21 
6.6. 
Dose Modification ..........................................................................................................21 
6.7. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................21 
6.8. 
Prior and Concomitant Therapy ......................................................................................21 
6.8.1. 
Rescue Medicine .............................................................................................................22 
6.9. 
Discontinuation of Study Intervention ............................................................................22 
6.10. 
Participant Discontinuation/Withdrawal from the Study ................................................22 
6.11. 
Lost to Follow up ............................................................................................................22 
7. 
Study Assessments and Procedures.............................................................................24 
7.1. 
Efficacy and/or Immunogenicity Assessments ...............................................................24 
7.2. 
Safety Assessments .........................................................................................................24 
7.2.1. 
Physical Examinations ....................................................................................................25 
7.2.2. 
Pregnancy Testing ...........................................................................................................25 
7.2.3. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................25 

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7.3. 
Adverse Events (AEs) Serious Adverse Events (SAEs), and 
Other Safety Reporting ...................................................................................................25 
7.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................25 
7.3.2. 
Method of Detecting AEs and SAEs ..............................................................................26 
7.3.3. 
Follow-up of AEs and SAEs ...........................................................................................26 
7.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................26 
7.3.5. 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs.............................................................................................26 
7.3.6. 
Medical Device Deficiencies ..........................................................................................27 
8. 
Statistical Considerations .............................................................................................29 
8.1. 
Statistical Hypotheses .....................................................................................................29 
8.1.1. 
Multiplicity Adjustment ..................................................................................................29 
8.2. 
Analysis Sets ...................................................................................................................29 
8.3. 
Statistical Analyses .........................................................................................................30 
8.3.1. 
General Considerations ...................................................................................................30 
8.3.2. 
Other Analyses ................................................................................................................30 
8.4. 
Sample Size Determination ............................................................................................31 
9. 
Supporting Documentation and Operational Considerations ..................................32 
9.1.1. 
Regulatory and Ethical Considerations ...........................................................................32 
9.1.2. 
Informed Consent Process ..............................................................................................32 
9.1.3. 
Data Protection................................................................................................................33 
9.1.4. 
Dissemination of Clinical Study Data.............................................................................33 
9.1.5. 
Data Quality Assurance ..................................................................................................33 
9.1.6. 
Source Documents ..........................................................................................................34 
9.1.7. 
Study and Site Start and Closure ....................................................................................34 
9.1.8. 
Publication Policy ...........................................................................................................35 
9.1.9. 
Definition of AE .............................................................................................................36 
9.1.10. Definition of SAE ...........................................................................................................37 
9.1.11. Recording and Follow-Up of AE and/or SAE ................................................................38 
9.1.12. Reporting of SAEs ..........................................................................................................39 
9.2. 
Appendix 1: Medical Device AEs, ADEs, SAEs, SADEs, 
USADEs and Device Deficiencies: Definitions and Procedures 
for Recording, Evaluating, Follow-up, and Reporting in Medical 
Device Studies ................................................................................................................40 
9.2.1. 
Definition of Medical Device AE and ADE ...................................................................40 
9.2.2. 
Definition of Medical Device SAE, SADE and USADE ...............................................40 
9.2.3. 
Definition of Device Deficiency .....................................................................................41 
9.2.4. 
Recording and Follow-Up of Medical Device AE and/or SAE 
and Device Deficiencies .................................................................................................41 
9.2.5. 
Reporting of Medical Device SAEs ................................................................................42 
9.2.6. 
Reporting of SADEs .......................................................................................................43 
10. 
References ......................................................................................................................44 

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List of Abbreviations  
  VAS 
Visual Analogue Scale 
  BPI-SF 
Brief Pain Inventory-Short Form 
  NOSE 
Nasal Obstruction Symptom Evaluation 
  AE  
Adverse Events 
  SAE 
Serious adverse events 
  SD 
Standard Deviation 
MCID 
Minimal clinically important difference 
 
 

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1. 
Protocol Summary 
1.1. 
Synopsis 
A parallel group treatment, phase 3, blinded, 2-arm study to investigate facial pain improvement with 
twice-daily use of a novel device combing acoustic vibration with oscillating expiratory pressure 
compared with a sham device in male and female participants > 18 years of age with sinus pain/headache 
lacking objective evidence of sinonasal inflammation.  
Rationale: 
Sinus headache is a widely prevalent chronic disabling condition associated with marked impairments in 
quality of life.  Patients commonly use the term sinus headache to refer to the concept of facial 
pain/headache originating in the sinonasal or facial region. However, studies have demonstrated that most 
patients with a chief complaint of sinus headache present without objective evidence of sinonasal 
inflammation and that symptoms are often related to a primary headache disorder.1–4 Headache disorders 
are an almost universal human experience. Migraine is the third most prevalent disorder and the seventh 
highest cause of disability worldwide. The direct and indirect socioeconomic costs of headache are 
estimated at 14 billion dollars per year. Embedded in the sinus headache patient population is a large 
group of patients with primary headache disorders. Therefore, much of the therapeutic investigation 
aimed at treatment of sinus headaches has mirrored the more established primary headache literature. 
Several studies evaluating empiric treatment of sinus headache patients have demonstrated that a majority 
of patients improve with triptan therapy.5–7 Perhaps the best study, published in 2007, is a multi-center (26 
centers in the United States) randomized, double-blinded, placebo-controlled investigation of sumatriptan 
for treatment of sinus headaches.8 Patients with sinus headache fulfilled IHS criteria for migraine, were 
without active or recent evidence of sinusitis, and had no prior treatment with migraine medications. A 
statistically significant benefit over placebo was noted with a single 50-mg dose of sumatriptan. Sixty-
nine percent and 76% of patients treated with sumatriptan had a positive headache response compared 
with a placebo response of 43% and 49% at 2 and 4 hours, respectively. 
Just as efficacy for triptans was first demonstrated and popularized in the primary headache literature 
before utilization in sinus headache studies, medical devices are following a similar trend with the recent 
advent of transcutaneous stimulation devices.9 Recently, two studies investigating use of acoustic 
vibration with oscillating expiratory pressure applied to the nasal cavity for treatment of nasal congestion 
were performed looking at cohorts of patients with complaint of congestion.10,11 One study demonstrated 
a significant improvement in objective measures of nasal obstruction and both demonstrated 
improvements in subjective measures of obstruction. Of note, in both studies, investigators noted 
improvements in facial pain/pressure.  We recently conducted an open label trial to determine if 
simultaneous administration of acoustic vibration and oscillating expiratory pressure (using Sinusonic 
device) affects the severity of facial pain among patients with complaint of sinus headache.  Twenty-nine 
patients (mean age 49 years, 55% female) completed our preliminary study without any major adverse 
events.   At   the   4-week   follow-up,   facial   pain   visual   analog   scale   (VAS)5   improved   from 
mean standard deviation(SD) of 59.6+/-15.7 to 34.6+/-21.7(p<0.001) and approximately 70% of patients 
achieving a minimal clinically important difference (MCID) across all pain metrics. Eighty-six percent of 
subjects would use device again and recommend it to others.  As the next step, we propose a randomized 
controlled trial. Preliminary data demonstrates that the device is low-risk, with high patient satisfaction, 
and patients are able to perform the intervention at home with ease.  

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Table 1: Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To assess relative improvements in facial 
pain/pressure after 8-weeks of twice daily 
use of the SinuSonic device compare to a 
sham device 
• 
Facial pain visual analogue scale (0-10) 
(1-week recall period)  
• 
Facial pain visual analogue scale (0-10) 
(immediate 5-minute post use recall) 
• 
Brief Pain Inventory-Short Form 
Secondary 
 
• 
Safety data 
• 
Device use satisfaction 
• 
Nasal obstruction 
 
• 
Percent achieving a minimal clinically 
important difference 
• 
Adverse events reported via questionnaire 
(pain, epistaxis, etc.) 
• 
Percentage willing to use again and 
recommend device to others 
• 
Nasal obstruction symptom evaluation 
(NOSE) Score change   
 
Overall Design: 
This is a parallel, placebo-controlled multicenter randomized trial. The study population will consist of 
healthy volunteers with sinus headache/pain lacking objective evidence of chronic sinusitis. This will be a 
single-blinded study blinded to the participants. Because this study will involve minimal intervention 
from the investigators (i.e. participants will fill out surveys remotely), there will be minimal influence 
from the investigators and analysts end. Participants will be randomized to the treatment or the sham-
placebo arm and the device they received (either device or sham), will be recorded in a secure database. 
Following screening, investigational intervention assignment will be performed by randomization in a 
1:1, investigational device: sham ratio. Data will be collected and stored in an electronic data storage 
system.  
Brief Summary: 
The purpose of this study is to measure facial pain/pressure with a novel device using acoustic vibrations 
with oscillating expiratory pressure compared with a sham device in participants with sinus pain/headache 
lacking objective evidence of sinonasal inflammation.  
Study details include: 
• 
The study duration will be up to 12 months. 
• 
The treatment duration will be up to 8 weeks. 

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• 
The visit frequency will be 0 visits. Participants will fill out questionnaires fielded via an 
electronic data capture system at 1 week, 2 weeks, 3 weeks, and 4 weeks of device use. 
Number of Participants: 
Approximately 120 participants will be screened to achieved 60 enrolled. 
A maximum of 60 participants will be enrolled  
Study Arms and Duration: 
The total duration of study participation with screening, run-in (i.e., delivery of device), and device use is 
11 weeks. Participants will use the investigational or sham device for 2 minutes, twice-daily for the entire 
8-week study duration. 
 
Data Monitoring/Other Committee:  
 
1.2. 
Schema 
 

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1.3. 
Schedule of Activities (SoA) 
 
Procedure 
 
 
 
 
 
Screening  
(up to 3 
weeks 
before 
Day 1) 
Baseline 
(up to 3 
weeks 
before 
Day 1) 
Intervention Period (8 weeks) 
E/D 
Notes 
 
E/D = Early 
Discontinuation 
Day 1 
+/- 3 Days 
Week 2 
+/- 3 
Days 
Week 4 
+/- 3 
Days 
Week 6 
+/- 3 
Days 
Week 8 
+/- 3 
Days 
Informed consent 
 
 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
Recheck clinical status 
before randomization 
and/or first dose of 
investigational 
intervention. 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history (includes 
substance use) 
X 
 
 
 
 
 
 
 
Substances: drugs, 
alcohol, tobacco, and 
caffeine 
Current medical 
conditions   
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Study intervention 
 
 
X 
X 
X 
X 
X 
 
 

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Procedure 
 
 
 
 
 
Screening  
(up to 3 
weeks 
before 
Day 1) 
Baseline 
(up to 3 
weeks 
before 
Day 1) 
Intervention Period (8 weeks) 
E/D 
Notes 
 
E/D = Early 
Discontinuation 
Day 1 
+/- 3 Days 
Week 2 
+/- 3 
Days 
Week 4 
+/- 3 
Days 
Week 6 
+/- 3 
Days 
Week 8 
+/- 3 
Days 
AE review  
 
 
=============================  
 
 
SAE review: Including 
solicited administration-
site events if applicable: 
pain or bleeding 
 
 
============================= 
X 
Pain Epistaxis 
 
Device deficiencies  
 
 
============================= 
X 
 
Concomitant medication 
review 
 
X 
 
 
 
 
 
 
 

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Procedure 
 
 
 
 
 
Screening  
(up to 3 
weeks 
before 
Day 1) 
Baseline 
(up to 3 
weeks 
before 
Day 1) 
Intervention Period (8 weeks) 
E/D 
Notes 
 
E/D = Early 
Discontinuation 
Day 1 
+/- 3 Days 
Week 2 
+/- 3 
Days 
Week 4 
+/- 3 
Days 
Week 6 
+/- 3 
Days 
Week 8 
+/- 3 
Days 
Efficacy questionnaire 
assessment: 
• 
VAS facial pain 
(1 week recall) 
 
X 
 
X 
X 
X 
X 
X 
 
 
Efficacy questionnaire 
assessment: 
• BPI-SF 
 
X 
X 
X 
X 
X 
X 
 
 
NOSE 
 
X 
 
 
 
 
X 
 
 
Device use satisfaction 
questionnaire 
 
 
 
 
 
 
X 
 
 
 
 

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2. 
Introduction 
Sinusonic is an FDA registered novel medical device employing simultaneous acoustic vibrations and 
positive expiratory pressure to the nasal cavity that has been studied for management of nasal congestion 
and, more recently, sinus headache.  
Sinus headache is a widely prevalent chronic disabling condition associated with marked impairments in 
quality of life.  Patients commonly use the term sinus headache to refer to the concept of facial 
pain/headache originating in the sinonasal or facial region. However, studies have demonstrated that most 
patients with a chief complaint of sinus headache present without objective evidence of sinonasal 
inflammation and that symptoms are often related to a primary headache disorder.4 Headache disorders 
are an almost universal human experience. Migraine is the third most prevalent disorder and the seventh 
highest cause of disability worldwide. The direct and indirect socioeconomic costs of headache are 
estimated at 14 billion dollars per year. Embedded in the sinus headache patient population is a large 
group of patients with primary headache disorders. Therefore, much of the therapeutic investigation 
aimed at treatment of sinus headaches has mirrored the more established primary headache literature. 
Several studies evaluating empiric treatment of sinus headache patients have demonstrated that a majority 
of patients improve with triptan therapy.5–7 Perhaps the best study, published in 2007, is a multi-center (26 
centers in the United States) randomized, double-blinded, placebo-controlled investigation of sumatriptan 
for treatment of sinus headaches.8 Patients with sinus headache fulfilled IHS criteria for migraine, were 
without active or recent evidence of sinusitis, and had no prior treatment with migraine medications. A 
statistically significant benefit over placebo was noted with a single 50-mg dose of sumatriptan. Sixty-
nine percent and 76% of patients treated with sumatriptan had a positive headache response compared 
with a placebo response of 43% and 49% at 2 and 4 hours, respectively. 
Just as efficacy for triptans was first demonstrated and popularized in the primary headache literature 
before utilization in sinus headache studies, medical devices are following a similar trend with the recent 
advent of transcutaneous stimulation devices.9 Recently, two studies investigating use of acoustic 
vibration with oscillating expiratory pressure applied to the nasal cavity for treatment of nasal congestion 
were performed looking at cohorts of patients with complaint of congestion.10,11 One study demonstrated 
a significant improvement in objective measures of nasal obstruction and both demonstrated 
improvements in subjective measures of obstruction. Of note, in both studies, investigators noted 
improvements in facial pain/pressure.   
We recently conducted an open label trial to determine if simultaneous administration of acoustic 
vibration and oscillating expiratory pressure (using Sinusonic device) affects the severity of facial pain 
among patients with complaint of sinus headache.  Twenty-nine patients (mean age 49 years, 55% 
female) completed our preliminary study without any major adverse events.   At  4-weeks   follow-up,   
facial   pain   visual   analog   scale   (VAS)   improved   from mean standard deviation(SD) of 59.6+/-
15.7 to 34.6+/-21.7(p<0.001) and approximately 70% of patients achieving a minimal clinically important 
difference (MCID) across all metrics. Eighty-six percent of subjects would use device again and 
recommend it to others.  As the next step, we propose a randomized controlled trial. Preliminary data 
demonstrates that the device is low-risk, with high patient satisfaction, and patients are able to perform 
the intervention at home with ease.  
In regards to device use, the device comes with a clear plastic tab a the base of the device. This tab must 
be removed prior to device use. For a full session, there is a trigger that must be held down after which 

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subjects should breathe in and out through their nose with a normal amount of force and speed. A gentle 
humming will be felt and heard and during exhalations, a fluttering sound will be appreciated. After a full 
session of use (2 minutes), the device will go into a rest mode for 6 minutes.  
2.1. 
Study Rationale 
An open label, single-arm trial to determine if simultaneous administration of acoustic vibration and 
oscillating expiratory pressure (using Sinusonic device) affects the severity of facial pain among patients 
with complaint of sinus headache was recently conducted.  Twenty-nine patients (mean age 49 years, 
55% female) completed this preliminary study without any major adverse events.   At  4-weeks   follow-
up,   facial   pain   visual   analog   scale   (VAS)   improved   from mean standard deviation(SD) of 
59.6+/-15.7 to 34.6+/-21.7(p<0.001) and approximately 70% of patients achieving a minimal clinically 
important difference (MCID) across all metrics. Eighty-six percent of subjects would use device again 
and recommend it to others.  As the next step, we propose a randomized controlled trial. Preliminary data 
demonstrates that the device is low-risk, with high patient satisfaction, and patients are able to perform 
the intervention at home with ease. The next step to determine device efficacy for the indication of sinus 
headache is to perform a randomized, controlled, clinical trial.  
2.2. 
Background 
The SinuSonic device utilizes acoustic vibration with oscillating expiratory pressure and was first studied 
for the indication of nasal obstruction. A previous study of acoustic vibrations with oscitating expiratory 
pressure found significant improvements in objective and subjective metrics of nasal 
congestion/obstruction suggesting that physiologic changes may occur within the nasal cavity in response 
to device use. There have been two studies from separate institutions investigating use of acoustic 
vibrations on nasal congestion and interestingly patients noted improvement in secondary symptoms of 
facial pain and pressure. Although these study were focused on patients with nasal congestion, subjects 
improvements in facial pressure was an interesting finding. The question thus arose whether a device 
employing simultaneous acoustic vibrations and positive expiratory pressure to the nasal cavity could 
improve symptoms in patients with chief complaint of sinus headache. We recently conducted an open 
label trial to determine if simultaneous administration of acoustic vibration and oscillating expiratory 
pressure (using Sinusonic device) affects the severity of facial pain among patients with complaint of 
sinus headache.  Twenty-nine patients (mean age 49 years, 55% female) completed our preliminary study 
without any major adverse events.   At   the   4-week   follow-up,   facial   pain   visual   analog   scale   
(VAS)   improved   from mean standard deviation(SD) of 59.6+/-15.7 to 34.6+/-21.7(p<0.001) and 
approximately 70% of patients achieving a minimal clinically important difference (MCID) across all 
facial pain metrics. Eighty-six percent of subjects would use device again and recommend it to others.  As 
the next step, we propose a randomized controlled trial. Preliminary data demonstrates that the device is 
low-risk, with high patient satisfaction, and patients are able to perform the intervention at home with 
ease.  
2.3. 
Benefit/Risk Assessment 
Based on available clinical studies, application of acoustic vibration with positive end expiratory pressure 
to the nasal cavity is a relatively low-risk intervention. In two separate studies investigating its use for 
nasal congestion, no adverse events were reported in 90 subjects. In a more recent study looking 
specifically at patients with sinus headache, one patient noted mild epistaxis that resolved following use. 

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Similarly, four patients noted some mild-moderate discomfort during device use. No permanent or major 
adverse events were noted.  
More detailed information about the known and expected benefits and risks and reasonably expected 
adverse events (AEs) of SinuSonic device may be found in the package insert and summary of product 
characteristics. 
2.3.1. 
Risk Assessment 
Theoretical risks of device use include transient discomfort, nasal irritation, and epistaxis. In order to 
minimize risks, patients with any nasal crusting or ulceration on exam, or history of severe epistaxis will 
be excluded from the study.   
 
2.3.2. 
Benefit Assessment 
Benefits include the potential for this therapy to be efficacious in treating sinus headache and offer a low-
risk solution with minimal side effects.  
 
2.3.3. 
Overall Benefit Risk Conclusion 
Taking into account the measures taken to minimize risk to participants participating in this study, the 
potential risks identified in association with the SinuSonic device are justified by the anticipated benefits 
that may be afforded to participants with Sinus headache. 

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3. 
Objectives, Endpoints, and Estimands 
 
Objectives 
Endpoints 
Primary 
 
• 
To determine superiority of SinuSonic 
intervention versus control in treatment of 
facial pain for patients with complaint of 
sinus headache that lack objective 
evidence of sinonasal inflammation 
• 
Change in facial pain visual analogue 
scale at 8 weeks 
• 
Change in Brief Pain Inventory Short 
Form at 8 weeks 
Secondary 
 
• 
To determine safety of device use 
• 
Number and percent of subjects reporting 
pain with device use 
• 
Number and percent of subjects reporting 
epistaxis 
• 
Change in Nasal Obstruction Symptom 
Evalution (NOSE) Score at 8 weeks 
Tertiary 
 
• 
To determine device use satisfaction 
 
• 
Number and percent of subjects that 
would use the device again 
• 
Number and percent of subjects that 
would recommend the device to others 
 
Primary estimand  
The primary clinical question of interest is:  
What is the improvement in facial pain measured by facial pain VAS, and BIP-SF in patients with sinus 
headache treated with SinuSonic device versus a sham device regardless of discontinuation of 
investigational intervention for any reason and regardless of initiation of rescue medication or change in 
background medication. 
The estimand is described by the following attributes: 
• 
Population: Patients with complaint of sinus headache lacking objective evidence of sinonasal 
inflammation of nasal endoscopy or imaging 
• 
Endpoint:  
change from baseline to 8 weeks in facial pain VAS, and BPI-SF 
• 
Treatment condition:  

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the investigational interventions regardless of discontinuation for any reason, with or without 
rescue medication or change in background medication (treatment policy strategy).  
• 
Remaining intercurrent events: 
The intercurrent events “intervention discontinuation for any reason” and “initiation of rescue 
medication or change in background medication (dose and product)” are addressed by the 
treatment condition of interest attribute. There are no remaining intercurrent events anticipated at 
this time. 
• 
Population-level summary:  
difference in mean changes between treatment conditions 
Rationale for estimand: Facial pain is the primary complaint impacting quality-of-life in patients with 
sinus headache. Thus, we propose using 3 validated pain metrics to assess response to therapy. , . 
Secondary estimand(s) 
The clinical question of interest is for the secondary objective :  
What is the difference in the proportion of sinus headache patients experiencing adverse events of pain 
and epistaxis between investigational SinuSonic treatment arm compared to sham control arm.  
The estimand is described by the following attributes: 
• 
Population:  
Patients with Sinus Headache 
• 
Endpoint:  
Number and percent of subjects reporting pain with device use. Number and percent of subjects 
reporting epistaxis.  
Nasal obstruction symptom evaluation (NOSE) Score change   
• 
Treatment condition:  
the investigational interventions regardless of discontinuation for any reason, with or without 
rescue medication or change in background medication (treatment policy strategy) 
• 
Remaining intercurrent events: 
• 
The intercurrent events “intervention discontinuation for any reason” and “initiation of rescue 
medication or change in background medication (dose and product)” are addressed by the 
treatment condition of interest attribute. There are no remaining intercurrent events anticipated at 
this time 
• 
Population-level summary:  
Difference in proportion of patients experiencing adverse event 
Rationale for estimand: Safety is a secondary endpoint and will be assessed by specifically tracking 
incidence of pain with device use and epistaxis. These adverse events are based on prior study results.  
 

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4. 
Study Design 
 
4.1. 
Overall Design 
• 
This is a parallel, two-arm, sham placebo controlled multicenter (Mayo AZ, Mayo FL and Mayo 
RST), clinical trial investigating use of the novel SinuSonic Device for sinus headache.  
• 
The control group will be a sham device of similar appearance to the investigational device 
• 
Participants will be healthy volunteers with complaint of sinus headache lacking objective 
evidence of sinonasal inflammation on exam or endoscopy 
• 
Primary outcome measures of facial pain measured using facial pain VAS and BPI-SF will be 
assessed at baseline, Day 1, 2 week, 4 week, 6 week, and 8 weeks.  
• 
Participants will be randomized in a 1:1 fashion; SinuSonic arm: Sham device, respectively. 
• 
Total Duration of study participation will be 11 weeks; 2-3 weeks for screening and 
randomization and 8 weeks for the intervention component.  
 
4.2. 
Scientific Rationale for Study Design 
Sinus headaches are a widely prevalent condition and accounts for a significant portion of 
Otolaryngologic clinic visit. Patients lacking objective evidence of sinonasal inflammation are thought to 
have a primary headache disorder. The direct and indirect socioeconomic costs of headache are estimated 
at 14 billion dollars per year. Established barriers to headache therapy include failure to consult the 
appropriate subspecialty professional, failure to arrive at a specific diagnosis, and lack of appropriate 
acute and preventative therapy.(Dodick) There are frequently long wait times for patients to see 
neurologists. Many otolaryngologists are unfamiliar with prescribing neuroactive medications. From a 
patient’s perspective, there is stigma associated with a diagnosis of headache disorders making it difficult 
sometimes for patients to accept this reality. SinuSonic utilizes acoustic vibration with positive end 
expiratory pressure and has been shown to improve subjective and objective measures of nasal 
obstruction. Interestingly, multiple studies using similar technology found improvements in patients 
complaining of facial pain. This led to a single-arm study investigating the devices use for treatment of 
sinus pain and results demonstrated a significant benefit across three pain metrics. The next logical step is 
to perform a randomized, sham-controlled trial. The parallel design comparing the investigational device 
to a sham device is best practice. The primary endpoint of interest includes facial pain measured by facial 
pain VAS, and BPI-SF,– two validated pain metrics. The primary end point of facial pain patient reported 
questionnaires directly impacts and assesses how patients feel and function. In order to be inclusive, all 
male and female patients 18 years and older are eligible to participate.  
 
4.3. 
Justification for Dose 
For this device, the term dose refers to the number of 3-minute treatment sessions.  
Justification for device use is based on manufacturer’s recommendation and efficacy with use in prior 
studies. The device will be turned on and silicone nasal mask placed over the nose and participants will 
breathe similar to their baseline nasal breathing against the device for 2 doses (two 3-minute treatment 
session). The device will be used twice daily, any the protocol will not allow any deviations in treatment.  

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4.4. 
End-of-Study Definition 
The end of the study is defined as the date of the last questionnaire submission of the last participant in 
the.  
A participant is considered to have completed the study if the participant has completed all periods of the 
study including submitting the final questionnaire, which is after 4 weeks of device use. 

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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol 
waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Participant must be >18 years of age inclusive, at the time of signing the informed consent. 
2. Participants who are overtly healthy as determined by medical evaluation including medical 
history and physical examination. 
3. Capable of giving signed informed consent  
4. Facial pain or pressure for > 3 months of symptom duration 
5. Pain/pressure VAS score of > 5 
6. Lund MacKay Score of < 3 with no single sinus score of 2 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. Upper respiratory illness within the last 2 weeks 
2. History of severe epistaxis 
3. Allergic sensitivity to silicone or any other component of device 
4. Sinonasal surgery in the last 3 months 
5. Topical decongestant use in the last week 
6. Nasal polyposis, purulence/edema, or other signs of sinusitis on exam 
7. Sinusitis on imaging 
8. Nasal crusting or ulceration on exam 
9. Inability to read or understand English 
5.3. 
Screen Failures 
A screen failure occurs when a participant who has consented to participate in the clinical study is not 
subsequently assigned to study intervention/entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
CONSORT publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.  
 

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6. 
Study Intervention(s) and Concomitant Therapy 
Study interventions are all pre-specified, investigational devices) intended to be administered to the study 
participants during the study conduct. 
6.1. 
Study Intervention(s) Administered 
 
Table 1.  Study Intervention(s) Administered 
Intervention 
Label 
Active 
Sham 
Intervention 
Name 
SinuSonic device 
Sham SinuSonic device 
Intervention 
Description 
The SinuSonic consists of a 
fully-disposable 
medical 
grade 
silicone 
nosepiece 
mounted to a resin body. The 
device is equipped with a 
flutter valve located at the top 
of the device which creates 
gentle, self-guided oscillating 
expiratory 
resistance. 
It 
provides administration of 
acoustic vibration at 128Hz 
and 
oscillating 
positive 
expiratory pressure.  
Sham device with similar 
appearance that lacks positive 
end expiratory pressure and 
emits noise at non-therapeutic 
frequency.  
Type  
Active Device 
  
Sham device  
Dose Formulation 
 Other 
Other 
Unit Dose 
Strength(s) 
2 minutes of device use 
2 minutes of device use 
Dosage Level(s) 
Sinusonic device for 2 
minutes, twice daily for 8 
weeks  
sham device for 2 minutes, 
twice daily for 8 weeks  
Route of 
Administration 
Other 
Other 
Use 
experimental  
sham comparator 
IMP and 
NIMP/AxMP. 
NIMP 
NIMP 
Sourcing 
Acquired from the  
Healthy 
Humming 
LLC, 
Columbia, SC by the study PI 
Acquired from the  
Healthy 
Humming 
LLC, 
Columbia, SC by the study PI 
Packaging and 
Labeling 
Device for study intervention 
will be provided in cardboard 
box. The active and sham 
device 
will 
be 
labelled 
identically and will include 
instructions 
on 
use 
and 
storage. 
Sham device will be provided 
in a cardboard box. The active 
and sham device will be 
labelled identically and will 
include instructions on use 
and storage. 

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Table 2.  Study Arm(s) 
 
 
 
 
 
 
6.1.1. 
Medical Devices 
1. The Healthy Humming LLC manufactured medical devices (SinuSonic and sham device) will be 
provided for use in this study. 
2. Instructions for medical device use are provided in document “Healthy Humming 
Instructional Booklet’ 
3. All device deficiencies (including malfunction, use error and inadequate labelling) shall be 
documented and reported by the investigator throughout the clinical investigation 
6.2. 
Preparation, Handling, Storage, and Accountability 
4. Only participants enrolled in the study may receive study intervention, and participants 
themselves may administer study intervention.  
5. The investigator is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
6.3. 
Assignment to Study Intervention 
On Day 0 (baseline), participants will be assigned a unique number (Subject ID) in ascending numerical 
order at each study site. The randomization will be implemented in the EDC system, according to the 
randomization schedule generated prior to the study by the statistics department at Mayo Clinic. Each 
participant will be dispensed blinded study intervention .  
6.4. 
Blinding, Masking 
Participants will be randomly assigned in a 1:1 ratio to receive study intervention. Investigators will 
remain blinded to each participant’s assigned study intervention throughout the course of the study. To 
maintain this blind, an otherwise uninvolved third party will be responsible for the reconstitution and 
dispensation of all study intervention and will endeavor to ensure that there are no differences in time 
taken to dispense following randomization. 
Arm Title 
Arm 1 
Arm 2 
Arm Type 
Active device 
Sham comparator 
Arm Description 
Sinusonic device for 2 
minutes, twice daily 
for 8 weeks  
sham device for 2 
minutes, twice daily for 
8 weeks  
Associated 
Intervention Labels 
Not applicable 
No applicable 

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Sponsor safety staff may unblind the intervention assignment for any participant with an SAE. If the SAE 
requires that an expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s intervention assignment, may be sent to investigators in accordance 
with local regulations and/or sponsor policy. 
6.5. 
Study Intervention Compliance 
Participant will self-administer the medical intervention and compliance with study intervention will be 
assessed at each visit. Compliance will be assessed by direct questioning during the study visits, where 
participants will be asked to report the number of days in past two weeks that they used the study 
intervention and documented in the source documents and relevant form. The adherence to the prescribed 
dosage regimen should be recorded.  
Intervention start and stop dates, including dates for intervention delays and/or dose reductions will also 
be recorded. 
6.6. 
Dose Modification 
Any dose modification, including the duration and frequency of administration of sinusonic/sham device 
will not be permitted. 
6.7. 
Continued Access to Study Intervention after the End of the Study 
There will be no provision to provide continued access to study intervention after the end of the study. 
However, the active study intervention (sinusonic device) is available for purchase commercially. 
6.8. 
Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational drugs, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of enrollment must be 
recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
There are no restrictions on the concomitant medications given that the Sinusonic device is not expected 
to have an interaction with the study medication. However, to prevent confounding effects of a newly 
initiated treatment, participants will be required to be stable on their medication for at least 7 days before 
the start of study intervention until completion of the follow-up visit, unless, in the opinion of the 
investigator and sponsor, the medication will not interfere with the study. 
Acetaminophen, at doses of ≤ 2 grams/day, is permitted for use any time during the study. Initiation of 
other concomitant medications during the study period may be considered on a case-by-case basis by the 
investigator. 

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6.8.1. 
Rescue Medicine 
The study site will not supply any rescue medication. 
The use of rescue medications is allowable at any time during the study. The date and time of rescue 
medication administration as well as the name and dosage regimen of the rescue medication must be 
recorded. 
 
6.9. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study intervention. If 
study intervention is permanently discontinued, the participant should, if at all possible, remain in the 
study to be evaluated for 1 week. See the SoA for data to be collected at the time of discontinuation of 
study intervention and follow-up and for any further evaluations that need to be completed. 
 
6.10. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at the participant’s own request for any 
reason (or without providing any reason). 
• 
A participant may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, or compliance reasons.  
• 
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
• 
The participant will be permanently discontinued from the study intervention and the study at that 
time. 
• 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
• 
If a participant withdraws from the study, the participant may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
6.11. 
Lost to Follow up 
A participant will be considered lost to follow-up if the participant repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain whether the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls, and if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, the participant will be considered to have 
withdrawn from the study.  

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• 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get study intervention. Public sources may be searched for vital status information. If 
vital status is determined as deceased, this will be documented and the participant will not be 
considered lost to follow-up. Sponsor personnel will not be involved in any attempts to collect 
vital status information. 

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7. 
Study Assessments and Procedures 
• 
Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions 
are not allowed. 
• 
Adherence to the study design requirements, including those specified in the SoA, is essential and 
required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
• 
Procedures conducted as part of the participant’s routine clinical management [(eg, blood count, 
ENT examination)] and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were performed 
within the timeframe defined in the SoA. 
• 
In the event of a significant study-continuity issue (eg, caused by a pandemic), alternate strategies 
for participant visits, assessments, medication distribution and monitoring may be implemented 
by the sponsor or the investigator, as per local health authority/ethics requirements.   
• 
Safety/laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded. 
 
7.1. 
Efficacy and/or Immunogenicity Assessments 
Study outcomes will be assessed using the facial pain visual analogue scale (VAS)5, and Brief Pain 
Inventory-Short Form (BPI-SF)13,14. The facial pain VAS score is a scale from 0-100 millimeters (mm) 
and asks patients to rate the severity of their facial pain over a previous one week recall period with 
higher scores indicating greater pain intensity. Additionally, a current VAS pain score and an immediate 
5-minute post-use current VAS pain score will be assessed. A prior study looking at orofacial pain 
reported a minimal clinically important difference (MCID) of 1.2 for VAS pain. The BPI-SF assesses 
pain at its “worst”, “least”, “mean”, and “now” (current pain). In clinical trials, the items “worst” and 
“mean” have been each used singly to represent the pain severity. Worst and mean pain will be assessed 
over a previous one week recall period. BPI-SF also measures how much pain interferes (BPI 
interference) with seven daily activities including general activity, walking, work, mood, enjoyment of 
life, relations with others, and sleep. BPI pain interference is typically scored as the mean of the seven 
interference items. All items are rated on a 0-10 scale with 0 representing no pain/no interference and 10 
representing pain as bad as you can imagine/interferes completely. A distribution-based approach using 
one-half the SD will be used to determine MCID values for BPI-SF, as there is a paucity of research 
assessing the MCIDs for these pain measures for facial pain/headache. Planned timepoints for all efficacy 
assessments are provided in the SoA. 
7.2. 
Safety Assessments 
The use of SinuSonic device is not associated with significant safety concerns in prior studies. However, 
to assess safety information, study team will conduct a detailed medical review of systems at each visit 
(including baseline) to establish the presence of any ongoing medical issues at the time of study entry and 
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also allow for detection of any new onset medical issue (that may post safety concern) with the use of 
SinuSonic device. Planned timepoints for all safety assessments are provided in the SoA. 
7.2.1. 
Physical Examinations 
• 
Patients will be evaluated in ENT clinic with nasal endoscopy and/or CT imaging prior to study 
enrollment as part of standard of care evaluation. If patient has complaint of sinus headache and 
is without objective evidence of sinonasal inflammation (Lund MacKay score < 3 without a 
single sinus score of 2), they will be offered referral to the study.  
• 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
7.2.2. 
Pregnancy Testing 
The use of SinuSonic device is not expected to impact fetus. Therefore, pregnancy testing will not be 
conducted during the course of study. However, if a participant reports becoming pregnant, it will be 
recorded in the study and outcome of the pregnancy will be monitored with participant’s permission. 
7.2.3. 
Suicidal Ideation and Behavior Risk Monitoring 
There will not be a separate suicidal ideation and behavior (SIB) risk monitoring as the study device 
(SinuSonic) is not known to be active in the CNS, will not be studied for activity in CNS, and is not being 
developed for any psychiatric or neurologic indication. The Sinusonic device is not known to affect 
mood, cognition, or behavior via their direct or indirect effects on the CNS and the study device is not 
similar to any other intervention that have had SIB reported. However, information about SIB will be 
collected as part of the assessment of psychiatric system in the medical review of system. 
 
7.3. 
Adverse Events (AEs) Serious Adverse Events (SAEs), and Other Safety Reporting 
The definitions of device-related safety events, adverse device effects (ADEs), and serious adverse device 
effects (SADEs) can be found in Appendix 1. Device deficiencies are covered in Section 8.4.9. 
The investigator and any qualified designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that are 
serious, considered related to the study intervention or study procedures, or that caused the participant to 
discontinue the study intervention (see Section 7). This includes events reported by the participant (or, 
when appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and transmitting SAE reports are provided in Appendix 1. 
7.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the start of study intervention until exit from the study at the timepoints 
specified in the SoA (Section 1.3). 
All AEs will be collected from the start of study intervention until the exit from study at the timepoints 
specified in the SoA (Section 1.3). 
Medical occurrences that begin before the start of study intervention but after obtaining informed consent 
will be recorded as medical history/current medical conditions, not as AEs. 

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All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 1. The investigator will submit any 
updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and the investigator considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the sponsor. 
7.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and nonleading 
verbal questioning of the participant is the preferred method to inquire about AE occurrences. 
7.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Further information on 
follow-up procedures is provided in Appendix 1. 
7.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, institutional review boards (IRBs)/independent ethics committees 
(IECs), and investigators. 
• 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then file it 
along with the IDFU and will notify the IRB/IEC, if appropriate according to local requirements. 
7.3.5. 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs or SAEs 
The following disease-related events (DREs) are common in participants with Sinus Headache and can be 
serious/life threatening: 
• 
None 
Because these events are typically associated with the disease under study, they will not be reported 
according to the standard process for expedited reporting of SAEs even though the event may meet 
the definition of an SAE. These events will be recorded within the appropriate timeframe. 
NOTE: However, if either of the following conditions applies, then the event must be recorded and 
reported as an AE/SAE (instead of a DRE): 
The event is, in the investigator’s opinion, of greater intensity, frequency, or duration than expected for 
the individual participant. 

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The investigator considers that there is a reasonable possibility that the event was related to study 
intervention. 
7.3.6. 
Medical Device Deficiencies 
Medical devices are being provided for use in this study as the study intervention. To fulfill regulatory 
reporting obligations worldwide, the investigator is responsible for the detection and documentation of 
events meeting the definitions of device deficiency that occur during the study with such devices. 
The definition of a medical device deficiency can be found in Appendix 1. 
NOTE: Deficiencies fulfilling the definition of an AE/SAE will follow the processes outlined in 
Appendix 1 of the protocol.  
7.3.6.1. 
Time Period for Detecting Medical Device Deficiencies 
• 
Medical device deficiencies that result in an incident will be detected, documented, and reported 
during all periods of the study in which the medical device is used. 
• 
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such a deficiency is considered reasonably related to a medical 
device provided for the study, the investigator will promptly notify the sponsor. 
The method of documenting medical device deficiencies is provided in Appendix 1. 
7.3.6.2. 
Follow-up of Medical Device Deficiencies 
• 
Follow-up applies to all participants, including those who discontinue study intervention. 
• 
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
• 
New or updated information will be recorded on the originally completed form with all changes 
signed and dated by the investigator. 
7.3.6.3. 
Prompt Reporting of Device Deficiencies to the Sponsor 
• 
Device deficiencies will be reported to the sponsor within 24 hours after the investigator 
determines that the event meets the protocol definition of a medical device deficiency. 
• 
The medical device deficiency report form will be sent to the sponsor by email. 
• 
The sponsor will be the contact for the receipt of device deficiency reports. 
7.3.6.4. 
Regulatory Reporting Requirements for Device Deficiencies 
• 
The investigator will promptly report all device deficiencies occurring with any medical device 
provided for use in the study in order for the sponsor to fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information relating to 
medical devices being used in clinical studies. 
• 
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to the 
reporting of device deficiencies to the IRB/IEC. 
 

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8. 
Statistical Considerations 
The analysis and reporting will be done on all data from all participants at the time the study ends. 
8.1. 
Statistical Hypotheses 
The primary objective is to demonstrate that Sinusonic device is superior to Sham control in achieving 
improvements in facial pain measured by facial pain VAS, and BPI-SF at 8 weeks. Thus, the null 
hypothesis to be tested in relation to the primary estimand is as follows: 
• 
Null hypothesis: Sinusonic is not different from sham control with respect to the achievement of 
improvement in facial pain VAS, and BPI-SF at 8 weeks. 
The null and alternative hypotheses corresponding to the secondary estimands are as follows: 
Secondary objective [1]: 
• 
Null hypothesis: SinuSonic device is not different from Sham control with respect to the 
achievement of adverse event rate at 8 weeks. 
Secondary objective [2]: 
• 
Null hypothesis: Sinusonic device is not different from Sham control with respect to device 
satisfaction rate at 8 weeks 
8.1.1. 
Multiplicity Adjustment 
A closed testing procedure that controls the family wise error rate in the strong sense at the overall [5]% 
level will be applied. The statistical comparisons for the primary efficacy endpoint and the key secondary 
endpoints will be carried out in the hierarchical order as indicated in Section 9.1. This means that the 
statistical hypotheses are tested in the prespecified order at the same significance level of α = [0.05] as 
long as all preceding hypotheses are rejected. Once a hypothesis is not rejected, subsequent hypotheses 
cannot be formally tested and therefore cannot be rejected. 
8.2. 
Analysis Sets 
Example 1: 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Full analysis set (FAS) 
• 
All randomized participants.  
Safety analysis set (SAS) 
• 
All participants who are exposed to investigational intervention. 
The full analysis set will be used to analyze endpoints related to the efficacy objectives and the safety 
analysis set will be used to analyze the endpoints and assessments related to safety.  
For the efficacy analyses, participants will be included in the analyses according to the planned 
investigational intervention; whereas for safety analyses, participants will be included in the analyses 
according to the investigational intervention they received. 

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8.3. 
Statistical Analyses 
8.3.1. 
General Considerations 
Statistical analysis will be conducted using SPSS version 25 (Armonk, NY: IBM Corp). Descriptive 
statistics such as means, range, standard deviations, frequencies, and percentages will be generated in 
order to present the baseline characteristics of both treatment arms. All continuous variables will be tested 
for normal distribution as determined by the Shapiro-Wilk test. To evaluate differences in outcome 
metrics between treatment arms (SinuSonic group vs sham control), paired t-tests will be used for 
normally distributed variables.  Wilcoxon signed rank tests were used for non-normally distributed or 
ordinal variables. For all tests, a value of p < 0.05 will be considered statistically significant.  The mean 
change between baseline and follow-up variables of interest will be calculated and measured against 
previously reported MCID thresholds when available or by using one-half of the baseline SD if not 
previously reported. Any missing data points will be excluded from analysis and handled similarly across 
all data points.  
 
8.3.1.1. 
Main Analytical Approach 
Statistical analysis will be conducted using SPSS version 25 (Armonk, NY: IBM Corp). Descriptive 
statistics such as means, range, standard deviations, frequencies, and percentages will be generated in 
order to present the baseline characteristics of both treatment arms. All continuous variables will be tested 
for normal distribution as determined by the Shapiro-Wilk test. To evaluate differences in outcome 
metrics between treatment arms (SinuSonic group vs sham control), paired t-tests will be used for 
normally distributed variables.  Wilcoxon signed rank tests were used for non-normally distributed or 
ordinal variables. For all tests, a value of p < 0.05 will be considered statistically significant.  The mean 
change between baseline and follow-up variables of interest will be calculated and measured against 
previously reported MCID thresholds when available or by using one-half of the baseline SD if not 
previously reported. Any missing data points will be excluded from analysis and handled similarly across 
all data points.  
8.3.2. 
Other Analyses 
Subgroup analyses of the primary endpoint and confirmatory secondary endpoints will be made to assess 
consistency of the investigational intervention effect across the following subgroups:  
• 
Age group: < 65 vs ≥ 65 years 
• 
Sex: female vs male 
• 
Race: white vs black vs. other 
If the number of participants is too small (less than [10%]) within a subgroup, then the subgroup 
categories may be redefined prior to unblinding the study. The analyses will be conducted using a test for 
heterogeneity and results will be presented on forest plots presenting the estimated study arm difference 
and 95% confidence intervals. Further details on the statistical analysis will be provided in the SAP. 

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8.4. 
Sample Size Determination 
Approximately 60 participants will be enrolled. The sample size calculation is based on the primary 
efficacy estimand and its endpoint.  
It is assumed that the proportion of participants achieving response for facial pain VAS is [30]% in the 
placebo intervention arm and [70]% in the arm receiving [intervention SinuSonic]. Using the normal 
approximation method for a 2-sided statistical test as described in Section 9.3.2, a study with an overall 
sample size of N = 60] participants will have over 90% power to detect a treatment difference between 
the two investigational interventions at a type-1 error level of 5%. 

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9. 
Supporting Documentation and Operational Considerations 
9.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
o Applicable ICH Good Clinical Practice (GCP) guidelines 
o Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, investigator’s brochure, IDFU, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate hazard 
to study participants.  
• 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants. 
• 
The investigator will be responsible for the following, as applicable: 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies, European Medical Device Regulation 2017/745 for clinical device research, and 
all other applicable local regulations 
Investigators and sub investigators will provide the sponsor with sufficient, accurate financial information 
as requested to allow the sponsor to submit complete and accurate financial certification or disclosure 
statements to the appropriate regulatory authorities. Investigators are responsible for providing 
information on financial interests during the course of the study and for 1 year after completion of the 
study. 
9.1.2. 
Informed Consent Process 
• 
The investigator or the investigator’s representative will explain the nature of the study, including 
the risks and benefits, to the potential participant and answer all questions regarding the study. 
• 
Potential participants must be informed that their participation is voluntary. They will be required 
to sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, privacy and data protection requirements, where applicable, and the 
IRB/IEC or study center. 

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• 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
• 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant. 
9.1.3. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
• 
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent  
• 
The participant must be informed that their medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
• 
The contract between sponsor and study sites specifies responsibilities of the parties related data 
protection, including handling of data security breaches and respective communication and 
cooperation of the parties. 
• 
Information technology systems used to collect, process, and store study-related data are secured 
by technical and organizational security measures designed to protect such data against accidental 
or unlawful loss, alteration, or unauthorized disclosure or access. 
 
9.1.4. 
Dissemination of Clinical Study Data 
The trial will be listed on clinicaltrial.gov and there is plan for publication following analysis of data to a 
peer-reviewed journal 
 
9.1.5. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic CRFs unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
• 
Guidance on completion of CRFs will be provided in online questionnaire. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source documents. 
• 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 

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• 
The sponsor or designee is responsible for the data management of this study, including quality 
checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 10 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
9.1.6. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
• 
Definition of what constitutes source data and its origin can be found in source data 
acknowledgement 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 
The sponsor or designee will perform monitoring to confirm that data entered into the CRF by 
authorized site personnel are accurate, complete, and verifiable from source documents; that the 
safety and rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH GCP, and 
all applicable regulatory requirements. 
9.1.7. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of participants. 
The first act of recruitment is the first site open and will be the study start date. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A study site 
is considered closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are not limited 
to: 
For study termination: 

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• 
Discontinuation of further study intervention development 
For site termination: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by the 
investigator 
• 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the investigators, 
the IECs/IRBs, the regulatory authorities, and any contract research organization(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate participant therapy and/or 
follow-up. 
9.1.8. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
• 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
 
 

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9.1.9. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study intervention. 
Definition of Unsolicited and Solicited AE 
• 
An unsolicited AE is an AE that was not solicited using a participant diary and that is 
communicated by a participant who has signed the informed consent. Unsolicited AEs include 
serious and nonserious AEs. 
• 
Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalization, emergency room visit, or visit to/by a healthcare provider). The participants will 
be instructed to contact the site as soon as possible to report medically attended event(s), as well 
as any events that, though not medically attended, are of participant concern. Detailed 
information about reported unsolicited AEs will be collected by qualified site personnel and 
documented in the participant’s records. 
• 
Unsolicited AEs that are not medically attended nor perceived as a concern by the participant will 
be collected during an interview with the participants and by review of available medical records 
at the next visit. 
• 
Solicited AEs are predefined local and systemic events for which the participant is specifically 
questioned, and which are noted by the participant in their diary. 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific judgment of 
the investigator (i.e., not related to progression of underlying disease, or more severe than 
expected for the participant’s condition) 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition 
• 
New condition detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
Events not Meeting the AE Definition 
• 
Any abnormal laboratory findings or other abnormal safety assessments that are associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for the 
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• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s condition 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen 
9.1.10. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the 
criteria listed: 
a. 
Results in death 
b. 
Is life threatening 
The term life threatening in the definition of serious refers to an event in which the participant was at risk 
of death at the time of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been admitted (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether hospitalization 
occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. 
Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) that may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised by the investigator in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition. These events should usually be considered serious. 

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o Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, convulsions not 
resulting in hospitalization, or development of intervention dependency or intervention 
abuse. 
9.1.11. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE information. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to one of the following categories:  
• 
Mild: 
A type of adverse event that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of daily 
living. 
• 
Moderate:  
A type of adverse event that is usually alleviated with additional specific therapeutic intervention.  
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research participant. 
• 
Severe:  
A type of adverse event that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.   
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. The investigator will use clinical judgment to determine the 
relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or arguments 
to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration, will be 
considered and investigated. 
• 
For causality assessment, the investigator will also consult the IB and/or product information, for 
marketed products. 
• 
The investigator may change their opinion of causality in light of follow-up information and send 
an SAE follow-up report with the updated causality assessment. 

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• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• 
New or updated information will be recorded in the originally submitted documents. 
9.1.12. 
Reporting of SAEs 
SAE Reporting to via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to medical monitor/SAE coordinator will be the 
electronic data collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data collection tool 
(see next section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be taken offline 
to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken offline, then the 
site can report this information on a paper SAE form (see next section) or to the medical 
monitor/SAE coordinator by telephone. 
SAE Reporting to medical monitor/SAE coordinator via Paper Data Collection Tool 
• 
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE data collection tool within the designated reporting timeframes. 
 
 

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9.2. 
Appendix 1: Medical Device AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting in Medical Device Studies 
• 
The definitions and procedures detailed in this appendix are in accordance with ISO 14155 and 
the European Medical Device Regulation (MDR) 2017/745 for clinical device research (if 
applicable).  
• 
Both the investigator and the sponsor will comply with all local reporting requirements for 
medical devices. 
• 
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study. See Section 6.1.1 for the list of sponsor medical 
devices. 
9.2.1. 
Definition of Medical Device AE and ADE 
Medical Device AE and ADE Definition  
• 
A medical device AE is any untoward medical occurrence in a clinical study participant, users, or 
other persons, temporally associated with the use of study intervention, whether or not considered 
related to the investigational medical device. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of an investigational medical device. This 
definition includes events related to the investigational medical device or comparator and events 
related to the procedures involved except for events in users or other persons, which only include 
events related to investigational devices. 
• 
An adverse device effect (ADE) is defined as an AE related to the use of an investigational 
medical device. This definition includes any AE resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
the investigational medical device as well as any event resulting from use error or from 
intentional misuse of the investigational medical device. 
9.2.2. 
Definition of Medical Device SAE, SADE and USADE 
A Medical Device SAE is an any serious adverse event that: 
a. Led to death  
b. Led to serious deterioration in the health of the participant, that either resulted in: 
• 
A life-threatening illness or injury. The term “life-threatening” in the definition of “serious” 
refers to an event in which the participant was at risk of death at the time of the event. It does not 
refer to an event, which hypothetically might have caused death if it were more severe. 
• 
A permanent impairment of a body structure or a body function. 
• 
Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing condition, or a 
procedure required by the protocol, without serious deterioration in health, is not considered an 
SAE. 
• 
Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function. 
• 
Chronic disease (MDR 2017/745). 
c. Led to fetal distress, fetal death, or a congenital abnormality or birth defect 

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SADE definition 
• 
An SADE is defined as an adverse device effect that has resulted in any of the consequences 
characteristic of an SAE. 
• 
Any device deficiency that might have led to an SAE if appropriate action had not been taken, 
intervention had not occurred, or circumstances had been less fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is defined as a serious 
adverse device effect that by its nature, incidence, severity, or outcome has not been identified in 
the current version of the risk analysis report (see Section 2.3). 
9.2.3. 
Definition of Device Deficiency 
• 
A device deficiency is an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety, or performance. Device deficiencies include malfunctions, use 
errors, and inadequacy of the information supplied by the manufacturer. 
9.2.4. 
Recording and Follow-Up of Medical Device AE and/or SAE and Device Deficiencies 
Medical Device AE, SAE, and Device Deficiency Recording 
• 
When an AE/SAE/device deficiency occurs, it is the responsibility of the investigator to review 
all documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE/device deficiency information in the 
participant’s medical records, in accordance with the investigator’s normal clinical practice and 
on the appropriate form. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
• 
For device deficiencies, it is very important that the investigator describes any corrective or 
remedial actions taken to prevent recurrence of the deficiency. 
o A remedial action is any action other than routine maintenance or servicing of a medical 
device where such action is necessary to prevent recurrence of a device deficiency. This 
includes any amendment to the device design to prevent recurrence. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE/SAE/device deficiency reported during 
the study and assign it to one of the following categories:  
• 
Mild:  
A type of adverse event that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of daily 
living. 
• 
Moderate:   
A type of adverse event that is usually alleviated with additional specific therapeutic intervention.  
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research participant. 

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• 
Severe:   
A type of adverse event that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.   
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE/device deficiency. The investigator will use clinical judgment to 
determine the relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or arguments 
to suggest a causal relationship, rather than a relationship, cannot be ruled out. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
• 
The investigator will also consult the IDFU or product information as part of the assessment. 
• 
The investigator must review and provide an assessment of causality for each AE/SAE/device 
deficiency and document this in the medical notes. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to medical monitor/SAE coordinator. However, it is 
very important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to medical monitor/SAE coordinator. 
• 
The investigator may change their opinion of causality in light of follow-up information and send 
an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of Medical Device AE/SAE and device deficiency 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by medical monitor/SAE coordinator to 
elucidate the nature and/or causality of the AE/SAE/device deficiency as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed form. 
• 
The investigator will submit any updated SAE data to medical monitor/SAE coordinator within 
24 hours of receipt of the information. 
9.2.5. 
Reporting of Medical Device SAEs 
Medical Device SAE Reporting to medical monitor/SAE coordinator via an Electronic Data 
Collection Tool 
• 
The primary mechanism for reporting an SAE to medical monitor/SAE coordinator will be the 
electronic data collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data collection tool 
(see next table) to report the event within 24 hours. 

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• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be taken offline 
to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken offline, then the 
site can report this information on a paper SAE form (see next table) or to the medical 
monitor/SAE coordinator by telephone. 
Medical Device SAE Reporting to medical monitor/SAE coordinator via Paper Data Collection Tool 
• 
Facsimile transmission of the SAE paper data collection tool is the preferred method to transmit 
this information to the medical monitor/SAE coordinator. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE paper data collection tool sent by overnight mail or courier 
service. 
• 
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE paper data collection tool within the designated reporting time frames. 
9.2.6. 
Reporting of SADEs 
SADE Reporting to medical monitor/SAE coordinator  
NOTE: There are additional reporting obligations for medical device deficiencies that are potentially 
related to SAEs that must fulfill the legal responsibility to notify appropriate regulatory authorities and 
other entities about certain safety information relating to medical devices being used in clinical studies. 
• 
Any device deficiency that is associated with an SAE must be reported to the sponsor within 24 
hours after the investigator determines that the event meets the definition of a device deficiency. 
• 
The sponsor will review all device deficiencies and determine and document in writing whether 
they could have led to an SAE. These device deficiencies will be reported to the regulatory 
authorities and IRBs/IECs as required by national regulations. 

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10. 
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Published online 2018. doi:10.2500/ajra.2018.32.4501 
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Lal D, Rounds A, Dodick DW. Comprehensive management of patients presenting to the 
otolaryngologist for sinus pressure, pain, or headache. Laryngoscope. Published online 2015. 
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Levine HL, Setzen M, Cady RK, et al. An otolaryngology, neurology, allergy, and primary care 
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2006;134(3):516-523. doi:10.1016/j.otohns.2005.11.024 
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Patel ZM, Kennedy DW, Setzen M, Poetker DM, Delgaudio JM. “Sinus headache”: Rhinogenic 
headache or migraine? An evidence-based guide to diagnosis and treatment. Int Forum Allergy 
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Kari E, Delgaudio JM. Treatment of sinus headache as migraine: The diagnostic utility of triptans. 
Laryngoscope. Published online 2008. doi:10.1097/MLG.0b013e318182f81d 
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Cady RK, Schreiber CP. Sinus headache or migraine? Neurology. 2002;58(9 suppl 6):S10-S14. 
doi:10.1212/WNL.58.9_SUPPL_6.S10 
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Dadgarnia MH, Atighechi S, Baradaranfar MH. The response to sodium valproate of patients with 
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Ishkanian G, Blumenthal H, Webster CJ, Richardson MS, Ames M. Efficacy of sumatriptan 
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Maul XA, Borchard NA, Hwang PH, Nayak J V. Microcurrent technology for rapid relief of sinus 
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Khanwalkar A, Johnson J, Zhu W, Johnson E, Lin B, Hwang PH. Resonant vibration of the 
sinonasal cavities for the treatment of nasal congestion. Int Forum Allergy Rhinol. 2021;(July):1-4. 
doi:10.1002/alr.22877 
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Soler ZM, Nguyen SA, Salvador C, et al. A novel device combining acoustic vibration with 
oscillating expiratory pressure for the treatment of nasal congestion. Int Forum Allergy Rhinol. 
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Melzack R. The short-form McGill pain questionnaire. Pain. Published online 1987. 
doi:10.1016/0304-3959(87)91074-8 
13.  
Cleeland C. The Brief Pain Inventory User Guide. Br Pain Invent. Published online 2009. 
14.  
Mease PJ, Spaeth M, Clauw DJ, et al. Estimation of minimum clinically important difference for 
pain in fibromyalgia. Arthritis Care Res. Published online 2011. doi:10.1002/acr.20449