A Prospective, Randomized, Crossover Study of Therapy Adherence With TheraPAP Compared to Automatic Adjusting Positive Airway Pressure (APAP) for the Treatment of Obstructive Sleep Apnea (OSA)
Phase: NA
Conditions: Obstructive Sleep Apnea
Sponsor: SleepRes Inc.

 
 
Title Page 
Protocol Title: A Prospective, Randomized, Crossover Study of Therapy Adherence with 
TheraPAP Compared to Automatic Adjusting Positive Airway Pressure (APAP) for the Treatment 
of Obstructive Sleep Apnea (OSA) 
Protocol Name: TheraPAP Adherence 1 
Sponsor Protocol #: Home 0001  
Version Number: 0.2 
Compound Number: TheraPAP 
Short Title: TheraPAP Adherence Crossover Study 
Sponsor Name and Legal Registered Address:  
SleepRes, PLLC 
1508 Carl Adams Dr  
Murfreesboro, TN 37129 
Regulatory Agency Identifying Number: Exempt  
Approval Date: 05/02/2024 
Date and Version of Previous Protocol: na 
 
Sponsor Signatory: 
 
 
William Noah, MD 
 
 
Date 
 
 

 
 
Table of Contents 
 
Table of Contents ............................................................................................................................ 2 
1 
Protocol Summary .................................................................................................................... 5 
1.1 
Synopsis ................................................................................................................................ 5 
1.2 
Schedule of Activities (SoA) ................................................................................................ 7 
2 
Introduction............................................................................................................................... 8 
2.1 
Study Rationale .................................................................................................................... 8 
2.2 
Background........................................................................................................................... 8 
2.2.1 
Obstructive Sleep Apnea .................................................................................................. 8 
2.2.2 
Unmet Medical Need ........................................................................................................ 9 
2.2.3 
Biological Rationale ......................................................................................................... 9 
3 
Endpoints .................................................................................................................................. 9 
4 
Study Design ........................................................................................................................... 10 
4.1 
Overall Design .................................................................................................................... 10 
4.2 
Detailed Design .................................................................................................................. 10 
4.2.1 
Pre-Screening ................................................................................................................. 10 
4.2.2 
Evening before the sleep study ............................... Errore. Il segnalibro non è definito. 
4.2.3 
In-laboratory overnight PSG .......................................................................................... 12 
4.2.4 
Morning after the sleep study ................................. Errore. Il segnalibro non è definito. 
4.3 
End of Study Definition...................................................................................................... 13 
5 
Study Population ..................................................................................................................... 13 
5.1 
Inclusion Criteria ................................................................................................................ 13 
5.1.1 
Age and Sex .................................................................................................................... 13 
5.1.2 
OSA Measures ................................................................................................................ 13 
5.1.3 
Weight ..................................................................... Errore. Il segnalibro non è definito. 
5.1.4 
Informed Consent ........................................................................................................... 13 
5.2 
Exclusion Criteria ............................................................................................................... 13 
5.2.1 
Medical Conditions ........................................................................................................ 14 
5.2.2 
Prior/Concomitant Therapy ............................................................................................ 14 
5.2.3 
Other Exclusions ............................................................................................................ 14 
5.3 
Screen Failures ................................................................................................................... 14 
5.4 
Preparation/Handling/Storage/Accountability ................................................................... 14 

 
 
5.5 
Measures to Minimize Bias ................................................................................................ 14 
5.6 
Concomitant Therapy ......................................................................................................... 15 
5.7 
Discontinuation of Study Treatment ................................................................................... 15 
5.8 
Stopping Criteria ................................................................................................................ 15 
5.8.1 
Individual Participant Stopping Criteria ......................................................................... 15 
5.9 
Participant Discontinuation/Withdrawal from the Study ................................................... 15 
5.10 Participant compensation.................................................................................................... 16 
6 
Study Assessments and Procedures ........................................................................................ 16 
6.1 
Overnight study .................................................................................................................. 16 
6.2 
Safety Assessments ............................................................................................................. 16 
6.2.1 
Vital Signs .............................................................. Errore. Il segnalibro non è definito. 
6.3 
Adverse Events and Serious Adverse Events ..................................................................... 16 
6.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................... 17 
6.3.2 
Method of Detecting AEs and SAEs ...................... Errore. Il segnalibro non è definito. 
6.3.3 
Follow-up of AEs and SAEs ........................................................................................... 17 
6.3.4 
Regulatory Reporting Requirements for SAEs .............................................................. 17 
7 
Statistical Considerations........................................................................................................ 18 
7.1 
Sample Size Determination ................................................................................................ 18 
7.2 
Randomization .................................................................................................................... 18 
7.3 
Populations for Analyses .................................................................................................... 18 
7.4 
Interim Analyses ................................................................................................................. 19 
8 
Supporting Documentation and Operational Considerations ................................................. 19 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................................... 20 
1. Regulatory and Ethical Considerations .................................................................................. 20 
2 
Financial Disclosure ............................................................................................................... 20 
3 
Informed Consent Process ...................................................................................................... 21 
4 
Data Protection ....................................................................................................................... 21 
5 
Data Quality Assurance .......................................................................................................... 21 
6 
Source Documents .................................................................................................................. 22 
7 
Publication Policy ................................................................................................................... 22 
8 
Protocol Approval and Amendment........................................................................................ 22 
9 
Liability and Insurance ........................................................................................................... 23 

 
 
10 Access to Source Data ............................................................................................................ 23 
Appendix 2: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting.......................................................................................................................... 24 
Appendix 3: List of Abbreviations ................................................................................................ 30 
References ..................................................................................................................................... 31 
 

 
 
1 Protocol Summary 
1.1 Synopsis 
Protocol Title: A Prospective, Randomized, Crossover Study of the TheraPAP Compared to 
Automatic Adjusting Positive Airway Pressure (APAP) for the Treatment of Obstructive Sleep 
Apnea (OSA) 
Protocol Name/Number: TheraPAP Adherence 1 
Sponsor: SleepRes, PLLC 
Rationale: TheraPAP is a prototype device (with full documented electrical and isolation safety) 
being developed by SleepRes for the treatment of obstructive sleep apnea (OSA) that can deliver 
either standard CPAP at a set pressure or what is called TPAP1. TPAP is a pressure control 
algorithm that lowers the pressure from the set pressure at the beginning of inspiration and does 
not return the pressure to the full set level until about halfway through expiration.  The present 
study, TheraPAP Adherence 1, is a randomized crossover study designed to examine the 
difference in therapy adherence between TPAP vs. CPAP alone in the treatment of OSA.   
Overall Design: 
The TheraPAP Adherence Study is a randomized, crossover study in treatment naive participants 
with OSA in which the adherence to therapy will be compared between TPAP and standard 
APAP.  Because all participants will breathe on both therapy types and those therapy types are 
individually unique in feel, blinding is not possible.  Participants will be chosen from a pool of 
patients who are PAP-naïve and who have received either a PSG (in-lab polysomnogram), split-
night study (in-lab PSG and pressure titration) or home sleep study (HST) within the previous 3 
months.   
Upon signing an informed consent, participants will be randomly assigned to start on either the 
TPAP or APAP arms when they arrive at the office to pick up their Sefam S.Box with TheraPAP 
algorithms integrated. Each participant will then be given their new equipment and will be 
trained in proper use for both arms of the study so that they will not need to appear at the office 
again until the study is completed.  In both the APAP and TPAP arms, participants will have their 
therapy set to 5-20 cmH2O for three nights.  The pressure range will then be narrowed to ± 2 
cmH2O around their 95% pressure level as assessed during the third night.  This same pressure 
range will be used during the second arm for each patient.   
 
1 TPAP will be used herein to refer to the active treatment. 

 
 
Within the TPAP arm, participants will be set to a double Comfort Setting drop according to the 
following table.  This drop schedule will be implemented even while the TPAP device is 
operating with automatic pressure adjustment.   
 
Pset  
(cmH2O) 
Pressure Drop 1 
(cmH2O) 
Pressure Drop 2 
(cmH2O) 
5.0 - 5.9 
0 
0 
6.0 – 6.9 
1 
0 
7.0 – 7.9 
2 
0 
8.0 – 8.9 
2 
1 
9.0 – 9.9 
2 
2 
10.0 – 20.0 
2 
3 
 
Table 1: Comfort Setting Pressure Drops 1 and 2 to be used at the specified target set pressure to 
the patient.   
 
Participants will use their starting therapy nightly at home for 6 weeks after which time they will 
undergo a washout period of 1 week where no therapy will be used.  Following the washout 
period, they will initiate another 6-week usage with the second therapy.  Afterward, they will 
return to the office to receive their permanent equipment.  Phone calls as reminders to end the 
first arm, start the washout period, then to start the second arm will be made.   
Immediately after both arms of the study are completed, the following will occur: 
• Eligibility criteria will be reviewed and confirmed 
• Participants will be asked to respond to the following 
o ESS (Epworth Sleepiness Scale) 
o FOSQ (Functional Outcomes of Sleep Questionnaire) 
During the home use period, subjects will be called at the following time points during each arm 
of the study. At each time point, adverse events and compliance with the device will be assessed.  
Subjects using the device less than an average of 5 hours per night during the first week will be 
contacted on a more regular basis (weekly until 5 hour per night use is achieved) to address any 
problems and encourage use.  If patients discontinue use of the device during the home use 
period, they will still be encouraged to return for all testing per protocol.  If a patient refuses to 
come in for further testing, they will be considered a lost to follow up and excluded from 
efficacy analysis.   
• 1 Day Phone Call (+2 days) 
• 7 Day Phone Call (+/- 3 days) 
• 14 Day Phone Call (+/- 3 days) IF deemed necessary per 7 Day compliance 
• 28 Day Phone Call (+/- 3 days) Check-in 

 
 
• Week 6 Phone Call (+/- 3 days) – End first arm, fill out questionnaires, start Washout 
Period 
• Week 7 Phone Call (+/- 3 days) - Review protocol, start 2nd arm 
• Week 12 (+/- 3 days) - Equipment Return 
 
Data collected from the therapy device will include the following: 
• Usage averaged over the 6-week period and nightly 
• Leak averaged over the 6-week period and nightly 
• P95 averaged over the 6-week period and nightly (for the CPAP/APAP arm only) 
• Sleep events averaged over the 6-week period and nightly 
 
Number of Participants: 
A total of 32 participants will be enrolled.  
Study Duration: 
Per subject study duration will be approximately 4 months (screening plus 90 days of home use).  
Total study duration will be approximately 9 months (6-month enrollment plus 35 days of home 
use). 
1.2 Schedule of Activities (SoA)  
 
Schedule of Activities 
Procedures  
Screening 
Office 
Home 
Telephone or outpatient contacts with participant 
X 
 
 
Informed consent when patient comes to office 
 
X 
 
Analysis of CPAP compliance data 
 
X 
 
Demographics 
 
X 
 
Medical history & medications 
 
X 
 
Height 
 
X 
 
Weight 
 
X 
 
Randomization 
 
X 
 
Provide equipment and training 
 
X 
 
1st Post- 6-Week Activity 
Review and confirm eligibility criteria 
X 
 
 
ESS 
 
 
X 
FOSQ 
 
 
X 
AE/SAE Monitoring 
 
 
X 

 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; ESS = Epworth Sleepiness Scale; FOSQ = Functional Outcomes of Sleep 
Questionnaire; PROMIS = Patient-Reported Outcomes Measurement Information System; SAE = serious adverse 
event 
 
2 Introduction 
2.1 Study Rationale 
A device able to provide inspiratory positive airway pressure (PAP) < expiratory PAP, designated 
TPAP, is being developed by SleepRes for the treatment of obstructive sleep apnea (OSA). In 
prior studies, the administration of higher inspiratory than expiratory PAP did not substantially 
increase treatment efficacy or adherence to continuous PAP (CPAP), which remains low. In our 
recent investigation, we demonstrated that the addition of a resistor to the CPAP circuit to reduce 
inspiratory PAP increased subjective comfort. The present study, TheraPAP Adherence, is a 
Crossover study designed to examine whether TPAP can improve adherence over CPAP as an at 
home treatment for OSA.   
2.2 Background 
2.2.1 
Obstructive Sleep Apnea 
The National Commission on Sleep Disorders Research identified sleep disorders as a major 
public health burden. OSA is the most common of the more serious sleep disorders and affects 
approximately 20 million people in the United States (US), with approximately 13% of men and 
6% of women affected (1). OSA is characterized by repetitive collapse or ‘obstruction’ of the 
pharyngeal airway during sleep, manifesting as repetitive episodes of hypopnea (i.e., shallow 
breathing) or apnea (i.e., paused breathing). These episodes of hypopnea or apnea may lead to 
hypoxemia, arousal from sleep, sleep fragmentation, excessive daytime sleepiness, and/or 
neuropsychological impairment. 
Long-term, OSA is associated with increased mortality and a number of adverse cardiovascular, 
neurocognitive, metabolic, and daytime functioning consequences (2-11). 
2nd Post- 6-Week Activity 
ESS 
 
 
X 
FOSQ 
 
 
X 
AE/SAE Monitoring 
 
 
X 
Return study equipment 
 
X 
 
Receive future home therapy equipment and training 
 
X 
 

 
 
2.2.2 
Unmet Medical Need 
The large majority of OSA patients are treated with positive airway pressure, the most common 
of which is CPAP, provided by a machine that mechanically maintains an open airway. However, 
long-term adherence to therapy remains a challenge for many patients (12, 13). Common 
complaints include inconvenience, lack of perceived benefit, discomfort related to improper 
fitting of the interface, and difficulty expiring against positive pressure (14, 15).  
As many patients cannot use CPAP because they find it intolerable, this represents a significant 
health concern, as OSA is associated with numerous adverse health outcomes and increased 
mortality. Strategies to improve tolerance of CPAP, and subsequently adherence, are needed. 
2.2.3 
Biological Rationale 
TPAP is an innovative device/algorithm designed to deliver a lower inspiratory than expiratory 
PAP.  The drop in inspiratory pressure can be modulated during the inspiratory phase. Previous 
research has shown that reducing inspiratory PAP by placing a resistor in the inspiratory line can 
enhance subjective comfort and decrease leaks when compared to CPAP, despite maintaining a 
similar residual apnea-hypopnea index (AHI). However, the resistor could only provide a fixed 
inspiratory PAP reduction based on existing PAP settings. TPAP addresses this limitation by 
allowing for adjustable drops in inspiratory PAP throughout the inspiration phase, offering a 
potentially more personalized and adaptive therapeutic approach. 
3 Endpoints 
 
2 Although there will not be any direct treatment vs. control comparison here, we will assume that CPAP is safe and 
that any abnormal value recorded in the next morning compared to the evening before the polysomnography is due 
to treatment with TPAP. 
 
Endpoints 
Primary 
• 
Nightly adherence (usage) with device (TPAP versus APAP) 
Secondary 
• 
Evaluation of P95, Leak and AHI over each 6-week period 
• 
6-week Subjective Questionnaires (TheraPAP versus APAP) following each arm 
o 
ESS 
o 
FOSQ 
• 
Adverse Event rate 
Safety Endpoints2 
• 
Spontaneous adverse events 

 
 
 
4 Study Design 
4.1 Overall Design 
Safety issues regarding this study are detailed in Appendix 1: Regulatory, Ethical, and Study 
Oversight Considerations.   
The TheraPAP Adherence 1 Study is a randomized, controlled, crossover study in PAP-naïve 
participants with OSA. Pre-screening is conducted to establish potential eligibility based on an 
in-lab polysomnogram (PSG), a PSG split-night PSG/titration or a home sleep study (HST) that 
has been conducted within the previous 3 months.  Participants would then be recruited as 
described below.  For those who consent, they will be given the equipment and instructions to 
complete both arms of the study but will have their therapy device set to the parameters 
necessary to start the first arm, which will be randomly assigned.  They will use the device 
nightly for 6 weeks, after which they will use no therapy for 1 full week (washout period).  
During this washout period, their therapy device will be remotely set to their second arm.  When 
they restart therapy, they will use the device nightly for a further 6 weeks.  During each arm, 
various data will be remotely collected from their therapy device, and after completion of each 
arm, they will fill out 3 questionnaires and average data during the 6 weeks of that arm will be 
downloaded.  Once all activities are completed, they will be eligible to receive the incentive pay 
and their involvement will be completed.   
4.2 Detailed Design 
4.2.1 
Pre-Screening 
The first phase of recruiting for the TheraPAP Adherence 1 study will be done during the phone 
follow up during which the patients will be scheduled to come to the office of Sleep Centers of 
Middle Tennessee (SCMT) to collect their CPAP equipment.  The following regarding the study 
will be conveyed to them: goals, a summary protocol, risks/benefits, other activities required by 
them, financial compensation and timing.  They will also be asked for verbal permission to 
review their records so that office personnel can conduct a preliminary screening for eligibility.  
If they agree and show interest based on the first phase, they will be added to the eligibility 
roster.   
 
The second phase of recruiting will be conducted when they come into the office to pick up the 
equipment.  The coordinator will review the material related to the study, as well as the details 
within the informed consent.  If the patient agrees to continue, they will sign the informed 

 
 
consent in ink and be enrolled in the study.  The coordinator will conduct a final check that the 
patient satisfies all enrollment criteria.  After this, they will be enrolled in the study.   
 
They will then be randomly assigned to start in either the APAP or TPAP arms of the study, and 
their equipment will be set up by the coordinating staff to operate according to the randomly 
chosen arm.  During this setup, the pressure range will also be set to 5-20 cmH2O irrespective of 
study arm.  They will receive this equipment for the study, then be given instructions for use on 
both arms both verbally and through material that they can take home.   
 
4.2.2 
First 6-Week Arm 
Patients will start using their equipment the first night.  The study coordinator will monitor usage 
nightly and after the third night with a minimum of 5 hours of use, they will remotely adjust the 
device pressure range to P95 ± 2 cmH2O, using the P95 from the third night.  This range will be 
used for the remainder of both arms of the study.  During the study, daily remote collection of 
usage will be conducted both for later primary endpoint analysis and to guide further contact 
with the patient if they need help.   
During usage in the first arm, P95 and AHI will be monitored to assure that the patient is 
receiving proper therapy.  If P95 is near the upper limit and the AHI is above 5 events per hour, 
the range will be bumped up by 2 cmH2O.   
A contact schedule will also be set up with each patient to follow up on any needs for help.  
Similar interaction is customary with new CPAP patients.  The schedule is as follows and will be 
conducted on both arms of the study: 
• 1 Day Phone Call (+2 days) 
• 7 Day Phone Call (+/- 3 days) 
• 14 Day Phone Call (+/- 3 days) IF deemed necessary per 7 Day compliance 
• 28 Day Phone Call (+/- 3 days) 
Participants using the device less than an average of 5 hours per night during the first week will 
be contacted on a more regular basis (weekly until 5 hour per night use is achieved) to address 
any problems and encourage use.  If patients discontinue use of the device during the home use 
period, they will still be encouraged to complete surveys per protocol.  If a patient refuses to 
complete such surveys, they will be considered lost to follow up and excluded from efficacy 
analysis.   
At the end of the 6-week period, patients will stop using any sleep therapy for 1 week as a 
washout between arms.  The study coordinator will remotely switch the mode of operation of the 

 
 
therapy device to that for the second arm employing the same pressure range as was used in the 
bulk of the first arm.  Patients will be asked to fill out the questionnaires during this period (ESS 
and FOSQ).  Additionally, the following data averaged over the 6-week period of the trial will be 
downloaded from the device: 
• Usage 
• Leak 
• P95 
• AHI 
 
4.2.3 
Second 6-Week Arm 
Following the one-week washout period, patients will start the second arm therapy for the next 
six weeks of nightly use.  The procedure will be exactly the same as for the first arm, described 
above except that the device pressure range will be retained at the same settings that were present 
during the bulk of the first arm.   
4.2.4 
TPAP Arm Specifics 
The TPAP arm involves other pressure settings because the therapy involves reducing pressure in 
two steps starting at inhalation and following through the peak of exhalation.  An auto-adjusting 
algorithm will continuously choose the pressure within the active pressure range, and the settings 
for the two pressure drops will also instantly and continuously adjust to those specified in Table 
1 above.   
4.2.5 
Risk-Benefit Analysis 
All patients will be using a Sefam S.Box as their therapy device.  Although the S.Box does not 
have 510K approval, it is CE-marked and approved for use in Europe.  All TheraPAP algorithms 
will be thoroughly verified and validated for safety and efficacy in each device according to the 
SleepRes QMS before being provided to a patient.  When not in use and when returned, these 
devices will be sequestered in a locked location.  TheraPAP is a new OSA therapy designed to 
improve CPAP comfort.  Testing in awake PAP-naïve patients thus far has shown a preference of 
it over CPAP.  Thus, we expect there are no risks associated with it.   
Regarding benefits to the participants: 
• It is anticipated that patients on the TheraPAP arm of the study will find it more 
comfortable than regular CPAP and hopefully sleep better.  

 
 
• The results of the study could yield future benefit to the participants in terms of wider 
treatment alternatives for their OSA.   
4.3 End of Study Definition 
Once the second 6-week arm is over and questionnaires have been completed, the patients will 
return their equipment to the office.  Once the equipment is returned, the participants’ 
involvement in the study will be complete and they will be able to receive their study incentive.  
They will also then be given their regular take-home equipment with usage instructions.   
5 Study Population 
Eligible participants will be recruited from the pool of PAP-naïve patients who have undergone 
some form of sleep study and will be receiving CPAP therapy equipment.   
5.1 Inclusion Criteria 
5.1.1 
Age and Sex 
1. Between 20 and 70 years of age, inclusive. 
5.1.2 
OSA Measures  
2. Diagnosis of OSA meeting all the following criteria: 
a. AHI > 10 on a previous PSG or HST (hypopneas requiring 4% desaturation).  
b. Central apneas < 25% of events 
c. PLM arousal index < 15 
5.1.3 
Informed Consent 
3. Subject is fluent in English and subject understands the study protocol and is willing and 
able to comply with study requirements and sign informed consent. 
4. Participant voluntarily agrees to participate in this study and signs an Institutional Review 
Board (IRB)-approved informed consent prior to performing any of the study-related 
procedures. 
5.2 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 

 
 
5.2.1 
Medical Conditions 
1. A female of child-bearing potential that is pregnant or intends to become pregnant. 
2. Any unstable or severe medical condition of any organ system including congestive heart 
failure, COPD, renal failure, neuromuscular disease, etc., or at the discretion of the site 
Principal Investigator (PI). 
3. Taking medication that may affect sleep, sleepiness, or alertness including hypnotics, 
sedatives, alerting agents, stimulants, anticonvulsants, etc. 
4. The presence of any other sleep disorder (insomnia, periodic limb movement disorder, etc). 
5.2.2 
Prior/Concomitant Therapy 
5. Prior therapy or treatment for OSA.  
6. Chronic oxygen therapy. 
5.2.3 
Other Exclusions 
7. Excessive alcohol consumption (>14 drinks/week). 
8. The use of any illegal drug(s). 
9. Any condition that in the investigator’s opinion would present an unreasonable risk to the 
participant, or which would interfere with their participation in the study or confound study 
interpretation. 
5.3 Screen Failures 
Patients that do not meet the inclusion/exclusion criteria at the outpatient screening visit will not 
be invited to, or further contacted to, participate in the study. 
5.4 Preparation/Handling/Storage/Accountability 
Devices will be provided by the sponsor and will be kept in a locked designated area within the  
DME (Durable Medical Equipment) office.  It will only be accessible by office personnel.  They 
will be used only for approved study purposes as designated by the study coordinator who will 
oversee their use in this study.   
5.5 Measures to Minimize Bias 
Each participant will begin the study in one of the treatment arms, (either APAP or TPAP). The 
starting treatment arm is determined by a random number generator, as described in Section 7.2.     

 
 
5.6 Concomitant Therapy 
Usual therapy is allowed as indicated by the patient’s general practitioner, except for oxygen 
therapy, which is an exclusion criterion. 
5.7 Discontinuation of Study Treatment 
If a clinically significant finding is identified, the Investigator or qualified designee will 
determine if the participant can continue in the study and if any change in participant 
management is needed. Any new clinically relevant finding should be reported as an adverse 
event (AE). 
5.8 Stopping Criteria 
5.8.1 
Individual Participant Stopping Criteria 
Participants reporting any SAE considered possibly related or related to study device will be 
withdrawn from the study. 
Any other AE that in the judgment of the Investigator necessitates the participant stopping to 
protect participant safety, will result in early withdrawal from the study. 
5.9 Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
administrative reasons. 
If the participant withdraws consent, the Sponsor may retain and continue to use any data 
collected before such a withdrawal of consent. 
All participants who withdraw from the study with an ongoing AE must be followed until the 
event is resolved or deemed stable. 
Participation may be terminated before completing the study and the reason recorded as follows: 
• Withdrawal due to AE 
• Participant withdrew consent at their own request, (e.g., intolerance to study procedures) 
• At the discretion of the Investigator for safety, behavioral, or administrative reasons 
• Other reasons, as they occur 

 
 
5.10 Participant compensation 
Participants will be compensated for their time and participation with an office credit of $200. 
 
6 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA. 
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. 
6.1 At Home Study 
• Methods: Equipment taken home for the study (Sefam S.Box and associated patient interface 
materials) has been given European approval via a CE mark.  Additions of TheraPAP 
algorithms, which have been tested extensively for safety and efficacy in our lab, will be 
evaluated on the S.Box machines via a testing procedure that is part of our quality system.   
• Regular contact with patients according to the call schedule will be conducted and any 
problems will be discussed and reported.   
• Study data reported by the S.Box (usage, P95, leak and AHI) will be averaged over a night 
and recorded daily through the S.Box remote access system, and will be stored according to 
HIPAA requirements at the sponsor’s office.   
6.2 Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
Safety assessments will include measurement of vital signs, monitoring and recording of AEs, 
SAEs, and recording of study or treatment discontinuations. Effects on OSA and sleep 
parameters (e.g., sleep time and sleep stages) will also be monitored by PSG. 
 
6.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Appendix 2: Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting.   

 
 
Adverse events will be reported by the participant.  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up on AEs that are serious, considered related to the study device or the study, or that caused the 
participant to discontinue the study. 
6.3.1 
Time Period and Frequency for Collecting AE and SAE 
Information 
All AEs and SAEs will be collected from randomization until the end of the study at the 
timepoints specified in the SoA. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 2.  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 AEs or SAEs after the conclusion of 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 he/she considers the event to be reasonably 
related to the study or study participation, the Investigator must promptly notify the Sponsor. 
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 2.   
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrence. 
6.3.2 
Follow-up of AEs and SAEs 
Ongoing AEs and SAEs will be followed until resolution or stability as determined by the 
Investigator.  
6.3.3 
Regulatory Reporting Requirements for SAEs 
Prompt notification (within 24 hours, see Appendix 2) 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 treatment 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 treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority and IRB. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
7 Statistical Considerations 
7.1 Sample Size Determination 
Sample sizes are estimated to achieve 80% power based on a 1-sided 5% significance level.  As 
this is an exploratory proof of concept trial, a 1-sided 5% significance level was selected.  The 
within subject standard deviation is assumed to be 1 hour and the minimum treatment difference 
is assumed to be 0.5 hours.   
When there are 2 treatments and a sample size of 14 in each of the 2 sequences, a 2x2 Williams 
Crossover Design will have approximately 82% power to detect a minimum pairwise difference 
of 0.5 or greater, assuming that the standard deviation of the paired differences is 1 at a one-sided 
5% significance level. 
 
Assuming ~20% dropout and total of 36 patients (18/sequence) is planned. 
 
7.2 Randomization 
The treatment arm is determined by random selection using an MS Excel spreadsheet on the 
night of the study. The spreadsheet generates a number between 1 and 10,000. The TPAP therapy 
will be the starting therapy when an even number is generated by the spreadsheet; the CPAP 
therapy will be the starting therapy when an odd number is generated.   
7.3 Populations for Analyses 
For the purposes of analysis, the following analysis sets are defined: 

 
 
Set 
Description 
Randomized 
All participants who were randomized. 
Modified Intent to Treat 
(mITT) Set 
The mITT set comprises all participants who are randomized, 
undergo at least 1 night in either study arm, and have at least 1 
measurement on the primary endpoint. Participants will be 
analyzed for equivalence. 
Safety Set 
The Safety Set consists of all participants who are randomized 
and undergo at least 1 night in either study arm.  
Per Protocol (PP) Set 
The PP Population consists of all participants without any major 
protocol violations and have considered to be evaluable for study 
analysis. 
 
7.4 Interim Analyses 
No interim analysis is planned.  
8 Supporting Documentation and Operational Considerations 
• Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
• Appendix 2: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
• Appendix 3: List of Abbreviations 
 
 

 
 
 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
• Applicable International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, and other relevant documents (e.g., advertisements) 
must be submitted to an IRB by the Investigator and reviewed and approved by the IRB before 
the study is initiated. 
Any amendments to the protocol will require IRB approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to 
study participants. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB. 
• Notifying the IRB of SAE or other significant safety findings as required by IRB 
procedures. 
• Overall conduct of the study at the site and adherence to requirements of 21 Code of 
Federal Regulations (CFR), ICH GCP guidelines, the IRB guidelines, and all other 
applicable local regulations. 
2 Financial Disclosure 
Investigators will provide the Sponsor with sufficient, accurate information in accordance with 
local regulations 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. 

 
 
3 Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant or 
his/her legally authorized representative and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act requirements, 
where applicable, and the IRB. 
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 consent to the most current version of the ICF(s) during their participation in 
the study. 
A copy of the signed ICF(s) must be provided to the participant.  
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IRB and 
signed by all participants subsequently enrolled in the study. 
4 Data Protection 
Participants will be assigned a unique identifier by the study site. 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 his/her 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. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities. 
5 Data Quality Assurance 
All participant data relating to the study will be recorded on electronic reports and spreadsheets. 
Any study data will be de-identified. The Investigator is responsible for verifying that data 
entries are accurate and correct by physically or electronically signing the study records. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the study records. 

 
 
The Investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the Investigator for 5 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. 
All data generated by the site personnel will be captured and stored in an internal password-
protected system. 
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 site. 
7 Publication Policy 
The Sponsor will generally support publication, reserving the right to review prior to submission.  
Authorship will be determined by mutual agreement and in line with the International Committee 
of Medical Journal Editors’ authorship requirements. 
A summary of the study results will also be posted in a publicly accessible database (e.g., 
www.ClinTrials.gov).  
8 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IRB/Competent Authorities, in accordance with local legal requirements. The Sponsor 
must ensure that all ethical and legal requirements have been met before the first participant is 
enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/Competent Authority approval 
prior to implementation (if appropriate). Any deviations from the protocol will be reported to the 
Sponsor as Protocol Deviations. 

 
 
Administrative changes (not affecting the participant benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
9 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance coverage in accordance with 
all local legal requirements. The civil liability of the Investigator, the persons instructed by him 
or her and the hospital, practice, or institute in which they are employed and the liability of the 
Sponsor with respect to financial loss due to personal injury and other damage that may arise as a 
result of the carrying out of this study are governed by the applicable law. 
The Sponsor will arrange for participants participating in this study to be insured against 
financial loss due to personal injury caused by medical steps taken during the study. 
10 Access to Source Data 
Regulatory authorities of certain countries, IRBs, and/or the Sponsor’s Clinical Quality 
Assurance Group (or designee) may wish to carry out source data checks and/or on-site audit 
inspections. Direct access to source data will be required for these inspections and audits; they 
will be carried out giving due consideration to data protection and medical confidentiality. The 
Investigator assures the Sponsor and affiliates or designees (such as a CRO) of the necessary for 
support at all times. 
 
 

 
 
Appendix 2: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a participant or clinical study 
participant, temporally associated with the use of a study treatment, whether 
considered related to the device product. 
• NOTE: An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease (new or exacerbated) temporally associated with the use of a study treatment. 
 
Events Meeting the AE Definition  
• Any abnormal safety assessments (e.g., 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). 
• Exacerbation of a chronic or intermittent pre-existing condition includes either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of 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. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as an AE or SAE if they fulfill the definition of an 
AE or SAE. 
 

 
 
Events NOT Meeting the AE Definition  
• Any clinically significant abnormal safety assessments which are associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected 
for the participant’s condition. 
• 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. 
• 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. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that: 
Results in death 
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. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (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 AE. 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. 
Results in persistent 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) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other situations 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical treatment to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
Recording and Follow-up of AE and 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, and diagnostics reports) related 
to the event. 
The Investigator will then record all relevant AE/SAE information in the CRF. 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records in lieu of completion of the AE/SAE CRF page. 
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records. 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, 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: An event that is easily tolerated by the participant, causing minimal discomfort, and 
not interfering with everyday activities. 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
The Investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE. 
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. 
The Investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
The Investigator will also consult the Instruction for Use, in his/her assessment. 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor. 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 the Sponsor. 
The Investigator may change his/her 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 AE and SAE 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. 
If a participant dies during participation in the study, the Investigator will provide the 
Sponsor with a copy of any post-mortem findings including histopathology. 
New or updated information will be recorded in the originally completed CRF. 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
 
Reporting of SAE  
SAE Reporting  
 
The Investigator must report any SAEs to the Sponsor within 24 hours of becoming 
aware of the event. 
The Investigator and the Sponsor (or Sponsor’s designated agent) will review each SAE 
report and the Sponsor/CRO will evaluate the seriousness and the causal relationship of 
the event to study treatment. In addition, the Sponsor (or Sponsor’s designated agent) will 
evaluate the expectedness according to the reference documents. Based on the 
Investigator and Sponsor’s assessment of the event, a decision will be made concerning 
the need for further action. 
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE, report to the Sponsor within 24 h. 
Contacts for SAE reporting can be found in the Study Operation Manual. 
 

 
 
All SAEs will be recorded from randomization until the end of the study. Serious adverse events 
occurring after the end of the study and coming to the attention of the Investigator must be 
reported only if they are considered (in the opinion of the Investigator) causally-related to study 
treatment. 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Any AE that is serious, associated with the use of the study treatment, and unexpected 
(SUSAR) has additional reporting requirements, as described below. 
If the SUSAR is fatal or life-threatening, associated with study treatment, and 
unexpected, regulatory authorities and IRB will be notified within 7 calendar days after 
the Sponsor learns of the event. Additional follow-up (cause of death, autopsy report, and 
hospital report) information should be reported within an additional 8 days (15 days 
total). 
If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with 
study treatment, and unexpected, regulatory authorities and IRBs will be notified within 
15 calendar days after the Sponsor learns of the event. 
 
 

 
 
Appendix 3: List of Abbreviations 
 
 
 
AE 
adverse event 
AHI 
Apnea-hypopnea index 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CPAP 
continuous positive air pressure 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
EOS 
end of study 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
OSA 
obstructive sleep apnea 
NREM 
non-rapid eye movement 
P90 / P95 
pressure levels that eliminate breathing obstructions for at least 90 / 95% of the 
sleep period 
PAP 
positive airway pressure 
PSG 
polysomnography 
REM 
rapid eye movement 
SAE 
serious adverse event 
SCMT 
SoA 
Sleep Centers of Middle Tennessee 
Schedule of Activities 
SUSAR 
suspected unexpected serious adverse reaction 
TPAP 
TheraPAP algorithm 
US 
United States 
 
 
 
 

 
 
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Declaration of the Investigator 
Title: Randomized Crossover Study to Compare Effectiveness of a Device Providing Pressure 
Drops During Inspiration (TPAP) to Continuous Positive Airway Pressure in Obstructive Sleep 
Apnea 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, study guide, and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
IRB. No changes will be made to the study protocol without the prior written approval of the 
Sponsor and the IRB, except where necessary to eliminate an immediate hazard to the 
participants. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
Responsible Investigator of the local study center 
 
_____________________________________ 
_____________________ 
Signature 
Date 
Abinash Joshi, MD_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number