The Effect on Subjective Comfort of a Device Providing Positive Airway Pressure (PAP) Drops During Inspiration (TPAP) Compared to Continuous Positive Airway Pressure (CPAP) in Obstructive Sleep Apnea Patients
Phase: NA
Conditions: Obstructive Sleep Apnea
Sponsor: SleepRes Inc.

 
 
Title Page 
Protocol Title: The Effect on Subjective Comfort of a Device Providing Positive Airway 
Pressure (PAP) Drops During Inspiration (TPAP) Compared to Continuous Positive Airway 
Pressure (CPAP) in Obstructive Sleep Apnea Patients 
Protocol Name: TheraPAP Comfort  
Sponsor Protocol #: Office 0001  
Version Number: 0.6 
Compound Number: TheraPAP 
Short Title: TPAP for Comfort in OSA 
Sponsor Name and Legal Registered Address:  
SleepRes 
1508 Carl Adams Dr  
Murfreesboro, TN 37129 
United States 
Regulatory Agency Identifying Number: Exempt  
Approval Date: February 23, 2024 
Protocol Number:  WCG IRB Protocol #: 20240612 
 
Sponsor Signatory: 
 
 
William Noah, MD 
 
 
Date 
 

 
 
 
 

 
 
Table of Contents 
 
Table of Contents ............................................................................................................................ 3 
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 
Baseline ................................................................................................................................ 8 
2.2.1 
Obstructive Sleep Apnea .................................................................................................. 8 
2.2.2 
Unmet Medical Need ........................................................................................................ 8 
2.2.3 
Biological Rationale ......................................................................................................... 9 
3 
Endpoints .................................................................................................................................. 9 
4 
Study Design ............................................................................................................................. 9 
4.1 
Overall Design ...................................................................................................................... 9 
4.2 
Detailed Design .................................................................................................................. 10 
4.2.1 
Recruitment .................................................................................................................... 10 
4.2.2 
In-office study................................................................................................................. 10 
4.3 
End of Study Definition.......................................................................................................11 
5 
Study Population ......................................................................................................................11 
5.1 
Inclusion Criteria .................................................................................................................11 
5.2 
Exclusion Criteria ............................................................................................................... 12 
5.3 
Screen Failures ................................................................................................................... 12 
5.4 
Preparation/Handling/Storage/Accountability ................................................................... 12 
5.5 
Measures to Minimize Bias ................................................................................................ 12 
5.6 
Concomitant Therapy ......................................................................................................... 12 
5.7 
Discontinuation of Study Treatment ................................................................................... 13 
5.8 
Stopping Criteria ................................................................................................................ 13 
5.8.1 
Individual Participant Stopping Criteria ......................................................................... 13 
5.9 
Participant Discontinuation/Withdrawal from the Study ................................................... 13 
5.10 Participant compensation.................................................................................................... 14 
6 
Study Assessments and Procedures ........................................................................................ 14 

 
 
6.1 
In-office study set-up .......................................................................................................... 14 
6.2 
Safety Assessments ............................................................................................................. 14 
6.3 
Adverse Events and Serious Adverse Events ..................................................................... 14 
6.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................... 15 
6.3.2 
Method of Detecting AEs and SAEs .............................................................................. 16 
6.3.3 
Follow-up of AEs and SAEs ........................................................................................... 16 
6.3.4 
Regulatory Reporting Requirements for SAEs .............................................................. 16 
7 
Statistical Considerations........................................................................................................ 16 
7.1 
Sample Size Determination ................................................................................................ 16 
7.2 
Randomization .................................................................................................................... 17 
7.3 
Populations for Analyses .................................................................................................... 17 
7.4 
Interim Analyses ................................................................................................................. 17 
8 
Supporting Documentation and Operational Considerations ................................................. 17 
8.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............................ 17 
8.1.1 
Regulatory and Ethical Considerations .......................................................................... 17 
8.1.2 
Financial Disclosure ....................................................................................................... 18 
8.1.3 
Informed Consent Process .............................................................................................. 18 
8.1.4 
Data Protection ............................................................................................................... 19 
8.1.5 
Data Quality Assurance .................................................................................................. 19 
8.1.6 
Source Documents .......................................................................................................... 20 
8.1.7 
Publication Policy ........................................................................................................... 20 
8.1.8 
Protocol Approval and Amendment ............................................................................... 20 
8.1.9 
Liability and Insurance ................................................................................................... 21 
8.2 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................................... 21 
8.3 
Appendix 5: List of Abbreviations ..................................................................................... 28 
9 
References............................................................................................................................... 29 
 

 
 
1 Protocol Summary 
1.1 Synopsis 
Protocol Title: The Effect on Subjective Comfort of a Device Providing Positive Airway 
Pressure (PAP) Drops During Inspiration (TPAP) Compared to Continuous Positive Airway 
Pressure (CPAP) in Obstructive Sleep Apnea Patients 
Protocol Name/Number: TheraPAP Comfort 
Phase: NA 
Sponsor: SleepRes, LLC 
Rationale: TheraPAP is a prototype device (with full documented electrical and isolation safety) 
being developed by SleepRes, LLC 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 Comfort, aims at assessing whether TPAP improves patient comfort vs. CPAP 
during supine wakefulness.  
Overall Design: 
The TheraPAP Comfort Study is an in-office study to assess comfort of TPAP vs. CPAP in 
CPAP-naïve patients with OSA during supine wakefulness. Patients will be recruited after 
routine outpatient visits. They will be asked to breath normally for approximately 1 minute in 
supine wakefulness while being administered 2 different pressure therapies for comparison.  For 
TPAP therapies, each baseline pressure (9 or 13 cmH2O) will consider 3 separate settings, TPAP 
A,TPAP B and TPAP C for 9, then TPAP D,TPAP E and TPAP F for 13.   
At the first baseline pressure, patients will be asked to choose their preference between CPAP 
and TPAP A.  This will be the primary endpoint.  If TPAP A is chosen, testing will move on to 
the second baseline pressure.  If CPAP is preferred, CPAP will then be compared to TPAP B.  If 
TPAP B is chosen, testing will move on to the second baseline pressure.  If CPAP is again chosen 
as preferred, it will be lastly compared to TPAP C, the latter two comparisons being secondary 
endpoints.   
 
1 TPAP will be used herein to refer to the actual modified PAP delivery. 

 
 
At the second baseline pressure, patients will be asked to choose their preference between CPAP 
and TPAP D.  This will be the primary endpoint.  If TPAP D is chosen, testing will move on to 
the second baseline pressure.  If CPAP is preferred, CPAP will then be compared to TPAP E.  If 
TPAP E is chosen, testing will move on to the second baseline pressure.  If CPAP is again chosen 
as preferred, it will be lastly compared to TPAP F, the latter two comparisons being secondary 
endpoints.   
  
 
Baseline CPAP 
(cmH2O) 
TPAP Setting 
  Pressure Drop 1 
(cmH2O) 
Pressure Drop 2 
(cmH2O) 
9 
TPAP A 
2 
2 
TPAP B 
1 
2 
TPAP C 
1 
1 
13 
TPAP D 
2 
3 
TPAP E 
2 
2 
TPAP F 
1 
2 
 
Table 1. Pressure Drops 1 and 2 refer to the first and the second drops in pressure that occur 
during inspiration and are maintained until about halfway through expiration. The overall 
pressure drops consist of Drop 1+ Drop 2. CPAP, continuous positive airway pressure. 
 
Number of Participants: 
A total of 384 participants will be enrolled.  
Study Duration: 
The overall study duration for each participant will be up to a half hour including recruitment 
screening and testing.

 
 
1.2 Schedule of Activities (SoA)  
 
 
 
 
 
 
 
 
 
 
 
Table 2. Schedule of Activities for the TheraPAP Comfort Study. 
 
Abbreviations: AE = adverse event; SAE = serious adverse event;   
 
Procedures 
In-office study 
Informed consent 
X 
Demographics 
X 
Height 
X 
Weight 
X 
Randomization 
X 
In-office procedure 
X 
AE/SAE monitoring 
X 

 
 
2 Introduction 
2.1 Study Rationale 
A therapy able to provide lower positive airway pressure (PAP) during inspiration than during 
expiration, designated TPAP, is being developed by SleepRes, LLC, for the treatment of 
obstructive sleep apnea (OSA). TPAP, as well as normal CPAP, are available on the SleepRes 
TheraPAP prototype device.  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 Comfort, is an in-office study designed to examine whether TPAP at two 
different levels of pressure relief provides more subjective comfort than CPAP in awake supine 
participants.   
2.2 Baseline 
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). 
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 PAP throughout inspiration and part of expiration, offering a 
potentially more personalized and adaptive therapeutic approach. 
3 Endpoints 
 
Table 3. Summary of TheraPAP Comfort Study endpoints. 
4 Study Design 
4.1 Overall Design 
The TheraPAP Comfort Study is an in-office study to assess patient-level comfort on TPAP vs. 
CPAP. Pre-screening is conducted to establish potential eligibility with a previous sleep study 
showing an AHI>10 events/hr. Eligible participants will undergo an in-office study in which they 
will breathe in the supine position during wakefulness on CPAP and on TPAP. In cases where 
CPAP is preferred, TPAP will be dropped to different levels based on the baseline CPAP levels, 
according to Table 1. CPAP and TPAP will be administered in one and in the opposite order per 
patient following a randomized design, to simulate patient blinding to treatment. 
 
Endpoints 
Primary 
 
• 
CPAP vs. TPAP A at 9 cmH2O 
• 
CPAP vs. TPAP D at 13 cmH2O 
Secondary 
• 
CPAP vs. TPAP B at 9 cmH2O 
• 
CPAP vs. TPAP C at 9 cmH2O 
• 
CPAP vs. TPAP E at 9 cmH2O 
• 
CPAP vs. TPAP F at 9 cmH2O 
Safety Endpoints 
• 
Spontaneous adverse events 

 
 
4.2 Detailed Design 
4.2.1 
Recruitment 
Individuals deemed potentially eligible for enrollment based on the assessment of their medical 
data during a scheduled outpatient visit will be recruited once they arrive at the clinic to collect 
their CPAP equipment. Participants selected for eligibility will be naïve CPAP OSA consistently 
with enrollment criteria.  
4.2.2 
In-office study  
Individuals who agree to participate will be asked to sign an informed consent prior to 
commencement of study procedures upon their arrival at the clinic.  
The following activities will also occur: 
• Height and weight will be measured. 
• Randomization of CPAP/TPAP order.   
To begin the study, each participant will lay in a supine position on a reclining chair in the office 
and all therapy comparisons will be made in this orientation.  Subsequently, each patient will be 
studied on two different baseline positive pressures: 9 and 13 cmH2O. At either of the above 
pressures, each patient will assess CPAP against 2 different pressure drops in one-to-one 
comparisons.  
For the baseline CPAP of 9 cmH2O, TPAP will be set to: 
• TPAP A  
• Followed by TPAP B if CPAP was previously preferred 
• Followed by TPAP C if CPAP was previously preferred 
For the baseline CPAP of 13 cmH2O, TPAP will be set to: 
• TPAP D  
• Followed by TPAP E if CPAP was previously preferred 
• Followed by TPAP F if CPAP was previously preferred 
Note that TPAP drops, designated as x/y, indicate first and second drop of PAP, starting during 
inspiration.  
Assessment of comfort will be made by comparing one-to-one TPAP against each other or 
against CPAP by having the patient breathe on the pressure for one minute (or more as needed 
based on the judgment of the Study Coordinator) and then indicating which is more comfortable 

 
 
by voice or hand sign.  The indicated choice will be recorded by the Study Coordinator. The 
patient will be able to ask to repeat settings as often as needed to make the most informed choice.  
4.2.2.1 
Risk-benefit Analysis 
The procedures involved in the studies include minimal risk, i.e., related to very short-term TPAP 
or CPAP administration (e.g., uncomfortable breathing, claustrophobia, lightheadedness, etc.). 
Upon experiencing any discomfort by the participant, the procedures will be interrupted.  
There is no direct benefit or treatment to the participants, however the results of the study can 
potentially yield future benefit to the participants in terms of wider treatment alternatives for 
their OSA. 
4.3 End of Study Definition 
A participant is considered to have completed the study if they have completed all TPAP and CPAP 
administration. 
5 Study Population 
Eligible participants will be recruited from the existing clinic population at the study site.  
Participants must be able to provide written consent and meet all the inclusion criteria and none 
of the exclusion criteria. 
5.1 Inclusion Criteria 
Age and Sex 
1. Between 18 to 70 years of age, inclusive. 
OSA Measures  
2. AHI > 10 on a previous HST.  
3. CPAP naïve individuals 
Weight 
4. BMI above 18 kg/m2, inclusive. 
Informed Consent 

 
 
5. 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. 
6. Participant must be able to understand the nature of the study and must have the 
opportunity to have any questions answered. 
5.2 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Any non-previously mentioned vulnerable population. 
2. 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. 
3. Any chronic lung diseases. 
4. Patients with hypoglossal nerve stimulation implant. 
5. Chronic oxygen therapy. 
6. A serious illness or infection in the past 30 days as determined by investigator. 
5.3 Screen Failures 
By definition, 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 
Prototype TheraPAP devices will be provided by the sponsor and will be kept in locked location 
when not in use.  These devices will be used only for approved study purposes as designated by 
the office coordinator who will oversee their use in the office.   
5.5 Measures to Minimize Bias 
The order of CPAP tested first or second for each of the  comparative tests for each baseline 
pressure will be randomized per patient, although the order of baseline pressure will be 
maintained for each patient starting with 9 cmH2O, then moving to 13 cmH2O.  
5.6 Concomitant Therapy 
Usual therapy is allowed as per the participants’ physicians’ indications, except for oxygen 
therapy that constitutes 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: 
o Withdrawal due to AE 
o Participant withdrew consent at own request (e.g., due to intolerance to study 
procedures) 
o At the discretion of the Investigator for safety, behavioral, or administrative reasons. 
o Other 

 
 
5.10 Participant compensation 
Participants will be compensated for their time and participation with a free V̇ -Com™ 
(approximately $30 value) upon full completion of the study. 
 
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 In-office study set-up 
• Methods: Participants will be connected to the TheraPAP circuit through a CPAP mask 
(which will be the same that they will be given for their at-home treatment) and two 22 mm 
hoses to prevent cross contamination. A panoramic of the setup in the patient room is shown 
in Figure 1. 
 
Figure 1. Continuous positive airway pressure (PAP)/TheraPAP circuit. TPAP, TheraPAP 
device. 
6.2 Safety Assessments 
Planned time points for all safety assessments are provided in the SoA.  Safety assessments will 
include monitoring and recording of AEs, SAEs, and recording of study discontinuations. 
6.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Regulatory authorities of certain countries, 
IRBs, IECs, 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 support at all times. 
Appendix 3. 
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 the start until the end of the study. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Regulatory authorities of certain countries, IRBs, IECs, 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 
support at all times. 
Appendix 3. 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 Regulatory authorities 
of certain countries, IRBs, IECs, 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 support at all times. 

 
 
Appendix 3. 
6.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrence. 
6.3.3 
Follow-up of AEs and SAEs 
Ongoing AEs and SAEs will be followed until resolution or stability as determined by the 
Investigator. 
6.3.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification (within 24 hours, see Regulatory authorities of certain countries, IRBs, IECs, 
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 support at all times. 
Appendix 3) 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, IRB, and Investigators. 
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 
A score of 1 and 2 will be combined for a preference of Pressure 1 and a score of 4 and 5 will be 
combined for a preference of Pressure 2.  A score of 3 indicates no preference.  In a 2x2 Williams 

 
 
Cross over design with 2 treatments, where the endpoint is a proportion, (i.e., the proportion that 
prefer one pressure over another) the sample size per sequence that is needed to achieve 80% 
power, based on a two-sided 5% significance level, with a total of 6 comparisons results in a total 
number of participants of 384.    
7.2 Randomization 
All comparisons for each baseline pressure level (9 and 13 cmH2O) will be randomized 
separately for either baseline pressure per patient by using CPAP first in one case then CPAP 
second in the other. However, the baseline pressure order will not be randomized so that PAP-
naïve patients can acclimate to PAP first at the lower pressure.   
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 pair of PAPs comparison (e.g., CPAP 9 cmH2O 
vs. TPAP), and have at least 1 measurement on the primary 
endpoint (). 
Safety Set 
The mITT set comprises all participants who are randomized, 
undergo at least 1 minute breathing on any TPAP setting. 
Per Protocol (PP) Set 
The PP Population consists of all participants without any major 
protocol violations that could influence efficacy assessment. 
 
7.4 Interim Analyses 
No interim analysis is planned.  
8 Supporting Documentation and Operational Considerations 
8.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
8.1.1 
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. 
8.1.2 
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. 
8.1.3 
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 IEC/IRB and 
signed by all participants subsequently enrolled in the study. 
8.1.4 
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 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. 
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. 
8.1.5 
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. 
8.1.6 
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 site. 
8.1.7 
Publication Policy 
The Sponsor will support publication upon review of the manuscript. 
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).  
8.1.8 
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 IR/Competent Authority approval 
prior to implementation (if appropriate).  
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. Any deviations from the protocol will be reported to the Sponsor as 
Protocol Deviations. 

 
 
8.1.9 
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 in the course of the study. 
8.1.9.1 
Access to Source Data 
Regulatory authorities of certain countries, IRBs, IECs, 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 
support at all times. 
8.2 Appendix 3: 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 or not 
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 including 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). 
 
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 eCRF 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 before submission to the 
Sponsor. 
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 Instructions for Use and/or Product Information, for 
marketed products, 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 to Sponsor 

 
 
SAE Reporting to the Sponsor 
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. 
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line 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 off-
line, then the site can report this information on a paper SAE form or by telephone. 
Contacts for SAE reporting can be found in the Study Reference 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 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 will be notified within 15 
calendar days after the Sponsor learns of the event. 
 
 

 
 
8.3 Appendix 5: 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 
PAP 
positive airway pressure 
SAE 
serious adverse event 
SoA 
Schedule of Activities 
SUSAR 
suspected unexpected serious adverse reaction 
TPAP 
TheraPAP algorithm 
VAS 
Visual analog scale 
US 
United States 
 
 
 
 

 
 
9 References 
1. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-
disordered breathing in adults. Am J Epidemiol 2013; 177: 1006-1014. 
2. Findley LJ, Unverzagt ME, Suratt PM. Automobile accidents involving patients with 
obstructive sleep apnea. Am Rev Respir Dis 1988; 138: 337-340. 
3. Hill CM, Hogan AM, Onugha N, Harrison D, Cooper S, McGrigor VJ, Datta A, Kirkham FJ. 
Increased cerebral blood flow velocity in children with mild sleep-disordered breathing: a 
possible association with abnormal neuropsychological function. Pediatrics 2006; 118: 
e1100-1108. 
4. Hoffstein V. Blood pressure, snoring, obesity, and nocturnal hypoxaemia. Lancet 1994; 344: 
643-645. 
5. Hung J, Whitford EG, Parsons RW, Hillman DR. Association of sleep apnoea with myocardial 
infarction in men. Lancet 1990; 336: 261-264. 
6. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D'Agostino RB, Newman AB, 
Lebowitz MD, Pickering TG. Association of sleep-disordered breathing, sleep apnea, and 
hypertension in a large community-based study. Sleep Heart Health Study. JAMA 2000; 
283: 1829-1836. 
7. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-
disordered breathing and hypertension. N Engl J Med 2000; 342: 1378-1384. 
8. Redline S, Strauss ME, Adams N, Winters M, Roebuck T, Spry K, Rosenberg C, Adams K. 
Neuropsychological function in mild sleep-disordered breathing. Sleep 1997; 20: 160-
167. 
9. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, O'Connor GT, Boland LL, 
Schwartz JE, Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-
sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001; 163: 
19-25. 
10. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in 
obstructive sleep apnea. J Clin Invest 1995; 96: 1897-1904. 
11. Wessendorf TE, Teschler H, Wang YM, Konietzko N, Thilmann AF. Sleep-disordered 
breathing among patients with first-ever stroke. J Neurol 2000; 247: 41-47. 
12. Rotenberg BW, Murariu D, Pang KP. Trends in CPAP adherence over twenty years of data 
collection: a flattened curve. J Otolaryngol Head Neck Surg 2016; 45: 43. 
13. Andry JM, Jr., Toban G, Chafin C, Noah W. Positive airway pressure therapy supplied by an 
integrated sleep practice associated with greater adherence among pre-Medicare-aged 
patients with sleep-disordered breathing. J Clin Sleep Med 2021; 17: 31-36. 
14. Shirlaw T, Hanssen K, Duce B, Hukins C. A Randomized Crossover Trial Comparing 
Autotitrating and Continuous Positive Airway Pressure in Subjects With Symptoms of 
Aerophagia: Effects on Compliance and Subjective Symptoms. J Clin Sleep Med 2017; 
13: 881-888. 
15. Pepin JL, Leger P, Veale D, Langevin B, Robert D, Levy P. Side effects of nasal continuous 
positive airway pressure in sleep apnea syndrome. Study of 193 patients in two French 
sleep centers. Chest 1995; 107: 375-381. 
 
 

 
 
Declaration of the Investigator 
Title: The Effect on Subjective Comfort of a Device Providing Positive Airway Pressure (PAP) 
Drops During Inspiration (TPAP) Compared to Continuous Positive Airway Pressure (CPAP) in 
Obstructive Sleep Apnea Patients 
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, Instructions for Use, and other scientific data. 
The study will not commence without the prior written approval of a properly constituted IRB or 
IEC. No changes will be made to the study protocol without the prior written approval of the 
Sponsor and the IRB or IEC, 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 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number