Randomized Crossover Study to Compare Effectiveness of a Device Providing Pressure Drops During Inspiration (TPAP) to Continuous Positive Airway Pressure (CPAP) in Obstructive Sleep Apnea (OSA)
Phase: NA
Conditions: Obstructive Sleep Apnea
Sponsor: SleepRes Inc.

 
 
Title Page 
Protocol 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 
Protocol Name: TheraPAP Equivalence  
Sponsor Protocol #: Lab 0001  
Version Number: 1.3 
Compound Number: TheraPAP 
Short Title: TheraPAP Equivalence Crossover Study 
Sponsor Name and Legal Registered Address:  
SleepRes, PLLC 
1508 Carl Adams Dr  
Murfreesboro, TN 37129 
Regulatory Agency Identifying Number: Exempt  
Approval Date: February 5, 2024 
Protocol Number: WCG IRB Protocol #: 20240345 
 
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 ........................................................................................................ 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 
Pre-Screening ................................................................................................................. 10 
4.2.2 
Evening before the sleep study ....................................................................................... 10 
4.2.3 
In-laboratory overnight PSG .......................................................................................... 10 
4.2.4 
Morning after the sleep study ..........................................................................................11 
4.3 
End of Study Definition.......................................................................................................11 
5 
Study Population ..................................................................................................................... 12 
5.1 
Inclusion Criteria ................................................................................................................ 12 
5.1.1 
Age and Sex .................................................................................................................... 12 
5.1.2 
OSA Measures ................................................................................................................ 12 
5.1.3 
Weight ............................................................................................................................. 12 
5.1.4 
Informed Consent ........................................................................................................... 12 
5.2 
Exclusion Criteria ............................................................................................................... 12 
5.2.1 
Medical Conditions ........................................................................................................ 12 
5.2.2 
Prior/Concomitant Therapy ............................................................................................ 13 
5.2.3 
Other Exclusions ............................................................................................................ 13 
5.3 
Screen Failures ................................................................................................................... 13 
5.4 
Preparation/Handling/Storage/Accountability ................................................................... 13 

 
 
5.5 
Measures to Minimize Bias ................................................................................................ 13 
5.6 
Concomitant Therapy ......................................................................................................... 14 
5.7 
Discontinuation of Study Treatment ................................................................................... 14 
5.8 
Stopping Criteria ................................................................................................................ 14 
5.8.1 
Individual Participant Stopping Criteria ......................................................................... 14 
5.9 
Participant Discontinuation/Withdrawal from the Study ................................................... 14 
5.10 Participant compensation.................................................................................................... 15 
6 
Study Assessments and Procedures ........................................................................................ 15 
6.1 
Overnight study .................................................................................................................. 15 
6.2 
Safety Assessments ............................................................................................................. 16 
6.2.1 
Vital Signs ...................................................................................................................... 16 
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 .............................................................................. 19 
6.3.3 
Follow-up of AEs and SAEs ........................................................................................... 19 
6.3.4 
Regulatory Reporting Requirements for SAEs .............................................................. 19 
7 
Statistical Considerations........................................................................................................ 20 
7.1 
Sample Size Determination ................................................................................................ 20 
7.2 
Randomization .................................................................................................................... 20 
7.3 
Populations for Analyses .................................................................................................... 20 
7.4 
Interim Analyses ................................................................................................................. 21 
8 
Supporting Documentation and Operational Considerations ................................................. 21 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................................... 22 
1. Regulatory and Ethical Considerations .................................................................................. 22 
2 
Financial Disclosure ............................................................................................................... 22 
3 
Informed Consent Process ...................................................................................................... 23 
4 
Data Protection ....................................................................................................................... 23 
5 
Data Quality Assurance .......................................................................................................... 23 
6 
Source Documents .................................................................................................................. 24 
7 
Publication Policy ................................................................................................................... 24 
8 
Protocol Approval and Amendment........................................................................................ 24 
9 
Liability and Insurance ........................................................................................................... 25 

 
 
10 Access to Source Data ............................................................................................................ 25 
Appendix 2: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting.......................................................................................................................... 26 
Appendix 3: List of Abbreviations ................................................................................................ 32 
References ..................................................................................................................................... 33 
 

 
 
1 Protocol Summary 
1.1 Synopsis 
Protocol 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 
Protocol Name/Number: TheraPAP Equivalence 
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 Equivalence, is a crossover study designed to examine the efficacy and safety of 
TPAP vs. CPAP alone in the treatment of OSA. 
Overall Design: 
The TheraPAP Equivalence Study is a randomized, controlled, crossover study in participants 
with OSA. A split-night polysomnogram (PSG) will be conducted on CPAP and TPAP 
(approximately 3.5 hr. each treatment arm) in previously diagnosed OSA patients, to test the 
effectiveness of TPAP vs. CPAP. The sequence of periods for each participant are assigned in 
random order. Therapeutic CPAP level will be defined based on each individual’s pressure levels 
from their currently used APAP device deemed to eliminate breathing obstructions for at least 
90/95% of the sleep period (P90/P95) + 1 cmH2O. P90/P95 will be defined based on the previous 
2 months of adherent APAP usage (defined as averaging > 5 hours/night). On TPAP, the pressure 
drop during inspiration is generally done in two steps and varies, as outlined in table 1, based on 
the set pressure level, with larger drops occurring when the set pressure is higher. However, the 
pressure never goes below 5 cmH2O. This lower pressure is returned to the set pressure level 
about halfway through expiration. These pressure drops are designed to make TPAP considerably 
more comfortable than CPAP.   
 
1 TPAP will be used herein to refer to the active treatment. 

 
 
To assure that the participant is blinded to the therapy arm, all participants will start on CPAP 
and will be either left at CPAP or switched to TPAP after falling asleep, depending on the arm to 
which they have been assigned.   
TPAP Pressure Drop values will be set according to the following table for (P90/P95) + 1 
cmH2O.   
Adjusted P90/P95 
cmH2O Value 
  Pressure Drop 1 
(cmH2O) 
Pressure Drop 2 
(cmH2O) 
6.0 to 6.5 
1 
0 
7.0 to 7.5 
1 
1 
8.0 to 8.5 
2 
1 
9.0 to 9.5 
2 
2 
10.0 to 20.0 
2 
3 
 
In the above chart, 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; P90/95 + 1 
will be the set patient pressure for CPAP and TPAP during the study.  To determine the Adjusted 
P90/P95 Value to get the correct Pressure Drops 1 & 2 settings: 
• 
If the participant’s machine-recorded P90/P95 is at a whole number, like 8.0, or a half pressure, 
like 8.5, add 1.0 cmH2O to get the Adjusted P90/P95 Value.   
• 
If the participant’s machine-recorded P90/95 is between a whole number and a half number, 
round to the next half or whole number, then, add 1.0 cmH2O to get the Adjusted P90/95 Value.   
• 
Find the Adjusted P90/95 Value in the left column and then use the corresponding values for 
Pressure Drop 1 and Pressure Drop 2.   
 
 
Key efficacy endpoints include the effect of TPAP on overall, non-rapid eye movement (NREM), 
REM, supine and lateral AHI, as well as sleep efficiency, sleep onset latency, sleep stage 
distribution, arousal index, total leak, and unintentional mask leaks vs. CPAP. 
Number of Participants: 
A total of 52 participants will be enrolled.  
Study Duration: 
The overall study duration for each participant will be up to two weeks including recruitment 
screening and one night in the lab.

 
 
1.2 Schedule of Activities (SoA)  
 
Schedule of Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; ESS = Epworth Sleepiness Scale; PSG = polysomnography; SAE = serious 
adverse event.   
 
 
2 Vital signs include the following: one measurement of seated blood pressure, pulse, respiratory rate. 
3 Pre-sleep questionnaire includes recent sleep history for the last 2-3 nights, medications, caffeinated beverages, 
and alcohol consumption. 
Procedures  
Screening 
Evening 
Overnight 
Morning 
Telephone or outpatient contacts with participant 
X 
 
 
 
Informed consent when patient comes to lab 
 
X 
 
 
Analysis of CPAP compliance data 
 
X 
 
 
Demographics 
 
X 
 
 
Medical history & medications 
 
X 
 
 
Height 
 
X 
 
 
Weight 
 
X 
 
 
Vitals2 
 
X 
 
X 
Randomization 
 
X 
 
 
Pre-sleep questionnaire3 
 
X 
 
 
PSG Exam 
 
 
X 
 
AE/SAE monitoring 
 
 
X 
X 
Post-sleep questionnaire 
 
 
 
X 

 
 
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 Equivalence, is a 
Crossover study designed to examine whether TPAP is equivalent to CPAP in the treatment of 
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). 
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 
4 Study Design 
4.1 Overall Design 
The TheraPAP Equivalence Study is a randomized, controlled, crossover study in participants 
with OSA. Pre-screening is conducted to establish potential eligibility with a previous sleep 
study showing an AHI>10 events/hour, and a minimum of two months of adherent CPAP usage 
(defined as averaging > 5 hours/night). Eligible participants will undergo a split-night, in-
laboratory polysomnogram (PSG) on CPAP and TPAP (3.5 hours for each treatment arm). The 
sequence of periods for each participant will be assigned in random order, although all 
participants will start on CPAP until asleep to blind them to the therapy arm. Therapeutic CPAP 
level will be defined based on each individual’s pressure P95/P90 + 1 cmH2O from the APAP 
 
4 10 minute per condition must be present for the endpoint to be considered. 
5 10 minute per condition must be present for the endpoint to be considered. 
6 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 
• 
TPAP vs. CPAP AHI 
Secondary 
• 
TPAP vs. CPAP NREM and REM AHI4 
• 
TPAP vs. CPAP NREM and REM AHI in supine and lateral position5 
• 
TPAP vs. CPAP Sleep efficiency, sleep stage distribution, sleep onset latency, 
arousal index  
• 
TPAP vs. CPAP Unintentional mask leaks  
• 
Subjective preference of TPAP vs CPAP 
• 
Subjective sleep quality 
Safety Endpoints6 
• 
Spontaneous adverse events 

 
 
device being used in the home over the previous two months. The drop in inspiratory PAP during 
the TPAP intervention arm will be based on the above P95/P90 according to Table 1. 
4.2 Detailed Design 
4.2.1 
Pre-Screening 
Recruiting for the TheraPAP Equivalence study will use an advertisement and a pre-screening 
checklist.  The advertisement will be an email sent by Sleep Centers of Middle Tennessee 
(SCMT) to all of its patients inquiring about their interest in participating in the study. The email 
will provide interested patients with a link to an online form that they complete by adding their 
name and contact information. After they submit the form, they will be contacted by the study 
coordinator, who will discuss the study with them. Participants selected for eligibility will have a 
previous history of OSA of a severity consistent with enrollment criteria, have enough CPAP 
usage in the previous two months, and meet all other inclusion and exclusion criteria.   
 
4.2.2 
Evening before the sleep study 
Upon arrival at the clinic, the participant will be asked to sign an informed consent.  
The following activities will also occur: 
• Document demographics and medical history, including medications. 
• Review previous two-month sleep data from the participant’s CPAP.  
• Height, weight, vital signs will be measured once. 
• Pre-sleep questionnaire (which includes recent sleep history for the last 2-3 nights, 
medications, caffeinated beverages, and alcohol consumption) 
• Randomization 
4.2.3 
In-laboratory overnight PSG 
The PSG will be conducted with a split-night design, i.e., approximately 3.5 hours on CPAP and 
3.5 hours on TPAP, in random order. The switch between CPAP and TPAP will be operated 
through the interface screen on the TPAP device. During testing, no expiratory pressure relief 
will be used during CPAP regardless of such use during normal therapy at home. All patients will 
be asked to bring in the mask they normally use at night so that it can be used in the study, and 
the patients will be tested using two 1.8 m lengths of 22 mm tubing to prevent cross 
contamination. A commercial humidifier will be used to provide humidification since 
humidification is not supplied with the TheraPAP prototype.   

 
 
4.2.3.1 
Risk-benefit analysis 
The procedures involved in the overnight study are similar to clinical routinary activities 
performed in the laboratory weekly, and therefore the study risk is minimal, with the only risks 
being related to the following: 
• Due to the monitoring equipment used in the lab and the different pressure delivery with 
TPAP, the participant may sleep poorly and be fatigued the following day. 
• If TPAP does not optimally treat the sleep apnea, the patient may have more 
apneas/hypopneas during the study than occur on CPAP at home. However, a single night 
of sub-optimally treated sleep apnea poses no real medical risk. 
Regarding benefits to the participants: 
• During the CPAP portion of the study, the lab personnel will be able to evaluate whether 
the participant’s current treatment at home is adequate. If increased respiratory events 
during the CPAP portion of the study are found, the settings on the participant’s CPAP 
can be adjusted at home or other corrections could be recommended.  Also, since the 
participants will be monitored as during a normal sleep study, evidence of other sleep 
disorders or heart disease could be identified and then addressed.  
• The results of the study could yield future benefit to the participants in terms of wider 
treatment alternatives for their OSA.   
4.2.4 
Morning after the sleep study 
The following activities will occur:  
• Vital signs will be measured once. 
• Post-sleep questionnaire.  
• Overall quantification and recording of any adverse event or serious adverse events 
related to the overnight procedures. 
4.3 End of Study Definition 
A participant is considered to have completed the study if they have completed all evening, 
overnight and morning procedures. 

 
 
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 
5.1.1 
Age and Sex 
1. Between 18 to 70 years of age, inclusive. 
5.1.2 
OSA Measures  
2. AHI > 10 on a previous PSG or HST.  
3. CPAP adherence for an average of 5 hours/night in the two months before the study 
5.1.3 
Weight 
4. BMI above 18 kg/m2, inclusive. 
5.1.4 
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: 
5.2.1 
Medical Conditions 
1. Current clinically significant sleep disorder other than OSA of a severity that would 
interfere with study participation or interpretability of data (including central sleep apnea, 
per central AHI > 5 events/hour). 
2. Current clinically unstable cardiac disease (e.g., rhythm disturbances, coronary artery 
disease or cardiac failure) or poorly controlled hypertension (>140/90mmHg). 
3. Current clinically significant neurological disorder, including epilepsy/convulsions. 

 
 
4. Other serious major organ system diseases include renal failure, lung disease, 
neuromuscular disease, or liver disease. 
5. Schizophrenia, schizoaffective disorder, or bipolar disorder according to Diagnostic and 
Statistical Manual of Mental Disorders-5 (DSM-5) or International Classification of 
Disease tenth edition criteria. 
6. Attempted suicide within 1 year prior to screening, or current suicidal ideation. 
7. History of substance use disorder as defined in DSM-V within 24 months prior to 
Screening Visit.  
8. A serious illness or infection in the past 30 days. 
9. Clinically significant cognitive dysfunction as determined by investigator. 
5.2.2 
Prior/Concomitant Therapy 
10. Chronic oxygen therapy. 
11. Patients with hypoglossal nerve stimulation implant. 
5.2.3 
Other Exclusions 
12. 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 locked designated sleep rooms in 
each laboratory facility along with the other sleep lab equipment in each room, accessible only 
from the laboratory personnel.  They will be used only for approved study purposes as 
designated by the sleep lab coordinator who will oversee their use in the sleep lab.   
5.5 Measures to Minimize Bias 
Each participant will begin the study in one of the treatment arms, (either CPAP or TPAP). The 
starting treatment arm is determined by a random number generator, as described in Section 7.2.  
All participants will start on CPAP until they fall asleep, then they will be switched to their 
designated therapy arm.   

 
 
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 a free mask (approximately 
$100 value). 
 
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 Overnight study 
• Methods: Standard overnight PSG recording, and data interpretation will be performed in 
accordance with the American Academy of Sleep Medicine (AASM) scoring manual. 
Participants will be instrumented with standard PSG electrodes and their usual at-home 
CPAP mask. This setup includes a finger pulse oximeter, chest and abdominal bands, EKG 
electrodes, a snore sensor on the neck, and anterior tibialis EMG electrodes. A manometer 
will be added between the end of the tube and the mask connecting tube to measure the 
participant’s pressure directly, and its analog output will feed into the PSG device. The 
patient flow signal will be extracted from the flowmeter embedded in TheraPAP device 
filtering off the leak flow from total flow (output). This TheraPAP flowmeter data will be 
directed to the DC input on the polysomnogram, generating a real-time signal. This signal 
can be viewed in the control room. A panoramic of the setup in the patient room is shown in 
figure 2.
 
Figure 1. Continuous positive airway pressure (PAP)/TheraPAP circuit. TPAP, TheraPAP 
device. PSG, polysomnography. 
Patients will report to the laboratory approximately two hours prior to their usual bedtime. 
Patients will be instructed not to drink alcohol or caffeinated beverages on the night of the 

 
 
study. Time of lights out will be established according to the participant’s approximate 
habitual bedtime. The participants will be given at least seven hours of time in bed 
(undergoing either CPAP or TPAP).  
• 
Participants should be actively encouraged to spend at least 1/3 of the night in the supine 
position and at least 1/3 of the night in the lateral position on each night of study. 
• Scoring: PSG studies will be scored for purposes of study endpoints by a registered PSG 
technician, blinded to treatment assignment. 
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. 
 
6.2.1 
Vital Signs 
Assessment of vital signs (seated blood pressure, pulse rate, body temperature, respiratory rate) 
will be performed at the time points indicated in the SoA.  
Vital signs will be measured in a seated position after 5 minutes rest and will include 
temperature, respiratory rate, systolic and diastolic blood pressure, and pulse. Measurements will 
be made only once.  
6.3 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in  
 

 
 
Appendix . 
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 . 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 . 
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  
 

 
 
Appendix ) 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 
The present study will be treated as a non-inferiority trial. An expected standard deviation of AHI 
between CPAP and TPAP of 12 requires 52 total participants to have 80% power using a 1-sided 
2.5% significance level, which accounts for a 5% dropout rate.   
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 h in any 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 h in any 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