Rescuing OSA Patients Unable to Tolerate CPAP Using Endotype-Targeted Combination Drug Therapy: a Randomized, Double-Blind, Placebo-Controlled Trial
Phase: PHASE2
Conditions: OSA, Obstructive Sleep Apnea
Sponsor: University of California, San Diego

 
Clinicaltrials.gov 
Record-Title: Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea 
Number: 191990 
Document Type: Study Protocol and Statistical Analysis Plan 
Document Date: 06/17/2021 
 

 
 
Biomedical IRB Application Instructions 
Page 2 
 
 
UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN 
Instructions for completing the Research Plan are available on the HRPP website. 
The headings on this set of instructions correspond to the headings of the Research Plan. 
General Instructions: Enter a response for all topic headings.  
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project. 
Version date: 9/30/2013 
1. 
PROJECT TITLE 
191990, RESCUE-Drug: Rescuing OSA Patients Unable to Tolerate CPAP Using Endotype-Targeted Drug 
Therapy 
 
2. 
PRINCIPAL INVESTIGATOR  
Christopher Schmickl, MD, PhD, Assistant Physician & T32 Postdoctoral Fellow, Department of Medicine, 
University of California San Diego (UCSD) 
 
3. 
FACILITIES 
- Sleep Research Offices and Sleep Research Laboratory in Altman Clinical and Translational Research 
Institute (ACTRI), 9452 Medical Center Drive, La Jolla, CA 92037 
 
4. 
ESTIMATED DURATION OF THE STUDY 
5 years 
 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
 
Obstructive sleep apnea (OSA) is a chronic disorder that affects ~1 billion people worldwide and is associated 
with many adverse health consequences. Many patients cannot or will not tolerate CPAP (continuous positive 
airway pressure) and alternatives are limited, thus many patients remain untreated. Consequently, there has 
been great interest in developing drug therapy for OSA, but single interventions have failed to provide more 
than just partial relief. Recognizing that individualized multimodal therapy is often required for many 
conditions (e.g. cancer, diabetes or hypertension) we believe this strategy may also hold the key to help the 
millions of currently untreated OSA patients. 
 
6. 
SPECIFIC AIMS 
 
AIM 1: Determine the Efficacy of Dual-Drug Therapy for OSA  
OSA is caused by four pathophysiological mechanisms or traits (“endotypes”). Using a cross-over, 
randomized, double-blind, placebo-controlled mechanistic trial design we will assess the effect of short-term 
dual-drug-therapy (two drugs that each target a different trait: acetazolamide [loop gain], eszopiclone [arousal 
threshold]) on the Apnea-Hypopnea Index (AHINREM,supine, primary outcome), endotypes, sleep parameters, 
sleepiness, and blood pressure in 20 OSA patients. 
 
AIM 2: Explore the Efficacy of Single and Triple-Drug Therapy for OSA 
Patients from aim 1 in whom dual therapy resolves OSA (AHINREM,supine reduction >50% & 
AHINREM,supine<10/h) will undergo an open-label study on single therapy acetazolamide (AZM)), whereas 
subjects in whom OSA did not resolve will undergo triple-drug therapy (acetazolamide [loop gain], 
eszopiclone [arousal threshold], venlafaxine [pharyngeal muscle recruitment]). Outcomes will be the same as 
in aim 1. This exploratory aim will allow us to estimate which proportion of OSA patients responds to single 

 
 
Biomedical IRB Application Instructions 
Page 3 
vs dual vs triple therapy and facilitate the design of long term trials. 
 
7. 
BACKGROUND AND SIGNIFICANCE 
 
OSA is Very Common and Associated with Many Adverse Health Outcomes 
OSA is characterized by a repetitive collapse of the upper airway during sleep leading to transient hypoxemia 
and arousals from sleep. Recent estimates suggest that about 10% of the US population suffer from clinically 
significant OSA, with global estimates approximating one billion. Untreated OSA has been associated with 
many adverse health outcomes, including neurocognitive (e.g. excessive fatigue/sleepiness, motor-vehicle 
accidents) and cardiovascular (e.g. hypertension, coronary artery disease and cardiovascular mortality) 
sequelae resulting in costs of more than 150 billion dollars per year in the United States alone. 
 
Patients with OSA are Often Untreated 
The standard of care is CPAP therapy, but most studies report long-term discontinuation rates between 40-
60%. Alternative therapies are limited, e.g. oral appliances require adequate dentition, have a more variable 
response and are generally reserved for patients with only mild-moderate disease. Furthermore, to mitigate 
side effects such as occlusal changes, administration of a custom-fitted device by a qualified dentist is 
recommended, resulting in a comparable economic burden as for CPAP and limiting its widespread 
availability. Other alternatives such as upper airway surgeries and implantation of a hypoglossal nerve 
stimulator are reserved for even fewer patient populations. It is therefore a clinical reality that a large fraction 
of OSA patients remain untreated and thus at risk of OSA sequelae. 
 
Endotype-Targeted Therapy as a Potential Rescue Strategy 
Thanks to the pioneering work of Dr Malhotra and Dr Owens (PI’s mentors & co-investigators) and others it 
is now accepted that OSA is a multifactorial disease caused by the interplay of an anatomical predisposition 
and at least three non-anatomical physiological traits or endotypes: poor pharyngeal muscle recruitment, 
unstable ventilatory control (high loop gain), and low arousal threshold (waking up too easily). A detailed 
discussion of these endotypes and their various implications can be found in a review article that we recently 
published.1 Thus, we will just highlight a few key aspects relevant for this study here: 
 
a.) Endotypes can be Measured: Using a validated custom algorithm modeling ventilatory drive from 
ventilation data, it is possible to quantify endotypes from routine polysomnography data.2 
 
b.) Single-Drug Manipulation of Endotypes Partially Improves OSA: Several single-intervention studies 
have demonstrated the feasibility and efficacy of manipulating non-anatomical traits pharmacologically: 
- Arousal Threshold: Following an airway obstruction, build-up of respiratory stimuli usually results in 
gradual recruitment of pharyngeal muscles restoring airway patency and thus stable sleep and breathing, 
unless premature awakening occurs. Consequently, in a small cross-over randomized placebo-controlled 
trial the hypnotic eszopiclone 3mg increased the arousal threshold (sleeping deeper) by 29% and improved 
the AHI by 23% in unselected OSA patients.3 
- Pharyngeal muscle recruitment: Augmentation of pharyngeal muscle tone via an implanted 
hypoglossal nerve stimulator improves OSA severity by about 70%, demonstrating the importance of this 
endotype. Recent pharmaceutical attempts to augment upper airway tone primarily aimed to increase 
norepinephrine levels. E.g. in one small study of the noradrenergic tricyclic antidepressant desipramine 
improved pharyngeal muscle recruitment but simultaneously lowered (i.e. worsened) the arousal threshold 
(waking up easier) thus resulting in near zero net-effect with regards to OSA severity. We found similar 
results when testing the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine 50mg vs placebo 
in a recently completed trial (IRB#141272; manuscript in peer review). Importantly, results from our study 

 
 
Biomedical IRB Application Instructions 
Page 4 
suggest that venlafaxine combined with a drug that increases the arousal threshold (e.g. eszopiclone) may 
improve the AHI by ~19%. 
- Unstable ventilatory control (high loop gain, LG): In high LG conditions such as central or complex 
sleep apnea ventilatory instability may result in frank periodic breathing; in OSA, loop gain primarily 
amplifies the effect of respiratory disruptions caused by other traits by delaying the return to stable 
breathing. For example, an apnea due to compromised upper airway anatomy may be followed by periods 
of excessive respiratory effort that may lead to arousals from sleep. Consequently, in a small cross-over 
randomized trial acetazolamide significantly reduced loop gain (-41%) and improved OSA severity by 
~50% in unselected OSA patients.4 
 
Summary of Background & Significance 
Novel, patient-acceptable therapies are urgently needed to reduce the large fraction of untreated OSA patients 
– drug therapy promises to be the answer but so far has remained elusive. Results from single-intervention 
therapies informed by recent insights in OSA pathophysiology have been promising, but on average provided 
only partial relief. To achieve full resolution the next frontier in pharmacological OSA research is multi-drug 
therapy. This study will address the following scientific gaps: 
1.) Theoretically and based on limited data, the combination of drugs targeting different underlying 
mechanisms/endotypes of OSA should be additive/synergistic. This study will test this concept and will be 
the first study assessing the efficacy of combination therapy with acetazolamide+eszopiclone for OSA. 
2.) It is largely unknown what proportion of subjects could be treated with single vs dual vs triple therapy, 
and if baseline endotypes (i.e. quantified from the placebo night) can predict response to these different 
regimens (i.e. help personalize treatment). 
 
8. 
PROGRESS REPORT 
N/A 
9. 
RESEARCH DESIGN AND METHODS 
 
We propose a phase II trial: all drugs are FDA approved and the dosages in the study are prescribed clinically. 
Phase I trials using the doses of Acetazolamide (AZM), Venlafaxine (VFX), and Eszopiclone (ESZ) we 
intend to use have been successfully completed.5-7 
 
AIM 1: Determine the Efficacy of Dual-Drug Therapy for OSA  
Rationale: In most cases, single-drug therapy with acetazolamide or eszopiclone improves, but does not 
resolve OSA. The goal of this aim is to assess the efficacy of combination therapy with 
acetazolamide+eszopiclone, two drugs that each target a different underlying mechanism. 
 
 

 
 
Bi o m e di c al I R B A p pli c ati o n I n str u cti o n s  
P a g e 5  
 
Fi g ure 1. St u d y Desi g n & Ti meli ne. A Z M Acetaz ola mi de, V F X Ve nlafa xi ne, E S Z Esz o picl o ne, P S G 
P ol y s o m n o gra p h y. Dr u gs will be a d mi nistere d 3 0 mi n utes bef ore be dti me o n t he da ys s h o w n. F or m ore details see te xt.  
 
A p pr o ac h:  T his is a ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d cr oss- o ver trial.  
Details of t he st u d y desi g n are s h o w n i n Fi g ure 1. As descri be d i n secti o n 1 0 & 1 1 we will i de ntif y eli gi ble 
s u bjects fr o m vari o us s o urces. O ne of t he ke y i ncl usi o n criteria is a pri or dia g n osis of O S A wit h a n 
A HI > 1 5/ h. S u bjects w h o scree n p ositi ve b ut i n w h o m t he c urre nt A HI is u nclear (e. g. wei g ht l oss si nce pri or 
slee p st u d y) will be offere d a h o me slee p test ( o pti o nal) t o c o nfir m eli gi bilit y pri or t o t he i n-la b baseli ne 
assess me nt descri be d ne xt.  
S u bjects w h o scree n p ositi ve will be i n vite d f or a baseli ne assess me nt ( Fi g ure 1, “ ni g ht visit 1”) t o f urt her 
c o nfirm fi nal eli gi bilit y: after writte n i nf or me d c o nse nt has bee n o btai ne d, t he s u bjects w h o scree ne d p ositi ve 
will u n der g o a baseli ne hist or y, e xa m a n d slee p st u d y i n o ur slee p researc h la b orat or y. If eli gi bilit y is 
c o nfir me d (e. g. a p nea- h y p o p nea i n de x, A HI N R E M,s u pi ne > 1 5/ h) s u bjects will be i ncl u de d i n t he trial, else 
s u bjects will be e xcl u de d fr o m f urt her st u d y. S u bjects w h o are i ncl u de d i n t he trial, will u n der g o t w o  p hases 
(acetaz ola mi de +esz o picl o ne [ A Z M + E S Z] vs place b o) i n ra n d o m or der. I n bet wee n p hases t here will be a 
was h - o ut peri o d of 4- 1 0 da ys. Of n ote, esz o picl o ne will o nl y be ta ke n d uri n g t he i n-la b o ver ni g ht slee p st u d y. 
T hirt y mi n utes bef ore be d, a slee p tec h n ol o gist will pr o vi de esz o picl o ne t o t he st u d y partici pa nt a n d o bser ve 
t he m ta ke it. D uri n g t he place b o p hase s u bjects will recei ve a n e q ual n u m ber of i de ntical a p peari n g pills. O n 
da ys 1 & 2  of eac h p hase s u bjects will ta ke t he assi g ne d st u d y dr u g ( A Z M vs place b o) at be dti me at h o me; o n 
da y 3 of eac h p hase s u bjects will be gi ve n t he st u d y dr u gs ( A Z M + E S Z vs place b o) u n der s u per visi o n a n d be 
o bser ve d o ver ni g ht i n t he slee p la b orat or y. U C S D A C T RI I n vesti gati o nal Dr u g Ser vice will ma n ufact ure, 
st ore a n d dis pe nse all st u d y dr u gs, Acti ve Dr u g a n d Matc hi n g Place b o f or t his st u d y. St u d y dr u gs a n d 
Matc hi n g Place b o will be st ore d f oll o wi n g U S P- 7 9 7 sta n dar ds or pac ka gi n g la bel acc or di n gl y. W he n t he 
s u bject has bee n ra n d o mize d, t he A C T RI dr u g ser vice will release t he st u d y dr u gs t o o ur researc h gr o u p. All 
dr u gs will be st ore d i n a l oc ker/safe, w hic h will t he n be place d i n t he PI’s l oc ke d ca bi net. 
T he f oll o wi n g pr oce d ures will be u n derta ke n: 
4- 1 0 d ay 
w as h -o ut
St u d y dr u g 
t a k e n at h o m e
Pl ac e b o
Pl ac e b o
Pl ac e b o
PL A C E B O
Pl ac e b o
A Z M 5 0 0 m g
A Z M 5 0 0 m g
ES Z 2 m g
D U AL -T h er a p y
A Z M 2 5 0 m g
A Z M 5 0 0 m g
A Z M 5 0 0 m g
ES Z 2 m g
D U AL -T h er a p y
A Z M 2 5 0 m g
Pl ac e b o
Pl ac e b o
Pl ac e b o
PL A C E B O
Pl ac e b o
St u d y dr u g 
t a k e n at h o m e
4- 1 0 d ay
w as h -o ut
Ni g ht
Visit 2
( P S G)
Ni g ht
Visit 3
( P S G)
R a n d o miz ati o n
Ni g ht
Visit 1
( P S G)
0- 7 d ay br e a k t o
f acilit at e sc h e d uli n g
Eli gi bilit y
c o nfir m e d ?
( A HI > 1 5/ h)
Yes
Excl u d e d
A Z M 5 0 0 m g
A Z M 5 0 0 m g
ES Z 2 m g
V F X 5 0 m g
O p e n -l a b el T RI PL E-T h er a p y
A Z M 2 5 0 m g
D U AL -
T h er a p y
r es ol v e d 
O S A?
Ni g ht
Visit 4
( P S G)
AI M 2
( E x pl or at or y)
A Z M 5 0 0 m g
A Z M 5 0 0 m g
O p e n -l a b el SI N GL E-T h er a p y
A Z M 2 5 0 m g
Yes
N o
St u d y dr u g 
t a k e n at h o m e
AI M 1
N o
Bri ef Hist or y & Ex a m
B as eli n e Sl e e p St u dy
D a y 1 
D a y 2 
D a y 3
P h as e I:
D a y 1 
D a y 2 
D a y 3
P h as e II:
D a y 1 
D a y 2 
D a y 3
P h as e III:
D a y 0

 
 
Biomedical IRB Application Instructions 
Page 6 
Daytime Visit #1 (45 minutes; only if a home sleep apnea test is needed for screening) 
Subjects who have not had a sleep study in the past 3 months or in whom a previous clinical sleep study is not 
available will be instructed on the use of a Home Sleep Test (HST) device. An HST is a small non-invasive 
diagnostic device worn for one night at home, with a nasal cannula to monitor airflow, an elastic chest band 
to monitor breathing effort, and a finger probe to monitor oxygen saturation and heart rate. The HST will be 
returned in person 1-2 days after it is completed. The results of the HST will be scored. If the subject’s AHI is 
≥ 15/h, the subject will be scheduled for overnight visit 1. This screening HST serves to avoid unnecessary 
baseline studies in the sleep lab.  
 
Overnight Visit #1 (10-12h) 
1. Anthropomorphic & medical history (30-45min): After signing written informed consent, baseline 
demographics and health status (OSA symptoms, medical problems, medications, allergies, social 
history) will be obtained. A basic exam, including height, weight, neck, hip, and waist circumference, 
blood pressure, and oxygen saturation will be obtained. 
Polysomnography: Monitoring for standard clinical polysomnography study will be applied to the 
subject, as follows: The subject will have EEG, EMG, EOG, and ECG electrodes, an adhesive body 
position sensor placed in standard locations. Pulse oximetry sensor will be attached either to a finger or 
ear lobe and secured by tape. The following parameters will be measured during sleep: 
electroencephalogram, eye movement, electrocardiogram, electromyogram, leg movement, snoring 
sounds, nasal pressure, and nasal-oral airflow by thermistor, respiratory effort and body position by 
piezo-electric bands of the thorax and abdomen or magnetometers, position sensors, and pulse oximetry. 
This equipment is standard for diagnostic polysomnography and should not be uncomfortable. Once all 
of this equipment has been comfortably and securely fastened, the subject will be allowed to fall asleep 
and data recording will begin. Subjects will be asked to remain in the supine position as much as 
possible. All data will be acquired on a Nihon Kohden. The study will end at approximately 6 AM, at 
which time the monitoring equipment will be removed. However, if the subject is still sleepy, they will 
be allowed to sleep until they feel rested. 
2. Sleepiness Measurement: In the morning, 30-minutes after the final awakening, subjects will be given the 
following standard sleep questionnaires prior to caffeine to assess sleepiness: Stanford Sleepiness Scale 
(SSS), Karolinska Sleepiness Scale (KSS), Promis Sleep Disturbance SF 8. 
3. PVT: Objective assessment of brain function will be done using 10-minute psychomotor vigilance test 
(PVT). In this computerized reaction assessment, the subject will be asked to quickly press the spacebar 
every instance a red dot appears on the screen.  
4. Blood Pressure: The technician will obtain blood pressure following standard procedures. 
5. Randomization/Study drugs: The overnight study will be scored in real-time during the study, thus at 
the latest within one hour of its completion we will know if a subject meets eligibility criteria for 
inclusion into the randomized trial: Ineligible subjects will receive their remuneration but will be 
excluded from further studies. Eligible subjects will be randomized and receive their assigned study drug 
(AZM vs placebo) to be taken at bedtime at home for 2 days. Subjects will be instructed on what day to 
start taking the study drug and when to return to the ACTRI sleep laboratory for administration of the 3rd 
dose of the assigned study regimen. 
 
Weekly Phone Calls 
After each wash out period is completed, subjects will be called to be reminded when to begin taking their 
study medication.  
 

 
 
Biomedical IRB Application Instructions 
Page 7 
Overnight Visit #2 (10-12h) 
Subjects will arrive to the research sleep laboratory at approximately 8PM and undergo the following 
procedures: 
1. Vitals and Pill Count: The technician will obtain blood pressure, and oxygen saturation. They will 
also verify that the study drug was taken according to the instructions provided. 
2. Medications: Thirty minutes before sleep, subjects will be provided with either AZM+ESZ or 
placebo. 
3. Polysomnography: Monitoring for standard clinical polysomnography study will be applied to the 
subject, as follows: The subject will have EEG, EMG, EOG, and ECG electrodes, an adhesive 
body position sensor placed in standard locations. Pulse oximetry sensor will be attached either to 
a finger or ear lobe and secured by tape. The following parameters will be measured during sleep: 
electroencephalogram, eye movement, electrocardiogram, electromyogram, leg movement, 
snoring sounds, nasal pressure, and nasal-oral airflow by thermistor, respiratory effort and body 
position by piezo-electric bands of the thorax and abdomen or magnetometers, position sensors, 
and pulse oximetry. This equipment is standard for diagnostic polysomnography and should not 
be uncomfortable. Once all of this equipment has been comfortably and securely fastened, the 
subject will be allowed to fall asleep and data recording will begin. Subjects will be asked to 
remain in the supine position as much as possible. All data will be acquired on a Nihon Kohden. 
The study will end at approximately 6 AM, at which time the monitoring equipment will be 
removed. However, if the subject is still sleepy, they will be allowed to sleep until they feel 
rested. 
4. Sleepiness Measurement: In the morning, 30-minutes after the final awakening, subjects will be 
given the following standard sleep questionnaires prior to caffeine to assess sleepiness: Stanford 
Sleepiness Scale (SSS), Karolinska Sleepiness Scale (KSS), Promis Sleep Disturbance SF 8. 
5. PVT: Objective assessment of brain function will be done using 10-minute psychomotor vigilance 
test (PVT). In this computerized reaction assessment, the subject will be asked to quickly press 
the spacebar every instance a red dot appears on the screen.  
6. Blood Pressure: The technician will obtain blood pressure following standard procedures. 
7. Phlebotomy: Venipuncture will be performed by a certified research staff or physician using 
standard techniques and appropriate blood borne pathogen precautions. Approximately 15-20 cc 
of blood will be drawn in the evening or morning at wake into serum separator, plasma separator 
and EDTA tubes. Serum samples will be immediately processed to separate serum, which will be 
stored in darkness at -70°C to preserve until analysis can be conducted. EDTA tubes will be 
processed and refrigerated for use within 24 hours. DNA will be isolated from the buffy coat in 
the EDTA tubes to examine entire genome sequence, targeted sequence, or select genetic markers 
to search for genotype-phenotype relationships. Blood will also be collected to measure 
bicarbonate, high sensitivity C Reactive Protein (hsCRP), insulin, glucose (to calculate HOMA-
IR), and cytokines such as IL-6 and TNF-alpha. Leukocytes from whole blood will be isolated for 
transcriptomic analysis. We will also store plasma for other potential markers, to explore other 
interactions, such as markers of liver disease like ALT and AST. Total RNA, including 
microRNAs, will be used to assess changes in gene expression. Fluids collected may be stored 
indefinitely and/or used in additional research to be conducted by sleep research study 
investigators conducting IRB approved research. Samples and data collected in the course of the 
study will be banked and may be sent to other research scientists anonymously (without 
identification). 
8. Study Drugs: Before leaving, subjects will receive the study drugs for the second study phase. 

 
 
Biomedical IRB Application Instructions 
Page 8 
After a 4-10 day wash-out period, the study drug (AZM vs placebo) is to be taken daily at home 
for 2 days. Subjects will be instructed on what day to start taking the study drug and when to 
return to the ACTRI sleep laboratory for the second overnight visit. 
 
Overnight Visit #3 (10-12h) 
Subjects will return to the sleep laboratory at 8PM for another overnight study and undergo the same 
procedures as during overnight visit #1: 
1. Vitals and Pill Count: The technician will obtain blood pressure, and oxygen saturation. They will also 
verify that the study drug was taken according to the instructions provided. 
2. Medications: Thirty minutes before sleep, subjects will be provided with either AZM+ESZ or placebo. 
3. Polysomnography: Monitoring for standard clinical polysomnography study will be applied to the 
subject, as follows: The subject will have EEG, EMG, EOG, and ECG electrodes, an adhesive body 
position sensor placed in standard locations. Pulse oximetry sensor will be attached either to a finger or 
ear lobe and secured by tape. The following parameters will be measured during sleep: 
electroencephalogram, eye movement, electrocardiogram, electromyogram, leg movement, snoring 
sounds, nasal pressure, and nasal-oral airflow by thermistor, respiratory effort and body position by 
piezo-electric bands of the thorax and abdomen or magnetometers, position sensors, and pulse oximetry. 
This equipment is standard for diagnostic polysomnography and should not be uncomfortable. Once all 
of this equipment has been comfortably and securely fastened, the subject will be allowed to fall asleep 
and data recording will begin. Subjects will be asked to remain in the supine position as much as 
possible. All data will be acquired on Nihon Kohden. The study will end at approximately 6 AM, at 
which time the monitoring equipment will be removed. However, if the subject is still sleepy, they will 
be allowed to sleep until they feel rested. 
4. Sleepiness Measurement: In the morning, 30-minutes after the final awakening, subjects will be given the 
following standard sleep questionnaires prior to caffeine to assess sleepiness: Stanford Sleepiness Scale 
(SSS), Karolinska Sleepiness Scale (KSS), Promis Sleep Disturbance SF 8. 
5. PVT: Objective assessment of brain function will be done using 10-minute psychomotor vigilance test 
(PVT). In this computerized reaction assessment, the subject will be asked to quickly press the spacebar 
every instance a red dot appears on the screen.  
6. Blood Pressure: The technician will obtain blood pressure following standard procedures. 
7. Phlebotomy: Venipuncture will be performed by a certified research staff or physician using standard 
techniques and appropriate blood borne pathogen precautions. Approximately 15-20 cc of blood will be 
drawn in the evening or morning at wake into serum separator, plasma separator and EDTA tubes. Serum 
samples will be immediately processed to separate serum, which will be stored in darkness at -70°C to 
preserve until analysis can be conducted. EDTA tubes will be processed and refrigerated for use within 
24 hours. DNA will be isolated from the buffy coat in the EDTA tubes to examine entire genome 
sequence, targeted sequence, or select genetic markers to search for genotype-phenotype relationships. 
Blood will also be collected to measure bicarbonate, high sensitivity C Reactive Protein (hsCRP), insulin, 
glucose (to calculate HOMA-IR), and cytokines such as IL-6 and TNF-alpha. Leukocytes from whole 
blood will be isolated for transcriptomic analysis. We will also store plasma for other potential markers, 
to explore other interactions, such as markers of liver disease like ALT and AST. Total RNA, including 
microRNAs, will be used to assess changes in gene expression. Fluids collected may be stored 
indefinitely and/or used in additional research to be conducted by sleep research study investigators 
conducting IRB approved research. Samples and data collected in the course of the study will be banked 
and may be sent to other research scientists anonymously (without identification) 
Data Analysis: Primary outcome will be the change in AHI (during supine non-rapid eye movement 

 
 
Biomedical IRB Application Instructions 
Page 9 
[NREM] sleep) from baseline to dual-therapy vs placebo which will be compared using a paired t-test (i.e. 
AZM&ESZ-baseline vs placebo-baseline). Secondary outcomes will be compared similarly and include other 
measures of OSA severity (e.g. SpO2 nadir), measures of sleep quality, blood pressure, sleepiness and 
vigilance. Further we will determine the proportion (+95% confidence interval) of subjects who fully 
responded (drop in AHI>50% to <10/h). Non-parametric alternatives will be considered, if parametric 
assumptions fail. Furthermore, we will test if endotypes or changes in serum bicarbonate predict response 
using linear/logistic regression. 
Sample size: 20 patients will give a power of >0.8 to detect a 50% (±75%) reduction in AHINREM,supine 
(primary outcome; equivalent to a reduction by 15 ± 22.5/h from 30/h) with an alpha level of 0.05 (pwr.t.test, 
R). To account for attrition we plan to enroll up to 40 subjects. 
 
AIM 2 Explore the Efficacy of Single and Triple-Drug Therapy for OSA 
Rationale: Based on the response of subjects in aim 1, this aim will explore if  
a.) subjects who responded to dual-therapy (AZM+ESZ) could also be treated with single-drug therapy (i.e. 
AZM alone);  
b.) subjects who did not respond to dual-therapy (AZM+ESZ) could be “rescued” by addition of 
venlafaxine (VFX), a drug targeting a third mechanism (i.e. triple therapy with AZM+ESZ+VFX). 
Approach: As shown in Figure 1, for this exploratory aim, subjects whose OSA resolved (AHI reduction by 
>50% and AHI<10/h) will undergo a third, open-label phase of single-therapy (AZM); conversely, subjects 
whose OSA did not resolve with dual-therapy will undergo a third, open-label phase of triple therapy 
(AZM+ESZ+VFX). As in aim 1, AZM will be administered for 2 days at home, and on the 3rd day subjects 
will receive the final dose of AZM or AZM+ESZ+VFX in the ACTRI sleep lab where a fourth overnight 
study will be performed with the following procedures:  
 
Overnight Visit #4 (10-12h) 
1. Vitals and Pill Count: The technician will obtain blood pressure, and oxygen saturation. They will also 
verify that the study drug was taken according to the instructions provided. 
2. Medications: Thirty minutes before sleep, subjects will be provided with either AZM or 
AZM+ESZ+VFX. 
3. Polysomnography: Monitoring for standard clinical polysomnography study will be applied to the 
subject, as follows: The subject will have EEG, EMG, EOG, and ECG electrodes, an adhesive body 
position sensor placed in standard locations. Pulse oximetry sensor will be attached either to a finger or 
ear lobe and secured by tape. The following parameters will be measured during sleep: 
electroencephalogram, eye movement, electrocardiogram, electromyogram, leg movement, snoring 
sounds, nasal pressure, and nasal-oral airflow by thermistor, respiratory effort and body position by 
piezo-electric bands of the thorax and abdomen or magnetometers, position sensors, and pulse oximetry. 
This equipment is standard for diagnostic polysomnography and should not be uncomfortable. Once all 
of this equipment has been comfortably and securely fastened, the subject will be allowed to fall asleep 
and data recording will begin. Subjects will be asked to remain in the supine position as much as 
possible. All data will be acquired on Nihon Kohden. The study will end at approximately 6 AM, at 
which time the monitoring equipment will be removed. However, if the subject is still sleepy, they will 
be allowed to sleep until they feel rested.  
4. Sleepiness Measurement: In the morning, 30-minutes after the final awakening, subjects will be given the 
following standard sleep questionnaires prior to caffeine to assess sleepiness: Stanford Sleepiness Scale 
(SSS), Karolinska Sleepiness Scale (KSS), Promis Sleep Disturbance SF 8. 
5. PVT: Objective assessment of brain function will be done using 10-minute psychomotor vigilance test 

 
 
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(PVT). In this computerized reaction assessment, the subject will be asked to quickly press the spacebar 
every instance a red dot appears on the screen.  
6. Blood Pressure: The technician will obtain blood pressure following standard procedures. 
7. Phlebotomy: Venipuncture will be performed by a certified research staff or physician using standard 
techniques and appropriate blood borne pathogen precautions. Approximately 15-20 cc of blood will be 
drawn in the evening or morning at wake into serum separator, plasma separator and EDTA tubes. Serum 
samples will be immediately processed to separate serum, which will be stored in darkness at -70°C to 
preserve until analysis can be conducted. Tubes will be processed and refrigerated for use within 24 
hours. DNA will be isolated from the buffy coat in the EDTA tubes to examine entire genome sequence, 
targeted sequence, or select genetic markers to search for genotype-phenotype relationships. Blood will 
also be collected to measure bicarbonate, high sensitivity C Reactive Protein (hsCRP), insulin, glucose 
(to calculate HOMA-IR), and cytokines such as IL-6 and TNF-alpha. Leukocytes from whole blood will 
be isolated for transcriptomic analysis. We will also store plasma for other potential markers, to explore 
other interactions, such as markers of liver disease like ALT and AST. Total RNA, including 
microRNAs, will be used to assess changes in gene expression. Fluids collected may be stored 
indefinitely and/or used in additional research to be conducted by sleep research study investigators 
conducting IRB approved research. Samples and data collected in the course of the study will be banked 
and may be sent to other UCSD research scientists. The blood samples will not be shared with other 
researchers/institutions outside of University of California, San Diego.  
 
Data Analysis: Primary outcomes will be the change in AHINREM,supine from baseline to single or triple 
therapy vs placebo, respectively, which will be compared using a paired t-test. Secondary outcomes will be 
compared similarly and include other measures of OSA severity (e.g. SpO2 nadir), measures of sleep quality, 
blood pressure, sleepiness and vigilance. Further we will determine the proportion (+95% confidence 
interval) of subjects who fully responded (drop in AHI>50% to <10/h). Non-parametric alternatives will be 
considered, if parametric assumptions fail. Furthermore, we will test if endotypes or changes in serum 
bicarbonate predict response using linear/logistic regression. Moreover, we will determine the proportion 
(+95% confidence interval) of subjects who fully responded (drop in AHI>50% to <10/h) to single or triple 
therapy, and use linear/logistic regression to test if endotypes predict response to the different combinations. 
Sample Size: Since aim 2 is an exploratory aim no separate sample size calculation has been performed. 
 
IND Exemption 
For this trial we will administer acetazolamide 500mg PO and/or venlafaxine 50mg PO and/or eszopiclone 
2mg PO. All three drugs are commonly used (PO) and safe. Further, we carefully chose dosages and 
eligibility criteria to minimize associated risks. FDA approved indications include glaucoma, epilepsy, high 
and altitude sickness for acetazolamide, insomnia for eszopiclone, and depression and anxiety for 
venlafaxine. Patients with sleep apnea were not excluded from the pivotal trials leading to these indications, 
and in clinical practice OSA patients do often get treated with these medications for comorbid conditions. In 
fact, there have been small trials demonstrating that acetazolamide4, eszopiclone3 and 
venlafaxine[IRB#141272; in peer review] improve obstructive sleep apnea in patients with similar 
characteristics as will be enrolled in the RESCUE-Drug trial. Thus, we believe that the proposed RESCUE-
Drug trial qualifies for an IND exemption. Specifically: 
(i) This investigation is not intended to be reported to FDA as a well-controlled study in support of a new 
indication for use nor intended to be used to support any other significant change in the labeling for the drugs. 
(ii) The drugs that are undergoing investigation are lawfully marketed as prescription drug products, but the 
investigation is not intended to support a significant change in the advertising for the products. 

 
 
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(iii) This investigation does not involve a route of administration or dosage level or use in a patient 
population or other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with the use of the drug products. 
(iv) This investigation will be conducted in compliance with the requirements for institutional review set forth 
in 21 CFR Part 56 and with the requirements for informed consent set forth in part 50. 
(v) This investigation will be conducted in compliance with the requirements of 21 CFR 312.7. 
 
The FDA has provided a letter confirming that this study meets criteria for an IND exemption.  
10. 
HUMAN SUBJECTS 
 
We will recruit up to 40 adult OSA patients who are untreated and meet the following eligibility criteria: 
 
 
Inclusion Criteria: 
- 
Age 18-65 years 
- 
BMI 18-40 kg/m2 
- 
Untreated Moderate or Severe OSA (AHINREM,supine>15/h) with a fraction of hypopneas >25% of all 
events 
 
Exclusion Criteria: 
- 
Pregnancy 
- 
Breastfeeding 
- 
Prisoners 
- 
Adherent with effective therapy for OSA 
- 
Other known untreated sleep fragmenting disorder, such as periodic limb movement disorder, or 
narcolepsy 
- 
Inability to sleep supine for overnight sleep studies  
- 
Circadian rhythm disorder 
- 
Unrevascularized coronary artery disease, angina, prior heart attack or stroke, congestive heart failure 
- 
Uncontrolled hypertension (SBP >160, DBP >95) 
- 
Presence of tracheostomy 
- 
Hospitalization within the past 90 days 
- 
Prior peptic ulcer disease, esophageal varicies, or gastrointestinal bleeding (< 5 years) 
- 
Prior gastric bypass surgery 
- 
Chronic liver disease or end-stage kidney disease 
- 
Active illicit substance use or >1.2 oz daily alcohol use (i.e. >2 12 oz bottles of  beers, >2 5 oz glasses 
of wine, >2 1.5 oz glasses of hard liquor (spirits, gin, whiskey, etc.) 
- 
Psychiatric disease, other than well controlled depression/anxiety 
- 
Cognitive impairment, inability to provide consent, or inability to complete research procedures (e.g. 
questionnaires that are only available/validated in English) 
- 
Chronically using study drugs or drugs with similar pharmacodynamic effects (acetazolamide - 
carbonic anhydrase inhibitors, eszopiclone – benzodiazepine receptor agonists, venlafaxine – 
serotonin/norepinephrine reuptake inhibitors and other antidepressants) 
- 
Regular use of medications known to affect control of breathing (opioids, benzodiazepines, 
theophylline) 
- 
Contraindications to taking study drugs, including allergies to any of the drugs or sulfa allergy; 
concomitant use of antidepressants, opioids, sedatives/hypnotics, thiazide diuretics or angiotensin-
receptor blockers; or severe nocturnal hypoxia (SpO2 nadir <70% on diagnostic sleep study). 

 
 
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11. 
RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH 
 
Subjects will be recruited from the following sources: 1) IRB-approved flyers or advertisements, with 
prospective subjects initiating contact with the research staff, 2) Persons who have participated in prior 
research studies from our laboratory or affiliated laboratories who have indicated that they would like to be 
contacted to hear about potential research studies, 3) Patients from the UCSD Pulmonary and Sleep Center 
who have indicated that they are interested in hearing about research opportunities, and 4) Persons who have 
been identified via SlicerDicer. 
  
Identifying Eligible Subjects with Partial HIPAA Waiver 
A temporary waiver of consent and partial waiver of HIPAA authorization is requested for this study in order 
to: 1) Pre-screen persons (from sources 2 and 3 above) who meet the inclusion and exclusion criteria, and 2) 
Perform telephone or in-person interviews with potential subjects for screening of inclusion and exclusion 
criteria prior to obtaining consent. The following points justify the waiver of consent: 1) Private information 
that will be reviewed is non-sensitive, and anyone pre-screened will have previously agreed to contact for 
research, 2) No research procedures will be performed without consent, so there should be minimal 
possibility of adverse effect on potential subjects, 3) Adequate enrollment could not be achieved without 
accessing this information, since specific medical conditions are being investigated, 4) All persons contacted 
will be provided with information about our screening procedures. For the partial HIPAA authorization: 1) 
Any PHI accessed for screening will be kept by research staff until either consent is obtained, or it will be 
destroyed immediately if consent and HIPAA authorization is not obtained, 2) Identifying potential subjects 
and then contacting/approaching them to discuss the research will require accessing PHI, 3) Minimal 
necessary PHI will be accessed and kept only temporarily while that subject is being screened, as above, 4) 
PHI will only be accessed by members of the research team included in the IRB, and will include name, date 
of birth, medical record number, contact information, diagnoses and dates of diagnostic tests.  
 
SlicerDicer 
Slicer Dicer will be used to identify both Summary & Patient Level Requests: 
Researchers plan to use UC San Diego Health’s Epic SlicerDicer, a self-service cohort discovery tool. 
Researchers will have access to direct summary and patient level data. Using SlicerDicer, researchers will:   
Review the charts at a patient level to identify potential patients for recruitment. We will be identifying 
patients based on the inclusion/exclusion study criteria. We will create a call list with the patient’s name, 
phone number, and email address. This call list will be stored digitally under password protection on a UCSD 
secured drive shared between the research team. Once identified, an investigator of the study team will 
contact the patient to ask if he/she is interested in hearing about sleep medicine research study opportunities. 
If yes, the study team member will provide full details about the study. If no, the patient will be removed 
from our call list. MRNs of uninterested patients will be retained on a no-call list. All Epic Slicer Dicer users 
will have access and security provided by UCSD’s Epic access team. 
 
If a potential subject does not answer their phone, we will leave a voicemail stating the name of the researcher 
calling, ask if they may be interested in participating in a sleep research study, and provide our call back 
number and email address to reach us, if interested.  
 
Prospective subjects will also be recruited from the community after individuals have initiated contact with 
the research staff. Permission to distribute IRB approved messages and flyers is being requested for the 
following sites and locations: 
 

 
 
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UCSD Listserve, UCSD Hospital Bulletin Board, Facebook, Craigslist, UCSD CTRI REDCap Survey  
IRB approved flyers will be digitally posted on the UCSD Listserv, Facebook, and Craigslist. The flyers will 
also be placed on UCSD Hospital Bulletin Boards by the Community Engagement Manager for the Clinical 
Transitional Research Institute (CTRI).   
 
Facebook Page Welcome Message  
We are requesting permission to have this message posted on a Facebook page created for recruitment 
purposes: 
Welcome to the UCSD Pulmonary and Sleep Medicine Research group’s Facebook page. We 
have ongoing research studies, primarily investigating obstructive sleep apnea. If you or 
someone you know has obstructive sleep apnea, please see our IRB approved flyers below. 
Occasionally, we are looking for healthy individuals without sleep disorders. Please regularly 
check our page for flyers describing these research opportunities.   
 
Research Match 
ResearchMatch will be used to contact prospective subjects with an IRB approved recruitment message. The 
message will be submitted for approval in an amendment if it is not already included with the initial project 
submission.  
 
Research Group Website 
The UCSD Pulmonary and Sleep Medicine Research group has a webpage hosted by UCSD health sciences. 
Wording from IRB approved flyers will be posted there.  
 
UCSD CTRI REDCap Survey  
Prospective subjects can voluntarily choose to fill out a UCSD CTRI REDCap Survey for this protocol. 
Information will be securely collected and stored via REDCap and will be used to determine if the 
prospective subject is eligible for the study.  
 
12. 
INFORMED CONSENT 
 
The research coordinator will screen the subjects over the telephone (or in person for clinic patients, time and 
patient preference allowing) following the screening script. A waiver of documented consent will be 
requested and once oral consent by the subject is obtained this consent will be used for the sole purpose of 
discussing the study with the subjects over the phone and performing the screening process as needed. The 
reason for this is because the only record linking the subject and the research would be the consent document 
and the principal risk would be potential harm resulting from a breach of confidentiality. Individuals 
interested in participating in this study will be given detailed explanation of the procedures, potential benefits, 
risks and discomforts of the study by the study researchers listed in the IRB application. All study staff are 
CITI certified and the importance of following GCP and HIPAA rules has been impressed upon them by the 
PI. Staff obtaining consent will have sufficient knowledge of the study to answer any questions that might 
arise during the consent process.  
 
A copy of the consent form will be given to the potential subject by email a minimum of 48 hours in advance 
of any planned baseline visit. If the individual agrees to participate, they will meet with research staff in 
person prior to any data collection to obtain written informed consent.  Subjects who have given a written 
consent will be given a copy of the signed consent form. The original consent and HIPAA authorization will 
be kept in the subject’s research file in a locked cabinet. No research procedures will be performed prior to 
obtaining informed consent. 
 

 
 
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English will be used in all discussions during the consent process. The patient will be excluded from the study if 
their preferred language is one other than English or if they do not understand English. The information being 
communicated will not include any exculpatory language through which the potential subject will waive or 
appear to waive any of the participant’s legal rights or release or appear to release the Researcher, Sponsor, the 
University or its agents from liability for negligence. Subjects unable to give their own consent will not be 
included in the study. 
 
13. 
ALTERNATIVES TO STUDY PARTICIPATION 
 
This study aims to test if certain investigational interventions can improve OSA severity in patients who 
declined or are not adherent with standard therapies. 
 
Thus, the alternative to study participation is continued follow up with his/her healthcare provider. 
 
14. 
POTENTIAL RISKS 
 
Overall, we believe there are few risks to participants in this study. In the following is a list of all the study 
procedures, their associated risks and the risk mitigation strategies: 
1. Screening will be based on a query and review of the electronic medical records. Further eligibility 
assessment will be based on a conversation with subjects who screened positive, either over the phone 
or in person. The main risk is breach of privacy which will be mitigated by ensuring conversations are 
private (i.e. no one can overhear it) and storing any resultant data in the secure REDCap database. Our 
research team undergoes extensive CITI and other training modules on an annual basis; further, we are 
well versed with this process and the critical importance of maintaining privacy. 
2. Standard home sleep apnea test: Select subjects who screen positive, but in whom the OSA diagnosis 
is unclear will undergo a home sleep apnea test as part of the screening process. The nasal cannula, 
respiratory belts, and oximeter used to monitor sleep and breathing may be mildly uncomfortable and 
could interfere with normal sleep. Thousands of routine home sleep studies are conducted every night 
across the country without incident. 
3. Subjects who are eligible based on screening will undergo a in-person visit to sign consent.. 
4. Anthropomorphic & medical history: Baseline demographics and health status (OSA symptoms, 
medical problems, medications, allergies, social history) will be obtained. A basic exam, including 
height, weight, neck, hip, and waist circumference, blood pressure, and oxygen saturation will be 
obtained. Assessment will occur in a private space in the research clinic and data will be directly 
entered into the REDCap database via eCFRs by staff to minimize any risk of privacy breach. Other 
potential risks include mild inconvenience, frustration, boredom, and fatigue from completing these 
assessments. 
5. Following this baseline assessment, subjects will undergo a baseline overnight sleep study to confirm 
eligibility. Standard Polysomnography: The nasal cannula, respiratory belts, electroencephalography, 
ECG and oximeter used to monitor sleep and breathing may be mildly uncomfortable and could 
interfere with normal sleep. Thousands of routine sleep studies are conducted every night across the 
country without incident. 
Subjects who are found to be ineligible (e.g. AHI<15/h) will receive remuneration for this baseline 
assessment but will be excluded from further study. Subjects whose eligibility is confirmed, will be provided 
with a 2-day supply of the randomly assigned study drug (AZM vs placebo) to be taken at home, with clear 
instructions of how and when to use them. During this period subjects will be able to contact research staff at 
any time to seek clarifications and/or report any side effects. On the 3rd day subjects will receive either 

 
 
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AZM+ESZ or placebo just prior to an overnight sleep study. Furthermore, after completion of aim 1, subjects 
will undergo a third phase of open-label therapy with either single or triple therapy. Similar as for aim 1, 
subjects will be provided with a 2-day supply of acetazolamide with clear instructions of how and when to 
use it; on the 3rd day subjects will receive either AZM alone (single therapy) or AZM+ESZ+VFX (triple 
therapy) just prior to an overnight sleep study. For both aims, subjects will be monitored for at least 8h 
following the administration of the study drugs in the laboratory: 
6. Standard Polysomnography: The nasal cannula, respiratory belts, electroencephalography, ECG and 
oximeter used to monitor sleep and breathing may be mildly uncomfortable and could interfere with 
normal sleep. Thousands of routine sleep studies are conducted every night across the country without 
incident. 
7. Sleepiness Measurement: this assessment will include the psychomotor vigilance test (10 minute 
assessment of reaction speed on a laptop) and some more questionnaires (e.g. Stanford Sleepiness 
Score). Risks and mitigation strategies are the same as for the assessment of “Anthropomorphic & 
medical history” discussed above. 
8. Venipuncture: Phlebotomy is a commonly performed procedure with no major risk apart from local 
discomfort, dizziness, bruising, hematoma and theoretically infection. There have not been observed 
major complications from this procedure in the context of our research studies. 
9. Study Drugs: All drugs are generally safe and well-tolerated. The safety data for acetazolamide, 
venlafaxine, and eszopiclone are reviewed below. No significant adverse interactions between these 
three drugs are expected. The risk of severe adverse events is expected to be very low (<1%), and 
there are multiple safeguards in place ranging from careful dose selection and exclusion of patients 
with risk factors that could increase the risk of side effects, to close monitoring including 24/7 
availability of research staff while subjects take acetazolamide vs placebo at home and overnight 
observation of subjects after ingestion of combination therapy 
(acetazolamide+venlafaxine+eszopiclone vs placebo).  
a) 
Acetazolamide (brand name Diamox) has been used for more than 60 years and is still 
commonly prescribed for various conditions such as prevention of high-altitude sickness. It is a 
carbonic anhydrase-inhibitor causing bicarbonate diuresis and thus mild metabolic acidosis 
with resultant increase of minute ventilation, which helps to stabilize ventilatory control (i.e. 
lowers loop gain). Acetazolamide up to 1000mg is generally well tolerated. Common side 
effects are paresthesias (tingling sensation in extremities), altered taste when drinking 
carbonated beverages, slightly increased urination, and fatigue. All of these side effects are 
fully reversible upon discontinuation of the drug; further, most of these side effects are dose-
dependent and thus less likely with the low-dose (500mg) we plan to use. Severe adverse 
events are virtually limited to patients with certain characteristics that will be excluded from 
this study (e.g. patients taking thiazide diuretics or angiotensin-receptor blockers will be 
excluded due to risk of hypokalemia). 
a. Eszopiclone (brand name Lunesta) is a well-tolerated hypnotic which has been evaluated for 
insomnia in several large clinical trials in which >1000 patients were followed for 6 or more 
months, and has been used in sleep medicine practice for more than a decade. Note, that OSA 
frequently co-exists with insomnia (some studies report a co-prevalence up to 69%) and in the 
above cited trials there was no specific screening to identify and exclude patients with OSA, 
therefore the resultant safety data are generalizable to OSA patients. Common side effects 
include: metallic taste in the mouth, nausea and somnolence. With regards to somnolence it is 
important to note, that two independent RCTs including a total of 48 healthy volunteers 
showed that 6.5 to 9h after ingestion there was no measurable impairment of objective 
psychomotor function or driving-related skills. Thus, after eszopiclone administration subjects 

 
 
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will be required stay 8h overnight in the research lab. Further, before leaving subjects will 
have to confirm in writing that they are alert and safe enough to drive. Importantly, subjects 
will be offered ad libitum sleep prior to leaving as needed. Those who continue to feel sleepy 
and unsafe to drive will be given a cab voucher which could be used to go home. 
b. Venlafaxine (brand name Effexor) is a serotonin and norepinephrine reuptake inhibitor 
(SNRI). Venlafaxine was approved by the U.S. FDA for the treatment of depression in 1993. It 
is also approved for treatment of generalized anxiety disorder, panic disorder and social 
anxiety disorder. In clinical practice venlafaxine is considered safe for -and often given to- 
OSA patients with co-morbid mood disorders, or to treat cataplexy in patients with co-morbid 
narcolepsy (off-label use). Furthermore, we recently completed a randomized trial 
(IRB#141272) comparing one dose of venlafaxine 50mg vs placebo in OSA patients with 
similar characteristics as in the proposed study and found that it was overall well tolerated: 
Two subjects reported mild nausea shortly after venlafaxine administration which resolved 
within 1h; in addition, one subject complained of nausea in the morning following placebo; no 
serious or unanticipated problems related to venlafaxine were observed during the study. In 
children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder 
(MDD) and other psychiatric disorders, venlafaxine has a very small risk of suicidal thoughts 
and behavioral change. Therefore, we will exclude patients with MDD or other psychiatric 
disorders. Adverse reactions include headache, insomnia, dizziness, diaphoresis, weight loss, 
nausea, xerostomia, anorexia, abnormal ejaculation and weakness. In rare cases, subjects may 
develop “serotonin syndrome” when venlafaxine is used in combination with other similar 
classes of medications or supplements that may increase the serotonin level; these symptoms 
include agitation, restlessness, dilated pupils and in severe cases high fever and irregular 
heartbeat. We will exclude subjects who are taking medications, which increase serotonin 
levels, therefore the likelihood of serotonin-syndrome risks is extremely low. Other rare side 
effects include vasodilation, palpitations, edema, anxiety, tachycardia, agitation, hypertonia, 
twitching, anorgasmia, paresthesia. Venlafaxine has the following common side effects: 
nausea, dry mouth, headache, sweating. Of note, half-life of venlafaxine is short (about 11 
hours) so any potential side effects from venlafaxine should dissipate within 1-2 days. 
10. Randomization: For aim1, participants will be assigned to one of two allocation-sequences 
(AZM+ESZ followed by placebo, or vice versa) in random order. Randomization is based on chance 
rather than a medical decision made by the researchers. Participants will have a 1 in 2 chance of being 
assigned to one sequence or the other. During the placebo phase subjects will receive matching 
placebo (a sugar pill), which has no active ingredients. The placebo pill is intended to have no effect, 
however, rarely individuals may experience symptoms such as constipation, nausea, or headaches. 
These effects should last a short time and will resolve on their own. 
 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
 
PROTECTIONS AGAINST RISK 
To ensure privacy and confidentiality, at no time will subject identities be revealed in any manner, whether in 
presentation, description or publication of the research for scientific purposes. All data obtained with subject 
identifiers will be kept in locked file cabinets to ensure confidentiality, and all paper file contents will be 
shredded before disposal. All subjects will be assigned a unique study number for use in the computer 
database and all electronic data are kept in password-protected computer files on secured servers to ensure 
confidentiality. 
As above, subjects in this proposed study may not sleep well in the testing environment, and may be sleepy 

 
 
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the next morning after the overnight PSG. They will have the option of sleeping without equipment for as 
long as they would like (ad libitum) before leaving the sleep laboratory to avoid any risk of drowsy driving. If 
they do not feel rested and safe to drive home, they will be provided with a cab voucher. Participants will be 
encouraged to ask someone else to drive them to and from the studies, or use public transportation (which is 
easily available 1 block from the sleep laboratory). Subjects who drive themselves must state that they are 
able to drive and sign a statement to that effect prior to leaving from the testing center. If the research staff 
(sleep technician or physician) feel that the subject is not safe to drive home, the subject may continue to rest 
longer in the laboratory, or a cab voucher will be used. After taking study drugs in the lab (which may 
potentially include eszopiclone) subjects will be required to stay in the lab for 8 hours before driving. 
It is expected that we will NOT find a new clinically relevant sleep problem given that subjects will have 
already undergone sleep testing and be diagnosed with OSA.  
However, it may be that other abnormalities, such as a cardiac arrhythmia or very high blood pressure, are 
noted during the study. In that case, the investigators will go over the results with the subject as soon as 
possible, a copy of these results will be given to the subject and, if so requested, the subject’s PCP. 
In case of any potentially life-threatening findings during the study, e.g. chest pain concerning for a heart 
attack or symptoms concerning for a stroke etc, research staff will immediately contact PI Schmickl (or his 
mentors), who is board certified in internal and sleep medicine and who will evaluate the situation.  
Any complications resulting from this study will be immediately reported to the UCSD HRPP. Each subject 
will be given 24-hour emergency contact information and will be able to contact the study PI and the study 
coordinator at any time regarding questions or complications. 
 
DATA AND SAFETY MONITORING (DSM) PLAN 
Given the relative low risk associated with the study, and that the majority of the interventions are commonly 
used in clinical practice in different contexts (e.g. eszopiclone for insomnia, and acetazolamide for central 
sleep apnea, venlafaxine for depression or cataplexy in narcolepsy patients), we believe that a DSM-Plan 
focusing on the PI (rather than a DSM-Board) to capture and promptly report abnormal clinically relevant 
data and adverse events is most adequate. 
PI Schmickl will be responsible for overall trial monitoring and reporting to the UCSD HRPP. However, he 
will be assisted by his mentor team (Dr Malhotra and Dr Owens), who will help adjudicate any potential 
adverse event. The PI, and his mentor team will jointly review the safety data at least once annually; during 
these meetings all the data included in the DSM report (see below) will be reviewed. 
Monitoring Procedures 
We will adhere to the following definitions (based on OHRP) for categorizing and reporting events: 
Adverse Event (AE): any untoward or unfavorable medical occurrence in a human subject, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject's participation in the research, whether or not considered related to the subject's 
participation in the research. Events will be self-rated by subjects as mild, moderate or severe. 
Serious adverse event (SAE): any adverse event that: (1) Results in death; (2) is life threatening, or places the 
subject at immediate risk of death from the event as it occurred; (3) Requires or prolongs hospitalization; (4) 
Causes persistent or significant disability or incapacity; (5) Results in congenital anomalies or birth defects; 
(6) is another condition which investigators judge to represent significant hazards. 
Unanticipated Problem (UP): any incident, experience, or outcome that meets all of the following criteria: 
unexpected, in terms of nature, severity, or frequency, given the research procedures that are described in the 
protocol-related documents, such as the IRB-approved research protocol and informed consent document; and 
the characteristics of the subject population being studied; related or possibly related to participation in the 

 
 
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research, in this guidance document, possibly related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved in the research; suggests that the 
research places subjects or others at a greater risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized. 
 
Adverse Events versus Unanticipated Problems: All adverse events are not necessarily unanticipated 
problems. All unanticipated problems are not necessarily adverse events. Some events may be both. Same 
applies to severe vs serious adverse events. 
At each visit subjects will be asked about side effects in an open-ended manner. In addition, each subject will 
be given 24-hour emergency contact information and will be able to contact the study PI and the study 
coordinator at any time regarding questions or complications. 
Any event noted by monitoring or reported by subjects will be captured on a separate electronic case report 
form (eCRF), which will be saved in the subject’s record within the REDCap database and promptly brought 
to the PI’s attention. 
 
DSM Report 
A data safety monitoring report will be prepared at least annually and included with reports to the UCSD 
HRPP (yearly continuing review) and the funding agency (yearly progress report). In addition to enrollment, 
it will track: 
1) All adverse events in which abnormal testing results were conveyed to the subject. 
2) All adverse events in which abnormal testing results were conveyed to a subject’s designated 
physician. (A record of this communication will be kept in the patient’s file) 
3) Any other adverse events, serious adverse events, and unanticipated problems, all of which will be 
adjudicated and classified as study-related or unrelated to the study. 
4) The report will also include amendments to the study protocol. 
This yearly report will be comprehensive; however, more prompt reporting may be needed. 
 
Adverse Event Reporting Mechanisms to the UCSD HRPP, plus Management of SAEs 
Any SAE determined to be study related or any UP will be reported within 1 business day to the UCSD 
HRPP. Although we do not anticipate any serious adverse event arising specifically from the proposed 
research, any SAE will be tracked until resolution by the investigators. If subjects are injured as a direct result 
of participation in the research, the University of California will provide any medical care needed to treat 
those injuries. This information, and contact information for the UCSD HRPP, is included in the consent 
form. Subjects in the study who have an SAE, whether related to the study or not, will be reviewed by the PI 
in order to determine whether to continue with the study. For example, a subject who completes part of the 
study and then has a prolonged intercurrent illness may be withdrawn from the study. 
 
HIPAA Compliance 
Almost all data will be entered directly into electronic CRFs that are created and maintained in a HIPAA-
compliant REDCap database, a secure web application designed for building and managing online surveys 
and databases. At UCSD, in order to access REDCap, users need to have a logon ID and password, which 
only allows viewing of the projects to which they are assigned. For instances where written records are 
needed (e.g. investigator’s notes from overnight sleep studies) these records will only have the subject’s 
anonymous study ID number and no personal health information (PHI). Additionally, the notes will be kept in 
a locked file cabinet in a locked room. As this study is being conducted solely at the University of California 
San Diego, we do not anticipate transmitting data outside of our institution.  

 
 
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Data Analysis 
This is a randomized controlled trial testing the feasibility and efficacy of interventions targeting the 
underlying OSA mechanisms (endotypes) with regards to improve OSA severity. However, this is more of a 
pilot study, with a relatively small number of participants and short duration of interventions. Therefore, there 
are no formal plans for interim analyses and no stopping rules. Data will be analyzed according to the 
research plan under the rigorous guidance of Professor of Biostatistics Dr Sonia Jain. 
 
Adverse Events and Blinding  
We recognize that adverse events may provide a clue as to which study arm (active vs placebo) subjects have 
been assigned to. To maintain blinding during the analysis of efficacy data, it will be performed separately 
from the analysis of safety data. 
 
Emergency Facilities 
We do not anticipate any cardiopulmonary arrests, but all research staff undergo the UCSD basic resuscitation 
training (BART) at least biannually. The UCSD Jacobs Medical Center Emergency Room is right across the 
street from the sleep research laboratory which is located on the ground floor of the ACTRI building. 
 
Adequacy of Resources 
The UCSD sleep research laboratory is a state-of-the art facility. It is led by Dr Malhotra and Dr Owens who 
have almost two decades of experience with research studies including overnight endotyping studies, 
randomized controlled trials and drug investigations. Our team further includes two staff research assistants 
and two sleep technicians who have extensive experience with all aspects of this trial. 
This study will be performed as part of a foundation grant obtained by the PI Schmickl who has an MD/PhD 
background. Dr Schmickl completed clinical training in internal medicine and sleep medicine (Harvard 
Combined Program) and several years of research experience including hands-on experience as a research 
fellow in clinical ICU-research at Mayo Clinic and formal training in epidemiology/biostatistics at Harvard 
School of Public Health. Currently Dr Schmickl has a dual appointment as Assistant Physician and as a T32 
fellow in the UCSD PCCSM Division/Department of Medicine. Contingent upon a career-development 
award Dr Schmickl will be proposed for a faculty position as Assistant Professor.  
 
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT 
 
All data will be collected and recorded for research purposes. Sources of data include: 
• The UCSD electronic medical record, which will only be accessed by the investigators in the manner 
approved by the UCSD Human Research Protections Program 
• Questionnaires (e.g. sleepiness scores) completed by the subjects 
• Physiological measurements made by the investigators, such as the values measured during the 
overnight sleep studies 
All data collected in this study will be maintained in a secure REDCap database on an internal server at 
UCSD. Information in the study database (not the screening database) will be stored for an indefinite period 
of time to allow for subsequent data analysis and future reference. All study documents that may be linked to 
a study subject will be shredded at completion of the study. Nearly all data will be collected from direct 
assessments and entered directly into the secure study database via electronic case report forms (eCRFs) 
either directly by subjects (in the case of questionnaires) or by research staff. Access to the REDCap database 
will be secured by two layers of passwords: first the staff must access the UCSD intranet via a password to 
access the link to the database, which can only be entered via another password. The UCSD intranet is 

 
 
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maintained by Next Generation Network (NGN), which provides and maintains all resources for access to the 
database and provides network security. Importantly, only members of the research team who are “invited” 
by the PI to have access to the research record can access the data. 
Blood samples will be processed and securely stored by ACTRI Clinic staff. Serum and plasma blood 
samples will be labelled with the subject’s unique de-identified code. De-identified DNA/RNA from each 
subject will be stored and may be utilized in future analysis as new discoveries related to genetic or 
physiological aspects of the study are made, i.e. to assess whether newly discovered genetic factors relate to 
phenotypes collected in this study.  The research group may choose to share stored DNA/RNA samples and 
associated physiological information with other investigators with the purpose of further answering research 
questions related to the same theme; however, any shared information will be de-identified and without 
behavioral data. 
It is not reasonably foreseeable that the study will have access to or collect information that Federal, State, 
and/or local laws/regulations requires or may require to be reported to other officials or ethically requires 
actions. 
 
17. POTENTIAL BENEFITS 
 
Subjects enrolled in this trial have un(der)treated moderate-severe OSA and are thus at risk of adverse health 
outcomes related to OSA. Therefore, subjects may benefit from participation temporarily in that their OSA 
and associated symptoms may temporarily improve. Additionally, we may uncover other important health 
information, such as hypertension, that may speed diagnosis and treatment. Thus, given the minor risks from 
the proposed research, we believe that the benefits of participation in this study outweigh the risks.  
 
More broadly, we expect that the findings of this study will be relevant for the large fraction of un(der)treated 
OSA patients in general, for whom this study may reveal a feasible strategy to provide alternative therapies. 
 
18. RISK/BENEFIT RATIO 
 
The investigators feel risks associated with these studies are outweighed by the benefits. 
 
19. EXPENSE TO PARTICIPANT 
 
There will be no cost to the subject for participating in this study. All of the tests and procedures that will be 
done for this research will be paid for by study funds. We will pay for any sleep studies done for research 
purposes.  
 
20. COMPENSATION FOR PARTICIPATION 
Subjects will be remunerated after completing each portion of the study, as outlined below: 
• Daytime Visit #1: $25 (if needed) 
• Overnight Visit 1: PSG: $100 
• Overnight Visit 2: PSG: $100 
• Overnight Visit 3: PSG: $100 
• Overnight Visit 4: $100 
• Weekly Phone Calls: $20/each 

 
 
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• Completion of All Visits: $100 
Subjects will be remunerated a total $560.00 for completion of all the study visits (with exception to the 
daytime visit). If the daytime visit is needed, the subject will be compensated $585.00 
If an additional daytime visit is needed for data collection: $25 
If data is inconclusive and an additional polysomnogram night is required, they will be paid $100. 
Parking will be available free of charge and participants will also be reimbursed for minor out of pocket 
expenses including meal vouchers, public transportation or taxi vouchers. If the subject terminates the study 
early, they will receive an amount based on the visits that have been completed. If any of the visits are 
missed, the subject will not be remunerated for those visits. 
 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
 
Christopher Schmickl MD, PhD is a T32 postdoctoral fellow and assistant physician with medical 
privileges at UCSD Medical Centers who will manage all day-to-day activities with close support from the 
mentor team and associated research assistance/sleep technicians. Thus, Dr Schmickl will be involved in all 
aspects of the clinical trial including screening, recruitment, data collection including overnight research 
studies, analysis, coordinate adverse event reporting and other safety reports during the conduct of the trial, 
and dissemination of findings via articles and presentations at conferences. 
Atul Malhotra PhD is a tenured Professor of Medicine and Vice Chair of Research in the Pulmonary, 
Critical Care and Sleep Medicine Division with medical privileges at UCSD Medical Centers who is an 
international expert on OSA mechanisms and has substantial experience with the design and conduct of both 
single center and multicenter clinical trials. Dr Malhotra will serve as Dr Schmickl’s primary mentor and 
provide guidance on all aspects of the trial. 
Robert Owens MD is a tenured Associated Professor in the Pulmonary, Critical Care and Sleep Medicine 
Division with medical privileges at UCSD Medical Centers who has co-developed the techniques used to 
measure the underlying OSA mechanisms (endotypes) and has also substantial experiences with clinical 
trials. He will serve as co-mentor and provide primarily hands-on support with design of the REDCap 
database, IRB relations, overnight research studies and analysis of resultant data using custom algorithms 
programmed in MATLAB. 
Jeremy Orr MD is an Assistant Professor in the Pulmonary, Critical Care and Sleep Medicine Division with 
medical privileges at UCSD Medical Centers. He has significant experience with overnight endotyping 
studies and analysis of such data and will provide help in this regard. 
Mathew Light MD is a physician in the Pulmonary, Critical Care and Sleep Medicine Division with medical 
privileges at UCSD Medical Centers. He will serve as a Co-Investigator.  
Sonia Jain PhD is a tenured Professor in Biostatistics and Bioinformatics who has helped design the studies, 
and who will provide support with statistical analysis on an as-needed basis. 
Tatum Simonson PhD is a tenured Assistant Professor in Physiology at UCSD. As a Co-Investigator, she 
will provide her expertise in genomics and lead DNA-based analyses of blood specimen.  
Dillon Gilbertson MS and Rebbecca Brena RPSGT, BS are experienced sleep technicians who will help 
with recruitment, and be responsible for overnight data acquisition, assessment of baseline characteristics and 
secondary outcomes (sleepiness measurements, blood pressure etc.).  

 
 
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Janelle Fine BS is a research assistant who will be responsible for recruitment and data collection.  
Pamela DeYoung BS RPSGT is a registered sleep technologist with long experience in clinical trials who 
will perform clinical scoring of sleep studies and will support Dillon Gilbertson with subject recruitment as 
needed. DeYoung will serve as the IRB contact.  
Naa-Oye Bosompra BA is an experienced research assistant who will help with recruitment and data 
collection. Bosompra will serve as the IRB administrative contact.  
Shannon Wright will serve as the Fiscal Contact for this protocol.  
 
Sultan Al Azzawi and Lana McGinnis are UCSD volunteer research assistants who will help with data 
collection and data analysis.  
 
 
22. BIBLIOGRAPHY 
 
1 Schmickl CN, Owens R, Edwards BA, et al. OSA Endotypes: What Are They and What Are Their PotentialClinical 
Implications? Current Sleep Medicine Reports (2018) 4:231–242.  
2 Sands SA, Edwards BA, Terrill PI, et al. Phenotyping Pharyngeal Pathophysiology Using Polysomnography in 
Patients with Obstructive Sleep Apnea. Am J Respir Crit Care Med. 2018 
3 Eckert DJ, Owens RL, Kehlmann GB, et al. Eszopiclone increases the respiratory arousal threshold and lowers the 
apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Respirology. 
2011;120:505-514. 
4 Edwards BA, Sands SA, Eckert DJ, et al. Acetazolamide improves loop gain but not the other physiological traits 
causing obstructive sleep apnoea. J Physiol. 2012;590:1199-1211. 
5 Friedberg CK, Halpern M, Taymor R. The effect of intravenously administered 6063, the carbonic anhydrase 
inhibitor, 2-acetylamino-1, 3, 4-thiadiazole-5-sulfonamide, on fluid and electrolytes in normal subjects and patients 
with congestive heart failure. J Clin Invest. 1952;31:1074-1081. 
6 Greenblatt DJ, Zammit GK. Pharmacokinetic evaluation of eszopiclone: clinical and therapeutic implications. Expert 
Opin Drug Metab Toxicol. 2012;8:1609-1618. 
7 Yano I, Takayama A, Takano M, et al. Pharmacokinetics and pharmacodynamics of acetazolamide in patients with 
transient intraocular pressure elevation. Eur J Clin Pharmacol. 1998;54:63-68. 
 
23. FUNDING SUPPORT FOR THIS STUDY 
 
The PI was awarded an unrestricted ATS grant ($40,000) for the proposed study, which is pending IRB 
approval. Costs related to this study exceeding the amount of the awarded grant, will be covered by the 
Malhotra/Owens sleep research laboratories.  
 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
N/A 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
N/A 
26. IMPACT ON STAFF 
N/A 
27. CONFLICT OF INTEREST 
N/A 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
N/A 

 
 
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29. OTHER APPROVALS/REGULATED MATERIALS 
N/A 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT 
N/A