Clinical Study to Investigate the Effect of Administration of Selective Serotonin Reuptake Inhibitors (SSRIs) and an Opioid on Ventilation
Phase: PHASE1
Conditions: Hypercapnia, Ventilatory Depression
Sponsor: Food and Drug Administration (FDA)

Study Title: Clinical Study to investigate the effect of administration of selective 
serotonin reuptake inhibitors and an opioid on ventilation 
 
Document Title: Clinical Study Protocol – Study No. SCR-012 
 
Document Date: 21 July 2022 
 
NCT Number: NCT05470465 

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Protocol Number: SCR-012 
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CLINICAL STUDY PROTOCOL 
 Clinical study to investigate the effect of administration of selective 
serotonin reuptake inhibitors and an opioid on ventilation 
 
PROTOCOL NO. SCR-012 
 
Sponsor: 
U.S. Food and Drug Administration 
White Oak Building #64, Room 2072 
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
 
Sponsor Study Lead: 
David Strauss, MD, PhD 
Director, Division of Applied Regulatory Science  
U.S. Food and Drug Administration 
Telephone: 301-796-6323 
Email: david.strauss@fda.hhs.gov 
 
 
Sponsor Medical 
Monitor: 
Keith Burkhart, MD 
U.S. Food and Drug Administration 
301-796-2226 
Email: keith.burkhart@fda.hhs.gov 
 
 
Project Manager: 
Jeffry Florian, PhD  
U.S. Food and Drug Administration  
Telephone: 301-796-4847  
Email: jeffry.florian@fda.hhs.gov 
 
 
 
Version of Protocol: 
1.1 
 
Date of Protocol: 
21 July 2022 
 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without the 
expressed written consent of the U.S. Food and Drug Administration. 
 
 

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SPONSOR SIGNATURE PAGE
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance 
with the following:
x The ethical principles that have their origin in the Declaration of Helsinki;
x International Council for Harmonisation (ICH) harmonised tripartite guideline E6 
(R2): Good Clinical Practice; and
x All applicable laws and regulations, including without limitation, data privacy laws 
and compliance with appropriate regulations, including human subject research 
requirements set forth by the Institutional Review Board (IRB).
David Strauss, MD, PhD
Director, Division of Applied 
Regulatory Science 
U.S. Food and Drug Administration
Date


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Protocol Number: SCR-012
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INVESTIGATOR SIGNATURE PAGE
I confirm that I have read and that I understand this protocol, the investigator brochure, 
and other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also protect the rights, safety, 
privacy, and well-being of study subjects in accordance with the following:
x
The ethical principles that have their origin in the Declaration of Helsinki;
x
ICH harmonised tripartite guideline E6 (R2): Good Clinical Practice;
x
All applicable laws and regulations, including without limitation data privacy laws 
and regulations;
x
Human subject research requirements set forth by the IRB;
x
Regulatory requirements for reporting of serious adverse events (SAEs) defined in 
Section 4.7.3.1 of this protocol; and
x
Terms outlined in the Clinical Study Site Agreement.
I further authorize that my personal information may be processed and transferred in 
accordance with the uses contemplated in Section 6 of this protocol.
Jan Matousek, D.O.
Principal Investigator
Date


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Protocol Number: SCR-012 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................................ 7 
1. INTRODUCTION ............................................................................................................................... 22 
2. STUDY OBJECTIVES .......................................................................................................................... 23 
2.1 PRIMARY OBJECTIVES .............................................................................................................................. 23 
2.2 SECONDARY OBJECTIVES ........................................................................................................................... 23 
2.3 EXPLORATORY OBJECTIVES ........................................................................................................................ 24 
3. STUDY ENDPOINTS .......................................................................................................................... 24 
3.1 PRIMARY ENDPOINTS ............................................................................................................................... 24 
3.2 SECONDARY ENDPOINTS ........................................................................................................................... 24 
3.3 EXPLORATORY ENDPOINTS ........................................................................................................................ 24 
4. INVESTIGATIONAL PLAN .................................................................................................................. 26 
4.1 STUDY DESIGN ....................................................................................................................................... 26 
4.1.1 Risk/Benefit ................................................................................................................................ 27 
4.2 SELECTION OF STUDY POPULATION ............................................................................................................. 30 
4.2.1 Inclusion Criteria ........................................................................................................................ 30 
4.2.2 Exclusion Criteria ........................................................................................................................ 31 
4.3 SCREENING FAILURES ............................................................................................................................... 33 
4.4 TERMINATION OF STUDY OR INVESTIGATIONAL SITE ....................................................................................... 34 
4.4.1 Criteria for Termination of the Study ......................................................................................... 34 
4.4.2 Criteria for Termination of the Investigational Site .................................................................... 34 
4.5 CRITERIA FOR SUBJECT WITHDRAWAL ......................................................................................................... 34 
4.5.1 Handling of Withdrawals ........................................................................................................... 35 
4.5.2 Replacement of Subjects ............................................................................................................ 35 
4.6 STUDY VISITS ......................................................................................................................................... 36 
4.6.1 Recruitment ................................................................................................................................ 36 
4.6.2 Compensation ............................................................................................................................ 36 
4.6.3 Screening .................................................................................................................................... 36 
4.6.4 Study Periods .............................................................................................................................. 37 
4.7 STUDY PROCEDURES ................................................................................................................................ 40 
4.7.1 Pharmacokinetic Assessments ................................................................................................... 40 
4.7.2 Pharmacodynamic Assessments ................................................................................................ 41 
4.7.3 Safety Assessments .................................................................................................................... 44 
4.7.4 Demographics and Medical History ........................................................................................... 48 
4.8 STUDY TREATMENTS ................................................................................................................................ 49 
4.8.1 Dose Strategy ............................................................................................................................. 49 
4.8.2 Treatments Administered ........................................................................................................... 49 
4.8.3 Dose Selection and Schedule ...................................................................................................... 50 
4.8.4 Method of Assigning Subjects to Treatment Sequence .............................................................. 51 
4.8.5 Identity of Study Drugs ............................................................................................................... 52 
4.8.6 Management of Clinical Supplies ............................................................................................... 53 
4.8.7 Blinding ...................................................................................................................................... 54 
4.8.8 Treatment Compliance ............................................................................................................... 55 
4.8.9 Prior and Concomitant Medications .......................................................................................... 55 
4.8.10 Subject Restrictions .................................................................................................................. 55 

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4.9 STATISTICAL METHODS ............................................................................................................................ 56 
4.9.1 Sample Size ................................................................................................................................ 56 
4.9.2 Analysis Populations .................................................................................................................. 57 
4.9.3 General Statistical Considerations ............................................................................................. 57 
4.9.4 Subject Disposition ..................................................................................................................... 57 
4.9.5 Demographics and Baseline Characteristics .............................................................................. 58 
4.9.6 Rebreathing Analyses ................................................................................................................. 58 
4.9.7 Pharmacokinetic Analysis .......................................................................................................... 59 
4.9.8 PK/PD Modeling ......................................................................................................................... 59 
4.9.9 Electrocardiogram Analyses ....................................................................................................... 60 
4.9.10 Additional Analyses .................................................................................................................. 60 
4.9.11 Safety Analyses ........................................................................................................................ 62 
4.9.12 Interim Analyses ....................................................................................................................... 63 
4.9.13 Missing Data ............................................................................................................................ 63 
4.10 DATA QUALITY ASSURANCE .................................................................................................................... 63 
4.11 DATA SHARING ..................................................................................................................................... 63 
5. ETHICAL CONSIDERATIONS .............................................................................................................. 64 
5.1 ETHICAL CONDUCT OF THE STUDY .............................................................................................................. 64 
5.2 INSTITUTIONAL REVIEW BOARD (IRB) ......................................................................................................... 64 
6. ADMINISTRATIVE PROCEDURES ....................................................................................................... 64 
6.1 RESPONSIBILITIES OF THE INVESTIGATOR ...................................................................................................... 64 
6.1.1 Form FDA 1572 ........................................................................................................................... 64 
6.1.2 Adherence to Protocol ................................................................................................................ 65 
6.1.3 Reporting Requirements ............................................................................................................ 65 
6.1.4 Source Documentation ............................................................................................................... 65 
6.1.5 Retention of Records .................................................................................................................. 65 
6.1.6 Financial Disclosure and Obligations ......................................................................................... 65 
6.2 CONFIDENTIALITY AND DISCLOSURE OF DATA ............................................................................................... 66 
6.3 SUBJECT CONSENT .................................................................................................................................. 66 
6.4 DATA COLLECTION .................................................................................................................................. 67 
6.5 PUBLICATIONS ........................................................................................................................................ 67 
7. STUDY MANAGEMENT ..................................................................................................................... 67 
7.1 MONITORING ......................................................................................................................................... 67 
7.2 MANAGEMENT OF PROTOCOL AMENDMENTS AND DEVIATIONS ....................................................................... 68 
7.2.1 Modification of the Protocol ...................................................................................................... 68 
7.2.2 Protocol Violations and Deviations ............................................................................................ 68 
REFERENCE LIST ................................................................................................................................... 70 
8. APPENDICES .................................................................................................................................... 76 
APPENDIX A – SCHEDULE OF EVENTS ................................................................................................................ 76 
APPENDIX B – LIST OF ABBREVIATIONS ............................................................................................................. 77 
APPENDIX C – PROTOCOL REVISION HISTORY ..................................................................................................... 79 
 
 
 

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LIST OF TABLES 
TABLE 4-1: STUDY SCHEDULE .............................................................................................................................. 26 
TABLE 4-2: STUDY TREATMENT GROUPS ............................................................................................................... 26 
TABLE 4-3: CLINICAL LABORATORY TESTS & DIAGNOSTIC SCREENING TESTS ................................................................. 47 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
Protocol Number: 
SCR-012 
Title: 
Clinical study to investigate the effect of selective serotonin reuptake 
inhibitors and an opioid on ventilation 
Investigators: 
Principal Investigator: Jan Matousek 
Study Physician: Jan Matousek 
Study Phase: 
1 
Study Period: 
This is a 3-period, double-blind, randomized crossover study. The 
duration of each treatment period will be 21 days in addition to a three-
week washout between periods. The duration of study participation will 
be 106 days (excluding the screening period). 
Study Site: 
Spaulding Clinical Research Unit, West Bend, Wisconsin 
Background and 
Motivation: 
A well-known and potentially fatal adverse reaction associated with 
opioid administration, particularly in the scenario of misuse, abuse, or 
when coadministered with certain other drugs is that people ‘stop 
breathing’. Research suggests this is caused by a reduced ventilatory 
response to increasing levels of carbon dioxide. In August 2016, the 
U.S. Food and Drug Administration (FDA) included boxed warnings 
about increased potential for respiratory depression with co-use of 
benzodiazepines and opioids.1 In response to this action, concerns were 
raised because patients may be prescribed other psychotropic drugs that 
may have similar adverse reactions when combined with opioids. 
Subsequently, FDA performed a review of the literature and identified 
13 psychotropic drugs for evaluation in an in vivo animal study (using a 
rat model). The in vivo study identified 4 drugs that had significant 
effects when combined with oxycodone on arterial carbon dioxide.2 
Two drugs (quetiapine and paroxetine) were selected for further 
evaluation in a human clinical study evaluating drug effects on 
hypercapnic ventilation.  
To study the effects of opioids alone or in combination with other 
psychotropic drugs on ventilation, FDA used a procedure referred to as 
Read rebreathing.3-4 With Read rebreathing, study participants rebreathe 
through a circuit with increased levels of O2 and CO2 . The artificially 
increased levels of CO2 trigger the subjects to increase ventilation. This 
“hypercapnic ventilatory response” can be decreased by opioids, 
benzodiazepines, and other drugs.5-19 
The previous study, which included 5-days of study drug dosing with 
oxycodone administered on day 1 or 5 showed quetiapine co-

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administered with oxycodone did not cause a significant decrease in 
hypercapnic ventilation compared to oxycodone alone.20 In contrast, 
paroxetine caused a decrease in hypercapnic ventilation compared to 
oxycodone alone, and an additive effect was seen when combined with 
oxycodone. This mechanism is due to a direct pharmacodynamic effect, 
rather than a pharmacokinetic interaction and most likely due to its 
serotonergic properties. Paroxetine is highly selective for inhibiting the 
serotonin transporter versus other monoamine transporters and other 
receptors in general.21-22 Although different types of serotonergic 
receptors and neurons can have differential effects on breathing, 
paroxetine does not bind to serotonin receptors at clinically-relevant 
therapeutic exposures.23-24 In addition, nonclinical and clinical studies 
have shown different SSRIs can have independent effects on ventilation, 
though SSRIs have not been shown to cause severe respiratory 
depression on their own.25-43 This supports the need for additional 
investigation on the effects of serotonergic drugs.  
The previous study evaluated effects on ventilation over 5-days of 
dosing. SSRIs take approximately 3 weeks to reach maximal therapeutic 
effect there, which correlates with the time required for pre-synaptic 
inhibitory serotonergic receptors to desensitize.44-46 Drug-effects on 
ventilation should be evaluated for a similar time period to confirm if 
effects persist under steady state conditions 
As part of this proposed study with a longer dosing duration and 
different SSRIs, hypercapnic ventilation will be assessed under 
hyperoxic and hypoxic gas levels using a modified Read rebreathing 
approach referred to as Duffin rebreathing. These modifications allow 
for critical physiological measurements and thresholds to be captured 
that can then be used to model the effects of drugs when there are 
dynamic changes in PO2 and PCO2, such as during a real-world opioid 
overdose.47-52  
Objectives and 
Endpoints: 
The objectives of this study are: 
Primary Objectives 
Primary objectives include the following: 
x To study ventilatory effects of SSRIs (paroxetine or 
escitalopram) combined with oxycodone compared to 
oxycodone alone after 21 days of SSRI dosing 
x To study ventilatory effects of SSRIs (paroxetine or 
escitalopram) compared to placebo after 20 days of SSRI dosing  
 
Secondary Objectives 
Secondary objectives include the following: 

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x To compare ventilatory effects of SSRIs (paroxetine or 
escitalopram) combined with oxycodone compared to 
oxycodone alone after 6 and 12 days of SSRI dosing 
x To compare ventilatory effects of SSRIs (paroxetine or 
escitalopram) compared to placebo after 5 and 11 days of SSRI 
dosing 
 
Exploratory Objectives 
x To study whether paroxetine or escitalopram affects the 
pharmacokinetics of oxycodone 
x To evaluate differences in hypercapnic ventilatory response 
under hyperoxic or hypoxic rebreathing  
x To study whether there is a direct pharmacodynamic interaction 
between paroxetine or escitalopram and oxycodone 
x To summarize additional pharmacokinetic parameters and 
pharmacodynamic measurements collected during the study 
The endpoints for this study are: 
Primary Endpoint 
x Minute ventilation at the 55mm Hg end tidal CO2 point (VE55) 
under hyperoxic conditions on day 21  
x VE55 under hyperoxic conditions on day 20 
 
Secondary Endpoints 
Secondary endpoints include the following: 
x VE55 under hyperoxic conditions on days 6 and 12 
x VE55 under hyperoxic conditions on days 5 and 11 
 
Exploratory Endpoints 
x The maximum observed plasma concentration (Cmax) and area 
under the plasma concentration time curve (AUC) of oxycodone 
and oxymorphone on days 6, 12, and 21  
x Baseline minute ventilation, ventilatory recruitment threshold, 
slope of the minute ventilation / end-tidal partial pressure of 
carbon dioxide (end-tidal PCO2) regression line, and 
extrapolated ventilatory recruitment threshold collected during 
hyperoxic and hypoxic rebreathing 
x The PK/PD relationship for study drugs when administered 
alone or in combination with oxycodone 
x Additional pharmacokinetic and pharmacodynamic (e.g., 
ventilation, pupillometry, ECG) endpoints as specified in the 
protocol 
 

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Study Design: 
This study will be a randomized, double blind, three period crossover 
study with approximately 25 healthy volunteer participants. This study 
will include three 21-day treatment periods with a 3-week washout 
between each period. Each subject will be randomized to 1 of 6 
treatment sequences (i.e., ABC, ACB, BAC, BCA, CAB, CBA). FDA 
will prepare the randomization schedule. 
Study Schedule: 
 
Study Treatments: 
 
 
 
Subjects will report to the study site for screening from Days -28 to -2. 
During the screening visit, the inclusion and exclusion criteria will be 
reviewed to ensure the subject is appropriate for the study. The informed 
consent form will be reviewed with the subject by a member of the 
study team and the subject will be encouraged to ask questions to ensure 
he or she has a good understanding of the study. If the subject is eligible 
and agrees to participate, the subject will be asked to sign the informed 
consent form before any study-specific procedure is performed, 
including randomization. 
After the consent process is complete, demographic data, medical 
history, and concomitant medications will be recorded. A physical 
examination will be performed by a study team member. Clinical 
laboratory tests (hematology, seum chemistry, and urinalysis) will be 
performed. Female subjects must have a negative pregnancy test result. 
Screening tests will be performed within 28 days of and no later than 2 
days before Day 1. 
At check-in for the first period (Day -1), eligibility criteria will be 
reviewed, any changes in medical history (including concomitant 
medications) will be documented. At check-in for all periods, vital sign 
Day -1  
Days 1-21 
Days 22-42 
Days 42-63 
Days 64-84  
Days 85-105 
Day 
106 
Check-
in  
Period 1 
Washout 
Period 2  
Washout  
Period 3  
Check-
out 
Treatment 
Day 
1-5 
6 
7-11 
12 
13-20 
21 
A 
Placebo QD 
Placebo + 
10 mg 
oxycodone 
Placebo QD 
Placebo +  
10 mg 
oxycodone 
Placebo QD 
Placebo  + 
10 mg 
oxycodone 
B 
40 mg 
paroxetine QD 
40 mg 
paroxetine + 
10 mg 
oxycodone 
60 mg 
paroxetine QD 
60 mg 
paroxetine + 
10 mg 
oxycodone 
60 mg 
paroxetine QD 
60 mg 
paroxetine + 
10 mg 
oxycodone 
C 
20 mg 
escitalopram 
QD 
20 mg 
escitalopram +  
10 mg 
oxycodone 
30 mg 
escitalopram 
QD 
30 mg 
escitalopram +  
10 mg 
oxycodone 
30 mg 
escitalopram 
QD 
30 mg 
escitalopram + 
10 mg 
oxycodone 

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measurements, and a 12-lead electrocardiogram (ECG) will be 
performed. In addition, clinical laboratory, drug, alcohol, two 
rebreathing assessments (one hyperoxic and one hypoxic), and a 
COVID-19 rapid antigen. An intravenous (IV) catheter may be inserted 
into the subject’s forearm region for blood collection (if needed).  
Participants will enter the clinic on a staggered basis in cohorts of 
approximately five so that no more than five subjects are undergoing 
rebreathing on any given day. Subjects will be staggered to allow for 
direct safety overview by medical staff during Duffin’s rebreathing.  
Participants will receive either placebo, paroxetine, or escitalopram on 
days 1-21 for each period. Oxycodone will be administered on days 6, 
12, and 21 of each period. Dosing of the study drugs will occur at time 0 
on each day. Oxycodone dosing will be at 3 h so that maximum 
concentration occurs for all drugs is at approximately the same time.   
Participants will be confined to the study clinic from day -1 until the 
first day of each washout period. There will be a three-week washout 
between each period. Subjects will be discharged from the study after 
completion of all study procedures. If a subject discontinues from the 
study prematurely, all procedures scheduled for the end of the study will 
be performed. Meal timing and components, activity levels, and general 
conditions in the study clinic will be as similar as possible on the 
treatment days. 
Upon return to clinic, on Days 42 & 84, eligibility criteria to continue 
study participation will be reviewed (see Schedule of Events for criteria 
listed on Days 42 & 84), any changes in medical history (including 
concomitant medications) will be documented. 
Subject Population: 
Approximately 25 healthy participants are planned for enrollment. 
Every effort will be made to maintain an approximate 50:50 male-to-
female sex distribution.  
Study and 
Reference Drugs, 
Dosage, and Route 
of Administration: 
For all drugs, standard drug doses or doses used in prior studies in 
healthy participants will be used in this study. Multiple doses of the 
assigned study drug will be administered to each subject during the 
treatment period. Oxycodone, paroxetine, escitalopram, ondansetron, 
and placebo will be administered orally. Subjects will complete each of 
the three treatments (A, B, and C) and will receive the following drugs 
alone or in combination:  
x Oxycodone 10 mg QD (2 x 5 mg tablets) on days 6, 12, and 21 
in each treatment (A-C)  
x Paroxetine 40 mg QD (2 x 20 mg tablet) on days 1-6 and 60 mg 
QD (3 x 20 mg tablets) on days 7-21 in treatment B 

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x Escitalopram 20 mg QD (2 x 10 mg tablet) on days 1-6 and 30 
mg QD (3 x 10 mg tablets) on days 7-21 in treatment C 
x Matching oral placebo for paroxetine and escitalopram 
x Participants will also receive ondansetron 4 mg orally 30 min 
before oxycodone administration 
Inclusion Criteria: 
Subjects who meet all the following inclusion criteria will be eligible to 
participate in the study:  
1. Subject signs an IRB approved written informed consent and 
privacy language as per national regulations (e.g., Health Insurance 
Portability and Accountability Act authorization) before any study 
related procedures are performed.  
2. Subject is a healthy, non-smoking man or woman, 18 to 50 years 
of age, inclusive, who has a body mass index of 18.5 to 33.0 
kg/m2, inclusive, at Screening. 
3. Subject has normal medical history findings, clinical laboratory 
results, vital sign measurements, pulse oximetry, 12-lead ECG 
results, and physical examination findings at screening or, if 
abnormal, the abnormality is not considered clinically significant 
(as determined and documented by the investigator or designee). 
4. Subject must have a negative test result for alcohol and drugs of 
abuse at screening and check-in days.  
5. Subject must test negative for severe acute respiratory syndrome 
corona virus 2 (SARS-CoV-2) by a rapid antigen test at check-in 
for all study periods. If a subject’s test comes back as invalid, the 
test can be repeated. 
6. Female subjects must be of non-childbearing potential (confirmed 
with follicle-stimulating hormone levels > 40 mIU/mL)  or, if they 
are of childbearing potential, they must: 1) have been strictly 
abstinent for 1 month before check-in (Day -1) and agree to remain 
strictly abstinent for the duration of the study and for at least 
1month after the last application of study drug; OR 2) be practicing 
2 highly effective methods of birth control (as determined by the 
investigator or designee; one of the methods must be a barrier 
technique) from at least 1 month before check-in (Day -1) until at 
least 1 month after the end of the study.  
7. Male subjects must agree to practice 2 highly effective methods of 
birth control (as determined by the investigator or designee) from 
at least 1 month before check-in (Day -1) until at least 1 month 
after the last dose of study drug. 
8. Subject is highly likely (as determined by the investigator) to 
comply with the protocol defined procedures and to complete the 
study. 
Exclusion Criteria: 
Subjects who meet any of the following exclusion criteria will not be 
eligible to participate in the study: 

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1. Subject has used any prescription or nonprescription drugs 
(including aspirin or NSAIDs and excluding oral contraceptives and 
acetaminophen) within 14 days or 5 half-lives (whichever is longer) 
or complementary and alternative medicines within 28 days before 
the first dose of study drug. This includes prescription or 
nonprescription ophthalmic drugs. 
2. Subject is currently participating in another clinical study of an 
investigational drug or has been treated with any investigational 
drug within 30 days or 5 half-lives (whichever is longer) of the 
compound. 
3. Subject has used nicotine-containing products (e.g., cigarettes, 
cigars, chewing tobacco, snuff, electronic cigarettes) within 
6 weeks of Screening. Subjects must refrain from using these 
throughout the study. 
4. Subject has consumed alcohol, xanthine containing products (e.g., 
tea, coffee, cola), caffeine, grapefruit, or grapefruit juice within 
24 h of check-in. Subjects must refrain from ingesting these 
throughout the study.  
5. Subject has a history or evidence of a clinically significant disorder, 
condition, or disease (e.g., cancer, human immunodeficiency virus 
[HIV], hepatic or renal impairment) that, in the opinion of the 
investigator would pose a risk to subject safety or interfere with the 
study evaluation, procedures, or completion. This includes subjects 
with any underlying medical conditions that put subjects at 
increased risk of severe illness from COVID-19 based on the 
Centers for Disease Control and Prevention (CDC) guidelines. 
6. Subject has any signs or symptoms at screening or check-in of any 
study period that are consistent with COVID-19. Per current CDC 
recommendations this includes subjects with the symptoms cough 
or shortness of breath or difficulty breathing, or at least two of the 
following symptoms: fever, chills, repeated shaking with chills, 
muscle pain, headache, sore throat, or new loss of taste/smell. In 
addition, the subject has any other findings suggestive of COVID-
19 risk in the opinion of the investigator. 
7. Subject has known or suspected allergies or sensitivities to any 
study drugs. 
8. Subject has clinical laboratory test results (hematology, serum 
chemistry and urinalysis) at Screening or period check-In that are 
outside the reference ranges provided by the clinical laboratory and 
considered clinically significant by the investigator. Clinical 
laboratory results may be repeated once, as needed, for confirming 
results at Screening and period check-in.   
9. Subject has a positive test result at Screening for HIV 1 or 2 
antibody, hepatitis C virus antibodies, or hepatitis B surface 
antigen. 

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10. Subject is unable or unwilling to undergo multiple venipunctures 
for blood sample collection because of poor tolerability or poor 
venous access. 
11. Female subject is currently pregnant or lactating or was within 3 
months of study enrollment. 
12. Subject has a history of opioid or psychotropic drugs within 60 days 
of the start of the study. 
13. Subject has a history of asthma that has required medication within 
the last five years. 
14. Subject has non-reactive or mishappen pupil(s) or damaged orbit 
structure or surrounding soft tissue is edematous or has an open 
lesion. 
15. Subject has a Mallampati score of >2. 
16. Subject’s Duffin rebreathing data is of poor quality or subject does 
not agree to remain clean-shaven for all days when the Duffin 
rebreathing procedure is performed. 
17. Subject has a history of sleep disorders, Panic disorders, Panic 
Attacks, Generalized Anxiety Disorder, or any associated DSM 
diagnosis or condition. 
18. Subject has a history of or currently has hypoventilation syndrome 
or sleep apnea and is on non-invasive ventilation. 
19. Subject has a history of unexplained syncope, structural heart 
disease, long QT syndrome, heart failure, myocardial infarction, 
angina, unexplained cardiac arrhythmia, TdP, ventricular 
tachycardia, or placement of a pacemaker or implantable 
defibrillator. Subjects will be also excluded if there is a family 
history of long QT syndrome (genetically proven or suggested by 
sudden death of a close relative to cardiac causes at a young age) or 
Brugada syndrome. 
20. Subject has a history of suicidal ideation or previous suicide 
attempts. 
21. Subject has a safety 12-lead ECG result at screening or check-in at 
any study period with evidence of any of the following 
abnormalities:  
x QTc using Fridericia correction (QTcF)>430 msec 
x  PR interval>220 msec or <120msec 
x QRS duration>110 msec 
x Second- or third-degree atrioventricular block 
x Complete left or right bundle branch block or incomplete right 
bundle branch block 
x Heart rate <50 or >90 beats per minute 
x Pathological Q-waves (defined as Q-wave>40 msec) 
x Ventricular pre-excitation  

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22. Subject has a skin condition likely to compromise ECG electrode 
placement. 
23. Any individual with breast implants.  
 
Sample Collection 
The following samples should be collected and processed as follows. 
Number of samples collected throughout the study can be found in the 
Schedule of Events (see Appendix): 
The PK blood samples (6 mL each) will be collected into tubes 
containing K2EDTA, inverted several times to mix the blood with the 
anticoagulant, and placed in an ice bath. Within 30 minutes of 
collection, the samples will be centrifuged for 10 minutes, at 3000 
relative centrifugal force (RCF), at 4°C, by a study team member. 
The plasma will be separated using a disposable plastic pipette and 
equally aliquoted into duplicate cryotube vials labeled as Aliquot A 
(primary) and Aliquot B (backup). The plasma samples will be 
appropriately labeled and stored frozen at -70°C or below within 30 
minutes after aliquoting until shipment. Temperature monitoring logs 
should be maintained and accessible for review by the study monitor.  
The Aliquot A samples (primary) will be shipped first, on dry ice, to the 
bioanalytical laboratory at FDA for processing when requested by the 
sponsor. The Aliquot B samples (backup) will be held for a second 
shipment after completion of all Aliquot A sample shipment(s) and the 
timing of the Aliquot B shipment will be communicated by the sponsor. 
None of the PK blood samples will be stored at the clinical facility for 
future use. 
Pharmacokinetic 
Assessments: 
Pharmacokinetic blood samples will be collected on the following days 
at the approximate times for each study period: 
x Day 5, 6, 11, 12, 20, and 21: 0 (pre-dose), 3, 4, 5, 8 hr (and 24 hr 
for Day 6, 12, and 21) 
x Day 2 and 16: 0 (pre-dose), 2, 3, 4, 5, 6, 8, 12, 24 hr 
Blood samples will be collected by direct venipuncture or by inserting 
an IV catheter. There will be a total of 51 PK samples per participant for 
each study period. 
For each participant, the following PK parameters will be determined 
for oxycodone and oxymorphone (days 6, 12, and 21) and paroxetine 
escitalopram, and escitalopram metabolites (days 2, 5, 6, 11, 12, 16, 20, 
and 21): 
x Maximum observed plasma concentration (Cmax) 
x Area under the plasma concentration time curve (AUC) 

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x Time at which Cmax occurs (Tmax) 
x Elimination rate constant (Kel) 
x Terminal half-life (t1/2) 
x Accumulation ratio (for escitalopram and paroxetine) 
 
Pharmacodynamic 
Assessments:  
 
Rebreathing assessments following Duffin’s rebreathing procedure (see 
separate Standard Operating Procedure [SOP]) will be performed on the 
following study days and time of each study period: 
x Day -1: one hyperoxic and one hypoxic assessment 
x Day 5, 6, 11, 12, 20, and 21: hyperoxic assessments at 0 (pre-
dose), 4 and 5 hours; one hypoxic assessment at 5 hours 
(following the hyperoxic assessment) 
During Duffin’s rebreathing procedure, subjects will be placed in an 
upright position (90o angle) on a bed and connected to the respiration 
measurement set up. Subjects will wear a facemask and breathe from a 
pre-filled rebreathing bag containing approximately 4 L of either a 
hyperoxic-hypercapnic (24% O2, 6% CO2, N2 balanced) or hypoxic-
hypercapnic (6% O2, 6% CO2, N2 balanced) gas mixture. During this 
study, subjects will be asked to breath room air for 5 minutes (relaxation 
stage) and then to hyperventilate (primarily through deep breathing) 
room air voluntarily for 5 minutes (hyperventilation stage). Thereafter, 
subjects will be switched to the rebreathing bag and perform rebreathing 
assessments at one of the 2 different isoxic end tidal PO2, i.e., 150 
mmHg and 50 mmHg. The isoxia at 150 mmHg or 50 mmHg end-tidal 
PO2 will be maintained by providing a computer-controlled flow of 
100% O2 to the rebreathing bag.  
Pupillary assessments (see separate SOP) will be performed before and 
after each rebreathing procedure (except not in between the hyperoxic 
and hypoxic paired assessment) while the ambient light is kept at a 
consistent level. The rubber cup of the pupillometer will be placed on 
the right eye and repeated on the same eye approximately 1 minute later. 
ECG assessments will be performed on the following study days and 
time of each study period: 
x Day 1: 0 (pre-dose) hr 
x Day 2 and 16: 0 (pre-dose), 2, 3, 4, 5, 6, 8, 12, 24 hr 
Ten second 12-lead ECG tracings with the most stable heart rate and 
highest signal-to-noise ratio will be extracted in at least 3 replicates at 
ECG extraction time points during each treatment period. 
During all ECG extraction periods, subjects will be placed in a supine 
position. Three ECG extractions will be performed for a baseline 

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measurement before the first oral dose on day 1 of each treatment 
period. The other ECG extractions/period time matched to the PK 
samples will be obtained before the PK sample collection time. Subjects 
will be isolated (not able to see each other) in a quiet environment that is 
free from external stimuli. 
Different ventilation, cardiovascular, pupillary, sedation, and ECG 
measures that will be summarized include, but are not limited to, the 
following: 
Ventilation and Cardiovascular Assessments:  
x During rebreathing stage 
o VE55 (minute ventilation at the 55mm Hg end tidal CO2 
point) 
o Baseline minute ventilation when end tidal PCO2 is less 
than the ventilatory recruitment threshold (represents 
non-chemoreflex drives to breathe) 
o Ventilatory recruitment threshold (end tidal PCO2 above 
which minute ventilation starts to increase linearly with 
further increases in end tidal PCO2) 
o Slope of the minute ventilation / end-tidal partial 
pressure of carbon dioxide (end-tidal PCO2) regression 
line that reflects the increase in minute ventilation 
relative to the increase in end tidal PCO2 (represents 
chemoreflex sensitivity) 
o Extrapolated ventilation recruitment threshold 
(intersection with X axis) 
x During relaxation stage 
o Minute ventilation, tidal volume, respiratory rate, end-
tidal PCO2, end-tidal PO2, oxygen saturation, and heart 
rate during the relaxation stage 
o Number of apneic events lasting > 10 s during the 
relaxation stage 
 
Pupillary Assessments  
x Maximum pupil diameter before constriction  
x Minimum diameter at peak constriction  
x Percent change between min/max diameter  
x Latency of constriction   
x Average constriction velocity  
x Maximum constriction velocity  
x Dilation velocity after peak constriction  
x Time to reach 75% recovery of maximum diameter  
 

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Sedation scores   
x Ramsey Sedation Scale   
x Visual Analogue Scale   
 
ECG Assessments  
x Change from baseline in QTc, PR, QRS, JTpeakC, TpeakTend and 
heart rate. 
 
In addition, PK/PD relationships will be evaluated between study drugs 
and a subset of pharmacodynamic endpoints (ventilation, pupillary, 
ECG).  
Safety Assessments: 
 
Safety will be evaluated in terms of adverse events (AEs), clinical 
laboratory results (hematology, serum chemistry, and urinalysis), vital 
sign measurements (blood pressure, heart rate, respiratory rate, and oral 
body temperature), safety 12-lead ECG, and physical examination 
findings. 
Sample Size and 
Threshold 
Determination: 
Approximately 25 healthy participants are planned for enrollment. A 
previous study (20 participants) with paroxetine showed a decrease of 
10.2 L/min in VE55 for paroxetine (40 mg) combined with oxycodone 
(10 mg) compared to oxycodone alone after 5 days of dosing with 
paroxetine. Similarly, there was a 9.3 L/min decrease in VE55 for 
paroxetine compared to placebo after 4 days of dosing with paroxetine. 
The standard deviation in assessments was approximately 6.5 L/min. 
Assuming a similar effect size with paroxetine and escitalopram at day 
20 and 21, the planned number of participants allows for a 40% drop out 
rate while maintaining at least 90% power for separate one-sided tests at 
a 0.025 significance level with the multiple primary endpoints.  
Statistical Methods: 
All data will be presented in data listings. Data from subjects excluded 
from an analysis population will be presented in the data listings but not 
included in the calculation of summary statistics. The number of 
subjects who enroll in the study and the number and percentage of 
subjects who complete each assessment will be presented. The 
frequency and percentage of subjects who withdraw or discontinue from 
the study and the reason for withdrawal or discontinuation will be 
summarized. Demographic and baseline characteristics will be 
summarized overall and by treatment for all subjects. 
Descriptive statistics will be used to summarize demographic and 
baseline subject characteristics. For continuous variables, the mean, 
median, standard deviation (SD), minimum, and maximum values will 

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be reported. For categorical (nominal) variables, the number and 
percentage of subjects (or observations) will be reported. 
The rebreathing analysis population will include all subjects who 
completed at least one rebreathing assessment on any day or at any 
timepoint. Specific information on analysis populations for different 
pharmacodynamic measures will be described in the Statistical Analysis 
Plan (SAP). 
 
Primary and Secondary Ventilation Analyses 
Multiple primary analyses are planned for each drug. The first primary 
analysis will be VE55 on day 21 at 5 h (hyperoxic) between oxycodone 
with paroxetine or escitalopram compared to oxycodone alone. The 
second primary analysis will be VE55 on day 20 at 5 h (hyperoxic) 
between paroxetine or escitalopram compared to placebo. Since Day 20 
and 21 are considered multiple primary endpoints, comparisons will 
have an adjustment for multiplicity using a Bonferroni correction (each 
day will be tested at a 0.025 significance level). No adjustments will be 
made for separate testing of paroxetine or escitalopram since the 
treatments are considered separate interventions in the study.  
A linear mixed effects model will be developed using all study data 
from hyperoxic assessments. Fixed effects will include treatment, 
period, sequence, and baseline VE55 (i.e., VE55 obtained at 0 h on Day 
-1 of each treatment period).  Subject will be included as a random 
effect on the intercept.  If a subject’s baseline VE55 for a treatment 
period is not available, then the baseline value for that period will be 
calculated based on the median of all other baseline values for that 
subject from other study periods. If a subject does not have any 
completed baseline VE55 data, the subject will be assigned a baseline 
VE55 equal to the median of the population.  
To demonstrate an effect when oxycodone is combined with paroxetine 
(or escitalopram) compared to oxycodone the upper bound of the one-
sided 97.5% CI of the least-square mean VE55 difference between 
treatments must not overlap 0 L/min.  Similarly, to demonstrate an 
effect of paroxetine (or escitalopram) compared to placebo the upper 
bound of the one-sided 97.5% CI of the least-square mean VE55 
difference between treatments must not overlap 0 L/min. Each 
comparison will be performed separately (i.e.,‘trt’ as ‘paroxetine’ or 
‘escitalopram’).:  
x H0: VE55oxy+trt - VE55oxy  0 L/min 
x HA: VE55oxy+trt - VE55oxy < 0 L/min 

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For secondary endpoints, effects of paroxetine or escitalopram with 
oxycodone compared to oxycodone alone will also be performed using 
the same comparisons on day 6 and day 12. 
As additional secondary endpoints, effects of paroxetine or escitalopram 
alone compared to placebo will be determined on day 5 and 11 using the 
same model. Additional details on testing of ventilation secondary 
endpoints are discussed in the SAP. 
Pharmacokinetics: Concentrations will be determined at approximately 
specified timepoints. Oxycodone and oxymorphone Cmax and AUC will 
be summarized on days 6, 12, and 21 using descriptive statistics. 
Differences in oxycodone or oxymorphone alone compared to exposures 
when coadministered with paroxetine or escitalopram will be compared. 
Cmax and AUC will be log-transformed and the values between study 
arms will be compared using a linear mixed effects model with 
treatment as a categorical variable and participant as a random effect.  
Paroxetine and escitalopram Cmax and AUC will be summarized on days 
2, 5, 6, 11, 12, 16, 20 and 21 using descriptive statistics.  
The PK parameters will be analyzed using noncompartmental methods 
based on actual sampling times. All parameters will be calculated using 
SAS or R software. Mean and individual concentration time profiles 
will be presented in graphs. 
Additional PK parameter analyses including but not limited to measures 
listed under Pharmacokinetic Assessments will be included in the SAP. 
Additional Pharmacodynamics on Ventilatory Assessment Days: 
Mean and standard deviations for baseline minute ventilation, 
ventilatory recruitment threshold, slope of the PCO2-ventilatory 
response curve, and the extrapolated ventilatory recruitment threshold 
will be calculated for each subject at each rebreathing assessment using 
data from the rebreathing stage. Mean and standard deviation for minute 
ventilation, tidal volume, respiratory rate, end-tidal PCO2, end-tidal 
PO2, oxygen saturation, and heart rate will be calculated using data from 
the relaxation stage. Number of apneic events lasting > 10s will be 
counted for each subject, day, and rebreathing assessment during the 
relaxation stage. Full details will be described in a separate SAP. 
Additional pupillary assessments (e.g., ventilation, respiratory rate, heart 
rate, maximum pupil diameter before constriction) as specified in the 
protocol will be reported with standard descriptive statistics. 
ECG Assessments  

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Intensive ECG assessments will be performed on Days 2 and Day 16. 
The QT interval will be corrected for heart rate using Fridericia’s 
formula (QTc=QT/RR1/3). The J-Tpeak interval will be corrected for heart 
rate using the formula (J-TpeakC = J-Tpeak/RR0.58). Baseline will be the 
mean of the 3 predose ECG extractions of Day 1. 
Exposure-response analyses will be performed for the change from 
baseline in QTc (and other ECG measurements; see ECG Analysis 
Plan), where the mean of the 3 predose ECG readings on Day 1 will be 
used as the Baseline. The concentration of the drug will be used as a 
covariate. Exposure-response analysis will be done following most 
recent best practices in concentration-QTc modeling. Additional details 
will be specified in the ECG Analysis Plan. 
 
Safety 
The safety population will include all subjects who receive at least 1 
dose of the study drug. All AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). The incidence of AEs, 
organized by system organ class and preferred term, will be summarized 
with a focus on treatment-emergent AEs. Vital sign measurements will 
be summarized using descriptive statistics by time point. All values will 
be evaluated for clinically notable results. Data for additional safety 
parameters (e.g., physical examination findings) will be listed. 
Date of Protocol: 
21 July 2022 
 
 
 

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1. INTRODUCTION 
A well-known and potentially fatal adverse reaction associated with opioid 
administration, particularly in the scenario of misuse, abuse, or when co-administered 
with certain other drugs is that people ‘stop breathing’. Research suggests this is caused 
by a reduced respiratory response to counteract increasing levels of systemic carbon 
dioxide (CO2). In August 2016, the U.S. Food and Drug Administration (FDA) included 
boxed warnings about increased potential for respiratory depression with co-use of 
benzodiazepines and opioids.1  In response to this action, concerns were raised because 
patients may be prescribed other psychotropic drugs that may have similar adverse 
reactions when combined with opioids.  
Subsequently, FDA performed a review of the literature and identified 13 psychotropic 
drugs for evaluation in an in vivo animal study (using a rat model). The in vivo study 
identified 4 drugs that had significant effects when combined with oxycodone on arterial 
carbon dioxide.2 Two drugs (quetiapine and paroxetine) were selected for further 
evaluation in a human clinical study evaluating drug effects on hypercapnic ventilation.  
To study the effects of opioids alone or in combination with other psychotropic drugs on 
ventilation, FDA used a procedure referred to as Read rebreathing.3-4 With Read 
rebreathing, study participants rebreathe through a circuit with increased level of O2 and 
CO2 (93% O2 and 7% CO2). The artificially increased levels of CO2 trigger the subjects to 
increase ventilation. This “hypercapnic ventilatory response” can be decreased by 
opioids, benzodiazepines, and other drugs.5-19     
The previous study, which included 5-days of study drug dosing with oxycodone 
administered on day 1 or 5 showed quetiapine co-administered with oxycodone did not 
cause a significant decrease in hypercapnic ventilation compared to oxycodone alone.20  
In contrast, paroxetine caused a decrease in hypercapnic ventilation compared to 
oxycodone alone, and an additive effect was seen when combined with oxycodone. This 
mechanism is due to a direct pharmacodynamic effect, rather than a pharmacokinetic 
interaction and most likely due to its serotonergic properties. Paroxetine is highly 
selective for inhibiting the serotonin transporter versus other monoamine transporters and 
other receptors in general.21-22 Although different types of serotonergic receptors and 
neurons can have differential effects on breathing, paroxetine does not bind to serotonin 
receptors at clinically-relevant exposures.23-24 In addition, nonclinical and clinical studies 
have shown different selective serotonin reuptake inhibitors (SSRIs) can have 
independent effects on ventilation, though SSRIs have not been shown to cause severe 
respiratory depression on their own.25-43 This supports the need for additional 
investigation on the effects of serotonergic drugs. Escitalopram is highly selective for the 
serotonin transporter, has low selectivity for serotonin receptors and muscarinic 

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receptors, and is widely prescribed, making it a good candidate as a second SSRI to 
evaluate in this study. 
The previous study evaluated effects on ventilation over 5-days of dosing. SSRIs take 
approximately 3 weeks to reach maximal therapeutic effect, which correlates with the 
time required for pre-synaptic inhibitory serotonergic receptors to desensitize.44-46 SSRI 
effects on ventilation in the proposed study would be evaluated for a similar period of 
time to confirm if effects on ventilation persist under steady state conditions.   
Finally, an additional modification in the proposed study will be the assessment of 
hypercapnic ventilation under hyperoxic and hypoxic gas levels using a modified Read 
rebreathing approach referred to as Duffin rebreathing. One limitation of the rebreathing 
procedure from the previous study design is all measurements are performed under 
hyperoxic conditions, which can have independent effects on ventilation. In addition, the 
data cannot necessarily be used to extrapolate to the dynamic changes in PO2 and PCO2 
that occur during real-world drug-induced respiratory depression when a patient is 
breathing room air. Duffin modified the Read rebreathing method to include 1) 
hyperventilation (primarily through deep breathing) prior to rebreathing to achieve an end 
tidal PCO2 or approximately 20-25 mm Hg prior to rebreathing, 2) maintaining an isoxic 
end tidal PO2 during rebreathing, and 3) repeating rebreathing at 2 different isoxic end 
tidal PO2 levels (i.e., at 150 mm Hg and 50 mm Hg). These modifications, which have 
been used by investigators for decades, allow for critical physiological measurements and 
thresholds to be captured that can then be used to model the effects of drugs when there 
are dynamic changes in PO2 and PCO2, such as during a real-world opioid overdose.47-52 
 
2. STUDY OBJECTIVES 
2.1 Primary Objectives 
x To study ventilatory effects of SSRIs (paroxetine or escitalopram) combined with 
oxycodone compared to oxycodone alone after 21 days of SSRI dosing. 
x To study ventilatory effects of SSRIs (paroxetine or escitalopram) compared to 
placebo after 20 days of SSRI dosing.   
2.2 Secondary Objectives  
x To compare ventilatory effects of SSRIs (paroxetine or escitalopram) combined 
with oxycodone compared to oxycodone alone after 6 and 12 days of SSRI 
dosing. 

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x To compare ventilatory effects of SSRIs (paroxetine or escitalopram) compared to 
placebo after 5 and 11 days of SSRI dosing. 
2.3 Exploratory Objectives  
x To study whether paroxetine or escitalopram affects the pharmacokinetics of 
oxycodone. 
x To evaluate differences in hypercapnic ventilatory response under hyperoxic or 
hypoxic rebreathing. 
x To study whether there is a direct pharmacodynamic interaction between 
paroxetine or escitalopram and oxycodone. 
x To summarize additional pharmacokinetic parameters and pharmacodynamic 
measurements collected during the study. 
 
3. STUDY ENDPOINTS 
3.1 Primary Endpoints 
The following primary endpoints will be evaluated: 
x Minute ventilation at 55mm Hg end tidal CO2 (VE55) under hyperoxic conditions 
on day 21 
x VE55 under hyperoxic conditions on day 20  
3.2 Secondary Endpoints  
The following secondary endpoints will be evaluated: 
x VE55 under hyperoxic conditions on days 6 and 12 
x VE55 under hyperoxic conditions on days 5 and 11 
3.3 Exploratory Endpoints 
The following exploratory PK parameters will be determined for oxycodone and 
oxymorphone (days 6, 12, and 21) and paroxetine, escitalopram, and escitalopram 
metabolites (days 2, 5, 6, 11, 12, 16, 20, and 21): 
x Maximum observed plasma concentration (Cmax) 
x Area under the plasma concentration time curve (AUC) 
x Time at which Cmax occurs (Tmax) 
x Elimination rate constant (Kel) 

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x Terminal half-life (t1/2) 
x Accumulation ratio (for escitalopram and paroxetine) 
Additionally, the following exploratory PD markers may be evaluated:  
Ventilation and Cardiovascular Assessments:  
x During rebreathing stage 
o VE55 (minute ventilation at the 55mm Hg end tidal CO2 point) 
o Baseline minute ventilation when end tidal PCO2 is less than the 
ventilatory recruitment threshold (represents non-chemoreflex drives to 
breathe) 
o Ventilatory recruitment threshold (end tidal PCO2 above which minute 
ventilation starts to increase linearly with further increases in end tidal 
PCO2) 
o Slope of the minute ventilation / end-tidal partial pressure of carbon 
dioxide (end-tidal PCO2) regression line that reflects the increase in 
minute ventilation relative to the increase in end tidal PCO2 (represents 
chemoreflex sensitivity) 
o Extrapolated ventilation recruitment threshold (intersection with X axis) 
x During relaxation stage 
o Minute ventilation, tidal volume, respiratory rate, end-tidal PCO2, end-
tidal PO2, oxygen saturation, and heart rate during the relaxation stage 
o Number of apneic events lasting > 10 s during the relaxation stage 
Pupillary Assessments  
x Maximum pupil diameter before constriction  
x Minimum diameter at peak constriction  
x Percent change between min/max diameter  
x Latency of constriction   
x Average constriction velocity  
x Maximum constriction velocity  
x Dilation velocity after peak constriction  
x Time to reach 75% recovery of maximum diameter  
Sedation scores   
x Ramsey Sedation Scale   

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x Visual Analogue Scale   
ECG Assessments  
x Change from baseline in QTc, PR, QRS, J-TpeakC, Tpeak-Tend and heart rate. 
An exploratory endpoint is the pharmacokinetic/pharmacodynamic (PK/PD) relationship 
for study drugs when administered alone versus in combination. 
 
4. INVESTIGATIONAL PLAN 
4.1 Study Design 
This study will be a randomized, double blind, three period crossover study with 
approximately 25 healthy volunteer participants. This study will include three 21-day 
treatment periods with a 3-week washout between each period. Each subject will be 
randomized to 1 of 6 treatment sequences (i.e., ABC, ACB, BAC, BCA, CAB, CBA). 
FDA will prepare the randomization schedule. 
Table 4-1: Study Schedule  
 
 
 
Table 4-2: Study Treatments: 
 
Participants will enter the clinic on a staggered basis in cohorts of approximately five so 
that no more than five subjects are undergoing rebreathing on any given day. Subjects 
will be staggered to allow for direct safety overview by medical staff during Duffin’s 
rebreathing.  
Participants will receive either placebo, paroxetine, or escitalopram on days 1-21 for each 
period. Oxycodone will be administered on days 6, 12, and 21 of each period. Dosing of 
the study drugs will occur at time 0 on each day. Oxycodone dosing will occur at 3 h so 
Day -1  
Days 1-21 
Days 22-42 
Days 42-63 
Days 64-84  
Days 85-105 
Day 106 
Check-in  
Period 1 
Washout 
Period 2  
Washout  
Period 3  
Check-out 
Treatment 
Day 
1-5 
6 
7-11 
12 
13-20 
21 
A 
Placebo 
Placebo +  
10 mg oxycodone 
Placebo 
Placebo +  
10 mg oxycodone 
Placebo 
Placebo + 
10 mg oxycodone 
B 
40 mg 
paroxetine  
40 mg paroxetine 
+ 10 mg 
oxycodone 
60 mg paroxetine 60 mg paroxetine 
+ 10 mg 
oxycodone 
60 mg paroxetine 60 mg paroxetine 
+ 10 mg 
oxycodone 
C 
20 mg 
escitalopram 
20 mg 
escitalopram +  
10 mg oxycodone 
30 mg 
escitalopram 
30 mg 
escitalopram +  
10 mg oxycodone 
30 mg 
escitalopram 
30 mg 
escitalopram + 10 
mg oxycodone 

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that maximum concentration occurs for all drugs is at approximately the same time. 
Participants will also receive ondansetron 4 mg 30 min before oxycodone administration.  
Participants will be confined to the study clinic from Day -1 the morning of Day 22 for 
each period. There will be a three-week washout between each period. Subjects will be 
discharged from the study after completion of all study procedures. If a subject 
discontinues from the study prematurely, all procedures scheduled for the end of the 
study will be performed. Meal timing and components, activity levels, and general 
conditions in the study clinic will be as similar as possible on the treatment days. 
Upon return to clinic, on Days 42 & 84, eligibility criteria to continue study participation 
will be reviewed (see Schedule of Events for criteria listed on Days 42 & 84), any 
changes in medical history (including concomitant medications) will be documented. 
4.1.1 Risk/Benefit 
Subjects will be informed that participation in a human clinical pharmacology study like 
the present one cannot be of benefit to healthy volunteers. Nevertheless, the information 
from the physical examination, vital sign measurements, and ECG results may be shared 
with the subject’s personal physician if this is the subject’s choice. Subjects will be 
informed that it is also their choice to inform their personal physician that they are 
participating in this research study. 
Subjects will be informed that their contribution to the study is of major importance to 
agencies like the FDA to understand the potential for respiratory depression with 
coadministration of SSRIs and opioids. However, since this is a study involving healthy 
volunteers, subjects will be informed that they have the option not to participate. 
Subjects will be informed that opioids have a box warning for life-threatening respiratory 
depression. To mitigate potential events, subjects will undergo continuous pulse oximetry 
monitoring, there will be stopping rules for the treatment, rescue medications for 
oxycodone will be present, and a safety management plan for staff will be implemented 
during the study which includes a requirement to have 1:1 advanced cardiac life support 
staff to subjects in addition to the study investigator.   
Subjects will be informed that they may be exposed to risks associated with the 
pharmacological properties of the study drug and the study procedures. The following 
summary of potential AEs for the study drugs will be provided to and discussed with the 
subjects: 
1. Oral oxycodone 5 mg IR tablets (up to 10 mg): The most common adverse events 
include typical opioid-related adverse reactions: nausea, constipation, vomiting, 
headache, pruritus, insomnia, dizziness, asthenia, agitation, anxiety, hallucinations, 
nightmares, and somnolence. Serious adverse reactions include: respiratory 

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depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, 
and/or shock.53 
2. Oral paroxetine 20 mg IR tablets (up to 60 mg): The most common adverse events 
include: somnolence, insomnia, agitation, tremor, anxiety, dizziness, constipation, 
nausea, diarrhea, dry mouth, vomiting, flatulence, asthenia, erectile dysfunction, 
delayed ejaculation, vaginal paresthesia, itching, and discharge, yawning, infection, 
sweating, decreased appetite, nervousness, impotence, and libido decreased.54 
3. Oral escitalopram 10 mg tablets (up to 30 mg): The most common adverse events 
include: insomnia, ejaculation disorder, drowsiness, impotence, nausea, sweating 
increased, fatigue, somnolence, decreased libido, anorgasmia, headache, diarrhea, dry 
mouth, dizziness, constipation, and indigestion. Additional adverse events include 
hypersensitivity reactions, seizures, syncope, QT interval prolongation, cardiac 
arrhythmias, enhanced clotting, and hepatic enzyme elevation.55  
4. Oral ondansetron 4 mg tablets given prior to oxycodone for nausea/vomiting and 4 
mg IV as needed: The most common adverse events include: diarrhea, headache, 
fever, malaise, fatigue, constipation, and hypoxia. Additional adverse events include: 
hypersensitivity reactions, including anaphylaxis and bronchospasm, QT interval 
prolongation and Torsade de Pointes, and serotonin syndrome (usually when 
prescribed with another serotoninergic medication such as select serotonin reuptake 
inhibitors and serotonin-norepinephrine reuptake inhibitors).56 
Selected doses of individual drugs are within the FDA approved labeled doses or are 
doses that have been used in prior healthy participant studies for similar durations. As 
drug combinations are being studied, the doses of oxycodone are less than that which has 
been used in prior studies in opioid naïve healthy volunteers undergoing rebreathing5-6,11 
or other similar procedures (see below). 
x Oxycodone - A prior study of the effects of decreased ventilatory response to 
hypercapnia of oxycodone with and without ethanol in opioid naïve healthy 
volunteers (young and elderly participants) used a dose of oxycodone 20 mg.5-6 
An additional ongoing study from these authors (unpublished) is using a dose of 
oxycodone 40 mg in opioid naïve healthy volunteers. Our previous study 
(unpublished) used 10 mg oxycodone, which decreased ventilation approximately 
5 L/min from baseline and was well-tolerated by study participants with no 
discontinuations due to the selected dose. The present study will also use 
oxycodone 10 mg.  
x Paroxetine – Paroxetine will be administered 40 mg/day for 6 days and 60 mg/day 
for 15 days. This is within the maximum labeled dose of paroxetine (60 mg/day). 
The dose is higher than the typical starting dose of 20 mg/day that is titrated up 

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over 1-week intervals, however starting doses up to 60 mg have been given safely 
to healthy volunteers.51 
x Escitalopram – Escitalopram will be administered at 20 mg/day for 6 days and 30 
mg/day for 15 days. This is above the maximal labeled dose of escitalopram (20 
mg/day) but doses up to 30 mg/day have been evaluated in a thorough QT study. 
The exposure with 30 mg is similar to the steady state concentration expected in 
CYP2C19 poor metabolizers following a therapeutic dose of 20 mg.55 
x Ondansetron – Ondansetron will be administered as a single 4 mg oral dose in all 
treatment periods prior to administration of oxycodone and will be available as 4 
mg IV as needed for nausea and vomiting. A dose of 4 mg is less than the highest 
labeled dosing for other ondansetron indications (24 mg as a single dose or 8 mg 
twice a day).56  
The study drugs will not be administered to anyone who is pregnant. All women must 
take a pregnancy test before receiving any study drug in this study. All women of 
childbearing potential enrolled on this study will be informed that they must use effective 
birth control methods (abstinence, intrauterine device, and contraceptive foam and a 
condom [i.e., double-barrier method]) during treatment. Subjects will be informed that 
they must notify the investigator if they or their female partners become pregnant during 
the course of the study. If a subject becomes pregnant, she will be informed that neither 
Spaulding Clinical Research nor the sponsor will be responsible for the cost of any 
obstetric or related care, or for the child’s care. 
Subjects will be informed that insertion of an IV catheter may be required for blood 
sample collection and, during insertion of the catheter, soreness, bruising, or infection at 
the insertion site are possible but unlikely. Subjects will also be informed that dizziness 
and lightheadedness may occur during direct venipuncture, insertion of the IV catheter, or 
during blood collection. 
Subjects will be informed that they will be participating in the Duffin rebreathing 
SURFHGXUHZKHUHWKH\ZLOOEUHDWKHௗDK\SHUR[LF-hypercapnic (24% O2, 6% CO2, N2 
balanced) or hypoxic-hypercapnic (6% O2, 6% CO2, N2 balanced) gas mixture through a 
mask. They will be informed that this mixture of oxygen, carbon dioxide and nitrogen 
provided will be different than is normally found in room air (21% O2, 0.04% CO2, N2 
balanced with minor amounts of other gasses). Subjects will be informed that the 
different gas concentrations, in particular the higher level of carbon dioxide breathed in, 
may result in a feeling of needing to breathe faster or more deeply. Subjects will be 
informed that this procedure has been used in many previous physiologic measurement 
studies and is non-LQYDVLYH'XULQJVFUHHQLQJVXEMHFWVZLOOEHVKRZQௗWKHUHEUHDWKLQJ
equipment and will be trained how to use it to understand if the procedure is tolerable.  

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Subjects will be informed that the confidentiality of their data will be respected at all 
times according to state law, and the study personnel handling their study data are bound 
by confidentiality agreements. 
Subjects will be informed that extra precautions will be put in place, including required 
screening tests, that will limit the risk of COVID-19. Precautions will be documented in a 
COVID-19 risk management plan. Subjects will be informed that despite the extra 
precautions there is still a risk of them contracting COVID-19. Any changes to the 
COVID-19 precautions (e.g., due to updated CDC recommendations or new testing 
becoming available) will be documented in the COVID-19 risk mitigation plan.  
Subjects will be informed that the study drug and all tests, procedures, and visits required 
by the study are provided at no cost to them. If subjects become ill or physically injured 
because of participation in this study, they will be informed that costs of treatment will 
not be covered by the sponsor. 
4.2 Selection of Study Population 
Subjects will be screened, and the data collected will be reviewed by the principal 
investigator. Only those subjects who meet all the eligibility criteria will be enrolled. 
Approximately 25 healthy subjects are planned for enrollment. Every effort will be made 
to maintain an approximate 50:50 male-to-female sex distribution. 
4.2.1 Inclusion Criteria 
Subjects who meet all the following inclusion criteria will be eligible to participate in the 
study:  
1. Subject signs an IRB-approved written informed consent and privacy language as 
per national regulations (e.g., Health Insurance Portability and Accountability Act 
authorization) before any study-related procedures are performed.  
2. Subject is a healthy, non-smoking man or woman, 18 to 50 years of age, inclusive, 
who has a body mass index of 18.5 to 33.0 kg/m2, inclusive, at Screening. 
3. Subject has normal medical history findings, clinical laboratory results, vital sign 
measurements, pulse oximetry, 12-lead ECG results, and physical examination 
findings at screening or, if abnormal, the abnormality is not considered clinically 
significant (as determined and documented by the investigator or designee). 
4. Subject must have a negative test result for alcohol and drugs of abuse at screening 
and check-in days.  
5. Subject must test negative for severe acute respiratory syndrome corona virus 2 
(SARS-CoV-2) by a rapid antigen test at check-in for all study periods. If a 
subject’s test comes back as invalid, the test can be repeated. 

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6. Female subjects must be of non-childbearing potential (confirmed with follicle-
stimulating hormone levels > 40 mIU/mL) or, if they are of childbearing potential, 
they must: 1) have been strictly abstinent for 1 month before check-in (Day -1) and 
agree to remain strictly abstinent for the duration of the study and for at least 
1month after the last application of study drug; OR 2) be practicing 2 highly 
effective methods of birth control (as determined by the investigator or designee; 
one of the methods must be a barrier technique) from at least 1 month before check-
in (Day -1) until at least 1 month after the end of the study.  
7. Male subjects must agree to practice 2 highly effective methods of birth control (as 
determined by the investigator or designee) from at least 1 month before check-in 
(Day -1) until at least 1 month after the last dose of study drug. 
8. Subject is highly likely (as determined by the investigator) to comply with the 
protocol defined procedures and to complete the study. 
4.2.2 Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible to 
participate in the study: 
1. Subject has used any prescription or nonprescription drugs (including aspirin or 
NSAIDs and excluding oral contraceptives and acetaminophen) within 14 days or 5 
half-lives (whichever is longer) or complementary and alternative medicines within 
28 days before the first dose of study drug. This includes prescription or 
nonprescription ophthalmic drugs. 
2. Subject is currently participating in another clinical study of an investigational drug 
or has been treated with any investigational drug within 30 days or 5 half-lives 
(whichever is longer) of the compound. 
3. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing 
tobacco, snuff, electronic cigarettes) within 6 weeks of Screening. Subjects must 
refrain from using these throughout the study. 
4. Subject has consumed alcohol, xanthine containing products (e.g., tea, coffee, cola), 
caffeine, grapefruit, or grapefruit juice within 24 h of check-in. Subjects must refrain 
from ingesting these throughout the study.  
5. Subject has a history or evidence of a clinically significant disorder, condition, or 
disease (e.g., cancer, human immunodeficiency virus [HIV], hepatic or renal 
impairment) that, in the opinion of the investigator would pose a risk to subject 
safety or interfere with the study evaluation, procedures, or completion. This 
includes subjects with any underlying medical conditions that put subjects at 

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increased risk of severe illness from COVID-19 based on the Centers for Disease 
Control and Prevention (CDC) guidelines. 
6. Subject has any signs or symptoms at screening or check-in of any study periods that 
are consistent with COVID-19. Per current CDC recommendations this includes 
subjects with the symptoms cough or shortness of breath or difficulty breathing, or at 
least two of the following symptoms: fever, chills, repeated shaking with chills, 
muscle pain, headache, sore throat or new loss of taste/smell. In addition, the subject 
has any other findings suggestive of COVID-19 risk in the opinion of the 
investigator. 
7. Subject has known or suspected allergies or sensitivities to any study drugs. 
8. Subject has clinical laboratory test results (hematology, serum chemistry and 
urinalysis) at Screening or period check-in that are outside the reference ranges 
provided by the clinical laboratory and considered clinically significant by the 
investigator. Clinical laboratory results may be repeated once, as needed, for 
confirming results at Screening and period check-in.   
9. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C 
virus antibodies, or hepatitis B surface antigen. 
10. Subject is unable or unwilling to undergo multiple venipunctures for blood sample 
collection because of poor tolerability or poor venous access. 
11. Female subject is currently pregnant or lactating or was within 3 months of 
enrollment. 
12. Subject has a history of opioid or psychotropic drugs within 60 days of the start of 
the study. 
13. Subject has a history of asthma that has required medication within the last five 
years. 
14. Subject has non-reactive or mishappen pupil(s) or damaged orbit structure or 
surrounding soft tissue is edematous or has an open lesion. 
15. Subject has a Mallampati score of >2. 
16. Subject’s Duffin rebreathing data is of poor quality or subject does not agree to 
remain clean-shaven for all days when the Duffin rebreathing procedure is 
performed. 
17. Subject has a history of sleep disorders, Panic disorders, Panic Attacks, Generalized 
Anxiety Disorder, or any associated DSM diagnosis or condition. 

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18. Subject has a history of or currently has hypoventilation syndrome or sleep apnea 
and is on non-invasive ventilation. 
19. Subject has a history of unexplained syncope, structural heart disease, long QT 
syndrome, heart failure, myocardial infarction, angina, unexplained cardiac 
arrhythmia, TdP, ventricular tachycardia, or placement of a pacemaker or 
implantable defibrillator. Subjects will be also excluded if there is a family history of 
long QT syndrome (genetically proven or suggested by sudden death of a close 
relative to cardiac causes at a young age) or Brugada syndrome. 
20. Subject has a history of suicidal ideation or previous suicide attempts. 
 
21. Subject has a safety 12-lead ECG result at Screening or check-in at any study period 
with evidence of any of the following abnormalities:  
x QTc using Fridericia correction (QTcF)>430 msec 
x  PR interval>220 msec or <120msec 
x QRS duration>110 msec 
x Second- or third-degree atrioventricular block 
x Complete left or right bundle branch block or incomplete right bundle branch 
block 
x Heart rate <50 or >90 beats per minute 
x Pathological Q-waves (defined as Q-wave>40 msec) 
x Ventricular pre-excitation  
22. Subject has a skin condition likely to compromise ECG electrode placement. 
23. Any individual with breast implants.  
4.3 Screening Failures 
Subjects who sign and date the informed consent form but who fail to meet the inclusion 
and exclusion criteria are defined as screening failures. A screening log, which 
documents the subject initials and reason(s) for screening failure, will be maintained by 
the investigator for all screening failures. A copy of the log should be retained in the 
investigator’s study files. 
If a subject fails the screening process because of an abnormal laboratory result, they can 
receive a copy of the results upon request. The investigator will determine if follow-up 
for the abnormal laboratory result is needed and will encourage the subject to follow-up 
with his or her personal physician as appropriate. All subjects will be informed as to the 

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reason(s) they are excluded from study participation, even if follow-up is not required. If 
a subject fails the screening process because of a positive test result for human 
immunodeficiency virus or hepatitis, the positive result will be reported to local health 
authorities as required by law. 
4.4 Termination of Study or Investigational Site 
4.4.1 Criteria for Termination of the Study 
The study will be completed as planned unless one of the following criteria is satisfied 
that requires early termination of the study. 
x New information regarding the safety or efficacy of the study drug(s) that indicates a 
change in the known risk profile for the study drug(s), such that the risk is no longer 
acceptable for subjects participating in the study. 
x Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objective or compromises subject safety. 
4.4.2 Criteria for Termination of the Investigational Site 
The study site may be terminated if the site (including the investigator) is found in 
significant violation of GCP, the protocol, the contractual agreement, or is unable to 
ensure adequate performance of the study. 
In the event that the sponsor elects to terminate the study or the investigational site, a 
study-specific procedure for early termination will be provided by the sponsor; the 
procedure will be followed by the applicable investigational site during the course of 
termination. 
4.5 Criteria for Subject Withdrawal 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn by the investigator without the approval of the subject based on the 
investigator’s clinical judgment. A subject is not required to provide a written request to 
withdraw from the study; however, a written request is required if a subject withdraws 
consent for his or her personal data to be used for study-related purposes. 
A subject may be discontinued for any of the following reasons: 
x AE: The subject has experienced an AE that, in the opinion of the investigator, 
requires early termination. The appropriate electronic case report form (eCRF) must 
be completed for each AE. If a subject is discontinued from the study due to an AE, 
the investigator is required to follow-up with the subject until the event resolves or 
becomes stable. If a subject dies during the study, the cause of death must be reported 
as a serious AE (SAE), with an outcome of death noted in the eCRF. 

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x Protocol Violation: The subject failed to meet protocol entry criteria or did not adhere 
to protocol requirements, and continued participation poses an unnecessary risk to the 
subject’s health. 
x Withdrawal by Subject: The subject (or other responsible individual [e.g., caregiver]) 
wishes to withdraw from the study in the absence of a medical need. 
NOTE: Withdrawal due to an AE should not be recorded in the “voluntary 
withdrawal” category. 
x Study Terminated by Sponsor: The sponsor, IRB, FDA, or other regulatory agency 
terminates the study. 
x Pregnancy: The subject is found to be pregnant. 
NOTE: If the subject is found to be pregnant, the subject must be withdrawn 
immediately. The pregnancy will be followed-up to term, and the outcome, including 
any premature termination will be recorded. All live births must be followed for a 
minimum of 30 days or until the first well-baby visit. 
x Other. 
NOTE: This category records withdrawals caused by an accidental or a medical 
emergency, unblinding, and other rare cases. The specific reason should be recorded 
in the comment space of the eCRF. 
4.5.1 Handling of Withdrawals 
The investigator may terminate a subject’s study participation at any time during the 
study when the subject meets the criteria described in Section 4.5. In addition, a subject 
may discontinue his or her participation without giving a reason at any time during the 
study. Subjects will be informed that their participation in the study is voluntary, that 
refusal to participate will involve no penalty or loss of benefits to which the subject is 
otherwise entitled, and that the subject may discontinue participation at any time without 
penalty or loss of benefits to which the subject is otherwise entitled. 
Should a subject’s participation be discontinued, the primary reason for termination must 
be recorded. In addition, efforts should be made to perform all procedures scheduled for 
the early termination visit. Any data and samples collected before subject withdrawal will 
become the property of the sponsor. 
4.5.2 Replacement of Subjects 
Approximately 25 healthy subjects are planned for enrollment and will be randomized to 
1 of 6 treatment sequences.  

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4.6 Study Visits 
4.6.1 Recruitment 
Recruitment materials (e.g., internet, radio, and print advertisements, social media posts) 
will be approved by the local IRB before telephone screening. The sponsor is responsible 
for registration of the study on clinicaltrials.gov. Recruitment may not occur until the 
study is fully registered on clinicaltrials.gov. 
4.6.2 Compensation 
Subjects will be offered payment for Screening; however, if the results of their alcohol 
and drug screening tests are positive, they will not be compensated. Subjects who 
complete the entire study will receive payment according to the schedule provided in the 
informed consent form. No special incentives are offered. Final payment will not be 
released until all follow-up procedures have been completed and accepted by the 
investigator. 
If a subject chooses to withdraw from the study prematurely, he or she will only be 
compensated for completed days. If subjects are withdrawn for medical reasons or if the 
study is halted temporarily or permanently, the subjects will receive compensation 
proportional to the time spent in the study. No compensation will be provided if a subject 
is dismissed from the study for noncompliance (e.g., improper conduct, ingesting alcohol 
and/or drugs [including recreational drugs], tampering with the study drug, consuming 
any prohibited foods or beverages). 
If subjects are required to stay in the clinic for a longer period for safety reasons, they 
will be compensated at a rate proportional to the entire compensation for the study. If a 
subject becomes ill or physically injured because of participation in this study, the subject 
will be referred for treatment. 
4.6.3 Screening  
The following procedures and assessments will be performed at Screening (Day -28 to -
2): 
x Obtain informed consent/HIPAA authorization. The informed consent process will be 
performed by a clinical research nurse in a private room. The subject will be given 
unlimited time to ask questions regarding study participation, and each subject will be 
questioned to ensure their understanding. 
After informed consent is obtained: 
x Review inclusion/exclusion criteria to confirm subject eligibility 
x Record demographic information 

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x Measure height, weight, and calculate body mass index 
x Perform serology screening (HIV antigen/antibody [Ag/Ab] Combo 1/2, HepC 
antibody, HBsAg) 
x Record medical history 
x Perform alcohol and drug screening (amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, alcohol, opiates, phencyclidine, propoxyphene, and 
methadone) 
x Perform urine cotinine test 
x Perform a serum pregnancy test (female subjects only) 
x Perform FSH measuring (postmenopausal [i.e., without menses for two years] female 
subjects only) 
x Record prior medications 
x Monitor for AEs 
x Perform clinical laboratory tests (hematology, serum chemistry, and urinalysis) 
x Measure vital signs (blood pressure, heart rate, respiratory rate, pulse oximetry, and 
oral body temperature) 
x Perform a safety 12-lead ECG 
x Perform a complete physical examination, including assessment of participant’s 
Mallampati score 
x Examine pupils for shape and reactivity 
x Perform Duffin’s rebreathing under hyperoxic and hypoxic conditions 
4.6.4 Study Periods 
This study will be a randomized, double blind, three period crossover study. This study 
will include three 21-day treatment periods with a 3-week washout between each period. 
Participants will be confined to the study clinic from day -1 until the first day of each 
washout period. There will be a three week washout between each period. Subjects will 
be discharged from the study after completion of all study procedures. 
4.6.4.1 Check-In 
The following procedures and assessments will be performed at Check-in [Day -1] and 
when participants check back into the clinic after each washout period: 

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x Perform/review results from SARS-CoV-2 rapid antigen test  
x Review inclusion/exclusion criteria to confirm subject eligibility 
x Review medical history 
x Perform alcohol and drug screening (amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, alcohol, opiates, phencyclidine, propoxyphene, and 
methadone) 
x Perform urine cotinine test 
x Perform a serum pregnancy test at all check-ins (female subjects only) 
x Admit subject to the study clinic 
x Randomization (after completion of check-in procedures or just before dosing on 
Day 1 of each study period)  
x Record concomitant medications 
x Monitor for AEs 
x Perform clinical laboratory tests (hematology, serum chemistry, and urinalysis) 
x Measure vital signs (blood pressure, heart rate, respiratory rate, pulse oximetry, and 
oral body temperature) 
x Perform a safety 12-lead ECG (only at initial check-in of each study period) 
x Perform a comprehensive physical examination 
x Perform Duffin’s rebreathing procedure under hyperoxic and hypoxic conditions 
x Collect whole blood sample for CYP2D6 genotype/phenotype (only at check-in for 
first study period) 
4.6.4.2 Treatment 
The following procedures and assessments will be performed during the treatment period 
according to the Schedule of Events (Appendix A): 
x Monitor for AEs 
x Record concomitant medications 
x Perform clinical laboratory tests at specified time points 
x Administer study drug according to the randomization schedule following all other 
pre-dose examinations and specimen collection 

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x Measure vital signs (blood pressure, heart rate, respiratory rate, pulse oximetry, and 
oral body temperature). If vital signs are scheduled at the same time as another event, 
vital signs will be measured after the ECG, but before blood sample collection 
x Perform safety 12-lead ECGs at timepoints specified in Section 4.7.2.4. If scheduled 
for the same time, safety 12-lead ECGs will always be performed before vital sign 
measurement and blood sample collection 
x Perform pulse oximetry monitoring as specified in Appendix A – Schedule of Events 
x Perform rebreathing assessments following Duffin’s rebreathing procedure at 
timepoints specified in Section 4.7.2.1. Preparatory steps for the Duffin Rebreathing 
procedure (i.e., relaxation, hyperventilation) should begin prior to the scheduled 
sample time. Timing of sample collection is planned so that the PD assessment begins 
at the specified time and a 3- to 15-minute window is planned for completion of the 
procedure. 
x Perform pupillary assessments as specified in Appendix A – Schedule of Events 
x Perform sedation assessments as described in Section 4.7.2.3 (Ramsey Sedation Scale 
and Visual Analogue Scale) 
x Collect PK blood samples (6 mL) at timepoints specified in Section 4.7.1.1 
4.6.4.3 Washout 
After each period, there will be a three week washout period. Prior to discharge for each 
washout period, the following procedures will be performed: 
x Record concomitant medications 
x Monitor for AEs 
x Perform targeted physical exam 
x Measure vital signs (blood pressure, heart rate, respiratory rate, pulse oximetry, and 
oral body temperature) 
x Collect PK blood samples (6 mL) at timepoints specified in Section 4.7.1.1 
x Pre-discharge sedation assessment 
When subjects check-in after each washout period, the procedures and assessments 
specified in Section 4.6.4.1 will be performed. 
4.6.4.4 Discharge (or Early Termination) 

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The following procedures and assessments will be performed before a participant is 
discharged at the end of the study or at early termination: 
x Record concomitant medications 
x Monitor for AEs 
x Measure height, weight, and calculate body mass index 
x Perform clinical laboratory tests (hematology, serum chemistry, and urinalysis) 
x Measure vital signs (blood pressure, heart rate, respiratory rate, pulse oximetry and 
oral body temperature) 
x Collect PK blood samples (6 mL) at the timepoints specified in Section 4.7.1.1 (only 
day 21 of each study period) 
x Assess for pre-discharge sedation 
x Perform a safety 12-lead ECG  
x Perform a complete physical examination 
x Discharge subject from the study clinic after completion of all study procedures 
4.7 Study Procedures 
4.7.1 Pharmacokinetic Assessments 
4.7.1.1 Pharmacokinetic Sample Collection  
Pharmacokinetic blood samples will be collected on the following days and at the 
approximate times for each study period: 
x Day 5, 6, 11, 12, 20, and 21: 0 (pre-dose), 3, 4, 5, 8 hr (and 24 hrs for Day 6, 12, 
and 21) 
x Day 2 and 16: 0 (pre-dose), 2, 3, 4, 5, 6, 8, 12, 24 hr 
Blood samples will be collected by direct venipuncture or by inserting an IV catheter. 
There will be a total of 51 PK samples per participant for each study period (Total of 153 
PK samples per participant for the entire study duration). 
Each blood sample will be labeled with subject number, study number, study day, time 
point, event, and a barcode that matches that belonging to the subject. 
Collection of the PK samples on the ECG collection days (Days 2 and 16 of each period) 
will be time-matched to the ECG extractions; therefore, the subjects will be supine for 
approximately 10 minutes before the defined time points and for approximately 5 minutes 
after for ECG extraction/PK sample collection. The PK sample will be collected after the 

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ECG extraction to avoid changes in autonomic tone associated with the psychological 
aspects of blood collection and the reduction in blood volume subsequent to blood 
collection. A 5-minute window for PK sample collection is allowed after the ECG 
extraction window. 
4.7.1.2 Pharmacokinetic Specimen Handling 
The PK blood samples (6 mL each) will be collected into tubes containing K2EDTA, 
inverted several times to mix the blood with the anticoagulant, and placed in an ice bath. 
Within 30 minutes of collection, the samples will be centrifuged for 10 minutes, at 3000 
RCF, at 4°C, by a study team member. 
The plasma will be separated using a disposable plastic pipette and equally aliquoted into 
duplicate cryotube vials labeled as Aliquot A (primary) and Aliquot B (backup). The 
plasma samples will be appropriately labeled and stored frozen at -70°C or below within 
30 minutes after aliquoting until shipment. Temperature monitoring logs should be 
maintained and accessible for review by the study monitor.  
The Aliquot A samples (primary) will be shipped first, on dry ice, to the bioanalytical 
laboratory at FDA for processing when requested by the sponsor. The Aliquot B samples 
(backup) will be held for a second shipment after completion of all Aliquot A sample 
shipment(s) and the timing of the Aliquot B shipment will be communicated by the 
sponsor. None of the PK blood samples will be stored at the clinical facility for future 
use. 
4.7.1.3 Pharmacokinetic Parameters 
The following exploratory PK parameters will be determined for oxycodone and 
oxymorphone (days 6, 12, and 21) and paroxetine, escitalopram, and escitalopram 
metabolites (days 2, 5, 6, 11, 12, 16, 20, and 21): 
x Maximum observed plasma concentration (Cmax) 
x Area under the plasma concentration time curve (AUC) 
x Time at which Cmax occurs (Tmax) 
x Elimination rate constant (Kel) 
x Terminal half-life (t1/2) 
x Accumulation ratio (for escitalopram and paroxetine) 
4.7.2 Pharmacodynamic Assessments 
4.7.2.1 Duffin Rebreathing Assessments 

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Training on the Duffin’s rebreathing procedure will be performed to exclude any subjects 
who cannot tolerate the procedure.   
During Duffin’s rebreathing procedure, subjects will be placed in an upright position (90o 
angle) on a bed and connected to the respiration measurement set up. Subjects will wear a 
facemask and breathe from a pre-filled rebreathing bag containing approximately 5 L of 
either a hyperoxic-hypercapnic (24% O2, 6% CO2, N2 balanced) or hypoxic-hypercapnic 
(6% O2, 6% CO2, N2 balanced) gas mixture. During this study, subjects will be asked to 
breath room air for 5 minutes (relaxation stage) and then to hyperventilate (primarily 
through deep breathing) room air voluntarily for 5 minutes (hyperventilation stage). 
Thereafter, subjects will be switched to the rebreathing bag and perform rebreathing 
assessments at one of the 2 different isoxic end tidal PO2,  i.e., 150 mmHg or 50 mmHg. 
The isoxia at 150 mmHg or 50 mmHg end-tidal PO2 will be maintained by providing a 
computer controlled flow of 100% O2 to the rebreathing bag.   
Subjects will perform one hyperoxic and one hypoxic rebreathing procedure at check-in 
of each study period and a total of 4 rebreathing procedures (three hyperoxic and one 
hypoxic) each day on Days 5, 6, 11, 12, 20, and 21 of each study period. Rebreathing 
procedures will be performed while fasting and will occur at 0, 4, and 5 hours post-doses 
on assessment days (hyperoxic at 0, 4 and 5 hours; a hypoxic assessment will be 
performed after the 5 hour hyperoxic assessment). Participants can communicate to staff 
to discontinue an assessment due to discomfort at any time. Additional considerations for 
discontinuing a rebreathing procedure are described in a separate SOP for the 
Rebreathing Procedure. 
Each rebreathing procedure (relaxation, hyperventilation, and rebreathing) should take 
approximately 13-15 minutes. Data collected throughout the procedure includes 
ventilatory flow and volumes as well as percent gas compositions of O2 and CO2, which 
are used to calculate multiple physiological variables.  
Data from the rebreathing procedure will be acquired using the Hans Rudolph 
SmartLabTM Data Acquisition System. Collected data will be analyzed using separate 
statistical software. Interim data analyses may be performed after each cohort of 
participants have completed. If reproducibility is acceptable and no procedural changes 
are needed, additional lead-in cohorts may not be enrolled. If any study procedure 
element changes are needed, they may be made and additional participants may be 
enrolled.  
The clock on the rebreathing recorder will be confirmed to be consistent with the study 
clock at the clinical site; this will be confirmed on each study day. Preparatory steps for 
the Duffin’s rebreathing procedure (i.e., relaxation, hyperventilation) should begin prior 

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to the scheduled sample time. Timing of sample collection is planned so that the 
rebreathing assessment begins at the specified time. Additional details on the Duffin’s 
rebreathing procedure is described in a separate SOP.  
The following physiologic measurements will be assessed multiple times throughout the 
study: 
x Minute ventilation 
x Tidal volume 
x Respiratory rate 
x End-tidal PCO2  
x End-tidal O2 
x Oxygen saturation (SpO2) 
x Heart rate 
4.7.2.2 Pupillary Assessments 
At Screening, subjects will be evaluated to ensure they meet requirements necessary for 
pupillary assessments (e.g., pupils are reactive and not misshapen). During the study, a 
pupillometer (a hand-held optical scanner) will be used to measure pupil size and 
dynamics in response to a light stimulus. Pupillary assessments will be performed before 
and after each rebreathing period (except not in between the hyperoxic and hypoxic 
paired assessment) while the ambient light is kept to a consistent level. The rubber cup of 
the pupillometer will be placed on the right eye. The actual data recording only takes 
seconds.   
4.7.2.3 Sedation Assessments 
The Ramsey sedation scale will be completed by an observer prior to the start of 
rebreathing assessment. 
• 
Level 1: Patient awake, anxious and agitated or restless, or both 
• 
Level 2: Awake, cooperative, orientated, and tranquil 
• 
Level 3: Patient awake and responds to commands only 
• 
Level 4: Asleep, brisk response to light glabellar tap or loud auditory stimulus 
• 
Level 5: Asleep, sluggish response to light glabellar tap or loud auditory stimulus 
• 
Level 6: Asleep, no response to light glabellar tap or loud auditory stimulus 
At the same time as performing the Ramsey sedation scale, a visual analog scale will be 
administered to subjects by having subjects mark on a 100 mm perpendicular line how 
sedated they are from ‘awake and alert’ to ‘very sedated’ (i.e. 0 and 100 on the scale, 

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respectively). The distance from the left end of the line to the perpendicular mark will be 
measured in mm. 
4.7.2.4 ECG Assessments 
ECG assessments will be performed on the following study days and time of each study 
period: 
- Day 1: 0 (pre-dose) hr 
- Day 2 and 16: 0 (pre-dose), 2, 3, 4, 5, 6, 8, 12, 24 hr 
Ten second 12-lead ECG tracings with the most stable heart rate and highest signal-to-
noise ratio will be extracted in at least 3 replicates at ECG extraction time points during 
each treatment period. During all ECG extraction periods subjects will be placed in a 
supine position. Three ECG extractions will be performed for a baseline measurement 
before the first oral dose on day 1 of each treatment period. The other ECG 
extractions/period time matched to the PK samples will be obtained before the PK sample 
collection time. Subjects will be isolated (not able to see each other) in a quiet 
environment that is free from external stimuli. 
 
4.7.3 Safety Assessments 
Safety will be evaluated in terms of AEs, clinical laboratory results (hematology, serum 
chemistry, and urinalysis), vital sign measurements (blood pressure, heart rate, 
respiratory rate, and oral body temperature), safety 12-lead ECG results, and physical 
examination findings.  
4.7.3.1 Adverse Events 
4.7.3.1.1 Adverse Event Definitions 
An AE is defined as any untoward and/or unintended sign, including an abnormal clinical 
laboratory finding, symptom, or disease temporally associated with the use of a study 
drug, whether or not considered related to the study drug. Events or conditions that 
increase in frequency or severity during or as a consequence of use of a drug in human 
clinical trials will also be considered AEs. 
A treatment emergent adverse event (TEAE) is defined as an AE that begins after study 
drug administration. 
An unexpected AE is any AE having a specificity or severity not consistent with the 
current investigator’s brochure for the study drug(s). 

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A serious adverse event (SAE) is defined as any AE occurring at any dose that meets the 
following criteria: 
x Results in death, 
x Is life threatening, 
x Requires hospitalization or prolongation of existing hospitalization, 
x Results in persistent or significant disability or incapacity, 
x Results in a congenital anomaly/birth defect due to exposure prior to conception or 
during pregnancy, or 
x Is an important medical event that may not meet the previous criteria but, based upon 
appropriate medical judgment, jeopardizes the subject or requires medical or surgical 
intervention to prevent one of the outcomes listed previously. 
4.7.3.1.2 Adverse Event Reporting 
The recording of AEs will begin after the subject signs the informed consent form and 
will continue until discharge (or early termination). All AEs, whether serious or 
nonserious and whether or not related to the study drug, must be recorded in the eCRF. 
Study subjects will be instructed to warn study staff if he or she has any unexpected 
symptoms. In addition, all subjects will receive a reminder telephone call approximately 
24 h before Check-in. 
Any SAE (whether expected or unexpected) must be entered into the eCRF system and 
reported by email to the medical monitor or designee using the SAE Reporting Form 
within 24 h of the investigator or study clinic staff becoming aware of the event. It is the 
responsibility of the investigator to report all SAEs to the medical monitor, to provide the 
most complete report possible, and to assess each SAE for its relationship to the study 
drug. The investigator is responsible for obtaining follow-up information on all SAEs and 
submitting follow-up SAE data. Any unexpected SAEs must be reported promptly to the 
investigator’s IRB as per the IRB’s requirements. 
In the event of a fatal or life-threatening SAE, the sponsor will notify the appropriate 
FDA authorities within 7 calendar days of receipt of the report. The sponsor will follow 
all 7-day alert reports with a written report within 10 working days of receipt of the case. 
Serious AE cases that concern nonfatal, nonlife-threatening events that are unexpected 
and at least possibly related to the study drug will be submitted in writing to the FDA 
within 10 working days of receipt. 
Furthermore, any AEs that are not expected, occur at a higher frequency, or would 
require modification of the study protocol and/or informed consent must be reported to 
the FDA within 10 working days. 

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Adverse events that are assessed by the investigator as possibly or probably related to the 
study drug will be followed until they resolve or stabilize. All SAEs will be followed 
until resolution. 
4.7.3.1.3 Assessment of Severity 
The investigator will assess the severity of each AE using the following scale: 
x Mild: The subject is aware of the AE but is still able to perform all activities; minimal 
or no medical intervention or therapy is required. 
x Moderate: The subject has to discontinue some activities due to the AE; minimal or 
no medical intervention or therapy is required. 
x Severe: The subject is incapacitated by the AE and is unable to perform normal 
activities; significant medical intervention or therapy is required, and hospitalization 
is possible. 
4.7.3.1.4 Assessment of Causality 
The investigator will assess the causal relationship/relatedness of each AE to the study 
drug using the following scale: 
x Not Related: Onset of the AE has no reasonable temporal relationship to 
administration of the study drug, a causal relationship to administration of the study 
drug is biologically implausible, or the event is attributed to an alternative etiology. 
x Unlikely Related: Onset of the AE has a reasonable temporal relationship to study 
drug administration and although a causal relationship is unlikely, it is biologically 
plausible. 
x Possibly Related: Onset of the AE has a strong temporal relationship to 
administration of the study drug, cannot be explained by the subject’s clinical state or 
other factors, and a causal relationship is biologically plausible. 
x Probably Related: Onset of the AE shows a distinct temporal relationship to 
administration of the study drug that cannot be explained by the subject’s clinical 
state or other factors, the AE is a known reaction to the product or chemical group, or 
can be predicted by the product’s pharmacology. 
4.7.3.1.5 Pregnancy 
A serum pregnancy test will be performed for female subjects at the time points presented 
in the Schedule of Events (Appendix A). If a subject becomes pregnant while on the 
study, this should be reported immediately to the investigator, the subject will be 
withdrawn from the study and the medical monitor and the subject will be instructed to 

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follow-up with his or her personal physician. All pregnancies are to be reported as an AE 
and followed for outcome. 
4.7.3.2 Clinical Laboratory Tests 
Clinical laboratory and diagnostic screening tests will be performed at the time points 
presented in the Schedule of Event and will be collected in accordance with acceptable 
laboratory procedures. Clinical laboratory testing will be performed by the clinical study 
contractor(s). The clinical laboratory tests that will be performed are presented in Table 
4-3. Unused clinical laboratory test samples will not be stored for future use. 
Table 4-3: Clinical Laboratory Tests & Diagnostic Screening Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count 
White blood cell count (with 
automated differential) 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Bilirubin (total, direct, and indirect) 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine (including calculated 
creatinine clearance) 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
Uric acid 
Appearance 
Bilirubin 
Blood 
Color 
Glucose 
Ketones 
Leukocyte esterase 
Microscopic examination: red blood 
cells, white blood cells, epithelial cells, 
bacteria, crystals, and casts (if present) 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Diagnostic Screening Tests: 
Serum 
Urine 
Whole Blood 
Serology (human 
immunodeficiency virus 
Ag/Ab Combo 1/2, hepatitis 
C virus antibody, and 
hepatitis B surface antigen) 
Female Subjects Only 
Human chorionic 
gonadotropin (for 
pregnancy) 
Follicle-stimulating 
hormone 
Drug screen including: 
amphetamines, barbiturates, 
benzodiazepines, cannabinoids, 
cocaine, alcohol, opiates, 
phencyclidine, propoxyphene, 
methadone, and cotinine 
Cytochrome P450 2D6 genotype (only 
performed at check-in for the first 
study period) 
 
Other 
SARS-CoV2 rapid antigen test  

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Clinical laboratory results will be reviewed by the investigator or designee together with 
data in the eCRF. Any values outside the reference range will be evaluated for clinical 
significance. If a value is determined to be clinically significant, the subject will be 
instructed to follow-up with his or her personal physician. The investigator or designee 
may repeat the clinical laboratory tests if deemed appropriate. The investigator will 
maintain a copy of the laboratory accreditation and the reference ranges for the laboratory 
used. 
4.7.3.3 Vital Sign Measurements 
Vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) will be 
measured using an automated device at the time points presented in the Schedule of 
Events (Appendix A). The subject should be in a supine position, if possible, for a 
minimum of 5 minutes before vital signs are measured.  
4.7.3.1 Pulse Oximetry 
Continuous pulse oximetry monitoring will be performed on rebreathing days (Days 5, 6, 
11, 12, 20, and 21 of each study period) specified in the Schedule of Events (Appendix 
A). 
4.7.3.2 Safety 12-lead Electrocardiograms 
Safety 12-lead ECGs will be obtained with the subjects in the supine position for a 
minimum of 10 minutes before recording. ECGs will be overread by the Principal 
Investigator or designee (e.g., a medically qualified subinvestigator). If an abnormality is 
observed, the subject will be instructed to follow-up with his or her personal physician. 
4.7.3.3 Physical Examinations 
A complete physical examination will be performed at the time points presented in the 
Schedule of Events (Appendix A). 
The complete physical examination will include, but not be limited to, assessments of the 
head, eyes, ears, nose, throat, skin, thyroid, nervous system, respiratory system, 
cardiovascular system, abdomen (liver and spleen), lymph nodes, and extremities. 
Height, weight (without shoes and wearing the lightest possible clothing), and calculation 
of body mass index will be performed at Screening and check-out. 
If a clinically significant abnormality is observed upon physical examination, the subject 
will be instructed to follow-up with his or her personal physician. 
4.7.4 Demographics and Medical History 
Demographic data (date of birth, gender, race, and ethnicity) will be collected at 
Screening. 

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Each subject will provide a complete medical history at Screening that will be reviewed 
at Check-in. Specific information relating to any prior or existing medical 
conditions/surgical procedures will be recorded in the subject’s eCRF. 
4.8 Study Treatments 
4.8.1 Dose Strategy  
Prior data with oxycodone alone using 20 mg doses, showed significant decreases in 
VE55 from baseline.5-6 Our previous study that administered 10 mg oxycodone showed 
approximately 5 L/min decrease with oxycodone alone compared to baseline.20 The goal 
with the oxycodone dose is to have an effect on the hypercapnic ventilatory response with 
oxycodone alone, but not too high (for safety considerations) as it will be combined with 
a SSRIs that may also have effects on ventilation.  
Paroxetine dosing in labeling starts at 20 mg/day and allows titration up to a maximum of 
60 mg/day for obsessive compulsive disorder (panic disorder starts at 10 mg/day and 
allows titration up to 60 mg/day). Dosing to 60 mg/day will allow assessment of effects 
on ventilation alone or combined with oxycodone under clinically relevant exposures 
Escitalopram dosing in labeling starts at 10 mg/day and allows titration up to 20 mg/day 
for treatment of major depressive disorder and treatment of generalized anxiety disorder. 
The study will administer up to 30 mg/day, which is above the maximal labeled dose of 
escitalopram (20 mg/day), but doses up to 30 mg/day have been evaluated in a thorough 
QT study. Escitalopram exposure with 30 mg/day is similar to the steady state 
concentration expected in CYP2C19 poor metabolizers following a therapeutic dose of 
20 mg/day. 
4.8.2 Treatments Administered  
For all drugs, standard drug doses or doses used in prior studies in healthy participants 
will be used in this study. Multiple doses of the assigned study drug will be administered 
to each subject during the treatment period. Oxycodone, paroxetine, escitalopram, 
ondansetron, and placebo will be administered orally. Subjects will complete each of the 
three treatments (A, B, and C):  
x Treatment A: Placebo on Days 1-5; Placebo + Oxycodone (10 mg IR) on Day 6; 
Placebo on Days 7-11; Placebo + Oxycodone (10 mg IR) on Day 12; Placebo on 
Days 13-20; Placebo + Oxycodone (10 mg IR) on Day 21 
x Treatment B: Paroxetine (40 mg) on Days 1-5; Paroxetine (40 mg) + Oxycodone (10 
mg IR) on Day 6; Paroxetine (60 mg) on Days 7-11; Paroxetine (60 mg) + 
Oxycodone (10 mg IR) on Day 12; Paroxetine (60 mg) on Days 13-20; Paroxetine (60 
mg) + Oxycodone (10 mg IR) on Day 21 

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x Treatment C: Escitalopram (20 mg) on Days 1-5; Escitalopram (20 mg) + Oxycodone 
(10 mg IR) on Day 6; Escitalopram (30 mg) on Days 7-11; Escitalopram (30 mg) + 
Oxycodone (10 mg IR) on Day 12; Escitalopram (30 mg) on Days 13-20; 
Escitalopram (30 mg) + Oxycodone (10 mg IR) on Day 21 
Paroxetine, escitalopram, or placebo will be administered at time 0 on each day. 
Oxycodone dosing will occur at 3 h on days 6, 12, and 21. Participants will also receive 
ondansetron 4 mg 30 min before oxycodone administration on days 6, 12, and 21. 
Study drugs will be administered by a clinical research nurse on the study clinic floor at 
the subject’s bedside. The pharmacist and investigator will be available if needed during 
study drug administration. Oral study drugs will be administered with 240 mL of 
room-temperature water. 
4.8.3 Dose Selection and Schedule 
Oxycodone: The oxycodone dose is 10 mg IR. Oxycodone dose selection is based on 
previous published results where oxycodone was administered alone or in combination 
using rebreathing procedures in healthy volunteers. Two studies by van der Schrier and 
others evaluated oxycodone 20 mg alone or in combination with ethanol.5-6 Sedation 
levels in the ethanol study in particular, which included a higher dose of oxycodone and 
was performed in the young and elderly, were moderate and well addressed by mild 
stimulation of the subjects. Varying dose combinations of oxycodone and morphine (total 
combined doses of 15 mg) have been safely evaluated using a similar system.7 Our 
previous study with oxycodone 10 mg IR showed that small (approximately 5 L/min) but 
detectable effects on hypercapnic ventilation could be safely observed with this dose with 
minimal effects on baseline ventilation.20   
Paroxetine: The paroxetine dose is 40 mg IR for Days 1-6 and 60 mg IR for Days 7-21. 
Paroxetine dose selection was based on available safety data from the original 
development program and to achieve sustained steady state exposures of paroxetine at the 
highest approved paroxetine dose for at least one week before the day 20 and 21 
assessments.  Target dosing range for paroxetine is 20-60 mg/day depending on the 
indication. Initial starting doses in labeling for general anxiety disorder, social anxiety 
disorder, posttraumatic stress disorder, obsessive compulsive disorder, and major 
depressive disorder are 20 mg/day with dose increases of 10-mg/day made in intervals of 
1 week. Paroxetine has been administered at 30 mg/day for 30-days in healthy volunteers 
and up to 60-mg as a single dose in healthy volunteers.51  
Escitalopram: The escitalopram dose is 20 mg for Days 1-6 and 30 mg for Days 7-21. 
Escitalopram dosing in labeling starts at 10 mg/day and allows titration up to 20 mg/day 
for treatment of major depressive disorder and treatment of generalized anxiety disorder. 
The study will administer up to 30 mg/day, which is above the maximal labeled dose of 

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escitalopram (20 mg/day), but doses up to 30 mg/day have been evaluated in a thorough 
QT study for a comparable duration of time. Escitalopram exposure with 30 mg/day is 
similar to the steady state concentration expected in CYP2C19 poor metabolizers 
following a therapeutic dose of 20 mg/day.55 
Ondansetron: The ondansetron dose is 4 mg orally given 30 minutes before oxycodone 
administration. Up to two additional doses of IV ondansetron 4 mg can be given in a day 
for nausea/vomiting. The selected ondansetron dose is less than the recommended dosing 
for labeled indications of nausea and vomiting associated with highly or moderately 
emetogenic cancer chemotherapy, radiotherapy, or postoperative nausea or vomiting.  
Naloxone: The naloxone dose is 0.4 mg administered intravenously, as needed, for 
respiratory depression as deemed necessary by the investigator. Naloxone may be 
administered as a rescue medication for opioid-induced respiratory depression. 
4.8.4 Method of Assigning Subjects to Treatment Sequence 
4.8.4.1 Randomization Process 
The project biostatistician will create the specifications that will be used to generate the 
randomization schedule. The specifications will be based on the protocol requirements 
and appropriate statistical programming with consideration for study design, number of 
treatments, number of subjects planned for enrollment, stratification, and blocking. 
Based on these specifications, the project biostatistician (or designee) will generate a 
dummy randomization schedule. The schedule is generated in R.  
The project biostatistician (or designee) distributes the ‘dummy’ randomization schedule 
to specified personnel for review. Any change (e.g., change in block size, change in 
stratification levels) that requires an update to the specifications will reset this process. 
Minor changes (e.g., display formatting) will not require a change to the specifications. 
After the approval of the ‘dummy’ randomization schedule, the project biostatistician (or 
designee) transfers the program used to generate the ‘dummy’ schedule to the 
randomization biostatistician (unblinded), who is an independent party and will not be 
participating in any programming or statistical decisions for the study before breaking the 
blind. No transfer is necessary if the unblinded randomization biostatistician also created 
the ‘dummy’ randomization. 
The randomization biostatistician is responsible for generating the final randomization 
schedule. The output is sent only to designated unblinded recipients, who will maintain a 
secured digital and printed copy for their use. 

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Archival of the programs and output is accomplished by the creation of an encrypted, 
password-protected ZIP file containing the program and output file(s). The ZIP file is 
copied to a secure storage drive on the sponsor’s site. 
Randomization will occur after informed consent is obtained, either after completion of 
check-in procedures on Day -1 or just before dosing on Day 1. Approximately 25 healthy 
male and female subjects are planned for enrollment. Thus, a maximum of 25 subjects 
will be exposed to study drugs and procedures during the study. 
Enrolled subjects will be randomly assigned to 1 of 6 different treatment sequences 
consisting of the treatment groups are presented in Table 4-2. 
All randomization information will be secured and housed in a locked storage area, 
accessible only by the randomization personnel and the assigned pharmacist and his or 
her verifier. 
4.8.5 Identity of Study Drugs 
Oxycodone HCl (referred to throughout this document as oxycodone) is indicated for the 
management of pain severe enough to require an opioid analgesic and for which 
alternative treatments are inadequate. Oxycodone tablets are available as 5, 10, 15, 20, or 
30 mg strengths. The tablets are designed for immediate release of the drug where about 
60% to 87% of the drug reaches systemic circulation in comparison to a parenteral dose. 
Oxycodone HCl has a molecular weight of 351.82 and the molecular formula 
C18H21NO4ƔHCl. The physical form is a white odorless crystalline powder derived from 
the opium alkaloid, thebaine. Oxycodone dissolves in water (1 g in 6 to 7 mL) and is 
considered slightly soluble in alcohol.53 
Paroxetine HCl (referred to throughout this document as paroxetine) is indicated for the 
treatment of major depressive disorder. Paroxetine HCl has a molecular weight of 374.8 
and the empirical formula is C19H20FNO3Ɣ+&OƔ1/2H2O. Paroxetine HCl is an odorless, 
off-white powder with a solubility of 5.4 mg/mL in water. Tablets are available for oral 
administration in 10, 20, 30, and 40 mg strengths.48  
Escitalopram oxalate (referred to throughout this document as escitalopram) is indicated 
for acute and maintenance treatment of major depressive disorder and acute treatment of 
generalized anxiety disorder. Escitalopram is the pure S-enantiomer of the racemic 
bicyclic phthalane derivative citalopram. Escitalopram oxalate has a molecular weight of 
414.4 and the empirical formula is C20H21FN2OƔC2H2O4. Escitalopram oxalate is a fine, 
white to slightly-yellow powder and is freely soluble in methanol and dimethyl sulfoxide, 
soluble in isotonic saline solution, sparingly soluble in water and ethanol, slightly soluble 
in ethyl acetate, and insoluble in heptane. Tablets are available for oral administration in 
5, 10, and 20 mg strengths.49 

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Ondansetron is indicated for the prevention of nausea and vomiting associated with 
highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 
mg/m2, initial and repeat courses of moderately emetogenic cancer chemotherapy, 
radiotherapy in patients receiving either total body irradiation, single high-dose fraction 
to the abdomen, or daily fractions to the abdomen, and prevention of postoperative 
nausea and/or vomiting. The empirical formula is C18H19N3OƔHClƔ2H2O, 
representing a molecular weight of 365.9. Ondansetron hydrochloride dihydrate is a 
white to off-white powder that is soluble in water and normal saline. Ondansetron is 
available for oral administration as 4 and 8 mg tablets. Ondansetron hydrochloride is 
supplied as 20 mL multi-dose vials, 2 mg/mL.56 
Naloxone hydrochloride injection is indicated for the complete or partial reversal of 
opioid depression, including respiratory depression, induced by natural and synthetic 
opioids. Naloxone hydrochloride is also indicated for the diagnosis of suspected or 
known acute opioid overdosage. Naloxone hydrochloride, an opioid antagonist, is a 
synthetic congener of oxymorphone, with a molecular weight of 363.84 and molecular 
formula of C19H21NO4ƔHCl. Naloxone hydrochloride injection may be diluted for 
intravenous infusion in 0.9% sodium chloride injection or 5% dextrose injection. The 
addition of 2 mg of naloxone hydrochloride in 500 mL of either solution provides a 
concentration of 0.004 mg/mL. Mixtures should be used within 24 h. After 24 h, the 
remaining unused solution must be discarded. Naloxone hydrochloride injection is 
supplied as 10 mL multi-dose vials, 4 mg/10 mL (0.4 mg/mL).52  
Placebo capsules containing only cornstarch will be used as the placebo oral control in 
this study. 
4.8.6 Management of Clinical Supplies 
4.8.6.1 Study Drug Packaging and Storage 
The active study drugs will be obtained from commercial sources. Storage instructions 
for the active study drugs are as follows: 
x Oxycodone tablets should be stored at 25°C (77°F) with excursions permitted 
from 15° to 30°C (59° to 86°F) and should be protected from moisture.53  
x Paroxetine tablets should be stored between 15° and 30°C (59° and 86°F).54 
x Escitalopram tablets should be stored between 20° and 25°C (68° and 77°F); 
excursions permitted to 15° and 30°C (59° and 86°F).55 
x Naloxone hydrochloride injection should be stored at 20° to 25°C (68° to 77°F).58 
x Ondansetron tablets should be stored at 2° to 30°C (36° to 86°F).56  

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x Ondansetron injection should be stored at 20° to 25°C (68° to 77°F).59 
Placebo capsules will be supplied by the clinical site, stored at controlled room 
temperature (15°C to 30°C; 59°F to 86°F), and protected from light and moisture. 
4.8.6.2 Study Drug Accountability 
Good clinical documentation practices will be employed to record the receipt, storage 
conditions, accountability, and use or return of the study drug. The study drug will be 
stored in a secure location with access to the study personnel who will be managing the 
storage, dispensing, and accountability of the study drug. 
Upon completion or termination of the study, final accountability review by the study 
monitor, and written authorization from the sponsor, all unused and/or partially used 
study drug should be returned or destroyed at the study clinic. It is the investigator’s 
responsibility to ensure that the sponsor has provided written authorization for study drug 
disposal, the disposal process follows the study clinic’s standard operating procedures, 
and appropriate records of the disposal are documented and maintained. No unused study 
drug may be disposed until fully accounted for by the study monitor (or designee). 
Documentation of unused study drug should include subject number, medication identity 
(medication #, period #), date, and quantity of study drug used. 
4.8.7 Blinding 
The study will be double-blind, and the blind will be maintained through a randomization 
schedule held by the dispensing pharmacist. Treatments (escitalopram, paroxetine, or 
placebo) will be over-encapsulated. The pharmacist (and designated staff member 
responsible for confirmation of study drug dose) will be unblinded to subject treatment 
assignment; however, the pharmacist will not perform any study procedures other than 
study drug preparation and dispensing.  
 
Additional details regarding blinding can be found in the Spaulding Blinding SOP which 
will be followed to ensure the blind is maintained throughout the study. 
4.8.7.1 Breaking the Blind 
The study drug blind will not be broken by the investigator or designee unless 
information concerning the study drug is necessary for the medical treatment of the 
subject. For unblinding a subject, the randomization information for unblinding can be 
obtained by contacting the dispensing pharmacist. The sponsor or medical monitor must 
be notified immediately if the study drug blind is broken. The date, time, and reason that 
the blind was broken will be recorded in the source documents. If the blind is broken by 
the investigator or designee, the study drug must be stopped immediately, and the subject 

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must be withdrawn from the study. Data or specimens already collected from subjects 
who discontinue prematurely and for whom the blind is broken will be made available for 
analysis if needed. 
4.8.8 Treatment Compliance 
At Screening, as part of the inclusion criteria, it will be confirmed that subjects are able to 
comply with the protocol-defined procedure of injecting subcutaneous study drug. All 
doses of the study drug will be administered in the study clinic either under direct 
observation of or administered by clinic personnel and recorded in the eCRF. If a subject 
vomits after dosing, the event will be documented as an AE. The decision to replace any 
subject who vomits after dosing will be made as described in Section 4.5.1. 
4.8.9 Prior and Concomitant Medications 
Subjects are prohibited from using any prescription or nonprescription drugs (including  
aspirin or NSAIDs and excluding oral contraceptives and acetaminophen) within 14 days 
or 5 half-lives (whichever is longer), or complementary and alternative medicines within 
28 days before the first dose of study drug. Subjects are prohibited from using any opioid 
or psychotropic drugs within 60 days of the start of the study. Subjects will be asked if 
they have used any of these substances and their responses will be recorded on the eCRF. 
Subjects are also prohibited from currently participating in another clinical study of an 
investigational drug and may not have been treated with any investigational drug within 
30 days or 5 half-lives (whichever is longer) of the compound. 
Subjects must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator. 
4.8.10 Subject Restrictions 
Subjects are not allowed to use nicotine containing products (e.g., cigarettes, cigars, 
chewing tobacco, snuff, electronic cigarettes) within 6 weeks before Screening. In 
addition, subjects are not allowed to ingest alcohol, xanthine containing products (e.g., 
tea, coffee, chocolate, cola), caffeine, grapefruit, or grapefruit juice within 24 h of check-
in of all study periods. Subject must refrain from ingesting these throughout the entire 
study. Subjects are not allowed to use aspirin or NSAIDs within 14 days before the first 
dose of study drug. Subjects will be asked if they have used any of these substances and 
their responses will be recorded on the eCRF. 
Subjects must be able to tolerate a controlled, quiet study conduct environment, including 
avoidance of music, television, movies, games, and activities that may cause excitement, 
emotional tension, or arousal during prespecified times (e.g., before and during ECG 

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extraction windows; before and during rebreathing procedures) throughout the duration 
of the study. 
Subjects must be willing to comply with study rules; attempting to void at specified 
times; remaining quiet, awake, undistracted, motionless, and supine during specified 
times; and avoiding vigorous exercise as directed throughout the duration of the study. 
Standardized meals will be served at consistent times relative to dosing, and no food or 
fluids will be served containing caffeine. Subjects will fast during days with rebreathing 
assessments (i.e., Day 5, 6, 11, 12, 20, and 21 of each period) until after the last 
rebreathing assessment. On ECG collection days (Day 2 and 16 of each period) subjects 
will have fasted for at least 8 hours prior to drug administration. Subjects should only eat 
meals and snacks that are provided during periods of their stay in the study clinic, and 
should consume each meal that is served at a reasonable pace (within 25 minutes). 
Outside of meal times, the subjects will only be allowed to intake water, which will be 
available ad libitum. 
Due to current precautions being taken for COVID-19, the following restrictions will be 
in place: 
x Subjects should be encouraged to wear masks except when in a private room without 
anyone else present or for a limited time for a study procedure (e.g., study drug 
administration or eating) when instructed by staff.  
x Subjects must practice social distancing, which will include having a maximum of 2 
subjects per room for overnight stays and access to common areas will be per clinical 
research site standards. While subjects are in house,  meals will be served per clinical 
research site standards. Subjects will spend most of their time in their rooms except 
for specified times for walking in the halls (with masks recommended). 
x Subjects must practice regular handwashing with soap and water, scrubbing hands for 
at least 20 seconds or with approved hand sanitizer as supplied by study staff.  
Designated isolation rooms will be set up to segregate any participant(s) that develop any 
symptoms of concern while housed in the unit and COVID-19 testing will be done when 
deemed necessary by the Investigator. If new information becomes available, there could 
be other precautions that lead to additional restrictions that will be documented in the 
COVID-19 Risk Management Plan and/or the study specific COVID-19 Procedure Plan. 
4.9 Statistical Methods 
4.9.1 Sample Size 
Approximately 25 healthy participants are planned for enrollment. A previous study (20 
participants) with paroxetine showed a decrease in 10.2 L/min in VE55 for paroxetine (40 

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mg) combined with oxycodone (10 mg) compared to oxycodone alone after 5 days of 
dosing with paroxetine. Similarly, there was a 9.3 L/min decrease in paroxetine compared 
to placebo after 4 days of dosing with paroxetine. The standard deviation in assessments 
was approximately 6.5 L/min. Assuming a similar effect size with paroxetine and 
escitalopram at day 20 and 21, the planned number of participants allows for a 40% drop 
out rate while maintaining at least 90% power for separate one-sided tests at a 0.025 
significance level with the multiple primary endpoint. Study sample size did not consider 
secondary endpoints. 
4.9.2 Analysis Populations 
The rebreathing analysis population will include all subjects who completed at least one 
rebreathing assessment on any day or at any timepoint. Specific information on analysis 
populations for different pharmacodynamic measures will be described in the Statistical 
Analysis Plan (SAP).  
A rebreathing assessment will be considered complete if the subject makes it through the 
entire procedure at a specific timepoint, if there are no identifiable issues with how the 
procedure was conducted, and if the VE55 regression converges.  Potential issues with 
how the procedure was conducted can included, but are not limited to, a leak from the 
system (e.g., substantially decreasing O2 during rebreathing or no evidence of an increase 
in CO2 during rebreathing) or inaccurate readings from the pneumotach (e.g., baseline 
minute ventilation readings less than 5 L/min).  
Subjects in this population will be used for the planned primary and secondary analyses 
related to evaluating drugs effects on the ventilatory response to hypercapnia.  If a subject 
does not contribute data from all treatments due to early discontinuations or other reasons, 
only those comparisons where the subject has all required data will be performed. 
The PK population will include all subjects who receive study drug and have at least 
one estimable PK parameter after dosing. 
The safety population will include all subjects who receive at least one dose of any of the 
study drugs. 
4.9.3 General Statistical Considerations 
All data will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings, but not included in the calculation of 
summary statistics. Demographic and baseline characteristics will be summarized overall 
and by treatment for all subjects. 
4.9.4 Subject Disposition 

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The number of subjects who enroll in the study and the number and percentage of 
subjects who complete each assessment will be presented. The frequency and percentage 
of subjects who withdraw or discontinue from the study and the reason for withdrawal or 
discontinuation will be summarized. 
4.9.5 Demographics and Baseline Characteristics 
Descriptive statistics will be used to summarize demographic and baseline subject 
characteristics. For continuous variables, the mean, median, standard deviation (SD), 
minimum, and maximum values will be reported. For categorical (nominal) variables, the 
number and percentage of subjects (or observations) will be reported. 
4.9.6 Rebreathing Analyses 
4.9.6.1 Primary Analysis  
The primary objective is to study ventilatory effects of SSRIs (paroxetine or 
escitalopram) combined with an opioid (oxycodone) compared to an opioid alone. The 
primary endpoint is VE55 under hyperoxic conditions on day 21.  
4.9.6.2 Data Analysis  
Minute ventilation and end-tidal pCO2 (PETCO2) data from the rebreathing stage of the 
Duffin rebreathing procedure will be analyzed at the specified primary timepoints using 
piecewise linear regressions. The regressions will be used to predict VE55. VE55 when 
the SSRIs (paroxetine or escitalopram) are combined with oxycodone will be compared 
to VE55 with oxycodone alone.  
Multiple primary analyses are planned for each drug. The first primary analysis will be 
VE55 on day 21 at 5 h (hyperoxic) between oxycodone with paroxetine or escitalopram 
compared to oxycodone alone. The second primary analysis will be VE55 on day 20 at 5 h 
(hyperoxic) between paroxetine or escitalopram compared to placebo. Since Day 20 and 
21 are considered multiple primary endpoints, comparisons will have an adjustment for 
multiplicity using a Bonferroni correction (each day will be tested at a 0.025 significance 
level). No adjustments will be made for separate testing of paroxetine or escitalopram since 
the treatments are considered separate interventions in the study.  
A linear mixed effects model will be developed using all study data from hyperoxic 
assessments. Fixed effects will include treatment, period, sequence, and baseline VE55 
(i.e., VE55 obtained at 0 h on Day -1 of each treatment period).  Subject will be included 
as a random effect on the intercept.  If a subject’s baseline VE55 for a treatment period is 
not available, then the baseline value for that period will be calculated based on the median 
of all other baseline values for that subject from other study periods.  If a subject does not 

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have any completed baseline VE55 data, the subject will be assigned a baseline VE55 equal 
to the median of the population.  
The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom for tests of  fixed effects. Normality assumption will be verified using the Shapiro-
Wilke test for normality. Homogeneity of variances will be verified using Levene’s test. If 
the data in its original or transformed form does not satisfy assumptions for normality and 
homogeneity, a Wilcoxon signed-rank test will be used for all comparisons rather than a 
linear mixed effect model. In the event that the data does not satisfy assumptions for 
normality and homogeneity then a Wilcoxon signed-rank test will be used for comparisons.  
To demonstrate an effect when an SSRI (paroxetine or escitalopram) is combined with 
oxycodone compared to oxycodone alone, the upper bound of the one-sided 97.5% CI of 
the least-square mean VE55 difference between treatments must not overlap 0 L/min.  
Similarly, to demonstrate an effect of paroxetine (or escitalopram) compared to placebo 
the upper bound of the one-sided 97.5% CI of the least-square mean VE55 difference 
between treatments must not overlap 0 L/min. Each comparison will be performed 
separately (i.e.,þtrt’ asþparoxetine’ orþescitalopram’):  
ЬH0: VE55oxy+trt - VE55oxy  0 L/min 
ЬHA: VE55oxy+trt - VE55oxy < 0 L/min 
For secondary endpoints, effects of SSRIs (paroxetine or escitalopram) with oxycodone 
compared to oxycodone alone will be performed on day 6 and day 12. 
As additional secondary endpoints, effects of SSRIs (paroxetine or escitalopram) alone 
compared to placebo will be determined on day 5 and 11 using the same model. Additional 
details on testing of ventilation secondary endpoints is discussed in the SAP. 
4.9.7 Pharmacokinetic Analysis 
The PK parameters Cmax, AUC0-t, Tmax, and Kel will be summarized using descriptive 
statistics (number of subjects, geometric mean, coefficient of variation [CV], mean, SD, 
median, minimum, and maximum) on Day 2, 5, 6, 11, 12, 16, 20 and 21 of each period 
for paroxetine, escitalopram, and escitalopram metabolites (Days 6, 12, and 21 for 
oxycodone and oxymorphone). The PK parameters will be analyzed using 
noncompartmental methods based on actual sampling times. Geometric mean and 
individual concentration-time profiles will be presented in graphs. 
4.9.8 PK/PD Modeling 
A nonlinear-mixed effect pharmacokinetic/pharmacodynamic model will be developed 
for VE55 and baseline-adjusted VE55 versus time for all treatments. The model will be 
developed using modeling software.  

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Additional details on PK/PD modeling will be discussed in a separate Modeling Analysis 
Plan. 
4.9.9 Electrocardiogram Analyses 
The QT interval will be corrected for heart rate using Fridericia’s formula 
(QTc=QT/RR1/3). The J-Tpeak interval will be corrected for heart rate using the formula 
(J-TpeakC = J-TpeakC/RR0.58).60 Baseline will be the mean of the 3 predose ECG extractions 
of Day 1. 
Exposure-response analyses will be performed for the change-from-baseline in QTc 
ǻ47FDQGFKDQJH from baseline in other ECG measurements (specified in ECG 
Analysis Plan), where the mean of the 3 predose ECG readings on Day 1 will be used as 
the Baseline. The concentration of the drug will be used as a covariate. Exposure-
response analysis will be done following most recent best practices in concentration-QTc 
modeling.61-62  
To assess the appropriateness of a linear model, normal QQ-plots for the residuals and 
plots of weighted residuals versus concentration and versus fitted values will be 
produced. A model with a quadratic term in concentration will be fitted and the quadratic 
term will be tested on the 2-sided 5% alpha level. In case of a significant quadratic term, 
nonlinear models, such as a log-linear model and an Emax model, will be investigated and 
the primary model will be selected based on the Akaike Information Criterion and 
plausibility arguments.  
Unless the prespecified test procedure for linearity indicates otherwise, the primary 
analysis will be based on a linear mixed effects model implemented in R software, with 
ǻ47FDVWKHGHSHQGHQWYDULDEOHGUXJSODVPDFRQFHQWUDWLRQDQGEDVHOLQH47FDV
continuous covariates, treatment and time point as categorical factors, and subject 
specific random effects for the intercept and slope. All post dose data will be used. The 
degrees of freedom for the model estimates will be determined by the Kenward-Rogers 
method. From the model, the slope (i.e., the regression parameter for the concentration) 
and the treatment effect will be estimated together with 2-sided 90% CIs. 
The predicted mean placebo-adjusted change from baseline QTc (ǻǻQTc) at the 
observed geometric mean Cmax LHWKHSURGXFWZLWKWKHVORSHHVWLPDWHௗௗWUHDWPHQWHIIHFW
[ǻQTcactive – ǻQTcplacebo]) and the 2-sided 90% CI of the estimate will be calculated.  
Additional details will be specified in the ECG Analysis Plan, including for analysis of 
other ECG measurements. 
 
4.9.10 Additional Analyses  

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4.9.10.1 Exploratory Respiratory Analyses  
Baseline minute ventilation, ventilatory recruitment threshold, slope of the PCO2-
ventilatory response curve, and the extrapolated ventilatory recruitment threshold will be 
calculated for each subject at each rebreathing assessment. Data collected during the 
Duffin Rebreathing procedure will be used to determine the slope of the minute 
ventilation / PETCO2 regression line.  Resting ventilation, tidal volume, end-tidal PCO2, 
and oxygen saturation will be determined using data from the relaxation portion of the 
Duffin Rebreathing procedure.  Apneic events lasting > 10 s will be determined using 
data collected during relaxation and preparation portion of the Duffin Rebreathing 
procedure.  An event is defined as the absence of inspiratory flow (as measured by the 
pneumotachograph) for at least 10 s during this period.  These parameters will be 
summarized using descriptive statistics, and time courses summaries will be generated for 
all treatment groups. Differences in hypercapnic ventilatory response under hyperoxic or 
hypoxic rebreathing at the 5-h timepoint will be performed using paired t-test. These 
analyses will be considered hypothesis-generating and exploratory. 
4.9.10.2 Pupillometry Analyses  
Maximum pupil diameter before constriction and dynamic pupillary measurements after a 
light stimulus will be measured before and after each rebreathing assessment (except not 
in between the hyperoxic and hypoxic paired assessment). These parameters will be 
summarized using descriptive statistics, and time courses summaries of both scores will 
be generated for all treatment groups.  Pupillary changes will be compared to baseline 
measurements and between treatments to evaluate the effect of different interventions on 
pupillary changes.  In addition, time course pupillary changes will be compared to time 
course ventilatory changes across treatments to evaluate concordance between these 
measures when subjects receive different drugs and drug combinations. These analyses 
will be considered hypothesis-generating and exploratory. 
4.9.10.3 Sedation Scores Analyses  
Ramsay Sedation Scale is an observer-based assessment of sedation that will be collected 
for each subject as during the relaxation period of each Duffin Rebreathing procedure.  In 
addition, subjects will be asked to provide their own assessment of sedation using the 
Visual Analog Scale during the same relaxation period. These are two measures for 
assessing an individual’s level of sedation and will provide a subjective assessment of 
how sedation the subject is experiencing during the study.  These parameters will be 
summarized using descriptive statistics, and time courses summaries of both scores will 
be generated for all treatment groups. These analyses will be considered 
hypothesis-generating and exploratory. 

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4.9.11 Safety Analyses 
4.9.11.1 Adverse Events 
All AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities. The incidence of TEAEs, organized by system organ class and frequency, will 
be summarized by seriousness, severity, relationship to treatment, and by treatment at 
onset of the TEAE. A detailed listing of serious AEs and TEAEs leading to withdrawal 
will also be provided. 
4.9.11.2 Clinical Laboratory Tests 
Clinical laboratory results will be reviewed by the investigator or designee together with 
data in the eCRF. Any values outside the reference range will be evaluated for clinical 
significance. If a value is determined to be clinically significant, the subject will be 
instructed to follow-up with his or her personal physician. The investigator or designee 
may repeat the clinical laboratory tests if deemed appropriate. The investigator will 
maintain a copy of the laboratory accreditation and the reference ranges for the laboratory 
used. 
Clinical laboratory results (hematology, serum chemistry, and urinalysis) will be 
summarized using descriptive statistics (number of subjects, mean, SD, minimum, 
median, and maximum). Clinical laboratory results will be classified as normal or 
abnormal, according to the reference ranges of the individual parameter. The number and 
percentage of subjects with abnormal laboratory results will be provided. No statistical 
testing will be performed on clinical laboratory data. 
4.9.11.3 Vital Sign Measurements 
Vital sign measurements and changes from Baseline will be summarized using 
descriptive statistics (number of subjects, mean, SD, minimum, median, and maximum) 
by treatment and time point. 
4.9.11.4 Pulse Oximetry 
Continuous pulse oximetry will be performed on rebreathing days. Events requiring 
intervention from the staff or discontinuation from the study will be recorded in 
appropriate logs. 
4.9.11.5 Safety 12-lead Electrocardiograms  
12-lead ECGs will be obtained with the subjects in the supine position for a minimum of 
5 minutes before recording. ECGs will be overread by a physician. If an abnormality is 
observed, the subject will be instructed to follow-up with his or her personal physician. 

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4.9.11.6 Physical Examinations 
 Physical examination findings will be presented in a data listing, and abnormal physical 
examination findings will be recorded as AEs. 
4.9.11.7 Other Safety Data 
All concomitant medication usage and medications that changed in daily dose, frequency, 
or both since the subject provided informed consent will be summarized for each subject. 
4.9.12 Interim Analyses 
No interim analyses are planned. 
4.9.13 Missing Data 
Missing data will not be imputed. Data that are excluded from the descriptive or 
inferential analyses will be included in the subject data listings. This will include data 
from subjects not in the particular analysis population, measurements from unscheduled 
visits, or extra measurements that may arise from 2 or more analyses of the biofluid 
sample at the same time point. Details on the handling of missing data will be further 
described in the SAP. 
4.10 Data Quality Assurance 
Completed eCRFs are required for each subject randomly assigned to treatment. 
Electronic data entry will be accomplished through the ClinSpark® remote electronic data 
capture system, which allows for on-site data entry and data management. This system 
provides immediate, direct data transfer to the database, as well as immediate detection of 
discrepancies, enabling site coordinators to resolve and manage discrepancies in a timely 
manner. Each person involved with the study will have an individual identification code 
and password that allows for record traceability. Thus, the system, and subsequently any 
investigative reviews, can identify coordinators, investigators, and individuals who have 
entered or modified records. 
 
Furthermore, the investigator retains full responsibility for the accuracy and authenticity 
of all data entered into the electronic data capture system. The completed dataset and 
their associated files are the sole property of the sponsor and should not be made 
available in any form to third parties, except for appropriate governmental health or 
regulatory authorities, without written permission of the sponsor. 
4.11 Data Sharing 

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De-identified subject-level data may be released to other researchers (including through a 
data warehouse or as a part of a publication) to enable secondary research. Additional 
secondary research may also be performed by the sponsor. 
 
5. ETHICAL CONSIDERATIONS 
5.1 Ethical Conduct of the Study 
This study will be performed in accordance with the recommendations guiding 
physicians in biomedical research involving human subjects adopted by the 18th World 
Medical Association General Assembly, Helsinki, Finland, 1964 and later revisions, as 
well as, United States Title 45 Code of Federal Regulations (CFR) Part 46 GCP, and 
International Council for Harmonisation (ICH) guidelines describing technical 
requirements for registration of pharmaceuticals for human use. 
5.2 Institutional Review Board (IRB) 
The FDA Project Lead or investigator will provide the designated IRB with all required 
documents, including the study protocol and informed consent form. The study will not 
be initiated until appropriate IRB approval is obtained from the designated IRB. The 
investigator will provide the FDA Project Lead with copies of the approval documents 
for the protocol, informed consent form, and all recruiting materials. The designated IRB 
will also receive copies of any original or amended information sheets or pamphlets 
given to the study subject in support of the informed consent process and any 
advertisements or other recruitment material. Such materials will not be employed in the 
study before approval by the designated IRB. 
 
Subjects will be informed that they have the right to contact the IRB or Office for Human 
Research Protections if they have any questions, concerns, complaints, or believe they 
have been harmed by the participation in this research study as a result of investigator 
negligence. Subjects will be given the address and phone number of the IRB. 
6. ADMINISTRATIVE PROCEDURES 
6.1 Responsibilities of the Investigator  
The following administrative items are meant to guide the investigator in the conduct of 
the study but may be subject to change based on industry and government standard 
operating procedures, working practice documents, or guidelines. Changes may be 
reported to the IRB but will not result in protocol amendments. 
6.1.1 Form FDA 1572 

U.S. FOOD AND DRUG ADMINISTRATION  
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Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
(Version 1.1) 
 
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The investigator will complete and sign the Form FDA 1572. 
6.1.2 Adherence to Protocol  
The investigator agrees to conduct the study as outlined in this protocol in accordance 
with the ICH E6(R2) and all applicable guidelines and regulations. 
6.1.3 Reporting Requirements 
 
By participating in this study, the investigator agrees to submit reports of SAEs according 
to the timeline and method outlined in the protocol (Section 4.7.3.1.2). In addition, the 
investigator agrees to submit reports to the IRB as appropriate. The investigator also 
agrees to provide the sponsor with an adequate report shortly after completion of the 
investigator’s participation in the study. 
6.1.4 Source Documentation  
By participating in this study, the investigator agrees to maintain adequate case histories 
for the subjects treated as part of the research under this protocol. The investigator agrees 
to maintain accurate eCRFs and source documentation as part of the case histories. 
6.1.5 Retention of Records  
The investigator agrees to keep the records stipulated in this protocol and those 
documents that include (but are not limited to) the study-specific documents, 
identification log of all participating subjects, medical records, source worksheets, all 
original signed and dated informed consent forms, subject authorization forms regarding 
the use of personal health information (if separate from the informed consent form), 
copies of all eCRFs, query responses, and detailed records of drug disposition, to enable 
evaluations or audits from regulatory authorities, the sponsor, or its designees. 
Furthermore, ICH 4.9.5 requires the investigator to retain essential documents specified 
in Section 8 of ICH E6(R2) until at least 2 years after the last approval of a marketing 
application for a specified drug indication being investigated or, if an application is not 
approved, until at least 2 years after the investigation is discontinued and regulatory 
authorities are notified. In addition, ICH 4.9.5 states that the study records should be 
retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the clinical study site agreement between the investigator and sponsor. 
Refer to the clinical study site agreement for the sponsor’s requirements on record 
retention. The investigator should contact and receive written approval from the sponsor 
before disposing of any such documents. 
6.1.6 Financial Disclosure and Obligations 

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The investigator is required to provide financial disclosure information to allow the 
sponsor to submit the complete and accurate certification or disclosure statements 
required under 45 CFR 46. In addition, the investigator must provide to the sponsor a 
commitment to update this information promptly if any relevant changes occur during the 
course of the investigation and for 1 year after the completion of the study. 
Neither the sponsor nor the study clinic is financially responsible for further testing or 
treatment of any medical condition that may be detected during the screening process. 
6.2 Confidentiality and Disclosure of Data 
All subjects will sign a HIPAA-compliant authorization form containing the mandated 
core elements and requirements before participation in this clinical study. The sponsor 
and designees affirm and uphold the principle of the subject’s right to protection against 
invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s electronic data capture system database or documentation via a unique 
identification number. As permitted by all applicable laws and regulations, limited 
subject attributes such as gender, age or date of birth, and subject initials may be used to 
verify the subject and accuracy of the subject’s unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires that the investigator allow review of the subject’s original medical 
records (source data or documents) by the study monitor, representatives from any 
regulatory authority (e.g., FDA), the sponsor’s designated auditors, and the appropriate 
IRB. These medical records will include, but will not be limited to, clinical laboratory 
test result reports, ECG reports, admission and discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports. Access 
to a subject’s original medical records requires the specific authorization of the subject as 
part of the informed consent process. 
Copies of any subject source documents that are provided to the sponsor must have 
personally identifiable information removed (i.e., subject name, address, and other 
identifier fields not collected in the subject’s eCRF). 
Data will be maintained and backed up in the electronic data capture system. All access 
to the data is protected by username and password, and each staff member and all sponsor 
staff will have separate access that requires a separate username and password. Access is 
only given to site staff and requested sponsor staff who have completed the appropriate 
training. 
6.3 Subject Consent 
Written informed consent in compliance with 45 CFR 46 will be obtained from each 
subject before entering the study or performing any unusual or nonroutine procedure that 

U.S. FOOD AND DRUG ADMINISTRATION  
CDER / Office of Translational Sciences / Office of Clinical 
Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
(Version 1.1) 
 
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involves risk to the subject. An informed consent template may be provided by the 
sponsor to the study clinic. If any institution-specific modifications to study-related 
procedures are proposed or made by the study clinic, the consent should be reviewed by 
the sponsor or its designee or both before IRB submission. Once reviewed, the consent 
will be submitted by the investigator to the IRB for review and approval before the start 
of the study. If the informed consent form is revised during the course of the study, all 
active participating subjects must sign the revised form. 
Before enrollment, each prospective subject will be given a full explanation of the study 
and be allowed to read the approved informed consent form. The informed consent 
process will be performed by a clinical research nurse in a private room. The subject will 
be given unlimited time to ask questions regarding study participation, and each subject 
will be questioned to ensure their understanding. Once the investigator is assured that the 
subject understands the implications of participating in the study, the subject will be 
asked to give consent to participate in the study by signing the informed consent form. 
The investigator will provide a copy of the signed informed consent form to the subject. 
The original form will be maintained in the subject’s medical records at the site. 
6.4 Data Collection 
Full details of procedures for data collection and handling will be documented in the data 
management plan, which is initiated with the final protocol receipt. The data management 
plan is a changing document that evolves over the course of the study and is finalized by 
database lock. 
6.5 Publications 
No information related to or generated by this study will be released to the public until it 
has been reviewed by the sponsor. The sponsor shall own intellectual rights for the data 
and analysis resulting from this study. Authorship on publications will be determined by 
standard journal requirements. 
 
7. STUDY MANAGEMENT 
7.1 Monitoring 
The sponsor or its designee will monitor the study to ensure that it is being conducted 
according to the protocol, GCP standards, and applicable region-specific requirements, 
and to ensure that study initiation, conduct, and closure are adequate. The investigators 
and the study clinic staff will be expected to cooperate fully with the study monitors and 
personnel or agents of the sponsor and be available during monitoring visits to answer 

U.S. FOOD AND DRUG ADMINISTRATION  
CDER / Office of Translational Sciences / Office of Clinical 
Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
(Version 1.1) 
 
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questions sufficiently and to provide any missing information. The investigators and their 
institutions will permit direct access to source data/documents for study-related 
monitoring activities, audits, IRB reviews, and regulatory inspections. 
During any on-site visits, the study monitor will:  
x Check and assess the progress of the study 
x Review all informed consent forms 
x Review study data collected 
x Conduct source document verification 
x Identify any issues and address their resolution 
x Verify that the facility remains acceptable 
x Conduct study drug accountability 
These monitoring activities will be done in order to verify that the:  
x Data are authentic, accurate, and complete. 
x The safety and rights of the subjects are being protected. 
x The study is being conducted in accordance with the currently approved protocol 
(including any amendments), GCP, and all applicable regulatory requirements. 
In addition, the sponsor, designated auditors, and government inspectors must be allowed 
access to eCRFs, source documents, and other study files that may be required to evaluate 
the conduct of the study. 
7.2 Management of Protocol Amendments and Deviations 
7.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent 
immediate hazard to the subject, must be submitted to the sponsor or designee and 
reviewed and approved by the local IRB before implementation. Amendments to the 
protocol must be submitted in writing to the investigator’s IRB for approval before 
subjects are enrolled into an amended protocol. 
7.2.2 Protocol Violations and Deviations 
Any significant protocol deviations that the investigator or study clinic staff believes are 
of major importance (e.g., incorrect randomizations, subject enrolled but not eligible) 

U.S. FOOD AND DRUG ADMINISTRATION  
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Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
(Version 1.1) 
 
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should be reported to the sponsor and the investigator’s IRB as soon as possible. 
Significant protocol deviations may include the following: 
x Deviations from the inclusion/exclusion criteria that may affect subject safety 
x Deviations (omission or delay) of safety monitoring procedures 
x Deviations in the administration of the study drug 
x Deviations in obtaining informed consent 
All subjects who are enrolled and receive the study drug, regardless of whether they have 
a major protocol violation, must continue to be followed for safety for all follow-up study 
visits. 
 
 
 

U.S. FOOD AND DRUG ADMINISTRATION  
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Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
(Version 1.1) 
 
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REFERENCE LIST 
1. FDA Drug Safety Communication found at https://www.fda.gov/drugs/drug-safety-
and-availability/fda-drug-safety-communication-fda-warns-about-serious-risks-and-
death-when-combining-opioid-pain-or. 
 
2. Xu, Lin, et al. (2021). "Effects of sedative psychotropic drugs combined with 
oxycodone on respiratory depression in the rat." Clinical and translational science 
14.6: 2208-2219. 
 
3. Read, D. J. (1967). A clinical method for assessing the ventilatory response to carbon 
dioxide. Australas Ann Med, 16(1), 20-32.  
 
4. Rebuck A S. (1976). Measurement of ventilatory response to CO2 by rebreathing. 
Chest. 70(1 Suppl), 118-21.  
 
5. van der Schrier R, Jonkman K, van Velzen M, Olofsen E, Drewes AM, Dahan A, 
Niesters M. (2017a). An experimental study comparing the respiratory effects of 
tapentadol and oxycodone in healthy volunteers. Br J Anaesth, 119(6), 1169-77. 
 
6. van der Schrier R, Roozekrans M, Olofsen E, Aarts L, van Velzen M, de Jong M, 
Dahan A, Niesters M. (2017b). Influence of Ethanol on Oxycodone-induced 
Respiratory Depression: A Dose-escalating Study in Young and Elderly Individuals. 
Anesthesiology, 126(3), 534-42. 
 
7. Ladd LA, Kam PC, Williams DB, Wright AWE, Smith MT, and Mather LE. (2005). 
Ventilatory responses of healthy subjects to intravenous combinations of morphine 
and oxycodone under imposed hypercapnic and hypoxaemic conditions. British 
Journal of Clinical Pharmacology, 59(5), 524-535. 
 
8. Bourke DL and Warley A. (1989). The steady-state and rebreathing methods 
compared during morphine administration in humans. Journal of Physiology, 419, 
509-17. 
 
9. Sarton E, Teppema L, and Dahan A. (1999). Sex differences in morphine-induced 
ventilatory depression reside within the peripheral chemoreflex loop. Anesthesiology, 
90, 1329-38. 
 
10. Rigg JR. Ventilatory effects and plasma concentration of morphine in man. Br J 
Anaesth. 1978;50(8):759-765. 
 
11. Webster, LR, Hansen E, Stoddard GJ, Rynders A, Ostler D, Lennon H. Ventilatory 
Response to Hypercapnia as Experimental Model to Study Effects of Oxycodone on 
Respiratory Depression. (2022) Curr Rev Clin Exp Pharmacol. 17(1):72-80 

U.S. FOOD AND DRUG ADMINISTRATION  
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Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
(Version 1.1) 
 
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12. Forster A, Gardaz JP, Sutur PM, and Gemperie M. (1980). Respiratory depression by 
midazolam and diazepam. Anesthesiology, 53, 494-97. 
13. Power SJ, Morgan M, and Chakrabarti MK. (1983). Carbon dioxide response curves 
following midazolam and diazepam. British Journal of Anesthesia, 55, 837.-41.  
 
14. Cohen R, Finn H, Steen S. (1969). Effect of Diazepam and Meperidine, Alone and in 
Combination, on Respiratory Response to Carbon Dioxide. Anesthesia & Analgesia, 
48, 353–55. 
 
15. Geddes DM, Rudolf M, Saunders KB. (1976). Effect of nitrazepam and flurazepam 
on the ventilatory response to carbon dioxide. Thorax, 31, 548–51. 
 
16. Bailey PL, Andriano KP, Goldman M, Stanley TH, and Pace NL. (1986). Variability 
of the respiratory response to diazepam. Anesthesiology, 64, 460-65. 
17. Freye, E., Azevedo, L., & Hartung, E. (1985). Reversal of fentanyl related respiratory 
depression with nalbuphine. Effects on the CO2-response curve in man. Acta 
Anaesthesiol Belg, 36(4), 365-374.  
 
18. Jarvis, D. A., Duncan, S. R., Segal, I. S., & Maze, M. (1992). Ventilatory effects of 
clonidine alone and in the presence of alfentanil, in human volunteers. 
Anesthesiology, 76(6), 899-905.  
 
19. Pavlin DJ, Coda B, Shen DD, Tschanz J, Nguyen Q, Schaffer R, Donaldson G, 
Jacobson RC, and Chapman CR. (1996). Effects of combining propofol and alfentanil 
on ventilation, analgesia, sedation, and emesis in human volunteers. Anesthesiology 
84, 23-37. 
20. Clinical Study to Investigate the Effect of the Combination of Psychotropic Drugs 
and an Opioid on Ventilation. Found at 
https://clinicaltrials.gov/ct2/show/NCT04310579. 
 
21. Gaulton A, Hersey A, Nowotka M, et al. The ChEMBL database in 2017. Nucleic 
Acids Res. 2017;45(D1):D945-D954. 
 
22. PubChem Compound Summary for CID 43815, Paroxetine. National Center for 
Biotechnology Information; 2004. 
https://pubchem.ncbi.nlm.nih.gov/compound/Paroxetine. 
23. Richerson GB. (2004). Serotonergic neurons as carbon dioxide sensors that maintain 
pH homeostasis. Nat Rev Neurosci.5(6):449-461. 
 
24. Dahan A, Aarts L, Smith TW.(2010). Incidence, Reversal, and Prevention of Opioid-
induced Respiratory Depression. Anesthesiology;112(1):226-238 

U.S. FOOD AND DRUG ADMINISTRATION  
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Pharmacology / Division Applied Regulatory Science 
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25. Xu L, Krishna A, Stewart S, Shea K, Racz R, Weaver JL, Volpe DA, Pilli NR, 
Narayanasamy S, Florian J, Patel V, Matta MK, Stone MB, Zhu H, Davis MC, 
Strauss DG, Rouse R. (2021). Effects of sedative psychotropic drugs combined with 
oxycodone on respiratory depression in the rat. Clin Transl Sci. 14(6):2208-2219. 
 
26. Bianchi AL, Denavit-Saubie M, Champagnat J. (1995). Central control of breathing 
in mammals: neuronal circuitry, membrane properties, and neurotransmitters. Physiol 
Rev.75(1):1-45. 
 
27. Mueller RA, Lundberg DB, Breese GR, Hedner J, Hedner T, Jonason J. (1982). The 
neuropharmacology of respiratory control. Pharmacol Rev. 34(3):255-285. 
 
28. Armijo JA, Florez J. (1974). The influence of increased brain 5-hydroxytryptamine 
upon the respiratory activity of cats. Neuropharmacology.13(10-11):977-986. 
 
29. Florez J, Delgado G, Armijo JA. (1972). Adrenergic and serotonergic mechanisms in 
morphine-induced respiratory depression. Psychopharmacologia. 24(2):258-274. 
 
30. Meldrum MJ, Isom GE. (1981).  Role of monoaminergic systems in morphine-
induced respiratory depression. Neuropharmacology. 20(2):169-175. 
 
31. Mueller RA, Lundberg D, Breese GR. (1980). Evidence that respiratory depression 
by serotonin agonists may be exerted in the central nervous system. Pharmacol 
Biochem Behav. 13(2):247-255. 
 
32. Annerbrink K, Olsson M, Hedner J, Eriksson E. (2010). Acute and chronic treatment 
with serotonin reuptake inhibitors exert opposite effects on respiration in rats: 
possible implications for panic disorder. J Psychopharmacol. 24(12):1793-1801. 
 
33. Henderson DR, Konkle DM, Mitchell GS. (1999). Effects of serotonin re-uptake 
inhibition on ventilatory control in goats. Respir Physiol. 115(1):1-10. 
 
34. Morrison JL, Chien C, Riggs KW, Gruber N, Rurak D. (2002). Effect of maternal 
fluoxetine administration on uterine blood flow, fetal blood gas status, and growth. 
Pediatr Res. 51(4):433-442. 
 
35. Olsson M, Annerbrink K, Bengtsson F, Hedner J, Eriksson E. (2004). Paroxetine 
influences respiration in rats: implications for the treatment of panic disorder. Eur 
Neuropsychopharmacol. 14(1):29-37. 
 
36. Robillard R, Saad M, Ray LB, BuJaki B, Douglass A, Lee EK, Soucy L, Spitale N, 
De Koninck J, Kendzerska T. (2021). Selective serotonin reuptake inhibitor use is 
associated with worse sleep-related breathing disturbances in individuals with 
depressive disorders and sleep complaints: a retrospective study. J Clin Sleep Med. 
17(3):505-513. 

U.S. FOOD AND DRUG ADMINISTRATION  
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Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
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37. Bertani A, Perna G, Arancio C, Caldirola D, Bellodi L. (1997).  Pharmacologic effect 
of imipramine, paroxetine, and sertraline on 35% carbon dioxide hypersensitivity in 
panic patients: a double-blind, random, placebo-controlled study. J Clin 
Psychopharmacol. 17(2):97-101. 
 
38. Perna G, Bertani A, Gabriele A, Politi E, Bellodi L. (1997). Modification of 35% 
carbon dioxide hypersensitivity across one week of treatment with clomipramine and 
fluvoxamine: a double-blind, randomized, placebo-controlled study. J Clin 
Psychopharmacol. 17(3):173-178. 
 
39. Gorman JM, Browne ST, Papp LA, Martinez J, Welkowitz L, Coplan JD, Goetz RR, 
Kent J, Klein DF. Effect of antipanic treatment on response to carbon dioxide. Biol 
Psychiatry. 1997;42(11):982-991. 
 
40. Bocola V, Trecco MD, Fabbrini G, Paladini C, Sollecito A, Martucci N. (1998). 
Antipanic effect of fluoxetine measured by CO2 challenge test. Biol Psychiatry. 
43(8):612-615. 
 
41. Hedegaard H, Bastian BA, Trinidad JP, Spencer M, Warner M. (2018). Drugs Most 
Frequently Involved in Drug Overdose Deaths: United States, 2011-2016. Natl Vital 
Stat Rep. 67(9):1-14. 
 
42. Zedler B, Xie L, Wang L, Joyce A, Vick C, Brigham J, Kariburyo F, Baser O, 
Murrelle L. (2015). Development of a Risk Index for Serious Prescription Opioid-
Induced Respiratory Depression or Overdose in Veterans' Health Administration 
Patients. Pain Med. 2015;16(8):1566-1579. 
 
43. Zedler BK, Saunders WB, Joyce AR, Vick CC, Murrelle EL. (2018). Validation of a 
Screening Risk Index for Serious Prescription Opioid-Induced Respiratory 
Depression or Overdose in a US Commercial Health Plan Claims Database. Pain 
Med. 19(1):68-78. 
 
44. Annerbrink K, Olsson M, Hedner J, Eriksson E. (2010). Acute and chronic treatment 
with serotonin reuptake inhibitors exert opposite effects on respiration in rats: 
possible implications for panic disorder. J Psychopharmacol.24(12):1793-1801. 
 
45. Nutt DJ, Forshall S, Bell C, Rich A, Sandford J, Nash J, Argyropoulos S. (1999). 
Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of 
psychiatric disorders. Eur Neuropsychopharmacol. 9 Suppl 3:S81-86. 
 
46. Czachura JF, Rasmussen K. (2000). Effects of acute and chronic administration of 
fluoxetine on the activity of serotonergic neurons in the dorsal raphe nucleus of the 
rat. Naunyn Schmiedebergs Arch Pharmacol. 362(3):266-275 
 

U.S. FOOD AND DRUG ADMINISTRATION  
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Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
(Version 1.1) 
 
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47. Casey K, Duffin J, McAvoy GV. (1987). The effect of exercise on the central-
chemoreceptor threshold in man. J Physiol. 383:9-18. 
 
48. Duffin J, McAvoy GV. (1988). The peripheral-chemoreceptor threshold to carbon 
dioxide in man. J Physiol. 406:15-26. 
 
49. Mahamed S, Duffin J. (2001). Repeated hypoxic exposures change respiratory 
chemoreflex control in humans. J Physiol. 534(Pt. 2):595-603. 
 
50. Amin HM, Sopchak AM, Esposito BF, Henson LG, Batenhorst RL, Fox AW, 
Camporesi EM. (1995). Naloxone-induced and spontaneous reversal of depressed 
ventilatory responses to hypoxia during and after continuous infusion of remifentanil 
or alfentanil. J Pharmacol Exp Ther. 274(1):34-39. 
 
51. Amin HM, Sopchak AM, Foss JF, Esposito BF, Roizen MF, Camporesi EM. (1994). 
Efficacy of methylnaltrexone versus naloxone for reversal of morphine-induced 
depression of hypoxic ventilatory response. Anesth Analg. 78(4):701-705 
 
52. Dong TW, MacLeod DB, Santoro A, Augustine Z, Barth S, Cooter M, Moon RE. 
(1985). A methodology to explore ventilatory chemosensitivity and opioid-induced 
respiratory depression risk. J Appl Physiol. 2020;129(3):500-507. 
 
53. Oxycodone Package Insert obtained from DailyMed dated 10/13/2021. Found at 
https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=928227bf-89c5-4c64-9823-
0e84cc669388   
 
54. Oral Paroxetine Package Insert obtained from DailyMed dated 09/23/2021. Found at 
https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ef3b5cbe-f9e1-c1ac-79da-
cfe14e3a7e7e  
 
55. Lexapro Package Insert obtained from DailyMed dated 09/20/2021. Found at 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=13bb8267-1cab-43e5-
acae-55a4d957630a  
 
56. Zofran Package Insert obtained from DailyMed dated 10/2017. Found at 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020103s036,020605s020
,020781s020lbl.pdf  
 
57. Heydorn W.E (1999). Paroxetine: A review of its pharmacology, pharmacokinetics, 
and utility in the treatment of variety of psychiatric disorders. Expert Opin Investig 
Drugs, 8(4), 417-41. 
 
58. Naloxone Package Insert obtained from DailyMed dated 03/20/2020. Found at 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8cc25cf1-008c-4808-
baec-49f35a887fae  

U.S. FOOD AND DRUG ADMINISTRATION  
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Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
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59. Ondansetron Package Insert obstained from DailyMed dates 10/15/2021. Found at 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa8c2931-35a7-4b4b-
8be2-eda701b51079  
 
60. Johannesen, L., Vicente, J., Mason, J. W., Sanabria, C., Waite-Labott, K., Hongm M., 
Strauss, D. G. (2014) Differentiating drug-induced multichannel black on the 
electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and 
verapamil. Clinical Pharmacology & Therapeutics, 96(5), 549-558. 
 
61. Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, Mehrotra D, Riley S, Sager 
P, Tornoe C, Wang Y (2018). Scientific white paper on concentration-QTc modeling. 
J Pharmacokinet Pharmacodyn, 45(3):383-397. 
 
62. E14/S7B Questions and Answers: Clinical and nonclinical evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential. Found at 
https://database.ich.org/sites/default/files/E14-S7B_QAs_Step4_2022_0221.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

U.S. FOOD AND DRUG ADMINISTRATION  
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Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
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8. APPENDICES 
Appendix A – Schedule of Events 
 

U.S. FOOD AND DRUG ADMINISTRATION  
CDER / Office of Translational Sciences / Office of Clinical 
Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
(Version 1.1) 
 
 
Appendix B – List of Abbreviations 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
Ag/Ab 
antigen/antibody 
AUC 
area under the concentration-time curve  
CDC 
Center for Disease Control 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease of 2019 
CO2 
carbon dioxide 
CV 
coefficient of variation 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HepC 
hepatitis C  
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonisation 
IR 
immediate release 
IRB 
Institutional Review Board 
IV 
intravenous 
J-Tpeak 
early repolarization interval 
J-TpeakC 
heart rate-corrected J-Tpeak interval 
ǻ--TpeakC 
change-from-baseline in J-TpeakC 
ǻǻ--TpeakC 
placebo-adjusted change-from-baseline J-TpeakC 
Kel 
elimination rate 
Kg 
kilogram 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
milligram 
NONMEM 
nonlinear mixed effects modeling 
NSAID 
nonsteroidal anti-inflammatory drug 
N2 
nitrogen 
OTC 
over-the-counter 
O2 
Oxygen 

U.S. FOOD AND DRUG ADMINISTRATION  
CDER / Office of Translational Sciences / Office of Clinical 
Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
(Version 1.1) 
 
 
pCO2 
partial pressure carbon dioxide 
PD 
pharmacodynamic 
PETCO2 
end-tidal partial pressure carbon dioxide 
PK 
pharmacokinetic 
pO2 
partial pressure oxygen 
QA 
quality assurance 
QD 
once daily 
QTc 
heart rate-corrected QT interval 
ǻ47F 
change-from-baseline in QTc 
ǻǻ47F 
placebo-adjusted change-from-baseline QTc 
QTcF 
heart rate-corrected QT interval using the Fridericia 
correction 
RCF 
relative centrifugal force 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOP 
standard operating procedure 
SpO2 
oxygen saturation 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time of Cmax 
VE55 
minute ventilation at 55 mmHg partial pressure carbon 
dioxide 
 
 
 
 

U.S. FOOD AND DRUG ADMINISTRATION  
CDER / Office of Translational Sciences / Office of Clinical 
Pharmacology / Division Applied Regulatory Science 
Protocol Number: SCR-012 
(Version 1.1) 
 
 
Appendix C – Protocol Revision History 
PROTOCOL REVISION HISTORY 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol 
Number 
Version 
Effective Date 
Summary of Changes 
SCR-012 
1 
21 June 2022 
Developed initial protocol  
SCR-012 
1.1 
21 July 2022 
Updated protocol to reflect revised 
endpoints, assessments, and analyses 
method.  

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