Clinical trial NCT04310579
Conditions: Hypercapnia Ventilatory Depression
Keywords: Opioids Sedative psychotropic drugs
Sponsor: Food and Drug Administration (FDA)
Start date: 2020-06-15; Completion date: 2021-05-25
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Opioids can decrease breathing and co-administration of benzodiazepines with opioids can further decrease breathing. It is unknown whether certain other drugs also decrease breathing when co-administered with opioids. The objective of this study is to determine whether certain drugs combined with an opioid decrease breathing compared to breathing with an opioid alone.

In order to assess this, this study will utilize the Read Rebreathing method, where study participants breathe increased levels of oxygen and carbon dioxide. The increased levels of carbon dioxide cause the study participants to increase breathing. This increased breathing response can be decreased by opioids and benzodiazepines, and potentially other drugs. Using this procedure, low doses of opioids or benzodiazepines can be administered that have minimal-to-no effects on breathing when study participants are going about normal activities breathing room air, however breathing increases less than expected as carbon dioxide levels are increased. This study will also obtain quantitative pupillometry measurements before and after each rebreathing assessment to allow for comparisons of pupillary changes to ventilatory changes when subjects receive different drugs and drug combinations.

This study includes three parts: A Lead-In Reproducibility Phase and two main parts (Part 1 and Part 2). The Lead-In Reproducibility Phase will measure the variability between study participants and between repeated uses of the method in the same study participant within a day and between days. Part 1 will study an opioid alone, benzodiazepine alone, and their combination to show the methodology will detect changes in breathing at low doses of the drugs that are known to affect breathing. Part 2 will assess whether two drugs, selected due to their effects on breathing in a nonclinical model, decrease the breathing response when combined with an opioid compared to when an opioid is administered alone.

Detailed description:
Opioids can cause respiratory/ventilatory depression, and this can be exacerbated when opioids are co-administered with benzodiazepines. Research suggests this is caused by a reduced respiratory/ventilatory response to counteract increasing levels of systemic carbon dioxide (CO2). It is unknown whether certain other sedative psychotropic drugs can exacerbate opioid-induced respiratory/ventilatory depression. Studies were conducted to evaluate the effects of selected drugs in a non-clinical model. This clinical study will evaluate two drugs (quetiapine and paroxetine) that caused an effect when combined with oxycodone in the non-clinical model.

Study designs were evaluated that would allow a safe and controlled assessment of the effects of drug combinations on respiratory/ventilatory depression and a methodology was selected called the Read breathing procedure which introduces increased levels of CO2 to cause study participants to increase ventilation by having study participants rebreathe through a circuit with 93% oxygen (O2) and 7% CO2. Previous studies have shown this "hypercapnic ventilatory response" can be decreased by opioids and benzodiazepines and potentially other drugs. Using this procedure, low doses of opioids or benzodiazepines can be administered that have minimal-to-no effects on respiration/ventilation when study participants are going about normal activities breathing room air, however ventilation is decreased relative to the expected increase in ventilation as CO2 levels are increased during rebreathing. Thus, there is minimal risk of true respiratory depression (i.e. inadequate gas exchange) and, if needed, the investigators can immediately halt the experiment and have the study participant breathe room air or 100% O2.

Using the Read rebreathing methodology, the current clinical study was designed to generate data characterizing changes in the ventilatory response to hypercapnia when administering quetiapine and paroxetine alone or in combination with oxycodone. Information obtained from this study will inform on the potential for the specific studied drugs to affect ventilation when combined with an opioid and may also demonstrate the utility of this study design and methodology as an approach for evaluating the effect of an investigational drug and drug combinations on ventilatory depression. Thus, this study includes a lead-in reproducibility phase to quantify the intra- and inter-subject variability within a day and between days. In addition, this study includes a positive control phase with relatively low doses of opioid (oxycodone) alone, benzodiazepine (midazolam) alone and their combination to help assess assay sensitivity. While opioids and benzodiazepines have been studied alone and in combination with the rebreathing method previously, many of these studies are older and it is important to define the reproducibility and effects of the drugs at relatively low doses. Together, these components of the study will further define the reproducibility and sensitivity of the methodology that could be applied to a broader range of investigational drugs in the future to assess their safety when combined with opioids.

In addition, pupillary measurements have been used to study the pharmacodynamic effects of opioids and opioid antagonists (Skulberg et al, 2018; Rollins et al, 2014) and there has been interest in expanding its use in clinical studies. However, there are limited data directly comparing pupillary changes to ventilatory changes and some drugs may influence the pupillary response to opioids (Kummer et al, 2011). As an exploratory endpoint, this study will obtain quantitative pupillometry measurements before and after each rebreathing assessment to allow for comparisons of pupillary changes to ventilatory changes when subjects receive different drugs and drug combinations.

This study includes three parts: A Lead-In Reproducibility Phase and two main parts (Part 1 and Part 2). The lead-in reproducibility phase will quantify the intra- and inter-subject variability of the Read Rebreathing methodology within a day and between days. Part 1 is a positive control phase with doses of an opioid (oxycodone) alone, benzodiazepine (midazolam) alone, their combination, and placebo to help assess ability of the procedure to detect changes in ventilation. Part 2 will assess whether two sedative psychotropic drugs (quetiapine and paroxetine), selected due to their effects in a nonclinical model, decrease the ventilatory response to hypercapnia compared to an opioid (oxycodone) alone. The doses of oxycodone and midazolam were selected to be less than those previously administered in healthy volunteers undergoing the Read Rebreathing or similar respiratory circuit procedures that increase the inspired level of CO2. The doses of quetiapine and paroxetine were selected to reach clinical steady-state levels.

The Lead-In Reproducibility Phase will have up to 10 healthy volunteer participants enrolled in two cohorts of approximately five. Participants will perform the Read Rebreathing procedure five times on day 1 and five times on day 2.

Part 1 will be a 4-period randomized crossover study with approximately 20 healthy volunteer participants. Participants will receive four different treatments (oxycodone, midazolam, oxycodone + midazolam, and placebo) in a random order across each of the 1-day study periods. There will be two days of washout between each period. During each period, participants will perform the Read Rebreathing procedure seven times, for a total of 28 rebreathing assessments in Part 1. For Part 1, blood samples will also be collected for determination of study drug concentration.

Part 2 will be a 3-period randomized crossover study with approximately 20 healthy volunteer participants. Participants will receive three different treatments (oxycodone, oxycodone + quetiapine, and oxycodone + paroxetine) in a random order across each of the 5-day periods. Oxycodone will only be administered on day 1 and day 5 of each treatment period. The other drugs will be administered every day of the treatment period such that there will be lower concentrations on day 1 and higher concentrations on day 5, which are the days when oxycodone is co-administered. Read Rebreathing assessments will be performed on day 1 and day 5 to investigate the effect of paroxetine and quetiapine when combined with oxycodone compared to oxycodone alone. In addition, Read Rebreathing assessments will be performed on day 4 to determine the effect of paroxetine alone and quetiapine alone compared to placebo. There will be seven days of washout between each period. During each period, participants will perform the Read Rebreathing procedure 17 times, for a total of 51 rebreathing assessments in Part 2. For Part 2, blood samples will also be collected for determination of study drug concentration.

Arms: arm 1: Read Rebreathing Reproducibility Assessment arm 2: In one period subjects receive oxycodone 10-15 mg immediate release (IR) tablets and intravenous (IV) placebo 1x per day.

In a second period (randomized cross-over), subjects receive midazolam 0.0375-0.075 mg/kg IV and oral placebo tablet 1x per day.

In a third period (randomized cross-over), subjects receive oxycodone 10-15 mg IR tablet and 0.0375-0.075 mg/kg midazolam IV 1x per day.

In a fourth period (randomized cross-over), subjects receive oral placebo tablet and placebo IV 1x per day.

Note: Initial doses of oxycodone will be 10 mg, but may be increased to 15 mg if necessary based on criteria specified in protocol. Initial doses of midazolam will be 0.0375 mg/kg but may be increased to 0.075 mg/kg based on criteria specified in protocol. arm 3: In one period, subjects receive: oxycodone 10-15 mg IR tablet 1x per day and oral placebo 3x per day on Days 1 and 5; and oral placebo 3x per day on Days 2-4.

In a second period (randomized cross-over), subjects receive: oxycodone 10-15 mg IR tablet 1x per day, paroxetine 40 mg tablet 1x per day, and oral placebo 1x per day on Days 1 and 5; and paroxetine 40 mg tablet 1x per day and oral placebo 2x per day on Days 2-4.

In a third period (randomized cross-over), subjects receive: oxycodone 10-15 mg IR tablet 1x per day, quetiapine 50 mg tablet 2x per day, and oral placebo 1x per day on Day 1; quetiapine 100 mg (2x50 mg tablets) 2x per day and oral placebo 1x per day on Day 2; quetiapine 150 mg (3x50 mg tablets) 2x per day and oral placebo 1x per day on Day 3; quetiapine 200 mg (4x50 mg tablets) 2x per day and oral placebo 1x per day on Day 4; and quetiapine 200 mg (4x50 mg tablets) 1x per day and oral placebo 1x per day on Day 5.
Interventions: intervention 1: Oxycodone and Midazolam intervention 2: Oxycodone, Paroxetine, and Quetiapine
Intervention descriptions: intervention 1: In one period subjects receive oxycodone 10-15 mg immediate release (IR) and placebo IV 1x per day.

In a second period (randomized cross-over), subjects receive midazolam 0.0375-0.075 mg/kg IV and oral placebo tablet 1x per day.

In a third period (randomized cross-over), subjects receive oxycodone 10-15 mg IR tablet and 0.0375-0.075 mg/kg midazolam IV 1x per day.

In a fourth period (randomized cross-over), subjects receive oral placebo tablet and placebo IV 1x per day. intervention 2: In one period, subjects receive: oxycodone 10-15 mg IR tablet 1x per day and oral placebo 3x per day on Days 1 and 5; and oral placebo 3x per day on Days 2-4.

In a second period (randomized cross-over), subjects receive: oxycodone 10-15 mg IR tablet 1x per day, paroxetine 40 mg tablet 1x per day, and oral placebo 1x per day on Days 1 and 5; and paroxetine 40 mg tablet 1x per day and oral placebo 2x per day on Days 2-4.

In a third period (randomized cross-over), subjects receive: oxycodone 10-15 mg IR tablet 1x per day, quetiapine 50 mg tablet 2x per day, and oral placebo 1x per day on Day 1; quetiapine 100 mg (2x50 mg tablets) 2x per day and oral placebo 1x per day on Day 2; quetiapine 150 mg (3x50 mg tablets) 2x per day and oral placebo 1x per day on Day 3; quetiapine 200 mg (4x50 mg tablets) 2x per day and oral placebo 1x per day on Day 4; and quetiapine 200 mg (4x50 mg tablets) 1x per day and oral placebo 1x per day on Day 5.

Protocol documents:
ICF_000.pdf: 
Study Title: Clinical study to investigate the effect of the combination of 
psychotropic drugs and an opioid on ventilation   
 
Document Title: Informed Consent Form – Study No. SCR-009 
 
Document Date : 22 December 2020 
 
NCT Number: NCT04310579 


U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 1 of 26 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
CONSENT TO TAKE PART IN A CLINICAL RESEARCH STUDY 
AND 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
 
Sponsor/Study Title: 
  
US Food and Drug Administration / “Clinical Study to Investigate the 
Effect of the Combination of Psychotropic Drugs and an Opioid on 
Ventilation.” 
 
Protocol Number: 
 
SCR-009 
Principal Investigator: Carlos Sanabria, MD 
(Study Doctor)  
 
 
Telephone: 
 
1 (800) 597-4507 
1 (855) 622-8100 (24 Hours) 
 
Address: 
 
Spaulding Clinical Research, LLC 
525 S Silverbrook Dr. 
West Bend, WI 53095 
 
SUBJECT SCREENING #_______ 
 
Please read this form carefully. Take time to ask the study doctor or study staff as many questions about 
the study as you would like. The study doctor or study staff can explain words or information that you do 
not understand. Reading this form and talking to the study doctor or study staff may help you decide 
whether to take part or not. If you decide to take part in this study, you must sign your name and date at 
the end of this form. You cannot take part in this research study until you sign and date this form. 
 
WHAT IS A VOLUNTEER INFORMED CONSENT? 
 
Please read this consent form carefully. This consent form provides important information about 
participating in a research study to help you decide whether or not you would like to participate as a 
research subject. This form contains important information about what you will be asked to do during the 
study, about the risks and benefits of the study, and about your rights as a research subject. You may 
discuss your decision with your family, your friends and/or your doctor. Take time to ask the study doctor 
or study staff as many questions about the study as you would like. The study doctor or study staff can 
explain words or information that you do not understand. If you decide to take part in this study, you must 
sign your name and date at the end of this form. Your participation is entirely voluntary. If you choose to 
participate you can change your mind at any time and withdraw from the study. You will not be penalized 
in any way or lose any benefits to which you would otherwise be entitled if you choose not to participate 
in this study or if you choose to withdraw. You cannot take part in this research study until you sign and 
date this form. A copy of the signed and dated form will be provided to you for your record. 
 
You are being asked to take part in a research study which will look at three things:  
• 
How three different study drugs (paroxetine, quetiapine and midazolam) affect the blood level of 
a fourth study drug (oxycodone) in the body.   
• 
Whether four study drugs (paroxetine, quetiapine, midazolam and oxycodone) on their own affect 
breathing (for example, if the amount of air you breathe in one minute is less with one of these 
study drugs compared to how much air you breathe normally). 


 
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Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
• 
Whether there is an interaction between one of three study drugs (paroxetine, quetiapine and 
midazolam) and oxycodone on breathing, and if there is, what the effects are (that is, if there is a 
change in the amount of air you breathe when taking oxycodone, is there an additional change 
seen when also taking one of the additional study drugs).  
 
Paroxetine, quetiapine, midazolam and oxycodone have been approved by the U.S. Food and Drug 
Administration (FDA). Paroxetine has been approved for treatment of depression; quetiapine has been 
approved for treatment of bipolar disorder, depression and other psychiatric conditions; midazolam 
has been approved for sedation with diagnostic or treatment procedures and at higher doses as an 
anesthetic for surgical procedures; and oxycodone has been approved for treatment of pain. However, 
their use in this study is investigational.  An investigational use is one that is not approved by the U.S. 
FDA. 
 
Before you decide to take part, you should understand the possible benefits and risks associated with 
this study. This process is known as informed consent and means that you will: 
 
• 
Receive detailed information about this research study. 
• 
Have a chance to ask and receive answers to any questions you may have. 
• 
Be asked to read and sign and date this informed consent, once you understand the study and wish 
to take part. 
• 
Be given a signed and dated copy of this informed consent to keep. 
 
Taking part in this study is entirely voluntary. 
 
 
WHY ARE THESE DRUGS BEING STUDIED? 
 
Oxycodone is an opioid drug. A well-known and potentially deadly side effect associated with opioid use, 
particularly when it is misused, or when given in combination with certain other drugs is that people ‘stop 
breathing’. It is thought that this is caused by the inability of the body to breathe hard enough to reduce 
the amount of carbon dioxide in the body which builds up when a person does not breath efficiently. 
Opioids and benzodiazepines have a warning on their packaging – known as a “boxed warning” - for 
possible effect on breathing when used together.  
 
There is a need to assess the effects of opioids and other drugs when used together on breathing. The 
outcome of this study may inform on the risk of combining opioids with other drugs and lead to a 
standardized approach for assessing the effects of new drugs being developed on breathing.  
 
Special Procedure: Read Rebreathing Procedure 
 
As part of this study, you will be given doses of study drugs that do not typically have significant effects 
on breathing. In order to study what might happen when higher doses are given, the study doctors will use 
equipment – a tight fitting face mask attached to oxygen, carbon dioxide and measuring equipment – to 
copy the effect of reduced breathing caused by opioid drugs  (see Figure 1). Through the face mask, 
covering your nose and mouth, you will be given a mix of oxygen and carbon dioxide that is higher than 
is normally in the air – 93% oxygen (normally 21% in room air) and 7% carbon dioxide (normally 0.4% 
in room air). The higher level of carbon dioxide breathed in will result in you feeling like you need to 
breathe faster. This technique is called Read Rebreathing. Read Rebreathing has been used in previous 
studies and has proven to be safe and able to study how opioids and other drugs affect breathing. By 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 3 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
doing this and giving the drugs in the study as outlined in this informed consent form (ICF), the data 
collected will help the FDA to understand better how these drugs can be given more safely.  This 
procedure is non-invasive, meaning no pieces of equipment enter your body. 
 
You will have Read Rebreathing explained to you at length during the ICF process, and you will have 
time to ask as many questions about this as you wish. The procedure will be conducted under medical 
supervision. You will also be shown the Read Rebreathing equipment and be trained how to use it to see 
if you can tolerate it (comfort level to breathe into a mask- similar to a sleep apnea (CPAP) mask) before 
being enrolled in the study.  
 
 
Figure 1: Rebreathing Procedure Equipment Setup 
HOW WILL THIS STUDY BE DONE? 
 
This study will be divided into three parts: Lead In, Part 1 and Part 2. You will not be allowed to select 
which part of the study you are in. If you are selected for the Lead In portion, after your participation is 
completed you would be eligible to rescreen for participation in Part 1 or Part 2 if desired.  
 
Lead In 
The Lead In part will have up to 10 healthy volunteers and will enable the study doctor to check if any 
changes need to be made to the way the study is conducted. There will be no study drugs given during 
this part of the study, but you will be expected to have the Read Rebreathing procedure. For the Lead In 
part of the study you will be confined at Spaulding Clinical from day -1 through day 3. 
 
Part 1 
In Part 1 of the study, 20 healthy volunteers will be enrolled who will receive four groups of study drugs 
or dose assignments (labeled A, B, C, D below) in a random order on days 1, 4, 7 and 10 with a washout 
period (meaning no study drugs are given) of two days in between each dose day.  


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
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Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
 
Oxycodone 
The initial dose selected for oral oxycodone is 10 mg IR (Immediate Release) tablet. Based on the results 
of the first 5 subjects, the dose may be increased to 15 mg IR. 
Midazolam 
The initial dose selected for midazolam is 0.0375 mg/kg intravenously (IV). Based on the results of the 
first 5 subjects, the dose may be increased to 0.075 mg/kg IV. 
 
Group 
Study Drugs 
A 
Oxycodone + placebo IV: oxycodone tablets 
plus an intravenous injection of placebo over 
5 minutes once per dose day 
B 
Oral placebo + midazolam IV: placebo 
tablets plus an intravenous injection of 
midazolam over 5 minutes once per dose day 
C 
Oxycodone + midazolam IV: oxycodone 
tablets plus an intravenous injection of 
midazolam over 5 minutes once per dose day 
D 
Oral placebo + placebo IV: placebo tablets 
plus an intravenous injection of placebo over 
5 minutes once per dose day 
 
To counter any possible nausea caused by oxycodone you will be given an anti-sickness medication – 
ondansetron as an oral tablet – 30 minutes prior to receiving the dose. You will also be expected to have 
the Read Rebreathing procedure as well as blood draws during the dose days.  
 
For Part 1 of the study, you will be confined at Spaulding Clinical from day -1 through day 11.  
 
Part 2 
In Part 2 of the study, 20 healthy volunteers will be enrolled who will complete three different study drug 
treatment groups (labeled E, F, and G below). Each study treatment group will have 5 days of dosing 
followed by 7 days of washout in each period. Subjects will complete each of these study treatment 
groups in a random order. For example, you may be assigned to complete Study Treatment Group G first, 
followed by E and F.  
 
• 
Oxycodone (10 or 15 mg IR tablet on the first and last day of each period)  
• 
Paroxetine (40 mg IR tablet daily for five days)  
• 
Quetiapine (50 mg twice a day on the first day, 100 mg twice a day on second day, 150 mg twice a 
day on the third day, 200 mg twice a day on the fourth day, and 200 mg once on the fifth day, tablet 
form) 
 
Group 
Days 1, 13, 25 
Days 2,14, 26 
Days 3, 15, 27 
Days 4, 16, 28 
Days 5, 17, 29 
E  
Morning: Placebo + 
Oxycodone  
Evening: Placebo 
Morning: Placebo  
Evening: Placebo 
Morning: Placebo  
Evening: Placebo 
Morning: Placebo  
Evening: Placebo 
Morning: Placebo + 
Oxycodone 


 
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Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
F 
Morning: 
Paroxetine + 
Oxycodone  
Evening: Placebo  
Morning: 
Paroxetine 
Evening: Placebo 
Morning: 
Paroxetine 
Evening: Placebo 
Morning: 
Paroxetine 
Evening: Placebo 
Morning: 
Paroxetine + 
Oxycodone  
G 
Morning: 
Quetiapine + 
Oxycodone 
Evening: 
Quetiapine  
Morning: 
Quetiapine  
Evening: 
Quetiapine 
Morning: 
Quetiapine  
Evening: 
Quetiapine 
Morning: 
Quetiapine  
Evening: 
Quetiapine 
Morning: 
Quetiapine + 
Oxycodone 
 
 
The three study treatment arms will be completed over time periods from day -1 through day 5 followed 
by a 7-day washout; day 13 through 17 followed by a 7-day washout: and day 25 through day 30. You 
will be confined at Spaulding Clinical for each of the study treatment periods (day -1 through the morning 
of day 6; the evening of day 12 through the morning of day 18; and the evening of day 24 through the 
morning of day 30). You will be released from Spaulding clinical for each 7-day washout period and 
return to the clinical site the evening before the start of the next study treatment period. 
 
Day -1 
Days 1-5 
Days 6-12 
Days 13-17 
Days 18-24 
Day 25-29 
Check-in 
Period 1 
Washout (check-
in Day 12) 
Period 2 
Washout (check-
in Day 24) 
Period 3 
 
To counter any possible nausea caused by oxycodone you will be given an anti-sickness medication – 
ondansetron as an oral tablet – 30 minutes prior to receiving the dose. You will also be expected to have 
the Read Rebreathing procedure and blood draws during the study treatment periods.  
 
WHO IS BEING ASKED TO TAKE PART IN THIS STUDY? 
 
Approximately 50 healthy male and female adult subjects, who meet the requirements following a 
screening visit, will be enrolled in the study.  
 
You have been asked to take part in this study because you are in general good health, are between 18 and 
50 years of age, have no history of heart or liver disease, no history of allergies, no symptoms consistent 
with coronavirus disease of 2019 (COVID-19), no underlying medical conditions that put you at higher 
risk for COVID-19 complications and have not participated in another research study for an experimental 
drug (or a medical device) within 30 days of the first dose of study drug.  
 
HOW MUCH TIME IS REQUIRED TO TAKE PART IN THE STUDY? 
 
If you decide to take part in the study, you will be asked to attend a screening visit. If you pass the 
screening visit, you will return to the clinic for either one period of 4 days and 3 nights (for the Lead In 
part of the study), one period of 12 days and 11 nights (for Part 1 of the study) or three 7-day and 6-night 
periods with 6 days of washout in between each period (where you will not stay at the clinic) in Part 2 of 
the study.     
 
The duration of your participation in the study from screening to final follow-up will be up to 58 days. 
 
INFORMATION FOR FEMALE VOLUNTEERS 
 
You should not screen for this study if: 
 
• 
There is any possibility that you may become, or are pregnant, 


 
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Carlos Sanabria, MD 
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• 
You have given birth in the last 3 months, or 
• 
You are breast feeding. 
 
You may screen for this study if:  
 
• 
You have had a hysterectomy (uterus removed) or bilateral oophorectomy (ovaries removed), 
confirmed with documentation, or 
• 
You are of post-menopausal age and have not had a menstrual period for 2 years, confirmed with 
hormone level at screening, or 
• 
You have a vasectomized partner who has been documented to no longer produce sperm, or 
• 
You are using TWO highly reliable methods of contraception to avoid pregnancy throughout the 
study and for at least 1 month after last study drug administration. Highly reliable methods of 
birth control include: 
 
o Hormonal implants/patch,  
o Oral hormonal contraceptives,  
o Injectable hormones,  
o Intra-uterine device (IUD), 
o Approved cervical ring,  
o Diaphragm with spermicide or condom (female or male) with spermicide 
 
One of the methods of birth control used must be a barrier method. The use of spermicide alone and 
condom alone are not acceptable methods of contraception.  
 
Except for continuous abstinence (no sexual intercourse with a male partner), no method of birth control 
can be considered 100% reliable in preventing pregnancy. Although the risk of becoming pregnant is low 
with many methods, unplanned pregnancies may occur with all birth control methods. Most occur 
because of improper or irregular use of the birth control method. If you are usually not sexually active but 
become sexually active, you must follow the advice documented above regarding contraceptive methods. 
 
All females enrolled in the Lead-in part of the study will have a pregnancy test performed at screening, at 
check-in on Day -1 and check out on Day 3. All females enrolled in Part 1 of the study will have a 
pregnancy test performed at screening, at check-in on Day -1 and check out on Day 11. All females 
enrolled in Part 2 of the study will have a pregnancy test performed at screening, at check-in on Day -1, 
Day 12, Day 24, and check out on Day 30.   
 
Please be aware that a pregnancy test may not be positive until 12 days after conception (fertilization of 
the egg by sperm). Therefore, if you do not follow the study birth control requirements and/or your birth 
control method has failed, you will not be able to count on a negative test to confirm that you are not 
pregnant. 
 
If you know that you have not followed the study birth control requirements outlined above, then you 
must immediately inform us. You must not take any dose of the study drug if you have not followed these 
requirements. If you become pregnant, your pregnancy will be followed to document the outcome.  All 
live births must be followed for a minimum of 30 days or until the first well-baby visit. 
 
 
 


 
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INFORMATION FOR MALE VOLUNTEERS  
 
The effect of the study drug on male sperm is unknown. In rare cases, drugs may damage sperm in ways 
that affect a child that is fathered. Affected sperm may be present in the semen for about 2 months. 
Therefore, it is recommended to avoid fathering a child for 90 days after the last dose of the study drug. 
 
Male subjects must ensure that TWO acceptable methods of contraception are used for the entire duration 
of the study, one of which must be a barrier method, up to the study follow-up visit, if applicable. 
 
Periodic abstinence and withdrawal are not acceptable methods of contraception. 
 
HOW WILL YOU KNOW IF YOU ARE ELIGIBLE TO TAKE PART? 
 
You will NOT need to fast prior to your arrival at Spaulding Clinical Research, LLC. for your screening 
visit. You may eat and drink as normal prior to arrival.  
 
At the beginning of the Screening visit, Informed Consent will be obtained. 
 
Before starting the study, the following screening procedures will be performed:  
 
• 
A complete medical history and physical examination (including height and weight 
measurements for Body Mass Index (BMI, a way to tell if your weight is proportional to your 
height). 
• 
Assessment of blood pressure, respiratory rate, heart rate, and oral temperature. 
• 
A complete history of relevant allergies or drug sensitivities. 
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart). 
• 
A pulse oximetry recording (painless recording of the oxygen concentration in your blood). 
• 
You will be asked if you have taken any medication recently, including some eye drops. 
• 
You will be asked if you have been feeling ill recently. 
• 
Clinical laboratory tests (urine and blood samples), including screening for drugs, alcohol, and 
pregnancy tests (all female subjects); screening for how your body processes certain drugs; and 
testing for HIV, hepatitis B and C. Positive results of HIV or hepatitis tests will be reported to 
local health authorities as required by state law. 
• 
Training on the Read Rebreathing procedure so you know what to expect and to ensure you can 
tolerate it.  
If you meet the “entry criteria” of the study, according to the study doctor, you will be tested again when 
you are admitted to Spaulding Clinical Research, LLC. You will have the entry criteria reviewed again to 
ensure that you still are eligible for the study.  
In addition, prior to admission you will have a diagnostic test performed to detect severe acute respiratory 
syndrome coronavirus 2 (called “coronavirus” from now on), which is the virus that causes COVID-19. 
Depending on the time required to return results, this may be performed ~2 days before check-in or may be 
performed on the check-in day. You will only be allowed to be admitted if your coronavirus test is negative. 
In addition, when entering the building for screening and check-in, triage for COVID-19 will take place. 
The exact details of what will occur at triage may change as additional information or testing is available, 
however as of now it is planned to include asking about any potential contacts with COVID-19, signs and 
symptoms associated with COVID-19, temperature monitoring and antibody screening for coronavirus. 
 
 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 8 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
WHAT TESTS AND PROCEDURES WILL BE USED IN THE STUDY? 
 
1. Lead In Study 
 
1.1. Check-in (Day -1) 
 
Upon admission to Spaulding Clinical Research, LLC., you will be given an identity band to wear 
throughout your entire stay in the unit. 
 
You will NOT need to fast prior to your arrival meaning you should eat and drink as normal.  
 
The following admission procedures will be performed:  
 
• 
Perform/review results from coronavirus test  
• 
Medical history updates. 
• 
Physical examination.  
• 
Clinical laboratory tests (urine and blood samples), including screening for drugs, alcohol, and 
pregnancy tests (all female subjects).  
• 
Assessment of blood pressure, respiratory rate, heart rate, and oral temperature. 
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart). 
• 
A pulse oximetry recording (painless recording of the oxygen levels in your blood). 
• 
You will be asked for details of any medication taken since the screening or previous visit. 
• 
You will be asked if you have been ill since the screening or previous visit. 
• 
You will be asked if you complied with study restrictions. 
• 
You will have further training to the Read Rebreathing procedure 
• 
You will be provided meals (lunch, dinner and a snack). 
• 
Inclusion/Exclusion assessment.  
 
The results from these tests will help the study staff determine whether you are still eligible to enter the 
study.  
 
1.2. Study Treatment (Days 1 and 2) 
 
• 
Adverse event assessment (check for side effects) and changes in concomitant medications 
(medicines you are currently taking). 
• 
Read Rebreathing procedure (5 times per day). 
• 
Eye assessments to measure pupil size. 
• 
Blood collection to look at levels of proteins and other constituents of your blood. 
• 
Meals (after last Read Rebreathing procedure – lunch, dinner and a snack). 
 
1.3. Check Out (Day 3) 
 
• 
A complete physical examination.  
• 
Assessment of blood pressure, respiratory rate, heart rate, and oral temperature. 
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart). 
• 
A pulse oximetry recording (painless recording of the oxygen levels in your blood). 
• 
You will be asked if you have taken any medication recently, including some eye drops. 
• 
You will be asked if you have been feeling ill recently. 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 9 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
Clinical laboratory tests (urine and blood samples), including pregnancy tests (all female 
subjects). 
 
2. Part 1  
 
2.1. Check In (Day -1) 
 
Upon admission to Spaulding Clinical Research, LLC., you will be given an identity band to wear 
throughout your entire stay in the unit. 
 
You will NOT need to fast prior to your arrival meaning you should eat and drink as normal.  
 
The following admission procedures will be performed:  
 
• 
Perform/review results from coronavirus test.  
• 
Medical history updates. 
• 
Physical examination.  
• 
Clinical laboratory tests (urine and blood samples), including screening for drugs, alcohol, 
and pregnancy tests (all female subjects).  
• 
Assessment of blood pressure, respiratory rate, heart rate, and oral temperature. 
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart). 
• 
A pulse oximetry recording (painless recording of the oxygen levels in your blood). 
• 
You will be asked for details of any medication taken since the screening or previous visit. 
• 
You will be asked if you have been ill since the screening or previous visit. 
• 
You will be asked if you complied with study restrictions. 
• 
You will have further training to the Read Rebreathing procedure.  
• 
Blood collection to look at levels of proteins and other constituents of your blood. 
• 
You will be provided meals (after last Read Rebreathing procedure – lunch, dinner and a 
snack). 
• 
Inclusion/Exclusion assessment and preparation for randomization. Randomization means 
that you will be assigned by chance, like the flip of a coin, to either study group. 
 
The results from these tests will help the study staff determine whether you are still eligible to enter the 
study.  
 
2.2. Study Treatment (Days 1, 4, 7 and 10) 
 
• 
Adverse event assessment and changes in concomitant medications. 
• 
Pharmacokinetic (PK) blood sampling. 
• 
Meals (after last Read Rebreathing procedure –, lunch, dinner and a snack). 
• 
Assessment of blood pressure, heart rate, respiratory rate and oral temperature.  
• 
Administration of study product. 
• 
Blood collection to look at levels of proteins and other constituents of your blood. 
• 
Telemetry (continuous, painless recordings of your heart’s rhythm). 
• 
Continuous pulse oximetry monitoring (continuous, painless monitoring of oxygen levels in 
your blood). 
• 
Read Rebreathing procedure with one-on-one monitoring by trained study staff during the 
procedure (7 times per day). 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 10 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
• 
Eye assessments to measure pupil size. 
• 
Sedation assessments to measure whether you feel awake/alert vs. sedated. 
 
2.3. Washout (Days 2, 3, 5, 6, 8 and 9) 
 
• 
Adverse event assessment and changes in concomitant medications. 
• 
Meals (breakfast, lunch, dinner and a snack).  
 
2.4. Check Out (Day 11) 
 
• 
Adverse event assessment and changes in concomitant medications. 
• 
Clinical laboratory tests (urine and blood samples)  
• 
Physical examination.  
• 
Assessment of blood pressure, heart rate, respiratory rate and oral temperature.  
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart). 
• 
A pulse oximetry recording (painless recording of the oxygen levels in your blood). 
• 
Discharge from Spaulding Clinical after all events are completed.   
 
3. Part 2 
 
3.1. Check In (Day -1): 
 
Upon admission to Spaulding Clinical Research, LLC., you will be given an identity band to wear 
throughout your entire stay in the unit. 
 
You will NOT need to fast prior to your arrival meaning you should eat and drink as normal.  
 
The following admission procedures will be performed:  
 
• 
Perform/review results from coronavirus test.  
• 
Medical history updates. 
• 
Physical examination.  
• 
Clinical laboratory tests (urine and blood samples), including screening for drugs, alcohol, and 
pregnancy tests (all female subjects).  
• 
Assessment of blood pressure, respiratory rate, heart rate, and oral temperature. 
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart). 
• 
A pulse oximetry recording (painless recording of the oxygen levels in your blood). 
• 
You will be asked for details of any medication taken since the screening or previous visit. 
• 
You will be asked if you have been ill since the screening or previous visit. 
• 
You will be asked if you complied with study restrictions. 
• 
You will have further training to the Read Rebreathing procedure.  
• 
You will be provided meals (lunch, dinner and a snack). 
• 
Inclusion/Exclusion assessment and preparation for randomization. Randomization means that 
you will be assigned by chance, like the flip of a coin, to either study group. 
 
The results from these tests will help the study staff determine whether you are still eligible to enter the 
study.  
 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 11 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
3.2. Study Treatment (Days 1 to 5, 13 to 17, and 25 to 29) 
 
• 
Adverse event assessment and changes in concomitant medications. 
• 
Pharmacokinetic (PK) blood sampling (Days 1, 4, 5, 13, 16, 17, 25, 28, and 29 only). 
• 
Meals (after last Read Rebreathing procedure – lunch, dinner and a snack). 
o On Days 1, 5, 13, 17, 25 and 29 an additional light snack will be provided between the 
last two Read Rebreathing procedures of the day. 
• 
Assessment of blood pressure, heart rate, respiratory rate and oral temperature.  
• 
Administration of study product. 
• 
Blood collection to look at levels of proteins and other constituents of your blood (Days 1, 4, 
5, 13, 16, 17, 25, 28, and 29 only). 
• 
Telemetry (continuous, painless recordings of your heart’s rhythm) (Days 1, 5, 13, 17, 25, 
and 29 only). 
• 
Continuous pulse oximetry monitoring (continuous, painless monitoring of oxygen levels in 
your blood) (Days 1, 4, 5, 13, 16, 17, 25, 28 and 29 only). 
• 
Read Rebreathing procedure with one-on-one monitoring by trained study staff (6 times per 
day on days 1,  5, 13,  17, 25,  and 29; 5 times per day on days 4, 16 and 28 only).  
• 
Eye assessments to measure pupil size (Days 1, 4, 5, 13, 16, 17, 25, 28, and 29 only). 
• 
Sedation assessments to measure whether you feel awake/alert vs. sedated (Days 1, 4, 5, 13, 
16, 17, 25, 28, and 29 only). 
 
3.3. Washout (Days 6 to 12 and 18 to 24) 
 
• 
Check-out days (Days 6 and 18) 
o Adverse event assessment.  
o Physical examination.  
o Assessment of blood pressure, heart rate, respiratory rate and oral temperature. 
o A pulse oximetry recording (painless recording of the oxygen levels in your blood). 
• 
Check-in days (Days 12 and 24) 
o Perform/review results from coronavirus test.  
o Physical examination. 
o Changes in concomitant medications. 
o Clinical laboratory tests (urine and blood samples) including screening for drugs and 
alcohol and pregnancy testing for all female subjects.  
o Assessment of blood pressure, heart rate, respiratory rate and oral temperature. 
o A pulse oximetry recording (painless recording of the oxygen levels in your blood). 
 
3.4. Check Out (Day 30)  
 
• 
Adverse event assessment and changes in concomitant medications. 
• 
Clinical laboratory tests (urine and blood samples) including pregnancy testing for all female 
subjects.  
• 
Physical examination.  
• 
Assessment of blood pressure, heart rate, respiratory rate and oral temperature.  
• 
An electrocardiogram (ECG), (a painless recording of the electrical activity of your heart). 
• 
A pulse oximetry recording (painless recording of the oxygen levels in your blood). 
• 
Discharge from Spaulding Clinical after all events are completed. 
 
 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 12 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
INFORMATION OBTAINED DURING THE STUDY 
 
Blood Sampling 
 
In Part 1 blood samples will be collected for measurement of levels of study drug at the following times: 
 
• 
Day 1: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 12 and 24 hours after dosing on days 1, 4, 7 and 10 for a total 
of 36 blood collections for determining study drug levels. 
In Part 2 blood samples will be collected for measurement of levels of study drug at the following times: 
 
• 
Day 1: 0 (pre-dose), 3, 4, 5, 6, 8, 9, 12 and 24 hours after dosing on days 1, 4, 5, 13, 16, 17, 25, 
28 and 29 for a total of 81 blood collections for determining study drug levels. 
 
Blood samples will be collected for measurement of proteins and other constituents of your blood at the 
following times: 
• 
Lead-in: Days 1 and 2 – time 0 
• 
Part 1: Days 1, 4, 7, 10 – time 0 
• 
Part 2: Days 1, 4, 5, 13, 16, 17, 25, 28, 29 – time 0  
• 
Total of 15 blood collections for measuring proteins and other constituents of your blood 
 
You will have numerous blood samples drawn during the entire study as shown above, and 2 safety 
laboratory draws in Part 1 or 4 safety laboratory draws in Part 2. The blood samples may be taken by 
individual needle sticks into one of your arm veins, or, if necessary, by an indwelling catheter (a thin 
plastic tube placed in a vein in your arm).  
 
The total amount of blood taken will be approximately 215 ml or 1 cup in Part 1 or 495 ml or 2 cups in 
Part 2.  
 
Some of the samples collected may undergo pharmacogenetic testing. Pharmacogenetics is the study of 
differences in how our bodies respond to or handle drugs. This research will look at genetic differences to 
better understand why people react or respond differently when they get the same drug. Any personal 
health information about you, including any genetic information, will be kept confidential. 
 
Urine Sampling 
 
You will have urine samples collected at screening, Day -1 (Check In), the last study day and on two 
additional days during the study if you are in Part 2. These will be used to screen for either alcohol or 
drugs or for routine safety analysis.  
 
ECG Measurements 
 
Safety ECG measurements will occur at your screening visit, Day -1 (Check In), and the last study day. 
For Part 1, you will have telemetry (continuous, painless recordings of your heart’s rhythm) on each of 
the study treatment days (Days 1, 4, 7, 10) for 24 hours. For Part 2, you will have telemetry on Days 1, 5, 
13, 17, 25, and 29 for 24 hours. There will be periods of time where you will need to lie very still to get 
precise readings of your heart’s rhythm. 
 
Some individuals may develop redness, irritation, or discoloration of the skin at the site of ECG 
electrodes placed on the chest/body. This may develop due to sensitivity to the electrodes or to our skin 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 13 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
preparation procedure. In order to get the quality results we need, it is necessary for us to lightly scrub the 
skin with an abrasive pad to remove any skin impedance such as oil, dead skin cells and lotions. We may 
trace each electrode site with a permanent marker to assure electrodes are placed in the same place on the 
body for each ECG event to maintain quality and consistent results. This tracing may occur as often as 
once a day during confinement. 
 
Pulse Oximetry 
 
For Part 1, you will have continuous pulse oximetry monitoring (continuous, painless monitoring of 
oxygen levels in your blood) on each of the study treatment days (Days 1, 4, 7, 10) for 24 hours. For Part 
2, you will have continuous pulse oximetry monitoring on Days 1, 4, 5, 12, 13, 16, 17, 25, 28 and 29 for 
24 hours. You will also have pulse oximetry quickly checked (not continuous) at screening and on check-
in and check-out days. 
 
Sedation Assessments 
 
You will have sedation assessments during Part 1 and Part 2 of the study prior to the start of each 
Rebreathing procedure. You will be asked to look at a visual scale and describe your level of sedation 
from awake and alert to very sedated. An observer will also be documenting your sedation level prior to 
the start of each rebreathing procedure.  
 
Read Rebreathing 
 
You will have measurements of your breathing done at specified times during the study through a device 
that controls and measures the amount of oxygen and carbon dioxide you receive through a close-fitting 
face mask.  This device in non-invasive.  
 
During the procedure you will be given instructions on how to breathe (either large deep breaths, quicker 
breaths, or normal breaths).  During screening you will be allowed to see the equipment to be used for the 
procedure and you will also be trained on the procedure by study staff so that you know what to expect 
and to see if you can tolerate it.    
 
The Read Rebreathing procedure will be overseen by study staff who have been fully trained on the 
procedure.  You will be overseen by a study doctor for up to 6 hours after dosing with oxycodone or 
midazolam. 
 
Eye Measurements 
 
You will have measurements of your eye done at specified times before and after the Read Rebreathing 
procedure by an automated device that takes a picture of your pupil and measures how it changes from a 
brief light stimulus. This is called pupillometry.  The study team will compare the changes in pupil 
measurements to the changes in breathing measurements.  The device is held up to one of your eyes while 
the other eye is covered and then the same is done with the opposite eye. The recording time on each eye 
takes less than 10 seconds and the procedure is painless.  
 
 
 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 14 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
WHAT ARE YOUR RESTRICTIONS DURING THE STUDY? 
 
You will need to avoid the following while taking part in this study, and most importantly from the time 
of your screening visit until you check in:  
 
 
Restricted Item: 
Duration: 
Alcohol 
48 hours before dose until the end of study visit. 
Caffeine or other xanthine containing products (for 
example, coffee, tea, cola or chocolate) 
48 hours before dose until the end of study visit.  
Grapefruit 
48 hours before dose until the end of study visit. 
Prescription medication 
14 days prior to dose 
NSAIDs (Ibuprofen, Naproxen) 
14 days prior to dose.  
Nicotine containing products 
6 weeks prior to screening until end of study visit.  
You will receive a diet that does not contain any alcohol or caffeine. You must eat all of each meal that is 
served to you and eat at a reasonable pace (within 25 minutes).  
 
You may eat only meals and snacks that are provided to you during the periods of your stay. After 
checking out of the clinic, there are no dietary restrictions aside from what is listed in the table above.  
 
You must be willing to comply with study rules, including the meal schedule (25 minutes to eat), 
attempting to void at specified times (for example, before rebreathing assessment windows), remaining 
quiet, awake, undistracted, motionless, and seated during specified times, and avoiding vigorous exercise 
as directed throughout the duration of the study. Subjects will not be allowed to sleep during any 
rebreathing assessment periods. 
 
You must not have facial hair (be clean shaven) on all days when the Read Rebreathing procedure will be 
performed (including screening). 
 
Due to current precautions being taken for COVID-19, the following restrictions will be in place: 
 
• 
Subjects must always 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, switching to rebreathing 
mask) when instructed by staff.  
• 
Subjects must practice social distancing, which will include having 1 subject per room for 
overnight stays and having common areas closed. Food will be served at subjects’ rooms with 
subjects sitting at their doorway to eat. Subjects will spend most of their time in their rooms 
except for specified times for walking in the halls (with masks). 
• 
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.  
 
If new information becomes available, there could be other precautions that lead to additional restrictions. 
 
ARE THERE RISKS TO YOU IF YOU ARE IN THIS STUDY? 
 
Please be advised that non-pharmacological treatments (such as heating pack, stretches, hydration, etc.) 
are our first line of therapy for mild adverse events. The study doctor will be notified if a subsequent 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 15 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
medication may be needed to treat an adverse event. Following the study plan guidelines, the study doctor 
will assess your adverse event and develop a treatment plan. 
 
Oxycodone and midazolam can reduce breathing and the effect can be increased when they are taken 
together. You will be given low doses that have a minimal effect when you are going about your normal 
activities. As described above, when you undergo the Read Rebreathing procedure the carbon dioxide 
levels that you breathe will be increased and it may make you breathe faster or deeper (which lasts 3-15 
minutes). If you are taking oxycodone, midazolam, and/or one of the other drugs in the study, you may 
not increase your breathing as much. Before, during, and after the procedure, you will be closely 
monitored by study staff, and you will have continuous, painless recordings of your heart’s rhythm and 
oxygen levels in your blood.  If needed, the study staff can administer oxygen and drugs to counteract 
effects from oxycodone and midazolam.    
 
Additional risks are possible side effects of the study drugs and those of taking blood and other study 
procedures: 
 
For Midazolam 
• 
Heart/blood vessel effects – minor variations in blood pressure and heart rate 
• 
Lung effects - non-life-threatening decrease in tidal volume (amount of air moved with each 
breath), decrease in respiratory rate (fewer breaths), apnea (pause in breathing), aspiration 
(inhaling contents into lungs such as saliva), cough 
• 
Abdominal effects – nausea, vomiting, hiccups 
• 
Neurological effects – headache, drowsiness, over sedation (tiredness) 
 
For Oxycodone 
• 
Abdominal effects – nausea, vomiting, constipation 
• 
Neurological effects – headache, insomnia (difficulty sleeping), asthenia (general weakness), 
lightheadedness, dizziness, drowsiness, agitation, anxiety, hallucinations, nightmares, somnolence 
(being sleepy) 
• 
Skin effects - itching 
• 
Less common, but serious adverse events include: 
o Lung effects -- respiratory depression/arrest (decreased/stopped breathing)  
o Heart/blood vessel effects –blood circulatory depression and hypotension (decreased 
blood pressure), cardiac arrest and/or shock (heart, lung, and circulatory changes that 
are potentially life threatening) 
 
For Paroxetine 
• 
Abdominal effects – nausea, diarrhea, vomiting, flatulence (passing gas), loss of appetite, dry 
mouth, constipation 
• 
Neurological effects – weakness, drowsiness, dizziness, anxiety, agitation, asthenia (general 
weakness), yawning, nervousness, tremors (shaking), insomnia (difficulty falling and/or staying 
asleep) 
• 
Eye effects - vision changes 
• 
Sexual effects - erectile dysfunction; delayed ejaculation; vaginal paresthesia (change in 
sensation), itching, and discharge; impotence; decreased libido (sex drive) 
• 
General effects – infection, sweating 
 
 
 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 16 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
For Quetiapine 
• 
Heart/blood vessel effects - postural hypotension (low blood pressure with change in position) 
• 
Abdominal effects – pharyngitis (sore throat), dyspepsia (heartburn), constipation, dry mouth, 
stomach pain, constipation, nausea, vomiting 
• 
Neurological effects – Drowsiness, asthenia (general weakness), lethargy, dizziness 
• 
General effects - weight gain 
• 
Liver effects - ALT increased (increased liver stress) 
 
For Ondansetron 
• 
Heart/blood vessel effects - hypoxia (decrease in oxygen to areas of the body) 
• 
Abdominal effects – diarrhea, constipation 
• 
Neurological effects – headache 
• 
General effects – fever, malaise (feeling of discomfort), fatigue 
• 
Additional, less common side effects include: 
o Allergic reactions – Hypersensitivity reactions including anaphylaxis and 
bronchospasm (serious allergic reactions) 
o Heart/blood vessel effects: QT interval prolongation and Torsade de Pointes (abnormal 
heart rhythm)  
o Serotonin syndrome (usually when prescribed with another serotoninergic medication 
which will not be done in this study – leads to fever, sweating, diarrhea and potential 
complications including seizures and muscle breakdown) 
 
You may be exposed to two additional drugs that are used as ‘rescue’ (reversing) medications. Naloxone 
may be administered if respiratory depression occurs following opioid administration. Additionally, 
flumazenil may be administered if needed to reverse the effects of midazolam. Side effects of these 
medications may include: 
 
For Naloxone 
• 
Heart/blood vessel effects – tachycardia (faster heart rate), hypertension (high blood pressure) 
• 
Lung effects - dyspnea (difficulty taking breaths) 
• 
Abdominal effects – nausea, vomiting, abdominal cramps 
• 
Neurological effects – tremulousness (trembling/shaking), seizures, restlessness, irritability, 
agitation 
• 
General effects – sweating, body aches, fever 
• 
Additional, less common side effects include: 
o Ventricular tachycardia/fibrillation (Serious, abnormal heart rhythms) and pulmonary 
edema (accumulation of fluid in lungs) 
 
For flumazenil 
• 
Heart/blood vessel effects – abnormal heart rhythm  
• 
Abdominal effects – nausea, vomiting 
• 
Neurological effects – agitation, tremors, dizziness, headaches, abnormal sensations, seizures, 
fatigue 
• 
Eye effects – blurred vision 
• 
Ear effects – abnormal hearing such as tinnitus (ringing in the ears) 
• 
General effects - injection site irritation, flushing, excessive sweating  
 
Problems or side effects that are not now known could also occur. You will be given any new information 
that may affect your willingness to start or continue in the study. 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 17 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
 
The tests done at each visit are standard medical tests. The most unpleasant is often having blood samples 
taken. The risks of taking blood may include: 
• 
Fainting 
• 
Pain 
• 
Bruising 
• 
Rarely, there may be a small blood clot or infection at the site of the needle puncture 
 
The blood pressure cuff may also cause discomfort or bruising to the upper arm.  
 
In rare instances where a study nurse, a study doctor, or a study technician, sustains an exposure to your 
blood, tissue or body fluids by needle stick, cut or splash to mucosa or damaged skin, it may be necessary 
to test your blood, tissue, or body fluid sample for certain viral infections including Hepatitis B and C and 
HIV on the sample already available. This is to enable that person to receive appropriate counseling, 
monitoring and treatment if necessary. In this instance, the study doctor or designee will offer you the 
information relevant to your health and advise you on the next steps. Confidentiality of your data will be 
respected at all times according to the state law. 
 
Risks or side effects associated with Read Rebreathing procedure include: 
• 
Heart/blood vessel effects – rapid heart rate, increased blood pressure, chest pain 
• 
Lung effects – difficulty breathing 
• 
Neurological effects – headache, dizziness, confusion 
• 
Abdominal effects – nausea, vomiting 
• 
General effects - muscle twitches, fatigue, sweating 
 
Unknown Risks 
 
As with any drug, it is possible that you could experience an allergic reaction to the study drug used in 
this study. Symptoms of any allergic reaction can include: 
• 
Rash  
• 
Hives  
• 
Itching 
• 
Angioedema:  
o Difficulty breathing 
o Closing of the throat  
o Swelling of the lips, tongue or face 
• 
Rarely, death 
 
If you think you are having a severe allergic reaction, while outside the study center call 9-1-1 and 
seek medical attention immediately. 
 
It is very important that you tell the study doctor and the study staff about any side effects that you might 
experience. 
 
You may experience side effects or discomforts that are not listed on this form. Tell your study doctor or 
study staff immediately if you have any problems. Your safety will be our priority and closely monitored 
throughout the study. 
 
 
 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
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Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
For ECG Monitoring 
 
It is possible to be sensitive to the adhesives used on the electrodes that are applied to your chest when 
having an ECG performed. If this is the case, you could develop a temporary redness, irritation, or 
discoloration of the skin where the electrodes were applied. 
 
HIV and Hepatitis B and C Testing 
 
The risks of HIV and Hepatitis B and C testing include psychological and social risks. A positive test can 
lead to restrictions in freedom of travel to some countries and possible prejudices in job employment, 
insurance eligibility, housing and other forms of discrimination. Positive HIV and Hepatitis B and C test 
results must be reported to health authorities under state law. A positive HIV and/or Hepatitis B or C 
result will exclude you from participation in the study. 
 
Reproductive Risks 
 
The effects of the study drug on human pregnancy and the unborn child (fetus) are unknown. Therefore, it 
is very important that you do everything within your power not to become pregnant, or father a child 
during this study and for 60 days following the last dose. Please ensure that you follow the study birth 
control requirements outlined in the sections regarding information for male and female subjects above. 
 
If you become pregnant during the course of the study, you will be withdrawn from the study 
immediately. Neither Spaulding Clinical Research, LLC. nor the sponsor will be responsible for the cost 
of any obstetric or related care, or for your child's care. Female subjects are agreeing, by signing and 
dating this form, that information about your pregnancy and birth of your child may be collected. The 
information collected will include your health and the health of your unborn child during pregnancy, 
pregnancy outcome (miscarriage, termination, live birth, etc.), and the health of the baby after it is born 
(up to 6 weeks after delivery). 
 
COVID-19 Risks 
 
Despite the extra precautions (e.g. COVID-19 triage at screening/check-in, coronavirus testing, 
mandatory masks for study subjects and staff, social distancing including single-occupancy rooms, extra 
hand washing) that will be in place, there is still a risk of developing COVID-19 just as there is when you 
are not at Spaulding Clinical. Tell your study doctor or study staff about any new symptoms you develop 
during the study.  
 
The U.S. Centers for Disease Control and Prevention (CDC) currently highlights that people with the 
following symptoms may have COVID-19: 
• 
Cough 
• 
Shortness of breath or difficulty breathing 
• 
Fever or chills 
• 
Fatigue 
• 
Muscle or body aches 
• 
Headache 
• 
Sore throat 
• 
New loss of taste or smell 
• 
Congestion or runny nose  
• 
Nausea or vomiting 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 19 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
• 
Diarrhea 
 
It is important to note that COVID-19 can also present with other symptoms and just because you develop 
any of the above symptoms does not mean that you have COVID-19. Your study doctor will evaluate if 
your symptoms warrant further isolation from other study subjects/staff, additional coronavirus testing, 
and/or any treatment. 
 
NEW FINDINGS 
 
Your study doctor will tell you of any information learned during the course of the study that might cause 
you to change your mind about taking part in the study. You may contact the study doctor at any time 
after your participation ends to find out if any new information about this study has become available. 
 
WHAT IS THE ALTERNATIVE TO BEING IN THE STUDY? 
 
Since this is a study involving healthy volunteers, your alternative is not to take part. 
 
WILL YOU BENEFIT FROM TAKING PART IN THE STUDY? 
 
You will not receive direct medical benefit from receiving the study drug. You may benefit by having 
your medical history recorded, undergoing a physical examination, and having blood and urine tests as 
they apply to this research project.  
 
Just by taking part in this research study, you may be helping future patients by providing important 
information about the study drug and by contributing to medical knowledge. 
 
WHO IS PAYING FOR THIS STUDY? 
 
The US Food and Drug Administration is the Sponsor of the study.  
 
The US Food and Drug Administration pays the study doctor to run this study. 
 
The study drug and all tests, procedures and visits required by the study are provided at no cost to you. 
The sponsor, the US Food and Drug Administration pays for them. 
 
Information about this study is confidential. This information belongs to the US Food and Drug 
Administration. We ask that you keep it private. You can discuss this information in private with your 
doctor or family to talk about your healthcare or to decide about taking part in this study. 
 
WILL YOU BE PAID FOR BEING IN THIS STUDY? 
 
Compensation for screening is as follows: 
 
• 
$100.00 if you qualify and take part in a study. $100.00 for your time and inconvenience if you 
do not qualify for a study.  
• 
If the results of the drug and alcohol tests are positive, or if you attempt to falsify your drug 
screen you will not receive any compensation. 
• 
If you screen for the study, qualify and are enrolled, your screening payment will be included in 
your first stipend payment. If you are not accepted into the study your screening payment will be 
processed and mailed within 7 calendar days of study enrollment. 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 20 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
 
Compensation for this study is as follows: 
 
For subjects in the Lead In part of the study that complete the entire study (Day -1 to Day 3), you will 
receive up to $1,700.00 This payment will be made in two separate payments as follows: 
 
• 
$1,200.00 will be paid after all check out procedures have been completed at the end of day 3, 
• 
The remaining $500.00 will be paid after any additional follow up procedures are completed, and 
all results are reviewed. 
 
For subjects in Part 1 that complete the entire study (Day -1 to Day 11), you will receive up to $4,900.00 
This payment will be made in two separate payments as follows: 
 
• 
$4000.00 will be paid after all check out procedures have been completed at the end of day 11, 
• 
The remaining $900.00 will be paid after any additional follow up procedures are completed, and 
all results are reviewed. 
 
For subjects in Part 2 that complete the entire study (Day -1 to Day 30), you will receive up to $8,900.00. 
This payment will be made in three separate payments as follows: 
 
• 
$3,950.00 will be paid after all check out procedures have been completed at the end of day 17. 
• 
$3,450.00 will be paid after all check out procedures have been completed at the end of day 30. 
• 
The remaining $1,500.00 will be paid after any additional follow up procedures are completed, 
and all results are reviewed. 
 
If you withdraw from the study early, you will only be paid for the visits you completed. You will receive 
$100.00 for each full day that you were in-house. 
 
NOTE: You may be required to return to the clinic for repeat blood test or other assessments (for 
example, ECG, physical, vital signs) in between periods or after the final check out. This is considered 
part of the study and no additional compensation is available. Your final payment will not be released 
until all follow up procedures have been completed and accepted by the study doctor. Once follow up 
procedures have been completed and accepted by study doctor, your final payment will be processed and 
mailed within 14 calendar days. 
 
NOTE: If you meet eligibility criteria you may be asked to be an alternate subject. Alternate subjects are 
eligible subjects that are in addition to the number of subjects in the event an enrolled subject drops out 
before their dose can take place or in the event it is not safe for a subject to move forward with dosing. If 
you are selected as an alternate subject and you agree to participate as an alternate subject, you may 
receive up to $250 if you are not needed to dose. If you are needed to replace a subject, you will be paid 
as stated for participating in and completing the study. If you agree to be an alternate subject, you will 
have all of the predose procedures as the enrolled subjects so that if you are needed, you will be ready to 
participate. If you are not needed you will be discharged shortly after completion of the dosing round. 
 
No deductions for any state or federal withholding or any other similar taxes will be made, and you are 
solely responsible for reporting such payments on your state and federal income tax returns.  
 
If you need to stay at Spaulding Clinical Research, LLC. for a longer period of time for safety reasons, 
you will be compensated at a rate proportional to the entire compensation for the study. 
 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 21 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
If you are dismissed from the study for medical reasons OR if the study is temporarily or permanently 
halted, your compensation will be proportional to the time you spend in the study. 
 
If you are dismissed from the study because you have not complied with the instructions of the study 
staff, no compensation is available. Non-compliance includes, but is not limited to, improper conduct, 
taking alcohol and/or any drugs (including recreational drugs), tampering with the study drug, or 
consuming any foods/beverages not allowed in the study. 
Subjects may be reimbursed for travels expenses depending on need and Sponsor approval. 
 
By signing and dating this consent, you expressly agree that you are an Independent Contractor for 
Spaulding Clinical Research, LLC. As an Independent Contractor, you will receive a 1099 form from 
Spaulding Clinical Research, LLC. The 1099 form shall document and report all payments and/or study 
stipends you received as an Independent Contractor for Spaulding Clinical Research, LLC. In addition, 
because you are an Independent Contractor and will be receiving payments and/or study stipends, those 
earnings are subject to wage garnishment. If Spaulding Clinical receives an Earnings Garnishment Notice 
(or similar) from a State or Federal legal entity, we will adhere to that garnishment.  
 
COMPENSATION FOR INJURY 
 
It is important that you follow carefully all the instructions given by the study doctor and his/her study 
staff regarding this study.  
 
If you become ill or are physically injured as a result of participation in this study, please contact the 
study doctor right away at the telephone number listed on page one of this consent form. He/she will treat 
you or refer you for treatment. 
 
Spaulding Clinical Research, LLC. and/or its affiliated institutions has not set aside funds to provide you 
with financial compensation or reimbursement for the cost of care provided to treat a research-related 
injury or for other expenses arising from a research-related injury. You or your insurer will be responsible 
for the payment of any medical treatments for research related injuries or illness. By signing and dating 
this consent form, you are not giving up any legal rights. If this research study is conducted in a negligent 
manner and you are injured as a direct result, you may be able to recover the costs of care and other 
damages from the individuals or organizations responsible for your injury as you still have the right to 
seek compensation for injury related to malpractice, negligence, fault, guilt or blame of those involved in 
the research. 
 
PROTECTING THE PRIVACY OF YOUR HEALTH DATA 
 
Unless required by law, your name will not be disclosed outside the research clinic. Your name will be 
available only to the following people or agencies: the study doctor and study staff; and authorized 
representatives of the study doctor; institutional review board, health authority inspectors, such as the US 
Food & Drug Administration and the European Medicines Agency; the US Food and Drug 
Administration, study monitors and auditors; and authorized Clinical Research Organization 
representatives. The above mentioned individuals will use the personal information collected as part of 
this study, including your medical records (“Study Information”) to check that the study is conducted 
correctly and to ensure the accuracy of the study information. These people are all obligated to maintain 
confidentiality by the nature of their work, or are bound by confidentiality agreements. If required, the 
study doctor may contact your personal doctor to collect additional medical information and your past 
medical history. 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 22 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
 
The study doctor may only share your study information with people whom you have permitted to see it. 
However once your study information is shared as authorized, it may no longer be protected by Federal 
law and may be re-disclosed without your permission. 
 
While participating in this study, the study doctor will replace your name with a special code that 
identifies you. This code, along with your study information, will be used by the study sponsor, the US 
Food and Drug Administration and their representatives, for the study purposes mentioned above and to 
help establish whether the study drug is safe and effective. The US Food and Drug Administration may 
share your coded information, as necessary, with the US Food and Drug Administration affiliates who 
work within the scope of this consent; people and companies who work with the US Food and Drug 
Administration and who work within the scope of this consent; Advarra IRB and Regulatory agencies 
such as the US Food & Drug Administration, the National Health Authorities, and the European 
Medicines Agency. 
 
You should be aware that some countries may not offer the same level of privacy protection as you are 
used to in the country where you live or where this study is conducted. However, the US Food and Drug 
Administration will keep any information it receives to the same standard of confidentiality as far as 
permitted by applicable local law. The US Food and Drug Administration has also entered into 
agreements with third parties working for the US Food and Drug Administration to secure adequate 
protection of your data and samples.  
 
The Study Information will be kept confidential within the limits of the law. This may include research 
performed by researchers outside of the FDA and Spaulding Clinical Research, LLC. This may be done 
by releasing de-identified data (data not linked to you) from the study to a data warehouse (location that 
will store the data) or as part of a publication. Researchers would only have access to de-identified data 
where you cannot be identified. If the results of this study are published or presented in a meeting, you 
will not be named and no one will be able to tell that you were in the study from the publication or 
presentation.  
 
Your participation in this study is voluntary and you may cancel this consent at any time and without any 
reason. If you do so, your participation in the study will end and the study staff will stop collecting 
information from you, however, you will be asked to come back to the site for an end of study visit. Your 
samples will then be destroyed. However, the US Food and Drug Administration will continue to retain 
and use any research results that have already been collected to verify the scientific integrity of the study. 
If you wish to leave the study inform your study doctor. 
 
You have the right to review your Study Information and medical records and request changes to the 
Study Information if it is not correct. However, please note that during the study, access to Study 
Information may be limited if it weakens the integrity of the research. You may have access to the Study 
Information held by the study doctor at the end of the study. 
 
If you have any questions about the collection and use of information about you, or would like to exercise 
rights that you may have regarding this information, you should ask your study doctor.  
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or have 
questions, concerns or complaints about the study, please contact the Investigator at the telephone number 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 23 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
listed on the first page of this consent document. If you seek emergency care, or hospitalization is 
required, alert the treating physician that you are participating in this research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the rights of 
research subjects. If you have any questions about your rights as a research subject, and/or concerns or 
complaints regarding this research study, contact: 
 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• 
or call toll free:  877-992-4724 
• 
or by email:     adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00041368. 
 
IS YOUR PARTICIPATION VOLUNTARY? 
 
Yes, your participation in this study is strictly voluntary. You may refuse to take part in it, or you may 
stop participating at any time, even after signing and dating this informed consent. There will be no 
penalty or loss of benefits to which you are otherwise entitled. However, if you decide to leave the study 
before it ends, the study doctor will need to see you before you are released from the study. 
 
The study doctor, Sponsor, FDA or Advarra may also decide to remove you from the study at any time 
without your consent. The study doctor may choose to take you out of the study because of unexpected or 
serious side effects, or for other scientific, technical, or safety considerations. 
 
Examples why you may be taken out of the study are: 
• 
Staying in the study would be harmful 
• 
You need treatment not allowed in this study 
• 
You failed to follow instructions 
• 
You become pregnant 
• 
The study is cancelled 
• 
Your study treatment arm is stopped 
If your participation ends for any reason, you will return to the study site for the following study 
procedures: 
• 
Physical examination. 
• 
Pregnancy test (if necessary). 
• 
Body weight and body temperature. 
• 
Blood pressure and pulse rate. 
• 
Pulse oximetry. 
• 
ECG. 
• 
Blood draws for hematology and chemistry. 
• 
Blood draws for PK. 
• 
Urine will be collected for urinalysis. 
• 
Adverse events and concomitant medications. 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 24 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
If you should decide to leave the study you should tell the study doctor or study staff. They will make 
sure that proper procedures are followed and a final visit is made for your safety. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time. 
 
STATEMENT OF CONSENT  
 
I have read this form and its contents were explained to me. I agree to be in this research study for the 
purposes listed above. All my questions were answered to my satisfaction. I will receive a signed and 
dated copy of this form for my records. I am not giving up any of my legal rights by signing and dating 
this form.  
 
___________________________________ 
 
____/____/____ 
Signature of Research Subject 
 
Date 
 
___________________________________ 
 
 
 
 
_______________ 
Printed Name of Research Subject 
 
 
 
 
 
Time (24hr) 
 
STATEMENT OF PERSON OBTAINING INFORMED CONSENT  
I have carefully explained to the subject the nature and purpose of the above study. There has been an 
opportunity for the subject to ask questions about this research study. I have been available to answer any 
questions that the subject has about this study. 
 
                                                                                          
 
____/____/____ 
Signature of Person Obtaining Informed Consent 
 
Date 
 
 
___________________________________ 
 
 
 
 
_______________ 
Printed Name of Person Obtaining Informed Consent 
 
 
 
Time (24hr) 
 
 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 25 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
HIPAA Authorization Agreement 
Permission to Review, Use and Release Information about You  
 
If you decide to be in this study, the study doctor and research team will use and share health data about 
you to conduct the study. Health data may include: 
 
• 
Your name. 
• 
Address.  
• 
Phone number. 
• 
Date of birth. 
• 
Medical history. 
• 
Information from your study visits, including all test results.  
 
Health data may come from your study records or from existing records kept by your doctor or other 
health care workers.  
 
For this study, the research team may share health data about you with authorized users. Authorized users 
may include: 
 
• 
Representatives of the US Food and Drug Administration 
• 
Representatives of Spaulding Clinical Research, LLC. 
• 
Representatives of Advarra IRB (an Institutional  Review Board that reviews this study). 
• 
The Food and Drug Administration (FDA) and other US governmental agencies. 
• 
Government agencies to whom certain diseases (like HIV, hepatitis, and STIs) must be reported. 
• 
Governmental agencies of other countries. 
• 
Labs working with the sponsor on this study. 
• 
Other authorized users. 
 
The sponsor and those working for the sponsor may use the health data sent to them: 
 
• 
To see if the study drug works and is safe. 
• 
To compare the study drug to other drugs. 
• 
For other research activities related to the study drug. 
 
Once your health data has been shared with authorized users, it may no longer be protected by federal 
privacy laws.  
 
Your permission to use and share health data about you will not end unless required by state law. If state 
law applies, your permission to use and share health data about you will end in 50 years unless you 
revoke it (take it back) sooner.  
 
You may take back your permission to use and share health data about you at any time by writing to the 
study doctor at the address listed on page one of this consent form. If you do this, you will not be able to 
stay in this study. No new health data that identifies you will be gathered after your written request is 
received. However, health data about you that has already been gathered may still be used and given to 
others as described in this form.  
 
Your right to access your health data in the study records will be suspended during the study to keep from 
changing the study results. When the study is over, you can access your study health data. 


 
U.S. Food and Drug Administration / Protocol Number SCR-009 
Page 26 of 26 
 
 
 
Carlos Sanabria, MD 
Advarra IRB Approved Version 22 Dec 2020 
 
 
If you decide not to sign and date this form, you will not be able to take part in the study. 
 
STATEMENT OF AUTHORIZATION 
 
I have read this form and its contents were explained. My questions have been answered. I voluntarily 
agree to allow study staff to collect, use and share my health data as specified in this form. I will receive a 
signed and dated copy of this form for my records. I am not giving up any of my legal rights by signing 
and dating this form.  
 
 
 
 
 
____/____/____ 
Signature of Research Subject 
 
 
Date 
 
___________________________________ 
 
 
 
 
Printed Name of Research Subject 
 
 
 
 
 
 
STATEMENT OF PERSON OBTAINING AUTHORIZATION 
 
I have carefully explained to the subject the nature and purpose of this form. I have been available to 
answer any questions that the subject has about this form. 
 
                                                                       
 
 
____/____/____ 
Signature of Person Obtaining Authorization 
 
 
Date 
 
___________________________________ 
 
 
 
 
_______________ 
Printed Name of Person Obtaining Informed Consent 
 
 
 
Time (24hr) 
 
 
 
 
 
 
 

SAP_002.pdf: 
Study Title: Clinical study to investigate the effect of the combination of 
psychotropic drugs and an opioid on ventilation 
 
Document Title: Statistical Analysis Plan – Study No. SCR-009 
 
Document Date: 3 August 2021 
 
NCT Number: NCT04310579 


Statistical Analysis Plan 
SCR-009: Clinical study to investigate the effect of the 
combination of psychotropic drugs and an opioid on 
ventilation
Page 1 of 29
Statistical Analysis Plan 
SCR-009: Clinical study to investigate the effect of the 
combination of psychotropic drugs and an opioid on 
ventilation
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
Telephone: 301-796-2226
Email: keith.burkhart@fda.hhs.gov
Project Manager:
Jeffry Florian, PhD
U.S. Food and Drug Administration 
Version of SAP:
3.0
Date of SAP:
3 August 2021
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.


Statistical Analysis Plan 
SCR-009: Clinical study to investigate the effect of the 
combination of psychotropic drugs and an opioid on 
ventilation
Page 2 of 29
Sponsor Signatures Page 
Prepared by
Jeffry Florian, PhD
Associate Director
Division of Applied Regulatory Science
U.S. Food and Drug Administration 
Date
Prepared by
Victoria Gershuny, PhD
Data Scientist
Division of Applied Regulatory Science 
U.S. Food and Drug Administration
Date
Approved by
David Strauss, MD, PhD
Director
Division of Applied Regulatory Science 
U.S. Food and Drug Administration
Date


Statistical Analysis Plan 
SCR-009: Clinical study to investigate the effect of the 
combination of psychotropic drugs and an opioid on 
ventilation
Page 3 of 29
Contents 
Sponsor Signatures Page..........................................................................................................2 
Contents..................................................................................................................................3 
1.
Introduction......................................................................................................................8
2. 
Study Objectives..............................................................................................................8 
2.1 
Primary Objective......................................................................................................8 
2.2 
Secondary Objectives.................................................................................................8 
2.3 
Exploratory Objectives..............................................................................................8 
3. 
Study Overview................................................................................................................8 
3.1 
Study Design.............................................................................................................8 
3.1.1 
Lead-In...............................................................................................................8 
3.1.2 
Part 1..................................................................................................................9 
3.1.3 
Part 2................................................................................................................10 
3.2 
Sample Size.............................................................................................................11 
4. 
Study Endpoints.............................................................................................................12 
4.1 
Primary Endpoints...................................................................................................12 
4.2 
Secondary Endpoints...............................................................................................12 
4.3 
Exploratory Endpoints.............................................................................................13 
5. 
Analysis Populations......................................................................................................14 
6. 
Data Screening and Acceptance......................................................................................15 
6.1 
Handling of Missing or Incomplete Data..................................................................15 
7. 
General Statistical Considerations...................................................................................15 
7.1 
Subject Disposition..................................................................................................15 
7.2 
Demographic and Baseline Characteristics................................................................15 
7.3 
Pharmacodynamic Analyses.....................................................................................15 
7.3.1 
Rebreathing Analyses.......................................................................................15 
7.3.2 
Exploratory Ventilation Measures.....................................................................22 
7.3.3 
Pupillometry Analyses......................................................................................22 
7.3.4 
Sedation Score Analyses...................................................................................23 
7.4 
Pharmacokinetic Analyses.......................................................................................23 


Statistical Analysis Plan 
SCR-009: Clinical study to investigate the effect of the 
combination of psychotropic drugs and an opioid on 
ventilation
Page 4 of 29
7.4.1 
Plasma Pharmacokinetics..................................................................................23 
7.4.2 
PK/PD Analyses...............................................................................................24 
7.5 
Additional Exploratory Analyses..............................................................................25 
7.5.1 
Sex Hormone Analyses.....................................................................................25 
7.5.2 
Genomic Analyses............................................................................................25 
7.6
Safety Analyses.......................................................................................................25
7.6.1 
Adverse Events.................................................................................................25 
7.6.2 
Clinical Laboratory Tests..................................................................................25 
7.6.3 
Vital Sign Measurements ..................................................................................25 
7.6.4
Safety 12-lead Electrocardiograms ....................................................................25
7.6.5 
Pulse Oximetry and Telemetry..........................................................................26 
7.6.6 
Physical Examinations......................................................................................26 
7.6.7 
Other Safety Data .............................................................................................26 
8. 
Data Quality Assurance..................................................................................................26 
9. 
Appendices ....................................................................................................................27 
9.1 
Randomization Schedule..........................................................................................27 
10. References.....................................................................................................................29 


Statistical Analysis Plan 
SCR-009: Clinical study to investigate the effect of the 
combination of psychotropic drugs and an opioid on 
ventilation
Page 5 of 29
Table of Abbreviation
Abbreviation
Definition
AE
adverse event
AUC
area under the concentration-time curve 
CI
confidence interval
CV
coefficient of variation 
Cmax
maximum observed concentration
ECG
electrocardiogram
eCRFs
electronic case report forms
FDA
Food and Drug Administration
IV
intravenous
Kel
elimination rate
pCO2
partial pressure of carbon dioxide 
PETCO2
end-tidal pCO2
PD
pharmacodynamic
PK
pharmacokinetic
SD
standard deviation
SOP
standard operating procedures
TEAE
treatment-emergent adverse event
Tmax
time of maximum concentration (Cmax)
t1/2
terminal half-life
VE55
minute ventilation at 55 mm Hg PETCO2
baseline-adjusted VE55
VRT
Ventilatory recruitment threshold


Statistical Analysis Plan 
SCR-009: Clinical study to investigate the effect of the 
combination of psychotropic drugs and an opioid on 
ventilation
Page 6 of 29
Change Log
Version Section
Changes
2.0
General Number of subjects/cohort 
Language has been added to account for flexibility in enrolling subjects in 
the event that 5 subjects are not eligible to enroll at check-in (e.g., 
“Participants will enter the clinic on a staggered basis in cohorts of 
approximately five…”)
5
Definition of a complete rebreathing procedure
Language has been added to define what is needed for a procedure to be 
included in the planned analysis (e.g., “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 include …”
7.3.1.1
Examples of poor-quality rebreathing procedure results added to the 
protocol
“If the subject’s data do not follow these trends due to a leak in the 
apparatus (e.g., incomplete seal between the mask and subject’s face), 
inaccurate readings from the pneumotach, or due to issues in operator 
recording of the data, the run will not be considered completed and will be 
excluded from subsequent data analysis.”
7.3.1.1
Data regression and outlier handling
Language added to allow for linear regression or additional removal of 
outliers if the initial nonlinear regression fails to converge.
7.3.1.2, 
7.3.1.3, 
7.3.1.4
Missing baseline values
Language has been added to describe how missing subject baseline values 
will be handled throughout the study (e.g., “Part 1:  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 Part 1 population.…”)
General Typographical changes included throughout
3.0
3.1.3
PD assessment timepoints for Part 2
Rebreathing assessment timepoints for Days 1, 4, and 5 of each treatment 
period in part 2 of the study have been updated as per the protocol. 
4.3
Exploratory endpoints clarification
Additional exploratory endpoints were added based on review of other 
published studies. Language has been added to clarify that the exploratory 
endpoints will be calculated for all stages of each rebreathing assessment


Statistical Analysis Plan 
SCR-009: Clinical study to investigate the effect of the 
combination of psychotropic drugs and an opioid on 
ventilation
Page 7 of 29
5
Procedures for blinded review of rebreathing assessments
Language was added outlining that all rebreathing assessments will 
undergo blinded reviewfor assessing completeness of the rebreathing data
including individual physiologic components/measurements.
6
Exclusion of anomalous results for pupillometry assessment
Language has been added to clarify that measurements automatically 
flagged as anomalous by the quantitative pupillometer device will not be 
used in analysis (per device manufacturer and manual recommendations).
7.3.1.1
Identification of Outlying Data Points for Regressions and 
Exploratory Endpoint Calculations
In addition to automated approaches, outlying values for the linear 
regression and exploratory endpoints will be identified during blinded 
review. Any automatically calculated values that do not accurately capture 
the underlying data will be flagged and both blinded reviewers will confer 
to determine if removal of outliers should be performed, and automated 
calculations will be re-run. 
7.3.1.1,
9.2
Regression method for calculating VE55
Review of blinded data revealed that the nonlinear regression method does 
not always converge. Linear regression on the rebreathing data where 
minute ventilation increases linearly as end-tidal pCO2 increases will be 
used as the primary method for determining VE55.
General Typographical changes included throughout


Statistical Analysis Plan 
SCR-009: Clinical study to investigate the effect of the 
combination of psychotropic drugs and an opioid on 
ventilation
Page 8 of 29
1. Introduction 
This document outlines the proposed statistical methods for data analysis of data collection from 
Protocol ‘SCR-009 Clinical study to investigate the effect of the combination of psychotropic 
drugs and an opioid on ventilation’. 
2. Study Objectives
2.1 Primary Objective 
The primary objective is to study whether combining psychotropic drugs (Part 1 – midazolam; 
Part 2 - paroxetine, quetiapine) with an opioid (oxycodone) decreases the ventilatory response to 
hypercapnia compared to an opioid alone.
2.2 Secondary Objectives 
Secondary objectives include the following:
To study whether each psychotropic drug (paroxetine, quetiapine, or midazolam) affects 
the pharmacokinetics (PK) of oxycodone. 
To study whether each drug (oxycodone, paroxetine, quetiapine, or midazolam) decreases 
the ventilatory response to hypercapnia on its own. 
2.3 Exploratory Objectives 
Exploratory objectives include the following:
To study whether there is a direct pharmacodynamic (PD) interaction between each 
psychotropic drug and oxycodone.
To summarize additional PK parameters and PD measurements collected during the 
study.  
3. Study Overview 
The study will be divided into a Lead-in reproducibility assessment phase and two main parts: 
Part 1 and Part 2. Each of the parts is briefly described below.  
3.1 Study Design 
3.1.1 Lead-In 
The Lead-in reproducibility assessment will have up to 10 healthy volunteer participants. Up to 
five participants will undergo the reproducibility assessment, and data analysis will be 
performed. If any changes in study procedures are needed, they will be made at this point. Then, 


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additional participants will be undergoing the reproducibility assessment (up to a total of 10 in 
the Lead-in phase), and data will be analyzed.
For the reproducibility assessment, participants will check-in on Day -1, have PD assessments on 
Day 1 and Day 2 and check-out on Day 3. PD assessments will be performed on Day 1 and 2 at 
0, 2, 3, 5, and 6 h. PD assessments will include a Read rebreathing assessment and pupillometry 
assessments before and after each rebreathing assessment. No dosing or PK sampling is planned 
for the Lead-In.
3.1.2 Part 1 
The study Part 1 will assess the primary, secondary and exploratory endpoints for oxycodone and 
midazolam and will inform oxycodone dose selection for study Part 2. The study will be a 4-
period randomized crossover study with planned dosing of approximately 20 healthy volunteer 
participants with the following design:
Day -1
Day 1
Days 2-3
Day 4
Days 5-6
Day 7
Days 8-9
Day 10
Day 11
Check-In
Period 1
Washout
Period 2
Washout
Period 3
Washout
Period 4
Checkout
The following 4 treatments will be evaluated over the four study periods.  Each subject will be 
randomized to one of four sequences (i.e., ABCD, BDAC, CADB, DCBA). Participants will 
enter the clinic on a staggered basis in cohorts of approximately five (i.e., only approximately 
five participants will undergo dosing, PK assessments, and PD assessments on any given day).
Treatment 
Code
Treatment 
A
Oxycodone + placebo intravenous (IV)
B
Oral placebo + midazolam IV
C
Oxycodone + midazolam IV
D
Oral placebo + placebo IV
Participants will check-in on Day -1 and receive dosing for the four respective periods on Days 
1, 4, 7, and 10. There will be two days of washout between each period. Participants will be 
confined in the study clinic from Day -1 until the morning of Day 11. On dosing days, the 
dosing, PK, and PD assessments will occur at the following time points:
• Dosing times: 0 h oxycodone, 115 min midazolam 
• PK assessment: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 12, 24 h
• PD assessment: 0 (pre-dose), 1, 2, 3, 4, 6, 24 h 
PD assessments will include a Read rebreathing assessment and pupillometry assessments before 
and after each rebreathing assessment.  In addition, pulse oximeter recordings (heart rate and O2
saturation) will be collected over a 24-h period on each treatment day. The 2-hour time point 
(bold/underlined above) is when the primary endpoint will be assessed.


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The total number of participants to be enrolled is approximately 20. Interim analyses will be 
performed after approximately 5 subjects finish and the doses of oxycodone and/or midazolam 
may be adjusted at that time. The oxycodone dose may be increased if the conditional power of 
concluding a decrease in oxycodone from placebo is less than 90%. Likewise, midazolam dose 
may be increased from 0.0375 mg/kg to 0.075 mg/kg if the conditional power of concluding a 
decrease of the combined effect of oxycodone and midazolam compared to oxycodone is less 
than 80%. The decision to dose escalate either drug will also consider clinical evaluations and 
whether stopping criteria was attained in any of the participants (refer to study protocol for full 
list of clinical evaluations and safety stopping criteria). The remaining subjects will complete the 
study at the updated doses in cohorts of approximately five participants each. 
The primary analysis will occur at the 2 h timepoint. If dose adjustments are not needed, the 
analysis will be based on all subjects. Otherwise, the analysis will be limited to the subjects 
administered updated doses of oxycodone and/or midazolam. 
3.1.3 Part 2 
The study Part 2 will assess the primary, secondary and exploratory endpoints for paroxetine,
quetiapine and oxycodone. The study will be a 3-period randomized crossover study with 
planned dosing of approximately 20 healthy volunteer participants. Each treatment period will 
have 5 days of dosing followed by 7 days of washout between periods. 
Day -1
Days 1-5
Days 6
7-11
12
Days 13-17
Days 18
19-23
24
Day 25-29
Day 30
Check-in
Period 1
Checkout
Washout
Check-in
Period 2
Checkout
Washout
Check-in
Period 3
Checkout
The following 3-treatments will be evaluated over the three study periods.  Each subject will be 
randomized to one of treatment six sequences (i.e., GEF, FEG, EGF, GFE, FGE, EFG).  
Participants will enter the clinic on a staggered basis in cohorts of up to approximately five (i.e.,
only approximately five participants will undergo dosing, PK assessments, and PD assessments 
on any given day).
Treatment
Code
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
E
Check-in
Oxycodone + 
Placebo
Placebo
Placebo
Placebo
Oxycodone + 
Placebo
Checkout
F
Check-in
Paroxetine + 
Oxycodone
Paroxetine
Paroxetine
Paroxetine
Paroxetine + 
Oxycodone
Checkout
G
Check-in
Quetiapine + 
Oxycodone
Quetiapine
Quetiapine
Quetiapine
Quetiapine + 
Oxycodone
Checkout


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Participants will check-in on Day -1 and checkout on the morning of Day 6 for each period.  
Dosing of the 3 drugs will be staggered so that time of maximum concentration (Tmax) occurs at 5 
h for all drugs and the 5-h time point will be used for primary analyses. PD and PK assessments 
on Days 1, 4, and 5 of each treatment period will occur at the following time points. Paroxetine 
(or placebo) doses will be administered at time 0 on each day. The first daily dose of quetiapine 
(or placebo) will occur at 3 h on dosing days, which will also include oxycodone on Days 1 and 
5; the second daily dose of quetiapine (or placebo) will be administered at approximately 14 h on 
Days 1 through 4:
PK assessment: 0 (pre-dose), 3, 4, 5, 6, 8, 9, 12, 24 h
PD assessment: 
- Day 1 and 5 of each period: 0 (pre-dose), 4, 5, 6, 8, 24 h
- Day 4 of each period: 0 (pre-dose), 4, 5, 6, 24* h
*Note: The 24h assessment on Day 4 and 0h (pre-dose) assessment on Day 5 will be the same 
assessment and will only be collected once.
PD assessments will include a Read rebreathing assessment and pupillometry assessments before 
and after each rebreathing assessment.  In addition, pulse oximeter recordings (heart rate and O2
saturation) will be collected over a 24-h period on Day 1, 4, and 5.  
Primary assessments for the two psychotropic drugs (paroxetine or quetiapine) combined with 
oxycodone versus oxycodone alone will occur on Days 1 and 5.  Each statistical test is planned 
to be conducted separately and will report on drug effects after a single dose (Day 1) or 
approaching steady state drug concentration (Day 5). The comparisons for paroxetine and 
quetiapine versus placebo will occur on Day 4. 
3.2 Sample Size 
Approximately 50 healthy participants are planned for enrollment. For this study a participant is 
considered enrolled if they completed screening and check-in and have been 
randomized/assigned to one of the study treatments.  Up to ten healthy participants are planned 
for enrollment for the Lead-In Reproducibility Assessment. Approximately 20 healthy 
participants will be enrolled for the study Part 1 and approximately 20 healthy subjects for the 
study Part 2. The planned number of subjects allows for a 10% drop out rate during Part 1 and a 
20% drop out rate during Part 2.
The primary endpoint is a comparison of minute ventilation at the 55 mm Hg end tidal pCO2
(VE55), termed VE55, between two treatments (oxycodone with the concomitant medication 
versus oxycodone alone) at protocol specified timepoints (Part 1: 2 h; Part 2: 5 h on Day 1 and 
Day 5).  Part 1 is powered with consideration to the effect of oxycodone plus midazolam versus 
oxycodone.  After the first cohort has completed, results from both oxycodone versus placebo 
and oxycodone plus midazolam versus oxycodone will be considered in determining whether the 


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oxycodone dose, midazolam dose, or both doses need to be changed. Assuming at least a -4
L/min effect size on VE55 and standard deviation (SD) of 5 L/min, there is greater than 90% 
power at a one-sided significance level. This estimated effect size and variability was determined 
based on publications using 20 mg oxycodone and a similar experimental technique (Van der 
Schrier et al, 2017a; Van der Schrier et al, 2017b) where peak VE55 effects of 12-18 L/min were 
observed with a reported SD of 4 L/min.  Because of uncertainty regarding variability with the 
experimental technique, the effect size at 10 mg oxycodone, and the effect when adding 
midazolam, the current study utilized putative assumptions for effect size and variability from 
these published values.  In the event that dose escalation of either oxycodone or midazolam are 
needed, the study has greater than 80% power at a one-sided significant level assuming these
same effect sizes at the higher dose or doses and at least 12 subjects with the necessary data. Part 
1 is not designed to terminate early for futility or success based on assessment of the first cohort.
Part 2 is powered with consideration to the effect of oxycodone plus concomitant medication 
(quetiapine or paroxetine) versus oxycodone on day 1 and day 5. Assuming a -4 L/min effect 
size on VE55 and SD of 5 L/min, there is greater than 90% power at a one-side significance 
level. The same assumptions and sample size calculations used to design Part 1 were also utilized 
to design Part 2.  Both concomitant medications will be considered as separate tests.  
Comparisons for Day 1 and Day 5 are considered multiple primary endpoints and will have an
adjustment for multiplicity. 
This study does not pre-specify enrollment of replacement subjects due to discontinuations.  In 
the event that higher than anticipated discontinuations are noted, the statistical analysis plan may 
be amended to allow for replacement subjects in specific parts of the study.  
4. Study Endpoints 
4.1 Primary Endpoints
The primary endpoint is a comparison of the minute ventilation at the 55 mm Hg end tidal pCO2
point (VE55) of each psychotropic drug (paroxetine, quetiapine, or midazolam) combined with 
oxycodone vs. oxycodone alone. Part 2 will include a comparison at both Day 1 and Day 5 of 
treatment.
4.2 Secondary Endpoints 
Secondary endpoints are:
Comparison of VE55 of each psychotropic drug (oxycodone, paroxetine, quetiapine, or 
midazolam) on its own compared to placebo. Oxycodone and midazolam will be 
assessed in Part 1, while paroxetine and quetiapine will be assessed in Part 2. For Part 2, 
this is a comparison of study result on Day 4 from each treatment period.


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The maximum observed plasma concentration (Cmax) and area under the plasma 
concentration-time curve (AUC) of oxycodone alone versus oxycodone in combination 
with a psychotropic drug (paroxetine or quetiapine or midazolam).
4.3 Exploratory Endpoints 
Exploratory endpoints are:
The PK/PD relationship for study drugs when administered alone vs. in combination. 
Additional pharmacokinetic and pharmacodynamic measures that will be evaluated 
include:
o
Pharmacokinetics
Tmax
Elimination rate constant (Kel)
Terminal half-life (t1/2)
o
Pharmacodynamics (respiratory and cardiovascular)
Minute ventilation, tidal volume, respiratory rate, PETCO2, oxygen 
saturation and heart rate during each stage of the rebreathing assessment 
Number of apneic events lasting > 10 s (during relaxed baseline breathing
with room air and 100% O2)
Slope of the minute ventilation / end-tidal partial pressure of carbon 
dioxide (PETCO2)regression line
X-axis intercept of the minute ventilation / PETCO2regression line
Intercept of mean baseline minute ventilation during 100% O2 breathing
with the minute ventilation / PETCO2 regression line
o
Pharmacodynamics (pupillary) (before and after rebreathing assessments)
Maximum pupil diameter before constriction
Dynamic pupillary measurements after a light stimulus 
Minimum diameter at peak constriction
Percent change between min/max diameter
Latency of constriction 
Average constriction velocity
Maximum constriction velocity
Dilation velocity after peak constriction
Time to reach 75% recovery of maximum diameter
o
Pharmacodynamics (sedation scores)
Ramsey Sedation Scale 
Visual Analogue Scale


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5. Analysis Populations 
The rebreathing analysis population for Lead-In, Part 1, and Part 2  will include all subjects who 
completed at least one rebreathing assessment on any day or at any timepoint.
For calculating the primary endpoint for Part 1 and Part 2, the rebreathing analysis population 
will be subset to those subjects with data from at least two treatments and rebreathing 
assessments up to the primary PD endpoint timepoint (2 h for Part 1 and 5 h for Part 2) resulting 
in complete data for calculating VE55 at the primary PD endpoint timepoint. In Part 2, a subject 
who discontinues dosing after the primary timepoint on Day 1 but before the primary timepoint 
on Day 5, would be part of the analysis population for the primary endpoint on Day 1 but not for 
Day 5.
Subjects in the rebreathing analysis 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. For 
example, to be included in the primary analysis from Part 1 it is necessary that a subject have a 
completed rebreathing assessment at 2 h for oxycodone with midazolam and oxycodone alone.
A rebreathing assessment will be considered complete if the subject makes it through the entire 
procedure (e.g., subject makes it to the rebreathing stage with sufficient data collected to 
estimate VE55) and if there are no identifiable issues with how the procedure was conducted.
Potential issues with how the procedure was conducted can include, 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), inaccurate readings from the pneumotach (e.g., non-
physiologic baseline minute ventilation readings), or a subject suddenly increasing minute 
ventilation without subsequent increases in minute ventilation as end tidal pCO2 increases
(suggesting stress-associated or other non-CO2 mediated hyperventilation confounding the 
ventilatory response to hypercapnia through [H+] chemoreceptors). Determination of the 
completeness of each rebreathing assessment and its individual components/measurements will 
be performed manually by two members blinded from treatment information (see Section 7.3).
The PK population will include all subjects who receive study drug and have at least 1 estimable
PK parameter after dosing.
The safety population will include all subjects who receive at least 1 dose of any of the study 
drugs.


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6. Data Screening and Acceptance 
6.1 Handling of Missing or Incomplete Data  
The following will be performed:
PK measurements below the quantification limits will be considered equal to zero for all 
analyses.
Missing PK or PD data (e.g., subject discontinued from study; subject could not 
successfully complete rebreathing at a time point) will not be imputed.  
Pupillometry data collected from the PLR®-3000 pupillometer device flagged as being 
anomalous based on device error codes will be excluded from analyses.
7. General Statistical Considerations 
All data will be presented in data listings by part (i.e., Lead-In, Part 1, and Part 2). Data from 
subjects excluded from an analysis population will be presented in the data listings, but not 
included in the calculation of summary statistics.
7.1 Subject Disposition 
The number of subjects who enroll in the study and the number and percentage of subjects who 
complete each assessment by study part 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.
7.2 Demographic and Baseline Characteristics 
Continuous demographic and baseline characteristic variables (age, height, weight, and body 
mass index) will be summarized by study part and by treatment using descriptive statistics 
(number of subjects, mean, SD, median, minimum, and maximum). The number and percentage 
of subjects in each class of categorical demographic and baseline characteristic variables will
also be summarized.
7.3 Pharmacodynamic Analyses 
7.3.1 RebreathingAnalyses 
The primary endpoint is a comparison of the VE55 of each psychotropic drug (paroxetine, 
quetiapine, or midazolam) combined with oxycodone versus oxycodone alone. Part 1 will be a 
comparison of the VE55 between oxycodone with midazolam versus oxycodone alone. Part 2 
will be a comparison of the VE55 comparison of oxycodone with paroxetine or quetiapine versus 
oxycodone alone on both Day 1 and Day 5. In Part 2, these will each be treated as separate 
comparisons as the aim is to determine if there is an interaction with either of the test drugs 
following single-dose (Day 1) or at approximate steady-state drug levels (Day 5).


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7.3.1.1 Analysis of the VE55 and Other Pharmacodynamic Endpoints 
For Lead-In, Part 1, and Part 2, VE55 will be determined through regression of time course data 
collected from the planned rebreathing procedure at each time point. Minute ventilation, end-
tidal pCO2, and other pharmacodynamic measures for secondary and exploratory analyses, will 
be collected following procedural steps outlined in the rebreathing standard operating procedures 
(SOP) document.   
Figure 1 shows a representative time-course result from a rebreathing procedure, with minute 
ventilation, oxygen percentage, and end-tidal pCO2 shown from top to bottom.  Throughout the 
procedure subjects will undergo different steps designed to reduce noise and variability.  
Initially, subjects breathe room air for 5 minutes and relax as much as possible. Around the 5-
minute mark, the valve is turned to allow inhalation of 100% oxygen supply (gas flow of 15
L/min) for 3 min after which they are encouraged to hyperventilate for another 1 min to deplete 
the CO2 stores. During this test, participants breathe from a bag filled with a specified gas 
mixture with an elevated level of CO2 (93%/7% O2/CO2) which stimulatesincreased ventilation. 
As the participants breathe from the gas bag, above a certain level of CO2, participants begin to 
increase their minute ventilation. This point, known as the ventilatory recruitment threshold 
(VRT), is the pressure of CO2 dissolved in the blood (known as pCO2) required to activate the 
respiratory chemoreceptors. After the VRT, ventilation increases linearly in a CO2-dependent 
fashion. 
Each of these steps can be noted on the example figure (note, the example figure has different 
timing than will be used in the experimental procedure for the study).  In this example, relaxation 
with breathing room air was performed for 3-minutes, as evident by O2% ranging between 21-
23%.  From 3 to 7 minutes, the test subject inhaled from 100% O2, and a corresponding jump in 
O2% to near 100% is observed.  At approximately 7 minutes to 9 minutes, the test subject begins 
hyperventilation under 100% O2, and slight decreases in O2% and pCO2with an increase in 
minute ventilation are observed.  Finally, the test subject begins rebreathing from the 93%/7% 
O2/CO2 bag at 9 minutes. After taking deep breaths,pCO2 in the rebreathing circuit and the 
lungs equilibrate and then pCO2increases linearly to approximately 55 mm Hg at the end of 
rebreathing in this subject. During rebreathing, at a certain point an increase in minute 
ventilation is triggered, and both measures increase until completion of the procedure based on 
subject tolerability or until other procedure stopping criteria are reached, such as reaching an
PETCO2 67.5 mmHg; see protocol for full list. If the subject’s data does not follow these trends 
due to a leak in the apparatus (e.g., incomplete seal between the mask and subject’s face),
inaccurate readings from the pneumotach, issues in operator recording of the data, or the subject 
not having a linear increase in minute ventilation as end tidal pCO2 increases prior to reaching 
pCO2 of 55 mm Hg, the run will not be considered completed and will be excluded from 
subsequent data analysis that is dependent on the minute ventilation / PETCO2regression line.


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Figure 1: Sample data from a test subject during relaxation, hyperventilation and rebreathing, 
with minute ventilation, O2 percentage, and pCO2 mm Hg over time during these experimental 
steps.
From these results, minute ventilation and PETCO2 levels over time will be matched. PETCO2will 
be calculated as the product of the % CO2 and the barometric pressure. A linear regression will 
be fit to data from when subjects are rebreathing from the 93%/7% O2/CO2bag (rebreathing 
stage). Because of potential inconsistencies in when the stage transition may have been flagged
by the device operator (pressed while hyperventilation was still ongoing) and as initial breathing 
with the rebreathing circuit may be below the VRT, the first 15 seconds of data from the 
rebreathing stage will be removed when calculating the linear regression. In addition, all other 
pharmacodynamic endpoints listed in Section 4.3 will be automatically calculated.
Because of the potential for outlying data points in the minute ventilation and/or end-tidal pCO2
signal at each individual breath, it is sometimes necessary to exclude outlying data points from 
the regression. Such outlying data points can be introduced by subject postural changes, sighing, 
hiccups, talking, or faulty sensors. In addition, there may be a need to remove additional data at 
the beginning of rebreathing (e.g., nonlinearity before VRT has been reached) or to remove data 
at the end of rebreathing (e.g., nonlinearity as subject approaches or exceeds PETCO255 mmHg).
Outlying values for the linear regression will be identified automatically through evaluation of 
standardized residuals after performing the initial regression (i.e., standardized residuals > 2).
Then, two team members will be provided with time course plots from the full assessment (all 
rebreathing procedure stages with stage transitions marked) and a linear regression using data 


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from the rebreathing stage. The two team members will evaluate the completeness of the 
rebreathing assessment and visually assess the automatically calculated values in comparison to 
the underlying data. Any automatically calculated values that do not accurately capture the 
underlying data will be flagged and both reviewers will confer to determine if removal of 
outliers/noise should be performed, and automated calculations will be re-run. A subject may
have incomplete rebreathing data not supporting calculation of VE55 and other linear regression-
dependent measures at a specific time point, but other endpoint measures would still be used for 
exploratory analyses (or the reverse).
The estimated VE55 from the linear regression will be used for primary endpoint analyses in all 
study parts. All modeling analyses for the regressions will be performed in statistical software.
Figure 2: Sample linear regression between minute ventilation and PETCO2.
This model will be used to predict minute ventilation at pCO2 of 55 mmHg (i.e. VE55). If a
subject does not reach 55 mmHg, the model will be extrapolated to predict the on-treatment 
minute ventilation at 55 mmHg.  Baseline-adjusted VE55 ( VE55) will be calculated for each 
subject at each time point by subtracting on-treatment VE55 from baseline (i.e., time 0 h for Day 
1 and 2 in the Lead-In, time 0 h from each period for Part 1, and time 0 h from Day 1 for Part 2).


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7.3.1.2 Lead-In Reproducibility Analysis 
VE55 data will be summarized by day and time point using descriptive statistics (number of 
subjects, mean, SD, median, minimum, and maximum). Both VE55 and VE55 time course 
profiles will be calculated and plotted for the overall group and individuals. Linear-mixed effect 
modeling will be used to determine between-occasion variability and between-subject variability 
from all Lead-In subject data (example below), where USUBJID and OCC are the subject 
identifier and measurements obtained at different times across the two-day period, respectively.
Fixed effects will include baseline VE55 (i.e., VE55 obtained at 0 h of each day).  If a subject’s 
baseline VE55 for a specific day is not available, then the baseline value from the other 
assessment day will be used.  If neither is available, the subject will be assigned a baseline VE55 
equal to the median of the Lead-In population:
VE55 ~ VE55base + (1|USUBJID/OCC)
7.3.1.3 Part 1 
The primary endpoint (see Section 4.1) for the VE55 analysis in Part 1 will be VE55 at 2 h for 
oxycodone with midazolam compared to oxycodone alone. VE55 will be compared between 
treatments using a linear mixed effects model.  Fixed effects will include treatment, period, 
sequence, and baseline VE55 (i.e., VE55 obtained at 0 h on the treatment day).  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 Part 1 population. All subjects contributing assessments from both treatments will be 
included in the analysis.  To demonstrate an effect of oxycodone with midazolam (‘oxy+mid’) 
compared to oxycodone alone (‘oxy’),it is necessary that the lower bound of the one-sided 95% 
confidence interval (CI) in the least-square mean VE55 difference between treatments < 0 L/min
H0: VE55oxy+mid - VE55oxy
0 L/min
HA: VE55oxy+mid - VE55oxy < 0 L/min
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.
For the secondary endpoint (see Section 4.2), VE55 at 2 h for midazolam or oxycodone 
compared to placebo will be compared using a linear mixed effect model.  A significant increase 
for each treatment compared to be placebo will be concluded if the lower bound of the one-sided 


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CI of the least-square mean VE55 difference between treatment versus placebo <0 L/min. These 
comparisons will be performed separately (i.e., ‘trt’ as ‘oxycodone’ or ‘midazolam’) and will be 
completed regardless of if the primary endpoint passes.
H0: VE55trt - VE55placebo
0 L/min
HA: VE55trt - VE55placebo < 0 L/min
Part 1 has a planned interim analysis after approximately 5 subjects complete.  The purpose of 
this assessment will be to determine the conditional power for the study to succeed based upon 
current assumptions and results obtained from approximately 5 subjects.  The analysis does not 
allow for early termination of the study due to success or futility and will only be used to inform 
decisions about changing the oxycodone and/or the midazolam dosing.  For this determination 
both the treatment effect for oxycodone compared to placebo and oxycodone with midazolam 
compared to oxycodone alone will be considered.  
As oxycodone alone has been evaluated in previous publications, there is an expectation that 
oxycodone 10 mg will have a sufficient effect size to differentiate from placebo.  However, in 
the event that the conditional power <90% for concluding the lower bound of the one-sided 95% 
CI of the least-square mean VE55 difference between oxycodone and placebo < 0 L/min, the 
oxycodone dose may be escalated to 15 mg. Similarly, if the conditional power <80% for 
concluding the lower bound of the one-sided 95% CI of the least-square mean VE55 difference 
between oxycodone and midazolam versus oxycodone alone < 0 L/min, the midazolam dose may 
be escalated to 0.075 mg/kg.  Conditional power calculations will be based on methodology from 
Jennison and Turnbull (2000):
( ) =
(
)
Where k is the interim stage (k=1 for the present case), K is the stage at which the study will 
complete (K=2 for the present case), Zk is the test statistic calculated from the observed data at 
stage k,
is the expected difference under the alternative hypothesis, Ik is the interim information 
level (number_subjects_cohort_1/SDinterim2 for the present case) and IK is the final information 
level (total_N/[interim_N L/min]2 for the present case).  The decision to dose escalate will also 
consider observed safety signals from the initial cohort and will not conclude to increase dose 
solely because conditional power is not achieved.  
If either the oxycodone or midazolam dose is increased, the primary and secondary analyses will 
be based on the remaining subjects in Part 1 and proceed as described above.  If neither the 
oxycodone nor midazolam dose is increased, the planned analyses will use all subjects.  As an 
interim look of the dataset has been performed after the first cohort, the proposed primary and 
secondary analyses will be updated to only reject the null hypothesis if the lower bound of the 


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one-sided 95.1% confidence interval < 0 L/min based on the least square mean difference 
between treatments.  This alpha spending allocation follows O’Brien Fleming approach for two 
planned analyses (i.e., 0.005 for k=1 and 0.0492 for k=2) with the exception that success cannot 
be concluded at the interim analysis.  Testing for normality and homogeneity will proceed as 
described above. 
VE55 data will be summarized by treatment and time point using descriptive statistics (number 
of subjects, mean, SD, median, minimum, and maximum). Both VE55 and VE55 time course 
profiles will be calculated and plotted for the overall treatments and for individuals.
7.3.1.4 Part 2 
The multiple primary endpoints (see Section 4.1) for the VE55 analysis in Part 2 will be VE55 at 
5 h for oxycodone with paroxetine or quetiapine compared to oxycodone alone on Day 1 and 
Day 5.  VE55 will be compared between treatments using a linear mixed effects model.  Fixed 
effects will include treatment, period, sequence, and baseline VE55 (i.e., VE55 obtained at 0 h 
on Day 1 for the treatment period).  Subject will be included as a random effect on the intercept.
Separate linear mixed effects models will be developed for Day 1 and Day 5.  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 Part 2 population. Testing for normality and 
homogeneity will proceed as described above.  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.
All subjects contributing assessments from both treatments necessary for a comparison will be 
included in the analysis.  To demonstrate an effect when oxycodone is combined with paroxetine 
(or quetiapine) compared to oxycodone alone it is necessary that the lower bound of the one-
sided 97.5% CI of the least-square mean VE55 difference between treatments be < 0 L/min.
Each comparison will be performed separately (i.e., ‘trt’ as ‘paroxetine’ or ‘quetiapine’ and ‘day’ 
as ‘Day 1’ or ‘Day 5’).  In all, four separate comparisons will be performed:
H0: VE55oxy+trt/day - VE55oxy/day
0 L/min
HA: VE55oxy+trt/day - VE55oxy/day < 0 L/min
For the secondary endpoint (see Section 4.2), VE55 at 5 h on Day 4 will be compared between 
oxycodone with paroxetine or quetiapine and oxycodone with placebo using a linear mixed 
effect model. Fixed effects will include treatment, period, sequence, and baseline VE55 (i.e., 
VE55 obtained at 0 h on Day 1 of the treatment period).  Subject will be included as a random 
effect on the intercept. Note, that by Day 4, oxycodone has not been administered since Day 1 
and should have washed out.  As such, the comparison on Day 4 is viewed as a comparison of 


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either paroxetine or quetiapine alone versus placebo.  Testing for normality and homogeneity 
will proceed as described above.  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. A
significant increase for each treatment compared to be placebo will be concluded if the lower 
bound of the one-sided CI of the least square means VE55 difference between treatment versus 
placebo <0 L/min.  These comparisons will be performed separately (i.e., ‘trt’ as ‘paroxetine’ or 
‘quetiapine’) and will be completed regardless of if the primary endpoint passes.  
H0: VE55trt - VE55placebo
0 L/min
HA: VE55trt - VE55placebo < 0 L/min
VE55 data will be summarized by treatment, treatment day (Day 1, 4, and 5), and time point 
using descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum). 
Both VE55 and VE55 time course profiles will be calculated and plotted for the overall 
treatments and for individuals.   
7.3.2 Exploratory Ventilation Measures 
Other exploratory respiratory measures will be calculated and summarized from information 
collected during planned rebreathing procedures (see Section 4.3).  Data collected during the 
procedure will be used to calculate the slope of the minute ventilation / PETCO2 regression line
(output from regression).  Data from the initial relaxation/resting portions of the procedure will 
be used to calculate ventilation, tidal volume and PETCO2.  All measures will be summary by 
day, treatment, and time, as appropriate for Lead-In, Part 1, and Part 2, respectively, using 
descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum). Time 
course profiles for all measures will be calculated and plotted.   
Apneic events lasting > 10 seconds will be determined using data collected during the relaxation 
and preparation portion of the rebreathing procedure (i.e., all recorded data prior to 
hyperventilation on 100% O2).  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 (number of subjects, number of events) by study part, 
treatment, day, and time, as appropriate.
7.3.3 Pupillometry Analyses 
Maximum pupil diameter before constriction and dynamic pupillary measurements after a light 
stimulus will be measured during relaxation and after each rebreathing assessment. This will 
include measurements before and after the rebreathing assessment and from the left and right 
eye. These exploratory parameters (see Section 4.3) will be summarized using descriptive 
statistics (number of subjects, mean, SD, median, minimum, and maximum), and time courses 
summaries of each pupillary measurement will be generated for all treatment groups.  Pupillary 
changes will be compared to baseline measurements (Day 1, 0 h for Part 1 and Part 2; Day 1 or 


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Day 2, 0 h for Lead-In) 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.
7.3.4 Sedation Score 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 rebreathing procedure in Part 1 and Part 2.  
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 sedated the subject 
is during the study.  These exploratory parameters will be summarized using descriptive 
statistics, and time courses summaries of both scores will be generated for all treatments from 
Part 1, and Part 2 (Day 1, 4, and 5). 
7.4 Pharmacokinetic Analyses 
7.4.1 Plasma Pharmacokinetics 
PK parameters will be calculated for the different drugs and metabolites and study days based on 
data collected from the time of drug administration to the 24-h sample on the specified day.  Cmax
and AUC (i.e. AUC0-24 for oxycodone, Part 1; AUC3-24,Day1 and AUC3-24,Day5 for oxycodone, Part 
2) will be computed for oxycodone on the specified days (i.e., Day 1 for Part 1 and Day 1 and 5 
for Part 2) as part of the secondary endpoints for this study (see Section 4.2). AUC and Cmax will 
be calculated for midazolam (Part 1, Day 1) and quetiapine and paroxetine (Part 2, Day 1, 4, and 
5) and relevant metabolites as exploratory PK parameters(see Section 4.3).
Additionally, the following exploratory PK parameters will be determined for oxycodone, 
midazolam, quetiapine, paroxetine, and metabolites on each specified day:
Tmax (Part 1 and Part 2 Day 1, 4, and 5)
Elimination rate constant (Kel) (Part 1 and Part 2 Day 1 [oxycodone and metabolites only] 
and Day 5)
Terminal half-life (t1/2) (Part 1 and Part 2 Day 1 [oxycodone and metabolites only] and 
Day 5)
The PK parameters will be analyzed using noncompartmental methods based on actual sampling 
times. All parameters will be calculated using R software and the PKNCA package. Serum 
concentrations below the limits of quantification will be set to zero for the purpose of this 
analysis (see Section 6). Kel and t1/2 for each analyte and subject will only be included if the 
subject has 3 or more concentration values on the terminal portion of the pharmacokinetic curve 


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and the linear regression of the log-concentration time curve has an adjusted coefficient of 
determination (R2) greater than 0.80. 
In Part 1, oxycodone Cmax and AUC will be log-transformed and the values from oxycodone 
alone versus oxycodone with midazolam will be compared using a linear mixed effects model 
(i.e., treatment as fixed effects and subject as random effects) to determine if oxycodone 
exposures differ between the two treatments.  The geometric mean ratio will be determined and 
no difference in exposure will be concluded if the two-sided 90% confidence interval includes 1.  
Similar comparisons will be performed between oxycodone with quetiapine or with paroxetine 
and oxycodone alone based on Cmax and AUC from Day 1 and Day 5 (separate comparisons) in 
Part 2.  
The PK parameters Cmax, AUCx-24, Tmax, and Kel will be summarized using descriptive statistics 
(number of subjects, mean, SD, coefficient of variation [CV], median, minimum, and maximum) 
on Day 1 for Part 1 and Day 1, 4, and 5 for Part 2 for each active drug and metabolites (note:  ‘x’ 
for AUCx-24 will depend on when the drug is administered and will be 0 h for oxycodone in Part 
1, 1.9 h for midazolam in Part 1, 0 h for paroxetine in Part 2, and 3 h for quetiapine and 
oxycodone in Part 2). Mean and individual concentration-time profiles will be presented in 
graphs.
7.4.2 PK/PD Analyses 
A nonlinear-mixed effect PK/PD model will be developed for VE55 versus time for all 
treatments (see Section 4.3). The model will be employed using NONMEM modeling software, 
version 7.3. 
The PK/PD analysis will be sequential, first running PK models for each of the four drugs 
evaluated in this study. These will be one- or two compartment models with linear absorption, as 
appropriate. The PK modeling will not include covariate exploration but will attempt to model 
active metabolites for oxycodone and quetiapine that are analyzed. As there is extensive 
experience with all of these compounds, models from the literature will serve as starting points 
for model evaluation.
The PD modeling will use predictions from the PK modeling as input. Different model structures 
will be evaluated, including an effect compartment coupled to an indirect response model or a 
modified Bateman function. No covariate exploration will be performed for the PD model, 
though stand-alone interactions between drug effects will be evaluated.  A separate modeling 
analysis plan will be developed for the planned analyses.


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7.5 Additional Exploratory Analyses
7.5.1 Sex Hormone Analyses 
Estrogen and progesterone levels will be collected at the start of all study days with a rebreathing 
assessment in the Lead-In, Part 1, and Part 2.  These parameters will be summarized using 
descriptive statistics (number of subjects, mean, SD, minimum, median, and maximum) and may 
be used to explore variation in ventilation and the response to study drugs across the menstrual 
cycle. Additional details regarding the statistical methods for these analyses will be described in 
a separate plan.
7.5.2 Genomic Analyses 
Gene (genotype) variances may be explored that may contribute to the PK or PD of the study 
drugs. Additional details regarding the statistical methods for these analyses will be described in a 
separate plan.
7.6 Safety Analyses 
7.6.1 Adverse Events 
All adverse events (AEs) will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities. The incidence of treatment-emergent adverse event (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.
7.6.2 Clinical Laboratory Tests
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.
7.6.3 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.
7.6.4 Safety 12-lead Electrocardiograms
Safety 12-lead ECG data will be summarized using descriptive statistics (number of subjects, 
mean, SD, minimum, median, and maximum) by treatment and time point.


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7.6.5 Pulse Oximetry and Telemetry 
Continuous telemetry monitoring will be performed on treatment days for Part 1 and on Days 1 
and 5 in Part 2.  Events requiring intervention from the staff or discontinuation from the study 
will be recorded in appropriate logs.
Oxygen saturation measurements obtained from 24-h pulse oximeters recordings will be used to 
plot time course profiles of oxygen saturation for treatments from Lead-In (Day 1 and 2), Part 1, 
and Part 2 (Day 1, 4, and 5).      
7.6.6 Physical Examinations 
Physical examination findings will be presented in a data listing, and abnormal physical 
examination findings will be recorded as AEs.
7.6.7 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.
8. Data Quality Assurance 
Completed electronic case report forms (eCRFs) are required for each subject randomly assigned 
to the study drug. 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. 


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9. Appendices 
9.1 Randomization Schedule 
The study will consist of three separate sections.  The first (i.e., Lead-In) will enroll up to10
subjects and has no planned randomization.  All subjects will participate in the same set of 
procedures over two days. No replacement subjects are planned for the Lead-In.
Part 1 is a 4-period, double-blind, crossover study where subjects will be enrolled in cohorts of 
approximately 5.  Subjects will be randomized to one of four sequences (i.e., ABCD, BDAC, 
CADB, DCBA) where treatment codes and interventions are summarized in the table below.  
Subjects will be randomized in blocks of 4.  The study plans for 1:1 enrollment of males and 
females, but the randomization will not account for sex and treatment sequence interactions.
Part 2 is a 3-period, double-blind, crossover study where subjects will be enrolled in cohorts of 
approximately 5.  Subjects will be randomized to one of six sequences (i.e., GEF, FEG, EGF, 
GFE, FGE, EFG) where treatment codes and interventions are summarized in the table below.  
Subjects will be randomized in blocks of 6.  The study plans for 1:1 enrollment of males and 
females, but the randomization will not account for sex and treatment sequence interactions.  
The project biostatistician created the specifications for generating the randomization schedule as 
described above. A dummy randomization schedule generated in R (version 3.6.3 or later).  The 
project biostatistician will transfer 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.
The randomization biostatistician will be responsible for generating the final randomization 
schedule. The output will be sent only to designated unblinded recipients.
Table 1:  Treatment Codes and Treatment Names for Part 1 and Part 2 of SCR-009
SCR-009 Part
Treatment Code
Treatment Name
Part 1
A
Oxycodone/placebo
Part 1
B
Placebo/midazolam
Part 1
C
Oxycodone/midazolam
Part 1
D
Placebo/placebo
Part 2
E
Oxycodone/placebo
Part 2
F
Oxycodone/paroxetine
Part 2
G
Oxycodone/quetiapine


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10.
References 
Jennison, C, and Turnbull, BW. (2000). Group sequential methods with applications to clinical 
trials. Chapman & Hall/CRC. New York.
O’Brien, PC and Fleming TR (1979). A multiple testing procedure for clinical trials. Biometrics, 
35(3), 549-556.
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.
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.

Prot_001.pdf: 
Study Title: Clinical study to investigate the effect of the combination of 
psychotropic drugs and an opioid on ventilation 
 
Document Title: Clinical Study Protocol – Study No. SCR-009 
 
Document Date: 3 December 2020 
 
NCT Number: NCT04310579