A Phase 2, Randomized, Open Label, Multiple-Dose, Comparator, Parallel-Group, Safety and Tolerance Study of Buprenorphine Sublingual Spray (0.5 mg TID) Versus Standard of Care Post-Operative Narcotic Therapy for the Treatment of Post-Operative Pain
Phase: PHASE2
Conditions: Pain, Postoperative
Sponsor: INSYS Therapeutics Inc

Insys Development Company, Inc. 
Protocol Number INS005-17-111 
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Clinical Trial Protocol 
A Phase 2, Randomized, Open Label, Multiple-Dose, Comparator,  
Parallel-Group, Safety and Tolerance Study of Buprenorphine Sublingual 
Spray (0.5 mg TID) versus Standard of Care Post-Operative Narcotic 
Therapy for the Treatment of Post-Operative Pain 
Confidentiality Statement 
This study will be performed in compliance with Good Clinical Practices (GCP) and applicable 
regulatory requirements. The confidential information in this document is provided to you as an 
investigator, potential investigator or consultant for review by you, your staff and applicable 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB). It is understood that 
the information will not be disclosed to others without written authorization from Insys 
Development Company, Inc., except to the extent necessary to obtain informed consent from 
those persons to whom the drug may be administered. 
Protocol Number: INS005-17-111 / NCT03254459 
Final Protocol Date: 02 Aug 2017 
Protocol Version: FINAL 1.0 
Investigational Product: Buprenorphine Sublingual Spray 
IND Number: 120,673 
Sponsor: Insys Development Company, Inc. 
1333 South Spectrum Blvd, Suite 100 
Chandler, AZ 85286 
Medical Monitor: 
, MD / 
, MD 

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B. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company:  Insys Development Company, Inc. 
Name of Investigational Product: Buprenorphine Sublingual Spray 
Name of Active Ingredient: Buprenorphine 
Title of Study: A Phase 2, Randomized, Open Label, Multiple-Dose, Comparator, Parallel-
Group, Safety and Tolerance Study of Buprenorphine Sublingual Spray (0.5 mg TID) versus 
Standard of Care Post-Operative Narcotic Therapy for the Treatment of Post-Operative Pain 
Study center(s): 2 
Studied period (years):  
Estimated date first patient enrolled: Q3 2017 
Estimated date last patient completed: Q4 2017 
Phase of development:  
Phase 2 
Objectives:  
Primary: 
To evaluate the safety and tolerability based on the incidence of adverse experiences of 
Buprenorphine Sublingual Spray (0.5 mg three times daily [TID]) compared with standard 
post-operative narcotic therapy in subjects with postoperative pain. Standard post-operative 
narcotic therapy is defined as Morphine Intravenous Injection (IV) (4 mg TID) followed by 
Oxycodone Hydrochloride Tablet (10 mg TID). 
Methodology:  
This is a Phase 2, randomized (stratified according to surgery and postoperative nausea and 
vomiting risk factors), open label, multiple-dose, comparator controlled, parallel-group, study 
to evaluate the safety and tolerability of Buprenorphine Sublingual Spray (0.5 mg TID) 
versus standard postoperative narcotic therapy in subjects with postoperative pain. Standard 
postoperative narcotic therapy is defined as Morphine IV (4 mg TID) for 24 hours followed 
by Oxycodone Hydrochloride Tablet (10 mg TID). 
The study will comprise four periods: Screening Period (Days -28 to -1), Surgical Period 
(Day 1), Treatment Period (Days 1 to 4 Inpatient / Days 4 to 7 Outpatient), and Follow-up 
Period (Day 8, +2 day window). 
Subjects will be admitted to the study site on the morning of the scheduled surgery (Day 1), 
will remain at the study site until Postoperative Day 4 (a total of 3 nights at the study site) 
then be evaluated to participate in the outpatient setting and meet criteria in order to proceed 
to the outpatient treatment period Days 4 to 7, and will return to the clinic for the Follow-up 
Visit on Day 8 (+2 day window). 
Screening Period: Subjects who meet all inclusion and no exclusion criteria will be eligible 
for enrollment. After providing written Informed Consent, subjects will undergo study 
specific screening procedures, including a review of inclusion and exclusion, demographics, 
medical history, concomitant medication use, assessment of postoperative nausea and 

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vomiting (PONV) risk factors, physical and oral cavity examination, baseline laboratory 
testing, alcohol breath test, urine drug screening, HIV and hepatitis screening, 12-lead 
electrocardiogram (ECG), and pregnancy testing. Eligible subjects will complete all 
screening procedures within 28 days before the surgery (Days -28 to -1). 
Surgical Period: On Day 1, anesthesia will be established using standardized techniques, as 
appropriate, for each surgical procedure. The surgical procedures will be bunionectomy, 
breast augmentation, and abdominoplasty. For nausea prophylaxis, all subjects will receive a 
uniform standard of care regimen which includes the following: 10 mg of dexamethasone at 
induction and 8 mg of ondansetron near the end of surgery. Vitals, pulse oximetry, and ECG 
measurements will be taken. Concomitant medications and Adverse Events will be recorded. 
Post surgury and prior to randomization, subjects may be treated with intravenous morphine 
and or fentanyl for post-surgical analgesia (dose and frequency per the discretion of the 
investigator). 
Treatment Period:  Within 4 hours after surgery, subjects who meet the post-surgical 
eligibility requirements will be randomized to treatment (see Post-surgical Eligibility 
Requirements). 
After meeting post-surgical eligibility requirements and subsequently being randomized to 
treatment, subjects may receive their first dose of investigational drug any time between 0-4 
hours after surgery. The first dose does not need to be immediately administered after 
meeting post-surgical eligibility requirements. 
During the Treatment Period, approximately 100 subjects will be randomly assigned to 1 of 2 
treatment groups: Buprenorphine Sublingual Spray 0.5 mg TID, or standard of care 
postoperative narcotic therapy. Randomization will be stratified according to surgical 
procedure and baseline PONV risk factors. Vitals, pulse oximetry, and ECG measurements 
will be taken. Concomitant medications and Adverse Events will be recorded.  
Pulse oximetry will be monitored continuously after surgery as a safety measure. An 
electrocardiogram (ECG) will be conducted after surgery but before the first dose of the 
study drug and serve as a baseline for comparison to subsequent tracings. The time of 
administration of the first dose of study drug will be defined as Time 0. During confinement, 
study drug will be administered by site staff to ensure appropriate dosing of study 
medication. Subjects should not have anything orally except room-temperature water within 
15 minutes of each dose. The inpatient Treatment Period will continue through 72 hours after 
Time 0. Additional ECGs will be performed at 90 minutes, 12 hours, 24 hours, 48 hours and 
72 hours after Time 0. 
Rescue for inadequate analgesic response:  
During confinement to the study center during the first 72 hours (Days 1-4), subjects 
requiring rescue medication for pain will be provided with acetaminophen 1000 mg every six 
hours and/or ketorolac 30 mg every six hours, as needed. On outpatient days 4-7, ketorolac 
will not be available to study subjects (because it is intravenous).  Therefore, subjects will be 

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provided with acetaminophen, and will be advised to take acetaminophen 1000 mg every six 
hours as needed for rescue analgesia.   
Rescue for postoperative nausea: During confinement to the study center during the first 72 
hours (Day 1-4), subjects requiring rescue medication for nausea will be provided with 
Zofran 4 mg IV per the discretion of the clinician. On outpatient days 4-7 subjects will be 
provided Zofran ODT (oral dissolvable tablet) to be taken as needed for postoperative 
nausea.  
Subjects whose pain or nausea cannot be adequately managed (in the investigator’s opinion) 
by a combination of study drug and rescue medication or who develop unacceptable side 
effects during the study will be discontinued from further study participation. Their pain or 
nausea will be managed according to usual standard of care at the investigator’s discretion. 
Site staff will train subjects on how to self-administer study drug. Investigators will 
determine if patients are able to proceed with the outpatient treatment period. Before 
discharge from the study site on Day 4, site personnel will dispense rescue medication and 
will train subjects on how to administer the study drug, educate patients on the signs and 
symptoms of Adverse Events, and observe subjects self-administer medication. After 
discharge, study drug will be administered by subjects at home according to the directions 
provided by study staff. Study personnel will dispense outpatient diary, study drug, rescue 
pain and nausea medication. Subjects will also be instructed to return the outpatient diary to 
study personnel at the Follow up Visit 8 + 2 days after surgery.                  
Follow-up Visit on Day 8 (+2 day window): Subjects will be instructed to return any 
unused outpatient study drug to study personnel. Vitals, pulse oximetry, and ECG will be 
measured. Concomitant medications and Adverse Events will be recorded. 
Subject outpatient diary will be collected and reviewed by study staff. 
Number of patients (planned):  Approximately 100 subjects (50 subjects assigned to 
Buprenorphine Sublingual Spray and 50 subjects assigned to standard post-operative pain 
management) will be enrolled. 
 
Diagnosis and main criteria for inclusion:  
Subjects must meet all of the following criteria and post-surgical eligibility criteria to be 
considered eligible to participate in the study. 
Criteria for Inclusion: 
1. Is able to speak and understand the language in which the study is being conducted, is 
able to understand and comply with the procedures and study requirements, and has 
voluntarily signed and dated an informed consent form approved by an Institutional 
Review Board before the conduct of any study procedure. 
2. Is a male or female ≥18 and ≤65 years of age. 
3. Scheduled for elective bunionectomy, breast augmentation (in women only), or 
abdominoplasty. 

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4. Is classified using the American Society of Anesthesiologists Physical Status 
Classification System as P1 to P2. 
5. If female, is either not of childbearing potential (defined as postmenopausal for at 
least 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy]) or practicing one of the following medically acceptable methods of 
birth control: 
a. Hormonal methods such as oral, implantable, injectable, vaginal ring, or 
transdermal contraceptives for a minimum of 1 full cycle (based on the 
subject’s usual menstrual cycle period) before study drug administration; 
b. Total abstinence from sexual intercourse since the last menses before study 
drug administration; 
c. Intrauterine device; OR 
d. Double-barrier method (condoms, sponge, or diaphragm with spermicidal 
jellies or cream). 
6. Has a body weight ≥45 kg and a body mass index (BMI) ≤40 kg/m2. 
7. Is willing and able to comply with study requirements (including diet, alcohol, and 
smoking restrictions), complete evaluations and diary, remain at the study site for ≥72 
hours, and return for follow up Day 8 + 2 days after surgery. 
 
Criteria for exclusion:  
Subjects who meet any of the following criteria will be excluded from participating in the 
study. 
1. Has a known history of allergic reaction or clinically significant intolerance to 
acetaminophen, aspirin, opioids, or any nonsteroidal anti-inflammatory drugs 
(NSAIDs); history of NSAID-induced bronchospasm (subjects with the triad of 
asthma, nasal polyps, and chronic rhinitis are at greater risk for bronchospasm and 
should be considered carefully); or hypersensitivity, allergy, or significant reaction to 
sulfa (including sulfonamide) medicines, ingredients of the study drug, or any other 
drugs used in the study, including anesthetics and antibiotics that may be required on 
the day of surgery. 
2. Has experienced any surgical complications or other issues that, in the investigator’s opinion, 
could compromise the subject’s safety if he or she continues into randomized treatment or 
could confound the results of the study. 
3. Has a known or suspected history of alcoholism or drug abuse or misuse within 2 
years of Screening or evidence of opioid tolerance or physical dependence before 
dosing with the study drug. 
4. Has any clinically significant unstable cardiac, respiratory, neurological, 
immunological, hematological, or renal disease, or any other condition that, in the 
investigator’s opinion, could compromise the subject’s welfare, ability to 
communicate with the study staff, or otherwise contraindicate study participation. 
5. Has long QT Syndrome, a family history of long QT Syndrome, or is taking Class IA 
or Class III antiarrhythmic medications. 

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6. Has a history or current diagnosis of a significant psychiatric disorder that, in the 
investigator’s opinion, would affect the subject’s ability to comply with the study 
requirements. 
7. Has tested positive either on the urine drug screen or on the alcohol Breathalyzer test. 
Subjects who test positive at Screening only and can produce a prescription in their 
name from their physician for the medication producing the positive test may be 
considered for study enrollment at the investigator’s discretion. However, they must 
test negative on the day of the surgery. 
8. Has a history of a clinically significant (in the investigator’s opinion) gastrointestinal 
(GI) event within 6 months before Screening or has any history of peptic or gastric 
ulcers or GI bleeding. 
9. Has an active infection, mucositis, cold sores, viral lesions, local irritation, or in the 
investigator’s opinion has significant periodontal disease of the oral cavity. In 
addition, recent (within 1 year) piercing of the tongue or anywhere in the oral cavity. 
10. Has a surgical or medical condition of the GI or renal system that, in the 
investigator’s opinion, might significantly alter the absorption, distribution, or 
excretion of any drug substance. 
11. Is considered by the investigator, for any reason (including, but not limited to, the 
risks described as precautions, warnings, and contraindications in the current version 
of the investigator’s brochure for Buprenorphine Sublingual Spray), to be an 
unsuitable candidate to receive the study drug. 
12. Is receiving systemic chemotherapy, has an active malignancy of any type, or has 
been diagnosed with cancer within 5 years before Screening (excluding squamous or 
basal cell carcinoma of the skin). 
13. Is currently receiving anticoagulants (eg, heparin or warfarin). Low-dose aspirin for 
cardioprotection is allowed. 
14. Has used drugs known to be a strong inhibitor or inducer of CYP3A4 within 1 weeks 
before surgery. 
15. Has received a course of systemic corticosteroids (either oral or parenteral) within 1 
months before Screening (inhaled nasal steroids and topical corticosteroids are 
allowed). 
16. Has a history of chronic use (defined as daily use for >2 weeks) of NSAIDs, opiates, 
or glucocorticoids (except inhaled nasal steroids and topical corticosteroids) within 1 
month before study drug administration. Aspirin at a daily dose of ≤325 mg is 
allowed for cardiovascular prophylaxis if the subject has been on a stable dose 
regimen for ≥30 days before Screening and has not experienced any relevant medical 
problem.  
17. Has a significant renal or hepatic disease, as indicated by clinical laboratory 
assessment (results ≥3 × the upper limit of normal [ULN] for any liver function test, 
including aspartate aminotransferase, alanine aminotransferase, and lactate 
dehydrogenase, or creatinine ≥1.5 × ULN). 
18. Has any clinically significant laboratory or 12-lead electrocardiogram finding at 
Screening that in the investigator’s opinion contraindicates study participation. 

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19. Has screening systolic blood pressure ≥160 mmHg and diastolic blood pressure >100 
mmHg (may be repeated one additional time after 5 minutes rest to verify). The 
investigator may, at his discretion, choose to exclude subjects with hypertensive 
levels lower than these if he deems it in the best interest of the subject. 
20. Has a history of sleep apnea or other obstructive airway disease. 
21. Has a history of nausea and vomiting with buprenorphine products. 
22. Has significant difficulties swallowing capsules or is unable to tolerate oral 
medication. 
23. Previously participated in another clinical study of Buprenorphine Sublingual Spray 
or received any investigational drug or device or investigational therapy within 30 
days before Screening. 
Post-surgical eligibility requirements:  
The subject will be assessed for the following postoperative eligibility criteria. 
1. Subjects must be awake, breathing spontaneously without significant respiratory 
depression. 
2. Subjects must not be actively vomiting or complaining of severe nausea. 
3. Subjects must be able to answer questions and follow commands.  
4. Subjects must not have surgical complications that could compromise safety of the 
subject or confound the results of the study.   
Investigational product, dosage and mode of administration:  
Buprenorphine Sublingual Spray, 0.5 mg manufactured for and supplied by Insys 
Development Company, Inc. 
Duration of treatment:  
The estimated duration of the study for each subject is approximately 5 weeks, which 
includes a Screening Period (Days -28 to -1), a Surgical Period (Day 1), a Treatment Period 
(Inpatient Days 1 to 4 / Outpatient Days 4 to 7), and a post-treatment Follow up Visit at the 
clinic (Day 8, + 2 day window).  
Reference therapy, dosage and mode of administration:  
Morphine IV, 4 mg TID for 24 hrs, followed by Oxycodone Hydrochloride Tablet, 10 mg 
TID 

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Criteria for safety evaluation: 
Primary Safety Endpoint 
 Incidence of Treatment Emergent Adverse Events (TEAEs) 
 
Secondary Safety Endpoints:   
 Proportion of subjects using rescue medication for nausea 
 Time to first use of rescue medication for nausea following each dose of the 
investigational product (IP) 
 Total use of rescue medication for nausea over 0 to 8 hours, 0 to 24 hours, over 0 to 
48 hours, over 0-72 hours and 0-7 days 
 Pulse oximetry recorded prior to study drug administration 
 ECGs at 90 minutes, 12, 24, 48 and 72 hours 
 Oral Examinations 
 
Statistical methods: 
Sample Size Determination 
No formal sample size estimate has been completed.  However, a sample size of 50 subjects 
per treatment group is considered sufficient to demonstrate that the incidence of nausea and 
vomiting associated with buprenorphine is consistent with that of standard post-operative 
narcotic therapy. 
Analysis Populations 
Statistical analysis will be done on the safety population, which will include all subjects who 
are treated with the study drug. The safety population is the population for all safety 
assessments. 
Safety Analyses 
Data listings will be provided for protocol specified safety data. The Medical Dictionary for 
Regulatory Activities (MedDRA; Version 19.0 or higher) will be used to classify all AEs 
with respect to system organ class and preferred term. Adverse event summaries will include 
only TEAEs, which will be summarized for each treatment group. 
 
Statistical analyses will be performed using SAS® 
Clinical laboratory and vital signs results and changes from baseline will be summarized at 
each time point. 
Incidence of abnormal ECG and PE findings will be summarized by treatment group.  Any 
clinically significant findings will be recorded as AEs. 
 
 
 
 

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C. 
TABLE OF CONTENTS 
 
A. 
PROTOCOL APPROVAL PAGE ................................................................................2 
B. 
PROTOCOL SYNOPSIS .............................................................................................3 
C. 
TABLE OF CONTENTS ...........................................................................................10 
D. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................14 
1. 
INTRODUCTION ......................................................................................................16 
1.1. 
Background .................................................................................................................16 
1.2. 
Clinical Experience .....................................................................................................17 
1.3. 
Dose Selection Rationale ............................................................................................17 
1.4. 
Summary of Potential Risks and Benefits ..................................................................17 
1.5. 
Primary Objective .......................................................................................................18 
2. 
STUDY OBJECTIVES ..............................................................................................18 
2.1. 
Primary Objective .......................................................................................................18 
3. 
INVESTIGATIONAL PLAN .....................................................................................18 
3.1. 
Overall Study Design ..................................................................................................18 
3.1.1. 
Surgical Period (Day 1): .............................................................................................18 
3.1.2. 
Treatment Period (Inpatient Days 1 to 4 / Outpatient Days 4 to 7): ...........................19 
3.1.3. 
Follow-up (Day 8): .....................................................................................................19 
3.2. 
Subject Selection ........................................................................................................19 
3.2.1. 
Inclusion Criteria ........................................................................................................19 
3.2.2. 
Exclusion Criteria .......................................................................................................20 
3.2.3. 
Post-surgical eligibility requirements: ........................................................................22 
3.3. 
Removal of Subjects from Therapy or Assessment ....................................................22 
3.4. 
Dose Adjustment Criteria ...........................................................................................22 
4. 
TREATMENTS ..........................................................................................................23 
4.1. 
Treatments Administered ............................................................................................23 
4.2. 
Identity of Investigational Product .............................................................................23 
4.3. 
Method of Assigning Subjects to Treatment Groups .................................................23 
4.4. 
Selection and Timing of Dose for Each Subject .........................................................23 
4.5. 
Blinding ......................................................................................................................23 
4.6. 
Treatment Compliance ................................................................................................23 

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4.7. 
Permitted and Prohibited Therapies ............................................................................24 
4.7.1. 
Permitted Therapies ....................................................................................................24 
4.7.2. 
Prohibited Therapies ...................................................................................................24 
4.8. 
Rescue Medication ......................................................................................................24 
5. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................25 
5.1. 
Labeling and Packaging ..............................................................................................25 
5.1.1. 
Labeling ......................................................................................................................25 
5.1.2. 
Packaging ....................................................................................................................25 
5.2. 
Dispensing and Storage ..............................................................................................25 
5.3. 
Drug Supply and Accountability ................................................................................25 
6. 
STUDY ASSESSMENTS ..........................................................................................26 
6.1. 
Efficacy Assessments .................................................................................................26 
6.2. 
Safety Assessments .....................................................................................................26 
6.2.1. 
Demographics and Medical History ...........................................................................26 
6.2.2. 
Physical Examinations ................................................................................................26 
6.2.3. 
Oral Cavity Examinations ...........................................................................................26 
6.2.4. 
Post-Operative Nausea and Vomiting (PONV) Risk Factor Assessment ..................27 
6.2.5. 
Vital Signs ..................................................................................................................27 
6.2.6. 
Pulse Oximetry ...........................................................................................................28 
6.2.7. 
Electrocardiograms .....................................................................................................28 
6.2.8. 
Clinical Laboratory Assessments ...............................................................................28 
6.2.9. 
Adverse Events and Serious Adverse Events .............................................................29 
7. 
STUDY PROCEDURES ............................................................................................33 
7.1. 
Screening (Day -28 to -1) ...........................................................................................33 
7.2. 
Surgical Period (Day 1) ..............................................................................................34 
7.2.1. 
Pre-surgery/Morning of Surgery.................................................................................34 
7.2.2. 
Surgery and Standardized Anesthesia ........................................................................34 
7.3. 
Treatment Period (Inpatient; Day 1-4) .......................................................................35 
7.3.1. 
Pre-Dose .....................................................................................................................35 
7.3.2. 
Drug Administration (Day 1; Time 0) ........................................................................35 
7.3.3. 
Inpatient Treatment Period (Day 1-4; Time 0-72) ......................................................35 
7.3.4. 
Discharge From Research Site (Day 4) ......................................................................36 
7.4. 
Treatment Period (Outpatient; Day 4-7) .....................................................................36 

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7.5. 
Follow-up Period/End of Study/Early Termination (Day 8, + 2 day window) ..........37 
8. 
STATISTICS ..............................................................................................................37 
8.1. 
Efficacy Endpoints ......................................................................................................37 
8.2. 
Safety Endpoints .........................................................................................................37 
8.3. 
Sample Size Determination ........................................................................................37 
8.4. 
Analysis Populations ..................................................................................................38 
8.5. 
Statistical Analyses .....................................................................................................38 
8.5.1. 
Disposition and Demographics ...................................................................................38 
8.5.2. 
Exposure and Compliance ..........................................................................................38 
8.5.3. 
Safety Analyses ..........................................................................................................39 
9. 
STUDY CONDUCT ...................................................................................................39 
9.1. 
Sponsor and Investigator Responsibilities ..................................................................39 
9.1.1. 
Sponsor Responsibilities .............................................................................................39 
9.1.2. 
Investigator Responsibilities .......................................................................................39 
9.2. 
Site Initiation ..............................................................................................................40 
9.3. 
Screen Failures ............................................................................................................40 
9.4. 
Study Documents ........................................................................................................40 
9.4.1. 
Investigator’s Regulatory Documents ........................................................................40 
9.4.2. 
Case Report Forms .....................................................................................................41 
9.4.3. 
Source Documents ......................................................................................................41 
9.5. 
Study Termination ......................................................................................................41 
9.6. 
Study Site Closure ......................................................................................................42 
9.6.1. 
Record Retention ........................................................................................................42 
9.6.2. 
Laboratory Sample Retention .....................................................................................42 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................42 
10.1. 
Changes To The Protocol ...........................................................................................42 
10.2. 
Monitoring ..................................................................................................................43 
10.3. 
Data Review Meeting .................................................................................................43 
10.4. 
Protocol Violations .....................................................................................................43 
10.5. 
Quality Assurance Audit .............................................................................................43 
11. 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................45 
11.1. 
Regulatory Authority Approval ..................................................................................45 
11.2. 
Ethical Conduct of the Study ......................................................................................45 

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11.3. 
Statement of Investigator/Delegation of Authority ....................................................45 
11.4. 
Subject Informed Consent ..........................................................................................45 
11.5. 
Investigator Reporting Requirements .........................................................................46 
12. 
DATA HANDLING ANG RECORD KEEPING ......................................................46 
12.1. 
Data Management .......................................................................................................46 
12.2. 
Case Report Forms and Source Documents ...............................................................46 
12.3. 
Documentation and Retention of Essential Documents .............................................46 
12.4. 
Financial Disclosure ...................................................................................................47 
13. 
ADDRESSESS ...........................................................................................................48 
14. 
USE OF INFORMATION AND PUBLICATION POLICY .....................................50 
14.1. 
Use Of Information .....................................................................................................50 
14.2. 
Publication Policy .......................................................................................................50 
15. 
REFERENCES ...........................................................................................................51 
16. 
INVESTIGATOR SIGNATURE PAGE ....................................................................52 
17. 
APPENDICES ............................................................................................................53 
17.1. 
Appendix 1: Surgical and Anesthesia Protocols .........................................................53 
17.2. 
Appendix 2: Naloxone Administration .......................................................................55 
17.3. 
Appendix 3: Dosing Instructions ................................................................................56 
17.4. 
Appendix 4: Schedule of Events .................................................................................57 
 
 

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D. 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse Event 
BMI 
Body Mass Index 
CRF 
Case Report Form  
ECG 
Electrocardiogram 
ET 
Early Termination 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IRB  
Institutional Review Board 
IB 
Investigator’s Brochure 
IP 
Investigational Product 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCP 
Primary Care Provider 
PI 
Principal Investigator 
The investigator who leads the study conduct at an 
individual study center.  Every study center has a principal 
investigator. 
PONV 
Post-Operative Nausea and Vomiting 
Mg 
Milligram 
mL 
Milliliter 
NSAIDS 
Nonsteroidal Anti-inflammatory Drugs 
ODT 
Oral Dissolvable Tablet 
Oz 
Ounce 
SpO2 
Peripheral Capillary Oxygen Saturation 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SPID 
Sum of Pain Intensity Difference 

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Abbreviation or Specialist Term 
Explanation 
TID 
3 times a day 
TEAEs 
Treatment Emergence Adverse Events 
PE 
Physical Examination 
 
 

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1. 
INTRODUCTION 
1.1. 
Background  
The majority of patients who undergo surgical procedures are likely to experience post-operative 
pain. Furthermore, 75% of those patients report the pain as moderate, severe or extreme (1). 
These patients require effective postoperative pain control in order to provide comfort, earlier 
mobilization, faster recovery, and decreased likelihood of post-operative complications. 
Traditionally, acute post-operative pain management has relied on opioid medications to target 
central mechanisms involved in the perception of pain. Opioids bind to receptors in the central 
nervous system and peripheral tissues and modulate the effect of the nociceptors. They can be 
administered via oral, transdermal, parenteral, neuraxial, and rectal routes. Morphine is the 
standard choice for opiates and is widely used for acute post-operative pain. However, morphine 
has significant amount of first-pass metabolism in the liver with only around 40 to 50% of the 
amount absorbed actually reaching the nervous system (2). Most of the morphine is processed in 
the kidneys and eliminated from the body in urine.  Oxycodone, another opioid agonist, is being 
widely used to alleviate moderate-to-severe pain but even then its bioavailability is 67–80% (3). 
It would be beneficial to manage patients’ post-operative pain effectively with opioids through a 
route that by-passes liver metabolism and is feasible in the ambulatory setting. An option would 
be the sublingual route which allows drug to diffuse to the blood through the tissues under the 
tongue and avoiding the first pass effect by the liver.  
Buprenorphine is currently approved by the FDA to be administered as a transdermal patch or a 
buccal film to treat chronic pain. Buprenorphine binds to mu-receptors with high affinity but less 
intrinsic activity compared to full opioid agonists. Because of its partial agonist features, the 
efficacy and adverse effects of buprenorphine are thought to plateau at higher doses. Past 
research suggests that buprenorphine may show a respiratory depression “ceiling effect” where 
analgesic efficacy continues to escalate at higher doses, but respiratory depression does not. 
Dahan et al. (4) found that when tested over a dose range, buprenorphine demonstrated a ceiling 
effect for respiratory depression but not for analgesia. In a separate study, Dahan et al. (5) found 
that the ceiling effect shown for buprenorphine-induced respiratory depression was not 
demonstrated for the full μ-agonist opioid fentanyl.  In addition, buprenorphine dissociates from 
the mu-receptor very slowly, which likely accounts for its longer duration of action than 
morphine, and its low level of manifested physical dependence. Actions at kappa-receptors, 
where buprenorphine is an antagonist, are believed to produce alterations in the perception of 
pain and the emotional response to pain. 
It is postulated that using buprenorphine for acute pain relief through the sublingual spray route 
may have multiple benefits over full opioids such as less constipation, milder withdrawal and 
less abuse potential, better efficacy in older population, and treatment in a broad range of pain 
types. In addition, its use through sublingual is advantageous over oral administration such that 
the effect is more direct and faster (6). 
The proposed study will evaluate the safety with the administration of buprenorphine delivered 
as a sublingual spray for post-operative pain. 

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1.2. 
Clinical Experience 
The drug being investigated in this study is the sublingual preparation spray of buprenorphine. 
Buprenorphine has been shown to be safe and effective in its currently marketed oral forms: 
tablet (Subutex®) and buccal film (Belbuca™) (www.accesseddata.fda.gov). Subutex® 
sublingual tablets have been studied in 1834 patients and Belbuca™ has been evaluated in three 
12-week double- blind, placebo-controlled clinical trials in opioid- na榨癥⁡
nd opioid-experienced 
patients with moderate-to-severe chronic low back pain. Two of the 3 studies showed efficacy in 
lower back pain. 
Buprenorphine Sublingual Spray has been studied in a Phase 3, multicenter, randomized, double-
blind, multiple-dose, parallel-group, placebo-controlled study (Study INS005-15-062) to 
evaluate the safety and efficacy of 3 dosing regimens (0.5 mg, 0.25 mg, or 0.125 mg 3 times 
daily [TID]) in subjects with moderate to severe pain after bunionectomy). In summary, the 
study demonstrated that the Buprenorphine Sublingual Spray given TID at doses of 0.125 mg, 
0.25 mg, or 0.5 mg had significantly higher efficacy than a placebo spray over 48 hours after the 
start of dosing as measured using the primary endpoint of SPID-48 score in subjects with acute 
pain following bunionectomy surgery. Overall, all doses of Buprenorphine Sublingual Spray 
evaluated in this study were safe and generally well tolerated. 
1.3. 
Dose Selection Rationale 
In study INS005-15-062, Buprenorphine Sublingual Spray 0.5 mg TID demonstrated the largest 
reduction in pain as assessed by SPID-48 and was statistically significant to placebo (p<0.0001).  
The 0.25 mg tid and 0.125 mg tid doses also demonstrated statistically significant reductions in 
SPID-48 (p = 0.0108 and p = 0.0120, respectively).  Because all treatments were generally well 
tolerated, the 0.5 mg TID dose is being studied. 
1.4. 
Summary of Potential Risks and Benefits 
There are no anticipated benefits of participation. 
The potentials risks of study participation include those associated with exposure to 
Buprenorphine Sublingual Spray and the risks of medical evaluation, including venipuncture. 
Adverse Events common with buprenorphine are constipation, dizziness, headache, nausea, 
sweating, and vomiting. Severe side effects that may occur with buprenorphine include rash, 
hives, itching, difficulty breathing, tightness in the chest, swelling of the mouth, face, lips, or 
tongue, anxiety or nervousness, dark urine, fast or irregular heartbeat, mental or mood changes, 
pale stools, pain, redness, or swelling at the injection site, slow or shallow breathing, unusual 
weakness, vision changes, yellowing of eyes or skin. Safety monitoring will occur during the in-
clinic period of the study. All subjects will be actively monitored with pulse-oximetry (SpO2) 
and ECG after surgery. 
A summary of the pharmaceutical properties and known potential risks of Buprenorphine 
Sublingual Spray is provided in the current version of the investigator’s brochure. The 

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investigator must become familiar with all sections of the investigator’s brochure and the 
prescribing information before the start of the study. 
1.5. 
Primary Objective 
To evaluate the safety and tolerability based on the incidence of adverse experiences of 
Buprenorphine Sublingual Spray (0.5 TID) compared with standard post-operative narcotic 
therapy in subjects with postoperative pain. Standard post-operative narcotic therapy is defined 
as Morphine Intravenous Injection (IV) (4 mg TID) followed by Oxycodone Hydrochloride 
Tablet (10 mg TID). 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
To evaluate the safety and tolerability based on the incidence of adverse experiences of 
Buprenorphine Sublingual Spray (0.5 TID) compared with standard post-operative narcotic 
therapy in subjects with postoperative pain. Standard post-operative narcotic therapy is defined 
as Morphine Intravenous Injection (IV) (4 mg TID) followed by Oxycodone Hydrochloride 
Tablet (10 mg TID). 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase 2, randomized (stratified according to surgery and postoperative nausea and 
vomiting risk factors), open label, multiple-dose, comparator controlled, parallel-group, study to 
evaluate the safety and tolerability of Buprenorphine Sublingual Spray (0.5 mg TID) versus 
standard postoperative narcotic therapy in subjects with postoperative pain. Standard 
postoperative narcotic therapy is defined as Morphine IV (4 mg TID) for 24 hours followed by 
Oxycodone Hydrochloride Tablet (10 mg TID).  
The study will make be composed of four periods: Screening Period (Day -28 to -1), Surgical 
Period (Day 1), Treatment Period (Inpatient Days 1 to 4 / Outpatient Days 4 to 7), and Follow-up 
Period (Day 8, +2 day window). 
Screening Period (Day -28 to -1): Subjects who meet all inclusion and no exclusion criteria will 
be eligible for enrollment. After providing written Informed Consent, subjects will undergo study 
specific screening procedures as outlined in Appendix 4: Schedule of Events. 
 
3.1.1. 
Surgical Period (Day 1):  
Subjects will be admitted to the study site on the morning of the scheduled surgery on Day 1. 
Anesthesia will be established using standardized techniques, as appropriate, for each surgical 
procedure. Surgical procedures will be bunionectomy, breast augmentation, and abdominoplasty. 
For nausea prophylaxis, all subjects will receive a uniform standard of care regimen including: 

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10 mg of dexamethasone at induction and 8 mg of ondansetron near the end of surgery. Vitals, 
pulse oximetry, and ECG measurements will be recorded as outlined in the Appendix 4: 
Schedule of Events. Concomitant medications and Adverse Events will be recorded as outlined 
in Appendix 4: Schedule of Events. 
3.1.2. 
Treatment Period (Inpatient Days 1 to 4 / Outpatient Days 4 to 7):  
Within 4 hours after surgery, subjects who meet post-surgical eligibility criteria will be assigned 
to 1 of 2 treatment groups: Buprenorphine Sublingual Spray 0.5 mg TID or standard of care 
postoperative narcotic therapy defined as Morphine 4 mg TID for 24 hours followed by 
Oxycodone 10 mg TID. Randomization will be stratified according to surgical procedure and 
baseline PONV risk factors. The first dose of investigational drug may be received any time 
between 0-4 hours after surgery and should be administered either in the surgical recovery room 
or in the clinical research unit and does not need to be immediately administered after meeting 
post-surgical eligibility requirements. The time of administration of the first dose of study drug 
will be defined as Time 0 and the inpatient Treatment Period will continue through 72 hours after 
Time 0 as per Appendix 4: Schedule of Events. 
Subjects will be admitted to the study site on the morning of the scheduled surgery (Day 1), will 
remain at the study site until Postoperative Day 4 (a total of 3 nights at the study site) then be 
evaluated to participate in the outpatient setting and must meet eligibility criteria in order to 
proceed to the outpatient treatment period Days 4 to 7.  
3.1.3. 
Follow-up (Day 8):  
Subjects will be instructed to return unused outpatient study drug and diary to study personnel at 
the Follow-up Visit on Day 8 (+2 day window). For additional assessments refer to Appendix 4: 
Schedule of Events. 
3.2. 
Subject Selection  
All subjects must satisfy the following criteria and post-surgical eligibility criteria to be 
considered eligible for the study. 
3.2.1. 
Inclusion Criteria 
1. Is able to speak and understand the language in which the study is being conducted, is 
able to understand and comply with the procedures and study requirements, and has 
voluntarily signed and dated an informed consent form approved by an Institutional 
Review Board before the conduct of any study procedure. 
2. Is a male or female ≥18 and ≤65 years of age. 
3. Scheduled for elective bunionectomy, breast augmentation (in women only), or 
abdominoplasty. 
4. Is classified using the American Society of Anesthesiologists Physical Status 
Classification System as P1 to P2. 
5. If female, is either not of childbearing potential (defined as postmenopausal for at least 1 
year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or 

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hysterectomy]) or practicing one of the following medically acceptable methods of birth 
control: 
a. Hormonal methods such as oral, implantable, injectable, vaginal ring, or 
transdermal contraceptives for a minimum of 1 full cycle (based on the subject’s 
usual menstrual cycle period) before study drug administration; 
b. Total abstinence from sexual intercourse since the last menses before study drug 
administration; 
c. Intrauterine device; OR 
d. Double-barrier method (condoms, sponge, or diaphragm with spermicidal jellies 
or cream). 
6. Has a body weight ≥45 kg and a body mass index (BMI) ≤40 kg/m2. 
7. Is willing and able to comply with study requirements (including diet, alcohol, and 
smoking restrictions), complete evaluations and diary, remain at the study site for ≥72 
hours, and return for follow up 8 + 2 days after surgery. 
 
3.2.2. 
Exclusion Criteria 
Subjects will be excluded for any of the following: 
1. Has a known history of allergic reaction or clinically significant intolerance to 
acetaminophen, aspirin, opioids, or any nonsteroidal anti-inflammatory drugs (NSAIDs); 
history of NSAID-induced bronchospasm (subjects with the triad of asthma, nasal polyps, 
and chronic rhinitis are at greater risk for bronchospasm and should be considered 
carefully); or hypersensitivity, allergy, or significant reaction to sulfa (including 
sulfonamide) medicines, ingredients of the study drug, or any other drugs used in the 
study, including anesthetics and antibiotics that may be required on the day of surgery. 
2. Has experienced any surgical complications or other issues that, in the investigator’s 
opinion, could compromise the subject’s safety if he or she continues into randomized 
treatment or could confound the results of the study. 
3. Has a known or suspected history of alcoholism or drug abuse or misuse within 2 years of 
Screening or evidence of opioid tolerance or physical dependence before dosing with the 
study drug. 
4. Has any clinically significant unstable cardiac, respiratory, neurological, immunological, 
hematological, or renal disease, or any other condition that, in the investigator’s opinion, 
could compromise the subject’s welfare, ability to communicate with the study staff, or 
otherwise contraindicate study participation. 
5. Has long QT Syndrome, a family history of long QT Syndrome, or is taking Class IA or 
Class III antiarrhythmic medications. 
6. Has a history or current diagnosis of a significant psychiatric disorder that, in the 
investigator’s opinion, would affect the subject’s ability to comply with the study 
requirements. 

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7. Has tested positive either on the urine drug screen or on the alcohol Breathalyzer test. 
Subjects who test positive at Screening only and can produce a prescription in their name 
from their physician for the medication producing the positive test may be considered for 
study enrollment at the investigator’s discretion. However, they must test negative on the 
day of the surgery. 
8. Has a history of a clinically significant (in the investigator’s opinion) gastrointestinal (GI) 
event within 6 months before Screening or has any history of peptic or gastric ulcers or 
GI bleeding. 
9. Has an active infection, mucositis, cold sores, viral lesions, local irritation, or in the 
investigator’s opinion has significant periodontal disease of the oral cavity. In addition, 
recent (within 1 year) piercing of the tongue or anywhere in the oral cavity. 
10. Has a surgical or medical condition of the GI or renal system that, in the investigator’s 
opinion, might significantly alter the absorption, distribution, or excretion of any drug 
substance. 
11. Is considered by the investigator, for any reason (including, but not limited to, the risks 
described as precautions, warnings, and contraindications in the current version of the 
investigator’s brochure for Buprenorphine Sublingual Spray), to be an unsuitable 
candidate to receive the study drug. 
12. Is receiving systemic chemotherapy, has an active malignancy of any type, or has been 
diagnosed with cancer within 5 years before Screening (excluding squamous or basal cell 
carcinoma of the skin). 
13. Is currently receiving anticoagulants (eg, heparin or warfarin). Low-dose aspirin for 
cardioprotection is allowed. 
14. Has used drugs known to be a strong inhibitor or inducer of CYP3A4 within 1 weeks 
before surgery. 
15. Has received a course of systemic corticosteroids (either oral or parenteral) within 1 
months before Screening (inhaled nasal steroids and topical corticosteroids are allowed). 
16. Has a history of chronic use (defined as daily use for >2 weeks) of NSAIDs, opiates, or 
glucocorticoids (except inhaled nasal steroids and topical corticosteroids) within 1 month 
before study drug administration. Aspirin at a daily dose of ≤325 mg is allowed for 
cardiovascular prophylaxis if the subject has been on a stable dose regimen for ≥30 days 
before Screening and has not experienced any relevant medical problem. 
17. Has a significant renal or hepatic disease, as indicated by clinical laboratory assessment 
(results ≥3 × the upper limit of normal [ULN] for any liver function test, including 
aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase, or 
creatinine ≥1.5 × ULN). 
18. Has any clinically significant laboratory or 12-lead electrocardiogram finding at 
Screening that in the investigator’s opinion contraindicates study participation. 
19. Has screening systolic blood pressure ≥160 mmHg and diastolic blood pressure >100 
mmHg (may be repeated one additional time after 5 minutes rest to verify). The 

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investigator may, at his discretion, choose to exclude subjects with hypertensive levels 
lower than these if he deems it in the best interest of the subject. 
20. Has a history of sleep apnea or other obstructive airway disease. 
21. Has a history of nausea and vomiting with buprenorphine products. 
22. Has significant difficulties swallowing capsules or is unable to tolerate oral medication. 
23. Previously participated in another clinical study of Buprenorphine Sublingual Spray or 
received any investigational drug or device or investigational therapy within 30 days 
before Screening. 
3.2.3. 
Post-surgical eligibility requirements:  
The subject will be assessed for the following postoperative eligibility criteria: 
1. Subjects must be awake, breathing spontaneously without significant respiratory 
depression. 
2. Subjects must not be actively vomiting or complaining of severe nausea. 
3. Subjects must be able to answer questions and follow commands.  
4. Subjects must not have surgical complications that could compromise safety of the 
subject or confound the results of the study.   
3.3. 
Removal of Subjects from Therapy or Assessment 
Subjects are free to terminate their participation in the study at any time and for any reason. 
Likewise, a subject may be terminated from the study by the Investigator if the Investigator 
determines that it is not the subject’s best interest to continue participation. The Investigator has 
the right to withdraw subjects from the study at any time for an effect that is intolerable or 
otherwise unacceptable to the subjects, for intolerable or unacceptable AEs, intercurrent illness, 
noncompliance with study procedures, administrative reasons, or in the investigator’s opinion to 
protect the patient’s best interest. Subjects may be considered terminated if they state an 
intention to terminate, or fail to comply or return for assessments/ visits, or become lost to follow 
up for any other reason.  If early termination occurs for any reason, the Investigator must 
determine the primary reason for a subject’s early termination from the study and this 
information must be recorded in the subject’s eCRF. Subjects will be required to return on Day 7 
if early termination occurs and they do not withdraw consent. 
Subjects whose pain or nausea cannot be adequately managed in the Investigator’s opinion by a 
combination of study drug and rescue medication will be discontinued from further study 
participation. Their pain or nausea will be managed according to usual standard of care at the 
Investigator’s discretion. In addition, subjects who develop unacceptable side effects during the 
study will be discontinued from further study participation. 
The Investigator must document early or other termination for randomization and drug 
reconciliation purposes. 
3.4. 
Dose Adjustment Criteria 
There will be no dose adjustments for IP and the reference drugs. 

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4. 
TREATMENTS 
4.1. 
Treatments Administered 
Eligible subjects meeting all study entry criteria will be randomly allocated in a 1:1 ratio to one 
of the following treatments: Buprenorphine Sublingual Spray (1 x 0.5 mg TID; total of 21 
doses); or reference drugs Morphine Intravenous Injection (1 x 4 mg TID for 24 hours; total of 3 
doses) followed by Oxycodone Hydrochloride Tablet (1 x 10 mg TID; total of 18 doses). 
4.2. 
Identity of Investigational Product  
The drug is formulated as a sublingual spray. The product is a clear solution filled into a glass 
vial, stoppered and assembled within a unit-dose sublingual spray pump. Priming is not required. 
Each spray pump delivers 0.5 mg of buprenorphine.  
4.3. 
Method of Assigning Subjects to Treatment Groups 
Up to 100 subjects will be dosed in this study. The sample size is not based on statistical 
considerations. The number of subjects planned for enrollment is considered sufficient to achieve 
the study objectives.  
Randomized treatment will be assigned utilizing a computer generated randomization scheme. 
Patients will be randomly assigned to treatment administered in a 1:1 assignment ratio according 
to the randomization scheme.  All study doses administered will be according to IWRS to ensure 
that study personnel will not be aware of the next subject’s treatment assignment until the 
decision to randomize that subject has been made. Randomization will be stratified by surgical 
procedure and baseline PONV risk factors. Patients with PONV risk factors of 0-2 will be 
stratified as low risk and 3-4 as high risk. 
4.4. 
Selection and Timing of Dose for Each Subject 
The buprenorphine dose was chosen based on a Phase 3 trial which showed that Buprenorphine 
0.5 mg Sublingual Spray TID is effective in reducing moderate-to-severe pain after 
bunionectomy compared to placebo and is generally well tolerated.  The reference drugs 
morphine 4 mg TID for 24 hours followed by oxycodone 10 mg TID was chosen because the 
regimen is accepted as standard postoperative narcotic therapy. 
4.5. 
Blinding 
This is an open-label study without treatment blinding. 
4.6. 
Treatment Compliance 
All subjects will receive IP at the study site under the surveillance of appropriate study personnel 
during Inpatient Treatment Days 1 to 4.  Subjects will receive IP to take home on Outpatient 
Treatment Days 4 to 7 and will be instructed how to correctly dose with IP at home. The IP lot 
number(s) will be recorded in the subject’s chart/source documents. Exposure (total dose of 
study drug) for the Inpatient, Outpatient and overall treatment periods will be recorded. 

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During Inpatient Treatment, any rescue medication administered to the subject will be recorded 
in the subject’s source.  
4.7. 
Permitted and Prohibited Therapies 
4.7.1. 
Permitted Therapies 
Prescription medications that in the opinion of the investigator will not potentially interact with 
buprenorphine, morphine, oxycodone, or interfere with its respiratory effects may be permitted 
during the course of the study. 
4.7.2. 
Prohibited Therapies 
The following therapies are prohibited: 
 Anticoagulants (e.g., heparin or warfarin). Aspirin at a daily dose of ≤325 mg is allowed 
for cardiovascular prophylaxis if the subject has been on a stable dose regimen for ≥30 
days before Screening and has not experienced any relevant medical problem. 
 Drugs known to be a strong inhibitor or inducer of CYP3A4 within 1 week before surgery. 
 Systemic corticosteroids (either oral or parenteral) within 1 month before Screening 
(inhaled nasal steroids and topical corticosteroids are allowed). 
 Chronic use (defined as daily use for >2 weeks) of NSAIDs, opiates, or glucocorticoids 
(except inhaled nasal steroids and topical corticosteroids) within 1 months before study 
drug administration. 
 Agents that could affect the analgesic response (such as central alpha agents [clonidine and 
tizanidine], neuroleptic agents, and other antipsychotic agents) within 2 weeks before 
Screening. Selective serotonin reuptake inhibitors and selective noradrenergic reuptake 
inhibitors are allowed if the subject has been on a stable dose for at least 8 weeks before 
Screening and does not anticipate a dose change during the course of the study. 
Subjects receiving excluded therapies will be ineligible for study enrollment or for continuation 
in the study. 
Subjects should not have anything orally except room-temperature water within 15 minutes of 
each dose. 
4.8. 
Rescue Medication 
Rescue for inadequate analgesic response during confinement to the study center during the first 
72 hours for pain will be acetaminophen 1000 mg every six hours and/or ketorolac 30 mg every 
six hours, as needed. On outpatient days 4-7 subjects will be provided with acetaminophen, and 
will be advised to take acetaminophen 1000 mg every six hours as needed for rescue analgesia.   
Rescue for postoperative nausea during confinement to the study center during the first 72 hours 
will be Zofran 4 mg IV per the discretion of the clinician. On outpatient days 4-7, subjects will 
be administered Zofran ODT (oral dissolvable tablet) to be taken as needed.  
The rescue medication and specific reason for use will need to be captured in the subject 
outpatient diaries.  

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5. 
STUDY DRUG MATERIALS AND MANAGEMENT 
5.1. 
Labeling and Packaging 
5.1.1. 
Labeling 
The labels for the investigational product will contain all information according to regulatory 
requirements. 
5.1.2. 
Packaging 
The test product is formulated as a sublingual spray. Buprenorphine sublingual spray is a clear 
solution filled into a glass vial that is stoppered and assembled within a unit-dose sublingual 
spray pump. Priming is not required. Each spray pump delivers 0.5 mg of buprenorphine. 
Morphine will be supplied in clear glass snap-ampules (1 mL) containing 4 mg of morphine. 
Oxycodone Hydrochloride Tablet will be supplied as uncoated tablet containing 10 mg of 
oxycodone hydrochloride. 
5.2. 
Dispensing and Storage 
The study treatments will be shipped to site upon receipt of appropriate Drug Enforcement 
Administration (DEA) documentation. Upon receipt of the study drug, the supplies will be 
inventoried and stored in an environmentally controlled and secure, limited access area. 
Buprenorphine Sublingual Spray will be stored at a temperature of 20 -25 degrees C (inclusive).  
5.3. 
Drug Supply and Accountability 
Insys Development Company, Inc. will supply sufficient quantities of Buprenorphine Sublingual 
Spray, Morphine IV, Oxycodone Hydrochloride Tablets, Acetaminophen, Ketorolac, Naloxone 
Zofran IV, and Zofran ODT to complete the study.  
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the IP, including the date, quantity, lot number, and identification of subjects 
(subject number and initials) who received the IP. The investigator will not supply the IP to any 
person except those named as sub-investigators on Form FDA 1572, designated study personnel, 
and subjects in this study. The Investigator will not dispense the IP from any study sites other 
than those listed on Form FDA 1572. The IP may not be relabeled or reassigned for use by other 
subjects. If any of the IP is not dispensed; is lost, stolen, spilled, unusable, or is received in a 
damaged container, this information must be documented and reported to Insys Development 
Company and appropriate regulatory agencies, as required. 
On the last study visit day, subjects will return any unused study drug.  
Upon completion of the study, all unused IP and other study materials are to be reconciled and 
returned to Insys Development Company (or designee) as per Insys Development Company’s 
written instructions. Reconciliation forms will be provided and must be included with all return. 
To prevent theft or diversion, study drug must be stored in a securely locked, substantially 
constructed cabinet or enclosure appropriate for a Schedule II drug. Any actual or suspected 
theft, diversion, or loss of study drug must be immediately reported to the principal investigator 

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at the study center and DEA license holder to ensure federal reporting requirements and sponsor 
notification requirements are met. 
Specific instructions as to how to handle the study drug, including storage, during the outpatient 
treatment period will be provided to the patients in the written informed consent form/opioid 
agreement, which the patient must sign to qualify for the study. The informed consent 
form/written opioid agreement will provide information about the medication the patient may be 
taking for pain management (Buprenorphine 0.5 mg sublingual spray) and to assure that the 
patient can comply with all state and federal regulations concerning the medical use of controlled 
substances. The patient will be responsible for keeping the assigned study drug in a safe and 
secure place, such as a locked cabinet or safe. The patient will be expected to protect the 
assigned study drug from loss or theft. Stolen study drug should be reported to the police and to 
the study physician immediately. If the assigned study drug is lost, misplaced, or stolen, the 
study investigator may choose not to replace the study drug and may terminate the patient from 
the study.  
6. 
STUDY ASSESSMENTS 
6.1. 
Efficacy Assessments 
No efficacy assessments will be measured. 
6.2. 
Safety Assessments 
Safety variables will include physical and oral cavity examinations, vital signs, pulse-oximetry, 
clinical laboratory testing, electrocardiogram collection (ECG), concomitant medications, and 
adverse event assessments. 
6.2.1. 
Demographics and Medical History 
Each potential study participant will have the following assessments by the Investigator or 
designee during the Screening Period, within 28 days prior to study start: demographic data, 
including sex, age, race, ethnicity, body weight (kg), height (cm), and body mass index (BMI 
[kg/m2]), medical and surgical history, medications history, and concomitant medications. 
Height/weight and BMI will also be recorded. BMI will be calculated using the following NIH 
website: https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmi-m.htm 
6.2.2. 
Physical Examinations 
A physical examination (excluding the genitourinary examination) will be performed as per 
Appendix 4: Schedule of Events. Systems include HEENT, cardiovascular, respiratory, 
gastrointestinal, neurological, dermatologic, and musculoskeletal systems. 
6.2.3. 
Oral Cavity Examinations 
Oral cavity examination will be performed at the time-points specified in Appendix 4: Schedule 
of Events. The oral examination at Screening will exclude subjects with any active infection, 
mucositis, cold sores, viral lesions, local irritation, or periodontal disease of the oral cavity. In 
addition, subjects with recent (within 1 year) piercing of the tongue or anywhere in the oral 

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cavity will be excluded. If there is a recent history of significant dental disease, the investigator 
may decide to exclude the subject. All other oral examinations will check for mucositis and local 
irritation. 
6.2.4. 
Post-Operative Nausea and Vomiting (PONV) Risk Factor Assessment 
PONV risk will be assessed at screening to assess the likelihood of nausea and vomiting after 
surgery using the Apfel scale (7) 
6.2.4.1. 
Table 1: (PONV) Risk Factor Assessment 
Risk Factors 
Points 
Post-operative Opioids (if planned) 
1 
Non Smoker 
1 
Female Gender 
1 
History of postoperative nausea and vomiting  / 
Motion Sickness 
1 
Risk score = sum 
0…4 
 
Score 
Probability of Postoperative Vomiting and 
Nausea (%) 
0 
10 
1 
21 
2 
39 
3 
61 
4 
79 
Assessment will be collected in the source documentation and entered into IWRS for 
randomization.  Patients with PONV risk factors of 0-2 will be classified as low risk and 3-4 as 
high risk. 
6.2.5. 
Vital Signs  
Vitals signs will be measured at time-points specified by Appendix 4: Schedule of Events. Vital 
signs will be taken after the subject has been sitting/reclined position for 5 minutes. Vital signs 
will also be measured before ET if a subject discontinues. Vital signs will include blood 

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pressure, heart rate, respiration rate, oral body temperature. Assessments will be repeated based 
on the Investigator’s discretion.  
6.2.6. 
Pulse Oximetry 
Pulse oximetry will be measured continuously for safety and recorded at selected times as 
specified by the time point in Appendix 4: Schedule of Events. Pulse oximetry will be taken after 
the subject has been sitting/reclined position for 5 minutes. 
6.2.7. 
Electrocardiograms 
A standard 12-lead ECG will be performed at the time-points specified in Appendix 4: Schedule 
of Events. The 12-lead ECG will be collected after the subject has been supine for 5 minutes. All 
ECG recordings will be identified with the subject number, initials, date, and time of the 
recording. The ECG will be evaluated for any clinically relevant cardiovascular conditions, 
defined as any clinically significant abnormalities identified by the reader related to coronary 
artery disease, coronary spasm, abnormal heart rhythm, hypertrophic cardiomyopathy, heart 
failure, rheumatic heart disease, or myocarditis. 
6.2.8. 
Clinical Laboratory Assessments 
Clinical laboratory tests will be performed as per Appendix 4: Schedule of Events. Pregnancy 
tests and urine drug screens will be performed at Screening and before surgery. Samples for the 
following laboratory tests will be collected: 
6.2.8.1. 
Hematology 
Hemoglobin, hematocrit, red blood cell count, red blood cell indices, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, platelet count (or estimate), and white 
blood cell count including differential. 
6.2.8.2. 
Serum Chemistry 
Albumin, total bilirubin, total protein, calcium, alkaline phosphatase, alanine aminotransferase, 
aspartate aminotransferase, blood urea nitrogen, cholesterol, glucose, sodium, potassium, 
chloride, bicarbonate, lactate dehydrogenase, uric acid, creatinine with calculated creatinine 
clearance (Cockcroft-Gault method). 
6.2.8.3. 
Urinalysis 
pH, specific gravity, blood, glucose, protein, and ketones. 
6.2.8.4. 
Pregnancy Screen 
For women of childbearing potential only; a serum test at Screening and a urine test before 
surgery. 
6.2.8.5. 
Urine Drug Screen 
Urine drug screen will be performed to test for amphetamines, barbiturates, benzodiazepines, 
cocaine, opiates, phencyclidine, and tetrahydrocannabinol. 

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6.2.8.6. 
Alcohol Breathalyzer 
An alcohol breathalyzer test will be performed as per Appendix 4: Schedule of Events. 
6.2.8.7. 
Virus Serology 
Virus serology will be completed to test for Hepatitis B surface antigen, antibodies to hepatitis C, 
and antibodies to HIV at the screening visit. 
6.2.9. 
Adverse Events and Serious Adverse Events 
6.2.9.1. 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product during the course of a clinical investigation. An AE can therefore be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the use of an 
investigational product, whether or not thought to be related to the investigational product. 
Subjects will be monitored throughout the study for AEs. Monitoring for treatment-emergent 
AEs will begin as soon as the subject is dosed. All AEs must be followed until they are resolved 
or stabilized, or until all attempts to determine resolution of the event are exhausted. The 
investigator should use their discretion in ordering additional tests as necessary to monitor the 
progress of such events. 
Adverse Events reported prior to dose administration will be recorded as part of the subject’s 
medical history. 
An AE may be: 
 A new illness, not documented in the subject’s medical history; 
 Worsening of a concomitant illness; 
 An effect of the study medication; it could be an abnormal laboratory value, as well 
as a significant shift from baseline within normal range which the qualified 
investigator or medical qualified designate considers to be clinically important; 
 A combination of two or more of these factors. 
Surgical procedures themselves are not AEs. They are therapeutic measures for conditions that 
required surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. Planned surgical measures permitted by the clinical study 
protocol and the conditions(s) leading to these measures are not AEs, if the condition(s) was 
(were) known before the start of study treatment. In the latter case, the condition should be 
reported as medical history. 
6.2.9.2. 
Classification of Adverse Events 
Adverse Events are to be recorded on the AE page of the subject’s case report form (CRF).  
Severity will be graded according to the following definitions: 
 Mild:  The subject experiences awareness of symptoms but these are easily tolerated 
or managed without specific treatment. 

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 Moderate:  The subject experiences discomfort enough to cause interference with 
usual activity, and/or the condition requires specific treatment. 
 Severe:  The subject is incapacitated with inability to work or do usual activity, 
and/or the event requires significant treatment measures. 
Action taken will be categorized as none, study drug discontinued, dose modified, required 
concomitant medication, required procedure, or other. 
Event outcome at resolution or time of last follow-up will recorded as event resolved, resolved 
with sequelae, ongoing, or death. 
6.2.9.3. 
Causality/Drug Relationship Assessment 
The relationship of the event to the study drug should be determined by the investigator 
according to the following criteria:  
 Definitely related: The event follows a reasonable temporal sequence from the time of 
drug administration that cannot be explained, follows a known or expected response 
pattern to the study drug, that is confirmed by improvement on stopping and 
reappearance of the event on repeated exposure and that could not be reasonably 
explained by other factors such as the subject’s clinical condition, intercurrent illness, 
or concomitant drug.  
 Probably related:  The event follows a reasonable temporal sequence from the time of 
drug administration, and/or follows a known response pattern to the study drug, and 
cannot be reasonably explained by other factors such as the subject’s clinical 
condition, intercurrent illness, or concomitant drugs. 
 Possibly related:  The event follows a reasonable temporal sequence from the time of 
drug administration, and/or follows a known response pattern to the study drug, but 
could have been produced by other factors such as the subject’s clinical condition, 
intercurrent illness, or concomitant drugs. 
 Unlikely related: The event follows little or no temporal sequence from the time of 
drug administration that makes a causal relationship improbable and/or other factors 
such as the subject’s clinical condition, intercurrent illness, or concomitant drugs is a 
more likely alternative. 
 Not related:  The event is most likely produced by other factors such as the subject’s 
clinical condition, intercurrent illness, or concomitant drugs, and does not follow a 
known response pattern to the study drug, or the temporal relationship of the event to 
study drug administration makes a causal relationship unlikely. 
6.2.9.4. 
Definition of Serious Adverse Events 
A serious AE (SAE) is any AE that fulfills any of the following criteria, as per 21 CFR 312.32: 
 Results in death; 
 Is life-threatening; 
 Requires in-patient hospitalization or prolongation of existing hospitalization; 

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 Results in persistent or significant disability or incapacity; 
 Is a congenital anomaly or birth defect; 
 Is medically significant or requires intervention to prevent one of the outcomes listed 
above. 
Serious AEs will be captured from the time of consent through the end of the study. 
6.2.9.5. 
Actions Taken for Serious Adverse Events 
Actions taken may consist of: 
 None: No action taken 
 Treatment: Standard of care measures instituted 
 Drug withdrawn: Study medication was permanently discontinued because of the AE 
 Unknown: Not known, not observed, not recorded, or refused 
6.2.9.6. 
Outcome at the Time of Last Observation for Serious Adverse Events 
The outcome at the time of last observation will be classified as: 
 Recovered/resolved 
 Recovered/resolved with sequelae 
 Not recovered/not resolved 
 Death 
 Unknown 
6.2.9.7. 
Adverse Event Recording and Reporting 
Adverse Events will be recorded throughout the study in the source documents and in the CRFs. 
The investigator will rate AEs for seriousness, intensity, causality, action taken, and outcome as 
described in the previous section. 
Expedited reporting is required for serious unexpected adverse drug reactions. Fatal or 
life-threatening unexpected drug reactions must be reported by the Sponsor to regulatory 
agencies no more than 7 days after the Sponsor’s first knowledge of the reaction; followed by as 
complete a report as possible within 8 additional days.  Unexpected drug reactions must be 
reported no later than 15 days after the Sponsor’s first knowledge of the reaction. In order to 
comply with these requirements, the investigator or delegate must inform the Sponsor 
immediately upon occurrence of any SAE. The site will complete the SAE Report Form as 
thoroughly as possible and email/fax it to Insys Development Company within 24 hours of the 
investigators first knowledge of the event. 
 
 
 

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Sponsor contact information is listed below: 
 
 
Insys Development Company Development Company, Inc.  
Email: 
 
Telephone: 
  
 
These SAE reports must contain the following information: 
A. Study name/number 
B. Study drug 
C. Investigator details (name, phone, fax, e-mail) 
D. Subject number 
E. Subject initials 
F. Subject demographics 
G. Clinical event 
1) 
Description 
2) 
Date of onset 
3) 
Treatment (drug, dose, dosage form) 
4) 
Adverse event relationship to study drug 
5) 
Action taken regarding study drug in direct relationship to the AE 
H. If the AE was fatal or life-threatening 
I. 
Cause of death (whether or not the death was related to study drug) 
J. 
Autopsy findings (if available) 
The Sponsor or its representative will be responsible for notification to regulatory agencies. 
6.2.9.8. 
Adverse Event Follow-Up 
All non-serious AEs that are not related or unlikely to be related to study treatment will be 
followed until the end of study participation. All SAEs or AEs that are considered as possibly, 
probably, or definitely related to treatment will be followed until resolution or stabilization. 

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6.2.9.9. 
Special Considerations 
Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the 
need to practice adequate birth control and on the importance of avoiding pregnancy during 
study participation. Women should be instructed to contact the investigator or study staff 
immediately if pregnancy occurs or is suspected. 
Pregnancy testing will be conducted before IP administration on every woman of childbearing 
potential. A woman who is found to be pregnant at the Screening Visit will be excluded from the 
study and considered to be a screening failure. 
If a subject becomes pregnant, the investigator must report the pregnancy within 24 hours of 
learning of the pregnancy. The investigator should contact the designated individual(s) who 
receive SAE notification and record information related to the pregnancy on the designated form. 
The investigator is responsible for following the pregnancy until delivery or termination. These 
findings must be reported on the designated form and forwarded to the designated individual(s). 
The event meets the SAE criterion only if it results in a spontaneous abortion or a congenital 
anomaly. 
Subjects who become pregnant during the course of the study will be followed to collect data on 
lactating women and health of the child (for births) or until termination of the pregnancy. 
7. 
STUDY PROCEDURES 
The assessments and procedures that will be conducted during this study are summarized in 
Appendix 4: Schedule of Events 
7.1. 
Screening (Day -28 to -1) 
The subject must be screened prior to enrollment in the study. The following procedures will be 
performed at screening: 
 Obtain written informed consent 
 Review inclusion/exclusion criteria 
 Collect demographic information, including height/weight, BMI 
 Record medical and surgical history  
 Perform a physical examination  
 Perform oral cavity exam 
 Measure resting vital signs (blood pressure [BP], heart rate [HR], respiratory rate [RR], 
temperature) 
 Measure pulse oximetry 
 Perform 12-lead electrocardiogram (ECG) 

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 Perform serum pregnancy test on women of child-producing potential 
 Collect hematology, chemistry, and urinalysis samples 
 Collect serology sample 
 Perform urine drug screen and alcohol breath test 
 Record concomitant medications and concomitant therapies, including current therapies 
taken 30 days prior to Screening (e.g. prescription and non-prescription medications) 
 Record Adverse Events 
 PONV risk assessment 
 X-ray and podiatric examination (applies only to subjects receiving bunionectomy) 
 ASA classification 
7.2. 
Surgical Period (Day 1) 
7.2.1. 
Pre-surgery/Morning of Surgery 
Subjects will be admitted to the study site on the morning of the scheduled surgery (Day 1). The 
following procedures will be performed prior to surgery: 
 Collect medical/surgical history (changes since screening) 
 Review inclusion/exclusion criteria 
 Perform a physical examination  
 Perform oral cavity exam 
 Measure vital signs (resting blood pressure, heart rate, respiratory rate, and oral body 
temperature) 
 Perform a urine pregnancy test on women of child-producing potential 
 Perform urine drug screen and alcohol breath test 
 Collect concomitant medications and concomitant therapies 
 Collect Adverse Events 
7.2.2. 
Surgery and Standardized Anesthesia 
Subjects who continue to meet all study entry criteria will undergo a surgical procedure 
(bunionectomy, breast augmentation, or abdominoplasty). Anesthesia will be established using 
standardized techniques. Surgical and Anesthesia protocol is summarized in Appendix 1: 
Surgical and Anesthesia Protocols. For nausea prophylaxis, all subjects will receive a uniform 
standard of care regimen which includes the following: 10 mg of dexamethasone at induction 
and 8 mg of ondansetron near the end of surgery. Subjects may be treated with intravenous 
morphine and or fentanyl for post-surgical analgesia (dose and frequency per the discretion of 
the investigator). Pulse oximetry will be monitored continuously after the procedure as a safety 
measure. 

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7.3. 
Treatment Period (Inpatient; Day 1-4) 
7.3.1. 
Pre-Dose 
Upon completion of surgery on Day 1, subjects who request pain medication within 4 hours after 
surgery will be assessed for post-surgical eligibility requirements. Subjects who meet all post-
surgical eligibility criteria 4 hours after surgery are able to be enrolled in the study. Subjects who 
do not meet all entry criteria within 4 hours after surgery will not be eligible for enrollment and 
will receive routine post-operative care at the investigator’s discretion. 
Prior to dosing on Day 1, the following assessments will be performed: 
 Perform 12-lead ECG 
 Randomize the subject via IWRS 
 Measure vital signs (resting blood pressure, heart rate, respiratory rate, and oral body 
temperature) 
 Perform an oral cavity exam 
 Collect Adverse Events 
 Collect Concomitant medications and procedures 
7.3.2. 
Drug Administration (Day 1; Time 0) 
Upon completion of all pre-dose procedures on Day 1, the following assessments will be 
performed: 
 First Dose of Study Medication administered within 4 hours of end of surgery.  
 Collect Adverse Events. 
 Collect concomitant medications and procedures. 
 Heart rate and respiration rate will be taken at study drug administration/Time 0. 
7.3.3. 
Inpatient Treatment Period (Day 1-4; Time 0-72) 
In the inpatient treatment period (Day 1-4; Time 0-72), the following assessment will be 
performed: 
 Heart rate and respiration rate will be taken 1 hour (± 10 minutes) after the first dose of 
study drug on Day 1, then every 2 hours (± 10 minutes) after Time 0. 
 Blood pressure will be taken every 4 hours (± 10 minutes) after the first dose of study drug 
on Day 1 (Time 0). 
 ECG will be measured at 90 minutes, 12, 24, 48 and 72 hours (± 10 minutes) after the first 
dose of study drug on Day 1 (Time 0). 
 Pulse Oximetry will be continuously monitored after surgery for safety; pulse oximetry 
will be recorded at screening and at selected times (±10 minutes), including baseline before 
Time 0 (prior to first dose) and at 90 minutes and 12, 24, 48, 72 hours after Time 0, and at 
Follow-up Visit/ET. 

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 Collect concomitant medications and procedures. 
 Study Medication Administration will be administered every 8 hours after the First dose of 
study drug (Treatment Days 1 – 4). 
 Oral cavity exam will be performed at 90 minutes, 12, 24, 48 and 72 hours (± 10 minutes) 
after the first dose of study drug on Day 1 (Time 0). 
 Physical examination will be performed at 72 hours (± 4 hours). 
 Collect Adverse Events. 
7.3.4. 
Discharge From Research Site (Day 4) 
Subjects will remain at the study site until all inpatient treatment procedures are completed on 
Day 4 (a total of 3 nights at the study site). Then the subjects will be evaluated by the 
investigator in order to participate in the outpatient treatment period Days 4 to 7. Prior to 
discharge on Day 4, the following assessments will be performed: 
 Investigator to assess patients ability to continue in the outpatient treatment  
o If subjects are eligible to participate in the outpatient phase: 
 Study staff to provide outpatient dosing instructions 
 Study staff to observe subject administration of study drug dosing 
 Study staff to dispense outpatient study drug 
 Study staff to dispense rescue pain medication and nausea medications 
 Study staff to instruct subject on guidance for rescue pain medication and 
nausea medication  
 Study staff to provide completion instructions and dispense Outpatient 
Diary  
 Discharge subject from research site 
o If subjects are not eligible to participate in the outpatient phase: 
 Discharge subject from research site 
 Collect Adverse Events. 
 Collect concomitant medications and procedures. 
7.4. 
Treatment Period (Outpatient; Day 4-7) 
During the outpatient section of the study, subjects should not drive, operate heavy machinery, 
climb ladders, drink alcohol or take any other narcotics.  Subjects will be instructed to call the 
research site prior to any additional dosing if they experience dizziness, lightheaded, sleepy, 
confused, slurred speech. 
The following assessments will be performed during this period: 
 Self-administration of study medication 
 Recording of study doses in the outpatient diary 
 Recording of Adverse Events in the outpatient diary 
 Recording concomitant medications and procedures in the outpatient diary 

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7.5. 
Follow-up Period/End of Study/Early Termination (Day 8, + 2 day 
window) 
Subjects will be instructed to return all outpatient study drug, rescue pain and nausea medication, 
and diaries to study personnel at the Follow-up Visit on Day 8 (+ 2 day window). The following 
assessments will be performed: 
 Resting vital signs (blood pressure [BP], heart rate [HR], respiratory rate [RR], 
temperature) 
 Measure pulse oximetry 
 Perform a physical examination 
 Collect hematology, chemistry, and urinalysis samples 
 Perform 12-lead ECG 
 Perform oral cavity exam 
 Concomitant medications and procedures 
 Assess and record AEs that have occurred since the last evaluation  
 Collect and review outpatient diary if applicable 
 Perform drug accountability and reconciliation  
 Discharge subject from study 
8. 
STATISTICS 
8.1. 
Efficacy Endpoints  
No efficacy endpoints will be assessed. 
8.2. 
Safety Endpoints 
The primary safety endpoints are the incidence of TEAEs. 
The secondary safety endpoints are as follows:  
 Proportion of subjects using rescue medication for nausea 
 Time to first use of rescue medication for nausea following each dose of the 
investigational product (IP) 
 Total use of rescue medication for nausea over 0 to 8 hours, 0 to 24 hours, over 0 to 48 
hours, over 0-72 hours and 0-7 days 
 Pulse oximetry recorded prior to study drug administration 
 ECGs at 90 minutes, 12, 24, 48 and 72 hours 
 
Oral examinations 
8.3. 
Sample Size Determination 
No formal sample size estimate has been completed.  However, a sample size of 50 subjects per 
treatment group is expected considered sufficient to demonstrate that the incidence of nausea and 

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vomiting associated with buprenorphine is similar consistent with to that of standard post-
operative narcotic therapy. 
8.4. 
Analysis Populations 
Statistical analysis will be done on the safety population, which will include all subjects who are 
treated with the study drug. The safety population is the population for all safety assessments. 
8.5. 
Statistical Analyses 
No formal statistical hypothesis testing will be performed for this safety study.   
Summary statistics will be provided for all safety variables by treatment group. For continuous 
variables, these statistics will typically include the number of subjects, mean, standard deviation 
(SD), median, minimum, and maximum. For categorical variables, these statistics will typically 
include the number and percentage of subjects in each category. A Statistical Analysis Plan that 
describes the details of the analyses to be conducted will be finalized prior to database lock. 
8.5.1. 
Disposition and Demographics 
8.5.1.1. 
Disposition and Withdrawals 
The numbers of subjects randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of subjects in each 
analysis population will be reported. 
8.5.1.2. 
Protocol Deviations 
Protocol deviations will be identified and classified as minor or major and summarized by 
treatment group. 
8.5.1.3. 
Demographics and Other Baseline Characteristics 
These analyses will be conducted for the safety populations. 
Demographic and baseline characteristics (including age, gender, race, weight, height, BMI, 
surgical procedure, surgery duration and PONV risk factor) will be summarized by treatment 
group and for the overall population by descriptive statistics. No formal statistical analyses will 
be performed.  
Medical history will be listed. 
Prior and concomitant medications will be classified by using the World Health Organization 
Drug Dictionary Anatomical Therapeutic Chemical classes and preferred terms and summarized 
by treatment group  
8.5.2. 
Exposure and Compliance 
The exposure to study medication during the treatment periods will be summarized by 
descriptive statistics. As the dose administration during the inpatient period is under the control 
of the study sites, compliance during that time will not be an issue. Compliance of the subject 
during the outpatient portion of the study will also be summarized. 

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8.5.3. 
Safety Analyses 
Safety analyses will be conducted using data from the safety population. No formal inferential 
analyses will be conducted for safety variables. Data listings will be provided for protocol-
specified safety data. 
8.5.3.1. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (Version 19.0 or higher) will be used to 
classify all AEs. Adverse event summaries will include only TEAEs, which will be summarized 
for each treatment group. 
The number and percentage of subjects with AEs will be displayed for each treatment group by 
system organ class and preferred term. Summaries of AEs by severity and relationship to the IP 
will also be provided. Serious Adverse Events and AEs resulting in discontinuation will be 
summarized separately in a similar manner. Subject listings of AEs and SAEs will be produced. 
8.5.3.2. 
Vital Signs  
Vital signs results and changes from baseline will be summarized at each time point. 
8.5.3.3. 
ECGs and Physical Exam 
Any abnormal ECG or Physical Exam finding at each time point will be summarized.   Clinically 
significant abnormalities in ECGs or PE will be recorded as AEs. 
9. 
STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel prior to the study, periodic monitoring visits, and meticulous data management. 
9.1. 
Sponsor and Investigator Responsibilities 
9.1.1. 
Sponsor Responsibilities 
The sponsor, and/or sponsor’s representative is obligated to conduct the study in accordance with 
strict ethical principles. The sponsor reserves the right to withdraw a subject from the study, to 
terminate participation of a study site at any time, and/or to discontinue the study. 
The sponsor, or sponsor’s representative, agrees to provide the investigator with sufficient 
material and support to permit the investigator to conduct the study according to the study 
protocol. 
9.1.2. 
Investigator Responsibilities 
By signing the Investigator’s Agreement, the investigator indicates that she/he has carefully read 
the protocol, fully understands the requirements, and agrees to conduct the study in accordance 
with the procedures and requirements described in this protocol. 
The investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including and in accordance with the April 

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1996 International Conference on Harmonisation (ICH) Guidance for Industry E6 Good Clinical 
Practice (GCP) and in agreement with the 1996 Version of the Declaration of Helsinki. While 
delegation of certain aspects of the study to sub-investigators and study coordinators is 
appropriate, the investigator will remain personally accountable for closely overseeing the study 
and for ensuring compliance with the protocol and all applicable regulations and guidelines. The 
investigator is responsible for maintaining a list of all persons that have been delegated study-
related responsibilities (e.g., sub-investigators and study coordinators) and their specific study-
related duties. 
Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, IPs, and their specific 
duties within the context of the study. Investigators are responsible for providing Medtronic with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
9.2. 
Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or sponsor’s representative that the study can be initiated at the study site. The 
study site will not be authorized for study initiation until: 
 The study site has received the appropriate institutional review board (IRB) approval 
for the protocol and the appropriate informed consent form (ICF). 
  All regulatory documents have been submitted to and approved by the sponsor or 
sponsor’s representative. 
 The study site has a clinical trial agreement in place. 
 Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
9.3. 
Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may not be rescreened for the study. Screen 
failures for scheduling issues may be rescreened at the investigators discretion.  
9.4. 
Study Documents 
All documentation and material provided by the sponsor, or sponsor’s representative for this 
study are to be retained in a secure location and treated as confidential material. 
9.4.1. 
Investigator’s Regulatory Documents 
The regulatory documents must be received from the investigator and reviewed and approved by 
the sponsor or sponsor’s representative before the study site can initiate the study and before the 
sponsor, or sponsor’s representative, will authorize shipment of investigational product (IP) to 
the study site. Copies of the investigator’s regulatory documents must be retained at the study 

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site in a secure location. Additional documents, including a copy of the protocol and applicable 
amendment(s), the IB, CRF/electronic case report form (eCRF) completion guidelines, copies of 
regulatory references, copies of IRB correspondence, and IP accountability records should also 
be retained as part of the investigator’s regulatory documents. It is the investigator’s 
responsibility to ensure that copies of all required regulatory documents are organized, current, 
and available for inspection. 
9.4.2. 
Case Report Forms 
By signing the Investigator’s Agreement, the investigator agrees to maintain accurate 
CRFs/eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor, or sponsor’s representative, will provide the necessary training on the 
use of the specific CRFs/eCRF system used during the study to ensure that the study information 
is captured accurately and appropriately. 
To ensure data accuracy, CRF/eCRF data for individual subject visits should be completed as 
soon as possible after the visit. All requested information must be entered in the CRF/electronic 
data capture (EDC) system according to the completion guidelines provided by the sponsor, or 
sponsor’s representative. 
9.4.3. 
Source Documents 
All information recorded in the CRF/EDC system must be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
During the study, select CRF/eCRF data may be used as original data collection tools as long as 
a description of this documentation process is maintained in the investigator’s study files. 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central laboratory to the sponsor or the sponsor’s representative. A paper copy of the laboratory 
results will be provided to the study site and should be retained with each subject’s source data. 
The investigator will provide direct access to source data and documents for trial-related 
monitoring, audits, IEC/IRB review, and regulatory requirements. 
9.5. 
Study Termination 
The study may be terminated at the sponsor’s discretion at any time and for any reason. Study 
sites may be asked to have all subjects currently participating in the study complete all of the 
assessments for the Follow-up visit 
In the event of study discontinuation, study sites may be asked to have all subjects currently 
participating in the study complete all of the assessments for the Early Termination Visit. 

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9.6. 
Study Site Closure 
At the end of the study, all study sites will be closed. The sponsor or sponsor’s representative 
may terminate participation of a study site at any time. Examples of conditions that may require 
premature termination of a study site include, but are not limited to, the following: 
 Noncompliance with the protocol and/or applicable regulations and guidelines 
 Inadequate subject enrollment 
9.6.1. 
Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the study, 
specifically including, but not limited to, those defined by GCP as essential until the following 
occur: 
 At least 2 years after the last marketing authorization for the Investigational Product 
has been approved or the sponsor has discontinued its research with the 
Investigational Product, or 
 At least 2 years have elapsed since the formal discontinuation of clinical development 
of the Investigational Product 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
9.6.2. 
Laboratory Sample Retention 
Laboratory samples may be used for purposes related to this research. The samples will be stored 
until the sponsor has determined that specimens are no longer needed and the decision has been 
made that none of the samples needs to be reanalyzed. In addition, identifiable samples can be 
destroyed at any time at the request of the subject. 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The sponsor or its designee will implement and maintain quality control and quality assurance 
procedures with written standard operating procedures to ensure the study is conducted and data 
are generated, documented, and reported in compliance with the protocol, GCP, and applicable 
regulatory requirements. This trial will be conducted in accordance with the provisions of the 
Declaration of Helsinki (October 1996) and all revisions thereof, and in accordance with the 
FDA CFR 312.50 and 312.56, and with the ICH guidelines on GCP (CPMP/ICH/135/95). 
10.1. 
Changes To The Protocol 
Only Insys Development Company may modify the protocol. Amendments to the protocol will 
be made only after consultation and agreement between the sponsor and the investigator. The 
only exception is when the investigator assesses a subject’s safety will be compromised without 
immediate action. In these circumstances, immediate approval of the chairman of the IEC/IRB 
must be sought, and the investigator should inform the sponsor and the full IEC/IRB within 5 
working days after the emergency occurred. All amendments that have an impact on subject risk 

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or the study objectives, or require revision of the informed consent form, must receive approval 
from the IEC/IRB prior to their implementation. 
10.2. 
Monitoring 
The sponsor or sponsor’s representative will conduct site visits to monitor the study and ensure 
compliance with the protocol, GCP, and applicable regulations and guidelines. The assigned 
clinical research associate(s) (CRA[s]) will visit the investigator and study site at periodic 
intervals and maintain periodic communication. The investigator agrees to allow the CRA(s) and 
other authorized sponsor/contract research organization (CRO) personnel access. The CRA(s) 
will maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
investigator and staff. 
10.3. 
Data Review Meeting 
The sponsor will review all data reported in CRFs of all subjects before database lock. The data 
review meeting determines whether or not all enrolled subjects can be included in the analysis 
population according to the specified definition of analysis populations and evaluates whether or 
not medical decisions of the Investigator were appropriate for important data affecting the safety 
and efficacy endpoint. 
10.4. 
Protocol Violations  
The Investigator will conduct the study in compliance with the protocol approved by the IRB. 
Modifications to the protocol should not be performed without agreement of both the 
Investigator and the sponsor. Changes to the protocol will require written IRB approval prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
subjects. 
The Investigator or sub-investigator should document any deviation from the protocol and the 
reason. If the Investigator performs a deviation from the protocol or a change of the protocol to 
eliminate an immediate hazard(s) to subjects, the record should be immediately submitted to the 
sponsor, the CRO, and the IRB by the Investigator and the IRB will provide expedited review 
and approval. After the Investigator has obtained approval of the IRB, the Investigator should 
obtain written permission of the CRO and written agreement of the sponsor. 
When deviation from the protocol is required to eliminate immediate hazard(s) to subjects, the 
Investigator will contact the sponsor, if circumstances permit, to discuss the planned course of 
action. Any deviations from the protocol must be fully documented in the CRF and source 
documentation. 
10.5. 
Quality Assurance Audit 
This study will be subject to audit by the sponsor, CRO, or designee. 
The sponsor or sponsor’s representative may conduct audits on a selection of study sites, 
requiring access to subject notes, study documentation, and facilities or laboratories used for the 
study. 

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The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB or regulatory authorities according 
to GCP guidelines. The investigator agrees to cooperate with the auditor during the visit and will 
be available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify sponsor or sponsor’s representative immediately. 

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11. 
REGULATORY AND ETHICAL CONSIDERATIONS 
11.1. 
Regulatory Authority Approval 
The investigator will ensure that the protocol and consent form are reviewed and approved by the 
appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) prior to the 
start of any study procedures. The IEC/IRB will be appropriately constituted and will perform its 
functions in accordance with Food and Drug Administration (FDA) regulations, International 
Conference on Harmonization (ICH) good clinical practice (GCP) guidelines, and local 
requirements as applicable. 
In addition, the IRB will approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, subject recruitment 
procedures, written information to be provided to the subjects, available safety information, 
information about payment and compensation available to subjects, the investigator’s curriculum 
vitae and/or other evidence of qualifications, and any other documents requested by the IRB/IEC 
and regulatory authority, as applicable. 
11.2. 
Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki and GCP according 
to ICH guidelines. Specifically, the study will be conducted under a protocol reviewed by an IRB 
or IEC; the study will be conducted by scientifically and medically qualified persons; the 
benefits of the study are in proportion to the risks; the rights and welfare of the subjects will be 
respected; the physicians conducting the study do not find the hazards to outweigh the potential 
benefits; and each subject will give his or her written, informed consent before any protocol-
driven tests or evaluations are performed. 
11.3. 
Statement of Investigator/Delegation of Authority 
As a condition for conducting the clinical investigation, the Principal Investigator will sign the 
FDA Form 1572, Statement of Investigator (21 Code of Federal Regulations [CFR] Part 312). 
The Principal Investigator will ensure that all persons assisting with the trial are adequately qualified, 
informed about the protocol, any amendments to the protocol, the study treatments, and their trial-related 
duties and functions. The qualified investigator will maintain a list of sub-investigator and other 
appropriately qualified persons to whom to delegate significant trial-related duties. Should the qualified 
investigator delegate the supervision of the investigational product administration to a designated person, 
this individual must have the appropriate medical qualifications to effectively conduct or supervise any 
potential resuscitation procedures. 
11.4. 
Subject Informed Consent 
The investigator or his/her designee will inform the subject of all aspects pertaining to their 
participation in the study. The process for obtaining subject informed consent will be in 
accordance with all applicable regulatory requirements (e.g., CFR Part 50 and ICH E6 Section 
4.8). The investigator or his/her designee and the subject must both sign and date the informed 
consent document (ICD) before the subject can participate in the study. The subject will receive 
a copy of the signed and dated form, and the original will be retained in the site’s study records. 
The decision to participate in the study that is made by the subject is entirely voluntary. The 

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investigator or his/her designee must emphasize to the subject that consent for study participation 
may be withdrawn at any time without penalty or loss of benefits to which the subject is 
otherwise entitled. If the ICD is amended during the study the investigator must follow all 
applicable regulatory requirements pertaining to approval of the amended ICD by the IRB, and 
use of the amended form, including the necessity of re-consenting ongoing subjects. 
11.5. 
Investigator Reporting Requirements 
In accordance with applicable local regulatory requirements, the investigator may be obligated to 
provide periodic safety updates on the conduct of the study at his/her site and notification of 
study closure to the IRB. Such periodic safety updates and notifications are the responsibility of 
the investigator and not of Insys Development Company or its delegate. 
12. 
DATA HANDLING ANG RECORD KEEPING 
12.1. 
Data Management 
The sponsor or sponsor’s representative will be responsible for activities associated with the data 
management of this study. The standard procedures for handling and processing records will be 
followed per GCP and the CRO’s SOPs. A comprehensive Data Management Plan will be 
developed including a data management overview, database contents, annotated CRF, pre-entry 
review list, self-evident correction conventions, query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. 
12.2. 
Case Report Forms and Source Documents 
The CRFs will be supplied by 
. The complete 
CRFs will be reviewed, signed, and dated by the qualified investigator and a copy returned to the 
Sponsor with the final report. 
Source documents are defined as original documents, data, and records. This may include 
hospital records, clinical and office charts, laboratory data/information, subjects’ diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media and/or X-rays. 
12.3. 
Documentation and Retention of Essential Documents 
All documents pertaining to the study, including a copy of the approved protocol, copy of the 
informed consent document, completed CRFs, source documents, drug accountability and 
retention records, and other study related documents will be retained in the permanent archives 
of the study site. These will be available for inspection at any time by the Sponsor or the FDA. 
Per 21 CFR 312, record retention for this study is required for a period of two years following 
the date on which this study agent is approved by the FDA for the marketing purposes that were 
the subject of this investigation; or, if no application is to be filed or if the application is not 

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approved for such indication, until two years following the date on which the entire study is 
completed, terminated, or discontinued, and the FDA is notified. 
The investigator will provide direct access to source data and documents for trial-related 
monitoring, audits, IEC/IRB review, and regulatory requirements. 
12.4. 
Financial Disclosure 
These issues will be addressed in a separate agreement between the sponsor and the Investigator. 
The US FDA Financial Disclosure by Clinical Investigators (21 Code of Federal Regulations 
[CFR] 54) regulations require sponsors to obtain certain financial information from investigators 
participating in covered clinical studies; each investigator and sub-investigator is required to 
provide the required financial information and to promptly update Insys Development Company, 
Inc., with any relevant changes to their financial information throughout the course of the clinical 
study and for up to 1 year after its completion.  This rule applies to all investigators and sub-
investigators participating in covered clinical studies to be submitted to the FDA in support of an 
application for market approval. 

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13. 
ADDRESSESS 
Sponsor 
Name: 
Insys Development Company, Inc. 
Address: 
1333 South Spectrum Blvd., Suite 100  
Chandler, AZ 85286 
Phone: 
 
Fax: 
 
Clinical Research Organization 
Name: 
 
Address: 
 
 
Phone: 
 
Drug Safety 
Name: 
Insys Development Company, Inc. 
Address: 
1333 South Spectrum Blvd., Suite 100 
Chandler, AZ 85286                  
Phone: 
 
Drug Safety: 
 
 
Packaging 
Name: 
 
Address: 
 
 
                                      
Manufacturing 
Name: 
Insys Manufacturing 
Address: 
2700 Oakmont Dr.  
Round Rock, TX 78665                                        
Central Lab 
Name: 
 

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Address: 
 
 
 
Report Writing  
Name: 
  
Address: 
 
 
 
 

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14. 
USE OF INFORMATION AND PUBLICATION POLICY 
14.1. 
Use Of Information 
All information concerning Buprenorphine Sublingual Spray 0.5 mg and Insys Development 
Company’ operations, such as Insys Development Company’ patent applications, formulas, 
manufacturing processes, basic scientific data, or formulation information, supplied by Insys 
Development Company and not previously published, is considered confidential information. 
This confidential information shall remain the sole property of Insys Development Company, 
shall not be disclosed to others without the written consent of Insys Development Company, and 
shall not be used except in the performance of this study. 
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study (by name and subject number).  This list will be maintained at the site, and 
will not be retrieved by Insys Development Company. 
14.2. 
Publication Policy 
Insys Development Company, Inc. will retain ownership of all data. All proposed publications 
based on this study will be subject to the sponsor’s approval requirements. 

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15. 
REFERENCES 
 
1) Apfelbaum JL, Chen C, Mehta SS, Gan TJ: Postoperative pain experience: Results from a 
national survey suggest postoperative pain continues to be undermanaged. Anesth Analg 
97:534-540, 2003. 
2) Kelly DJ, Ahmad M, Brull SJ. Preemptive analgesia I: physiological pathways and 
pharmacological modalities. Can J Anaesth. 2001; 48:1000.1. 
3) Dahan A, Yassen A, Romberg R, Sarton E, Teppema L, Olofsen E, Danhof M; 
Buprenorphine induces ceiling in respiratory depression but not in analgesia. Br J 
Anaesth 2006; 96 (5): 627-632.  
4) Dahan A, Yassen A, Bijl H, Romberg R, Sarton E, Teppema L, Olofsen E, Danhof M; 
Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in 
humans and rats. Br J Anaesth 2005; 94 (6): 825-834.  
5) Garimella,V , Cellini C. Postoperative pain control. Clin Colon Rectal Surg. 2013 Sep; 
26(3): 191–196. 
6) Moradi M, Esmaelli S, Shoar S, et al. Use of oxycodone in pain management. 
Anesthesiology and Pain Medicine. 2012 March; 1(4): 262-264. 
7) Apfel, C. C., et al. (1999). A simplified risk score for predicting postoperative nausea and 
vomiting: conclusions from cross-validations between two centers. Anesthesiology. 91(3): 
693-700. 
 
 
 

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16. 
INVESTIGATOR SIGNATURE PAGE 
 
TITLE: 
A Phase 2, Randomized, Open Label, Multiple-Dose, Comparator 
Controlled, Parallel-Group, Safety and Tolerance Study of 
Buprenorphine Sublingual Spray (0.5 mg TID) versus Standard of 
Care Post-Operative Narcotic Therapy for the Treatment of Post-
Operative Pain 
PROTOCOL NUMBER: 
INS005-17-111 
PHASE OF STUDY: 
Phase 2 
PROTOCOL DATE: 
Version 1.0, 28 July 2017 
STUDY SPONSOR: 
Insys Development Company, Inc. 
1333 South Spectrum Blvd, Suite 100 
Chandler, AZ 85286 
 
 
 
PRINCIPAL INVESTIGATOR COMMITMENT: 
 
I, the undersigned Principal Investigator, submit this statement of commitment as evidence that I 
understand my responsibilities pursuant to the Code of Federal Regulations (21 CFR § 312.60 
through § 312.70, 21 CFR § 11, 50, 54, 56) and ICH E6 Good Clinical Practice guidelines, as 
well as with any and all applicable federal, state and/or local laws and regulations, and agree to 
conduct the study in accordance with the protocol referenced herein. 
 
 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
 
 
 
Principal Investigator Signature 
 
Date 

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17. 
APPENDICES 
17.1. 
Appendix 1: Surgical and Anesthesia Protocols 
Below are surgical and anesthetic protocols for the allowed surgical procedures in this protocol. 
The anesthetic regimens listed for each surgical model are a guide that should be followed to 
minimize interpatient variability to the greatest extent possible. However, it is understood that 
hemodynamic fluctuations and other intraoperative events may necessitate some deviation from 
this standard regimen and that is acceptable. 
Bunionectomy  
Subjects will undergo primary unilateral first metatarsal bunionectomy with no other collateral 
procedures. The use of midazolam, fentanyl, nitrous oxide and propofol are allowed with doses 
at discretion of anesthesia.  A small dose of lidocaine (up to 5 mL of 1% lidocaine without 
epinephrine) may be administered prior to medications to reduce peripheral vein irritation. A 
standard Mayo block will be established using 2% lidocaine (plain), not to exceed 24 mL. For 
nausea prophylaxis, all subjects will receive a uniform standard of care regimen which includes 
the following: 10 mg of dexamethasone at induction and 8 mg of ondansetron near the end of 
surgery.  Airway management is at the discretion of anesthesia (typically LMA vs MAC). The 
bunionectomy procedure time should not exceed 90 minutes. No Popliteal nerve block should be 
used. Post surgically and prior to randomization, subjects may be treated with intravenous 
morphine and or fentanyl for post-surgical analgesia (dose and frequency per the discretion of 
the investigator). 
Breast Augmentation  
Subjects will undergo a bilateral submuscular augmentation mammoplasty via an inframammary 
approach under general anesthesia utilizing saline implants not to exceed 500cc each. Ancillary 
procedures (liposuction, breast reduction, breast lift, abdominoplasty etc.) are prohibited. 
Midazolam, Fentanyl, Sevoflurane, nitrous oxide and propofol are allowed with doses at 
discretion of anesthesia. A small dose of lidocaine (up to 5 mL of 1% lidocaine without 
epinephrine) may be administered prior to medications to reduce peripheral vein irritation. For 
nausea prophylaxis, all subjects will receive a uniform standard of care regimen which includes 
the following: 10 mg of dexamethasone at induction and 8 mg of ondansetron near the end of 
surgery.  LMA without muscle relaxation is preferred for all subjects however ET intubation 
may be performed if deemed necessary. Post surgically and prior to randomization, subjects may 
be treated with intravenous morphine and or fentanyl for post-surgical analgesia (dose and 
frequency per the discretion of the investigator). 
Mini-Abdominoplasty 
Subjects will undergo a mini-abdominoplasty procedure (defined as a cosmetic surgery involving 
skin, muscle and adipose tissue, but no relocation of the umbilicus). The approach should be 
anterior. Surgical drains should be placed per the discretion of the surgeon. The incision should 
in general be from one ASIS (anterior superior iliac spine) to the other. It is understood that the 
exact incision length will vary depending on the subject’s anatomy and the desired cosmetic 
outcome. Ancillary procedures (liposuction, breast reduction etc.) are prohibited. Midazolam, 

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Sevoflurane, nitrous oxide, fentanyl and propofol are allowed with doses at discretion of 
anesthesia. A small dose of lidocaine (up to 5 mL of 1% lidocaine without epinephrine) may be 
administered prior to medications to reduce peripheral vein irritation. For nausea prophylaxis, all 
subjects will receive a uniform standard of care regimen which includes the following: 10 mg of 
dexamethasone at induction and 8 mg of ondansetron near the end of surgery. LMA without 
muscle relaxation is preferred for all subjects however ET intubation may be performed if 
deemed necessary. Post surgically and prior to randomization, subjects may be treated with 
intravenous morphine and or fentanyl for post-surgical analgesia (dose and frequency per the 
discretion of the investigator). 
 
 
 
 
 
 

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17.2. 
Appendix 2: Naloxone Administration 
1. Administer at a dose of 0.1 mg to 0.2 mg IV at every 2- to 3- minute’s intervals until 
desired response is achieved.  
2. Additional doses may be necessary and depends on the buprenorphine dose and the 
correct naloxone dose window 
3. Because respiratory depression from buprenorphine may last longer than the effects of 
naloxone boluses or short infusions, continued close supervision of the subject is until 
vital signs including respiratory rate and oxygen saturation levels stabilize over an 
extended period of time 
4. Naloxone IV is the preferred route of administration (In the event of lost IV access, 
naloxone may be administered IM and SQ as an alternative) 
 
 
 

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17.3. 
Appendix 3: Dosing Instructions 
Buprenorphine SL Spray  
1. Prior to administration, ask subject to swallow contents of mouth. 
2. Ask subject to lift tongue. 
3. Bring the unit as close as possible to the mouth. 
4. During the treatment period to which the subject is assigned, administer one spray UNDER 
the tongue at a 45° angle. 
5. Subject should be instructed to bring back the tongue to resting position immediately upon 
administering the product. 
6. Instruct the subject NOT to swallow the drug 
7. Instruct the subject to avoid swallowing immediately after administering the spray. 
8. The subject should hold solution under the tongue for approximately 60 seconds. The 
medication should not be expectorated or the mouth rinsed.   
Drug should be sprayed in area shown by arrow in diagram below: 
 
 
 
 
 

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17.4. 
Appendix 4: Schedule of Events  
 
Assessments  
Screening 
Period 
Surgical Period (Day 1) 
Treatment Period 
(Inpatient; Day 1-4) 
Treatment Period 
(Outpatient; Day 4-7) 
Follow-
up Period 
Day -28 to -
1 
Pre-surgery/ 
Morning of 
Surgery 
Surgery 
Pre- 
Dose 
Drug Admin / 
Time 0 
 
T0 - T72 
Discharge 
from Research 
Site  
(Day 4) 
Outpatient 
Treatment 
(Day 4 – 7) 
Day 
8/EOS, + 
2 day 
window / 
ET 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
Demographicsi 
X 
 
 
 
 
 
 
 
 
Medical and Surgical Historyii 
X 
X 
 
 
 
 
 
 
 
ASA Classificationiii  
X 
 
 
 
 
 
 
 
 
PONV Risk Assessment  
X 
 
 
 
 
 
 
 
 
Physical Examiv 
X 
X 
 
 
 
X 
 
 
X 
Clinical laboratory tests (hematology, chemistry, 
urinalysis, serology)v 
X 
 
 
 
 
 
 
 
X 
12-lead Electrocardiogramvi  
X 
 
 
X 
 
X 
 
 
X 
Urine Drug Test and Alcohol Breathalyzer Test vii 
X 
X 
 
 
 
 
 
 
 
Pregnancy Test for female subjectsviii 
X (Serum) 
X (Urine) 
 
 
 
 
 
 
 
X-ray and podiatric examinationix 
X 
 
 
 
 
 
 
 
 
Surgeryx 
 
 
X 
 
 
 
 
 
 
Post-Surgical Eligibility 
 
 
 
X 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
Study Medication Administrationxi 
 
 
 
 
X 
X 
X 
X 
 
Vital Signsxii 
X 
X 
 
X 
X 
X 
 
 
X 
Pulse Oximetryxiii 
X 
 
 
X 
 
X 
 
 
X 
Oral Cavity  Examxiv 
X 
X 
 
X 
 
X 
 
 
X 
Adverse Event Collectionxv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medicationsxvi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator Assessment of Outpatient Treatment   
 
 
 
 
 
 
X 
 
 
Dosing Instructions for Outpatientxvii  
 
 
 
 
 
 
X 
 
 
Observe Self-Administration of Study Drugxviii 
 
 
 
 
 
 
X 
 
 
Dispense Outpatient Study Drug 
 
 
 
 
 
 
X 
 
 
Dispense Rescue Pain Medication and Nausea 
Medicationsxix 
 
 
 
 
 
 
X 
 
 
Staff to instruct subject on guidance for recues pain 
medication and nausea  medication  
 
 
 
 
 
 
X 
 
 
Provide completion instructions and Dispense Subject 
Diary xx 
 
 
 
 
 
 
X 
 
 

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Assessments  
Screening 
Period 
Surgical Period (Day 1) 
Treatment Period 
(Inpatient; Day 1-4) 
Treatment Period 
(Outpatient; Day 4-7) 
Follow-
up Period 
Day -28 to -
1 
Pre-surgery/ 
Morning of 
Surgery 
Surgery 
Pre- 
Dose 
Drug Admin / 
Time 0 
 
T0 - T72 
Discharge 
from Research 
Site  
(Day 4) 
Outpatient 
Treatment 
(Day 4 – 7) 
Day 
8/EOS, + 
2 day 
window / 
ET 
Recording of study doses in outpatient diary 
 
 
 
 
 
 
 
X 
 
Collect Outpatient Medication and Review Diary  
 
 
 
 
 
 
 
 
X 
Subjects confinement at research site 
 
X 
X 
X 
X 
X 
 
 
 
Discharge subject from the study site 
 
 
 
 
 
 
X 
 
 
Discharge from study 
 
 
 
 
 
 
 
 
X 

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i Demographics: Includes Height, weight, and body mass index 
ii Medical/Surgical History: Medical history should be reviewed for any changes from Screening 
iii ASA: Must be classified using the American Society of Anesthesiologists Physical Status Classification System as P1 to P2. 
iv Physical Exam: A complete physical examination (HEENT, cardiovascular, respiratory, gastrointestinal, neurological, dermatologic, and musculoskeletal systems; 
excluding the genitourinary examination), includes an examination of the subject’s surgical site. A physical exam will be conducted at screening, before surgery on Day 1, 
72 hours (±4 hours) after first dose of study drug (Time 0), and at the Follow-up Visit/ET.  
v Clinical Lab Tests: Hematology, chemistry (including LFTs) and UA and serology samples will be taken at screening. At the Follow-up Visit/ET, clinical lab testing 
includes only hematology and chemistry (including LFTs), urinalysis (with microscopic examination if indicated). Assessments will be repeated based on the Investigator’s 
discretion 
vi Electrocardiogram: An ECG will be performed at screening, before the first dose of study drug, and then at 90 minutes (±10 minutes), and at 12, 24, 48 hours, 72 hours  
(±10 minutes) after Time 0. And ECG will also be collected Follow-up Visit/ET. 
vii Urine Drug Test & Alcohol Breath Test: A urine drug screen and alcohol breath test will be collected at Screening and before surgery on Day 1. The test results must be 
negative for the subject to continue in the study, except in cases where a valid physician’s prescription can be verified. 
viii Pregnancy Test: Females of child-bearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to surgery on Day 1. 
ix X-ray and podiatry exam: An x-ray and podiatry exam will only be collected on subject undergo a bunionectomy procedure. Radiographs taken within 6 months before 
Screening will be acceptable. 
x Surgery: The surgical procedures will be bunionectomy, breast augmentation, and abdominoplasty. Anesthesia will be established using standardized techniques, as 
appropriate, for each surgical procedure.  
xi Study Medication Administration: After meeting post-surgical eligibility requirements and subsequently being randomized to treatment, subjects may receive their first 
dose of study drug any time between 0-4 hours after surgery. The first dose does not need to be immediately administered after meeting post-surgical eligibility 
requirements. Subjects should not have anything orally except room-temperature water within 15 minutes of each dose. Study Medication Administration after the First 
dose will be administered every 8 hours (Treatment Days 1 – 7).  
xii Vital Signs:  Includes blood pressure, heart rate, respiratory rate, and oral temperature, will be measured after the subject has been in a resting position for 5 minutes. Blood 
pressure, heart rate, respiratory rate, and oral temperature will be measured at Screening, before surgery on Day 1, and at baseline before Time 0 (prior to first dose). Heart 
rate and respiratory rate will be measured at study drug administration/Time 0, 1 hour, and every 2 hours (±10 minutes) after first dose of study drug /Time 0 during the 
inpatient Treatment Period. Blood pressure will be measured every 4 hours after first dose of study drug /Time 0 during the inpatient Treatment Period. Vital signs will also 
be measured at Follow-up Visit/ET. 
xiii Pulse oximetry:  Will be measured continuously after surgery for safety; pulse oximetry will be recorded at screening and at selected times (±10 minutes), including 
baseline before Time 0 (prior to first dose) and at 90 minutes and 12, 24, 48, 72 hours after Time 0, and at Follow-up Visit/ET. 
xiv Oral Cavity Exam: Study staff will perform a sublingual assessment, noting the colour of mucosa and whether inflammation is present.  Check for mucositis and local 
irritation. The oral cavity examinations should be conducted at screening, pre-surgery, before the first dose of study drug, and then at 90 minutes (±10 minutes), and at 12, 
24, 48 hours, 72 hours (±10 minutes) after Time 0.  An oral examination will also be collected at Follow-up Visit/ET. Assessments will be repeated based on the 
Investigator’s discretion. 
xv AE Collection: Serious Adverse Events will be collected from time of consent through 30 days following study participants. Non-serious Adverse Events will be collected 
from time of first dose of study medication through the end of study participation.   
xvi Concomitant Medications: Study staff will collect concomitant medications taken within 30 days of screening Visit 1 and throughout the study.  Subjects will be 
instructed to record all study drug and concomitant medications taken in addition to adverse events (AEs) experienced after discharge in their take-out outpatient diary. 
                                                 

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Subjects will also be instructed to return the outpatient study drug and subject diary to study personnel at the Follow-up Visit on Day 8 (+ 2 day window).  See Appendix 3 
for Naloxone guidance.  
xvii Dosing Instructions for Outpatient:  Study staff will train subjects on how to administer the study drugs 1) On outpatient Day 4-7 subjects will be provided 
Buprenorphine 0.5 mg Sublingual Spray TID or reference drugs oxycodone 10 mg TID. 2) On outpatient Day 4-7 subjects will be provided with acetaminophen, and will 
be advised to take acetaminophen 1000 mg every six hours as needed for rescue analgesia. 3) On outpatient Day 4-7, subjects will be administered Zofran ODT (oral 
dissolvable tablet) to be taken as needed. The rescue medication and specific reason for use will need to be captured in the subject outpatient diaries. 
xviii Observe Study Drug Administration: Site staff will train subjects on how to self-administer study drug. Investigators will determine if patients are able to proceed with 
the outpatient treatment period. Before discharge from the study site on Day 4, site personnel will dispense rescue medication and will train subjects on how to administer 
the study drug, educate patients on the signs and symptoms of adverse events, and observe subjects self-administer medication. After discharge, study drug will be 
administered by subjects at home according to the directions provided by study staff. 
xix Outpatient Rescue Pain Medication and Nausea Medication: Outpatient medication will be dispensed before discharge from the study site on Day 4.   
xx Subject Diary: Study personnel will dispense outpatient diary, study drug, rescue pain and nausea medication. Subjects will also be instructed to return the outpatient diary 
to study personnel at the Follow up Visit 8 + 2 days after surgery.