Clinical trial NCT03254459
Conditions: Pain, Postoperative
Sponsor: INSYS Therapeutics Inc
Start date: 2017-09-12; Completion date: 2017-11-13
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety and tolerability based on the incidence of adverse experiences of buprenorphine sublingual spray (0.5 milligrams \[mg\] three times daily \[TID\]) compared with standard post-operative narcotic therapy in participants with postoperative pain. Standard post-operative narcotic therapy is defined as morphine intravenous (IV) injection (4 mg TID) followed by oxycodone hydrochloride tablet (10 mg TID).

Detailed description:

Arms: arm 1: Buprenorphine Sublingual Spray 0.5 milligrams (mg) three times a day (TID) for 7 days. arm 2: Morphine intravenous (IV), 4 mg TID for 24 hours, followed by oxycodone hydrochloride tablet, 10 mg TID for 6 days.
Interventions: intervention 1: Buprenorphine Sublingual Spray intervention 2: Morphine intervention 3: Oxycodone Hydrochloride intervention 4: Zofran
Intervention descriptions: intervention 1: 0.5 mg Sublingual Spray intervention 2: 4 mg Intravenous Injection intervention 3: 10 mg tablet intervention 4: 4 mg oral disintegrating tablet (ODT) or IV injection given at the investigator's discretion for nausea

Protocol documents:
Prot_000.pdf: 
Insys Development Company, Inc. 
Protocol Number INS005-17-111 
Version 1.0 02Aug2017
      CONFIDENTIAL     
1 
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 
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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 
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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. 
                                                 


Insys Development Company, Inc. 
                        Protocol Number INS005-17-111  
 
Version 1.0 02Aug2017                            CONFIDENTIAL                                                        60 
 
  
 
                                                                                                                                                                                                                         
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.   
 
 
 
 

SAP_001.pdf: 
Sponsor: Insys Development Co, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Number: INS005-17-111 
Date: 08Sep2017 
- 1 -
STATISTICAL ANALYSIS PLAN 
08SEP2017 V1.0 
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 
Protocol Number: INS005-17-111 / NCT03254459 
Protocol Version 1.0 (02AUG2017) 
INS005-17-111_Admin Protocol Clarification_Final 1.0 (10AUG2017) 
INS005-17-111_Admin Protocol Clarification_Final 2.0 (22AUG2017) 
INS005-17-111_Admin Protocol Clarification_Final 3.0 (30AUG2017) 
INS005-17-111_Admin Protocol Clarification_Final 4.0 (07SEP2017) 
SPONSORED BY 
Insys Development Company, Inc. 
1333 South Spectrum Blvd, Suite 100 
Chandler, AZ 85286 
PREPARED BY 
 
 
 
 
 
 


Sponsor: Insys Development Co, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
- 2 - 
This document is confidential and proprietary to Insys Development Company, Inc..  Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein will be 
reproduced, published, or otherwise disclosed without the prior written approval of Insys Development 
Company, Inc., except that this document may be disclosed to appropriate Institutional Review Boards under 
the condition that they keep the information confidential. 


Sponsor: Insys Development Co, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
- 3 - 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
V0.1 
17AUG2017 
First Draft for Internal review 
V0.2(S) 
22AUG2017 
First Draft for Sponsor review 
V0.3(s) 
05SEP2017 
Incorporate sponsor comments, 
include Mock Shells for review 
V1.0 
08Sep2017 
Final v1.0  
 
 






Sponsor: Insys Development Co, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
- 4 - 
APPROVALS 
Author: 
 
 
 
 
 
 
 
 
Date: 
 
 
Reviewed:  
 
 
 
 
 
 
 
 
 
Date: 
 
 
Approved 
 
 
 
 
Insys Development Company, Inc. 
 
 
 
 
Approved: 
 
 
 
 
 
 
Insys Development Company, Inc. 
 
Date: 


Sponsor: Insys Development Co, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
- 5 - 
TABLE OF CONTENTS 
LIST OF IN-TEXT TABLES AND FIGURES .............................................................. - 7 - 
LIST OF ABBREVIATIONS ....................................................................................... - 8 - 
1. 
PURPOSE OF THE ANALYSES ....................................................................... - 10 - 
2. 
PROTOCOL SUMMARY ................................................................................... - 11 - 
2.1 
Study Objectives .................................................................................... - 11 - 
2.1.1 
Safety ........................................................................................... - 11 - 
2.1.2 
Efficacy ......................................................................................... - 11 - 
2.2 
Overall Study Design and Plan .............................................................. - 11 - 
2.3 
Study Population .................................................................................... - 13 - 
2.4 
Treatment Regimens.............................................................................. - 14 - 
2.4.1 
Study Material ............................................................................... - 14 - 
2.4.2 
Comparator Group ........................................................................ - 14 - 
2.5 
Treatment Group Assignments or Randomization .................................. - 14 - 
2.6 
Sample Size Determination .................................................................... - 15 - 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS............................. - 16 - 
4. 
ANALYSIS POPULATIONS .............................................................................. - 18 - 
4.1 
Efficacy Population ................................................................................ - 18 - 
4.2 
Safety Population ................................................................................... - 18 - 
4.3 
Disposition of Subjects ........................................................................... - 18 - 
4.4 
Major Protocol Deviations ...................................................................... - 18 - 
5. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................... - 19 - 
5.1 
Demographics and Baseline Characteristics .......................................... - 19 - 
5.2 
Medical History ...................................................................................... - 19 - 
5.3 
Prior and Concomitant Medications/Surgeries Details ............................ - 19 - 
6. 
MEASUREMENTS OF TREATMENT COMPLIANCE ....................................... - 20 - 
6.1 
Study Medication Compliance ................................................................ - 20 - 


Sponsor: Insys Development Co, Inc. 
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Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
- 6 - 
7. 
SAFETY EVALUATION .................................................................................... - 21 - 
7.1 
Overview of Safety Analysis Methods .................................................... - 21 - 
7.2 
Adverse Events ...................................................................................... - 21 - 
7.3 
Rescue Medication ................................................................................ - 23 - 
7.4 
Clinical Laboratory Evaluation ................................................................ - 24 - 
7.5 
Vital Signs .............................................................................................. - 24 - 
7.6 
Physical, Oral and ECG Exams ............................................................. - 25 - 
7.7 
Serology Screens, Drug of Abuse and Alcohol Screens, Pregnancy Test .- 25 
- 
8. 
EFFICACY EVALUATION ................................................................................ - 26 - 
9. 
OTHER ANALYSES ......................................................................................... - 27 - 
10. INTERIM ANALYSES AND DATA MONITORING ............................................ - 28 - 
11. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ................... - 29 - 
12. REFERENCES .................................................................................................. - 30 - 
13. APPENDICES ................................................................................................... - 31 - 
13.1 
List of Tables for Final Study Report ...................................................... - 31 - 
13.2 
List of Figures for Final Study Report ..................................................... - 33 - 
13.3 
List of Listings for Final Study Report ..................................................... - 33 - 
13.4 
TABLE, FIGURE AND LISTING SPECIFICATIONS ................................... 36 
14. GENERAL PROGRAMMING NOTES .................................................................... 41 
14.1 
FIGURE SPECIFICATIONS ........................................................................ 69 
14.2 
LISTING SPECIFICATIONS ....................................................................... 70 
 
 


Sponsor: Insys Development Co, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
- 7 - 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 2-1 
Protocol-Specified Visits and Visit Windows ............................. - 13 - 
Table 7-1 
Table of AE Start Date Imputation Rules .................................. - 23 - 
 
 


Sponsor: Insys Development Co, Inc. 
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Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
- 8 - 
LIST OF ABBREVIATIONS 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CRF 
Case Report Form 
 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
ET 
Early Termination 
HEENT 
Head, Ears, Eyes, Nose and Throat 
HIV 
Human Immunovirus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
IP 
Investigational Product 
IV 
Intra-Venous 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
ODT 
Oral Dissolvable Tablet 
PONV 
Post-Operative Nausea and Vomiting 
PT 
Preferred Term 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event/Experience 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM  
Standard Data Table Model 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TID 
Three Times Per Day 


Sponsor: Insys Development Co, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
- 9 - 
WHO 
World Health Organization 


Sponsor: Insys Development Co, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
- 10 - 
1. PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is being developed after review of the Insys 
Development Company. Inc., protocol number INS005-17-111 Final Version 1.0, dated 
02Aug2017 but before any analyses of the data.  The SAP contains detailed information 
to aid in the performance of the statistical analysis and reporting of the study data for use 
in the final clinical study report (CSR).  This SAP is being written with due consideration 
of the recommendations outlined in the most recent International Conference on 
Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical Principles 
for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports and the most recent FDA draft Guidance 
for Industry - Analgesic Indications: Developing Drug and Biological Products, dated 
February 2014. 
This SAP describes the data sets that will be analyzed and the subject characteristics, and 
safety assessments that will be evaluated.  There will be no efficacy analysis in this study.  
This SAP provides details of the specific statistical methods that will be used.  If 
additional analyses are required to supplement the planned analyses described in this 
SAP, they may be completed and will be identified in the CSR. 
 


Sponsor: Insys Development Co, Inc. 
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Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
- 11 - 
2. PROTOCOL SUMMARY 
2.1 Study Objectives 
2.1.1 Safety  
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).  
2.1.2 Efficacy 
This is a safety and tolerability only study and so has no efficacy objectives. 
2.2 Overall Study Design and Plan 
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).  
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.  Subjects will subsequently return to the clinic for the 
Follow-up Visit on Day 8 (+2 day window).  Subjects will be allowed rescue medication for 
pain and /or nausea at the investigator’s discretion. 
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 (please refer to the Protocol for complete list of procedures), including a 
review of inclusion and exclusion, demographics, medical history, concomitant medication 
use, assessment of postoperative nausea and 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).  


Sponsor: Insys Development Co, Inc. 
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Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
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Surgical Period: On Day 1, anesthesia will be established using standardized techniques, as 
appropriate, for each surgical procedure.  The surgical procedures will be either bunionectomy, 
breast augmentation, or abdominoplasty. For nausea prophylaxis, all subjects will receive a 
uniform standard of care regimen including 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. Please refer to the 
Protocol for complete list of procedures. 
Post-surgery 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 - Inpatient:  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.  Study 
medication administration after the first dose are to be administered every 8 hours (Treatment 
Period Days 1 – 7). 
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 assigned by IWRS and 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.  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. Please refer to the Protocol for complete 
list of procedures. 
Treatment Period – Outpatient:  Investigators will determine if patients are able to proceed 
with the outpatient treatment period.  After discharge to the outpatient portion of the trial, 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, and rescue medication for 
pain and nausea. Please refer to the Protocol for complete list of procedures. 
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. 


Sponsor: Insys Development Co, Inc. 
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Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
- 13 - 
Concomitant medications and Adverse Events will be recorded.  Subject outpatient diary will 
be collected and reviewed by study staff. Please refer to the Protocol for complete list of 
procedures. 
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 provided with Zofran ODT (oral dissolvable tablet) to be taken as needed.  
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. 
The protocol-defined visits are presented in the following table: 
Table 2-1 
Protocol-Specified Visits and Visit Windows 
Study Phase 
Visit Time 
Screening 
From days -28 to -1 
Surgical Period 
Day 1 
Treatment Period - Inpatient 
Days 1 to 4 
Treatment Period - Outpatient 
Days 4 to 7 
Follow-up Visit 
Day 8 (±2 days) 
 
2.3 Study Population 
The study population will be males or females ≥18 and ≤65 years of age, with body 
weight ≥45 kg and a body mass index (BMI) ≤40 kg/m2, and scheduled for elective 
bunionectomy, breast augmentation (in women only), or abdominoplasty.  
 


Sponsor: Insys Development Co, Inc. 
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Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
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2.4 Treatment Regimens 
2.4.1 Study Material 
Buprenorphine Sublingual Spray, 0.5 mg TID manufactured for and supplied by Insys 
Development Company, Inc. 
2.4.2 Comparator Group 
Morphine IV, 4 mg TID for 24 hrs, followed by Oxycodone Hydrochloride Tablet, 10 mg 
TID.   
2.5 Treatment Group Assignments or Randomization 
Randomized treatment will be assigned utilizing a computer generated randomization 
scheme.  Subjects who meet the inclusion criteria, do not fulfill any of the exclusion 
criteria and meet post-surgical eligibility requirements will be eligible for randomization 
into the study.   
All study doses administered will be according to the IWRS specified treatment to ensure that 
study personnel will not be aware of the next subject’s treatment assignment before the 
decision to randomize that subject has been made.  The IWRS randomization algorithm will 
be such that the subjects will be stratified by surgical procedure and baseline PONV risk 
factors and randomly assigned to treatment administered in a 1:1 assignment ratio within the 
stratification categories.  PONV risk will be assessed at screening to assess the likelihood of 
nausea and vomiting after surgery using the Apfel scale  
(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  
Patients with PONV risk factors of 0-2 will be stratified as low risk and 3-4 as high risk. 


Sponsor: Insys Development Co, Inc. 
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Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
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2.6 Sample Size Determination 
No formal sample size estimate has been completed.  A sample size of 50 subjects per 
treatment group is expected to be sufficient to achieve the study objectives. 
 


Sponsor: Insys Development Co, Inc. 
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Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
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3. GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of the 
data from the study.  Departures from these general policies are provided in the specific 
detailed sections of this SAP.  When this situation occurs, the rules set forth in the 
specific section take precedence over the general policies. 
All continuous study assessments will be summarized by treatment and time point (as 
applicable) using descriptive statistics (n, mean, SD, median, minimum, and maximum).  
All of the categorical study assessments will be summarized by treatment and time point 
(as applicable) using frequency counts and percentages.  Changes from baseline for 
continuous outcomes will be presented as their corresponding continuous measures for 
post-baseline visits.  All relevant study data will be listed by treatment group, subject, 
and time point (as applicable).   
No preliminary rounding will be performed; rounding will only occur after the analysis.  
To round, consider the digit to the right of the last significant digit:  if <5, then round 
down; if ≥5, then round up.  Means and medians will be presented with one more decimal 
place than the precision of the data.  Standard deviations will be presented with two more 
decimal places than the precision of the data.  Percentages will be presented with one 
decimal place.  Minimums and maximums will be presented with the same precision as 
the original data. 
All analyses will be performed using the SAS System® version 9.3 or higher.  The 
domain (Study data tabulation Model [SDTM]) and analysis (Analysis Data Model 
[ADaM]) data sets will be taken as input to the SAS programs that generate the report-
ready tables, figures and listings.  The submission ready SDTM and ADaM data sets will 
be provided to the sponsor along with display deliveries.  The specifications for the 
domain data sets and analysis data sets will be provided in a separate document. 
For all analyses, subjects will be analyzed by treatment group according to the actual 
product received during treatment, i.e., “as treated.” 
The following conventions will be used throughout the study analysis: 
 Assessment visit times are defined by time of treatment administration. 
 Baseline value is defined as the last valid measurement prior to the first treatment 
administration. 


Sponsor: Insys Development Co, Inc. 
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Statistical Analysis Plan 
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Date: 08Sep2017 
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 Change from baseline is defined as post-baseline value minus baseline value. 
 Duration of an AE will be computed in days as the stop date of the event minus 
the start date plus 1.  If reported as ongoing at the time of database lock, the stop 
date is defined as the date of the last visit or the last date of any AE for the subject 
in the database, whichever is later.  Missing dates will be imputed as described in 
Section 7.2. 
 The number of days in the study is computed as: 
Date of study completion /withdrawal - the date of first treatment 
administration (Day 1) + 1.   
 If duplicate values are obtained at a given visit (e.g., repeated vital sign 
measurements), the last value will be used unless it is noted that the measurement 
was in error for that value.  Values that compromise interpretation will not be 
used in summaries (e.g., values that were obtained post-dose will not be 
summarized as pre-dose values). 


Sponsor: Insys Development Co, Inc. 
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Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
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4. ANALYSIS POPULATIONS 
4.1 Efficacy Population 
This study has no efficacy analysis and so no efficacy population.   
 
4.2 Safety Population 
The safety population will include all subjects who received at least 1 dose of study drug.   
 
4.3 Disposition of Subjects 
Subjects will be considered enrolled into the study only when they have received study 
drug.  If a subject is randomized but does not receive study drug, they will not be counted 
in any summaries. 
All enrolled subjects will be listed.  Subjects who are screened and who fail screening or 
withdraw consent prior to randomization will not be entered into the database or 
presented in summaries or data listings.  Subjects who are randomized, treated, subjects 
included in the safety population, subjects who complete follow-up as well as subjects 
who withdraw early from the study and the reason for withdrawal will be summarized by 
treatment group and overall in the subject disposition summary table.  
4.4 Major Protocol Deviations 
Patient specific protocol deviation information will be collected on the CRF.  Site 
specific deviations will be collected by the CRA and logged in the trip reports. 
 will 
prepare a final Excel export of all CRF deviations and append to this Excel all Site 
specific deviations to create a final Excel Database of Deviations. All protocol deviations 
in this database will be designated as major or minor prior to CRF database lock by the 
sponsor’s medical monitor.  A major deviation is typically one that may affect the 
outcome, analysis or interpretation of the study.  All protocol deviations will be presented 
in a by-subject listing. 


Sponsor: Insys Development Co, Inc. 
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Statistical Analysis Plan 
Protocol Number: INS005-17-111 
 
Date: 08Sep2017 
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5. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
5.1 Demographics and Baseline Characteristics 
Demographic variables include age, gender, race, ethnicity, surgical procedure, and 
PONV risk factor.  Baseline characteristics include height (cm), weight (kg), and BMI 
(kg/m2).  Demographics and baseline characteristics will be presented in by-subject 
listings and summarized overall and by treatment group.   
5.2 Medical History 
Medical history, as collected at screening, will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 19.0 and presented in a by-subject listing using 
the coded and verbatim history terms.   
5.3 Prior and Concomitant Medications/Surgeries Details 
Prior medications/surgeries are those that stop prior to the start of the first study drug 
treatment administration.  Any medication/therapy that stops at or after this time or with 
missing stop dates is considered concomitant medication/therapy. 
Prior and concomitant medications are collected at screening and updated throughout the 
study as needed.  Prior and concomitant medications will be coded using WHO/ATC 
classification index version March 2016 and summarized separately by drug class and 
preferred name, overall and by treatment group, for the safety population. 
Prior and concomitant therapies will be presented in a by-subject listing of verbatim and 
coded terms.  Non-medical therapies will appear in a separate data listing.  


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6. MEASUREMENTS OF TREATMENT COMPLIANCE 
6.1 Study Medication Compliance 
The exposure to study medication during the treatment periods will be listed by-subject and 
summarized by descriptive statistics for both the inpatient and outpatient portions of the 
study, and overall.  As the dose administration during the inpatient period is under the control 
of the study sites, compliance during that time will not be summarized.  
Compliance of the subject during the outpatient portion of the study will be assessed by 
summarizing the number of doses taken during the outpatient portion of the trial, and by the 
average number of doses taken per day during the outpatient portion of the trial, calculated as 
the number of doses taken divided by the number of days the subject remains in the 
outpatient portion of the study.  
Subjects assigned to standard of care during the outpatient portion of the trial were instructed 
to take study medication only when they experienced pain. Subjects assigned Buprenorphine 
were instructed to maintain the TID dosing for the entire outpatient period. 


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7. SAFETY EVALUATION 
7.1 Overview of Safety Analysis Methods 
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 0-8 hours, 0 to 24 hours, over 0 to 
48 hours, over 0-72 hours and 0-7 days  
 Pulse oximetry  
 ECGs at 90 minutes, 12, 24, 48 and 72 hours  
 Oral examinations  
 
7.2 Adverse Events 
Treatment-emergent AEs are defined as AEs that start or worsen in severity after the first 
exposure to study medication.  Verbatim terms used by investigators to identify AEs in 
the CRFs will be mapped to the appropriate preferred term (PT) and system organ class 
(SOC) using a standardized coding dictionary (MedDRA Version 19.0).  All coding will 
be reviewed prior to database lock.  All recorded AEs will be listed, but only TEAEs will 
be summarized.   
A serious adverse event (SAE) is any AE that meets any of the following causes:  
 
Results in death;  
 
Is life-threatening;  
 
Requires in-subject hospitalization or prolongation of existing hospitalization; 
 
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. 
An overall summary will be prepared giving, for each treatment group and overall, both 
the number of events, and the number of subjects with events for the following events:  


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 all TEAEs,  
 serious TEAEs  
 treatment related TEAEs,   
 SAEs and TEAEs leading to premature discontinuation of study.   
In addition, the overall summary will be produced by the study stratification variables:  
PONV risk group and surgical procedure. 
Incidence of TEAEs will be summarized for each treatment group by SOC and PT sorted 
in descending frequency by system organ class (SOC), and then by preferred term (PT) 
within SOC.  Separate tables will be created for each of the following event sets: 
 All TEAEs 
 Treatment related TEAEs (defined as Possibly, Probably or Definitely related) 
 TEAEs leading to premature discontinuation from study 
 Serious AEs 
 TEAEs by maximum severity 
 
The following AE listings will be created:  all AEs, treatment related AEs, serious AEs, 
deaths, and AEs leading to premature discontinuation. 
If a given subject experiences a TEAE that maps to the same PT more than once, the 
subject will be counted once for the PT at its greatest severity (i.e., mild, moderate, or 
severe) and causality (i.e., attribution to treatment).   
Duration of a TEAE will be computed in days as the stop date of the event minus the start 
date plus 1 and included in by subject listings.  If reported as ongoing at the time of 
database lock, the stop date is defined as the date of the last visit or the last date of any 
event for the subject in the database, whichever is later.  If a TEAE is considered 
resolved, but the stop date is missing, the last day of the month will be imputed if the 
month and year are available. If only the year is available, and the year is the same as the 
year of the last visit, the stop date will be the latest of the last visit date or latest event for 
the subject in the database.  If the year of the event is prior to the year of the last 
treatment, the end day and month will be set to 31 December. 
For missing or partial start dates, it is most conservative to impute them as temporally 
related to the first dose of study medication.  The following chart will be used to impute 
start date: 


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Table 7-1 
Table of AE Start Date Imputation Rules 
Missing Start 
Date Portion 
Prior to 
Treatment 
Same as 
Treatment Start 
Date 
After Treatment Start 
Date 
Day 
Month and Year < 
Month and Year of first 
treatment: 
 
Day = 1 
Month and Year = 
Month and Year of 
first treatment: 
 
Day = Day of first 
treatment 
Month and Year > 
Month and Year of 
First Treatment: 
 
Day = 1 
Day and 
Month 
Year < Year of first 
treatment: 
 
Day = 1, 
Month = July 
Year = Year of 
first treatment: 
 
Day = Day of first 
treatment,  
Month = Month of 
first treatment 
Year > Year of first 
treatment: 
 
Day = 1,  
Month = January 
Day, Month, 
and Year 
 
To be conservative, completely missing start dates will be set to the 
date of first treatment 
After following these imputation rules, if the start date is imputed as a date after the end 
date, the start date will be set to the end date to provide a positive duration for the event 
incidence.   
Missing assessments for AE study medication relationship or severity will be 
summarized as definitely related or severe respectively.  No other imputation is planned 
for safety data. 
7.3 Rescue Medication 
The total use of rescue and the proportion of patients given rescue medication for nausea 
relief will be summarized by treatment group and by cumulative time point (0-8 hours, 0-
24 hours, 0-48 hours, 0-72 hours and 0-7 days) and overall.  A by-subject listing presenting 
the use of nausea rescue medication over time will be given.   
Time to first rescue medication for nausea is the time (in minutes) elapsed from the time 
of first dose of IP to time the first dose of rescue medication for nausea is given.  A 


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Date: 08Sep2017 
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summary table will present the median time to first rescue use and 95% confidence 
intervals of the medians by treatment group as determined by log-rank analysis 
performed using SAS PROC LIFETEST.  A summary figure will present the time to first 
rescue use as a Kaplan-Meier survival plot.  If a subject does not take rescue medication 
for nausea but prematurely discontinues from the study, then for analysis purposes the 
subject will be censored at the time of discontinuation.  If a subject never takes rescue 
medication for nausea and completes the treatment phase of the study, then the subject 
will be considered censored for analysis purposes at 7 days.   
7.4 Clinical Laboratory Evaluation 
The following clinical laboratory tests will be performed for individual subjects.   
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).  
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.  
Urinalysis:  pH, specific gravity, blood, glucose, protein, and ketones. 
Baseline for clinical laboratory parameters will be defined as the last evaluation before 
dosing with study treatment.  For each continuous parameter, summary statistics of 
values and change from baseline will be presented by treatment group and overall; 
categorical urinalysis test parameters will be summarized using number and proportion of 
normal and abnormal results at each visit.  All clinical laboratory values will be listed. 
7.5 Vital Signs 
Vital signs results including pulse oximetry, BP [systolic and diastolic], pulse rate, 
respiration rate, and body temperature will be listed for individual subjects.  Baseline for 
vital signs measurements will be defined as the last evaluation before dosing with study 
medication.  Summary statistics of values and changes from baseline to each study time 
point will be presented by treatment group and overall  


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7.6 Physical, Oral and ECG Exams  
All findings of physical, oral and ECG examinations will be listed for individual subjects 
and abnormal findings will be summarized by time point. 
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.  Physical 
examination systems include HEENT, cardiovascular, respiratory, gastrointestinal, 
neurological, dermatologic, and musculoskeletal systems. 
An oral cavity exam will consist of a sublingual assessment, noting the colour of mucosa 
and whether inflammation is present, a 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, and at Follow-up Visit/ET.  Assessments will be repeated 
based on the Investigator’s discretion.  
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. 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 at Follow-up Visit/ET 
7.7 Serology Screens, Drug of Abuse and Alcohol Screens, Pregnancy 
Test 
Results of, HIV and hepatitis B and C screens, drug of abuse and alcohol screens, and 
pregnancy tests will be listed for individual subjects.  Each test result will be defined to 
be “negative” or “positive” according to the normal reference range from the clinical 
laboratory.   
 


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8. EFFICACY EVALUATION 
There is to be no efficacy analysis in this study.  


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9. OTHER ANALYSES 
Any additional analyses conducted will be considered exploratory and enumerated in the 
CSR. 
 
 


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10. INTERIM ANALYSES AND DATA MONITORING 
There are no planned interim analyses for this study. 


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11. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
Any deviations from the statistical plan will be described and a justification given in the 
CSR. 


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12. REFERENCES 
 
US Federal Register. (1998) International Conference on Harmonization; Guidance for 
Industry: Statistical Principles for Clinical Trials. Department of Health and Human 
Services: Food and Drug Administration.  Federal Register, Vol. 63, No. 179, September 
16, 1998, page 49583. 
 
US Federal Register. (1996) International Conference on Harmonization; Guidance for 
Industry: Structure and Content of Clinical Study Reports. Department of Health and 
Human Services: Food and Drug Administration.  Federal Register Vol. 61, July 17, 
1996, page 37320.  
 
Guidance for Industry (2014) Analgesic Indications: Developing Drug and Biological 
Products  -  Draft Guidance.  Department of Health and Human Services: Food and Drug 
Administration.  Center for Drug Evaluation and Research (CDER) February 2014 
Clinical/Medical. 
 


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13. APPENDICES 
13.1 List of Tables for Final Study Report 
Table 14.1.1 
All Subjects 
Summary of Subject Disposition   
Table 14.1.2 
Safety Population 
Summary of Demographic and Baseline Characteristics 
Table 14.1.3 
Safety Population 
Summary of Prior Medications   
Table 14.1.4 
Safety Population 
Summary of Concomitant Medications   
Table 14.1.5 
Safety Population 
Summary of Study Medication Compliance (Outpatient)   
Table 14.1.6 
Safety Population 
Summary of Study Medication Exposure   
Table 14.3.1.1.1 
Safety Population 
Overall Summary of Treatment-Emergent Adverse Events (TEAEs) 
Table 14.3.1.1.2 
Safety Population 
Overall Summary of TEAEs By PONV Classification 
Table 14.3.1.1.3 
Safety Population 
Overall Summary of TEAEs By Type Of Surgery 
Table 14.3.1.2 
Safety Population 
Summary of TEAEs by System Organ Class (SOC) and Preferred Term 
(PT) 
Table 14.3.1.3 
Safety Population 
Summary of Treatment Related TEAEs by SOC and PT 
Table 14.3.1.4 
Safety Population 
Summary of SAEs by SOC and PT 


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Table 14.3.1.5 
Safety Population 
Summary of TEAEs Leading To Study Drug Discontinuation by SOC 
and PT 
Table 14.3.1.6 
Safety Population 
Summary of TEAEs by System Organ Class, Preferred Term and 
Maximum Severity 
Table 14.3.1.7 
Safety Population 
Summary of Total Rescue Use and Proportion Of Subjects Using 
Rescue Medication For Nausea By Time Interval 
Table 14.3.1.8 
Safety Population 
Summary Of Time To First Rescue For Nausea 
Table 14.3.2.1.1 
Safety Population 
Summary of Chemistry Results by Study Visit 
Table 14.3.2.1.2 
Safety Population 
Summary of Hematology Results by Study Visit 
Table 14.3.2.1.3 
Safety Population 
Summary of Urinalysis Results by Study Visit Continuous Assays 
Table 14.3.2.1.4 
Safety Population 
Summary of Urinalysis Results by Study Visit Categorical Assays 
Table 14.3.3 
Safety Population 
Summary of Vital Signs and Changes from Baseline by Study Visit 
Table 14.3.4 
Safety Population 
Summary of Physical Exam Findings   
Table 14.3.5 
Safety Population 
Summary of Oral Cavity Exam Findings   
Table 14.3.6 
Safety Population 
Summary of ECG Exam Findings   
Table 14.3.7 
Safety Population 
Summary of ECG Results and Changes from Baseline by Study Visit 
 


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13.2 List of Figures for Final Study Report 
Figure 14.1 
Safety Population 
Time To First Use Of Rescue Medication for Nausea 
 
13.3 List of Listings for Final Study Report 
Listing 16.2.1.1 
All Subjects 
Subject Enrollment and Randomization  
Listing 16.2.1.3 
All Subjects 
Subject Disposition 
Listing 16.2.2.1 
Safety Population 
Protocol Deviations 
Listing 16.2.4.1 
Safety Population 
Demographics and Baseline Characteristics 
Listing 16.2.4.2 
Safety Population 
Medical/Surgical History 
Listing 16.2.4.3 
Safety Population 
Prior and Concomitant Medications 
Listing 16.2.4.4 
Safety Population 
Non-Medication Therapy 
Listing 16.2.4.5 
Safety Population 
Serology Laboratory And Pregnancy Test Results 
Listing 16.2.4.6 
Safety Population 
Alcohol Breath Test And Urine Drug Screen   


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Listing 16.2.4.7 
Safety Population 
Surgery 
Listing 16.2.5.1 
Safety Population 
Study Drug Administration 
Listing 16.2.5.2 
Safety Population 
Discharge To Outpatient Treatment 
Listing 16.2.5.3 
Safety Population 
Study Drug Accountability 
Listing 16.2.5.4 
Safety Population 
Rescue Medication Administration 
Listing 16.2.7.1 
Safety Population 
All Treatment Emergent Adverse Events (TEAEs) 
Listing 16.2.7.2 
Safety Population 
Treatment Related TEAEs 
Listing 16.2.7.3 
Safety Population 
Serious TEAEs 
Listing 16.2..7.4 
Safety Population 
Deaths 
Listing 16.2.7.5 
Safety Population 
TEAEs Leading To Study Drug Discontinuation 
Listing 16.2.8.1.1 
Safety Population 
Chemistry Laboratory Results 
Listing 16.2.8.1.2 
Safety Population 
Hematology Laboratory Results 
Listing 16.2.8.1.3 
Safety Population 
Urinalysis Laboratory Results 
Listing 16.2.8.2 
Safety Population 
Vital Signs 
Listing 16.2.8.3.1 
Safety Population 
Physical Examinations 
Listing 16.2.8.3.2 
Safety Population 
Oral Cavity Examinations 


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Listing 16.2.8.4 
Safety Population 
ECG Exam Assessment 
Listing 16.2.8.5 
Safety Population 
Comments 
 


 
13.4 TABLE, FIGURE AND LISTING SPECIFICATIONS  
 
 


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Table 14.1.1 Summary of Subject Disposition  All Subjects ...................... 42 
Table 14.1.2 Summary of Demographic and Baseline Characteristics  Safety Population 43 
Table 14.1.3 Summary of Prior Medications [1] Safety Population ............ 45 
Table 14.1.4 Summary of Concomitant Medications  Safety Population ... 46 
Table 14.1.5  Summary of Study Medication Compliance (Outpatient) Safety Population 47 
Table 14.1.6  Summary of Study Medication Exposure  Safety Population48 
Table 14.3.1.1.1 Overall Summary of Treatment-Emergent Adverse Events (TEAEs) Safety Population 49 
Table 14.3.1.1.2 Overall Summary of Treatment-Emergent Adverse Events (TEAEs) By PONV Classification 
Safety Population ............................................................................ 51 
Table 14.3.1.1.3 Overall Summary of Treatment-Emergent Adverse Events (TEAEs) By Type Of Surgery Safety 
Population........................................................................................ 53 
Table 14.3.1.2 Summary of TEAEs by System Organ Class (SOC) and Preferred Term (PT) Safety Population 55 
Table 14.3.1.3 Summary of Treatment Related TEAEs by SOC and PT Safety Population 56 
Table 14.3.1.4 Summary of SAEs by SOC and PT Safety Population ........ 56 
Table 14.3.1.5 Summary of TEAEs Leading To Study Drug Discontinuation by SOC and PT Safety Population 56 
Table 14.3.1.6 Summary of TEAEs by System Organ Class, Preferred Term and Maximum Severity Safety 
Population........................................................................................ 57 
Table 14.3.1.7  Summary of Total Rescue Use and Proportion Of Subjects Using Rescue Medication For Nausea 
By Time Interval Safety Population ................................................ 58 


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Table 14.3.1.8 Summary Of Time To First Rescue For Nausea Safety Population 59 
Table 14.3.2.1.1 Summary of Chemistry Results by Study Visit Safety Population 60 
Table 14.3.2.1.2 Summary of Hematology Results by Study Visit Safety Population 
61 
Table 14.3.2.1.3 Summary of Urinalysis Results by Study Visit Continuous Assays Safety Population 61 
Table 14.3.2.1.4 Summary of Urinalysis Results by Study Visit Categorical Assays Safety Population 62 
Table 14.3.3 Summary of Vital Signs and Changes From Baseline by Study Visit Safety Population 
63 
Table 14.3.4 Summary of Physical Exam Findings  Safety Population ..... 65 
Table 14.3.5 Summary of Oral Cavity Exam Findings  Safety Population . 66 
Table 14.3.6 Summary of ECG Exam Findings  Safety Population ............ 67 
Table 14.3.7 Summary of ECG Results and Changes from Baseline by Study Visit  Safety Population 68 
Figure 14.1 Time To First Use Of Rescue Medication  Safety Population . 69 
Listing 16.2.1.1 Subject Enrollment and Randomization  All Subjects ...... 71 
Listing 16.2.1.3 Subject Disposition All Subjects ....................................... 72 
Listing 16.2.2.1 Protocol Deviations Safety Population ............................. 73 
Listing 16.2.4.1 Demographics and Baseline Characteristics Safety Population 
74 
Listing 16.2.4.2 Medical/Surgical History Safety Population ...................... 75 
Listing 16.2.4.3 Prior and Concomitant Medications Safety Population ... 76 
Listing 16.2.4.4 Non-Medication Therapy Safety Population ..................... 77 
Listing 16.2.4.5 Serology Laboratory And Pregnancy Test Results Safety Population 
78 


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Listing 16.2.4.6 Alcohol Breath Test and Urine Drug Screen[1]  Safety Population 79 
Listing 16.2.4.7 Surgery Safety Population ................................................. 80 
Listing 16.2.5.1 Study Drug Administration Safety Population .................. 81 
Listing 16.2.5.2 Discharge to Outpatient Treatment Safety Population ..... 82 
Listing 16.2.5.3 Study Drug Accountability Safety Population .................. 83 
Listing 16.2.5.4 Rescue Medication Administration Safety Population ..... 84 
Listing 16.2.7.1 All Treatment Emergent Adverse Events (TEAEs) Safety Population 
85 
Listing 16.2.7.2 Treatment Related TEAEs Safety Population ................... 86 
Listing 16.2.7.3 Serious TEAEs Safety Population ..................................... 86 
Listing 16.2.7.4 Deaths Safety Population ................................................... 86 
Listing 16.2.7.5 TEAEs Leading To Premature Study Discontinuation Safety Population 86 
Listing 16.2.8.1.1 Chemistry Laboratory Results Safety Population ......... 87 
Listing 16.2.8.1.2 Hematology Laboratory Results Safety Population ...... 88 
Listing 16.2.8.1.3 Urinalysis Laboratory Results Safety Population .......... 89 
Listing 16.2.8.2 Vital Signs Safety Population ............................................. 90 
Listing 16.2.8.3.1 Physical Examinations Safety Population ..................... 91 
Listing 16.2.8.3.2 Oral Cavity Examinations Safety Population ................. 92 
Listing 16.2.8.4 ECG Exam Assessment Safety Population ....................... 93 
Listing 16.2.8.5 Comments Safety Population ............................................ 94 


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41 
14. GENERAL PROGRAMMING NOTES 
All continuous study assessments will be summarized by treatment and time point (as applicable) using descriptive statistics (n, mean, 
standard deviation, median, and range (minimum, maximum)). All categorical study assessments will be summarized by treatment and 
time point (as applicable) using frequency counts and percentages.  All study data will be listed by treatment group, subject and time 
point (as applicable).   
 
No preliminary rounding should be performed; rounding should only occur after analysis.  To round, consider digit to right of last 
significant digit:  if < 5 then round down, if ≥ 5 then round up.  Means and medians will be presented with one more decimal place 
than the precision of the data.  Standard deviations will be presented with two more decimal places than the precision of the data.  
Percentages will be presented with one decimal place.  Minimums and maximums will be presented with the same precision as the 
original data. 
 
Study Conventions: 
 Day 1 is the day of baseline and first exposure study treatment.  
 Assessment time point times are defined by time after administration of study drug. 
 Baseline value is defined as the last valid measurement prior to treatment. 
 Change from baseline is defined as post-baseline value minus baseline value. 
 Duration of an adverse event will be computed in days as the [stop date of the event minus the start date] plus 1.  See SAP for 
imputation rules for missing dates. 
 The number of days in the study is computed as: [Date of study completion (or withdrawal) - the date of first dose (Day 1)] + 
1.   
 If duplicate values are obtained at a given time point (e.g., repeated vital sign measurements), the last value will be used unless 
it is noted that the measurement was in error for that value.  Values that compromise interpretation will not be used in 
summaries (e.g., values that were obtained post-dose will not be summarized as pre-dose values). 
 


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42 
 
Table 14.1.1 
Summary of Subject Disposition  
All Subjects 
 
 
 
Standard Narcotic 
Therapy[1] 
N=xxx 
Buprenorphine SL 
Spray (0.5 mg TID) 
N=xxx 
Overall 
N=xxx 
 
 
 
 
 
 
 
 
Subjects Randomized 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
Subjects in Safety Population (received treatment), n (%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
Subjects completing study, n (%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
Completed Inpatient Treatment/Completed Outpatient Treatment/ 
Completed Follow-up 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
Completed Inpatient Treatment/ Not Completed Outpatient 
Treatment/ Not Completed Follow-up 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
Completed Inpatient Treatment/Completed Outpatient Treatment/ 
Not Completed Follow-up 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
Treatment/Not completed Outpatient Treatment/ Not completed 
Follow-up 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
Subjects with early termination, n (%)  
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
    Adverse event, n (%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
Death, n (%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
Withdrawal of consent by subject, n (%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
    Subject Non-compliance, n (%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
    Protocol Violation, n (%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
    Lost to follow-up, n (%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
Other, n (%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
Footnote: 
[1] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
 


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43 
 
 
Table 14.1.2 
Summary of Demographic and Baseline Characteristics  
Safety Population 
 
 
 
 
 
Standard Narcotic Therapy[1] 
Buprenorphine SL Spray (0.5 
mg TID)  
Overall  
 
N = xx 
N = xx 
N = xx 
Age 
 
 
 
  N 
XXX 
XXX 
XXX 
  Mean (SD) 
XXX.X (XX.X) 
XXX.X (XX.X) 
XXX.X (XX.X) 
  Median 
XXX 
XXX 
XXX 
  Range (Min, Max) 
XXX, XXX 
XXX, XXX 
XXX, XXX 
 
 
 
 
Sex, n (%) 
 
 
 
  Male 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Female 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
Race, n (%) 
 
 
 
  White 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Black or African American 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Asian 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  American Indian or Alaskan Native 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Native Hawaiian or Pacific Islander 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Multiple 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Other 
 
 
 
 
 
 
 
Ethnicity, n (%) 
 
 
 
  Hispanic or Latino 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Non-Hispanic or Latino 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Unknown 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
Baseline Height (cm) 
 
 
 
  N 
XXX 
XXX 
XXX 
  Mean (SD) 
XXX.X (XX.X) 
XXX.X (XX.X) 
XXX.X (XX.X) 
  Median 
XXX 
XXX 
XXX 
  Range (Min, Max) 
XXX, XXX 
XXX, XXX 
XXX, XXX 
 
 
 
 
 
 
 
 


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Standard Narcotic Therapy[1] 
Buprenorphine SL Spray (0.5 
mg TID)  
Overall  
 
N = xx 
N = xx 
N = xx 
 
 
 
 
Baseline Weight (kg) 
 
 
 
  N 
XXX 
XXX 
XXX 
 
 
 
 
  Mean (SD) 
XXX.X (XX.X) 
XXX.X (XX.X) 
XXX.X (XX.X) 
  Median 
XXX 
XXX 
XXX 
  Range (Min, Max) 
XXX, XXX 
XXX, XXX 
XXX, XXX 
 
 
 
 
Baseline BMI (kg/m2) [2] 
 
 
 
  N 
XXX 
XXX 
XXX 
  Mean (SD) 
XXX.X (XX.X) 
XXX.X (XX.X) 
XXX.X (XX.X) 
  Median 
XXX 
XXX 
XXX 
  Range (Min, Max) 
XXX, XXX 
XXX, XXX 
XXX, XXX 
 
 
 
 
Baseline PONV Risk Factor 
 
 
 
  0 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  1 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  2 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  3 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  4 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
Baseline PONV Risk Factor 
 
 
 
  Low Risk 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  High Risk 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
Surgical Procedure 
 
 
 
  Bunionectomy 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Breast Implant 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Abdominoplasty 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
 
 
 
 
 
Footnotes: 
Percentages are based on the number of subjects (N) in a given treatment group for the population analyzed. 
[1] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
[2] BMI is calculated as BMI = Weight(kg) / [Height(m)^2]. 
Programmer Notes:  
For categorical variables, missing categories (e.g. no Hispanics) should appear with an n and % of zero. 
 
 


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Table 14.1.3 
Summary of Prior Medications [1] 
Safety Population 
System Organ Class  
 Preferred Term 
Standard Narcotic 
Therapy[2] 
Buprenorphine SL Spray (0.5 
mg TID) 
Overall 
N=xx 
N=xx 
N=xx 
Number of Subjects with Any Prior Medication, 
n (%) [3] 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
ATC Class 1[4] 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 Preferred Term 1 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 Preferred Term 2 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
ATC Class 2 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 Preferred Term 1 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 Preferred Term 2 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
Etc. 
 
 
 
Footnotes: 
[1] Prior medications include all medications that were started and stopped prior to study drug initiation. 
[2] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period. 
[3] n = Number of subjects reporting at least one medication within an ATC Class and Preferred Term;(%) = Percentage of subjects among 
Treatment Group (N).  A subject reporting more than one medication for a particular ATC Class or Preferred Term is counted only once 
for each ATC Class or Preferred Term. 
[4] ATC Class and Preferred Term are based on the WHO/ATC classification index version March 2016 drug coding dictionary. 
 
Programmer Notes:  
Table entries should be sorted in decreasing order by overall n of ATC Class and by PT overall n within ATC Class based on the pooled 
EB-001 column. 
 
 
 


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Table 14.1.4 
Summary of Concomitant Medications  
Safety Population 
 
 
System Organ Class  
  Preferred Term 
Standard Narcotic Therapy[1] 
Buprenorphine SL Spray (0.5 mg 
TID) 
 
N=xx 
N=xx 
Number of Subjects with Any Concomitant Medication, n 
(%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
ATC Class 1 
XXX (XX.X%) 
XXX (XX.X%) 
  Preferred Term 1 
XXX (XX.X%) 
XXX (XX.X%) 
  Preferred Term 2 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
ATC Class 2 
XXX (XX.X%) 
XXX (XX.X%) 
  Preferred Term 1 
XXX (XX.X%) 
XXX (XX.X%) 
  Preferred Term 2 
XXX (XX.X%) 
XXX (XX.X%) 
Etc. 
 
 
Footnotes: 
[1]Concomitant medications include all medications that were started or stopped after study drug initiation or those with missing stop 
dates.  
[2] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period. 
[3] n = Number of subjects reporting at least one medication within an ATC Class and Preferred Term;(%) = Percentage of subjects among 
Treatment Group (N).  A subject reporting more than one medication for a particular ATC Class or Preferred Term is counted only once 
for each ATC Class or Preferred Term. 
[4] ATC Class and Preferred Term are based on the WHO/ATC classification index version March 2016 drug coding dictionary. 
 
 
Programmer Notes:  
Table entries should be sorted in decreasing order by overall n of ATC Class and by PT n within ATC Class based on the pooled EB-001 
column. 
 


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47 
 
Table 14.1.5 
 Summary of Study Medication Compliance (Outpatient) 
Safety Population 
 
 
Standard Narcotic 
Therapy[1] 
Buprenorphine SL Spray 
(0.5 mg TID)  
Overall 
 
N = xx 
N = xx 
N = xx 
Total Number of Doses taken during Outpatient period 
[2] 
 
 
 
    n 
X 
X 
X 
    Mean  
X.X 
X.X 
X.X 
    SD 
X.XX 
X.XX 
X.XX 
    Median 
X.X 
X.X 
X.X 
    Range (Min, Max) 
(X.X – X.X) 
(X.X – X.X) 
(X.X – X.X) 
 
 
 
 
Average Number of Doses per Day During Outpatient 
period [3] 
 
 
 
    n 
X 
X 
X 
    Mean  
X.X 
X.X 
X.X 
    SD 
X.XX 
X.XX 
X.XX 
    Median 
X.X 
X.X 
X.X 
    Range (Min, Max) 
(X.X – X.X) 
(X.X – X.X) 
(X.X – X.X) 
 
 
 
 
 
 
 
 
 
Footnote:  
[1] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
[2] The number of doses taken is the number dispensed – number returned. Subjects assigned Standard Narcotic Therapy during the 
outpatient portion of the trial were instructed to take study medication only when they experienced pain. Subjects assigned 
Buprenorphine SL Spray (0.5 mg TID) were instructed to maintain the TID dosing for the entire outpatient period. 
[3] Average number of doses is calculated as the number of doses taken divided by the number of days the subject remained in the 
outpatient portion of the study. 
 
 


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Table 14.1.6 
 Summary of Study Medication Exposure  
Safety Population 
 
 
 
Standard Narcotic Therapy [1] 
Buprenorphine SL Spray 
(0.5 mg TID) [2] 
 
Morphine 
Oxycodone 
 
 
N = xx 
N = xx 
N = xx 
Total Exposure during Inpatient period (mg) 
 
 
 
    n 
X 
X 
X 
    Mean  
X.X 
X.X 
X.X 
    SD 
X.XX 
X.XX 
X.XX 
    Median 
X.X 
X.X 
X.X 
    Range (Min, Max) 
(X.X – X.X) 
(X.X – X.X) 
(X.X – X.X) 
 
 
 
 
Total Exposure during Outpatient period (mg) [3] 
 
 
 
    n 
 
X 
X 
    Mean  
 
X.X 
X.X 
    SD 
 
X.XX 
X.XX 
    Median 
 
X.X 
X.X 
    Range (Min, Max) 
 
(X.X – X.X) 
(X.X – X.X) 
 
 
 
 
Total Exposure Overall (mg) 
 
 
 
    n 
X 
X 
X 
    Mean  
X.X 
X.X 
X.X 
    SD 
X.XX 
X.XX 
X.XX 
    Median 
X.X 
X.X 
X.X 
    Range (Min, Max) 
(X.X – X.X) 
(X.X – X.X) 
(X.X – X.X) 
Footnotes:  
[1] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
[2] Subjects assigned to Buprenorphine SL Spray (0.5 mg TID) received Buprenorphine sublingual spray 0.5 mg TID for the entire 
treatment period.   
[3] During the outpatient portion of the trial, subjects assigned to Standard Narcotic Therapy were instructed to take study 
medication only when they experienced pain, while subjects assigned to Buprenorphine SL Spray (0.5 mg TID) were instructed to maintain 
the TID dosing for the entire outpatient period.  
 
 
 


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49 
 
 
 
Table 14.3.1.1.1 
Overall Summary of Treatment-Emergent Adverse Events (TEAEs) 
Safety Population 
 
 
 
Standard Narcotic 
Therapy[4] 
Buprenorphine SL 
Spray (0.5 mg TID)  
Overall 
 
N=xx 
N=xx 
N=xx 
Number of TEAEs Reported 
XX 
XX 
XX 
Number of Subjects with Any TEAEs Reported [1] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
Number of Treatment related TEAEs Reported  
XX 
XX 
XX 
Number of Subjects with Treatment related TEAE Reported [1][2] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Number of Serious TEAEs Reported  
 
 
 
Number of Subjects with Any Serious TEAE Reported [1] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
Number of Subjects with TEAEs by Severity [3] 
 
 
 
     Mild  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Moderate  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Severe  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
Number of Subjects with TEAEs Resulting in Study Drug 
Discontinuation 
 
 
 
 
 
 
 
 
Footnotes: 
[1] Subjects are only counted once at each level of summarization. 
[2] AEs are considered treatment related if they are identified as definitely, probably or possibly treatment (study drug) related.  
They are considered unrelated if they are identified as unlikely related or not related. 
[3] Subjects are counted once under the maximum severity if a subject experiences multiple adverse events.  
AEs with ‘Severity Unknown or Not Reported’ are summarized as serious AEs in summary tables by system organ class and preferred term. 
[4] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
 
 
Programming Note: The row ‘Number of AEs Reported’ displays the number of unique AE counts. For example, if a subject has the same AE 
(same preferred term) more than once, the subject is counted only once for the same AE. If a subject has different AEs (like headache 


Protocol No.: INS005-17-111 
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50 
and skin rash), then the subject is counted more than once. (In other words, a subject is counted more than once for different AEs, 
but only once for the same AE occurring multiple times). 
 
 
 


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Table 14.3.1.1.2 
Overall Summary of Treatment-Emergent Adverse Events (TEAEs) By PONV Classification 
Safety Population 
 
 
 
PONV 
Low Risk 
High Risk 
 
Standard 
Narcotic 
Therapy[4] 
Buprenorphine 
SL Spray (0.5 
mg TID)  
Overall 
Standard 
Narcotic 
Therapy[4] 
Buprenorphine 
SL Spray (0.5 
mg TID)  
Overall 
 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
Number of TEAEs Reported 
XX 
XX 
XX 
XX 
XX 
XX 
Number of Subjects with Any TEAEs Reported 
[1] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
Number of Treatment related TEAEs Reported  
XX 
XX 
XX 
XX 
XX 
XX 
Number of Subjects with Treatment related 
TEAE Reported [1][2] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
Number of Serious TEAEs Reported  
 
 
 
 
 
 
Number of Subjects with Any Serious TEAE 
Reported [1] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
Number of Subjects with TEAEs by Severity 
[3] 
 
 
 
 
 
 
     Mild  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Moderate  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Severe  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
Number of Subjects with TEAEs Resulting in 
Study Drug Discontinuation 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
Footnotes: 
[1] Subjects are only counted once at each level of summarization. 
[2] AEs are considered treatment related if they are identified as definitely, probably or possibly treatment related.  They are 
considered unrelated if they are identified as unlikely related or not related. 
[3] Subjects are counted once under the maximum severity if a subject experiences multiple adverse events.  
AEs with ‘Severity Unknown or Not Reported’ are summarized as serious AEs in summary tables by system organ class and preferred term. 
[4] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
 


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Programming Note: The row ‘Number of AEs Reported’ displays the number of unique AE counts. For example, if a subject has the same AE 
(same preferred term) more than once, the subject is counted only once for the same AE. If a subject has different AEs (like headache 
and skin rash), then the subject is counted more than once. (In other words, a subject is counted more than once for different AEs, 
but only once for the same AE occurring multiple times). 
 
 


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Table 14.3.1.1.3 
Overall Summary of Treatment-Emergent Adverse Events (TEAEs) By Type Of Surgery 
Safety Population 
 
 
Surgery Type  
Bunionectomy 
Breast Augmentation 
Abdominoplasty 
 
Standard 
Narcotic 
Therapy[4] 
Buprenor-
phine SL 
Spray (0.5 
mg TID) 
Overall 
Standard 
Narcotic 
Therapy[4] 
Buprenor-
phine SL 
Spray (0.5 
mg TID) 
Overall 
Standard 
Narcotic 
Therapy[4] 
Buprenor-
phine SL 
Spray (0.5 
mg TID) 
Overall 
 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
Number of TEAEs 
Reported 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
Number of Subjects 
with Any TEAEs 
Reported [1] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
Number of 
Treatment 
related TEAEs 
Reported [2] 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
Number of Subjects 
with Treatment 
related TEAE 
Reported [1][2] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
Number of Serious 
TEAEs Reported  
 
 
 
 
 
 
 
 
 
Number of Subjects 
with Any 
Serious TEAE 
Reported [1] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Subjects 
with TEAEs by 
Severity [3] 
 
 
 
 
 
 
 
 
 
     Mild  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Moderate  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
     Severe  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 


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Surgery Type  
Bunionectomy 
Breast Augmentation 
Abdominoplasty 
 
Standard 
Narcotic 
Therapy[4] 
Buprenor-
phine SL 
Spray (0.5 
mg TID) 
Overall 
Standard 
Narcotic 
Therapy[4] 
Buprenor-
phine SL 
Spray (0.5 
mg TID) 
Overall 
Standard 
Narcotic 
Therapy[4] 
Buprenor-
phine SL 
Spray (0.5 
mg TID) 
Overall 
 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
Number of Subjects 
with TEAEs 
Resulting in 
Study Drug 
Discontinuation 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
 
 
 
Footnotes: 
[1] Subjects are only counted once at each level of summarization. 
[2] AEs are considered treatment related if they are identified as definitely, probably or possibly treatment related.  They are 
considered unrelated if they are identified as unlikely related or not related. 
[3] Subjects are counted once under the maximum severity if a subject experiences multiple adverse events.  
AEs with ‘Severity Unknown or Not Reported’ are summarized as serious AEs in summary tables by system organ class and preferred term. 
[4] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
 
 
Programming Note: The row ‘Number of AEs Reported’ displays the number of unique AE counts. For example, if a subject has the same AE 
(same preferred term) more than once, the subject is counted only once for the same AE. If a subject has different AEs (like headache 
and skin rash), then the subject is counted more than once. (In other words, a subject is counted more than once for different AEs, 
but only once for the same AE occurring multiple times). 
 


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Table 14.3.1.2 
Summary of TEAEs by System Organ Class (SOC) and Preferred Term (PT) 
Safety Population 
 
 
 
 
System Organ Class  
  Preferred Term  
Standard Narcotic 
Therapy[1] 
Buprenorphine SL Spray 
(0.5 mg TID)  
Overall 
 
N=xx 
N=xx 
N=xx 
 
n   (%)   #AEs 
n   (%)   #AEs 
n   (%)   #AEs 
Subjects with any TEAE [Overall Number of AEs] 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
 
 
 
 
System Organ Class 1 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
  Preferred Term 1 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
  Preferred Term 2 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
 
 
 
 
System Organ Class 2  
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
  Preferred Term 1 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
  Preferred Term 2 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
XX (XX.X%) [XX] 
 
 
 
 
 
Footnotes:  
[1] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
Subjects are counted only once at each level of summarization (SOC or PT).  
Summaries are sorted by SOC and PT within SOC by descending order of frequency of subjects. 
System Organ Class and Preferred Term are based on the Version 19.0 of the MedDRA coding dictionary. 
Programmer Notes:  
Table entries should be sorted in decreasing order by overall n of SOC and then by PT n within SOC based on the pooled EB-001 column. 
 
 
 
 


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Non-unique tables:  
 
 
Table 14.3.1.3 
Summary of Treatment Related TEAEs by SOC and PT 
Safety Population 
 
 
Programmer Notes:  
1) Change row label 'Subjects With Any TEAE' to 'Subjects With Any Treatment Related TEAE’ 
2) Table entries should be sorted in decreasing order by overall n of SOC and then by PT n within SOC based on the pooled EB-001 
column. 
 
 
 
 
Table 14.3.1.4 
Summary of SAEs by SOC and PT 
Safety Population 
 
 
Programmer Notes:  
1) Change row label 'Subjects With Any TEAE' to 'Subjects With Any SAE’ 
2) Table entries should be sorted in decreasing order by overall n of SOC and then by PT n within SOC based on the pooled EB-001 
column. 
 
 
 
 
 
Table 14.3.1.5 
Summary of TEAEs Leading To Study Drug Discontinuation by SOC and PT 
Safety Population 
 
 
Programmer Notes:  
1) Change row label 'Subjects With Any TEAE' to 'Subjects With Any TEAE Leading to Discontinuation’ 
2) Table entries should be sorted in decreasing order by overall n of SOC and then by PT n within SOC based on the pooled EB-001 
column. 
 
 
 
 
 
 


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57 
 
Table 14.3.1.6 
Summary of TEAEs by System Organ Class, Preferred Term and Maximum Severity 
Safety Population 
 
 
 
 
Standard Narcotic Therapy[1] 
Buprenorphine SL Spray (0.5 mg 
TID)  
Overall 
 
N = xx 
N = xx 
N = xx 
 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
 
 
 
 
 
 
 
 
 
 
Patients with any TEAE 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
  Preferred Term 1 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
  Preferred Term 2 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
… 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
Footnotes: 
[1] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
Subjects are counted only once at each level of summarization (SOC or PT). A patient will be counted once in each row of the table at 
the maximum severity reported for that system organ class or preferred term. 
Patients missing severity for an AE are categorized as severe for that AE. 
Programmer Notes:  
Table entries should be sorted in decreasing order by overall n of SOC and then by PT n within SOC based on the pooled EB-001 column. 
 
 
 


Protocol No.: INS005-17-111 
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58 
 
Table 14.3.1.7 
 Summary of Total Rescue Use and Proportion Of Subjects Using Rescue Medication For Nausea By Time Interval 
Safety Population 
 
 
 
 
Standard Narcotic Therapy[1] 
Buprenorphine SL Spray (0.5 mg 
TID)  
Overall  
 
N=xx 
N=xx 
N=xx 
Total Use of Rescue for Nausea 
(number of doses) 
 
 
 
 
 
 
 
Within 0-8 Hours 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Within 0-24 Hours 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Within 0-48 Hours 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Within 0-72 Hours 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Within 0-7 Days 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
At any time during the 
treatment period  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
 
 
 
Proportion of Subjects given 
Rescue for Nausea 
 
 
 
 
 
 
 
Within 0-8 Hours 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Within 0-24 Hours 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Within 0-48 Hours 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Within 0-72 Hours 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Within 0-7 Days 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
At any time during the 
treatment period  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Footnote: 
[1] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
 
 
 


Protocol No.: INS005-17-111 
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59 
 
Table 14.3.1.8 
Summary Of Time To First Rescue For Nausea 
Safety Population 
 
 
 
 
Standard Narcotic 
Therapy[4] 
(N = XX) 
Buprenorphine SL Spray 
(0.5 mg TID) 
(N = XX) 
Overall 
(N = XX) 
 
 
 
 
Time to First Rescue use for Nausea (min) 
 
 
 
 
 
 
 
Median Time [1] 
XXX 
XXX 
XXX 
Range (Min,max) [2] 
 
 
 
95% CI [3] 
 
(XX.X, XX.X) 
(XX.X, XX.X) 
(XX.X, XX.X) 
Censored Observations n (%)[4] 
 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Subjects receiving nausea rescue medication n (%) 
 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Footnotes: 
[1] Median Time = Median time to first use of nausea rescue medication.  
[2] Min and Max of uncensored observations. 
[3] CI = Confidence Interval. 
[4] If a subject does not take rescue medication for nausea but prematurely discontinues from the study, then the subject will be 
censored at the time of discontinuation.  If a subject never takes rescue medication for nausea and completes the treatment phase of 
the study, then the subject will be considered censored at 7 days. 
[5] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
 
 
 


Protocol No.: INS005-17-111 
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60 
 
Table 14.3.2.1.1 
Summary of Chemistry Results by Study Visit 
Safety Population 
 
 
Albumen (for example) 
 
Standard Narcotic Therapy[1] 
N=XX 
Buprenorphine SL Spray (0.5 mg TID)  
N=xx 
Overall 
N=xx 
Time point  
  Statistic 
Value 
Change From 
Baseline 
Value 
Change From 
Baseline 
Value 
Change From 
Baseline 
Screening (Baseline) 
 
 
 
 
 
 
  N 
XXX 
 
XXX 
 
XXX 
 
  Mean (SD) 
XX.X (XX.XX) 
 
XX.X (XX.XX) 
 
XX.X (XX.XX) 
 
  Median 
XXX 
 
XXX 
 
XXX 
 
  Range (Min, Max) 
(XXX, XXX) 
 
(XXX, XXX) 
 
(XXX, XXX) 
 
 
 
 
 
 
 
 
Follow-up 
 
 
 
 
 
 
  N 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
  Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
  Median 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
  Range (Min, Max) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
 
 
 
 
 
 
 
Footnote: 
[1] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
 
 
Programmer note:   
Chemistry parameters are listed alphabetically. 
Include scheduled time points only. 
Include the following for 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). 
 
 
 


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61 
 
Non-unique tables:  
 
Table 14.3.2.1.2 
Summary of Hematology Results by Study Visit 
Safety Population 
 
Footnotes: 
[1] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
Programmer note:   
Hematology parameters are listed alphabetically. 
Include scheduled time points only. 
Include the following for hematology values: 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. 
 
Table 14.3.2.1.3 
Summary of Urinalysis Results by Study Visit 
Continuous Assays 
Safety Population 
 
Footnotes: 
[1] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
Programmer note:   
Laboratory parameters are listed alphabetically 
Include scheduled time points only. 
Include continuous urinalysis assays only. 
 


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62 
Table 14.3.2.1.4 
Summary of Urinalysis Results by Study Visit 
Categorical Assays 
Safety Population 
 
pH (for example) 
System Organ Class  Preferred Term 
Standard Narcotic 
Therapy[1] 
Buprenorphine SL Spray (0.5 
mg TID)  
Overall 
 
N=xx 
N=xx 
N=xx 
Lab Parameter 
 
 
 
 
 
 
 
Screening (Baseline) 
 
 
 
  Category 1 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Category 2 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Category 3 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Category 4 
XXX (XX.X%) 
 
 
 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
Follow-up 
 
 
 
  Category 1 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Category 2 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Category 3 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
  Category 4 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
Footnote: 
Footnotes: 
[1] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
Programmer note:   
Laboratory parameters are listed alphabetically 
Include scheduled time points only. 
Include categorical urinalysis assays only. 
 
 
 


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63 
 
 
 
Table 14.3.3 
Summary of Vital Signs and Changes From Baseline by Study Visit 
Safety Population 
 
Systolic blood pressure (mmHg) (for example) 
 
Standard Narcotic Therapy[2] 
N=XX 
Buprenorphine SL Spray (0.5 mg 
TID)  
N=XX 
Overall 
N=XX 
Study Visit/ 
 Time point [1]  
  Statistic 
Actual 
Change From 
Baseline 
Actual 
Change From 
Baseline 
Actual 
Change From 
Baseline 
Screening (Baseline) 
 
 
 
 
 
 
  n 
XXX 
 
XXX 
 
XXX 
 
  Mean (S.D.) 
XX.X (XX.XX) 
 
XX.X (XX.XX) 
 
XX.X (XX.XX) 
 
  Median 
XXX 
 
XXX 
 
XXX 
 
  Range (Min, Max) 
(XXX, XXX) 
 
(XXX, XXX) 
 
(XXX, XXX) 
 
 
 
 
 
 
 
 
Pre-surgery 
 
 
 
 
 
 
  n 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
  Mean (S.D.)) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
  Median 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
  Range (Min, Max) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
 
 
 
 
 
 
 
Pre-dose 
 
 
 
 
 
 
  n 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
  Mean (S.D.)) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
  Median 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
  Range (Min, Max) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
Footnotes: 
 
[1] During treatment period: 
Blood Pressure will be measured every 4 hours after first dose. 
Pulse rate and respiratory rate will be measured at T0, 1h and every 2 hours after first dose. 
Pulse Oximetry will be measured at 90 min, 12h, 24h, 48h, and 72h after first dose. 
[2] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  


Protocol No.: INS005-17-111 
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64 
Programmer note:  Vital signs are: Systolic and diastolic blood pressure, heart rate, respiratory rate, oral temperature and pulse 
oximetry. Include scheduled time points only. 
 
 


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65 
 
 
 
Table 14.3.4 
Summary of Physical Exam Findings  
Safety Population 
 
 
 
 
 
Standard Narcotic 
Therapy[1] 
Buprenorphine SL Spray 
(0.5 mg TID)  
Overall 
 
 
N=xx 
N=xx 
N=xx 
Study Visit 
Exam Finding 
n  (%) [1] 
n  (%) [1] 
n  (%) [1] 
 
 
 
 
 
Screening 
n 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Abnormal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Not Done 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Pre-surgery 
n 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Abnormal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Not Done 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Treatment Period/ 72 h 
n 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Abnormal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Not Done 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 
 
Etc. 
 
 
 
 
 
Footnote: 
[1] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
 
 
Programmer note:   
Include scheduled time points only. 
 
 
 


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66 
 
Table 14.3.5 
Summary of Oral Cavity Exam Findings  
Safety Population 
 
 
 
 
 
Standard Narcotic 
Therapy[2] 
Buprenorphine SL Spray 
(0.5 mg TID)  
Overall 
 
 
N=xx [1] 
N=xx [1] 
N=xx [1] 
Study Visit/ 
 Time point [1] 
Exam Finding 
n  (%) 
n  (%) 
n  (%) 
 
 
 
 
 
Screening 
n 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Active Infection 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Mucositis 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Cold Sores 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
… 
 
 
 
 
Recent Hx Dental 
Disease 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Other 
 
 
 
 
 
 
 
 
Pre-surgery 
n 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Active Infection 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Mucositis 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Cold Sores 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
… 
 
 
 
Pre-dose 
n 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Active Infection 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Mucositis 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
Cold Sores 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
… 
 
 
 
Etc. 
 
 
 
 
 
 
Footnote: 
[1] During treatment period, oral cavity exam will be performed at 90 min, 12h, 24h, 48h, and 72h after dosing. 
[2] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
 
Programmer note:   
Include scheduled time points only.  
 
 
 


Protocol No.: INS005-17-111 
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67 
 
Table 14.3.6 
Summary of ECG Exam Findings  
Safety Population 
 
 
 
 
 
Standard Narcotic 
Therapy[2] 
Buprenorphine SL 
Spray (0.5 mg TID)  
Overall 
 
ECG Findings 
 
N = xx 
N = xx 
N = xx 
Study Visit / Time Points [1] 
 
 
 
 
 
Screening 
n 
X.X (X.XX) 
X.X (X.XX) 
X.X (X.XX) 
 
Normal 
X.X (X.XX) 
X.X (X.XX) 
X.X (X.XX) 
 
Abnormal 
X.X (X.XX) 
X.X (X.XX) 
X.X (X.XX) 
 
Not Done 
X.X (X.XX) 
X.X (X.XX) 
X.X (X.XX) 
 
 
 
 
 
Pre-dose 
n 
X.X (X.XX) 
X.X (X.XX) 
X.X (X.XX) 
 
Normal 
X.X (X.XX) 
X.X (X.XX) 
X.X (X.XX) 
 
Abnormal 
X.X (X.XX) 
X.X (X.XX) 
X.X (X.XX) 
 
Not Done 
X.X (X.XX) 
X.X (X.XX) 
X.X (X.XX) 
 
 
 
 
 
Treatment Period / 90 min 
n 
X.X (X.XX) 
X.X (X.XX) 
X.X (X.XX) 
 
Normal 
X.X (X.XX) 
X.X (X.XX) 
X.X (X.XX) 
 
Abnormal 
X.X (X.XX) 
X.X (X.XX) 
X.X (X.XX) 
 
Not Done 
X.X (X.XX) 
X.X (X.XX) 
X.X (X.XX) 
Etc. 
 
 
 
 
 
 
 
 
 
 
Footnotes: 
[1] During treatment period, ECG exam will be performed at 90 min, 12h, 24h, 48h, and 72h after dosing. 
[2] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
Programmer note:   
Include scheduled time points only. 
 
 
 


Protocol No.: INS005-17-111 
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68 
 
Table 14.3.7 
Summary of ECG Results and Changes from Baseline by Study Visit  
Safety Population 
 
 
HR (beats/min) (for example) 
 
Standard Narcotic Therapy[2] 
N=XX 
Buprenorphine SL Spray (0.5 mg 
TID)  
N=XX 
Overall 
N=XX 
Study Visit/ 
 Time point [1]  
  Statistic 
Actual 
Change From 
Baseline 
Actual 
Change From 
Baseline 
Actual 
Change From 
Baseline 
Screening (Baseline) 
 
 
 
 
 
 
  n 
XXX 
 
XXX 
 
XXX 
 
  Mean (S.D.) 
XX.X (XX.XX) 
 
XX.X (XX.XX) 
 
XX.X (XX.XX) 
 
  Median 
XXX 
 
XXX 
 
XXX 
 
  Range (Min, Max) 
(XXX, XXX) 
 
(XXX, XXX) 
 
(XXX, XXX) 
 
 
 
 
 
 
 
 
90 min 
 
 
 
 
 
 
  n 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
  Mean (S.D.)) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
  Median 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
  Range (Min, Max) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
  n 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
  Mean (S.D.)) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
  Median 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
  Range (Min, Max) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
(XXX, XXX) 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
[1] During treatment period, ECG exam will be performed at 90 min, 12h, 24h, 48h, and 72h after dosing 
Footnotes: 
[2] Subjects assigned Standard Narcotic Therapy were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period.  
 
 


Protocol No.: INS005-17-111 
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14.1 FIGURE SPECIFICATIONS  
 
Figure 14.1 
Time To First Use Of Rescue Medication  
Safety Population 
 
 
Footnote: 
If a subject does not take rescue medication for nausea but prematurely discontinues from the study, then the subject will be censored 
at the time of discontinuation.  If a subject never takes rescue medication for nausea and completes the treatment phase of the study, 
then the subject will be considered censored at 7 days. 
Points on graph represent censored events. 
 
 
 0  0
 4
 5
 8
10
11 11
14
17
17
17
17
17
 2  4
 4
 8
11
15
15 17
20
21
21
21
21
21
Standard (N = 24)
Buprenorphine (N = 22)
Percent Using (% of Patients)
0%
20%
40%
60%
80%
100%
Time (In Hours)
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Reference SAS Program: Insys Time to rescue (06SEP17 , 9:09 )
Standard
Buprenorphine


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14.2 LISTING SPECIFICATIONS  
 
 


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Listing 16.2.1.1 
Subject Enrollment and Randomization  
All Subjects 
 
 
 
Site-Subject 
Subject 
Initials 
Date of 
Informed 
Consent 
Protocol 
Version 
Date 
ICF 
Version 
Date 
Random
ized? 
Date (Time) 
of Random-
ization 
Rand 
Number 
Randomized 
Treatment  
Safety 
Population 
XXX-XXX 
XXX 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
Yes 
ddMMMyyyy 
(hh:mm) 
XXXX 
Buphrenorphine 
SL Spray (0.5 
mg TID) 
Yes/No 
XXX-XXX 
XXX 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
No 
 
 
 
 
XXX-XXX 
XXX 
ddMMMyyyy 
ddMMMyyyy 
ddMMMyyyy 
Yes 
ddMMMyyyy 
(hh:mm) 
XXXX 
Standard 
Narcotic 
Therapy 
Yes/No 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.1.3 
Subject Disposition 
All Subjects 
 
Treatment: Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
End of Study 
status [1] 
Date of Last 
Study Visit 
(Study 
Day[2]) 
Date of 
Last 
Subject 
Contact 
Primary 
Reason for 
Early 
Termination 
[3] 
If AE 
Specify AE 
# 
If Protocol 
Deviation, 
Specify # 
If Death, 
Specify 
Date 
If Other - 
Specify 
 
 
 
 
 
 
 
 
 
XXX-XXX 
XXXXXX 
ddMMMyyyy 
(xx) 
ddMMMyyyy 
XXXXXXX 
XX 
XX 
ddMMMyyyy 
XXXXXXX 
XXX-XXX 
XXXXXX 
ddMMMyyyy 
ddMMMyyyy 
XXXXXXX 
XX 
XX 
ddMMMyyyy 
XXXXXXX 
XXX-XXX 
XXXXXX 
ddMMMyyyy 
ddMMMyyyy 
XXXXXXX 
XX 
XX 
ddMMMyyyy 
XXXXXXX 
Etc. 
 
 
 
 
 
 
 
 
 
Footnotes: 
 
[1] End of study status can be: Study completer, Early termination. 
[2]Study Day = Date of Last Visit - Date of First Treatment + 1. 
[3] Primary Reason for Early Termination can be:  Adverse event (specify AE #), Death (specify date), Lost to follow-up, Protocol 
Violation (specify deviation #), Withdrawal of Consent by Subject, Subject Noncompliance, Study Enrollment Stopped, Other (Specify). 
 
 
 
 


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Listing 16.2.2.1 
Protocol Deviations 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Any 
Deviation? 
Deviation 
Number 
Date of 
Deviation 
Deviation 
Category 
[1] 
Deviation Description 
Major Deviation? 
XXX-XXX 
Yes/No/NA 
XX 
ddMMMyyyy 
XXX 
XXXXXXXXXXXXXXXXXXXXXXX 
Yes/No 
XXX-XXX 
Yes/No/NA 
XX 
ddMMMyyyy 
XXX 
XXXXXXXXXXXXXXXXXXXXXXX 
Yes/No 
XXX-XXX 
Yes/No/NA 
XX 
ddMMMyyyy 
XXX 
XXXXXXXXXXXXXXXXXXXXXXX 
Yes/No 
Etc. 
 
XX 
 
 
 
 
Footnote:   
[1] Deviation category can be:  Informed consent procedure, inclusion/exclusion criteria, study medication, prohibited medications, 
study procedures, visit or assessment time window, missed visit or assessment, other. 
 
 
 


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Listing 16.2.4.1 
Demographics and Baseline Characteristics 
Safety Population 
 
Treatment: Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Date of Birth 
Age (yrs) 
[1] 
Sex 
Race [2] Ethnicity 
[3] 
Baseline 
PONV Score 
[4] 
/Category 
Baseline 
Height 
(cm) 
Baseline 
Weight 
(kg) 
Baseline 
BMI (kg/m2) 
XXX-XXX 
ddMMMyyyy 
XX 
M/F 
XXXXX 
XXXXX 
X /Low Risk 
XXX 
XX.X 
XX.X 
XXX-XXX 
ddMMMyyyy 
XX 
M/F 
XXXXX 
XXXXX 
X /High 
Risk  
XXX 
XX.X 
XX.X 
XXX-XXX 
ddMMMyyyy 
XX 
M/F 
XXXXX 
XXXXX 
X 
XXX 
XX.X 
XX.X 
Etc. 
 
 
 
 
 
 
 
 
 
 
Footnotes:   
[1] Age is calculated at date of Informed Consent. 
[2] Race can be:  White, Black or African American, Asian, American Indian or Alaskan Native, Native Hawaiian or Other Pacific 
Islander, or Other. 
[3] Ethnicity can be:  Hispanic or Latino or Not Hispanic or Latino. 
[4] PONV score can be from 0 to 4, Scores of 0-2 are categorized as Low Risk, Scores of 3-4 are categorized as High Risk. 
 
 
 
 


Protocol No.: INS005-17-111 
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Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
75 
 
 
 
Listing 16.2.4.2 
Medical/Surgical History 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Any 
Medical 
Hx? 
HX Number 
Diagnosis / Condition 
/ Event 
System 
Organ 
Class[1] 
Preferred 
Term[1] 
Start Date 
(Time) 
Stop Date 
(Time) 
Ongoing? 
XXX-XXX 
Yes/No 
XX 
XXXXXXXXXX 
XXXXXXXXXX 
XXXXXXXXXX 
ddMMMyyyy 
(hh:mm) 
ddMMMyyyy 
(hh:mm) 
Yes/No 
XXX-XXX 
Yes/No 
XX 
XXXXXXXXXX 
XXXXXXXXXX 
XXXXXXXXXX 
ddMMMyyyy 
(hh:mm) 
ddMMMyyyy 
(hh:mm) 
Yes/No 
XXX-XXX 
Yes/No 
XX 
XXXXXXXXXX 
XXXXXXXXXX 
XXXXXXXXXX 
ddMMMyyyy 
(hh:mm) 
ddMMMyyyy 
(hh:mm) 
Yes/No 
Etc. 
Yes/No 
XX 
XXXXXXXXXX 
XXXXXXXXXX 
XXXXXXXXXX 
ddMMMyyyy 
(hh:mm) 
ddMMMyyyy 
(hh:mm) 
Yes/No 
Footnotes: 
[1] System Organ Class and Preferred Term are based on the Version 19.0 of the MedDRA coding dictionary. 
 
 


Protocol No.: INS005-17-111 
Page 76 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
76 
Listing 16.2.4.3 
Prior and Concomitant Medications 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site- 
Subject 
Any 
med
s? 
Med # 
ATC Class / 
 Pref. Term/ 
  Verbatim Term 
Dose / 
Units / 
Frequenc
y / 
Route 
[1] 
Start 
Date 
(Time)  
Stop 
Date 
(Time) 
On-
going? 
Prior/ 
Con-
comitant[3] 
Category 
[2]/ 
Indication 
Was 
treatme
nt 
given 
for AE 
or MH? 
AE 
# 
MH # 
XXX-XXX 
Yes
/No 
XX 
Antithrombotic 
Agent/ 
 Acetylsalicylic 
acid /   
  Aspirin 
81 mg / 
QID / PO 
ddMMMyyy
y 
(hh:mm) 
ddMMMyyy
y 
(hh:mm) 
Yes/No P/C 
Concomitant 
Med / 
Cerebrovasc
ular 
Accident 
Prophylaxis 
Yes/No 
XX 
XX 
XXX-XXX 
Yes
/No 
XX 
XXXXXXXXXX / 
XXXXXXXXXX / 
XXXXXXXXXX 
XX XX / 
XXX / 
XXX 
ddMMMyyy
y 
(hh:mm) 
ddMMMyyy
y 
(hh:mm) 
Yes/No  
 
Yes/No 
XX 
XX 
XXX-XXX 
Yes
/No 
XX 
XXXXXXXXXX / 
XXXXXXXXXX / 
XXXXXXXXXX 
XX XX / 
XXX / 
XXX 
ddMMMyyy
y 
(hh:mm) 
ddMMMyyy
y 
(hh:mm) 
Yes/No  
 
Yes/No 
XX 
XX 
Etc. 
Yes
/No 
XX 
 
 
ddMMMyyy
y 
(hh:mm) 
ddMMMyyy
y 
(hh:mm) 
Yes/No  
 
Yes/No 
XX 
XX 
 
Footnote:   
[1] Unit can be:  Mg, mcg, ml, Capsule, Tablet, or Other. 
Route can be:  Oral, Inhalation, Topical, IV, IM, Other. 
Frequency can be:  QD, BID, TID, QID, Once, PRN, or Other. 
[2] Category can be:  Prior Medication, Concomitant Medication, or Prophylaxis. 
[3] Prior medications are those that stop prior to the start of the first study drug administration.  Any medication that stops at or 
after the start of the first study drug administration or with missing stop dates is considered a concomitant medication. 
 
 
 


Protocol No.: INS005-17-111 
Page 77 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
77 
 
 
 
Listing 16.2.4.4 
Non-Medication Therapy 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Any 
Thera
py? 
Ther
apy 
Numb
er 
ATC Class / 
 Pref. Term/ 
  Rescue 
Medication 
Name 
Dose / 
Units / 
Frequenc
y / 
Route 
Indicatio
n 
Start 
Date 
(Time) 
Stop 
Date 
(Time) 
On-
going? 
Prior/ 
Concomitan
t[1] 
Was 
treatmen
t given 
for AE 
or MH? 
A
E 
# 
M
H 
# 
XXX-XXX 
Yes/N
o 
X 
XXXXXXXXXX / 
XXXXXXXXXX / 
XXXXXXXXXX 
81 mg / 
QID / PO 
XXXXXXXXX 
ddMMMyyy
y 
(hh:mm) 
ddMMMyyy
y 
(hh:mm) 
Yes/No 
P/C 
Yes/No 
X
X 
X
X 
XXX-XXX 
Yes/N
o 
X 
XXXXXXXXXX / 
XXXXXXXXXX / 
XXXXXXXXXX 
XX XX / 
XXX / 
XXX 
XXXXXXXXX 
ddMMMyyy
y 
(hh:mm) 
ddMMMyyy
y 
(hh:mm) 
Yes/No 
 
Yes/No 
X
X 
X
X 
XXX-XXX 
Yes/N
o 
X 
XXXXXXXXXX / 
XXXXXXXXXX / 
XXXXXXXXXX 
XX XX / 
XXX / 
XXX 
XXXXXXXXX 
ddMMMyyy
y 
(hh:mm) 
ddMMMyyy
y 
(hh:mm) 
Yes/No 
 
Yes/No 
X
X 
X
X 
Etc. 
Yes/N
o 
X 
XXXXXXXXXX / 
XXXXXXXXXX / 
XXXXXXXXXX 
XX XX / 
XXX / 
XXX 
XXXXXXXXX 
ddMMMyyy
y 
(hh:mm) 
ddMMMyyy
y 
(hh:mm) 
Yes/No 
 
Yes/No 
X
X 
X
X 
Footnote: 
[1] Prior therapies are those that stop prior to the start of the first study drug administration.  Any therapy that stops at or after 
the start of the first study drug administration or with missing stop dates is considered a concomitant therapy. 
 
 
 


Protocol No.: INS005-17-111 
Page 78 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
78 
 
Listing 16.2.4.5 
Serology Laboratory And Pregnancy Test Results 
Safety Population 
 
 Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Age 
Sex 
If Female, Is Subject 
of Child Bearing 
Potential? 
Test Performed 
Study Visit 
Date (Time) 
Result 
XXX-XXX 
XX 
M/F 
Yes/No 
HIV Test Results 
Screening 
ddMMMyyyy (HH:MM) 
Negative/Positive 
XXX-XXX 
XX 
M/F 
Yes/No 
Hep B Antigen Results 
Screening 
ddMMMyyyy (HH:MM) 
Negative/Positive 
XXX-XXX 
XX 
M/F 
Yes/No 
Hep C Antigen Results 
Screening 
ddMMMyyyy (HH:MM) 
Negative/Positive 
XXX-XXX 
XX 
M/F 
Yes/No 
Serum Pregnancy 
Screening 
ddMMMyyyy (HH:MM) 
Negative/Positive 
XXX-XXX 
XX 
M/F 
Yes/No 
Urine Pregnancy 
Pre-Surgery 
ddMMMyyyy (HH:MM) 
 
XXX-XXX 
XX 
M/F 
Yes/No 
HIV Test Results 
Screening 
ddMMMyyyy (HH:MM) 
 
Etc. 
 
 
 
 
 
 
 
 
 
 


Protocol No.: INS005-17-111 
Page 79 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
79 
 
Listing 16.2.4.6 
Alcohol Breath Test and Urine Drug Screen[1]  
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Test performed? 
Study Visit 
Was Test 
Performed? 
Date (Time)  
Result 
XXX-XXX 
Alcohol Test 
Screening 
Y 
ddMMMyyyy (HH:MM) 
Negative/Positive 
XXX-XXX 
 
Day 1 
Y 
ddMMMyyyy (HH:MM) 
Negative/Positive 
XXX-XXX 
Urine Drug Screen 
Screening 
Y 
ddMMMyyyy (HH:MM) 
Negative/Positive 
Etc. 
 
Day 1 
N 
 
 
 
Footnote:   
[1]Screened Drugs Found can be:  Amphetamines, Barbiturates, Benzodiazepines, Cocaine, Marijuana, Methadone, Methamphetamines, 
Opiates, Oxycodone, Phencyclidine (PCP) Tricyclic antidepressant, or Methylenedioxymethamphetamine, Other. 
 


Protocol No.: INS005-17-111 
Page 80 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
80 
 
 
 
Listing 16.2.4.7 
Surgery 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Surgical Procedure [1] 
Target foot for 
Bunionectomy 
Breast Implant 
Size: Left/Right 
Date 
Start Time 
Stop Time 
XXX-XXX 
XXXXXXXX 
 
xxx / yyy 
ddMMMyyyy 
hh:mm 
hh:mm 
XXX-XXX 
XXXXXXXX 
Left 
 
ddMMMyyyy 
hh:mm 
hh:mm 
XXX-XXX 
XXXXXXXX 
 
 
ddMMMyyyy 
hh:mm 
hh:mm 
Etc. 
XXXXXXXX 
 
 
ddMMMyyyy 
hh:mm 
hh:mm 
 
Foootnote:   
[1] The surgical procedures will be bunionectomy, breast augmentation, or abdominoplasty. 
 
 
 


Protocol No.: INS005-17-111 
Page 81 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
81 
 
Listing 16.2.5.1 
Study Drug Administration 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Study 
Treatment 
Period [1] 
Study Medication 
Dose [2] 
Was Dose 
Administered? 
Date (Time) 
If No, Specify?  
Did the subject hold spray 
under tongue for 30 sec 
before swallowing?[3] 
XXX-XXX 
Inpatient 
Dose 1 
Yes/No 
ddMMMyyyy 
(HH:MM) 
XXXXXXXXXX 
Yes/No 
XXX-XXX 
Inpatient 
Dose 2 
Yes/No 
ddMMMyyyy 
(HH:MM) 
XXXXXXXXXX 
Yes/No 
XXX-XXX 
Inpatient 
Etc. 
Yes/No 
ddMMMyyyy 
(HH:MM) 
XXXXXXXXXX 
Yes/No 
XXX-XXX 
Outpatient 
Dose 1 
Yes/No 
ddMMMyyyy 
(HH:MM) 
XXXXXXXXXX 
Yes/No 
XXX-XXX 
Outpatient 
Etc. 
Yes/No 
ddMMMyyyy 
(HH:MM) 
XXXXXXXXXX 
Yes/No 
XXX-XXX 
Inpatient 
Dose 1 
Yes/No 
ddMMMyyyy 
(HH:MM) 
XXXXXXXXXX 
Yes/No 
Etc. 
 
 
 
 
 
 
 
Footnote:   
[1] Study Treatment Period can be Inpatient (Days 1-4), or Outpatient (Days 4-7). 
[2] There are a possible 12 doses each for each Treatment Period. 
[3] For Buprenorphine SL Spray (0.5 mg TID) subjects only. 
 
 


Protocol No.: INS005-17-111 
Page 82 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
82 
 
 
Listing 16.2.5.2 
Discharge to Outpatient Treatment 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Did subject 
continue to 
Outpatient 
Treatment 
Did subject sign 
the Opioid 
Agreement? 
Discharge Date 
(Time) 
Did subject receive 
all Outpatient 
instructions per 
protocol? 
Did staff 
dispense 
outpatient 
diaries? 
Did staff 
dispense 
study drug? 
XXX-XXX 
Yes/No 
Yes/No 
ddMMMyyyy (HH;MM) 
Yes/No 
Yes/No 
Yes/No 
XXX-XXX 
Yes/No 
Yes/No 
ddMMMyyyy (HH;MM) 
Yes/No 
Yes/No 
Yes/No 
XXX-XXX 
Yes/No 
Yes/No 
ddMMMyyyy (HH;MM) 
Yes/No 
Yes/No 
Yes/No 
XXX-XXX 
Yes/No 
Yes/No 
ddMMMyyyy (HH;MM) 
Yes/No 
Yes/No 
Yes/No 
XXX-XXX 
Yes/No 
Yes/No 
ddMMMyyyy (HH;MM) 
Yes/No 
Yes/No 
Yes/No 
XXX-XXX 
Yes/No 
Yes/No 
ddMMMyyyy (HH;MM) 
Yes/No 
Yes/No 
Yes/No 
XXX-XXX 
Yes/No 
Yes/No 
ddMMMyyyy (HH;MM) 
Yes/No 
Yes/No 
Yes/No 
 
Yes/No 
Yes/No 
ddMMMyyyy (HH;MM) 
Yes/No 
Yes/No 
Yes/No 
Note: 
Subjects assigned Standard  Narcotic Therapy of care were given morphine IV 4 mg TID for 24 hours, followed by Oxycodone Hydrochloride 
tablet, 10 mg TID for the remainder of the treatment period. Subjects assigned to Buprenorphine SL Spray (0.5 mg TID) received 
Buprenorphine sublingual spray 0.5 mg TID for the entire treatment period.  During the outpatient portion of the trial, subjects 
assigned to Standard Narcotic Therapy of care were instructed to take study medication only when they experienced pain, while subjects 
assigned to Buprenorphine SL Spray (0.5 mg TID) were instructed to maintain the TID dosing for the entire outpatient period.  
 
 
 


Protocol No.: INS005-17-111 
Page 83 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
83 
 
Listing 16.2.5.3 
Study Drug Accountability 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Dispensed 
Date 
(Time)[1] 
Number of 
study 
devices or 
pills 
dispensed 
Did 
subject 
return 
Outpatient 
Diaries? 
If No, 
specify 
reason 
Date 
Did the 
subject 
return 
study 
drug? 
Date 
Number 
of 
unused 
study 
devices 
or pills 
returned 
Number of 
used study 
devices 
returned 
Did the 
subject return 
fewer than 
expected 
devices or 
pills? If Yes, 
was an IP 
irregularities 
form 
completed? 
XXX-XXX 
ddMMMyyyy 
(HH;MM) 
XX 
Yes 
ddMMMyyyy 
Yes/No 
ddMMMyyyy 
XX 
XX 
Yes, Yes 
XXX-XXX 
ddMMMyyyy 
(HH;MM) 
XX 
No, 
XXXXXXX 
 
Yes/No 
ddMMMyyyy 
XX 
XX 
No 
XXX-XXX 
ddMMMyyyy 
(HH;MM) 
XX 
Yes/No 
ddMMMyyyy 
Yes/No 
ddMMMyyyy 
XX 
XX 
Yes/No 
XXX-XXX 
ddMMMyyyy 
(HH;MM) 
XX 
Yes/No 
ddMMMyyyy 
Yes/No 
ddMMMyyyy 
XX 
XX 
Yes/No 
XXX-XXX 
ddMMMyyyy 
(HH;MM) 
XX 
Yes/No 
ddMMMyyyy 
Yes/No 
ddMMMyyyy 
XX 
XX 
Yes/No 
XXX-XXX 
ddMMMyyyy 
(HH;MM) 
XX 
Yes/No 
ddMMMyyyy 
Yes/No 
ddMMMyyyy 
XX 
XX 
Yes/No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Footnote: 
[1] Subjects were dispensed diaries and study drug for outpatient treatment period at the Site Discharge.  
 
 


Protocol No.: INS005-17-111 
Page 84 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
84 
 
Listing 16.2.5.4 
Rescue Medication Administration 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Was Rescue 
Medication 
Administered? 
Rescue 
Medication # 
ATC Class / 
 Pref. Term/ 
  Rescue Medication 
Name 
Dose / Unit / 
Route [1] 
Date (Time) 
Medication 
Category 
XXX-XXX 
Yes/No 
1 
XXXXXXXXXX / 
XXXXXXXXXX / 
XXXXXXXXXX 
XXX / XXX/ XXXX 
ddMMMyyyy (HH:MM) 
Pain/Nausea 
XXX-XXX 
Yes/No 
2 
XXXXXXXXXX / 
XXXXXXXXXX / 
XXXXXXXXXX 
XXX / XXX/ XXXX 
ddMMMyyyy (HH:MM) 
Pain/Nausea 
XXX-XXX 
Yes/No 
Etc. 
XXXXXXXXXX / 
XXXXXXXXXX / 
XXXXXXXXXX 
XXX / XXX/ XXXX 
ddMMMyyyy (HH:MM) 
Pain/Nausea 
XXX-XXX 
Yes/No 
XX 
XXXXXXXXXX / 
XXXXXXXXXX / 
XXXXXXXXXX 
XXX / XXX/ XXXX 
ddMMMyyyy (HH:MM) 
Pain/Nausea 
XXX-XXX 
Yes/No 
XX 
XXXXXXXXXX / 
XXXXXXXXXX / 
XXXXXXXXXX 
XXX / XXX/ XXXX 
ddMMMyyyy (HH:MM) 
Pain/Nausea 
XXX-XXX 
Yes/No 
XX 
XXXXXXXXXX / 
XXXXXXXXXX / 
XXXXXXXXXX 
XXX / XXX/ XXXX 
ddMMMyyyy (HH:MM) 
Pain/Nausea 
Etc. 
 
 
 
 
 
 
 
Footnote: 
[1] Route can be Oral or Intravenous. 
 
 
 


Protocol No.: INS005-17-111 
Page 85 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
85 
 
Listing 16.2.7.1 
All Treatment Emergent Adverse Events (TEAEs) 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
AE 
Number 
System Organ Class / 
Preferred Term[1] / 
Verbatim Term 
Start Date (Time) / 
Stop Date (Time) / 
Duration 
Ongoing? /     
Outcome [2] 
Causality[3]/ 
 Severity[4]/ 
  Action 
Taken[5] 
Serious? / 
 Specify 
Cause[6]/ 
  SAE Outcome[7] 
XXX-XXX 
1 
Injury, poisoning and 
procedural complications / 
 Concussion / 
  Concussion secondary to 
xxxx  
01Jan2013 (8:45) / 
 10Jan 2013 (9:00) / 
10 days 
No / Resolved 
Not related  
 /Severe   
  /None 
Yes / 
 Is Life 
Threatening / 
  Drug Withdrawn 
XXX-XXX 
 
 
 
 
 
 
XXX-XXX 
 
 
 
 
 
 
XXX-XXX 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
Footnotes: 
[1] SOC and PT are determined by coding the verbatim term using the MedDRA Version 19.0 dictionary. 
[2] Outcome can be:  Event Resolved, Resolved with sequelae, Ongoing, or Death.  If SAE, outcome can be:  Not Recovered/Not Resolved, 
Death or Other.  
[3] Causality can be:  Definitely Related, Probably Related, Possibly Related, Unlikely Related, or Not Related. 
[4] Severity can be:  Mild, Moderate, or Severe. 
[5] Action Taken can be:  None, Study Drug Discontinued, Dose Modified, Required Concomitant Medication, Required Procedure, or Other.   
[6] Specify cause can be: Death, Life-threatening, In-patient hospitalization or prolongation of existing hospitalization, Persistent 
or significant disability or incapacity, Congenital anomaly or birth defect, is medically significant or requires intervention to 
prevent one of the outcomes listed above. 
[7] If SAE, action taken can be:  None, Treatment, Unknown or Drug Withdrawn. 
 
 
 


Protocol No.: INS005-17-111 
Page 86 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
86 
Non-Unique Tables 
 
Listing 16.2.7.2 
Treatment Related TEAEs 
Safety Population 
 
Listing 16.2.7.3 
Serious TEAEs 
Safety Population 
 
Listing 16.2.7.4 
Deaths 
Safety Population 
 
Listing 16.2.7.5 
TEAEs Leading To Premature Study Discontinuation 
Safety Population 
 
 
 
 


Protocol No.: INS005-17-111 
Page 87 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
87 
 
 
 
Listing 16.2.8.1.1 
Chemistry Laboratory Results 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Study Visit 
Date (Time) 
Test[1,2] 
Value 
Units 
Lower Limit 
of Normal 
Upper Limit 
of Normal 
XXX-XXX 
Screening 
ddMMMyyyy 
(hh:mm) 
Albumin 
XX.X 
XX 
XX.X 
XX.X 
 
 
ddMMMyyyy 
(hh:mm) 
Alk Phos 
XX.X 
XX 
XX.X 
XX.X 
 
Follow-up 
ddMMMyyyy 
(hh:mm) 
Albumin 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Alk Phos 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Etc. 
XX.X 
XX 
XX.X 
XX.X 
XXX-XXX 
Screening 
ddMMMyyyy 
(hh:mm) 
Albumin 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Alk Phos 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Etc. 
XX.X 
XX 
XX.X 
XX.X 
 
Follow-up 
ddMMMyyyy 
(hh:mm) 
Albumin 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Alk Phos 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Etc. 
XX.X 
XX 
XX.X 
XX.X 
Footnotes: 
[1] Laboratory parameters are listed alphabetically. 
[2] Include the following tests for 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). 
 
 


Protocol No.: INS005-17-111 
Page 88 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
88 
 
 
Listing 16.2.8.1.2 
Hematology Laboratory Results 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Study Visit 
Date 
Test [1,2] 
Value 
Units 
Lower Limit 
of Normal 
Upper Limit 
of Normal 
XXX-XXX 
Screening 
ddMMMyyyy 
WBC Count 
XX.X 
XX 
XX.X 
XX.X 
 
 
ddMMMyyyy 
RBC Count 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Etc. 
XX.X 
XX 
XX.X 
XX.X 
XXX-XXX 
Follow-up 
ddMMMyyyy 
WBC Count 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
RBC Count 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Etc. 
XX.X 
XX 
XX.X 
XX.X 
XXX-XXX 
Screening 
ddMMMyyyy 
WBC Count 
XX.X 
XX 
XX.X 
XX.X 
 
 
ddMMMyyyy 
RBC Count 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Etc. 
XX.X 
XX 
XX.X 
XX.X 
XXX-XXX 
Follow-up 
ddMMMyyyy 
WBC Count 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
RBC Count 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Etc. 
XX.X 
XX 
XX.X 
XX.X 
 
Footnotes: 
[1] Laboratory tests are listed alphabetically. 
[2] Include the following tests for hematology values: 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. 
 
 


Protocol No.: INS005-17-111 
Page 89 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
89 
 
 
Listing 16.2.8.1.3 
Urinalysis Laboratory Results 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Study Visit 
Date 
Test [1,2] 
Value 
Units 
Lower Limit 
of Normal 
Upper Limit 
of Normal 
XXX-XXX 
Screening 
ddMMMyyyy 
Specific Gravity 
XX.X 
XX 
XX.X 
XX.X 
 
 
ddMMMyyyy 
pH 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Etc. 
XX.X 
XX 
XX.X 
XX.X 
XXX-XXX 
Follow-up 
ddMMMyyyy 
Specific Gravity 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
pH 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Etc. 
XX.X 
XX 
XX.X 
XX.X 
XXX-XXX 
Screening 
ddMMMyyyy 
Specific Gravity 
XX.X 
XX 
XX.X 
XX.X 
 
 
ddMMMyyyy 
pH 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Etc. 
XX.X 
XX 
XX.X 
XX.X 
XXX-XXX 
Follow-up 
ddMMMyyyy 
Specific Gravity 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
pH 
XX.X 
XX 
XX.X 
XX.X 
 
 
 
Etc. 
XX.X 
XX 
XX.X 
XX.X 
 
Footnotes:   
[1]Urinalysis tests are listed alphabetically. 
[2] Include the following for urinalysis: pH, specific gravity, blood, glucose, protein, and ketones. 
 
 
 


Protocol No.: INS005-17-111 
Page 90 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
90 
 
 
Listing 16.2.8.2 
Vital Signs 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Study Visit /  
 Time Point 
Date 
(Time) 
Height 
(cm) 
Weight 
(kg) 
OralTemp 
(oC) 
Systolic 
BP 
(mmHg) 
[1] 
Diastolic 
BP (mmHg) 
[1] 
Pulse 
Rate 
(bpm) 
[2] 
Respiratory 
Rate (bpm) 
[2] 
Pulse 
Oximetry 
(Spo2) 
[3] 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
ddMMMyyyy 
(HH;MM) 
XXX 
XXX 
XX.X 
XXX 
XXX 
XXX 
XX 
XXX 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
ddMMMyyyy 
(HH;MM) 
XXX 
XXX 
XX.X 
XXX 
XXX 
XXX 
XX 
XXX 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
ddMMMyyyy 
(HH;MM) 
XXX 
XXX 
XX.X 
XXX 
XXX 
XXX 
XX 
XXX 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
ddMMMyyyy 
(HH;MM) 
XXX 
XXX 
XX.X 
XXX 
XXX 
XXX 
XX 
XXX 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
ddMMMyyyy 
(HH;MM) 
XXX 
XXX 
XX.X 
XXX 
XXX 
XXX 
XX 
XXX 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
ddMMMyyyy 
(HH;MM) 
XXX 
XXX 
XX.X 
XXX 
XXX 
XXX 
XX 
XXX 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
ddMMMyyyy 
(HH;MM) 
XXX 
XXX 
XX.X 
XXX 
XXX 
XXX 
XX 
XXX 
 
 
ddMMMyyyy 
(HH;MM) 
XXX 
XXX 
XX.X 
XXX 
XXX 
XXX 
XX 
XXX 
 
Footnotes:  
During treatment period, 
[1] Blood Pressure is measured every 4 hours after first dose. 
[2] Pulse rate and respiratory rate are measured at T0, 1h and every 2 hours after first dose. 
[3] Pulse Oximetry is measured at 90 min, 12h, 24h, 48h, and 72h after first dose. 
 
 


Protocol No.: INS005-17-111 
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Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
91 
 
Listing 16.2.8.3.1 
Physical Examinations 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Study Visit 
Was the 
Physical 
Examination 
performed? 
Date (Time) 
Body System [1] 
Status [2] 
Clinical 
Significance 
[3] 
XXX-XXX 
 
Yes/No 
ddMMMyyyy 
(HH:MM) 
Dermatologic 
XXXXX 
XXX 
XXX-XXX 
 
Yes/No 
ddMMMyyyy 
(HH:MM) 
HEENT 
XXXXX 
XXX 
XXX-XXX 
 
Yes/No 
ddMMMyyyy 
(HH:MM) 
Etc. 
 
XXX 
XXX-XXX 
 
Yes/No 
ddMMMyyyy 
(HH:MM) 
Dermatologic 
XXXXX 
XXX 
XXX-XXX 
 
Yes/No 
ddMMMyyyy 
(HH:MM) 
HEENT 
XXXXX 
XXX 
XXX-XXX 
 
Yes/No 
ddMMMyyyy 
(HH:MM) 
Etc. 
 
XXX 
 
 
 
 
 
 
 
 
Footnotes:   
[1] Body System can be:  HEENT, Cardiovascular, Respiratory, Gastrointestinal, Neurologic, Dermatologic, Musculoskeletal, or Other 
(Specify). 
[2] Status can be:  Normal, Abnormal, or Not Done. 
[3] Clinical Significance can be:  CS=Clinically Significant or NCS=Not Clinically Significant. 
 
 


Protocol No.: INS005-17-111 
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Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
92 
 
 
 
Listing 16.2.8.3.2 
Oral Cavity Examinations 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Study Visit /  
 Time Point [1] 
Was the Oral Cavity 
Examination performed? 
Date (Time) 
Observation [2] 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
Yes/No 
ddMMMyyyy (HH:MM) 
Active Infection, Tongue piercing 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
Yes/No 
ddMMMyyyy (HH:MM) 
XXXXXXXXXXXXXXXXXX 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
Yes/No 
ddMMMyyyy (HH:MM) 
XXXXXXXXXXXXXXXXXX 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
Yes/No 
ddMMMyyyy (HH:MM) 
XXXXXXXXXXXXXXXXXX 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
Yes/No 
ddMMMyyyy (HH:MM) 
XXXXXXXXXXXXXXXXXX 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
Yes/No 
ddMMMyyyy (HH:MM) 
XXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
Footnotes:   
[1] During treatment period, oral cavity exam will be performed at 90 min, 12h, 24h, 48h, and 72h after dosing. 
[2] Observation can be: None, Active Infection, Mucositis, Cold Sores, Viral Lesions, Local Irritation, Periodontal Disease, Current 
piercings of the tongue or anywhere in the oral cavity, Evidence of prior piercings of the tongue or anywhere in the oral cavity, 
recent history of significant dental disease. Subjects may have multiple findings at each exam. 
 
 


Protocol No.: INS005-17-111 
Page 93 of 94 
Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
93 
 
 
Listing 16.2.8.4 
ECG Exam Assessment 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Study Visit /  
 Time Point [1] 
Was the ECG 
performed? 
Date (Time) 
Parameter 
Findings [2] 
If Abnormal, Please 
Describe Findings 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
Yes/No 
ddMMMyyyy (HH:MM) 
HR 
XX 
 
 
 
 
 
P-R Interval 
XX 
 
 
 
 
 
… 
 
 
 
 
 
 
Interpretation 
Normal 
 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
Yes/No 
ddMMMyyyy (HH:MM) 
HR 
XX 
 
 
 
 
 
P-R Interval 
XX 
 
 
 
 
 
… 
 
 
 
 
 
 
Interpretation 
Abnormal-CS 
XXXXXXXXX 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
Yes/No 
ddMMMyyyy (HH:MM) 
 
XX 
 
XXX-XXX 
XXXXXXXXX / 
 XXXXXX 
Yes/No 
ddMMMyyyy (HH:MM) 
 
XX 
 
 
 
 
 
 
 
 
 
Footnotes:   
[1] During treatment period, ECG exam will be performed at 90 min, 12h, 24h, 48h, and 72h after dosing. 
[2] Findings can be: Normal, Abnormal Clinically Significant (CS) or Abnormal Not Clinically Significant (NCS). 
 
 


Protocol No.: INS005-17-111 
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Sponsor:  Insys Development Company, Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
94 
 
 
 
 
Listing 16.2.8.5 
Comments 
Safety Population 
 
Treatment:  Buprenorphine SL Spray (0.5 mg TID) 
Site-Subject 
Study Visit 
Date 
CRF Page 
Comment 
XXX-XXX 
XXXXXXXX 
ddMMMyyyy 
XXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
XXX-XXX 
XXXXXXXX 
ddMMMyyyy 
XXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
XXX-XXX 
XXXXXXXX 
ddMMMyyyy 
XXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
Etc. 
XXXXXXXX 
ddMMMyyyy 
XXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX