Clinical trial NCT03348423
Conditions: Pain
Keywords: Peri-procedural pain Pain Anxiety Analgesia Anxiolysis
Sponsor: Baudax Bio
Start date: 2017-11-15; Completion date: 2018-01-18
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the analgesic efficacy of DEX-IN compared with placebo and active control (fentanyl), in subjects undergoing painful outpatient and office based procedures.

Detailed description:

Arms: arm 1: Dexmedetomidine Intranasal Spray arm 2: Intravenous Fentanyl arm 3: Placebo
Interventions: intervention 1: DEX-IN intervention 2: Fentanyl intervention 3: Placebo
Intervention descriptions: intervention 1: IN Dexmedetomidine + IV placebo intervention 2: IN Placebo + IV Fentanyl intervention 3: IN Placebo + IV Placebo

Protocol documents:
Prot_000.pdf: 
 
 
 
REC-17-023 
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo- and Active-
Controlled, Evaluation of the Efficacy and Safety of DEX-IN following Painful 
Outpatient Procedures 
 
NCT03348423 
 
Study Protocol 
 
05 September 2017 


Recro Pharma, Inc. 
Protocol REC-17-023 
CONFIDENTIAL 
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05 September 2017 
CLINICAL STUDY PROTOCOL 
Compound Name: 
Protocol Number: 
Protocol Title:  
Date of Protocol: 
Study Designated 
Physician: 
Contacts: 
Dexmedetomidine intranasal spray (DEX-IN) 
REC-17-023  
 A Phase 2, Multicenter, Randomized, Double-Blind, Placebo- and 
Active-Controlled, Evaluation of the Efficacy and Safety of DEX-IN 
following Painful Outpatient Procedures  
05 September 2017 
Stewart McCallum, MD 
490 Lapp Rd 
Malvern, PA 19355 
Telephone: 484-395-2411 
Mobile:  
Fax: 484-395-2471 
Email: smccallum@recropharma.com 
Randy Mack 
SVP, Development 
490 Lapp Rd 
Malvern, PA 19355 
Telephone: 484-395-2406 
Email: rmack@recropharma.com 
Unauthorized copying or use of this information is prohibited. 


Recro Pharma, Inc. 
Protocol REC-17-023 
CONFIDENTIAL 
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05 September 2017 
INVESTIGATOR’S AGREEMENT 
 
By signing below I confirm that I have read this protocol and agree 
 to assume responsibility for the proper conduct of the study at this site 
 to conduct the study according to the procedures described in this protocol and any future 
amendments 
 not to implement any deviation from, or changes to, the protocol without agreement of 
the sponsor and written approval from the Institutional Review Board or Independent 
Ethics Committee, except where necessary to eliminate an immediate hazard to subject(s) 
 that I am aware of and will comply with all applicable regulations and guidelines 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 
 
 
 
Principal Investigator’s Title (Print) 
 
 
 
 
 
 
 
 
Site Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SYNOPSIS (PAGE 1 OF 5) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-023 
Name of Study Drugs:  DEX-IN 
(Dexmedetomidine Intranasal Spray) 
Protocol Title:  A Phase 2, Multicenter, Randomized, 
Double-Blind, Placebo-and Active-Controlled, Evaluation 
of the Efficacy and Safety of DEX-IN following Painful 
Outpatient Procedures 
Name of Active Ingredient: 
Dexmedetomidine HCl 
Phase of Development:  2 
Objective:  The primary objective of this study is to evaluate the analgesic efficacy of DEX-IN 
compared with placebo and active control (fentanyl), in subjects undergoing painful outpatient and 
office based procedures. 
Secondary objectives of this study will include: 
 
To evaluate the anxiolytic effects of DEX-IN  
 
To determine the safety and tolerability of DEX-IN as evaluated with vital sign collection, and 
incidence of Adverse Events (AEs) and Serious AEs (SAEs). 
Methodology:   
This is a Phase 2, randomized, multicenter, double-blind, placebo- and active-controlled evaluation of 
the efficacy and safety of DEX-IN in adult subjects undergoing painful outpatient and office based 
procedures.  The study will enroll up to 250 subjects across up to 5 study cohorts, with approximately 
50-75 subjects per cohort.  Each study cohort will include subjects undergoing a specific painful 
procedure which may include, but is not limited to, cosmetic procedures (face peel, 
liposuction/liposculpture, sclerotherapy, etc.), dental procedures, biopsy procedures (prostate, 
colposcopy, etc.), or other procedures. The procedures to be evaluated in this study will be selected on 
an ongoing basis. 
Subjects planned to undergo a selected procedure, age 18 to 65 years inclusive, will be screened for 
participation at up to 5 study centers in the United States.  Screening will occur within 28 days before 
study drug administration.  After signing the informed consent, demographics and medical history, 
physical examination, clinical laboratory testing, 12-lead electrocardiogram (ECG), pregnancy testing, 
and vital sign measurements will be completed during the screening visit. 
On the day of the procedure (Day 1), eligible subjects will be randomized to treatment (1:1:1) with 
DEX-IN 50 µg, intravenous (IV) fentanyl 50 µg, or placebo.  Subjects will be administered a study 
dose in a double dummy fashion, that is, each subject will receive an intranasal (IN) dose (DEX-IN or 
placebo) approximately 1 hour prior, and an IV injection (fentanyl or placebo) approximately 15 
minutes prior to the start of the procedure.  The end of the study procedure will be defined as Hour 0.  
Study assessments of pain and anxiety will be completed at various intervals starting 1 hour before the 
procedure through Hour 4 following the end of the procedure.  
Subjects will be eligible to be discharged home following completion of the Hour 4 assessments at the 
discretion of the investigator.  Subjects may remain beyond Hour 4 at the study center based on their 
physical status.  A follow-up telephone contact will be scheduled for Day 7±2 to assess any 
subsequent safety events. 
Efficacy assessments will include assessment of pain intensity, anxiety intensity, and subject 
satisfaction with pain experienced during the procedure.  Safety assessments will include monitoring 
of AEs and SAEs, and vital sign measurements.   


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 SYNOPSIS (PAGE 2 OF 5) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-023 
Name of Study Drugs:  DEX-IN 
(Dexmedetomidine Intranasal Spray) 
Protocol Title:  A Phase 2, Multicenter, Randomized, 
Double-Blind, Placebo-and Active-Controlled, Evaluation 
of the Efficacy and Safety of DEX-IN following Painful 
Outpatient Procedures 
Name of Active Ingredient: 
Dexmedetomidine HCl 
Phase of Development:  2 
Number of subjects to be enrolled:  It is planned to enroll up to 250 subjects (approximately 50-75 
subjects per cohort in up to 5 study cohorts) 
Number of study sites:  Up to 5 
Study country location:  United States 
Criteria for inclusion:  Subjects must meet all of the following criteria to be considered eligible to 
participate in the study: 
1. Voluntarily provide written informed consent. 
2. Male or female 18 to 65 years of age at screening, inclusive. 
3. Be planned to undergo an office-based or outpatient procedure including, but not limited to, 
cosmetic procedures, dental procedures, biopsy procedures, or other outpatient and office based 
procedure, to be performed within the criteria defined in the procedure specific cohort manual.  
4. Be naïve to the planned procedure, i.e. no repeated or revision procedures. 
5. Be classified as American Society of Anesthesiology (ASA) physical status category 1 or 2. 
6. Female subjects are eligible only if all of the following apply: 
 
Not pregnant (female subjects of child bearing potential [FOCBP] must have a 
negative serum pregnancy test at screening and negative urine pregnancy test before 
procedure); 
 
Not lactating; 
 
Not planning/attempting to become pregnant during the study; 
 
Commits to the use of a highly effective contraceptive method (e.g. abstinence, 
intrauterine device [IUD], hormonal [estrogen/progestin] contraceptives, or double 
barrier method) for at least 1 menstrual cycle prior to study enrollment through the Day 
7 follow-up; or be menopausal defined as 12 months of amenorrhea in the absence of 
other biological or physiological causes; or post-menopausal for at least 1 year; or be 
surgically sterile (documented hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy). 
7. Male subjects must be surgically sterile (biologically or surgically) or commit to the use of a 
highly effective contraception method (e.g., abstinence or double barrier method) with female 
partner(s) from Screening through the Day 7 follow-up. 
8. Have a body mass index ≤35.0 kg/m2 at screening 


Recro Pharma, Inc. 
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05 September 2017 
SYNOPSIS (PAGE 3 OF 5) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-023 
Name of Study Drugs:  DEX-IN 
(Dexmedetomidine Intranasal Spray) 
Protocol Title:  A Phase 2, Multicenter, Randomized, 
Double-Blind, Placebo-and Active-Controlled, Evaluation 
of the Efficacy and Safety of DEX-IN following Painful 
Outpatient Procedures 
Name of Active Ingredient: 
Dexmedetomidine HCl 
Phase of Development:  2 
Criteria for inclusion (continued): 
9. Be able to understand the study procedures, comply with all study procedures, and agree to 
participate in the study program. 
Criteria for exclusion:  Subjects who meet any of the following criteria will be excluded from 
participating in the study: 
1. Have a known allergy to dexmedetomidine or other alpha-2-agonist, any excipient 
DEX-IN/placebo, fentanyl, or to any medications used in the planned study procedure. 
2. Have a clinically significant abnormal clinical laboratory tests value according to the judgment 
of the investigator. 
3. Have, as determined by the investigator or the sponsor’s medical monitor, a history or clinical 
manifestations of significant renal, hepatic, cardiovascular, metabolic, neurologic, psychiatric, 
or other condition that would preclude participation in the study. 
4. Have a history of migraine or frequent headaches, seizures, or are currently taking 
anticonvulsants. 
5. Have another painful physical condition or anxiety related diagnosis that, in the opinion of the 
investigator, may confound study assessments. 
6. Have a history of syncope or other syncopal attacks. 
7. Have evidence of a clinically significant 12-lead ECG abnormality according to the judgment 
of the investigator. 
8. Have a history of alcohol abuse or prescription/illicit drug abuse in the last 5 years. 
9. Have positive results on the urine drug screen or alcohol breath test indicative of illicit drug or 
alcohol abuse at screening or at check-in prior to randomization.  
10. Have a history or evidence of orthostatic hypotension at screening or at check-in prior to 
randomization. 
11. Have a resting heart rate of < 50 beats per minutes or systolic blood pressure <100 mmHg on 
evaluation of vital signs at screening or at check-in prior to randomization. 
12. Use concurrent therapy that could interfere with the evaluation of efficacy or safety, such as 
any drugs which in the investigator’s opinion may exert significant analgesic or anxiolytic 
properties or act synergistically with DEX-IN. 


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SYNOPSIS (PAGE 4 OF 5) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-023 
Name of Study Drugs:  DEX-IN 
(Dexmedetomidine Intranasal Spray) 
Protocol Title:  A Phase 2, Multicenter, Randomized, 
Double-Blind, Placebo-and Active-Controlled, Evaluation 
of the Efficacy and Safety of DEX-IN following Painful 
Outpatient Procedures 
Name of Active Ingredient: 
Dexmedetomidine HCl 
Phase of Development:  2 
Criteria for exclusion (continued) 
13. Be unable to discontinue medications that have not been at a stable dose for at least 14 days 
prior to the scheduled procedure; medications not at a stable dose to be discontinued 
approximately 5 half lives of the specific prior medication prior dosing with study medication 
(or, if half life is not known, approximately 48 hours). 
14. Have utilized any intranasal medications within 10 days prior to the procedure. 
15. Have signs or a history of significant rhinitis or rhinorrhea (constant or chronic), nasal polyps, 
mucosal lesions of the nostril, postnasal drip of any etiology (constant or chronic), nasal ulcers, 
septal perforation or deviation, any nasal surgery, anosmia, nasal piercings, or frequent 
nosebleeds or other nasal pathology, that in the investigator’s opinion is sufficient to interfere 
with intranasal drug delivery. 
16. Have had an upper respiratory tract infection within 14 days of screening or procedure, or at 
any time during the conduct of the study. 
17. Have received any investigational product within 30 days before dosing with study medication. 
18. Have previously received DEX-IN in clinical trials 
Investigational product:  DEX-IN 50 µg (Dexmedetomidine Intranasal Spray) will be supplied by the 
sponsor, for administration by subjects according to their randomization 
Reference therapy:  IV fentanyl 50 µg; IV and IN placebo 
Duration of treatment:  Study drug will be administered in double dummy fashion in order to 
maintain the study blind. Each subject will receive one IN dose (DEX-IN or Placebo) and one IV 
injection (Fentanyl or Placebo) during their participation in the study.  Subjects will be asked to remain 
at the study center from a minimum of 1 hour before the study procedure through approximately 4 
hours after the procedure on Day 1.  Subjects will be asked to complete a follow-up assessment by 
phone on Day 7±2. 
 


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SYNOPSIS (PAGE 5 OF 5) 
Name of Sponsor/Company:  
Recro Pharma, Inc. 
Protocol Number:  REC-17-023 
Name of Study Drugs:  DEX-IN 
(Dexmedetomidine Intranasal Spray) 
Protocol Title:  A Phase 2, Multicenter, Randomized, 
Double-Blind, Placebo-and Active-Controlled, Evaluation 
of the Efficacy and Safety of DEX-IN following Painful 
Outpatient Procedures 
Name of Active Ingredient: 
Dexmedetomidine HCl 
Phase of Development:  2 
Criteria for Evaluation 
Efficacy:  The primary efficacy endpoint will be the mean PI score during the study procedure.   
Secondary efficacy endpoints include: 
1) Mean PI score at other intervals (start of procedure to Hour 1, start of procedure to Hour 4) 
2) Worst pain intensity 
3) Mean anxiety score at various intervals. 
4) Subject satisfaction with pain during and following the procedure. 
Safety:  
The safety endpoints will include the following: 
1) incidence of AEs and SAEs 
2) change from baseline in vital signs; incidence of clinically significant changes in vital signs 
Statistical methods: 
Sample size determination:  The sample size for this study was selected empirically without a power 
calculation. 
Study populations:   
Intent-to-Treat (ITT) Analysis Set: The ITT set will include all subjects randomized.  The ITT subjects 
may or may not receive randomized treatment.  
Safety Analysis Set:  The safety analysis set will include all subjects treated with study drug.  
Efficacy Analysis Set: the efficacy analysis set will include all subjects in the Safety analysis set who 
had at least one pain assessment post dosing of study drug. 
Efficacy analysis:  Efficacy parameters will be summarized within each cohort by treatment group.  
Where appropriate, data may be pooled from multiple cohorts for additional summary.  
Safety analysis:  The Medical Dictionary for Regulatory Activities (Version 20 or higher) will be used 
to classify all AEs with respect to system organ class and preferred term.  AEs will be summarized by 
treatment.  Changes in vital signs at each post dosing time point will be summarized by treatment using 
descriptive statistics without formal statistical tests.     
 
 


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TABLE OF CONTENTS 
SYNOPSIS (PAGE 1 OF 5) ........................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 8 
LIST OF ABBREVIATIONS ....................................................................................................... 12 
1. 
INTRODUCTION ...................................................................................................... 14 
2. 
STUDY OBJECTIVE ................................................................................................. 16 
3. 
INVESTIGATIONAL PLAN ..................................................................................... 17 
3.1. 
Overall Study Design .................................................................................................. 17 
3.2. 
Rationale for Study Design and Control Groups ........................................................ 17 
4. 
STUDY POPULATION ............................................................................................. 19 
4.1. 
Inclusion Criteria ........................................................................................................ 19 
4.2. 
Exclusion Criteria ....................................................................................................... 19 
4.3. 
Discontinuation of Subjects ........................................................................................ 21 
4.3.1. 
Procedures for Withdrawal ......................................................................................... 21 
4.3.2. 
Replacement of Subjects ............................................................................................. 21 
4.4. 
Lifestyle Guidelines .................................................................................................... 21 
4.4.1. 
Confinement ................................................................................................................ 21 
4.4.2. 
Diet .............................................................................................................................. 21 
5. 
TREATMENTS .......................................................................................................... 22 
5.1. 
Office Based/Outpatient Procedure ............................................................................ 22 
5.2. 
Administration of Study Medication .......................................................................... 22 
5.3. 
Identity of Study Medication ...................................................................................... 23 
5.3.1. 
IN Dosing .................................................................................................................... 23 
5.3.2. 
IV Dosing .................................................................................................................... 23 
5.4. 
Method of Assigning Subjects to Treatment Groups .................................................. 23 
5.5. 
Selection of Doses....................................................................................................... 23 
5.6. 
Selection of Timing of Dose ....................................................................................... 24 
5.7. 
Blinding and Unblinding of Study Medications ......................................................... 24 
5.8. 
Treatment Compliance ................................................................................................ 24 
5.9. 
Drug Accountability.................................................................................................... 25 
5.10. 
Packaging, Labeling, and Storage ............................................................................... 25 
5.11. 
Prior and Concomitant Medications ........................................................................... 25 


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5.12. 
Prohibited Medications ............................................................................................... 25 
5.13. 
Concomitant Interventions and Procedures ................................................................ 26 
6. 
STUDY PROCEDURES ............................................................................................ 27 
6.1. 
Demographic and Efficacy Assessment...................................................................... 27 
6.1.1. 
Demographics ............................................................................................................. 27 
6.1.2. 
Medical History .......................................................................................................... 27 
6.1.3. 
Physical Examination.................................................................................................. 27 
6.1.4. 
Pain Intensity (PI) ....................................................................................................... 27 
6.1.5. 
Worst Pain Intensity .................................................................................................... 27 
6.1.6. 
Anxiety Assessment .................................................................................................... 28 
6.1.7. 
Subject Satisfaction with Pain Experience ................................................................. 28 
6.2. 
Safety Assessments Description ................................................................................. 28 
6.2.1. 
Clinical Laboratory Tests ............................................................................................ 28 
6.2.2. 
Vital Sign Measurements ............................................................................................ 29 
6.2.3. 
12-Lead Electrocardiogram (ECG) ............................................................................. 29 
6.3. 
Assessments by Visit .................................................................................................. 30 
6.3.1. 
Screening Visit ............................................................................................................ 30 
6.3.2. 
Day 1 (Pre-Procedure) ................................................................................................ 30 
6.3.3. 
Day 1 (Peri- and Post-Procedure) ............................................................................... 31 
6.3.4. 
Day 7 ± 2 Days ........................................................................................................... 31 
6.4. 
Appropriateness of Assessments................................................................................. 31 
6.5. 
Clinical Stopping Rules .............................................................................................. 31 
7. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND SERIOUS 
SUSPECTED ADVERSE REACTIONS ................................................................... 32 
7.1. 
Definition of an Adverse Event .................................................................................. 32 
7.2. 
Definition of a Serious Adverse Event ....................................................................... 32 
7.3. 
Definition of a Suspected Adverse Reaction (SAR) ................................................... 33 
7.4. 
Definition of a Serious Suspected Adverse Reaction (SSAR).................................... 33 
7.5. 
Recording and Evaluating Adverse Events and Serious Adverse Events ................... 34 
7.5.1. 
Assessment of Intensity .............................................................................................. 34 
7.5.2. 
Assessment of Causality ............................................................................................. 34 
7.5.3. 
Assessment of Outcome .............................................................................................. 35 
7.5.4. 
Assessment of Expectedness....................................................................................... 35 


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7.6. 
Follow-up of Adverse Events and Serious Adverse Events ....................................... 35 
7.7. 
Prompt Reporting of Serious Adverse Events to the Sponsor .................................... 36 
7.8. 
Regulatory Reporting Requirements ........................................................................... 37 
7.9. 
Special Reporting Situations: Pregnancy .................................................................... 37 
8. 
STATISTICAL METHODOLOGY ........................................................................... 39 
8.1. 
Determination of Sample Size .................................................................................... 39 
8.2. 
Study Endpoints .......................................................................................................... 39 
8.2.1. 
Efficacy Endpoints ...................................................................................................... 39 
8.2.2. 
Safety Endpoints ......................................................................................................... 39 
8.3. 
General Considerations for Statistical Analysis ......................................................... 39 
8.3.1. 
Analysis Datasets ........................................................................................................ 39 
8.3.2. 
Test Hypothesis and P Value Justification ................................................................. 40 
8.3.3. 
Procedures for Handling Missing Data ....................................................................... 40 
8.3.4. 
Definitions for Assessment Windows ......................................................................... 40 
8.4. 
Study Population Summaries ...................................................................................... 40 
8.4.1. 
Disposition .................................................................................................................. 40 
8.4.2. 
Demographics and Procedure Characteristics ............................................................ 40 
8.4.3. 
Protocol Deviations ..................................................................................................... 40 
8.4.4. 
Treatment Compliance ................................................................................................ 41 
8.4.5. 
Prior and Concomitant Medications ........................................................................... 41 
8.5. 
Efficacy Analysis ........................................................................................................ 41 
8.5.1. 
PI Analyses ................................................................................................................. 41 
8.5.2. 
Worst Pain Intensity .................................................................................................... 41 
8.5.3. 
Anxiety Assessment .................................................................................................... 41 
8.5.4. 
Subject Satisfaction with Pain Experience ................................................................. 41 
8.5.5. 
Subgroup Analyses for Efficacy ................................................................................. 41 
8.6. 
Safety and Tolerability Evaluations ............................................................................ 42 
8.6.1. 
Extent of Exposure ...................................................................................................... 42 
8.6.2. 
Adverse Events ........................................................................................................... 42 
8.6.3. 
Clinical Laboratory Tests ............................................................................................ 42 
8.6.4. 
Vital Sign Measurements ............................................................................................ 42 
8.6.5. 
Electrocardiograms ..................................................................................................... 43 
8.6.6. 
Subgroup Analyses for Safety Endpoints ................................................................... 43 


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9. 
STUDY ADMINISTRATION.................................................................................... 44 
9.1. 
Regulatory and Ethical Considerations ....................................................................... 44 
9.1.1. 
Regulatory Authority Approval .................................................................................. 44 
9.1.2. 
Ethical Conduct of the Study and Ethics Approval .................................................... 44 
9.1.3. 
Informed Consent........................................................................................................ 45 
9.1.4. 
Investigator Reporting Requirements ......................................................................... 46 
9.2. 
Study Monitoring ........................................................................................................ 46 
9.3. 
Quality Assurance ....................................................................................................... 46 
9.4. 
Study and Site Closure ................................................................................................ 46 
9.5. 
Records Retention ....................................................................................................... 47 
9.5.1. 
Health Insurance Portability and Accountability Act of 1996 .................................... 47 
9.5.2. 
Financial Disclosure.................................................................................................... 47 
9.5.3. 
Access to Original Records ......................................................................................... 47 
9.5.4. 
Archiving of Study-Related Documents ..................................................................... 47 
9.6. 
Provision of Study Results and Information to Investigators ..................................... 48 
9.7. 
Information Disclosure and Inventions ....................................................................... 48 
9.7.1. 
Ownership ................................................................................................................... 48 
9.7.2. 
Confidentiality ............................................................................................................ 48 
9.7.3. 
Publication .................................................................................................................. 48 
9.7.4. 
Data Management ....................................................................................................... 49 
9.7.5. 
Data Security ............................................................................................................... 49 
9.8. 
Subject Tracking ......................................................................................................... 49 
10. 
REFERENCES ........................................................................................................... 50 
APPENDIX A. OVERVIEW OF STUDY SCHEDULE ........................................................... 51 
APPENDIX B. INVESTIGATOR OBLIGATIONS ................................................................. 52 
APPENDIX C. STUDY-SPECIFIC INFORMATION .............................................................. 54 
Appendix C.1: 
Pain Assessments - Numeric Pain Rating Scale (NPRS) .................................. 54 
Appendix C.2: 
Anxiety Assessment .......................................................................................... 55 
Appendix C.3: 
Subject Satisfaction with Pain Experience ....................................................... 56 
APPENDIX D. AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL STATUS 
CLASSIFICATION SYSTEM ................................................................................... 57 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
BMI 
body mass index 
BP 
Blood Pressure 
BPM 
Beats per minute 
BSA-CF 
body-surface-area conversion factor 
CFR 
(United States) Code of Federal Regulations 
ºC 
degrees Centigrade 
CL 
Clearance 
eCRF 
Electronic case report form 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
ºF 
degrees Fahrenheit 
FOCBP 
Female of Childbearing Potential 
GCP 
Good Clinical Practice 
H 
Hour 
HCl 
Hydrochloride 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IN 
Intranasal 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intend-to-treat 
IV 
Intravenous 
Kg 
Kilogram 
L 
Liter 
m2 
square meters 
Mg 
Milligram 
Min 
Minute 
mITT 
Modified intend-to-treat 
mL 
Milliliter 
mm Hg 
millimeters of mercury 


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Abbreviation 
Definition 
NF 
National Formulary 
Ng 
Nanogram 
NPRS 
Numeric Pain Rating Scale 
NRS 
Numeric Rating Scale 
pH 
negative log of hydrogen ion concentration 
PI 
Pain Intensity 
PK 
Pharmacokinetic 
PRN 
As needed 
SAR 
suspected adverse reaction 
SAE 
serious adverse event 
SBP 
Systolic Blood Pressure 
SpO2 
peripheral oxygen saturation 
SSAR 
Serious suspected adverse reaction 
SUSAR 
Serious unexpected suspected adverse reaction 
UDS 
Urine Drug Screen 
µg 
Microgram 
µL 
Microliter 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
VD 
Volume of distribution 
WBC 
white blood cell 
 


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1. 
INTRODUCTION 
Since the year 2000, when the Joint Commission revised their standards for the assessment and 
management of pain, the treatment of pain has taken an increasingly significant position in 
medical care.  Often referred to as the “fifth vital sign”, subjects must now be routinely evaluated 
for pain symptoms so that therapy may be appropriately adjusted. 
While this increased focus has brought more attention to the issue of subject comfort and quality 
of life, our range of tools has remained largely the same.  Current medications run the gamut in 
duration of activity, ranging from acute medications that provide relief for 1-2 hours, to 
alternative formulations which can provide as much as 72 hours of analgesia.  At the same time, 
these dosage forms commonly rely on a similar set of active ingredients, which often work 
through the same opioid pathway to provide relief (morphine, oxycodone, fentanyl).1  The result, 
while there is generally not a ceiling on the effect provided by opiate medications, the use of 
high doses, and multiple opiate medications may lead to an increased occurrence of adverse 
events, which may force a decision between symptoms and side effects. 
Dexmedetomidine is a selective α2-aderenoceptor agonist, with selectivity approximately 10-fold 
that of clonidine.  Dexmedetomidine has an extensive history of safe intravenous use in acute 
care and surgical settings, utilizing its sedative properties, and is indicated for use under the trade 
name Precedex®.  At lower doses, dexmedetomidine has been observed to provide analgesic2 and 
anxiolytic3 benefits, without risk of respiratory depression.4 
Following IV dosing, dexmedetomidine undergoes rapid distribution.  Dexmedetomidine 
undergoes extensive hepatic metabolism, with very little unchanged drug detected in the urine 
and feces.  The elimination half-life of dexmedetomidine following IV administration is 
approximately 2 hours.  Due to the primarily hepatic elimination of dexmedetomidine, dose 
adjustment may be required in subjects with hepatic impairment.  
Doses of nasal dexmedetomidine were initially explored by Recro in canine models, with safety 
in humans supported by clinical studies in the published literature utilizing nasal 
dexmedetomidine.  These published studies have shown dexmedetomidine to be well tolerated in 
studies in pediatric patients with doses up to 1.5 µg/kg.  Subsequent studies conducted by Recro 
have explored single 17.5 and 35 µg doses, as well as repeated dosing at the 35 µg dose level 
with 7 doses administered at 6 hour intervals.  These doses have been well tolerated both locally 
and systemically.  Further, in a study of healthy subjects undergoing bunionectomy surgery, 
doses of 25 and 50 µg DEX-IN every 6 hours for a minimum of 8 doses have been evaluated.  
Dosing with DEX-IN in these studies were generally well tolerated.  These studies and their 
findings are discussed further in the DEX-IN Investigators Brochure.  
The use of an intranasal dosage form with dexmedetomidine is intended to provide a noninvasive 
mechanism for rapid drug uptake.  This accelerated uptake facilitates a quick pharmacologic 
response, with potential benefit for patients experiencing acute pain and anxiety symptoms.  
Dexmedetomidine has the potential to control pain without additional sedation or respiratory 
depression. 
The current study is planned to evaluate the use of single doses of DEX-IN in an office based or 
outpatient surgery/procedure setting where patients may receive limited or no analgesic 
medications.  Patients undergoing these procedures generally experience a range of pain and 
anxiety symptoms that may not be well managed under the current standard of care.  This study 


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will utilize a placebo control, as well as an active control arm using IV fentanyl to verify the 
efficacy of DEX-IN dosing. 


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2. 
STUDY OBJECTIVE 
The primary objective of this study is to evaluate the analgesic efficacy of DEX-IN compared 
with placebo and active control (fentanyl), in subjects undergoing painful outpatient and office 
based procedures. 
Secondary objectives of this study will include: 
 To evaluate the anxiolytic effects of DEX-IN 
 To determine the safety and tolerability of DEX-IN as evaluated with vital sign 
collection, and incidence of Adverse Events (AEs) and Serious AEs (SAEs). 
 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase 2, randomized, multicenter, double-blind, placebo- and active-controlled 
evaluation of the efficacy and safety of DEX-IN in adult subjects undergoing painful outpatient 
and office based procedures.  The study will enroll up to 250 subjects across up to 5 study 
cohorts, with approximately 50-75 subjects per cohort.  Each study cohort will include subjects 
undergoing a specific painful procedure which may include, but is not limited to, cosmetic 
procedures (face peel, liposuction/liposculpture, sclerotherapy, etc.), dental procedures, biopsy 
procedures (prostate, colposcopy, etc.), or other procedures. The procedures to be evaluated in 
this study will be selected on an ongoing basis. 
Subjects requiring a selected procedure, age 18 to 65 years inclusive, will be screened for 
participation at up to 5 study centers in the United States.  Screening will occur within 28 days 
before study drug administration.  After signing the informed consent, demographics and 
medical history, physical examination, clinical laboratory testing, 12-lead electrocardiogram 
(ECG), pregnancy testing, and vital sign measurements will be completed during the screening 
visit. 
On the day of the procedure (Day 1), eligible subjects will be randomized to treatment (1:1:1) 
with DEX-IN 50 µg, intravenous (IV) fentanyl 50 µg, or placebo.  Subjects will be administered 
a study dose in a double dummy fashion, that is, each subject will receive an intranasal (IN) dose 
(DEX-IN or placebo) approximately 1 hour prior, and an IV injection (fentanyl or placebo) 
approximately 15 minutes prior to the start of the procedure.  The end of the study procedure will 
be defined as Hour 0.  Study assessments of pain and anxiety will be completed at various 
intervals starting 1 hour before the procedure through Hour 4 following the end of the procedure.  
Subjects will be eligible to be discharged home following completion of the Hour 4 assessments 
at the discretion of the investigator.  Subjects may remain beyond Hour 4 at the study center 
based on their physical status.  A follow-up telephone contact will be scheduled for Day 7±2 to 
assess any subsequent safety events. 
Efficacy assessments will include assessment of pain intensity, anxiety intensity, and subject 
satisfaction with pain experienced during the procedure.  Safety assessments will include 
monitoring of AEs and SAEs, and vital sign measurements.    
3.2. 
Rationale for Study Design and Control Groups 
This study will evaluate the efficacy and safety of a known drug substance administered via an 
alternative route of delivery.  Previous research has demonstrated the safety and efficacy of 
single and repeated doses of dexmedetomidine when administered by the intranasal route in 
healthy and postoperative (bunionectomy) populations.    
This study will explore the analgesic and anxiolytic effects of dosing with DEX-IN in a 
population of subjects undergoing painful office-based and outpatient procedures.  Dosing will 
occur in a single dose setting prior to the procedure to evaluate the benefits of DEX-IN in 
reducing the incidence of more severe pain during and following the procedure, as well as 
reducing anxiety which may further increase satisfaction with the procedure overall.  These 
effects will be compared between DEX-IN and placebo and active controls.  Fentanyl IV is 


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included as an active control arm to act as a positive control for an analgesia signal.  Though not 
an ideal analgesic for use clinically in this setting due to the requirement for IV access, for 
research purposes, its established analgesic profile will better gauge the efficacy of DEX-IN 
dosing.  In order to maintain the double blind, study drug will be administered in a double 
dummy fashion so each subject will receive an IN dose (DEX-IN or placebo) and an IV dose 
(fentanyl or placebo).    


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate in the 
study: 
1. Voluntarily provide written informed consent. 
2. Male or female 18 to 65 years of age at screening, inclusive. 
3. Be planned to undergo an office-based or outpatient procedure including, but not limited 
to, cosmetic procedures, dental procedures, biopsy procedures, or other outpatient and 
office based procedure, to be performed within the criteria defined in the procedure 
specific cohort manual.  
4. Be naïve to the planned procedure, i.e. no repeated or revision procedures. 
5. Be classified as American Society of Anesthesiology (ASA) physical status category 1 or 
2. 
6. Female subjects are eligible only if all of the following apply: 
 Not pregnant (female subjects of child bearing potential [FOCBP] must have a 
negative serum pregnancy test at screening and negative urine pregnancy test 
before procedure); 
 Not lactating; 
 Not planning/attempting to become pregnant during the study; 
 Commits to the use of a highly effective contraceptive method (e.g. abstinence, 
intrauterine device [IUD], hormonal [estrogen/progestin] contraceptives, or 
double barrier method) for at least 1 menstrual cycle prior to study enrollment 
through the Day 7 follow-up; or be menopausal defined as 12 months of 
amenorrhea in the absence of other biological or physiological causes; or post-
menopausal for at least 1 year; or be surgically sterile (documented hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy). 
7. Male subjects must be surgically sterile (biologically or surgically) or commit to the use 
of a highly effective contraception method (e.g., abstinence or double barrier method) 
with female partner(s) from Screening through the Day 7 follow-up. 
8. Have a body mass index ≤35.0 kg/m2 at screening 
9. Be able to understand the study procedures, comply with all study procedures, and agree to 
participate in the study program. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in the study: 


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1. Have a known allergy to dexmedetomidine or other alpha-2-agonist, any excipient 
DEX-IN/placebo, fentanyl, or to any medications used in the planned study procedure. 
2. Have a clinically significant abnormal clinical laboratory tests value according to the 
judgment of the investigator. 
3. Have, as determined by the investigator or the sponsor’s medical monitor, a history or 
clinical manifestations of significant renal, hepatic, cardiovascular, metabolic, 
neurologic, psychiatric, or other condition that would preclude participation in the study. 
4. Have a history of migraine or frequent headaches, seizures, or are currently taking 
anticonvulsants. 
5. Have another painful physical condition or anxiety related diagnosis that, in the opinion 
of the investigator, may confound study assessments. 
6. Have a history of syncope or other syncopal attacks. 
7. Have evidence of a clinically significant 12 lead ECG abnormality according to the 
judgment of the investigator. 
8. Have a history of alcohol abuse or prescription/illicit drug abuse in the last 5 years. 
9. Have positive results on the urine drug screen or alcohol breath test indicative of illicit 
drug or alcohol abuse at screening or at check-in prior to randomization.  
10. Have a history or evidence of orthostatic hypotension at screening or at check-in prior to 
randomization. 
11. Have a resting heart rate of < 50 beats per minutes or systolic blood pressure 
<100 mmHg on evaluation of vital signs at screening or at check-in prior to 
randomization. 
12. Use concurrent therapy that could interfere with the evaluation of efficacy or safety, such 
as any drugs which in the investigator’s opinion may exert significant analgesic or 
anxiolytic properties or act synergistically with DEX-IN. 
13. Be unable to discontinue medications that have not been at a stable dose for at least 14 
days prior to the scheduled procedure; medications not at a stable dose to be discontinued 
approximately 5 half-lives of the specific prior medication prior dosing with study 
medication (or, if half-life is not known, approximately 48 hours). 
14. Have utilized any intranasal medications within 10 days prior to the procedure. 
15. Have signs or a history of significant rhinitis or rhinorrhea (constant or chronic), nasal 
polyps, mucosal lesions of the nostril, postnasal drip of any etiology (constant or 
chronic), nasal ulcers, septal perforation or deviation, any nasal surgery, anosmia, nasal 
piercings, or frequent nosebleeds or other nasal pathology, that in the investigator’s 
opinion is sufficient to interfere with intranasal drug delivery. 
16. Have had an upper respiratory tract infection within 14 days of screening or procedure, or 
at any time during the conduct of the study. 
17. Have received any investigational product within 30 days before dosing with study 
medication. 


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18. Have previously received DEX-IN in clinical trials. 
4.3. 
Discontinuation of Subjects 
4.3.1. 
Procedures for Withdrawal 
A subject may be discontinued from the study by the investigator or the sponsor at any time if 
either determines that it is not in the subject’s best interest to continue participation.  Subjects 
who receive the study dose and withdraw from the study should be encouraged to complete the 
Hour 4 assessments prior to discharge.  Subjects will be encouraged to complete the Day 7±2 
follow-up contact.  The date the subject is withdrawn and the primary reason for discontinuation 
will be recorded in the subject’s electronic case report form (eCRF). 
4.3.2. 
Replacement of Subjects 
Discontinued subjects will not be replaced in this study. 
4.4. 
Lifestyle Guidelines 
4.4.1. 
Confinement 
Prior to the procedure (Day 1), subjects will arrive at the study center in sufficient time to 
prepare for the procedure, confirm eligibility to participate in the study, and begin study 
assessments approximately 1 hour prior to the procedure.  Following the procedure, subjects will 
complete study assessments through approximately 4 hours post-procedure. 
4.4.2. 
Diet 
Subjects should not consume any poppy seeds within 48 hours prior to arrival at the study center, 
or any alcohol or xanthines (i.e. tea, coffee, caffeine or cola drinks or chocolate) containing 
foods or beverages within 24 hours before or during the study procedure visit.  


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5. 
TREATMENTS 
5.1. 
Office Based/Outpatient Procedure  
On Day 1, subjects will undergo a painful office based or outpatient procedure according to their 
enrolled cohort.  Procedures may include, but are not limited to, cosmetic procedures (face peel, 
liposuction/liposculpture, sclerotherapy, etc.), dental procedures, biopsy procedures (prostate, 
colposcopy, etc.), and other outpatient and office based procedures.   
Prior to enrolling any subjects for a study cohort, the procedure to be performed in that cohort 
will be defined and a procedure specific cohort manual will be prepared to provide additional 
operational details.  Details provided in the procedure specific cohort manual may include, but 
are not limited to, duration of the procedure, materials and techniques to be utilized, number and 
types of samples to be collected or sites to be treated, etc.  The procedure specific cohort manual 
will be distributed to all investigators who will be eligible to enroll subjects in that cohort for 
review and training. 
5.2. 
Administration of Study Medication 
Blinded study personnel will administer all doses of study drug according to the randomization.  
In order to maintain the study blind, study drug will be administered in a double-dummy fashion 
and each subject will receive a single IN dose (DEX-IN or placebo) approximately 1 hour prior 
to the scheduled procedure, and a single IV dose (fentanyl or placebo) approximately 15 minutes 
prior to the scheduled procedure.  Study doses will be administered according to the study 
randomized treatment assignment with IV and IN doses administered as described in Table 1. 
Table 1:  Summary of Study Treatment Doses 
Randomized Treatment 
Group 
IN Dose 
1 Hour Prior to Procedure 
IV Dose 
15 Minutes Prior to Procedure 
DEX-IN 
DEX-IN 50 µg 
Placebo 
Fentanyl 
Placebo 
Fentanyl 50 µg 
Placebo 
Placebo 
Placebo 
 
The exact time of administration of the IN and IV dose will be documented in the subject eCRF.  
Study IN doses will be administered by the subject as a single spray into the right or left nostril.  
Study IV doses will be administered by study staff as a slow IV push over approximately 1-2 
minutes. 
Prior to IN administration, the nostrils should be cleared by blowing into a tissue.  A single dose 
(i.e., a single spray) will be administered into one nostril with the untreated nostril covered with 
a finger.  The subject’s head should be held in an upright or semi upright position with the spray 
applicator inserted approximately ½-inch into the treated nostril.  The subject should inhale 
gently through the treated nostril as the device is squeezed and the dose is delivered.  The subject 
should inhale normally through the nose and exhale through the mouth for 10-20 seconds while 
maintaining the head upright after dosing. 


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5.3. 
Identity of Study Medication 
5.3.1. 
IN Dosing 
DEX-IN will contain 50 µg dexmedetomidine in each 100 µL of solution (DEX-IN.02 
formulation), as well as excipients including: citric acid, sodium citrate, sodium chloride, 
phenylethyl alcohol, disodium EDTA, and purified water.  DEX-IN doses are calibrated to 
deliver 50 µg (100 µL) with each dose actuation 
Placebo solution will contain citric acid, sodium citrate, sodium chloride, phenylethyl alcohol, 
disodium EDTA, and purified water.  Placebo doses are calibrated to deliver 100 µL with each 
dose actuation 
Doses of DEX-IN/placebo will utilize a unit dose spray device containing the appropriate 
volume of study drug to deliver the assigned dose for administration into the nostril.  
5.3.2. 
IV Dosing 
Fentanyl IV doses will be administered using fentanyl citrate injection USP 50 µg/mL to be 
sourced locally by the clinical site(s).  Each IV fentanyl dose will be administered as 50 µg 
(1 mL) via slow IV push. 
Placebo IV doses will utilize normal saline, 0.9% sodium chloride injection USP, to be sourced 
locally by the clinical site(s). Each IV placebo dose will be administered as 1 mL via slow IV 
push. 
5.4. 
Method of Assigning Subjects to Treatment Groups 
A computer generated randomization scheme will be prepared prior to study initiation for each 
procedure cohort.  Subjects will be randomly assigned to treatment with DEX-IN, IV fentanyl, or 
placebo in a 1:1:1 assignment ratio according to the randomization scheme.   
5.5. 
Selection of Doses 
Doses of dexmedetomidine have been selected following review of pharmacokinetic data in man 
and canine.  Study REC-10-007 evaluated three doses of DEX-IN (17.5 µg in one nostril, or 35 
µg in one nostril or divided between nostrils) in healthy human volunteers.  This study found all 
doses to be well tolerated, with the most rapid and extensive absorption seen with a single 
100 µL volume dose, containing 35 µg dexmedetomidine, administered into a single nostril.  
This dose achieved plasma concentrations that were observed to produce analgesia in a previous 
study of dexmedetomidine administered by the sublingual route. 
Upon subsequent evaluation in a repeated dose study in the U.S. (Study REC-11-008), this 35 µg 
dose yielded mean observed plasma concentrations below those seen in REC-10-007.  Based on 
this observation, the formulation of DEX-IN was modified to contain 50 µg dexmedetomidine 
base equivalent per 100 µL.  This was explored in a single dose study of efficacy, safety and 
pharmacokinetics in a group of subjects with chronic low back pain (REC-11-010).  This study 
utilized doses of 25 and 50 µg per actuation and demonstrated significant efficacy at the 50 µg 
dose level.   


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Based on these data, DEX-IN doses of 35 and 50 µg per actuation were evaluated in two studies 
of moderate to severe postoperative pain in subjects undergoing bunionectomy (REC-13-012 and 
REC-14-013).  Data from these studies demonstrated efficacy of the 50 µg dose in subjects with 
more moderate pain severity, while consistent efficacy was not seen with the 35 µg dose level.  
Therefore a dose of 50 µg has been selected for evaluation in this study.     
The fentanyl dose was selected to provide analgesia for pain of moderate severity lasting for a 
period of less than 4 hours without causing excessive adverse and prolonged effects, based on the 
fentanyl prescribing information. 
5.6. 
Selection of Timing of Dose 
Randomized subjects will receive IN study dosing approximately 1 hour prior to the initiation of 
the study procedure.  This pre-procedural dosing will enable peak plasma concentrations to be 
achieved prior to the procedure for improved pain control, while providing pre-procedural relief 
of anxiety symptoms due to the rapid uptake seen with IN administration of dexmedetomidine.  
IV dosing will be performed at 15 minutes prior to the start of the study procedure due to the 
rapid onset and short duration of effect for IV fentanyl.  
The time of IN and IV dose administrations will be recorded in the subject’s eCRF.   
5.7. 
Blinding and Unblinding of Study Medications 
Study doses will be prepared by an incompletely unblinded study pharmacist; blinded to IN 
treatment assignment, unblinded to IV treatment assignment. 
All doses administered in this study will be under double-blind conditions; both the subject and 
the investigator/site staff will be blinded to the treatment assignment. That is, the study drug will 
be administered in a double-dummy fashion and each subject will receive a single IN dose 
(DEX-IN or placebo) and a single IV dose (fentanyl or placebo).   
The study blind may be broken only if the safety of a subject is at risk and the treatment plan for 
that subject depends on which study medication he or she received.  If knowledge of the 
treatment assignment is absolutely necessary for the management of a subject’s safety, the blind 
may be broken by removing the blind card provided for the assigned randomization number.  
Unless the subject is at immediate risk, the investigator must make diligent attempts to contact 
the sponsor before unblinding the subject’s data.  If a subject’s data are unblinded without the 
prior knowledge of the sponsor, the investigator must notify the sponsor as soon as possible and 
no later than the next business morning.  All circumstances surrounding a premature unblinding 
must be clearly documented. 
5.8. 
Treatment Compliance 
Study subjects will receive a single IN and a single IV study dose during their participation in the 
study.  All study doses will be observed by (IN) or administered by (IV) study personnel while 
the subject is at the study center.  The exact date and time each dose is administered will be 
recorded in the subject’s eCRF.   


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5.9. 
Drug Accountability 
The investigator (or designee) will sign for the study medications when they are received.  The 
study medication must be handled and stored as described and dispensed only to those subjects 
formally entered into the study. 
At the completion of the study, and after reconciliation of all delivery and usage records, any 
unused study medication supplied by the sponsor will be returned to the sponsor (or designee) or 
destroyed per written instructions from the sponsor. 
5.10. 
Packaging, Labeling, and Storage 
Intranasal study medication will be provided in single use, unit-dose, blind labeled nasal spray 
devices.  DEX-IN solution will contain a dexmedetomidine base equivalent of 50 µg/100 µL.  
Study medication labeling will include the study number.   
Intravenous study medication (fentanyl and placebo [normal saline]) will be sourced locally by 
the study center(s). 
Sealed randomization envelopes will be provided and should be stored in a locked area with 
controlled access until required to break the blind in the event of an emergent condition in a 
treated subject. 
DEX-IN and IN placebo should be stored at the study site at 25ºC (77ºF), although a range of 
15ºC to 30ºC (59ºF to 86ºF) will be permitted.   
IV fentanyl and placebo (saline) should be stored according to the conditions defined within the 
product labeling. 
All study medication at the study site(s) should be stored in a locked area with restricted access. 
As a schedule 2 (CII) medication, additional inventory and dispensing records should be 
maintained for fentanyl according the practice of the study center and appropriate federal and 
local regulatory requirements.  A temperature log or chart should be maintained to monitor the 
environment at the study site. 
5.11. 
Prior and Concomitant Medications 
All medications and other treatments taken by subjects within 5 days before dosing and during 
the study will be recorded in the eCRF. 
All medications that have not been at a stable dose for at least 14 days prior to the scheduled 
procedure will be prohibited within five half-lives of the specific prior medication (or, if half-life 
is unknown, within 48 hours) before study dosing. 
5.12. 
Prohibited Medications 
The following medications or drug classes will be prohibited on the day of the procedure: 
 Any anxiolytics (benzodiazepines, selective serotonin reuptake inhibitors, serotonin 
norepinephrine reuptake inhibitors, tricyclic antidepressants, or other antidepressants) 
 Any analgesics (NSAIDs, opioids, etc.). 


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5.13. 
Concomitant Interventions and Procedures 
All interventions or procedures, whether diagnostic or therapeutic, will be recorded in the eCRF, 
along with time, date, and reason for the intervention or procedure.  If an intervention or 
procedure is implemented to treat an AE, the event must be recorded as an AE, along with all 
relevant information. 
  


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6. 
STUDY PROCEDURES 
A schedule of study procedures for overall study assessments and day-of-dosing assessments is 
provided in Appendix A. 
6.1. 
Demographic and Efficacy Assessment 
6.1.1. 
Demographics  
Demographics information will be collected during screening visit including age, sex, ethnicity, 
race, weight, height, and BMI. 
6.1.2. 
Medical History 
The investigator or designee will document each subject’s medical history during the screening 
visit.  Medical history will be updated on Day 1 when the subject reports for the procedure, and 
the subject’s eligibility will be reviewed to confirm that they continue to meet the required study 
criteria. 
6.1.3. 
Physical Examination 
The investigator or designee will perform a physical examination (HEENT, cardiovascular, 
respiratory, gastrointestinal, neurological, dermatologic, and musculoskeletal systems) during the 
screening visit and at check-in (Day 1) to the study site prior to randomization.     
The investigator may perform a physical examination (the extent of which is determined by the 
study investigator) at any time during the study if indicated by change in a subject’s medical 
history or condition. 
6.1.4. 
Pain Intensity (PI) 
PI will be assessed by the study subject for their current pain according to an 11-point numeric 
pain rating scale (NPRS; 0 - 10); see Appendix C.1.   
PI will be assessed 1 hour (within 5 minutes prior to IN dosing), 15 minutes (within 5 minutes 
prior to IV dosing), and 5 minutes before the start of the procedure.  PI assessment during and 
following the procedure will be determined based on the procedure type selected for the study 
cohort.  The schedule of PI assessments will be defined in the procedure specific cohort manual, 
prior to enrollment of subjects in the cohort.  
6.1.5. 
Worst Pain Intensity  
Subjects will also assess their worst pain intensity during the procedure and in the post-procedure 
period using the 11-point NPRS; see Appendix C.1.  The worst pain during the procedure will be 
collected at Hour 0 (end of procedure); at that time subjects will be asked to rate their worst pain 
experienced during the procedure.  At Hour 4, prior to discharge, subjects will be asked to rate 
their worst pain experienced in the time since the end of the procedure. 
Assessments to be completed within 15 minutes of the scheduled time point. 


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6.1.6. 
Anxiety Assessment 
6.1.6.1. 
Numeric Rating Scale (NRS) 
Anxiety will be assessed by the study subject for their current level of anxiety using an 11-point 
numeric rating scale (NRS); see Appendix C.2.   
Anxiety will be assessed using the NRS 1 hour (within 5 minutes prior to IN dosing), 15 minutes 
(within 5 minutes prior to IV dosing), 5 minutes before the start of the procedure, and 
immediately prior to the start of the procedure (within 1 minute).  Anxiety assessment during and 
following the procedure will be determined based on the procedure type selected for the study 
cohort.  The schedule of anxiety assessments will be defined in the procedure specific cohort 
manual, prior to enrollment of subjects in the cohort.   
6.1.6.2. 
Six Item Spielberger State-Trait Anxiety Inventory (STAI-6) 
Anxiety will also be assessed by the subject using the 6-Item Spielberger State-Trait Anxiety 
Inventory (STAI-6); see Appendix C.2. 
Anxiety will be assessed using the STAI-6 at screening, 1 hour (within 5 minutes prior to IN 
dosing), and 5 minutes before the start of the procedure.  Anxiety assessment during and 
following the procedure will be determined based on the procedure type selected for the study 
cohort.  The schedule of anxiety assessments will be defined in the procedure specific cohort 
manual, prior to enrollment of subjects in the cohort. 
6.1.7. 
Subject Satisfaction with Pain Experience 
Subjects will report their satisfaction with the degree of pain experienced during the procedure 
and in the post-procedure period according to a 7-point Likert scale including categories of: 
completely dissatisfied (1), mostly dissatisfied (2), somewhat dissatisfied (3), neither satisfied 
nor dissatisfied (4), somewhat satisfied (5), mostly satisfied (6), and completely satisfied (7); see 
Appendix C.3.  
The subject assessment of satisfaction will be completed for pain experienced during the 
procedure at Hour 0, and completed for the pain experienced during the post-procedure period at 
Hour 4; both assessments to be completed within 15 minute of the scheduled time point. 
6.2. 
Safety Assessments Description  
6.2.1. 
Clinical Laboratory Tests 
During the screening visit, subjects will have blood and urine samples collected for routine 
clinical laboratory testing as follows: 
 hematology:  complete blood count consisting of white blood cell (WBC) and red blood 
cell count, platelet count, hemoglobin, hematocrit, and differential counts (total 
neutrophils, eosinophils, basophils, lymphocytes, and monocytes) 
 clinical chemistry tests:  urea, glucose, creatinine, sodium, potassium, chloride, 
bicarbonate, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, 


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total bilirubin, direct bilirubin, gamma-glutamyl transferase, lactate dehydrogenase, 
calcium, total protein, magnesium, phosphate, albumin, and uric acid 
Additional urine or blood samples will be collected and tested as follows: 
 urine drug screen (UDS) and alcohol breath test at the screening visit and at check-in 
prior to randomization on Day 1.  Urine drug screen will include screening of (at 
minimum): cocaine, opiates, amphetamines, benzodiazepines, and methadone. 
 serum pregnancy testing at the screening visit, and urine pregnancy testing prior to 
randomization on Day 1 for FOCBP.  
6.2.2. 
Vital Sign Measurements 
Resting vital signs will include blood pressure, pulse, and peripheral oxygen saturation (SpO2), 
and must be obtained after resting (seated/semi-recumbent) for ≥ 5 minutes.     
At screening and on Day 1 prior to randomization, resting vital signs will be collected in three 
determinations approximately 2 minutes apart to ascertain subject’s true baseline heart rate and 
blood pressure values. The average values will be used to determine subject eligibility for 
participation. 
After randomization, subjects will have resting (seated/semi-recumbent) vital signs measured 
and recorded at the following predefined times: 1 hour (prior to IN dose), 15 minutes (prior to IV 
dose) and 5 minutes prior to the procedure, at the end of the procedure (Hour 0), and 0.5, 1, 1.5, 
2, 3, and 4 hours after the end of the procedure. Vital signs will have a collection window of ± 10 
minutes.   
Postural vital signs will be determined at screening, on Day 1 prior to randomization for 
inclusion purposes, within 15 minutes following Hour 0, and at Hour 4 prior to discharge; 
performed following resting assessments.  Postural vital signs will include blood pressure and 
heart rate – to be taken resting, then after standing for one minute. 
Actual times will be recorded for all events, and any deviation outside the specified ranges must 
be clearly documented in the subject’s study records. 
6.2.3. 
12-Lead Electrocardiogram (ECG) 
A 12-lead ECG will be completed for all subjects at screening to exclude subjects with a 
clinically significant abnormal ECG.  No ECG data will be collected. 


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6.3. 
Assessments by Visit 
6.3.1. 
Screening Visit 
Subjects meeting the eligibility criteria listed in Section 4 may be enrolled in the study after the 
nature and purpose of the protocol have been explained to them, and they have voluntarily 
granted written informed consent to participate.  All subjects will have a screening evaluation 
within 28 days before the study procedure (Day 1).  After informed consent is obtained, the 
following procedures will be performed at the screening visit for all subjects: 
 Review of inclusion/exclusion criteria eligibility (Section 4.1 and Section 4.2) 
 Demographics and medical history (Section 6.1.2) 
 Physical examination (Section 6.1.3) 
 Measurement of vital signs (Section 6.2.2) 
 12-lead ECG (Section 6.2.3) 
 Clinical laboratory tests (Section 6.2.1) 
 Drug and alcohol screen (Section 6.2.1) 
 Serum pregnancy test (FOCBP only; Section 6.2.1) 
 Assessment of anxiety (Section 6.1.6) 
 Collection of prior and concomitant medications (Section 5.11) 
6.3.2. 
Day 1 (Pre-Procedure) 
The following assessments will be conducted on the day of the study procedure (Day 1) for all 
subjects prior to the start of the procedure:  
 Medical history update (Section 6.1.2) 
 Physical examination (Section 6.1.3) 
 Measurement of vital signs (Section 6.2.2) 
 Drug and alcohol screen (Section 6.2.1) 
 Urine pregnancy test (FOCBP only; Section 6.2.1) 
 Randomized study dosing (Section 5.2) 
 Assessment of pain intensity (Section 6.1.4) 
 Assessment of anxiety (Section 6.1.6) 
 Collection of prior and concomitant medications (Section 5.11) 
 Monitoring of AEs (Section 7) 


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6.3.3. 
Day 1 (Peri- and Post-Procedure) 
The following assessments will be conducted on the Day 1, during and following the study 
procedure: 
 Measurement of vital signs (Section 6.2.2)  
 Assessment of pain intensity (Section 6.1.4; according to schedule defined in the 
procedure specific cohort manual) 
 Assessment of worst pain intensity (Section 6.1.5) 
 Assessment of anxiety (Section 6.1.6; according to schedule defined in the procedure 
specific cohort manual) 
 Assessment of satisfaction with pain experience (Section 6.1.7) 
 Collection of prior and concomitant medications (Section 5.11) 
 Monitoring of AEs (Section 7) 
6.3.4. 
Day 7 ± 2 Days 
The following procedures will be performed during a telephone contact at Day 7±2 days: 
 Collection of prior and concomitant medications (Section 5.11) 
 Monitoring of AEs (Section 7) 
6.4. 
Appropriateness of Assessments 
The efficacy measures utilized in this study are appropriate to evaluate the study endpoints, and 
include scales common to studies of acute pain.  The timing of assessments is intended to 
evaluate the efficacy parameters pre-, peri-, and post-procedure. 
Safety measures used in this study are standard for clinical trials of investigational medications.  
6.5. 
Clinical Stopping Rules 
This study will be discontinued if it is determined that there is a significant safety risk posed 
towards study subjects.  Potential safety risks will be evaluated continuously throughout the 
course of enrollment in the study.  


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7. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND 
SERIOUS SUSPECTED ADVERSE REACTIONS 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE, SAE, or Serious Suspected Adverse Reaction (SSAR) as provided in 
this protocol.  During the study, when there is a safety evaluation, the investigator or site staff 
will be responsible for detecting AEs and SAEs, as detailed in this section of the protocol. 
7.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
An AE may be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a study medication, whether or not 
considered causally associated with the use of the study medication.  Any abnormal laboratory 
value deemed clinically significant by the investigator, regardless of causal relationship, must be 
reported as an AE beginning after administration of study medication. 
Examples of an AE include the following: 
 significant or unexpected worsening or exacerbation of the condition or indication under 
study 
 exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency or intensity of the condition (e.g., abnormal physical examination 
finding) 
 signs, symptoms, or clinical sequelae of a suspected interaction 
 signs, symptoms, or clinical sequelae of a suspected overdose of the study medication or 
a concurrent medication (overdose per se should not be reported as an AE or SAE, unless 
nonserious or serious sequelae occur) 
The following examples are not considered AEs: 
 medical or surgical procedure (e.g., endoscopy, appendectomy), although the condition 
that leads to the procedure is an AE 
 anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) (including 
laboratory values) present or detected at the start of the study that do not worsen 
 the disease or disorder being studied, or expected progression, signs, or symptoms of the 
disease or disorder being studied, unless they become more severe or occur with a greater 
frequency than expected for the subject’s condition 
All AEs, whether volunteered, elicited, or noted on physical examination, and regardless of 
causality or seriousness, will be assessed and recorded in the eCRF beginning after 
administration of study medication through the end of the study.  
7.2. 
Definition of a Serious Adverse Event 
An SAE is defined as any event that meets the following criteria: 


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 It results in death or is life-threatening (i.e., presents an immediate risk of death from the 
event as it occurred).  (This criterion is not intended to include an AE that, had it 
occurred in a more severe form, might have caused death.) 
 It results in persistent or substantial disability or incapacitation.  (This criterion is not 
intended to include experiences of relatively minor medical significance, such as 
uncomplicated headache, diarrhea, or sprained ankle.) 
 It results in hospitalization. 
 It results in prolongation of an existing hospitalization. 
 It is a congenital anomaly or birth defect (in the offspring of a subject using the study 
medication regardless of time to diagnosis). 
 It requires medical or surgical intervention to prevent any of the above outcomes.  
 It is considered an important medical event. 
Medical and scientific judgment should be exercised in determining whether an AE is serious 
when considering important medical events that may not be immediately life-threatening or 
result in death or hospitalization, but may jeopardize the subject or may require intervention to 
prevent any of the other outcomes listed.  Examples of such medical events that may also be 
considered serious include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline does not meet the definition of an SAE. 
Social or convenience admission to a hospital or prolongation of a hospitalization for social or 
convenience reasons not associated with the occurrence of an AE does not meet the definition of 
an SAE. 
SAEs will be assessed and recorded in the eCRF after the signing of informed consent through 
the end of the study.  If an investigator becomes aware of an SAE or death that occurs in a 
subject more than 30 days after the subject receives study drug and considers the event to be 
related to the study drug, the investigator is obligated to report the SAE to the sponsor. 
7.3. 
Definition of a Suspected Adverse Reaction (SAR) 
A SAR is defined as any adverse event for which there is a reasonable possibility that the 
adverse event was caused by the study drug.  For the purposes of IND safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug 
and the adverse event.  A suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction, which means any adverse event caused by a drug. 
7.4. 
Definition of a Serious Suspected Adverse Reaction (SSAR) 
A SSAR is any Suspected Adverse Reaction (SAR) that is determined to be serious, based on the 
outcomes of a SAE described in Section 7.2; i.e. death, life-threatening, causes or prolongs 


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inpatient hospitalization, causes a persistent of significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital abnormality/birth defect. 
7.5. 
Recording and Evaluating Adverse Events and Serious Adverse 
Events 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, or other clinical information.  In such cases, the diagnosis, not the individual signs or 
symptoms, should be documented as the AE or SAE. 
7.5.1. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study, using his or her clinical judgment.  The intensity of each AE and SAE recorded in the 
eCRF should be assigned to one of the following categories: 
 mild:  an event that is easily tolerated by the subject, causes minimal discomfort, and 
does not interfere with everyday activities 
 moderate:  an event that is sufficiently discomforting to interfere with normal everyday 
activities 
 severe:  an event that prevents normal everyday activities 
An AE that is assessed as severe should not be confused with an SAE.  Severity is a term used to 
describe the intensity of a specific event, and both AEs and SAEs can be assessed as severe.  The 
event itself, however, may be of relatively minor medical significance (such as a severe 
headache).  This is not the same as serious, which is based on the subject’s or event’s outcome or 
on action criteria usually associated with events that pose a threat to a subject’s life or 
functioning (see Section 7.2). 
7.5.2. 
Assessment of Causality 
The investigator is obligated to use his or her clinical judgment to assess the relationship 
between the study medication and the occurrence of each AE or SAE.  The investigator will 
assess the relationship to the study medication by using the following criteria: 
 Definitely Related:  An AE has a strong temporal relationship to the study drug.  The AE 
is most likely explained by study drug.  Dechallenge and rechallenge (if possible) are 
positive.  The AE is consistent with a known response to the study drug.  Another 
etiology is unlikely or significantly less likely. 
 Probably Related:  An AE has a strong temporal relationship to the study drug.  The AE 
is more likely explained by study drug than by another cause.  Dechallenge (if 
performed) is positive. 
 Possibly Related:  An AE has a reasonable temporal relationship to study drug.  The AE 
could have been due to another equally likely cause.  Dechallenge is positive. 
 Not Related:  The subject did not receive the study drug OR the AE has no temporal 
relationship to study drug OR the AE has a much more likely alternate etiology OR the 
AE is due to an underlying or concurrent illness or effect of another drug. 


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Even in situations in which minimal information is available for the initial SAE report, it is 
important that the investigator always make an assessment of causality for every event before 
transmitting the SAE reporting form and completing the AE eCRF page(s).  The causality 
assessment is one of the criteria used when determining regulatory reporting requirements.  The 
investigator may change his or her opinion of causality in light of follow-up information and 
amend the SAE reporting form and AE eCRF page(s) accordingly. 
7.5.3. 
Assessment of Outcome 
All SAEs must be followed until they are resolved, the condition stabilizes, the events are 
otherwise explained, or the subject is lost to follow-up.  The investigator will assess the outcome 
of the event by using the following terms: 
 Resolved:  The event resolved or the subject recovered without sequelae.  An event 
(either serious or nonserious) occurred and had an endpoint, and the subject experienced 
no restrictions.  Examples include stent placement for coronary artery disease (a device 
implanted is not a sequela), an appendectomy (a scar is not a sequela), a postoperative 
wound infection, or an upper respiratory tract infection. 
 Resolved with sequelae:  The event has at least one secondary outcome that may result 
in permanent disability, functional limitation, or both.  Such sequelae are usually limited 
to SAEs.  Examples include hip replacement resulting in foot drop (foot drop is not the 
intended outcome but is a risk of surgery), stroke resulting in paralysis, or emboli 
formation after a bacterial infection resulting in a renal infarct and loss of renal function. 
 Not resolved:  At the end of the study, a nonserious event either has not changed in 
intensity or may not have recovered to baseline values, and the outcome is unknown.  
Examples include headache, low-grade fever, or nausea. 
 Unknown: The subject has withdrawn from the study prematurely or is lost to follow-up, 
and the status of the event is unknown. 
 Death 
7.5.4. 
Assessment of Expectedness 
For the purposes of IND safety reporting, expectedness of the SAE will be assessed by the 
Sponsor.  An AE or SAR is considered unexpected if it is not listed in the investigator brochure 
or is not listed at the specificity or severity that has been observed; or, if an investigator brochure 
is not required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. 
7.6. 
Follow-up of Adverse Events and Serious Adverse Events 
Nonserious AEs will be followed after the last scheduled study visit, until an appropriate 
resolution can be documented. 
After the occurrence of an AE or SAE, the investigator is required to follow each subject 
proactively and provide further information on the subject’s condition.  All AEs and SAEs 
documented at a previous visit or contact are designated as ongoing and will be reviewed at 
subsequent visits or contacts. 


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SAEs will be followed until the event resolves, the condition stabilizes, the event is otherwise 
explained, or the subject is lost to follow-up.  The investigator will ensure that follow-up 
information provided to the sponsor includes results of any additional laboratory tests or 
investigations, histopathologic examinations, or consultations with other healthcare professionals 
that serve to clarify the nature of the event, the cause of the event, or both. 
New or updated information will be recorded on the originally completed SAE reporting form 
and entered into the eCRF pages, with all changes signed and dated by the investigator.  The 
updated SAE reporting form should be resubmitted to the sponsor within the time frames 
outlined in Section 7.7. 
7.7. 
Prompt Reporting of Serious Adverse Events to the Sponsor 
Once the investigator determines that an event meets the protocol definition of an SAE, he or she 
must notify the sponsor within 24 hours. 
ANY SAE OR ANY OUTCOME OF DEATH DUE TO ANY CAUSE, WHICH OCCURS 
DURING THE COURSE OF THIS STUDY, REGARDLESS OF RELATIONSHIP TO 
STUDY MEDICATION, MUST BE REPORTED TO THE SPONSOR IMMEDIATELY 
(within 24 hours). 
COMPLETE THE SAE DETAILS REPORTING FORM AND FORWARD BY E-MAIL 
TO THE FOLLOWING SPONSOR CONTACT: 
Medical Safety 
Recro Pharma, Inc. 
 
Telephone:  484-395-2470 
Fax:  484-395-2472 
E-mail: AE@recropharma.com 
In the initial e-mail, the investigator must provide to the sponsor the following eCRF pages, 
completed to the greatest extent possible: 
 AE record 
 medical history 
 prior and concomitant medications 
Also, the following documents are to be forwarded: any laboratory results, diagnostic test results, 
or medical reports relevant to the SAE. 
E-mail transmission is the preferred method to transmit SAE information.  In rare circumstances 
and in the absence of e-mail capacity, notification by fax or telephone is acceptable, with a copy 
of the SAE reporting form sent by overnight mail.  Initial notification via telephone does not 
replace the need for the investigator to complete the SAE reporting form and eCRF pages within 
the time frames outlined. 
If the investigator does not have all information regarding an SAE, he or she must not wait to 
receive additional information before notifying the sponsor of the event.  The form must be 
updated when additional information is received.  Follow-up information received on all SAEs 


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must be forwarded to the sponsor by using the same procedure and timelines as for an initial 
report. 
7.8. 
Regulatory Reporting Requirements  
The investigator must promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 7.7, “Prompt Reporting of Serious Adverse Events to the Sponsor.”  The 
sponsor has a legal responsibility to notify, as appropriate, both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation.  Prompt 
notification of SAEs by the investigator to the appropriate project contact for SAE receipt is 
essential so that SSARs that are either unexpected or observed with increasing occurrence, be 
reported and legal obligations and ethical responsibilities regarding the safety of other subjects 
are met. 
Investigator letters are prepared according to sponsor policy and are forwarded to the 
investigators as necessary.  An investigator letter is prepared for any SAR that is attributable to 
study medication, serious, and unexpected.  The purpose of the investigator letter is to fulfill 
specific regulatory and Good Clinical Practice (GCP) requirements regarding the product under 
investigation. 
The investigator, or responsible person according to local requirements, must comply with 
requirements related to the reporting of SAEs to the IRB or IEC. 
7.9. 
Special Reporting Situations: Pregnancy 
Reports of pregnancy exposure in a female subject (maternal exposure) or female partner of male 
subject (paternal exposure), where the embryo or fetus may have been exposed to investigational 
product through the placenta or semen will be reported. A subject should be instructed to notify 
the investigator immediately of a maternal/paternal pregnancy exposure.  The sponsor must be 
notified of all pregnancies reported to the investigator (see Section 7.7 for contact information). 
A female subject who becomes pregnant during the study must discontinue further study drug 
administration.   
Any uncomplicated maternal/paternal pregnancy exposures that occurs in a subject or female 
partner of a male subject during this clinical study will be reported for tracking purposes only.  
All subject maternal/paternal pregnancy exposures that are identified during or after this study, 
where the estimated date of conception is determined to have occurred within 30 days of 
receiving study medication need to be reported, followed to conclusion (delivery or termination), 
and the outcome reported, even if the subject is discontinued from the study. The investigator 
should report all pregnancies within 24 hours using the Pregnancy Report/Outcome Form, 
according to the usual timelines and directions for SAE reporting provided in Section 7.7. 
Monitoring of the pregnancy should continue until conclusion of the pregnancy; and follow-up 
detailing the outcome of the pregnancy submitted using the Pregnancy Report/Outcome Form. 
For purposes of follow-up on a paternal pregnancy exposure, in order to collect information on 
the pregnancy and outcome of the pregnancy, informed consent will be requested from the male 
subject and a Pregnant Partner Consent Form completed. 


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Pregnancy itself is not regarded as an AE unless there is suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Likewise, elective abortions without complications are not considered AEs.  
Any SAEs associated with pregnancy (e.g., congenital abnormalities/birth defects/spontaneous 
miscarriages, ectopic pregnancy or any other serious events) must additionally be reported as 
such using the SAE report form according to the usual timelines and directions for SAE 
reporting provided in Section 7.7. 
 


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8. 
STATISTICAL METHODOLOGY 
The following outlines some of the key elements of the data analysis approach. A formal 
statistical analysis plan will be developed for this study in which statistical models, data 
derivation methods and rules will be described in details. 
8.1. 
Determination of Sample Size 
The sample size for this study was selected empirically without a formal power calculation.   
8.2. 
Study Endpoints 
8.2.1. 
Efficacy Endpoints 
Efficacy measures include pain intensity, worst pain intensity, anxiety score, and satisfactory 
score with pain during and following the procedure.  The efficacy measurements will be 
collected at various time points, including time points prior to, during, and post procedure.   The 
exact time point for each procedure will be determined when the cohort manual is prepared for 
each cohort. 
The primary efficacy endpoint will be the average pain score during the study procedure.  The 
average PI score defined as time weighted PI score, or it is equivocal to say that it is area under 
the PI score curve divided by the duration of observation.  This parameter will be derived for 
each subject. 
Secondary efficacy endpoints include 
1) Pain score at each time point 
2) Worst pain intensity by time point 
3) Anxiety score by time point 
4) Subject satisfaction score by time point 
8.2.2. 
Safety Endpoints 
The safety endpoints will include the following: 
1) incidence of AEs and SAEs 
2) change from baseline in vital signs; incidence of clinically significant changes in vital 
signs 
8.3. 
General Considerations for Statistical Analysis 
The following outlines some of the key elements of the data analysis approach.  A formal 
statistical analysis plan will be developed for this study in which statistical models, data 
derivation methods and rules will be described in detail. 
8.3.1. 
Analysis Datasets  
Intent-to-Treat (ITT) Analysis Set: The ITT set will include all subjects randomized.  The ITT 
subjects may or may not receive randomized treatment.  


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Safety Analysis Set:  The safety analysis set will include all subjects treated with study drug.    
Efficacy Analysis Set: All subjects in the safety analysis set who had required procedure will be 
included in the efficacy analysis. 
8.3.2. 
Test Hypothesis and P Value Justification 
The null hypothesis is that there is no difference between the treatment arms.  The alternative 
hypothesis is that the treatment groups are different. 
Differences between DEX-IN, fentanyl, and placebo groups will be evaluated via 2-sided 2-
sample t-test at the 0.05 level of significance. Nominal p-values for secondary and exploratory 
comparisons will be reported without adjustment for multiplicity. 
8.3.3. 
Procedures for Handling Missing Data  
Unless indicated otherwise, no imputation will be done for missing data.  However, AEs with 
missing severity assessments will be tabulated as “severe,” and AEs with missing relationship 
assessments will be tabulated as “related” for the purpose of analysis; and the missing data will 
be presented in data listing as is. 
8.3.4. 
Definitions for Assessment Windows 
For the purpose of data analysis, baseline measures for a given period will be the last 
measurements taken before the subject receives the study medication. 
8.4. 
Study Population Summaries 
Population summaries will be provided for the safety analysis set included in this study. 
8.4.1. 
Disposition 
The summary tables will provide frequency counts for subject disposition (all treated subjects, 
subjects who completed the study, subjects who discontinued from the study, and reason for 
discontinuation) by treatment group and study overall.   
Disposition in terms of number of subjects excluded from each analysis sets (ITT, safety, 
efficacy) will also be provided by treatment group and study overall. 
8.4.2. 
Demographics and Procedure Characteristics 
The demographic summary will include descriptive statistics for age, sex, race, weight, height, 
and BMI for the overall and by treatment group. 
Procedure characteristics will also be tabulated such as procedure type, site, and duration. The 
exact information collected for each procedure will be defined in the cohort manual to be 
prepared for each study cohort.  
8.4.3. 
Protocol Deviations 
All protocol deviations will be identified.  Tabulation may be provided if data warrant. 


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8.4.4. 
Treatment Compliance 
All doses of study medication will be administered by, or under the observation of, study 
personnel while subjects are at the study site.  The exact time of administration of study 
medication will be documented within each subject’s eCRF.  No formal summary of treatment 
compliance will be produced. 
8.4.5. 
Prior and Concomitant Medications 
All prior and concomitant medications will be tabulated for the overall study population.  Prior 
and concomitant medications will be coded to the therapeutic drug classes and generic drug 
names using the World Health Organization (WHO) Drug classifications version 1Q2017 or 
higher. 
8.5. 
Efficacy Analysis 
8.5.1. 
PI Analyses 
PI scores will be summarized by treatment at each timepoint within each cohort.  Average PI 
score will be derived for each subject and will be tabulated by treatment group and cohort.  
Analysis of variance may be used to compare the differences between the treatment groups if 
data warrants. 
8.5.2. 
Worst Pain Intensity 
Worst pain intensity scores will be summarized by treatment at each timepoint within each 
cohort.   
8.5.3. 
Anxiety Assessment 
Anxiety assessment scores will be summarized for the NRS and STAI-6 separately by treatment 
at each timepoint within each cohort.  Mean scores will be calculated for various intervals 
including: pre-procedure, during the procedure, Hour 0 to Hour 1, Hour 0 to Hour 2, and Hour 0 
to Hour 4 after the procedure. 
8.5.4. 
Subject Satisfaction with Pain Experience 
Subject satisfaction scores will be summarized by treatment at each timepoint within each 
cohort. 
8.5.5. 
Subgroup Analyses for Efficacy 
Subjects from each cohort will be analyzed separately.  Data across cohorts may be pooled for 
analysis if data warrants. Additional subgroups may be identified if data warrants. 


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8.6. 
Safety and Tolerability Evaluations 
8.6.1. 
Extent of Exposure 
This is a single dose study, therefore the maximum anticipated exposure in any subject will be 
50 µg dexmedetomidine for subjects in the DEX-IN treatment group, and 50 µg fentanyl for 
subjects in the fentanyl treatment group.   
Evaluation of the extent of exposure for the treatment period will be assessed via number of 
doses taken. 
8.6.2. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (Version 20 or higher) will be used to classify 
all AEs with respect to system organ class and preferred term. 
Three types of summaries will be produced for the AE summary: 
1. an overall summary of AEs: number of subjects with at least one event and number of 
events for all AEs, and SAEs 
2. a summary table of AEs and SAEs by system organ class and preferred term and severity  
3. a summary table of AEs and SAEs by preferred terms in descending order of total 
incidence 
AEs will be tabulated by study cohort and treatment group.  AEs that lead to premature 
discontinuation from the study or to death will be listed separately via data listings.    
8.6.3. 
Clinical Laboratory Tests 
Laboratory values will be collected at screening and Day 1 for enrollment purposes, no data 
summary will be prepared.   
8.6.4. 
Vital Sign Measurements 
Resting vital sign values and postural vital sign values at each time point collected will be 
summarized by treatment and time point without formal statistical testing.  Potentially clinically 
significant changes (PCSC) in vital signs will be tabulated by cohort, treatment, and time point.  
Postural and resting blood pressure measures will be listed side-by-side for subjects with 
reported orthostatic hypotension. Vital sign listing will be prepared separately for subjects with 
at least one incidence of PCSC in the study.  Time point where the PCSC is observed will be 
flagged. 
PCSC in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) 
measurements will be defined as follows: 
 Hypotension: SBP < 90 mm Hg with a decrease  20 mm Hg from predose, or a DBP  
50 mm Hg and decrease  15 mm Hg from predose.   
 Hypertension: SBP ≥ 180 mm Hg with an increase of ≥ 20 mm Hg from predose, or a 
DBP ≥105 and an increase ≥ 15 mm Hg from predose 
 Bradycardia: HR  50 BPM with a decrease 15 BPM from predose 


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 Tachycardia: HR ≥ 120 BPM with an increase ≥15 BPM from predose. 
8.6.5. 
Electrocardiograms 
ECGs will be performed at screening for enrollment purposes only, no data summary will be 
prepared. 
8.6.6. 
Subgroup Analyses for Safety Endpoints 
No subgroup analysis is planned for this study. 
 


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9. 
STUDY ADMINISTRATION 
9.1. 
Regulatory and Ethical Considerations 
9.1.1. 
Regulatory Authority Approval 
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country specific regulatory requirements before any site may 
initiate the study in that country. 
9.1.2. 
Ethical Conduct of the Study and Ethics Approval 
This study will be conducted according to GCP; US 21 Code of Federal Regulations (CFR) 
Part 50 (Protection of Human Subjects); US 21 CFR Part 56 (IRBs); US 21 CFR Part 54 
(Financial Disclosure); International Conference on Harmonization (ICH) Guidance for Industry, 
E6 GCP: Consolidated Guidance; the Nuremberg Code; and, where applicable the principles of 
the Declaration of Helsinki (Recommendations guiding Medical Doctors in Biomedical Research 
Involving Human Subjects), and with the NH&MRC National Statement on Ethical Conduct in 
Human Research (2007).   
9.1.2.1. 
Ethics Committees 
The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the 
site’s informed consent form, and any other information that will be presented to potential 
subjects (e.g., advertisements or information that supports or supplements the informed consent 
form) are reviewed and approved by the appropriate IRB or IEC.  The investigator agrees to 
allow the IRB or IEC direct access to all relevant documents.  The IRB or IEC must be 
constituted in accordance with all applicable regulatory requirements.  The sponsor will provide 
the investigator with relevant documents or data needed for IRB or IEC review and approval of 
the study.  Before investigational products can be shipped to the site, the sponsor must receive 
copies of the IRB or IEC approval, the approved informed consent form, and any other 
information that the IRB or IEC has approved for presentation to potential subjects. 
If the protocol, the informed consent form, or any other information that the IRB or IEC has 
approved for presentation to potential subjects is amended during the study, the investigator is 
responsible for ensuring that the IRB or IEC reviews and approves, where applicable, these 
amended documents.  The investigator must follow all applicable regulatory requirements 
pertaining to the use of an amended informed consent form, including obtaining IRB or IEC 
approval of the amended form, before new subjects consent to take part in the study using the 
new version of the form.  The investigator must promptly forward to the sponsor copies of the 
IRB or IEC approval of the amended informed consent form or other information and the 
approved amended informed consent form or other information.  IRB or IEC approval of the 
consent forms must be obtained in addition to the approval given for the clinical study.  
Regulatory review and approval may be required in some countries before IRB or IEC approval 
can be sought. 
9.1.2.2. 
General Considerations 
The ethical standards defined within GCP are intended to ensure the following: 


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 Human subjects are provided with an adequate understanding of the possible risks of 
their participation in the study, and they have a free choice to participate or not. 
 The study is conducted with diligence and in conformance with the protocol in such a 
way as to ensure the integrity of the findings. 
 The potential benefits of the research justify the risks. 
Recro Pharma, Inc. is the sponsor of study REC-17-023.  The sponsor is responsible for all of the 
following: 
 selecting qualified investigators 
 providing investigators with the information they need to conduct the investigation 
properly 
 ensuring proper monitoring of the investigation 
 ensuring that appropriate regulatory agencies and all participating investigators are 
properly informed of significant new information regarding AEs or risks associated with 
DEX-IN 
9.1.3. 
Informed Consent 
The sponsor will provide investigators with a sample informed consent form for this study.  
Investigators are encouraged to use the sample form; however, they may adapt the information to 
suit the needs of their institution, if necessary (although it must reflect the required elements of 
informed consent specified in 21 CFR Part 50.25).  The final informed consent form must be 
accepted by the sponsor and approved by the IRB or IEC.  Investigators must provide the 
sponsor with an unsigned copy of the final informed consent form before and after it is approved 
by the IRB or IEC.  If any new information becomes available that might affect subjects’ 
willingness to participate in the study, or if any amendments to the protocol require changes to 
the informed consent form, the sponsor will provide investigators with a revised informed 
consent form.  The IRB or IEC must provide written approval of any revisions to the informed 
consent form in advance of its use. 
Investigators must provide subjects with all the information necessary to make an informed 
decision about their participation in the study, including the nature and intended purpose of the 
study, possible benefits, and possible risks. 
All information in the informed consent form should be provided in a language (whether written 
or spoken) that is as nontechnical as practical and that is understandable to the subjects. 
Before written informed consent is obtained, the subject should be given ample time and 
opportunity to inquire about the details of the study.  All questions must be answered to the 
satisfaction of the subject (or his or her legally authorized representative). 
Before a subject undergoes procedures specific to the protocol, the informed consent form must 
be signed and dated by the subject (or his or her legally authorized representative) and any other 
signatories as required by the IRB or IEC. 
If a subject (or legally authorized representative) cannot read, a short form approved by the IRB 
or IEC may be used.  Only the short form itself is to be signed by the subject or the 


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representative.  However, the witness shall sign both the short form and a copy of the summary, 
and the person actually obtaining the consent shall sign the copy of the summary in accordance 
with 21 CFR 50.27 (b2). 
After all required signatures have been obtained, a copy of the informed consent form should be 
provided to the subject, and the original must be kept on file at the site and made available for 
review by the sponsor.  Documentation of the informed consent discussion must be noted in the 
subject’s case history. 
9.1.4. 
Investigator Reporting Requirements 
The investigator is responsible for completing and maintaining adequate and accurate eCRFs and 
source documentation.  Source documentation constitutes original records (first point of entry, 
either hard copy or electronic), which may include progress notes, medication administration 
records, operation reports, laboratory reports, discharge summaries, and so on.   
9.2. 
Study Monitoring 
The sponsor is responsible for ensuring the proper conduct of the study with regard to subject 
protection, ethics, protocol adherence, site procedures, and integrity of the data.  At regular 
intervals during the study, the sponsor’s study monitors will contact the study site via visits to 
the site, telephone calls, and letters in order to review study progress and eCRF completion and 
to address any concerns or questions regarding the study conduct.  During monitoring visits, the 
following aspects of study conduct will be carefully reviewed: subjects’ informed consent 
documents, subject recruitment procedures, subjects’ compliance with the study procedures, 
source-data verification, drug accountability, use of concomitant therapy by subjects, AE and 
SAE documentation and reporting, and quality of data. 
9.3. 
Quality Assurance 
The sponsor, a regulatory authority, or an IRB representative may visit the study site at any time 
during the study or after completion of the study to perform audits or inspections.  The purpose 
of a sponsor audit or regulatory inspection is to examine systematically and independently all 
study-related activities and documents to determine whether these activities were conducted 
according to the protocol, GCP, ICH guidelines, and any other applicable regulatory 
requirements.  Investigators should contact the sponsor immediately if contacted by a regulatory 
agency about an inspection at their site. 
9.4. 
Study and Site Closure 
If the sponsor, investigator, or officials from regulatory agencies discover conditions arising 
during the study that indicate that the study should be halted or that the study site should be 
closed, this action may be taken after appropriate consultation between the sponsor and 
investigator.  Conditions that may warrant termination of the study include, but are not limited 
to, the following: 
 discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in the 
study 


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 submission of knowingly false information from the research facility to the sponsor, 
study monitor, or regulatory agencies 
 failure of the investigator to comply with GCP (e.g., ICH guidelines, regulatory agency 
guidelines) 
 insufficient adherence to protocol requirements or an unacceptably high rate of missing, 
erroneous, or improperly collected data 
 evidence from the blinded data of sufficient technical problems with the study that one 
could believe with a high degree of certainty that subjects are being exposed to the 
investigational drug without a realistic expectation of evaluable data 
 a decision on the part of the sponsor to suspend or discontinue testing evaluation or 
development of the product 
 failure of the investigator to enroll subjects into the study at an acceptable rate 
9.5. 
Records Retention 
9.5.1. 
Health Insurance Portability and Accountability Act of 1996 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subjects’ health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 CFR Parts 160 and 164 (the 
Health Insurance Portability and Accountability Act of 1996 privacy regulation).  The 
investigator shall ensure that study subjects authorize the use and disclosure of protected health 
information in accordance with the privacy regulations of the Health Insurance Portability and 
Accountability Act and in a form satisfactory to the sponsor. 
9.5.2. 
Financial Disclosure 
Financial disclosure is required for this study. 
9.5.3. 
Access to Original Records 
Regulatory authorities expect that monitors, auditors, and representatives of national and 
international government regulatory agency bodies have access to original source documentation 
(see examples in Section 9.1.4) to ensure data integrity.  “Original” in this context is defined as 
the first documentation of an observation and does not differentiate between hard-copy and 
electronic records. 
9.5.4. 
Archiving of Study-Related Documents 
Records related to this clinical study must be retained either for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  The sponsor 
will notify the investigator as to when these documents no longer need to be retained for this use. 


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9.6. 
Provision of Study Results and Information to Investigators 
When a clinical study report is completed, the sponsor will provide the major findings of the 
study to the investigators. 
In addition, details of the study treatment assignment will be provided to the investigators to 
enable them to review the data to determine the outcome of the study for their subjects. 
The sponsor may list and summarize the results from coded samples by subject number in the 
clinical study report.  In this event, the investigator and study staff would have access to the 
research results and would be able to link the results to a particular subject.  The investigator and 
study staff would be directed to hold this information confidentially. 
9.7. 
Information Disclosure and Inventions 
9.7.1. 
Ownership 
All information provided by the sponsor and all data and information generated by the site as 
part of the study (other than a subject’s medical records) are the sole property of Recro Pharma, 
Inc. 
All rights, title, and interests in any inventions, know-how, or other intellectual or industrial 
property rights that are conceived or reduced to practice by site staff during the course of or as a 
result of the study are the sole property of Recro Pharma, Inc. and are hereby assigned to Recro 
Pharma, Inc. 
If a written contract is executed between Recro Pharma, Inc. and the study site for the conduct of 
the study and that contract includes ownership provisions inconsistent with this statement, that 
contract’s ownership provisions shall apply rather than this statement. 
9.7.2. 
Confidentiality 
All information provided by Recro Pharma, Inc. and all data and information generated by the 
site as part of the study (other than a subject’s medical records) will be kept confidential by the 
investigator and other site staff.  This information and data will not be used by the investigator or 
other site personnel for any purpose other than conducting the study.  These restrictions do not 
apply to the following:  1) information that becomes publicly available through no fault of the 
investigator or site staff, 2) information that must be disclosed in confidence to an IEC or IRB 
solely for the evaluation of the study results, 3) information that must be disclosed in order to 
provide appropriate medical care to a study subject, or 4) study results that may be published as 
described in Section 9.7.3.  If a written contract for the conduct of the study is executed and that 
contract includes confidentiality provisions inconsistent with this statement, that contract’s 
confidentiality provisions shall apply rather than this statement. 
9.7.3. 
Publication 
For multicenter studies, the first publication or disclosure of study results shall be a complete, 
joint, multicenter publication or disclosure coordinated by Recro Pharma, Inc.  Thereafter, any 
secondary publications will reference the original publication(s).  If no multicenter publication is 
submitted for publication within 18 months of study database hard lock, then the site shall be 
free to disclose its own results, subject to sponsor rights under Section 9.7.1. 


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Before submitting material for publication, presentation, or use for instructional purposes, or 
before otherwise disclosing the study results generated by the site (collectively, a “publication”), 
the investigator shall provide Recro Pharma, Inc. with a copy of the proposed publication and 
allow Recro Pharma, Inc. a period of at least 90 days to review the proposed publication.  
Proposed publications shall not include either Recro Pharma, Inc. confidential information (other 
than the study results) or the personal data (such as name or initials) of any subject. 
At Recro Pharma, Inc.’s request, the submission or other disclosure of a proposed publication 
will be delayed a further 90 days to allow Recro Pharma, Inc. to seek patent or similar protection 
of any inventions, know-how, or other intellectual or industrial property rights disclosed in the 
proposed publication. 
If a written contract is executed for the conduct of the study and that contract includes 
publication provisions inconsistent with this statement, that contract’s publication provisions 
shall apply rather than this statement. 
9.7.4. 
Data Management 
The investigator (or designee) will enter subject data by using the eCRF defined by Recro 
Pharma, Inc. Clinical data management will be performed in accordance with applicable Recro 
Pharma, Inc. standards and data-cleaning procedures.   
In addition, validated laboratory data will be transmitted electronically from the clinical 
laboratory to Recro Pharma, Inc. or its designee. 
The investigator or designee must record all required data using the previously specified data 
collection method defined by Recro Pharma, Inc.  An explanation must be documented for any 
critical data points.  The investigator must sign and date a declaration in the eCRF attesting that 
he or she is responsible for the quality of all data recorded and that the data represent a complete 
and accurate record of each subject’s participation in the study. 
9.7.5. 
Data Security 
Access to the data will be strictly controlled. 
9.8. 
Subject Tracking 
Drug accountability logs, a subject identification log (to be retained by the investigator only), 
and a subject enrollment log will be used to track subject participation in the study. 


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10. 
REFERENCES 
1. Swarm R. et al. NCCN Clinical Practice Guidelines in Oncology: Adult Cancer Pain.  
Journal of the National Comprehensive Cancer Network. 2007 Sept; 5(8):726-51. 
2. Jaakola ML, Salonen M, Lehtinen R, Scheinen H. The analgesic action of 
dexmedetomidine – a novel α2-adrenoceptor agonist – in healthy volunteers. Pain. 1991 
Sept; 46(3):281-285. 
3. Bhana N, Goa KL, McClellan KJ. Dexmedetomidine. Drugs. 2000 Feb; 59(2):112-118. 
4. Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The Effects of Increasing Plasma 
Concentrations of Dexmedetomidine in Humans. Anesthesiology, 2000 Aug; 93(2):382-
394. 
 
 
 
 
 
 


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APPENDIX A. OVERVIEW OF STUDY SCHEDULE 
 
Screening 
(Day -28 
to -1) 
Day 1  
Day 7 ± 2 
Follow-
Up 
Pre-Procedure 
Procedure 
Post-Procedure 
Check-
In 
1 Hr 
Prior 
15 Min 
Prior 
5 Min 
Prior 
Immediately 
Prior  
Hr 0  Hr 0.5  Hr 1  Hr 1.5  Hr 2  
Hr 3  Hr 4  
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
Xserum 
Xurine, c 
 
 
 
 
 
 
 
 
 
 
 
 
 
UDS & Alcohol Breath Test 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resting Vital Signs 
Xa 
Xa, c 
Xd 
Xd 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Postural Vital Signs 
X 
Xc 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
12 Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IN Study Drug Administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IV Study Drug Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pain Intensity 
 
 
Xd 
Xd 
X 
 
Xb 
 
Worst Pain Intensity 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Anxiety - NRS 
 
 
Xd 
Xd 
X 
X 
Xb 
 
Anxiety – STAI-6 
X 
 
Xd 
 
X 
 
Xb 
 
Satisfaction with Pain 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Adverse Event Monitoring 
 
 
X 
Prior and Concomitant Medications 
X 
a   At screening and on Day 1 prior to dosing, resting vital signs will be collected in three determinations approximately 2 minutes apart to ascertain subject’s true 
baseline heart rate and blood pressure values. The average values will be used to determine subject eligibility for participation.   
b   PI and anxiety scores will be assessed according to the schedule defined in the procedure specific cohort manual. 
c   Assessment to be performed prior to dose randomization 
d   Assessment to be performed prior to dosing


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APPENDIX B. INVESTIGATOR OBLIGATIONS 
As an investigator, you are responsible for ensuring that the study is conducted according to the 
protocol, the signed Statement of Investigator, and all applicable regulations. 
Debarment 
Individuals ineligible to conduct or be involved with clinical studies, including those ineligible as 
a result of debarment under the Generic Drug Enforcement Act of 1992, will not be allowed to 
conduct or work on studies sponsored by Recro Pharma, Inc.  You are required to disclose 
immediately to the sponsor, in writing, if any person involved in the conduct of the study is 
debarred pursuant to a hearing by FDA under this antifraud law or if any proceeding for 
debarment is pending or is (to the best of your knowledge) threatened. 
Institutional Review Board 
You are required to obtain initial and continuing review and approval by an IRB or IEC that 
complies with the requirements specified in 21 CFR Part 56.  Before initiating the trial, you must 
have written approval from the IRB or IEC for the protocol, informed consent form, subject 
recruitment procedures (e.g., advertisements), and any other written information to be provided 
to the subjects.  You must submit the Investigator’s Brochure and any updates to the IRB or IEC 
for review.  The IRB or IEC must also provide written approval of any amendments to the 
protocol that affect the conduct of the study and any changes to the informed consent form in 
advance of use.  If the duration of the study is longer than 1 year, reapproval by the IRB or IEC 
must be obtained on a yearly basis (or at more frequent intervals if required by the IRB or IEC).  
All IRB or IEC approvals must be forwarded to the sponsor. 
You must provide reports of all SAEs from your site to the IRB or IEC.  You are also responsible 
for providing the IRB or IEC with Safety Reports of any SAEs from any other study conducted 
with the study medication.  The latter will be provided to you by the sponsor. 
Confidentiality and Safety of Subjects 
You are responsible for protecting the rights, safety, and welfare of subjects under your care and 
for the control of the drug(s) under investigation. 
You are responsible for keeping a record of all screened subjects, including full names and last 
known addresses.  All subjects will be identified on the eCRFs by subject number.  Demographic 
information including date of birth, sex, and race will also be recorded on the eCRFs.  
Confidentiality of subject data will be maintained in accordance with local laws. 
In addition to your responsibilities for reporting AEs identified during the course of a subject’s 
participation in the study, you must also report any SAEs that occur within 30 days after the last 
dose of study medication (regardless of relationship to study medication) and any serious adverse 
drug reactions (SAEs for which you consider that there is a reasonable possibility that the study 
medication caused the response) that you become aware of at any time (even if the event occurs 
more than 30 days after the subject’s last exposure to study medication).  This obligation is in 
addition to any protocol-specified requirement for reporting AEs occurring after the last dose of 
study medication.  Please refer to Sections 7.7 and 7.8 of this protocol for contact information 
and SAE reporting requirements. 


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Study-Related Records 
You are required to maintain complete and accurate study documentation in compliance with 
current GCP standards and all applicable federal, state, and local laws, rules, and regulations 
related to the conduct of a clinical study. 
You are required to make all study documentation promptly available for inspection, review, or 
audit at your study site upon request by the sponsor, its representatives, or any appropriate 
regulatory agencies. 
Accountability of the Investigational Product 
You or your designee (i.e., the pharmacist) is responsible for accountability of the investigational 
product at the site.  You or your designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each subject, and the return to the sponsor or alternative 
disposition of any unused product.  These records must include dates; quantities; batch, serial, or 
lot numbers; and expiration dates (if applicable). 
You should ensure that the investigational product is used only in accordance with the protocol. 


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APPENDIX C. STUDY-SPECIFIC INFORMATION 
Appendix C.1: 
Pain Assessments - Numeric Pain Rating Scale (NPRS) 
 
Pain Intensity Assessments:  On a scale of 0-10, please rate your pain by marking an ‘X” in 
the appropriate box that best describes your pain now. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
 
 
worst 
imaginable 
pain 
 
Worst Pain Hour 0:  On a scale of 0-10, please rate your pain by marking an ‘X” in the 
appropriate box that best describes the worst pain you experienced during the procedure. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
 
 
worst 
imaginable 
pain 
 
Worst Pain Hour 4:  On a scale of 0-10, please rate your pain by marking an ‘X” in the 
appropriate box that best describes the worst pain you experienced since the end of the 
procedure. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
 
 
 
worst 
imaginable 
pain 
 


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Appendix C.2: 
Anxiety Assessment  
Anxiety - NRS 
On a scale of 0-10, please rate your anxiety by marking an ‘X” in the appropriate box that best 
describes the level of anxiety you are experiencing now. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
anxiety 
 
 
 
 
 
 
 
 
 
worst 
imaginable 
anxiety 
 
Anxiety – STAI-6 
A number of statements which people have used to describe themselves are given below. Read 
each statement and then circle the most appropriate number to the right of the statement to 
indicate how you feel right now, at this moment. There are no right or wrong answers. Do not 
spend too much time on any one statement but give the answer which seems to describe your 
present feelings best. 
 
 
Not at all 
Somewhat 
Moderately 
Very much 
1. I feel calm 
1 
2 
3 
4 
2. I am tense 
1 
2 
3 
4 
3. I feel upset 
1 
2 
3 
4 
4. I am relaxed 
1 
2 
3 
4 
5. I feel content 
1 
2 
3 
4 
6. I am worried 
1 
2 
3 
4 
 
 
 
 
 


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Appendix C.3: 
Subject Satisfaction with Pain Experience 
 
Hour 0 Assessment: 
“Overall, please rate your satisfaction with the degree of pain you experienced during the 
procedure.” 
 
Response to the question will be: (Mark (X) one box) 
 Completely Dissatisfied (1) 
 Mostly Dissatisfied (2) 
 Somewhat Dissatisfied (3) 
 Neither Dissatisfied nor satisfied (4) 
 Somewhat Satisfied (5) 
 Mostly Satisfied (6) 
 Completely Satisfied (7) 
 
Hour 4 Assessment: 
“Overall, please rate your satisfaction with the degree of pain you experienced following 
the procedure.” 
 
Response to the question will be: (Mark (X) one box) 
 Completely Dissatisfied (1) 
 Mostly Dissatisfied (2) 
 Somewhat Dissatisfied (3) 
 Neither Dissatisfied nor satisfied (4) 
 Somewhat Satisfied (5) 
 Mostly Satisfied (6) 
 Completely Satisfied (7) 
 
 
 


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APPENDIX D.   AMERICAN SOCIETY OF ANESTHESIOLOGISTS 
PHYSICAL STATUS CLASSIFICATION SYSTEM 
 
I 
Normal healthy patient 
 
II  
Patient with mild systemic disease; no functional limitation – e.g. smoker with well-
controlled hypertension 
 
III  
Patient with severe systemic disease; definite functional impairment – e.g. diabetes and 
angina with relatively stable disease, but requiring therapy 
 
IV 
Patient with severe systemic disease that is a constant threat to life – e.g. diabetes and 
angina and congestive heart failure; patients with dyspnea on mild exertion and chest 
pain 
 
V 
Unstable moribund patient who is not expected to survive 24 hours with or without 
operation 
 
VI 
Brain dead patient whose organs are removed for donation to another 
 
E 
Emergency operation of any type, which is added to any of the above six categories, an in 
ASA II E 
 

SAP_001.pdf: 
 
 
 
REC-17-023 
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo- and Active-
Controlled, Evaluation of the Efficacy and Safety of DEX-IN following Painful 
Outpatient Procedures 
 
NCT03348423 
 
Statistical Analysis Plan 
 
19 January 2018 
 


REC-17-023 
Statistical Analysis Plan  
Version 1.0 
Date:19 January, 2018
 
 
Page 1 of 24 
 
ARTICLE I.  
 
 
 
Statistical Analysis plan 
 
Protocol Number: REC-17-023 
Protocol Title:  
 A Phase 2, Multicenter, Randomized, Double-Blind, 
Placebo- and Active-Controlled, Evaluation of the Efficacy 
and Safety of DEX-IN following Painful Outpatient 
Procedure  
Date of Protocol:  05 September 2017 
 


REC-17-023 
Statistical Analysis Plan  
Version 1.0 
Date:19 January, 2018
 
 
Page 2 of 24 
 
REVISION HISTORY 
Version No. 
Version Date 
Author 
Description of Modification 
0.1 
10Nov2017 
J. Nezzer 
Initial Draft for Internal Review 
0.2 
28Nov2017 
J. Nezzer 
Updated per initial sponsor and internal 
review comments 
0.3 
05Jan2018 
J. Nezzer 
Updated per sponsor review 
1.0 
19Jan2018 
J. Nezzer 
Final version issued 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


REC-17-023 
Statistical Analysis Plan  
Version 1.0 
Date:19 January, 2018
 
 
Page 4 of 24 
 
TABLE OF CONTENTS 
REVISION HISTORY ............................................................................................ 2 
SIGNATURES .......................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................ 4 
LIST OF ABBREVIATIONS ................................................................................. 7 
1. INTRODUCTION ............................................................................................. 8 
2. STUDY OVERVIEW ......................................................................................10 
2.1. 
Study Design and Objectives ....................................................................................................... 10 
2.1.1. 
Cohort 1 Procedure Specific Overview ................................................................................. 10 
2.1.2. 
Cohort x Procedure Specific Overview .................................................................................. 11 
2.2. 
Study Assessments Schedule ....................................................................................................... 12 
2.3. 
Efficacy Assessments ................................................................................................................... 12 
2.3.1. 
Pain Intensity (PI) .................................................................................................................. 12 
2.3.2. 
Worst Pain Intensity .............................................................................................................. 13 
2.3.3. 
Anxiety................................................................................................................................... 13 
2.3.4. 
Subject Satisfaction with Pain Experience ............................................................................ 14 
2.4. 
Study Endpoints ........................................................................................................................... 14 
2.4.1. 
Efficacy Endpoints ................................................................................................................. 14 
2.4.2. 
Safety Endpoints ................................................................................................................... 14 
2.5. 
Sample Size Consideration .......................................................................................................... 14 


REC-17-023 
Statistical Analysis Plan  
Version 1.0 
Date:19 January, 2018
 
 
Page 5 of 24 
 
3. GENERAL CONSIDERATIONS ..................................................................15 
3.1. 
Analysis Population ..................................................................................................................... 15 
3.2. 
Test Hypothesis and P Value Justification ................................................................................ 15 
3.3. 
Procedures for Handling Missing Data ...................................................................................... 15 
3.4. 
Baseline Definitions ...................................................................................................................... 16 
3.5. 
Derived Variables......................................................................................................................... 16 
3.5.1. 
Average PI Score .................................................................................................................... 16 
3.5.2. 
Average Anxiety Scores ......................................................................................................... 16 
3.5.3. 
Potentially Clinically Significant Changes in Vital Signs ......................................................... 16 
4. STUDY POPULATION SUMMARIES ........................................................17 
4.1. 
Disposition .................................................................................................................................... 17 
4.2. 
Demographics and Procedure Characteristics .......................................................................... 17 
4.3. 
Protocol Deviations ...................................................................................................................... 17 
4.4. 
Treatment Compliance ................................................................................................................ 18 
4.5. 
Prior and Concomitant Medications .......................................................................................... 18 
5. EFFICACY ANALYSIS .................................................................................19 
5.1. 
Pain Intensity ................................................................................................................................ 19 
5.2. 
Anxiety Assessment ...................................................................................................................... 19 
5.3. 
Subject Satisfaction with Pain Experience ................................................................................ 19 
5.4. 
Subgroup Analyses for Efficacy ................................................................................................. 19 
6. SAFETY AND TOLERABILITY EVALUATIONS ...................................20 


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6.1. 
Extent of Exposure ....................................................................................................................... 20 
6.2. 
Adverse Events ............................................................................................................................. 20 
6.3. 
Clinical Laboratory Tests ............................................................................................................ 20 
6.4. 
Vital Sign Measurements ............................................................................................................ 20 
6.5. 
Electrocardiograms...................................................................................................................... 21 
6.6. 
Subgroup Analyses for Safety Endpoints .................................................................................. 21 
7. REFERENCES ................................................................................................22 
APPENDIX 1 - TABLE OF CONTENTS OF PLANNED ANALYSIS ...........23 
APPENDIX 2 - TABLE OF CONTENTS OF DATA LISTINGS ....................24 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
abs 
absolute value 
AE 
adverse event 
BMI 
body mass index 
BPM 
Beats per minute 
CFB 
Change from baseline 
eCRF 
Electronic case report form 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
HR 
Heart Rate 
ICH 
International Conference on Harmonization 
IN  
Intranasal  
ITT  
Intent-to-treat  
IV 
Intravenous 
mm Hg 
millimeters of mercury 
NPRS  
Numeric Pain Rating Scale  
NRS  
Numeric Rating Scale  
PCFB 
Percent change from baseline 
PCSC 
Potentially Clinically Significant Change 
PE 
Physical Exam 
PI 
Pain Intensity 
PID 
Pain Intensity Difference 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard deviation 
STAI-6 
Six Item Spielberger State-Trait Anxiety Inventory 
TEAE 
treatment emergent adverse event 


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1. 
INTRODUCTION 
The study (Protocol REC-17-023) is planned to evaluate the use of single doses of DEX-IN in an 
office based or outpatient surgery/procedure setting where patients may receive limited or no 
analgesic medications. Patients undergoing these procedures generally experience a range of pain 
and anxiety symptoms that may not be well managed under the current standard of care. This 
study will utilize a placebo control, as well as an active control arm (IV fentanyl) to  evaluate the 
efficacy of DEX-IN dosing.  
This Statistical Analysis Plan (SAP), prepared for Study REC-17-023, provides a more technical 
and detailed elaboration of the principal statistical features stated in the protocol.  The objective 
of the SAP is to reasonably assure that the statistical methodologies to be used for analysis are 
complete and accurate.   
In the development of this SAP, the following documents were used: 
• Protocol REC-17-023,  05 September 2017 
• REC-17-023 Cohort 1 Manual Face Peel – FINAL, 11SEP2017 
• REC-17-023, eCRF, Final 1.0 31 October 2017  
The principles in the following guidance documents are followed in preparation of this SAP: 
• ICH E3 (1995): Structure and Content of Clinical Study Reports 
• ICH E6 (1996): Guideline for Good Clinical Practice 
• ICH E9 (1998): Statistical Principles for Clinical Trials 
In the event that a discrepancy is found between the descriptions in the statistical section of the 
protocol and this document, the description in this document supersedes the descriptions in the 
statistical section of the protocol. 
This SAP has been prepared based on the first cohort of the study.  The data from each cohort 
will be unblinded and reviewed in interim analyses as appropriate to inform program 
development.   
Data summary and analysis approaches identified for Cohort 1 in this SAP will be followed for 
other cohorts as appropriate. If new assessments are identified and included in the other cohorts, 
a SAP addendum will be prepared to document any cohort specific assessments and/or analysis.  
If the same assessment (ie, PI score, anxiety score) is applied with a different nominal time point 
in the new cohorts, the SAP will not need to be appended and summary tables will be produced 
based on the nominal time point and/or intervals for the specific cohort. 


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Exploratory or additional summaries not identified in this SAP (or subsequent addendum) that 
are performed post-hoc (ie. on data that has been unblinded) will be clearly identified as such in 
the CSR. 


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2. 
STUDY OVERVIEW 
2.1. 
Study Design and Objectives 
Protocol REC-17-023 is a Phase 2, randomized, multicenter, double-blind, placebo- and active-
controlled evaluation of the efficacy and safety of DEX-IN in adult subjects undergoing painful 
outpatient and office based procedures. The study will enroll up to 250 subjects across up to 5 
study cohorts, with approximately 50-75 subjects per cohort. Each study cohort will include 
subjects undergoing a specific painful procedure which may include, but is not limited to, 
cosmetic procedures (face peel, liposuction/liposculpture, sclerotherapy, etc.), dental procedures, 
biopsy procedures (prostate, colposcopy, etc.), or other procedures. The procedures to be 
evaluated in this study will be selected on an ongoing basis.   
This study will enroll an adequate number of subjects to have approximately 50-75 subjects per 
cohort (25-37 subjects per treatment group) for the intent-to-treat (ITT) analysis set.  For the 
current (Facial Peel) cohort approximately 45 subjects are expected to complete (15 per 
treatment group). 
The primary objective of this study is to evaluate the analgesic efficacy of DEX-IN compared 
with placebo and active control (fentanyl), in subjects undergoing painful outpatient and office 
based procedures. 
Secondary objectives of this study will include: 
• To evaluate the anxiolytic effects of DEX-IN 
• To determine the safety and tolerability of DEX-IN as evaluated with vital sign 
collection, and incidence of Adverse Events (AEs) and Serious AEs (SAEs). 
Subjects planned to undergo a selected procedure, age 18 to 65, inclusive, will be qualified for 
enrollment at up to 5 sites in the United States.  The study has a Screening Period, three Periods 
on the Day of the Procedure: 1) Pre-Procedure period, 2) Peri-Procedure period, and 3) Post-
Procedure period, and a Follow-up period.   
Efficacy assessments will include assessment of pain intensity, anxiety intensity, and subject 
satisfaction with pain experienced during the procedure. Safety assessments will include 
monitoring of AEs and SAEs, and vital sign measurements. 
2.1.1. 
Cohort 1 Procedure Specific Overview 
Subjects enrolled in the first cohort will undergo a chemical face peel after completing study 
dosing.  
Chemical peel procedures will be performed in the office setting using trichloroacetic acid to be 
applied over approximately 50% or greater of the facial surface. The trichloroacetic acid should 
be used at a concentration between 15 and 30%. 


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The acid will be applied to areas as determined by the investigator and subject prior to the 
procedure, and will remain in place for approximately 20 minutes, before being 
neutralized/removed using water or another neutralizing solution. 
The start of the procedure should be the time that the acid is applied to the facial skin. The end of 
the procedure (Hour 0) will be the time when the removal of the acid is completed. 
Procedure specific details to be recorded in Cohort 1 will include: 
• Start of acid application (Start time of the procedure) 
• Completion of acid application 
• Start of acid removal  
• Completion of acid removal (End time of the procedure ) 
• Approximate surface area (%) treated 
• Acid concentration 
• Other significant notes 
2.1.2. 
Cohort x Procedure Specific Overview 
As Cohorts are selected for inclusion in the study protocol, a SAP addendum will be prepared if 
necessary to document any cohort specific assessments. 
 
 
 


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2.2. 
Study Assessments Schedule 
Demographics information will be collected during screening visit including age, sex, ethnicity, 
race, weight, height, and BMI. The investigator or designee will document each subject’s 
medical history during the screening visit. Medical history will be updated on Day 1 when the 
subject reports for the procedure, and the subject’s eligibility will be reviewed to confirm that 
they continue to meet the required study criteria. The investigator or designee will perform a 
physical examination (HEENT, cardiovascular, respiratory, gastrointestinal, neurological, 
dermatologic, and musculoskeletal systems) during the screening visit and at check-in (Day 1) to 
the study site prior to randomization. 
Efficacy assessments will include pain intensity, anxiety measurements (NRS - Numeric Rating 
Scale and STAI-6 - Six Item Spielberger State-Trait Anxiety Inventory), and Subject Satisfaction 
with Pain Experience.  Safety assessments will include monitoring of AEs and vital sign 
measurements. 
Clinical Labs and ECGs will be assessed at screening to determine eligibility, but will not be 
recorded in the eCRF.  A Schedule of Events is presented in the Protocol REC-17-023 Appendix 
A and in the Cohort Manual. 
2.3. 
Efficacy Assessments 
Where assessments are performed at the same time point, the following sequence of events 
should be utilized whenever possible: 
1. Pain Intensity 
2. Anxiety – NRS 
3. Worst Pain Intensity 
4. Anxiety – STAI-6 
5. Satisfaction with Pain Experience 
2.3.1. 
Pain Intensity (PI) 
PI will be assessed by the study subject for their current pain according to an 11-point numeric 
pain rating scale (NPRS; 0 - 10) at the following time points: 
Pre-procedure: PI will be assessed 1 hour (within 5 minutes prior to IN dosing), 15 minutes 
(within 5 minutes prior to IV dosing), and 5 minutes before the start of the procedure. 
Peri-procedure: PI will be assessed immediately after completing application of the acid (within 
1 minute), and every 2±1 minutes during the procedure until immediately prior to removal of the 
acid. 


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Post-procedure: PI will also be assessed at Hour 0 (immediately following completion of acid 
removal), and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, and 4 hours following the end of procedure. 
2.3.2. 
Worst Pain Intensity 
Subjects will assess their worst pain intensity during the procedure and in the post-procedure 
period using the 11-point NPRS at the following time points.  
• The worst pain during the procedure will be collected at Hour 0 (end of procedure); at 
that time subjects will be asked to rate their worst pain experienced during the procedure.  
• At Hour 4, prior to discharge, subjects will be asked to rate their worst pain experienced 
in the time since the end of the procedure. 
2.3.3. 
Anxiety 
2.3.3.1. 
Numeric Rating Scale 
Anxiety will be assessed by the study subject for their current anxiety according to an 11-point 
numeric rating scale (NRS; 0 - 10) at the following time points: 
Pre-Procedure: Anxiety will be assessed using the NRS 1 hour (within 5 minutes prior to IN 
dosing), 15 minutes (within 5 minutes prior to IV dosing), 5 minutes before the start of the 
procedure, and immediately prior to the start of the procedure (within 1 minute). 
Peri-procedure: Anxiety will be assessed using the NRS immediately after completing 
application of the acid (within 1 minute), and every 5±1 minutes during the procedure until 
immediately prior to removal of the acid. 
Post-procedure: Anxiety will also be assessed using the 11-point NRS at Hour 0 (immediately 
following completion of the acid removal), and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, and 4 hours following 
the end of procedure. 
2.3.3.2. 
Six Item Spielberger State-Trait Anxiety Inventory (STAI-6) 
Anxiety will also be assessed by the subject using the 6-Item Spielberger State-Trait Anxiety 
Inventory (STAI-6) at the following time points:  
Pre-Procedure: Anxiety will be assessed using the STAI-6 at screening, 1 hour (within 5 
minutes prior to IN dosing), and 5 minutes before the start of the procedure. 
Post-procedure: Anxiety will be assessed using the STAI-6 at Hour 0 (immediately following 
completion of the acid removal); no peri-procedural assessments will be completed. 


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2.3.4. 
Subject Satisfaction with Pain Experience 
Subjects will report their satisfaction with the degree of pain experienced during the procedure 
and in the post-procedure period according to a 7-point Likert scale at the  
• The subject assessment of satisfaction will be completed for pain experienced during the 
procedure at Hour 0,  
• At Hour 4, prior to discharge, subject assessment of satisfaction will be completed for the 
pain experienced during the post-procedure period.  
2.4. 
Study Endpoints 
2.4.1. 
Efficacy Endpoints 
The primary efficacy endpoint will be the mean PI score during the study procedure.  
Secondary efficacy endpoints include:  
1. Mean PI score at other intervals (Pre- and Post-procedure)  
2. Worst pain intensity during and following the procedure  
3. Mean anxiety score (NRS and STAI-6) at various intervals (Pre-procedure, during the 
procedure [from the start of the procedure to the end of the procedure], and post-
procedure) 
4. Subject satisfaction with pain during and following the procedure.  
2.4.2. 
Safety Endpoints  
The safety endpoints will include the following: 
1. 
Incidence of AEs and SAEs 
2. 
Change from baseline in vital signs; incidence of clinically significant changes in 
vital signs 
2.5. 
Sample Size Consideration  
The sample size for this study was selected empirically without a power calculation.  


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3. 
GENERAL CONSIDERATIONS  
3.1. 
Analysis Population 
The following analysis sets will be identified for this study. 
Intent-to-Treat (ITT) Analysis Set:  The ITT set will include randomized subjects.  This 
dataset may also be referenced as the ‘Randomized Set’.  The ITT subjects may or may not 
receive randomized treatment.    
Safety Set:  The safety set will include all treated subjects and will be used for safety and 
tolerability summaries.   
Efficacy Analysis Set:  The Efficacy analysis set will include all subjects in the Safety analysis 
set who had at least one pain intensity assessment post dosing of study drug and will be used for 
all efficacy summaries.  
3.2. 
Test Hypothesis and P Value Justification 
The null hypothesis is that there is no difference between the treatment arms.  The alternative 
hypothesis is that the treatment groups are different. 
Differences between DEX-IN, fentanyl, and placebo groups will be evaluated via a 2-sided 
2-sample t-test at the 0.05 level of significance.  Nominal p-values for secondary endpoints will 
be reported without adjustment for multiplicity.     
3.3. 
Procedures for Handling Missing Data  
Unless indicated otherwise, no missing data imputation will be performed and all data will be 
shown as collected in listings.  However, AEs with missing severity assessments will be 
tabulated as “severe,” and AEs with missing relationship assessments will be tabulated as 
“related” for the purpose of analysis. 
 
 


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3.4. 
Baseline Definitions  
Baseline:  Baseline will be the last measurements taken before the subject receives the study 
medication 
3.5. 
Derived Variables 
3.5.1. 
Average PI Score  
Average PI score at each interval (ie, pre-procedure, peri-procedure, and post-procedure) will be 
derived for each subject as a simple average of all non-missing PI scores within the interval from 
the subject.  
3.5.2. 
Average Anxiety Scores 
Average anxiety scores using the 11-point NRS scale at each interval (ie, pre-procedure, peri-
procedure, and post-procedure) will be derived for each subject as simple average of all non-
missing anxiety scores within the interval from the subject.  
3.5.3. 
Potentially Clinically Significant Changes in Vital Signs 
To identify potentially clinically significant changes (PCSC) in vital signs through the study, 
Change from baseline (CFB) and percent change from baseline (PCFB) in vital signs will be 
calculated for each post dosing vital signs as follows. 
CFB = Post Baseline – Baseline 
PCFB = 100*(CFB / Baseline) 
 


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4. 
STUDY POPULATION SUMMARIES 
4.1. 
Disposition 
A summary table (Table 14.1.1) will provide frequency counts for subject disposition 
(randomized (ITT), all treated subjects, subjects who completed the procedure day assessments, 
subjects who completed the follow up visit, subjects who discontinued from the study and reason 
for discontinuation) by treatment group and overall within the cohort based on safety set.   
Disposition in terms of the number of subjects included from each analysis set will also be 
provided by treatment group and overall within the cohort in the disposition summary. 
4.2. 
Demographics and Procedure Characteristics 
The demographic summary will include descriptive statistics for age, sex, race, ethnicity, weight, 
height, and BMI for overall and by treatment group.  
Procedure specific summaries for Cohort 1 will include: 
• Duration of the procedure (start of acid application to completion of acid removal) 
• Approximate surface area (%) treated 
• Acid concentration 
Any additional parameters that are collected for other cohorts will also be included in the 
demographics and procedure characteristics for the corresponding cohort(s).    
Demographics and baseline characteristics will be tabulated for the safety set (Table 14.1.2) by 
treatment groups and overall within a cohort.      
4.3. 
Protocol Deviations 
All protocol deviations will be identified and categorized according to the following:  
• Informed Consent Procedures 
• Inclusion / Exclusion Criteria 
• Prohibited Medications 
• Study Procedures 
• Study Drug Assignment / Treatment 
• Visit or Assessment Time Window 
• Missed Visit or Assessment 
• Other 


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At the end of the study, and prior to database lock, the medical monitor will assign deviations as 
“deviation” or important deviation”.  Protocol deviations will be addressed in the study report 
without formal tabulation. 
4.4. 
Treatment Compliance 
Doses of study medication will be administered to the study subjects under the observation of 
study personnel while confined to the study site.  The exact time of administration of study 
medication will be documented within each subject’s source record and eCRF.  No formal 
summary of treatment compliance will be produced. 
4.5. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded to the therapeutic drug classes and generic drug 
names using the World Health Organization (WHO) Drug classifications version March 1, 2017.  
No formal tabulations will be produced for concomitant medications. 


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5. 
EFFICACY ANALYSIS 
All efficacy parameters will be tabulated within each cohort by treatment groups and nominal 
time points.  All efficacy tables will be based on the efficacy set.  
5.1. 
Pain Intensity   
PI score at each nominal time point, the average PI score during each study interval (pre-, peri- 
and post-procedure) and the worst PI score at Hour 0 and 4-hours post procedure will be 
tabulated by treatment group (Table 14.2.1). Pairwise comparison between each group will be 
made via analysis of variance model that include the main effect of treatment.   
5.2. 
Anxiety Assessment 
Anxiety assessment scores using the 11-point NPRS scale at each nominal time point and the 
average anxiety score at each interval will be tabulated by treatment group (Table 14.2.2).  Pair-
wise comparisons between each group will be made via analysis of variance model that include 
the main effect of treatment. 
Anxiety assessment scores using the STAI-6 scale at each nominal time point will be tabulated 
by treatment group (Table 14.2.3). Pair-wise comparisons between each group will be made via 
analysis of variance model that include the main effect of treatment. 
5.3. 
Subject Satisfaction with Pain Experience 
Subject satisfaction scores will be summarized (Table 14.2.4) by treatment at each nominal time 
point. The summary table will include distribution [subjects (%)] in each subject satisfaction 
category (1-Completely Dissatisfied, 2-Mostly Dissatisfied, 3-Somewhat Dissatisfied, 4-Neither 
Dissatisfied nor Satisfied, 5- Somewhat Satisfied, 6- Mostly Satisfied, or 7-Completely Satisfied) 
and the average score and standard deviation without any inferential test.  
5.4. 
Subgroup Analyses for Efficacy 
Subjects from each cohort will be analyzed separately. Data across cohorts may be pooled for 
analysis if data warrants. Additional subgroups may be identified if data warrants.  No subgroup 
within a cohort is planned.   


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6. 
SAFETY AND TOLERABILITY EVALUATIONS 
6.1. 
Extent of Exposure 
This is a single dose study, therefore the maximum anticipated exposure in any subject will be 50 
μg dexmedetomidine for subjects in the DEX-IN treatment group, and 50 μg fentanyl for 
subjects in the fentanyl treatment group.  All subjects treated with a specific treatment will 
receive the same dose.  No formal summary of treatment exposure will be produced. 
6.2. 
Adverse Events 
Adverse events reported post dosing throughout the final follow-up (7 days) will be considered 
as treatment emergent adverse events (TEAEs) and summarized.  The Medical Dictionary for 
Regulatory Activities (Version 20.1) will be used to classify all AEs with respect to system 
organ class and preferred term. 
Three types of summaries will be produced for the AE summary:  
1. an overall summary of AEs: number of subjects with at least one event and number of 
events for all AEs, and SAEs (Table 14.3.1.1) 
2. a summary table of AEs(Table 14.3.1.2)  by system organ class and preferred term and 
severity  
3. a summary table of AEs (Table 14.3.1.3)  by preferred terms in descending order of total 
incidence   
AEs will be tabulated by study cohort and treatment group. AEs that lead to premature 
discontinuation from the study and all SAEs will be presented in a data listing.  
6.3. 
Clinical Laboratory Tests 
Laboratory values, will be collected at screening to assess subject eligibility, but will not be 
collected in the eCRF. No formal summary of laboratory results will be produced.  
6.4. 
Vital Sign Measurements 
Resting vital sign values and postural vital sign values at each time point collected will be 
summarized by treatment and time point without formal statistical testing (Table 14.3.2.1).   
PCSC in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) 
measurements will be defined as follows: 
• Hypotension: SBP < 90 mm Hg with a decrease ≥ 20 mm Hg from predose, or a DBP ≤ 
50 mm Hg and decrease ≥ 15 mm Hg from predose. 


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• Hypertension: SBP ≥ 180 mm Hg with an increase of ≥ 20 mm Hg from predose, or a 
DBP ≥105 and an increase ≥ 15 mm Hg from predose 
• Bradycardia: HR ≤ 50 BPM with a decrease ≥15 BPM from predose 
• Tachycardia: HR ≥ 120 BPM with an increase ≥15 BPM from predose. 
A summary table will be produced to examine number (%) subjects meeting the PCSC criteria 
(SBP abs(CFB) ≥ 20 mm Hg or DBP abs(CFB) ≥ 15 mm Hg) at various time points where 
abs=absolute value (Table 14.3.2.2). 
6.5. 
Electrocardiograms 
12-Lead ECG will be performed at screening to assess subject eligibility, but will not be 
collected in the eCRF. No formal summary of ECG results will be produced.  
6.6. 
Subgroup Analyses for Safety Endpoints 
No subgroup analysis is planned for this study.  


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7. 
REFERENCES 
None 
 


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APPENDIX 1 - TABLE OF CONTENTS OF PLANNED ANALYSIS 
 
Number 
Title 
Analysis Set 
Tables 14.1.1 
Disposition Summary 
ITT Set 
Tables 14.1.2 
Demographic and Baseline Characteristics  
Safety Set 
 
 
Efficacy Endpoints Summary 
 
Tables 14.2.1 
Summary of Pain Intensity Score by Time Point, Average 
Pain Intensity Score by Interval, and Worst Pain Intensity 
by Time Point Treatment 
Efficacy Set 
Tables 14.2.2 
Summary of Anxiety Intensity (NRS) Score by Time 
Point and Average Anxiety Score by Interval 
Efficacy Set 
Tables 14.2.3 
Summary of Anxiety Intensity (STAI-6) by Time Point  
Efficacy Set 
Tables 14.2.4 
Summary of Subject Satisfaction with Pain Experience by 
Time Point 
Efficacy Set 
 
 
Safety Endpoint Overall Summary 
 
Tables 14.3.1.1 
Topline Summary of Treatment Emergent Adverse 
Events
Safety Set 
Tables 14.3.1.2 
All TEAE by SOC, Preferred Term and Severity 
Safety Set 
Tables 14.3.1.3 
All TEAE by Preferred Term – Displayed in Descending 
Order of Total Events
Safety Set 
Table 
14.3.2.1
Values and Changes from Baseline in Vital Signs by 
Time Point
Safety Set
Table 
14.3.2.2
Incidence of PCSC in Blood Pressure by Time Point
Safety Set
 
 
 
 
 
 
 


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APPENDIX 2 - TABLE OF CONTENTS OF DATA LISTINGS 
Number  
 Listings Title 
 Analysis Set 
16.2.1
All Adverse Events from Subjects Who Had ≥1 SAE, an AE resulting in 
Death or  Subjects Who Discontinued Due to AE   
Safety Set
 


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Table 14.1.1 .....................................................................................................................................................2 
Disposition Summary ...............................................................................................................................2 
Intent-to-Treat Analysis Set......................................................................................................................2 
Table 14.1.2 .....................................................................................................................................................3 
Demographic and Baseline Characteristics ..............................................................................................3 
Safety Analysis Set ...................................................................................................................................3 
Table 14.2.1 .....................................................................................................................................................6 
Summary of Pain Intensity Score by Time Point, Average Pain Intensity Score by Interval, and Worst 
Pain Intensity by Time Point– ANCOVA Analysis ...................................................................6 
Efficacy Analysis Set ...............................................................................................................................6 
Table 14.2.2 .....................................................................................................................................................7 
Summary of Anxiety Intensity (NRS) Score by Time Point and Average Anxiety Score by Interval .....7 
Efficacy Analysis Set ...............................................................................................................................7 
Table 14.2.3 .....................................................................................................................................................7 
Summary of Anxiety Intensity Endpoints (STAI-6) by Time Point .........................................................7 
Efficacy Analysis Set ...............................................................................................................................7 
Table 14.2.4 .....................................................................................................................................................8 
Summary of Subject Satisfaction with Pain Experience by Time Point ...................................................8 
Efficacy Analysis Set ...............................................................................................................................8 
Table 14.3.1.1 ..................................................................................................................................................9 
Topline Summary of Treatment Emergent Adverse Events .....................................................................9 
Safety Analysis Set ...................................................................................................................................9 
Table 14.3.1.2 ................................................................................................................................................ 12 
All TEAE by SOC, Preferred Term and Severity ................................................................................... 12 
Safety Analysis Set ................................................................................................................................. 12 
Table 14.3.1.3 ................................................................................................................................................ 14 
All TEAE by Preferred Term – Displayed in Descending Order of Total Events .................................. 14 
Safety Analysis Set ................................................................................................................................. 14 
Table 14.3.2.1 ................................................................................................................................................ 15 
Values and Change from Baseline in Vital Signs by Time Point ........................................................... 15 
Safety Analysis Set ................................................................................................................................. 15 
Table 14.3.2.2 ................................................................................................................................................ 16 
Incidence of PCSC in Blood Pressure by Time Point ............................................................................ 16 
Safety Analysis Set ................................................................................................................................. 16 
 
 


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Table 14.1.1 
Disposition Summary 
Intent-to-Treat Analysis Set 
 
Placebo 
Fentanyl 
IV 
DEX-IN  
Total 
 
n (%) 
n (%) 
n (%) 
n (%) 
Subjects randomized (ITT) 
XXX 
XXX 
XXX 
XXX 
Subjects treated with study drug (Safety) 
XX (X.X) 
XX (X.X) 
XX (X.X) 
XX (X.X) 
Subjects completed Procedure Day Assessments 
XX (X.X) 
XX (X.X) 
XX (X.X) 
XX (X.X) 
Subjects completed 7 day Follow Up  
XX (X.X) 
XX (X.X) 
XX (X.X) 
XX (X.X) 
 
 
 
 
 
 
 
 
 
 
Efficacy Analysis Set 
XX (X.X) 
XX (X.X) 
XX (X.X) 
XX (X.X) 
 
 
 
 
 
Subjects discontinued from study 
 
 
 
 
Reason for discontinuation from study 
 
 
 
 
 
Adverse Event 
XX (X.X) 
XX (X.X) 
XX (X.X) 
XX (X.X) 
 
Death 
XX (X.X) 
XX (X.X) 
XX (X.X) 
XX (X.X) 
 
Withdrawal of Consent by Subject 
XX (X.X) 
XX (X.X) 
XX (X.X) 
XX (X.X) 
 
Investigator Decision 
XX (X.X) 
XX (X.X) 
XX (X.X) 
XX (X.X) 
 
Protocol Deviation 
XX (X.X) 
XX (X.X) 
XX (X.X) 
XX (X.X) 
 
Lost to follow up 
XX (X.X) 
XX (X.X) 
XX (X.X) 
XX (X.X) 
 
Other 
XX (X.X) 
XX (X.X) 
XX (X.X) 
XX (X.X) 
 
 
 
 
 
 
[1] Percentages are based on the number of randomized subjects in each group. 
All subjects were grouped based on their randomized treatment group.   
 
 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 3 of 16 
 
Table 14.1.2 
Demographic and Baseline Characteristics 
Safety Analysis Set 
 
Category or  
Statistics 
 Placebo 
(N=XX) 
Fentanyl 
IV 
(N=XX) 
DEX-IN 
(N=XX) 
Total 
(N=XX) 
Age (years) 
n 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
X.X 
X.X 
X.X 
X.X 
 
Minimum 
XX 
XX 
XX 
XX 
 
Median 
XX 
XX 
XX 
XX 
 
Maximum 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
Sex: n (%) 
Male 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Female 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
Race: n (%) 
White 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Black or African American 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Asian 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
American Indian or Alaskan Native 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Native Hawaiian/Other Pacific Islander 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Other 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
Ethnicity: n (%) 
Hispanic 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
Non-Hispanic 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 4 of 16 
 
Table 14.1.2(continued) 
 
Category Or 
Statistics 
 Placebo 
(N=XX) 
Fentanyl IV 
(N=XX) 
DEX-IN 
(N=XX) 
Total 
(N=XX) 
Baseline Height (cm) 
n 
XX 
XX 
XX 
XX 
 
Mean 
X.X 
X.X 
X.X 
X.X 
 
SD 
X.XX 
X.XX 
X.XX 
X.XX 
 
Minimum 
XX 
XX 
XX 
XX 
 
Median 
XX 
XX 
XX 
XX 
 
Maximum 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
Baseline Weight (kg) 
n 
XX 
XX 
XX 
XX 
 
Mean 
X.X 
X.X 
X.X 
X.X 
 
SD 
X.XX 
X.XX 
X.XX 
X.XX 
 
Minimum 
XX 
XX 
XX 
XX 
 
Median 
XX 
XX 
XX 
XX 
 
Maximum 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
Baseline BMI (kg/m^2) 
n 
XX 
XX 
XX 
XX 
 
Mean 
X.X 
X.X 
X.X 
X.X 
 
SD 
X.XX 
X.XX 
X.XX 
X.XX 
 
Minimum 
XX 
XX 
XX 
XX 
 
Median 
XX 
XX 
XX 
XX 
 
Maximum 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
 
 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 5 of 16 
 
Table 14.1.2 (continued) 
 
Category Or 
Statistics 
 Placebo 
(N=XX) 
Fentanyl IV 
(N=XX) 
DEX-IN 
(N=XX) 
Total 
(N=XX) 
Procedure Duration (hr) 
n 
XX 
XX 
XX 
XX 
 
Mean 
X.X 
X.X 
X.X 
X.X 
 
SD 
X.XX 
X.XX 
X.XX 
X.XX 
 
Minimum 
XX 
XX 
XX 
XX 
 
Median 
XX 
XX 
XX 
XX 
 
Maximum 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
Approximate Surface Area (%) 
treated 
n 
XX 
XX 
XX 
XX 
 
Mean 
X.X 
X.X 
X.X 
X.X 
 
SD 
X.XX 
X.XX 
X.XX 
X.XX 
 
Minimum 
XX 
XX 
XX 
XX 
 
Median 
XX 
XX 
XX 
XX 
 
Maximum 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
Acid Concentration 
n 
XX 
XX 
XX 
XX 
 
Mean 
X.X 
X.X 
X.X 
X.X 
 
SD 
X.XX 
X.XX 
X.XX 
X.XX 
 
Minimum 
XX 
XX 
XX 
XX 
 
Median 
XX 
XX 
XX 
XX 
 
Maximum 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
Note to programmer:  
1) Create a Missing category only if there are missing data; percentages are calculated per non-missing 
data in each group. 
 
 
 
 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 6 of 16 
 
 
Table 14.2.1 
Summary of Pain Intensity Score by Time Point, Average Pain Intensity Score by Interval, and Worst Pain 
Intensity by Time Point 
Efficacy Analysis Set 
 
Parameter 
Time Point 
Statistics  
Placebo 
 (N=XX) 
Fentanyl IV 
(N=XX) 
DEX-IN 
 (N=XX) 
Pain 
Intensity 
60 min Pre 
n 
XX 
XX 
XX 
 
 
Mean 
XX.X 
XX.X 
XX.X 
 
 
SD 
X.XX 
X.XX 
X.XX 
 
 
Minimum 
XX.X 
XX.X 
XX.X 
 
 
Median 
XX.X 
XX.X 
XX.X 
 
 
Maximum 
XX.X 
XX.X 
XX.X 
 
 
P Value Active vs Placebo 
 
0.xxxx 
0.xxxx 
 
 
P Value DEX-IN vs Fentanyl 
 
 
0.xxxx 
 
 
 
 
 
 
 
15 min Pre 
n 
XX 
XX 
XX 
 
 
Mean 
XX.X 
XX.X 
XX.X 
 
 
SD 
X.XX 
X.XX 
X.XX 
 
 
Minimum 
XX.X 
XX.X 
XX.X 
 
 
Median 
XX.X 
XX.X 
XX.X 
 
 
Maximum 
XX.X 
XX.X 
XX.X 
 
 
P Value Active vs Placebo 
 
0.xxxx 
0.xxxx 
 
 
P Value DEX-IN vs Fentanyl 
 
 
0.xxxx 
 
 
 
 
 
 
 
2 min Post 
 
 
 
 
 
Etc for 
all time 
points 
 
 
 
 
 
 
 
 
 
 
Average Pain 
Intensity 
Pre-
Procedure 
n 
XX 
XX 
XX 
 
 
Mean 
XX.X 
XX.X 
XX.X 
 
 
SD 
X.XX 
X.XX 
X.XX 
 
 
Minimum 
XX.X 
XX.X 
XX.X 
 
 
Median 
XX.X 
XX.X 
XX.X 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 7 of 16 
 
[1] Difference = DEX-IN – Placebo or DEX-IN - Fentanyl; ANCOVA analysis with Treatment as a main effect.  
Table 14.2.2  
Summary of Anxiety Intensity (NRS) Score by Time Point and Average Anxiety Score by Interval  
Efficacy Analysis Set 
See Mock Table 14.2.1 – include Anxiety NRS at each time point and Average Anxiety at study interval parameters 
Table 14.2.3  
Summary of Anxiety Intensity Endpoints (STAI-6) by Time Point  
Efficacy Analysis Set 
See Mock Table 14.2.1 – include Anxiety NRS at each time point and Average Anxiety (STAI-6) at study time points 
 
 
 
Maximum 
XX.X 
XX.X 
XX.X 
 
 
P Value Active vs Placebo 
 
0.xxxx 
0.xxxx 
 
 
P Value DEX-IN vs Fentanyl 
 
 
0.xxxx 
 
Etc 
 
 
 
 
 
 
 
 
 
 
Worst Pain 
Hour 0 
Etc. 
 
 
 
 
 
 
 
 
 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 8 of 16 
 
  
Table 14.2.4  
Summary of Subject Satisfaction with Pain Experience by Time Point 
Efficacy Analysis Set 
 
Time Point 
 
Category/Statistics [1] 
Placebo 
 (N=XX) 
Fentanyl IV 
(N=XX) 
DEX-IN 
 (N=XX) 
Hour 0 
1-Completely dissatisfied  
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
2-Mostly Dissatisfied 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
3-Somewhat Dissatisfied 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
4-Neither Dissatisfied nor 
Satisfied 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
5- Somewhat Satisfied 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
6- Mostly Satisfied 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
7-Completely Satisfied 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
Average (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
 
 
 
 
 
Hour 4 
1-Completely dissatisfied  
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
2-Mostly Dissatisfied 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
3-Somewhat Dissatisfied 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
4-Neither Dissatisfied nor 
Satisfied 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
5- Somewhat Satisfied 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
6- Mostly Satisfied 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
7-Completely Satisfied 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
Average (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
XX.X (XX.XX) 
 
 
 
 
 
 
 
 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 9 of 16 
 
Table 14.3.1.1 
Topline Summary of Treatment Emergent Adverse Events 
Safety Analysis Set 
Category  
[1, 2] 
Category 
/Statistics 
Placebo 
 (N=XX) 
Fentanyl IV 
(N=XX) 
DEX-IN 
 (N=XX) 
Total 
 (N=XX) 
 
 
n (%) 
Events 
n (%) 
Events 
n (%) 
Events 
n (%) 
Events 
Reported >=1 
TEAE 
 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
 
 
 
 
 
 
 
 
 
TEAE by 
Severity 
Mild 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Moderate 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Severe 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
 
 
 
 
 
 
 
 
 
TEAE by 
Seriousness 
Serious 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Not Serious 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
 
 
 
 
 
 
 
 
 
TEAE by 
Relationship 
Not Related 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Possibly Related 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Probably Related 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Definitely 
Related 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
 
 
 
 
 
 
 
 
 
TEAE by 
Outcome 
Resolved 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Resolved with 
Sequelae 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Not Resolved 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Unknown 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Death 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 10 of 16 
 
‘n’ = subjects in a category; percentage was calculated from total subjects in a group. ‘Events’ = Total 
number of events in a category. 
[1] A subject could be counted in more than one category but only once per category for summary of 
‘Subjects’, Hence, sum of subjects across all categories could be greater than the total number of subjects 
in the study.   
[2] All events in each category were included in the ‘Total Events’.  
 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 11 of 16 
 
 (Table 14.3.1.1 continued) 
Category [1, 2] 
Category 
/Statistics 
Placebo 
 (N=XX) 
Fentanyl IV 
(N=XX) 
DEX-IN 
 (N=XX) 
Total 
 (N=XX) 
 
 
n (%) 
Events 
n (%) 
Events n (%) Events 
n (%) 
Events 
 
 
 
 
 
 
 
 
 
 
Total Number of TEAEs 
by subject 
n 
 
XX 
 
XX 
 
XX 
 
XX 
 
Mean 
 
XX.X 
 
XX.X 
 
XX.X 
 
XX.X 
 
SD 
 
X.XX 
 
X.XX 
 
X.XX 
 
X.XX 
 
Minimum 
 
X 
 
X 
 
X 
 
X 
 
Median 
 
X 
 
X 
 
X 
 
X 
 
Maximum 
 
X 
 
X 
 
X 
 
X 
[1] A subject could be counted more than one category but only once per category for summary of ‘Subjects’, 
Hence, sum of subjects across all categories could be greater than the total number of subjects in the 
study.   
[2] All events in each category were included in the ‘Events’.  
 
 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 12 of 16 
 
Table 14.3.1.2 
All TEAE by SOC, Preferred Term and Severity 
Safety Analysis Set 
SOC 
  Preferred Term 
(MedDRA 19.1) 
Intensity 
[1] 
Placebo 
 (N=XX) 
Fentanyl IV 
(N=XX) 
DEX-IN 
 (N=XX) 
Total 
 (N=XX) 
 
 
n (%) 
Events 
n (%) 
Events 
n (%) 
Events 
n (%) 
Events 
Subjects with >=1 
Event  
All 
XX (X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Mild 
XX (X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Moderate 
XX (X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
Severe 
XX (X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
 
 
 
 
 
 
 
 
 
SOC 1 
All 
XX (X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
 
Mild 
XX (X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
 
Moderate 
XX (X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
 
Severe 
XX (X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
 
 
 
 
 
 
 
 
 
 
  Preferred Term 1 
All 
XX (X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
 
Mild 
XX (X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
 
Moderate 
XX (X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
 
Severe 
XX (X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
XX 
(X.X) 
 
  Preferred Term 2 
(repeat 
above) 
 
 
 
 
 
 
 
 
  Preferred Term 3 
(repeat 
above) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC 2 
All 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 13 of 16 
 
SOC 
  Preferred Term 
(MedDRA 19.1) 
Intensity 
[1] 
Placebo 
 (N=XX) 
Fentanyl IV 
(N=XX) 
DEX-IN 
 (N=XX) 
Total 
 (N=XX) 
 
Moderate 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Preferred Term 1 
(repeat 
above) 
 
 
 
 
 
 
 
 
 
(repeat 
above) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 [1] ‘n’ = Number of subjects reported >=1 event of the preferred term;   A subject was counted only once, 
in the most severe category, if the subject had the multiple events in different intensity category; the 
subject was counted once in the  ‘All’ summary.      
 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 14 of 16 
 
 
Table 14.3.1.3 
All TEAE by Preferred Term – Displayed in Descending Order of Total Events 
Safety Analysis Set 
Preferred Term  
(MedDRA 19.1) 
Total  
Events 
[1] 
Placebo 
 (N=XX) 
Fentanyl IV 
(N=XX) 
DEX-IN 
 (N=XX) 
Total 
 (N=XX) 
 
 
n (%) 
Events 
n (%) 
Events 
n (%) 
Events 
n (%) 
Events 
Subjects with >=1 
Event  
XXXX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
 
 
 
 
 
 
 
 
 
Preferred Term 1 
120 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
Preferred Term 2 
109 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
Preferred Term 3 
95 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
Preferred Term 4 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
Preferred Term 5 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
Preferred Term 6 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
Preferred Term 7 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
Preferred Term 8 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
Preferred Term 9 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
Preferred Term 10 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
Preferred Term 11 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
XX 
(X.X) 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] ‘n’ = Number of subjects reported >=1 event of the preferred term;  ‘Total Events’ = total number of 
events across all treatment groups. A subject was counted only once per preferred term but all events were 
included in the ‘Events’.      
 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 15 of 16 
 
Table 14.3.2.1  
Values and Change from Baseline in Vital Signs by Time Point  
Safety Analysis Set 
 
 
[1]CFB = Change from Baseline: Post Baseline – Baseline Result. CFB (%) = Post Baseline – Baseline / 
Baseline *100. 
   
 
 
Time 
Point 
Statistics 
Placebo 
 (N=XX) 
Fentanyl IV 
(N=XX) 
DEX-IN 
 (N=XX) 
Total 
 (N=XX) 
 
 
Value 
CFB 
CFB 
(%) 
Value 
CFB 
CFB 
(%) 
Value 
CFB 
CFB 
(%) 
Value 
CFB 
CFB 
(%) 
Pre-Dose 
n 
XX 
 
 
XX 
 
 
XX 
 
 
XX 
 
 
1 Hour 
Mean 
XX.X 
 
 
XX.X 
 
 
XX.X 
 
 
XX.X 
 
 
 
SD 
X.XX 
 
 
X.XX 
 
 
X.XX 
 
 
X.XX 
 
 
 
Minimum 
XX.X 
 
 
XX.X 
 
 
XX.X 
 
 
XX.X 
 
 
 
Median 
XX.X 
 
 
XX.X 
 
 
XX.X 
 
 
XX.X 
 
 
 
Maximum 
XX.X 
 
 
XX.X 
 
 
XX.X 
 
 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Dose 
n 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
15 Min 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
Minimum 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Maximum 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Repeat 
for  
 
 
 
 
 
 
 
 
 
 
 
 
 
All 
remaining 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time 
points 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Recro Pharma, Inc. 
 
Page X of Y 
Protocol REC-17-023 
 
 
Clinical Study Report 
 
 
 
Page 16 of 16 
 
Table 14.3.2.2  
Incidence of PCSC in Blood Pressure by Time Point 
Safety Analysis Set 
 
Time Point 
 
Category/Statistics [1] 
Placebo 
 (N=XX) 
Fentanyl IV 
(N=XX) 
DEX-IN 
 (N=XX) 
Total 
 (N=XX) 
Pre-Dose 
Hypotension 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
1 Hour 
Hypertension 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
Bradycardia 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
Tachycardia 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
 
 
 
 
 
 
Hypertension 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
Pre-Dose 
Bradycardia 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
15 Min 
Tachycardia 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
Hypotension 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
XX (X.X%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Repeat for  
 
 
 
 
 
All 
remaining 
 
 
 
 
 
Time points 
 
 
 
 
 
Note: Hypotension: SBP < 90 mm Hg with a decrease ≥ 20 mm Hg from predose, or a DBP ≤ 50 mm Hg and decrease 
≥ 15 mm Hg from predose. Hypertension: SBP ≥ 180 mm Hg with an increase of ≥ 20 mm Hg from predose, or a 
DBP ≥105 and an increase ≥ 15 mm Hg from predose, Bradycardia: HR ≤ 50 BPM with a decrease ≥15 BPM from 
predose, Tachycardia: HR ≥ 120 BPM with an increase ≥15 BPM from predose.