A Randomized, Double-Blind, Placebo- and Active-Controlled Study to Determine the Efficacy and Safety of CL-108 5 mg (Hydrocodone 5 mg/Acetaminophen 325 mg/Promethazine 12.5 mg) as a Treatment for Moderate-to-Severe Acute Pain and the Prevention of Opioid-Induced Nausea and Vomiting (OINV) Following Orthopedic Surgery
Phase: PHASE3
Conditions: Pain, Nausea, Vomiting
Sponsor: Charleston Laboratories, Inc

 
 
 
 
    
 
 
 
 
 
 
Official Title:  A Randomized, Double-Blind, Placebo- and Active-Controlled Study to Determine the 
Efficacy and Safety of CL-108 5 mg (hydrocodone 5 mg/acetaminophen 325 mg/ promethazine 12.5 mg) as 
a Treatment for Moderate-to-Severe Acute Pain and the Prevention of Opioid-Induced Nausea and Vomiting 
(OINV) following Orthopedic Surgery 
 
NCT Number: NCT03657810 
 
Applicant/MAH: Charleston Laboratories Inc. 
 
Version Date: 17 August 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 

16. 
APPENDICES 
 
16.1 
Study Information 
 
16.1.1 
Protocol and Protocol Amendments 
Protocol Amendment 02 Version 3.0 dated 17 August 2017 
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Protocol Number: CLCT-018
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TABLE OF CONTENTS 
1 
SYNOPSIS ................................................................................................................................................................... 6 
1.1 
TITLE ...................................................................................................................................................................... 6 
1.2 
OBJECTIVES ............................................................................................................................................................ 6 
1.3 
STUDY DESIGN ........................................................................................................................................................ 6 
1.4 
ENDPOINTS ............................................................................................................................................................. 9 
1.4.1 
Co-Primary Endpoints ............................................................................................................................. 9 
1.4.2 
Key Secondary Endpoints ........................................................................................................................ 9 
1.5 
SETTING AND PATIENTS .......................................................................................................................................... 9 
1.6 
STUDY TREATMENTS ............................................................................................................................................ 10 
1.7 
SAMPLE SIZE ......................................................................................................................................................... 10 
1.8 
STUDY FLOW CHART ...................................................................................................................................... 11 
2 
BACKGROUND AND RATIONALE FOR THE STUDY .................................................................................... 12 
3 
OBJECTIVES OF THE STUDY ............................................................................................................................. 13 
4 
TRIAL DESIGN ........................................................................................................................................................ 13 
4.1 
VISIT 1 .................................................................................................................................................................. 13 
4.2 
VISIT 2 .................................................................................................................................................................. 14 
4.3 
OUTPATIENT PHASE (DAYS 3-7) ........................................................................................................................... 17 
4.4 
VISIT 3 .................................................................................................................................................................. 17 
5 
PATIENT SELECTION AND WITHDRAWAL ................................................................................................... 18 
5.1 
INCLUSION CRITERIA ............................................................................................................................................ 18 
5.2 
EXCLUSION CRITERIA ........................................................................................................................................... 19 
5.3 
USE IN FEMALES ................................................................................................................................................... 21 
5.4 
PREGNANCY OCCURRING DURING A CLINICAL TRIAL .......................................................................................... 21 
5.5 
USE OF SUPPLEMENTAL (RESCUE) MEDICATION .................................................................................................. 21 
5.6 
WITHDRAWAL ....................................................................................................................................................... 22 
5.6.1 
Investigator’s Reasons for Patient Withdrawal ...................................................................................... 23 
5.6.2 
Handling of Withdrawals ....................................................................................................................... 24 
6 
STUDY PROCEDURES ........................................................................................................................................... 24 
6.1 
EVALUATIONS OF SAFETY AND ELIGIBILITY ......................................................................................................... 24 
6.2 
EVALUATIONS OF EFFICACY AND SAFETY (SEE APPENDICES FOR SAMPLE INDICES) ............................................ 25 
6.2.1 
Categorical Pain Intensity Scale (PI-CAT) ............................................................................................ 25 
6.2.2 
Numerical Pain Intensity Rating Scale (PI-NRS) .................................................................................. 26 
6.2.3 
Nausea Scale (NS) ................................................................................................................................. 26 
6.2.4 
Vomiting Frequency Scale (VFS) .......................................................................................................... 26 
6.2.5 
Opioid Symptom Scales (OSS) (from the Symptom Distress Scale)4 ................................................... 26 
6.2.6 
Uses of Supplemental (Rescue) Analgesic Medication ......................................................................... 27 
6.2.7 
Uses of Anti-emetic (Rescue) Medication ............................................................................................. 27 
6.2.8 
Patient Reports of Adverse Events (Elicited and Volunteered) ............................................................. 27 
6.3 
STUDY CONDUCT .................................................................................................................................................. 27 
6.3.1 
Pre-Screening Procedures ...................................................................................................................... 27 
6.3.2 
Screening Procedures (Visit 1) .............................................................................................................. 28 
6.3.3 
Surgery Day (Visit 2) ............................................................................................................................. 30 
6.3.4 
Post-Surgical Eligibility Assessments and Dosing ................................................................................ 32 
6.3.5 
Study Times Initial 12 Hours Post-Initial Dose ..................................................................................... 34 
6.3.6 
Study Times: 12 Hours Post-Initial Dose through 48 Hours .................................................................. 35 
6.3.7 
Study Time: Additional Assessments at 24 hours (±15 Minutes) .......................................................... 35 
6.3.8 
Study Time: 48 hours (±15 Minutes) ..................................................................................................... 36 
6.3.9 
Outpatient Activities:  Day 3 through Day 7 ......................................................................................... 37 
6.3.10 
Follow-Up Telephone Call:  approximately 24 hours after discharge (+2 days, to account for 
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weekends) ............................................................................................................................................................. 37 
6.3.11 
Follow-Up Visit 3 on Day 8 (± 2 days).................................................................................................. 38 
6.4 
CONCOMITANT THERAPY ...................................................................................................................................... 38 
6.5 
ASSIGNMENT OF NUMBERS ................................................................................................................................... 38 
6.6 
TREATMENT .......................................................................................................................................................... 39 
6.7 
CLINICAL ADVERSE EVENTS ................................................................................................................................. 39 
6.8 
RISKS/PRECAUTIONS ............................................................................................................................................. 39 
6.9 
OVERDOSAGE ....................................................................................................................................................... 39 
7 
DATA COLLECTION AND ANALYSIS ............................................................................................................... 40 
7.1 
RECORDING OF DATA ........................................................................................................................................... 40 
7.2 
CONTROL METHODS ............................................................................................................................................. 40 
7.3 
SAFETY ASSESSMENTS .......................................................................................................................................... 40 
7.4 
STATISTICAL ANALYSIS ........................................................................................................................................ 41 
7.4.1 
Primary Hypotheses ............................................................................................................................... 41 
7.4.2 
Sample Size Justification ....................................................................................................................... 42 
7.4.3 
Key Secondary Endpoints ...................................................................................................................... 42 
7.4.4 
Labeling Endpoints ................................................................................................................................ 43 
7.4.5 
Study Populations .................................................................................................................................. 44 
7.4.6 
Predefined Subgroups ............................................................................................................................ 44 
7.4.7 
Missing Data Conventions ..................................................................................................................... 44 
7.4.8 
Use of Supplemental Medication ........................................................................................................... 44 
7.4.9 
Statistical Analysis ................................................................................................................................. 45 
7.4.10 
Descriptive Statistics:............................................................................................................................. 45 
7.4.11 
Analysis of the OINV Co-Primary Endpoint: ........................................................................................ 45 
7.4.12 
Analysis of Analgesia Co-Primary Endpoint: ........................................................................................ 45 
7.4.13 
Sensitivity Analysis of Primary Endpoints ............................................................................................ 45 
7.4.14 
Analyses of Key Secondary Endpoints: ................................................................................................. 46 
7.4.15 
Statistical Significance: .......................................................................................................................... 46 
7.4.16 
Safety ..................................................................................................................................................... 46 
7.4.17 
Interim Analyses .................................................................................................................................... 46 
7.4.18 
Protocol Deviations ................................................................................................................................ 47 
8 
CLINICAL SUPPLIES ............................................................................................................................................. 47 
8.1 
PACKAGING .......................................................................................................................................................... 47 
8.2 
LABEL ................................................................................................................................................................... 47 
9 
INVESTIGATOR OBLIGATIONS ......................................................................................................................... 48 
9.1 
ADVERSE EVENT REPORTING OBLIGATIONS ......................................................................................................... 48 
9.1.1 
Definition of an Adverse Event ............................................................................................................. 48 
9.1.2 
Definition of a Serious Adverse Event (SAE) ....................................................................................... 49 
9.1.3 
Recording and Documenting Adverse Events ....................................................................................... 50 
9.1.4 
Intensity of Adverse Events ................................................................................................................... 50 
9.1.5 
Relationship to Study Medication .......................................................................................................... 51 
9.1.6 
Therapeutic Failure as an Adverse Event ............................................................................................... 51 
9.1.7 
Treatment Period .................................................................................................................................... 52 
9.1.8 
Investigator Report of a Serious Adverse Event .................................................................................... 52 
9.1.9 
Other Investigations ............................................................................................................................... 53 
9.1.10 
Ethics Committee Notification............................................................................................................... 53 
9.1.11 
Post-study Serious Adverse Events ........................................................................................................ 53 
9.1.12 
Regulatory Aspects ................................................................................................................................ 53 
9.2 
DRUG ACCOUNTABILITY....................................................................................................................................... 53 
9.2.1 
Storage of Investigational Drug ............................................................................................................. 53 
9.2.2 
Receipt of Drug Shipment ..................................................................................................................... 53 
9.2.3 
Materials Control ................................................................................................................................... 54 
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9.2.4 
Return of Drug to Sponsor ..................................................................................................................... 54 
9.3 
DEVIATIONS FROM PROTOCOL .............................................................................................................................. 54 
9.4 
DISCLOSURE OF DATA .......................................................................................................................................... 54 
9.4.1 
Confidentiality ....................................................................................................................................... 54 
9.4.2 
Publication ............................................................................................................................................. 55 
9.5 
STUDY RECORDS AND SOURCE DOCUMENTS ........................................................................................................ 55 
9.6 
INVESTIGATOR DOCUMENTATION ......................................................................................................................... 56 
9.6.1 
Patient Consent ...................................................................................................................................... 56 
9.6.2 
Ethics Committee Review ...................................................................................................................... 56 
9.6.3 
Curriculum Vitae and FDA Form 1572 ................................................................................................. 57 
9.6.4 
Financial Disclosure............................................................................................................................... 57 
9.6.5 
Tax ID No. and Form W-9 ..................................................................................................................... 57 
9.6.6 
Laboratory Certification and Normal Values ......................................................................................... 57 
9.6.7 
Final Report to the IRB .......................................................................................................................... 57 
10 TERMINATION OF STUDY .................................................................................................................................. 57 
11 INVESTIGATOR'S PROTOCOL AGREEMENT ................................................................................................ 57 
12 REFERENCES .......................................................................................................................................................... 58 
13 APPENDICES ........................................................................................................................................................... 59 
13.1 
APPENDIX 1. ANALGESIC RATING SCALES ....................................................................................................... 59 
13.2 
APPENDIX 2: NAUSEA/VOMITING RATING SCALES .......................................................................................... 60 
13.3 
APPENDIX 3: OPIOID SYMPTOMS SCALES (OSS) .............................................................................................. 61 
13.4 
APPENDIX 4.  NAUSEA PRONE QUESTIONNAIRE (CALLED “HEALTH QUESTIONNAIRE” IN THE CRF) ............... 62 
14 INVESTIGATOR'S PROTOCOL AGREEMENT ................................................................................................ 69 
15 PROTOCOL AMENDMENT 1: TABLE OF CHANGES .................................................................................... 70 
16 PROTOCOL AMENDMENT 2: TABLE OF CHANGES .................................................................................... 83 
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List of Abbreviations 
 
˚F 
degrees Fahrenheit 
APAP 
acetaminophen 
BOCF 
baseline observation carried forward 
CL 
Charleston Laboratories, Inc. 
CL-108 
hydrocodone 7.5 mg/APAP 325 mg/promethazine 12.5 mg 
CL-108 5 mg 
hydrocodone 5 mg/APAP 325 mg/promethazine 12.5 mg 
CRO 
Contract Research Organization 
eCRF 
Electronic CRF 
ESAS 
Edmonton Symptom Assessment Scales 
DMC 
Data Monitoring Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HC/APAP 
hydrocodone 5 mg/APAP 325 mg 
HCG 
human chorionic gonadotropin  
hr 
hour 
ICF 
informed consent form 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mo 
month 
Norco® 
hydrocodone 5 mg/APAP 325 mg 
NS 
Nausea Scale 
NNT 
Number-needed to treat 
NPQ 
Nausea-Prone Questionnaire 
OINV 
opioid-induced nausea and vomiting 
OSS 
Opioid Symptoms Scales 
PI-CAT 
categorical pain intensity rating scale 
PI-NRS 
numerical pain intensity rating scale 
PID 
pain intensity difference 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SPID24 
summed pain intensity differences over 24 hours 
SPID48 
summed pain intensity differences over 48 hours 
SDS 
Symptoms Distress Scale 
US 
United States 
VFS 
Vomiting Frequency Scale 
WHO-DD 
World Health Organization-Drug Dictionary 
WOCF 
Worst observation carried forward 
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Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
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1 
SYNOPSIS 
1.1 
Title  
A Randomized, Double-Blind, Placebo- and Active-Controlled Study to Determine the Efficacy and 
Safety of CL-108 5 mg (hydrocodone 5 mg/acetaminophen 325 mg/ promethazine 12.5 mg) as a 
Treatment for Moderate-to-Severe Acute Pain and the Prevention of Opioid-Induced Nausea and 
Vomiting (OINV) following Orthopedic Surgery. 
1.2 
Objectives 
To determine the analgesic efficacy of CL-108 5 mg by comparison with placebo and the anti-emetic 
efficacy of CL-108 5 mg by comparison with hydrocodone 5 mg/acetaminophen 325 mg 
(HC/APAP).  
1.3 
Study design 
This is a phase 3, randomized, double-blind, multiple-dose, multi-site controlled study of CL-108  5 
mg (hydrocodone 5 mg/APAP 325 mg/promethazine 12.5 mg) compared to placebo and to a 
standard formulation of hydrocodone 5 mg/APAP 325 mg (Norco®) in patients with moderate-to-
severe pain following unilateral first metatarsal bunionectomy (with osteotomy and internal fixation) 
without collateral procedures.    
Adults 18 years at time of consent of age and older who have a bunion on the foot which they want 
removed and who are possibly at risk for OINV will have a Screening Visit (Visit 1) when a foot x-
ray will be obtained (if not in possession of a foot x-ray within the past 6 months) and reviewed by 
the surgeon (between Visit 1 and Visit 2 prior to surgery). Admission criteria will be reviewed, a 
screening physical examination will be performed, urine will be collected (for drug screening and 
cotinine on all patients) and pregnancy testing (for all female patients regardless of childbearing 
potential). 
The medical history will be obtained, including a Nausea-Prone Questionnaire (NPQ). This 
instrument was developed for previous Phase 3 studies to increase assay sensitivity by enriching the 
study sample with patients who, by history, are assumed to be at risk of developing OINV according 
to accepted criteria (e.g., by a history of previous OINV, nausea/vomiting after a surgical procedure 
or operation, exposure to an opioid, or motion sickness).1-3,6-8  patients whom the Investigators 
consider possibly at risk of OINV according to their responses on the NPQ will be scheduled for 
surgery within 3 months. 
Urine pregnancy tests will be performed on all female patients and urine drug screening tests and 
urine cotinine test will be performed on all patients prior to surgery at Visit 2. After sedation 
(midazolam and/or propofol) is achieved, regional anesthesia will be established with a popliteal 
sciatic nerve block (PSB), after which patients will undergo primary, unilateral, first metatarsal 
bunionectomy surgery (osteotomy and internal fixation) without collateral procedures. Surgery will 
be performed under regional anesthesia and propofol sedation. If the PSB is not sufficient to provide 
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CONFIDENTIAL 
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adequate anesthesia, a standard Mayo block may be established. Prophylactic or post-operative anti-
emetic or analgesic medications other than protocol-defined medications will not be permitted (see 
Section 5.2). 
After surgery the regional anesthesia will be continued via a continuous anesthetic infusion until 
approximately 3 am of the morning after surgery (see Section 6.3.3). Supplementary analgesic 
medication (IV or IM ketorolac) may be administered as needed for breakthrough pain. Patients will 
be observed in the research center for up to 9 hours after the PSB is discontinued to observe if they 
report the presence of moderate or severe pain by a rating of 2 or 3 on a 0-3 categorical pain intensity 
scale (PI-CAT).  
Baseline pain intensity must be confirmed by a rating ≥4 on a 0-10 numerical rating scale (PI-NRS) 
in order to be eligible for randomization. 
Temperature (aural), pulse, respiratory rate, systolic and diastolic blood pressure (semi-recumbent 
for 5 minutes) will be obtained at Baseline.   
To determine if nausea and vomiting or other symptoms associated with opioids (e.g., drowsiness, 
dizziness, ability to concentrate, itch, constipation) are present before exposure to study medication, 
patients will then complete these measures of patient-reported outcomes: 
• 
Nausea Scale (NS), a binary scale to assess the presence/absence of nausea 
• 
Vomiting Frequency Scale (VFS), a 0-to-3 ordinal scale to assess the occurrence of vomiting 
over the past hour (not at all, 1 time, 2 times, 3 or more times) 
• 
Opioid Symptoms Scales (OSS), derived from the Symptom Distress Scales,4 to assess the 
presence and severity of other opioid-related side effects (e.g., drowsiness, dizziness, ability to 
concentrate, itch, constipation) 
Qualifying patients (n=330) will be assigned a randomization number and randomized under 
double-blind conditions to one of the three treatment groups:  CL-108 5 mg, hydrocodone 5 
mg/APAP 325 mg (HC/APAP), or placebo.  All randomized patients will remain at the research 
site for the primary initial 48-hour treatment observation period when the same assigned study 
medication will be administered on schedule for a total of 10 doses.  Subjects should be awoken 
for dosing, as needed to remain on the dosing schedule. 
In the Clinic Diary, after baseline assessments, pain intensity (on the PI-NRS) and nausea (on the 
NS) will be assessed every 30 minutes over the next 12 hours (while awake). 
Beginning at 1 hour through 12 hours after the first dose, the VFS will be completed hourly to assess 
the occurrence and frequency of retching and/or vomiting. 
After 12 hours, the patient will complete the PI-NRS, NS and VFS every hour (if awake) until 48 
hours. 
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To provide evaluations of other opioid-related side effects after multiple doses of study medication 
over the first and second day of therapy, patients will repeat the OSS at 24 hours and 48 hours. 
In addition to these actively solicited assessments of nausea, vomiting and other opioid side effects, 
the Study Coordinator will also observe the patient’s status on an hourly basis throughout the entire 
initial 48-hour treatment observation period in the clinic.   At these hourly intervals during the day 
and at night (if the patient is awake) patients will also be asked how they are feeling and to report 
any other adverse events.  The Investigator will rate the severity of all side effects on a 3-category 
severity scale (mild, moderate, severe) and determine relationship of the adverse event to study 
drug.  These data will be documented on the AE page of the eCRF.  Subjects should be awoken for 
dosing, as needed to remain on the dosing schedule. 
 
Temperature (aural), pulse, respiratory rate, systolic and diastolic blood pressure (semi-recumbent 
for 5 minutes) will be obtained every 6 hours (if awake) until 24 hours post-dosing and at 48 hours.  
Patients may take supplementary (rescue) analgesic medication, ibuprofen 400 mg, as needed at any 
time according to label directions (every 4-6 hours, up to 2,400 mg over 24 hours), but they will be 
encouraged to wait at least 2 hours after the initial dose of study medication, if possible, to allow 
time for evaluation of only the study medication.  
Anti-emetic (rescue) medication (prescribed by the Investigator according to standard clinical 
practice) is permitted any time after the initial dose of study medication.   
No other post-operative medications are permitted. 
Throughout the entire initial 48-hour treatment observation period, scheduled dosing of study 
medication will not be interrupted by use(s) of rescue medication.  As a result, all patients will 
receive 5 doses of study medication during each 24-hour period (for a total of 10 doses over 48 
hours).      
At the completion of the 48-hour assessments, patients will be discharged as outpatients for Days 3-7 
of the study.  They will receive instructions for routine post-op care and for self-dosing with the 
same assigned study medication as needed for pain every 4-6 hours (for a maximum of 6 doses in a 
24-hour period), documenting the date and time of each dosing with study medication in an 
Outpatient Diary.   
Patients will also use the Outpatient Diary to record the date and time of taking (rescue) 
supplemental analgesic medication (ibuprofen 400 mg) and/or prescribed anti-emetic medication and 
any adverse events they experienced over the past 24 hours.   
Approximately 24 hours after the patient is discharged from the clinic after Visit 2, the Study 
Coordinator will telephone the patient to inquire about his/her post-op status, adverse events, uses of 
study medication and (rescue) supplemental medications, and use of the Diary and to confirm the 
follow-up appointment. 
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Approximately 8 (± 2) days after surgery, patients will return to the clinic for Visit 3, when the 
patient’s Outpatient Diary, use of study medication and supplemental medications, and all adverse 
events will be reviewed. Vital signs will be measured for all patients, and a third urine cotinine test 
will be performed on all patients and urine pregnancy test will be performed on all female patients. 
All patients will then be discharged from the study. Routine post-op care will be provided according 
to standard clinical practice, with telephone follow-up for any ongoing side effects until resolution or 
stabilization. 
1.4 
Endpoints 
1.4.1 Co-Primary Endpoints 
• 
Occurrence of opioid-induced nausea and vomiting (OINV*) over 48 hours, 
comparing CL-108 5 mg to hydrocodone 5 mg/APAP 325 mg 
* OINV defined as a 2-component endpoint:  any vomiting or use of anti-emetic 
medication (indicative of nausea) 
• 
Relief of moderate to severe acute pain over 48 hours (SPID48), comparing CL-108 5 
mg to placebo 
1.4.2 Key Secondary Endpoints  
1) Absence of any nausea, any vomiting, or any use of anti-emetic medication over 48 
hours (complete absence of OINV), comparing CL-108 5 mg to hydrocodone 5 
mg/APAP 325 mg 
2) Percentage of patients without any vomiting over 48 hours, comparing CL-108 5 mg to 
hydrocodone 5 mg/APAP 325 mg  
3) Percentage of patients without any nausea over 48 hours, comparing CL-108 5 mg to 
hydrocodone 5 mg/APAP 325 mg  
4) Percentage of patients without any nausea or vomiting 48 hours, comparing       CL-108 
5 mg to hydrocodone 5 mg/APAP 325 mg  
1.5 
Setting and Patients 
Approximately three hundred and thirty (330) patients undergoing a primary, unilateral 
metatarsal bunionectomy (osteotomy and internal fixation without collateral procedures) will be 
randomized to study medication at different research centers in the US. 
Males and non-pregnant, non-lactating females aged 18 years and older that experience moderate 
or severe acute pain will be eligible to participate in the randomized, double-blind clinical trial. 
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Protocol No. CLCT-018 
 
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1.6 
Study Treatments 
All study treatments appear identical.   
Each study medication dose will consist of one over-encapsulated tablet containing either:  
• CL-108 5 mg (hydrocodone 5 mg/APAP 325 mg/promethazine 12.5 mg); 
• hydrocodone 5 mg/APAP 325 mg (Norco®); or 
• placebo.  
1.7 
Sample Size 
The study is sized to determine the occurrence of vomiting or the use of anti-emetics(opioid-
induced nausea and vomiting, or OINV) of CL-108 5 mg compared to hydrocodone 5 mg/APAP 
325 mg over 48 hours (Section 7.4.2 below). 
Approximately three hundred and thirty (330) patients will be enrolled so that three hundred 
(300) completed patients can be evaluated within three treatment groups: CL-108 5 mg   (n = 
120), hydrocodone 5 mg/APAP 325 mg (n = 120), placebo (n = 60). 
 
 
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1.8 
STUDY FLOW CHART 
  
       
V1 
Screen 
V2 
( ≤3 
mo) 
 0 
0.5 hr -
12 hrs 
13-24 
hrs 
24-48 
hrs 
Day 
3-7 
V3    
(±2 d) 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History  
X 
X 
 
 
 
 
 
 
Nausea Prone Questionnaire (NPQ) Health 
Questionnaire 
X 
 
 
 
 
 
 
 
Foot X-ray6 
X 
X 
 
 
 
 
 
Physical Examination 
X 
X10 
 
 
 
 
 
Urine Drug Screen 11 
X 
X 
 
 
 
 
 
Urine cotinine test 
X 
X 
 
 
 
 
X 
Urine Pregnancy Test7 
X 
X 
 
 
 
 
X 
Vitals Signs (aural temp, HR, BP, RR)8 
X 
X 
X 
X 
X 
X 
 
X 
Height and weight (BMI) 
X 
 
 
 
 
 
 
 
Surgical Procedure 
 
X 
 
 
 
 
 
 
Pain Intensity Categorical Scale (PI-CAT) 
 
 
X 
 
 
 
 
 
Pain Intensity Numerical Rating Scale (PI-NRS)1,2  
 
 
X 
X 
X 
 
 
 
Nausea Scale (NS)1,2 
 
 
X 
X 
X 
 
 
 
Vomiting Frequency Scale (VFS)3 
 
 
X 
X 
X 
 
 
 
Opioid Symptom Scales (OSS)4 
 
 
X 
 
 
X 
 
 
Administration of Study Medication9 
 
 
X 
X 
X 
X 
X 
 
Follow-up Telephone Call5 
 
 
 
 
 
 
X 
 
Adverse Events                               
 
 
 
X 
X 
 
X 
X 
Use of Rescue and other Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
Suture Removal 
 
 
 
 
 
 
 
X 
Return Diary, Medication Bottle 
 
 
 
 
 
 
 
X 
1 PI-NRS and NS administered half-hourly (scheduled time) from 30 mins - 12 hrs. 
2 PI-NRS and NS (with VFS) administered hourly from 13 - 48 hrs (when the patient is awake).  
3 VFS administered hourly from 1-48 hrs (when the patient is awake).   
4 OSS administered at baseline, 24 hrs and 48 hrs. 
5 The Study Coordinator will telephone the patient approximately 24 hours (+2 days) after discharge from the study. 
6  The Investigator will examine a foot x-ray before surgery at Visit 2 if not completed at Visit 1 (e.g., if the x-ray was not obtained in the 
last 6 months of Visit 1 or is unavailable). 
7 All female patients (regardless of childbearing potential) will undergo urine pregnancy testing at the beginning of Visits 1, 2 and 3. 
8 At screening (Visit 1), body temperature (aural), heart rate, blood pressure and respiratory rate will be measured while semi-recumbent for 
at least 5 minutes.  The same measurements will also be performed (semi-recumbent for at least 5 minutes) before surgery, at Baseline, at 
6 hours, at 12 hours, at 18 hours, at 24 hours, at 48 hours, and at Visit 3 before discharge. 
9 Each patient should receive 1 dose of study medication at 4-hour intervals (for a total of 5 doses of study medication) over the initial 24 
hours of the study and 1 dose of study medication at 4-hour intervals (for a total of 5 doses of study medication) over the final 24 hours of 
the study while in-clinic (for a total of 10 doses over 48 hours).  On Days 3-7 each patient may self-dose with study medication every 4-6 
hours as needed. 
10 A brief physical exam will be performed at V2 prior to surgery. 
11 A positive urine drug screen will exclude the subject from participating in the study. 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 12 of 86 
 
2 
Background and Rationale for the Study 
CL-108 is a bi-layered tablet (containing hydrocodone 7.5 mg/APAP 325 mg in one layer, rapid-
release promethazine 12.5 mg in the other layer) formulated to provide pain relief and to prevent or 
reduce opioid-induced nausea and vomiting (OINV).  Because of its direct action on the receptors of 
the nausea-trigger zone (NTZ) in the brain stem which are stimulated by opioids, promethazine is 
well-suited as anti-emetic treatment of OINV. (Promethazine is approved for the prevention and 
treatment of nausea and vomiting as tablets, each containing 12.5 mg, 25 mg, or 50 mg, with 
directions for using 1-2 tablets every 4-6 hours.) Two randomized, double-blind, placebo-controlled 
Phase 3 trials (CLCT-002, CLCT-003) have been conducted demonstrating significant effects on 
pain by CL-108 compared to placebo and on OINV compared to the active control (hydrocodone 7.5 
mg/APAP 325 mg).    
Other hydrocodone/APAP products (such as Norco®) are approved that contain hydrocodone 5 mg 
with APAP 325 mg per tablet.  
The purpose of the current study is to demonstrate the efficacy and safety of a 5-mg version of CL-
108: CL-108 5 mg is a bi-layered tablet containing hydrocodone 5 mg/ APAP 325 mg in one layer, 
rapid-release promethazine 12.5 mg in the other layer. 
The design of the current trial is consistent with the study designs developed for previous 
randomized controlled trials on CL-108.  Included in the current trial, for example, is a Nausea-Prone 
Questionnaire, or NPQ, an enrichment instrument that was used in both previous Phase 3 trials to 
improve assay sensitivity by identifying patients who are possibly likely to develop OINV according 
to accepted risk criteria (e.g., a history of previous OINV, nausea/vomiting after a surgical procedure 
or operation, exposure to an opioid, or motion sickness). 1-3, 6-8   
The co-primary OINV objective of the current Phase 3 trial (CLCT-018) is to demonstrate the 
prevention of OINV by comparing the occurrence of OINV over 48 hours in patients treated with 
CL-108 5 mg and those treated with hydrocodone 5 mg/APAP 325 mg (Norco®).  There are two 
components of the OINV endpoint: the occurrence of any vomiting or use of anti-emetic medication 
(indicative of nausea) over 48 hours.  The occurrence and frequency of vomiting will be measured 
on a 0-3 Vomiting Frequency Scale, the occurrence of nausea will be measured on a binary Nausea 
Scale, and the use of anti-emetic medication will be documented in diaries.  
The other co-primary endpoint of this trial is the relief of moderate to severe pain.  Summed pain 
intensity differences over 48 hours (SPID48) will be compared for patients treated with CL-108 5 mg 
and those treated with placebo.  Pain intensity will be measured on a 0-10 Pain Intensity Numerical 
Rating Scale. 
A standard pain model, the bunionectomy pain model that was used in CLCT-003, was selected for 
this multiple-dose, randomized, double-blind, placebo- and active-controlled trial.       
The study will be conducted in compliance with the protocol, Good Clinical Practice Guidelines 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
Page 13 of 87
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 13 of 86 
 
(GCP), and all applicable regulatory requirements. 
3 
Objectives of the Study 
• To compare CL-108 5 mg to hydrocodone 5 mg/APAP 325 mg in terms of the occurrence of 
OINV (any vomiting or use of anti-emetic) over 48 hours 
• To compare CL-108 5 mg to placebo in terms of pain reduction over 48 hours (SPID48) 
4 
Trial Design 
This is a Phase 3, double-blind, randomized, placebo- and active-controlled, multiple-dose study 
conducted at different research centers in the U.S. comparing CL-108 5 mg, hydrocodone 5 
mg/APAP 325 mg, and placebo in patients after first metatarsal bunionectomy (osteotomy with 
fixation of the head of the first metatarsal bone). 
4.1 
Visit 1 
Patients who have called the research center (spontaneously, by referral or in response to local 
advertisements or notification from the center) to have a bunion on the big toe removed and who 
are potentially qualified according to a pre-screen questionnaire will be scheduled for this 
screening visit.  After patients sign an Informed Consent Form at Visit 1, a foot x-ray will be 
taken and reviewed by the surgeon between Visit 1 and Visit 2 prior to surgery (unless an x-ray 
was obtained within the past 6 months of Visit 1 another foot x-ray will be obtained).  The 
patient’s Medical History will be obtained and a physical examination will be performed.  Height 
and weight will be measured (to calculate BMI).  After the patient has been resting in the semi-
recumbent position for a minimum of 5 minutes, vital signs will be measured including 
temperature, pulse, respiratory rate, blood pressure. A urine drug screen and urine cotinine test 
will be performed on all patients. A urine pregnancy test will be performed on each female 
patient regardless of childbearing potential. Inclusion and exclusion criteria will be reviewed to 
determine eligibility.  
To identify the patient’s nausea-prone status as suggested on the pre-screen questionnaire, each 
patient will complete the Nausea-Prone Questionnaire (NPQ), documenting previous medical 
and non-medical conditions associated with the development of nausea, including exposure to 
opiates, motion sickness, cigarette smoking, etc. By reviewing responses on the NPQ and using 
specific criteria (Section 6.3.2 below), the Investigator will determine if the patient could be 
considered at risk (or not) of opioid- induced nausea and vomiting. Patients who are not 
considered possibly at risk for OINV or whose nausea-prone status is uncertain or unknown will 
not be admitted to the trial.  Patients who meet other admission criteria and whom the 
Investigator considers possibly at risk of OINV will progress to Visit 2. 
Prior to leaving the clinic patients will be scheduled for surgery at Visit 2 within 3 months. They 
will take nothing by mouth after midnight on the night before surgery (including, in particular, 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 14 of 86 
 
no analgesic or anti-emetic medication, although antibiotic prophylaxis for endocarditis may be 
prescribed, if indicated).   
All patient entries in the Clinic Diary from Visit 1 will be entered onto the electronic case report 
forms (eCRFs) by site personnel.   
4.2 
Visit 2 
On the day of surgery (Baseline/Treatment Visit) prior to surgery, the medical history will be 
reviewed, including pre-admission entry criteria, and a brief preoperative physical examination 
will be performed with vital signs, which include body temperature (aural), respiratory rate, 
pulse, and blood pressure (reclining for 5 minutes).  A urine drug screen and urine continue test 
will be performed on all patients and a urine pregnancy test on all female patients.  
Midazolam will be administered according to standard practice pre-operatively (and intra-
operatively, if necessary).  Regional anesthesia will be established using intravenous propofol 
and a popliteal sciatic nerve block (PSB) using 0.5% ropivacaine.  Patients will undergo primary, 
unilateral, first metatarsal bunionectomy surgery (osteotomy and internal fixation) with no 
additional collateral procedures.  If the PSB is not sufficient to provide adequate intraoperative 
anesthesia, a standard Mayo block may be established using short-acting lidocaine 1% or 2% 
(plain).  Preoperative antibiotic (e.g., cephalexin) will be administered to all patients; if there are 
signs of post-operative infection, a patient may receive additional post-op antibiotic (which will 
be documented).  Prophylactic antibiotic for endocarditis, ASA ≤ 325 mg for cardiovascular 
prophylaxis and chronic medications that are not contraindicated (Section 4.2 below) are also 
permitted.  Except as permitted by protocol, other medications (in particular, opioid, anti-emetic) 
are not permitted during or after surgery.  
The PSB will be continuous until approximately 3 am (± 15 minutes) of the morning after 
surgery.  Patients will also receive IM or IV ketorolac 15 or 30 mg (by body weight) at the 
conclusion of surgery, then every 6 hours as needed for breakthrough pain until 1:30 am on the 
morning after surgery (see Section 6.3.3).  
Patients will be observed in the research center for 9 hours after the popliteal sciatic block is 
discontinued to determine if they develop moderate or severe pain as measured on a categorical 
pain intensity rating scale (PI-CAT).   
Moderate or severe baseline pain intensity must be confirmed on a 0-10 numerical rating scale 
(PI-NRS) in order to be eligible for randomization. Patients who do not report baseline PI-NRS ≥ 
4 are screen failures. 
Patients who do not qualify on the PI-CAT and the PI-NRS within 9 hours after discontinuation 
of the PSB will be discharged from the study with routine care.  
All patients with at least moderate pain assessments on the PI-CAT and PI-NRS will complete 
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Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 15 of 86 
 
scales measuring different opioid side effects, including:  
• a conventional binary Nausea Scale (NS) to document the presence/absence of nausea;  
• a Vomiting Frequency Scale (VFS) to document episodes of vomiting, a measurement 
instrument which was used in CLCT-002; 
• Opioid Symptoms Scales (OSS), derived from the Symptom Distress Scale to identify 
other opioid effects,4 which were used in CLCT-002 and CLCT-003  
Study medication will be allocated to qualifying patients based on a computer-generated 
randomization code: CL-108 5 mg (n = 120), hydrocodone 5 mg/APAP 325 mg (HC/APAP,   n = 
120), or placebo (n = 60).  Study medication will be administered to patients under double-blind 
conditions.  
Following the initial dose of study medication, patients will remain in the clinic for the entire 48-
hour treatment observation period. The Study Coordinator will impress on the Patients the 
importance of using a Clinic Diary correctly, completing all assessments for the initial 12 hours 
and, when awake, for the remaining 36 hours of the 48-hour primary treatment observation 
period. 
Vital signs, including temperature (aural), pulse, respiratory rate and blood pressure (semi-
recumbent for at least 5 minutes) will be measured at Baseline immediately prior to dosing, then 
every 6 hours until 24 hours post-dosing. During the initial 12 hours of the treatment evaluation 
period, patients will record assessments every 30 minutes for pain intensity (on the PI-NRS) and 
the presence/absence of nausea (on the NS).  
During the initial 12 hours (beginning at 1 hour) of the treatment evaluation period, at hourly 
intervals patients will use the VFS to assess the occurrence and frequency of vomiting over the 
past hour. 
During the remaining 36 hours of the 48-hour primary treatment evaluation period (i.e., at hours 
13-48), when awake, patients will record hourly assessments on the PI-NRS, NS and VFS.  
To provide evaluations of other opioid-related side effects after multiple doses of study 
medication taken over 48 hours, patients will repeat the OSS at 24 hours and 48 hours while in 
the research center. 
In order to document side effects and any other changes in his/her medical condition during the 
48 hours after surgery (including nighttime), the Study Coordinator will make hourly 
observations of the patient’s status.  All patient reports of adverse events will be documented on 
the AE page of the eCRF.   
In order to assure that all patients assigned to CL-108 5 mg and HC/APAP receive the same total 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
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Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 16 of 86 
 
amount of hydrocodone/APAP during the primary 48-hour treatment observation period, patients 
will be dosed on a fixed schedule. To comply with label directions for HC/APAP to not dose 
more frequently than every 4 hours as treatment for moderate/severe acute pain, the Study 
Coordinator will give the patient the second dose of study medication 4 hours after the initial 
dose and the 3rd, 4th and 5th doses also at 4-hour intervals.  As a result, all patients will receive 5 
doses of study medication over the initial 24-hour treatment period (i.e., midway between 4 and 
6 total daily doses that are permitted for hydrocodone/APAP).  Dosing every 4 hours for 5 
additional doses during the final 24-hour treatment period will assure that all patients are 
exposed to the same total amount of analgesic (in particular, hydrocodone) over 48 hours, 
contributing to the co-primary SPID48 and OINV endpoints of the study. Subjects should be 
awoken for dosing, as needed to remain on the dosing schedule. 
Patients may take supplementary (rescue) medication for pain (ibuprofen 400 mg) as needed at 
any time after taking the initial dose of study medication (every 4-6 hours, up to 2,400 mg over 
24 hours), but they will be encouraged to wait at least 2 hours after the initial dose of study 
medication to allow sufficient time for evaluation of only the study drug.   
Similarly, patients will be encouraged to take a subsequent scheduled dose of study medication 
rather than ibuprofen if the next dose of study medication is due within 1 hour.  However, a 
patient will receive supplementary (rescue) medication for pain any time it is required.  
Anti-emetic rescue medication (prescribed by the Investigator according to standard clinical 
practice) is permitted any time after the initial dose of study medication.  
The date(s) and time(s) of taking rescue medications will be recorded in the eCRF.   
Patients will be instructed to provide ratings on the PI-NRS, NS and VFS prior to each time they 
take rescue medication(s) over the initial 48-hour treatment observation period unless rescue 
medication is taken within 5 minutes after regularly scheduled 30- or 60-minute assessments.   
Similarly, if a patient who used rescue medication has provided ratings on the PI-NRS, NS and 
VFS within 5 minutes before regularly scheduled PI-NRS, NS and VFS assessments, these 
regularly-scheduled assessments do not need to be repeated then.   
At all other times regularly scheduled PI-NRS, NS, and VFS assessments will not be interrupted 
by the time of using rescue medication.  
If a patient vomits, reports nausea, or takes a dose of analgesic or an anti-emetic rescue 
medication and then falls asleep, the patient will be awakened for the next scheduled 
assessments. 
Scheduled dosing of study medication will also not be interrupted by the use(s) of rescue 
medication throughout the 48-hour treatment observation period. All patients should take all 10 
doses of study medication over 48 hours. 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
Page 17 of 87
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 17 of 86 
 
Patients who take supplemental medication for pain and/or for nausea/vomiting are expected to 
document all evaluations and side effects throughout the initial 48-hour treatment evaluation 
period in the clinic (and for the remainder of the 7-day study as an outpatient). 
Patients should continue to use study medication throughout the study in addition to 
supplemental medication needed for pain or nausea/vomiting. 
At the completion of the 48-hour PI-NRS, NS, VFS and OSS assessments, vital signs will be 
repeated in the semi-recumbent position, adverse events will be reviewed, and patients will 
receive instructions for routine post-op care according to standard clinical practice.  
They will be instructed as outpatients for Study Days 3-7 to self-dose with the same assigned 
study medication as needed for pain every 4-6 hours (for a maximum of 6 doses in a 24-hour 
period), documenting the date and time of each dosing with study medication (and rescue 
analgesic and anti-emetic medications) in an Outpatient Diary. All patients will receive a bottle 
of ibuprofen tablets (analgesic rescue medication) and a prescription for an anti-emetic of the 
investigator’s choice (anti-emetic rescue medication) to be used as needed during Study Days 3-
7. 
At the conclusion of Visit 2 patients will be discharged from the clinic with a responsible adult. 
All patient efficacy and safety entries in the Clinic Diary from Visit 2 will be entered onto the 
electronic case report forms (eCRFs) by site personnel.   
4.3 
Outpatient Phase (Days 3-7) 
Patients will use an Outpatient Diary each day to document the dose, date and time of each self-
dosing with study medication, each self-dosing with rescue analgesic medication (ibuprofen 400 
mg) and/or prescribed rescue anti-emetic medication, and any other permitted medication (e.g., 
chronic medication). 
Whether or not they used study medication or rescue medication each day, patients will use the 
Outpatient Diary on Days 3-7 to document any symptoms (adverse events) they experienced.  
The Study Coordinator will telephone the patient approximately 24 hours after discharge from 
the clinic after Visit 2 (+2 days, to allow for weekends) to inquire about his/her post-op status, in 
particular, adverse events and uses of pain medication and (rescue) supplemental medications, 
and use of the Outpatient Diary, and to confirm the follow-up appointment. 
4.4 
Visit 3 
Approximately 8 days (± 2) after surgery, patients will return to the clinic for a final visit, when 
the patient’s Outpatient Diary, uses of study medication, supplemental/rescue medications and 
concomitant medications, and all adverse events will be reviewed.  
Vital signs will be measured for all patients (aural temperature, pulse, respiratory rate), and blood 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 18 of 86 
 
pressure (semi-recumbent for 5 minutes), and a third urine pregnancy test will be performed on 
all female patients and a urine cotinine test will be performed on all patients. All patients will 
then be discharged from the study. Routine post-op care will be provided according to standard 
clinical practice, with telephone follow-up for any ongoing side effects until resolution. 
All patient safety entries in the Outpatient Diary will be entered onto the electronic case report 
forms (eCRFs) by site personnel.   
Routine post-operative care will be provided after discharge from the study. For any continuing 
side effects, the Study Coordinator will call the patient every 48 hours (or routine follow-up) 
until the resolution or stabilization of the side effect. 
5 
Patient Selection and Withdrawal 
5.1 
Inclusion Criteria 
A patient will be eligible for inclusion in this study if all of the following criteria apply: 
 
1. 
Informed consent 
Signed informed consent form obtained at screening 
prior to any procedures being performed. 
2. 
Gender 
Male or non-pregnant and non-lactating female.  A 
female of child-bearing potential is eligible to participate 
in this study if she has a negative urine pregnancy test 
and is using an acceptable method of birth control (i.e., 
hormonal, transdermal, or implanted contraceptives, 
intrauterine device, diaphragm, condom, abstain from 
heterosexual sex, or surgical sterilization). See Section 
5.3. 
3. 
Age 
4. 
OINV status 
18 years or older at time of consent. 
Determined by the Investigator as possibly at risk of 
opioid-induced nausea and vomiting according to 
accepted criteria, as documented on the Nausea Prone 
Questionnaire. 
5. 
Foot condition 
Primary 
unilateral 
first 
metatarsal 
bunionectomy 
(osteotomy and internal fixation) with no additional 
collateral procedures.  
6. 
Pain Severity 
Presence of moderate or severe pain (rating of 2 or 3) on 
the 0-3 categorical pain intensity scale (PI-CAT) at 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 19 of 86 
 
 
7. 
Pain Confirmation 
Baseline. 
Rating ≥ 4 on the 0-10 numerical pain intensity scale 
(PI-NRS) at Baseline.  
8. 
Diary Completion 
9. 
Safe Transportation Home 
Be willing and able to record safety and efficacy ratings 
in the Diaries. 
Patient must have arrangements for transportation home 
from the research center accompanied by a responsible 
adult. 
5.2 
Exclusion Criteria 
A patient will not be eligible for this study if one or more of the following apply: 
 
1. Medical condition 
Presence of a serious medical condition (e.g., poorly 
controlled hypertension or diabetes, neurological 
disease including Parkinson’s or other condition 
associated with a movement disorder, chronic pain, 
significantly 
impaired 
cardiac, 
renal, 
hepatic, 
respiratory, or thyroid function), intolerance to NSAIDs 
(e.g., dyspepsia), or any other medical condition which, 
in the opinion of the Investigator, makes the patient 
unsuitable for participation. 
2. Infection 
Acute infection of the surgical site at the time of surgery 
that could confound post-surgical evaluation. 
3. Drug Allergy                   
History of hypersensitivity (i.e., allergy1) to an opioid 
drug 
(such 
as 
hydrocodone), 
promethazine, 
acetaminophen, NSAID (such as ibuprofen or aspirin), 
midazolam, propofol, mepivacaine, ropivacaine or 
ketorolac or history of a dystonic/dyskinetic reaction to 
anti-emetic or anti-psychotic medication. 
4. Confounding and 
Other than protocol-permitted medications administered 
                                                 
 
1 Because this is a study on opioid-induced nausea and vomiting (OINV), patients with a history of these opioid effects 
will not be excluded from the study. In fact, “nausea-prone” patients (especially those with a history of OINV) are sought 
in order to enrich enrollment in this study. Thus, for example, if patients erroneously consider themselves “allergic” to a 
narcotic, such as codeine, because they felt nauseated or “sick to my stomach” after using a cough medicine, they are 
admissible. Only medically-defined allergic reactions to an opioid (e.g., rash, hives) should prevent a patient from being 
admitted into this study. 
 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 20 of 86 
 
Contraindicated Drugs 
pre-operatively or during surgery: use within 14 days 
before or during the surgical procedure of any systemic 
corticosteroid or use within 24 hours or during the 
surgical procedure of any confounding prescription or 
non-prescription drug (e.g., analgesic, anti-emetic, 
sedating antihistamine, sedative, alcohol,  or CNS/ 
psychotropic 
agent, 
including 
sleep 
aides, 
benzodiazepines, 
performance/attention 
enhancers, 
marijuana, anti-depressants) or any drug contraindicated 
with hydrocodone, acetaminophen, or promethazine. 
[Note: Antibiotic for endocarditis prophylaxis (except if 
known to cause nausea) and aspirin (ASA) ≤ 325 mg for 
cardiovascular prophylaxis are permitted during the 
study.]  
 
History of consuming more than 2 alcoholic drinks per 
day every day for the last month or a positive urine test 
for 
opiates, 
benzodiazepines, 
barbiturates, 
THC, 
methamphetamines, cocaine, oxycodone, cotinine at 
screening or the morning of surgery will exclude the 
patient from the trial. 
5. Caffeine Use 
Ingestion of any caffeine-containing beverage or 
chocolate since midnight on the night before surgery. 
6. Nicotine Use 
 
Use of any nicotine-containing product (cigarettes, e-
cigarettes, patches, etc.) within the past 30 days.  
7. Investigational Drug Use 
Use of an investigational drug within the past 30 days. 
8. Participated in Study 
Previous participation in this study. 
9. Pregnancy, Lactation 
Women who are pregnant or lactating. 
    10.   Compliance 
    11.   Participant relationship 
Inability to swallow capsules whole. 
Employee at the research center, employee of the 
Principal Investigator, Sub-Investigators, Charleston 
Laboratories or Daiichi Sankyo or relative of the 
Investigator, Sub-Investigators or research staff who is 
involved in this study. 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 22 of 86 
 
at his/her own professional discretion according to standard clinical practice with dosing 
according to labelled directions for use.   
Every time a patient receives a supplemental (rescue) analgesic or anti-emetic, the medication 
name, date, time, and dose of supplemental medication will be recorded in the source document 
and in the eCRF.   
During the initial 48-hour treatment period patients will be instructed to record ratings on the 
PI-NRS, NS and VFS prior to each time they take rescue medication(s).   
If a rescue time is within 5 minutes before the time for any regularly scheduled PI-NRS, NS and 
VFS assessments, the regularly scheduled assessments do not need to be completed in addition 
to the assessments at the time of taking an analgesic or anti-emetic rescue medication.  If a 
rescue time is within 5 minutes after the time of recording any regularly scheduled PI-NRS, NS 
and VFS assessments, assessments at the time of rescue do not need to be repeated 
At all other times during the initial 48-hour treatment period regularly scheduled PI-NRS, NS, 
and VFS assessments will not be interrupted by the time of using rescue medication.  
To assure that all patients in the CL-108 5 mg and the hydrocodone 5 mg/APAP 325 mg 
treatment groups receive the same amount of analgesic medication (10 doses) over 48 hours, the 
schedule for the administration of study medication will not be interrupted by use(s) of any 
rescue/supplementary analgesic or anti-emetic medication.   
After discharge from the clinic, if patients require anti-emetic treatment during Days 3-7 they 
may take the anti-emetic medication which the Investigator has prescribed according to local 
practice in addition to their study medication for pain. Every time a patient takes an anti-emetic 
medication on Days 3-7, he/she will be required to record the name, date(s) and time(s) of 
taking each dose in the Outpatient Diary. 
Patients who use anti-emetic medication during Days 3-7 should continue to use study 
medication if needed for pain.  If supplemental/rescue analgesic is needed on Days 3-7, the 
patient may take ibuprofen 400 as needed at any time according to label directions (every 4-6 
hours, up to 2,400 mg over 24 hours).  Every time a patient takes rescue analgesic medication 
on Days 3-7, he/she will be required to record the name, date(s) and time(s) of taking each dose 
in the Outpatient Diary. 
Patients who take supplemental/rescue medication for pain and/or for nausea/vomiting on Days 
3-7 are expected to document any side effects experienced each day in the Outpatient Diary. 
5.6 
Withdrawal  
Patients may withdraw from the study or withdraw his or her consent at any time without 
penalty of loss of clinical care or patient rights to which they are entitled.   
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 23 of 86 
 
If a patient drops out of the study during the initial 48 hours of the study, he/she will be asked to 
record on the PI-NRS, NS, VFS and OSS at that time, and the date and time will be recorded on 
a separate CRF page.  Instructions for using these scales at the time of withdrawal are: 
For the PI-NRS – On a scale of 0 to 10, where 0 is “no pain” and 10 is “severe pain,” 
circle the number that best describes your pain now. 
For the NS - Over the past half-hour, have you had any nausea (feeling like you wanted 
to throw up)? 
For the VFS – How many times did you vomit (throw up) over the past hour? 
For the OSS - Circle the number that best describes each symptom you’ve had since you 
began taking study medication. 
The Investigator should also perform the following evaluations and procedures before discharge 
from Visit 2: 
• Pregnancy test (in females) 
• Clinical adverse event assessment (which will be followed until resolution in 
consultation with the Medical Monitor) 
• Review of use of concomitant medications 
• Review of use of study medication 
• Review of use of rescue medications 
• Review of completeness of diary entries 
5.6.1 Investigator’s Reasons for Patient Withdrawal  
The Investigator may withdraw a patient from the study if:  
• a patient is unable to understand or use any of the rating scales; 
• a patient has an exclusion criterion after study enrollment (e.g., positive urine 
pregnancy test, cotinine test, or drug screening test prior to surgery); 
• continuing to participate in the study would, in the opinion of the Investigator, 
pose a risk to the safety and welfare of the patient. 
The Investigator will also withdraw a patient upon request of Charleston Laboratories or 
if Charleston Laboratories terminates the study.  
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
Page 24 of 87
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 24 of 86 
 
Upon occurrence of a serious or intolerable adverse event, the Investigator or designee 
will confer immediately with the Medical Monitor. Serious adverse events will be 
reported to Charleston Laboratories within 24 hours of determination. If a patient is 
discontinued due to an adverse event, the event will be followed until resolved or 
stabilized. 
5.6.2 Handling of Withdrawals  
If a patient withdraws or is withdrawn from the study because of a serious or intolerable 
adverse event after Visit 2, the Investigator must make every effort to perform the 
following evaluations and procedures at a follow-up visit: 
• Pregnancy test (in females) 
• Clinical adverse event assessment (which will be followed until resolution in 
consultation with the Medical Monitor) 
• Review of use of concomitant medications 
• Review of use of study medication 
• Review of use of rescue medications 
• Review of completeness of diary entries 
These data are to be entered into the case report form and comprise an essential safety 
evaluation, which should be completed before discharge from the study. 
If a patient withdraws from the study at any time prior to completion at the patient's 
request or the Investigator's discretion, the reason(s) for withdrawal shall be recorded by 
the Investigator on the appropriate electronic case report form (eCRF). If possible at a 
follow-up visit, all patients who withdraw from the study after dosing for non-adverse 
event-related reasons will undergo all procedures and assessments listed above at that 
time.  
Patients who withdraw from treatment because of an adverse event or a serious adverse 
event after dosing will be followed until resolution. 
6 
Study Procedures 
6.1 
Evaluations of Safety and Eligibility 
Safety evaluations will include the following to determine eligibility to participate in the study 
and to detect any changes from baseline: 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
Page 25 of 87
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 25 of 86 
 
Medical history and physical examination:  At the screening visit a medical history, including 
medication history, will be obtained from the patient, and a limited pre-surgery physical 
examination will be performed to determine that the patient qualifies for the study (e.g., without 
medical or concurrent pharmacologic contraindications). 
Vital Signs: At screening, body temperature (aural), heart rate, blood pressure and respiratory 
rate will be measured after the patient has been in the semi-recumbent position for at least 5 
minutes, and height and weight (to determine BMI).  The same measurements will also be 
performed (with the patient semi-recumbent for 5 minutes): before surgery at Visit 2; at 
Baseline; every 6 hours (± 10 minutes) following dosing for 24 hours post initial dose if the 
patient is awake; at 48 hours (± 10 minutes); and at Visit 3, before discharge from the study.  
Drug Screen: A urine toxicology screen test (including opiates, benzodiazepines, barbiturates, 
THC, methamphetamines, cocaine, and oxycodone) will be performed on each patient at the 
Screening Visit and on the morning before surgery.  A positive result will exclude the patient 
from participating in the trial.   
Cotinine Test:  A urine cotinine test will be performed on each patient at the Screening Visit and 
on the morning before surgery. A positive result will exclude the patient from participating in the 
trial. A urine cotinine test will also be performed at Visit 3.  A positive result will indicate that 
the patient used nicotine during the trial. 
Pregnancy Test: All females regardless of childbearing potential must have a urine beta HCG 
pregnancy test performed at screening and on the morning before surgery.  A positive result will 
exclude the patient from participating in the trial.  
A repeat beta HCG urine pregnancy test will be performed at follow-up Visit 3. 
Pain Assessments:  Patients will be asked to record their level of post-operative pain on the 0-to-
3 (no pain, mild pain, moderate pain, severe pain) categorical pain intensity scale, or PI-CAT.  
Only patients with moderate or severe pain ratings (2 or 3) are eligible for the trial. 
Confirmation of at least moderate pain is required on the 0-to-10 numerical pain intensity scale, 
or PI-NRS (i.e., a Baseline rating ≥ 4). 
Clinical adverse event assessment: All adverse events will be recorded by the Study Coordinator 
or designee in the electronic case report form (eCRF) according to Section 9.1 of this protocol.  
All adverse events will be followed until resolution or stabilization. 
6.2 
Evaluations of Efficacy and Safety (See Appendices for Sample Indices) 
6.2.1 Categorical Pain Intensity Scale (PI-CAT) 
(called “Pain” in the Clinic Diary) 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
Page 26 of 87
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 26 of 86 
 
The patient will be asked at baseline to “Circle the number that best describes your pain 
now” on a 0-to-4 Likert scale. (No Pain/Mild Pain/Moderate Pain/ Severe Pain) 
6.2.2 Numerical Pain Intensity Rating Scale (PI-NRS)   
(called “Pain Severity” in the Clinic Diary) 
The patient will be asked at baseline and at every post treatment assessment time to 
“Circle the number that best describes your pain now” on a 0-to-10 Likert scale.   
The Numerical Pain Intensity Rating Scale is the measurement instrument for the co-
primary analgesia endpoint. 
6.2.3 Nausea Scale (NS)  
(called “Nausea” in the Clinic Diary) 
Nausea will be defined for each patient at baseline (“Nausea is feeling like you want to 
throw up”).  
At baseline and every 30 minutes after initial treatment until 12 hours, the patient will be 
asked “Over the past half-hour, have you had any nausea (feeling like you wanted to 
throw up)?” using a binary scale (no nausea, nausea).   
The patient will use the Nausea Scale every 60 minutes from 13 hours through 48 hours 
(when the patient is awake) in response to the question: “Over the past hour, Have you 
had any nausea (feeling like you wanted to throw up)?”   
The Nausea Scale is the measurement instrument for documenting the occurrence (or 
absence) of nausea. 
6.2.4 Vomiting Frequency Scale (VFS)  
(called “Vomiting” in the Clinic Diary) 
The patient will be instructed at baseline and every hour post treatment over the initial 48 
hours after dosing: “How often did you vomit (throw up) over the past hour?” using an 
ordinal scale (not at all, one time, two times, three or more times). 
The Vomiting Frequency Scale is the measurement instrument for documenting the 
occurrence of vomiting in the co-primary OINV endpoint, as in CLCT-002. 
6.2.5 Opioid Symptom Scales (OSS) (from the Symptom Distress Scale)4  
(called “Other Symptoms” in the Clinic Diary) 
To document each of 9 other symptoms commonly experienced by patients using opioids 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
Page 27 of 87
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 27 of 86 
 
(dizziness, drowsiness, constipation, difficulty voiding, confusion, headache, itch, 
difficulty concentrating, dry mouth), at Baseline, at 24 hours, and at 48 hours the patient 
will be instructed “For each symptom you’ve had over the past 24 hours, circle the 
number that describes how severe it was for you” using an 11-point numerical rating 
scale for each symptom. 
The Opioid Symptom Scales are measurement instruments for documenting the 
occurrence and severity of each other opioid-related symptom, as in CLCT-002 and 
CLCT-003. 
6.2.6 Uses of Supplemental (Rescue) Analgesic Medication   
The date, time, name (ibuprofen), and dose (400 mg) of each use of supplemental (rescue) 
medication for pain will be recorded in the eCRF. 
6.2.7 Uses of Anti-emetic (Rescue) Medication  
The date, time, name, and dose of each use of anti-emetic medication prescribed by the 
Investigator will be recorded in the eCRF. 
6.2.8 Patient Reports of Adverse Events (Elicited and Volunteered) 
Patients will be asked how they are feeling on an hourly basis throughout the initial in-
clinic 48-hour treatment evaluation period (when they are awake).  The Investigator will 
rate each side effect on a 1-3 scale (mild, moderate, severe).  All ratings of adverse events, 
their relationship to study medication, remedial treatments, etc. will be documented and 
entered on the Adverse Events page of the eCRF. 
Expected post-operative side effects (i.e., side effects such as localized erythema and 
numbness that the investigator considers related to the surgery) will not be recorded as 
AEs. 
6.3 
Study Conduct 
6.3.1 Pre-Screening Procedures 
Patients who respond to local advertisements or who are otherwise recruited to the 
research center (by social media, patient rosters at the clinic, etc.) will be pre-screened 
over the telephone or in person as potential patients for the study using a screening 
questionnaire.  In addition to routine demographic questions, patients who want to have a 
bunion removed will also be asked questions to determine if they are possibly at risk for 
OINV (e.g., any allergy to a medication, including pain-killers; any reactions such as 
nausea or vomiting after surgery; any history of motion sickness; current smoking 
status/use of nicotine-containing products) and asked about their willingness to comply 
with study requirements (e.g., 3 visits, use of a diary) if they are accepted into the study.  
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
Page 28 of 87
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 28 of 86 
 
Patients who appear to qualify for the study will receive appointments for Visit 1 within 
the next month. 
6.3.2 Screening Procedures (Visit 1)  
Patients 18 years of age and older who request a bunionectomy will be evaluated at the 
Screening Visit.  After the informed consent form has been signed, the following 
procedures will be completed in order to assure eligibility according to the admission 
criteria: 
• Urine drug screen on all patients 
• Urine cotinine test on all patients 
• Urine pregnancy test on all female patients (regardless of child-bearing  potential) 
• Physical examination, height and weight (to calculate BMI), vital signs (semi-
recumbent for 5 minutes) including temperature (aural), pulse, respiratory rate, 
systolic and diastolic blood pressure 
• Evaluation of a foot x-ray taken within the past 6 months prior to screening visit. 
If a patient does not have a foot x-ray taken within the past 6 months, it will be 
obtained and reviewed by the surgeon (to confirm the diagnosis of a first 
metatarsal bunion) at Visit 1 and/or prior to surgery at Visit 2  
• Medical History including admission criteria, gender, smoking status/use of 
nicotine-containing products, and medications taken in the past 30 days 
• Nausea-Prone Questionnaire (NPQ) (See Appendix 3) 
As part of medical-history taking, patients will be asked to complete a “Health 
Questionnaire” which contains more than the Medical History and is designed to identify 
patients who are possibly at risk of opioid-induced nausea and vomiting (OINV).  
Patients will be asked a series of questions about different conditions associated with 
nausea (e.g., previous OINV, nausea after a post-op medication, nausea/vomiting after 
Vicodin, “allergy” to cough medicines, previous exposure to an opioid medication, sea 
sickness, other types of motion sickness) based on risk factors identified by Apfel et al1-3 
and Gan et al.6-8  
Responses on the NPQ will be used by the Investigator to qualify a patient as being 
possibly at risk for OINV according to pre-determined criteria (A-D): 
Criterion A:  Any one of the following 5 responses to Questions 4-5, 7, 8 on the 
NPQ will be interpreted as meaning the patient is possibly at risk of OINV: 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
Page 29 of 87
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 29 of 86 
 
 Reports being “allergic” to an opioid-containing drug and the symptoms 
reported are determined to be nausea or vomiting (Q 4-5) 
 Has taken an opioid-containing drug and became nauseated or vomited (Q 4-
5) 
 Has taken an unknown medication after an operation or surgical procedure 
and became nauseated or vomited (Q7-8) 
 Reports being “allergic” to cough medicine and the symptoms reported are 
determined to be nausea or vomiting (Q4-5) 
 Has taken a cough medicine (naming the opioid in it or not) and became 
nauseated or vomited (Q4-5) 
Criterion B:  If a patient has at least one of the following 5 responses to Questions 
26-27, 30, 32-34, (relating to motion sickness) on the NPQ, the patient will be 
considered possibly at risk of OINV: 
• Easily becomes nauseated when riding in a car (or requires an open window 
when riding in a car) (Q26-27) 
• Easily becomes nauseated when riding backwards in a train (Q30) 
• Easily becomes nauseated when on a roller-coaster (Q32) 
• Easily becomes nauseated when spun around (Q33)Easily becomes 
nauseated when bending over (Q34) 
Criterion C:  Any rating ≥ 3 on Question 43 of the NPQ (which is a 0-10 Nausea-
Prone Scale) will also be interpreted as meaning the patient is possibly at risk of 
OINV. 
Criterion D:  If Criteria A-C does not qualify a patient, the Investigator may 
consider a patient possibly at risk of OINV based on other responses on the NPQ 
(which the Investigator will identify, such as Questions 16-18, 21, 25, 28, 31, 39, 
gender, smoking status). The Investigator may thus use “clinical judgment” to admit 
up to approximately 10% of the total number of qualifying patients at his/her research 
center. 
In sum, as a result of using the NPQ the Investigator will admit patients with a history 
suggestive of a predisposition for developing OINV, thus providing an enriched group of 
patients for evaluation at Visit 2. 
The Investigator will cite each question on the NPQ that led to his/her determination that 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
Page 30 of 87
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 30 of 86 
 
the patient is possibly at risk for OINV.   
Admission criteria will be reviewed to assure eligibility to the study.  Patients who 
qualify will be scheduled for surgery within 90 days.   
Patients who do not qualify will have their reason(s) for “screen failure” documented in 
the eCRF and will not progress in the study. 
6.3.3 Surgery Day (Visit 2) 
Within 90 days after Visit 1, screened patients who qualify for the study will report in the 
morning to the center having fasted since midnight.  
(Exception:  If a subject has consumed a small sip of liquid or small amount of food since 
midnight, the Investigator will determine if it is safe for the subject to have surgery under 
local anesthesia.)  
Prior to surgery, the following will be performed: 
• Documentation of concomitant medications (see Section 5.2, Exclusion #4) 
• Urine drug screen 
• Urine cotinine test 
• Urine pregnancy test for all female patients 
• Review of the Medical History 
• Vital signs (semi-recumbent for 5 minutes), including temperature (aural), heart 
rate, respiratory rate and blood pressure (systolic and diastolic) 
• Surgeon’s assessment of the foot x-ray (at Visit 1, between Visits 1 and 2, or prior 
to surgery at Visit 2)  
Moderate regional anesthesia will be standardized for all patients: patients will receive 
midazolam and/or propofol for initial sedation at the anesthesiologist’s discretion.  After 
adequate sedation is achieved, the anesthesiologist will inject approximately 5 mL 
lidocaine 1% or 2% (plain) locally to anesthetize the skin and will determine the location 
of the sciatic nerve for the popliteal sciatic block (PSB) using a nerve stimulator per 
standard technique.  Once the appropriate location is determined and the catheter secured, 
the anesthesiologist will inject approximately 40 mL of ropivacaine 0.5% to establish the 
PSB via the catheter.  Subsequently, the catheter will remain in place in the proximity of 
the popliteal sciatic nerve for delivery of postoperative anesthesia.   
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
Page 31 of 87
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 31 of 86 
 
Patients will undergo primary, unilateral, first metatarsal bunionectomy surgery 
(osteotomy and internal fixation) with no additional collateral procedures.  If the PSB is 
not sufficient to provide adequate intraoperative anesthesia, a standard Mayo block may 
be established using short-acting lidocaine 1% or 2% (plain, without epinephrine), not to 
exceed 25 ml..  
Pre-operative antibiotic (e.g., cephalexin) will be administered to all patients; if there are 
signs of post-operative infection, a patient may receive additional post-op antibiotic 
(which will be documented).  
Prophylactic antibiotic for endocarditis, ASA ≤ 325 mg for cardiovascular prophylaxis 
and chronic medications that are not contraindicated (see 4.2) are also permitted.  Except 
as permitted by protocol, other medications (in particular, opioid and anti-emetic) and 
any nicotine-containing product are not permitted during or after surgery.  
Patients will receive IM or IV ketorolac 15 or 30 mg (by body weight, per label) at the 
conclusion of surgery.  
Patients who had bunionectomy surgery performed at the research center and patients 
were transferred to the research center after surgery will stay at the research center for 
study observations and routine post-surgical care.  
The popliteal sciatic block will be maintained until approximately 3 am (± 15 minutes) of 
the morning after surgery.  
Postoperative pain will be controlled by a continuous anesthetic infusion through the 
catheter previously placed adjacent to the popliteal sciatic nerve.  Two methods of 
continuous anesthetic infusion are permitted. Mepivacaine 0.5% (plain) will be infused 
starting at 8 mL per hour and not to exceed 14 mL per hour.   
During this continuous infusion period, patients may receive supplemental analgesia for 
breakthrough pain in the following fashion:  
• First, bolus of mepivacaine (10 mL boluses injected via the catheter with no more 
than three 10 mL boluses allowed per hour) and/or increase rate of continuous 
local anesthetic infusion by 2 mL/hr (up to a maximum rate of 14 mL/hr).  All use 
of mepivacaine will be discontinued at approximately 3 am on the morning 
following surgery. 
Then, ketorolac (patients less than 65 years of age and greater than 50 kg:  30 mg IM or 
IV every 6 hours as needed with maximum daily dose 120 mg; patients greater than or 
equal to 65 years of age or less than 50 kg: 15 mg IM or IV every 6 hours as needed with 
maximum daily dose 60 mg).  All use of ketorolac will be discontinued at 1:30 am on the 
morning following surgery.    
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
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Alternatively, postoperative pain will be controlled by a continuous ropivacaine 0.2% 
infusion via PSB catheter on a PCA pump at a continuous rate of 1 ml/hr.  .  Up to two, 3 
ml boluses of Ropivacaine 0.2% may be given per hr.  If pain is not adequately controlled 
after two boluses, infusion may be increased by 2ml/hr.  All use of ropivacaine will be 
discontinued at approximately 3 am on the morning following surgery.   
 
During this continuous infusion period, patients may receive supplemental analgesia for 
breakthrough pain (patients less than 65 years of age and greater than 50 kg:  ketorolac 30 
mg IM or IV every 6 hours as needed with a maximum daily dose of 120 mg; patients 
greater than or equal to 65 years of age or less than 50 kg: ketorolac 15 mg IM or IV 
every 6 hours as needed with a maximum daily dose of 60 mg).  All use of ketorolac will 
be discontinued at 1:30 am on the morning following surgery.   
If the regional anesthetic infusion and allowed supplemental analgesia do not effectively 
control the patient’s postoperative pain, then the patient will be discontinued from the 
study.  
During this period, the patient will be instructed how to use the rating scales in the In-
Clinic Diary.  
The patient will remain in the study center for routine post-surgical care (but no topical 
or systemic analgesic treatment) and for observation for up to 9 hours to observe if the 
patient develops moderate-to-severe pain after the PSP is discontinued. During this 
period, the patient will be instructed how to use the rating scales in the Diary. 
6.3.4 Post-Surgical Eligibility Assessments and Dosing 
During the post-surgical period until 10 minutes pre-dosing, patients may consume non-
caffeinated liquids and food (no chocolate).  No other treatment is permitted.    
When the patient has pain at the surgical site, s/he will be asked to rate his/her pain on a 
categorical pain intensity scale (PI-CAT). The patient is required to have moderate or 
severe pain to be eligible for the clinical trial as indicated by a score ≥ 2 on the PI-CAT.  
The Study Coordinator will ask patients with moderate or severe pain on the PI-CAT to 
rate their pain using the PI-NRS pain intensity scale (PI-NRS).  The PI-NRS must 
indicate at least moderate pain (rating ≥ 4) for the patient to be randomized.  This 
qualifying PI-NRS rating constitutes the Baseline pain score, which will be recorded in 
the eCRF.   
If 9 hours have transpired since the popliteal sciatic block was discontinued and the 
patient does not indicate moderate or severe pain on the PI-CAT and PI-NRS, the patient 
does not qualify for the study and will be considered a screen failure.   These patients 
will be discharged from the study and routine post-operative care will be provided.   
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For patients who qualify on the PI-CAT and PI-NRS the Study Coordinator will: 
1. Record pulse, respiratory rate, blood pressure (semi-recumbent for 5 minutes), 
temperature (aural). 
2. After defining nausea (“Nausea is feeling like you want to throw up”), administer: 
a) Nausea Scale (NS) 
b) Vomiting Frequency Scale (VFS)  
c) Opioid Symptoms Scales (OSS) 
3. Select the next-numbered randomization study medication. 
4. Assure that the patient has not had any food or drink for 10 minutes prior to 
receiving study medication. 
5. Administer assigned study medication (1 capsule) to the patient with 4-8 oz. of 
water.  This is the Baseline time. 
6. Examine the patient’s mouth to assure that the capsule was swallowed. 
7. Set the timer for 30 minutes. 
8. Record the study treatment number and the date and time of administration in the 
source and electronic CRF. 
For subsequent dosing of study medication, the Study coordinator will administer one 
dose (1 capsule) of study medication every 4 hours over the initial 12 hours of the 
treatment period for a total of 4 doses of study medication.  The 5th dose of study 
medication will be administered 4 hours after the 4th dose.  Thus each patient will 
receive the same total amount of study medication, a total of 5 doses over the initial 24 
hours (i.e., mid-way between the total per-label amounts of 4-6 doses of hydrocodone/ 
APAP over 24 hours).  Subjects should be awoken for dosing, as needed to remain on 
the dosing schedule. 
 
The Study Coordinator will follow the same schedule of dosing (every 4 hours (± 10 
minutes) for 5 doses) over the final 24 hours of the treatment observation period in the 
clinic so that all patients receive the same total amount of study medication (10 doses) 
over 48 hours. 
The study treatment number and the date and time of administration of each dose of 
study medication are to be entered into the eCRF. 
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When dosing with study medication and assessments of PI-NRS, NS, and VFS are due at 
the same time, the assessments should be done first, followed by dosing. 
Patients are to be in a semi-recumbent position at least 15 minutes prior to each 
scheduled assessment time. 
All doses are to be administered with 4-8 oz. of water, and the study staff should 
examine patient’s mouth to ensure capsule is swallowed.   
Patients should not have food or drink 10 minutes prior to receiving study medication or 
prior to completing assessments.  Throughout the 48-hour treatment observation period, 
patients may consume non-caffeinated liquids and food (no chocolate) during the 20-
minute period following any set of assessments (i.e., patients may not receive food or 
liquids 10 minutes before any scheduled assessment). Use of any nicotine-containing 
product is also not permitted throughout the 48-hour treatment observation period (or at 
any time during the 7-day study). 
No topical treatments for pain and no other medications will be administered except 
supplemental (rescue) analgesic and anti-emetic prescribed by the Investigator, if needed.  
6.3.5 Study Times Initial 12 Hours Post-Initial Dose  
(every 30 minutes over the initial 12 hours: at 30 minutes, 1 hour, 1.5 hours, 2.0, 2.5, 
3.0, 3.5, 4.0, 4.5, 5.0, 5.5 hours, etc. until 12 hours after the initial administration of 
study medication) 
Every 30 minutes (±5 Minutes) the Study Coordinator will: 
1. Instruct the patient to rate pain intensity (PI-NRS). 
2. Then instruct the patient to complete the NS. 
3. Set the timer for 30 minutes. 
Every 60 minutes (±5 Minutes) the Study Coordinator will: 
1. Instruct the patient to complete the VFS.  
2. Set the timer for 30 minutes. 
Throughout this period the Study Coordinator will: 
1. Record each use of study medication every 4 hours so that a total of 4 doses of 
assigned study medication are administered over the initial 12-hour treatment 
period. 
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2. Record use(s) of supplemental/rescue analgesic and anti-emetic medication(s). 
3. Observe for and record all observed or volunteered adverse events as rated by the 
Investigator (mild, moderate, severe). 
6.3.6 Study Times: 12 Hours Post-Initial Dose through 48 Hours 
(every 60 minutes (if awake) over next 36 hours: at 13 hours, 14 hours, 15 hours, etc. 
until 48 hours after the initial administration of study medication)  
Every 60 minutes (±5 Minutes) the Study Coordinator will: 
1. Instruct the patient to rate pain intensity (PI-NRS) if the patient is awake. 
2. Instruct the patient to rate NS if the patient is awake.  
3. Instruct the patient to rate VFS if the patient is awake.  
4. Set the timer for 60 minutes. 
5. Observe and record patient status (e.g. adverse events) hourly. 
6. Record uses of study medication:  
a) 1 dose administered 4 hours after the 4th dose so that a total of 5 doses of 
study medication are administered over the initial 24-hour treatment period; 
b) 1 dose administered every 4 hours for 5 additional doses during the remaining 
24 hours at the research center, so that a total of 10 doses of study medication 
are administered over the entire 48-hour treatment observation period.  
Subjects should be awoken for dosing, as needed to remain on the dosing 
schedule. 
7. Record use(s) of supplemental/rescue medication(s) if needed. 
8. Record all observed or volunteered adverse events as rated by the Investigator 
(mild, moderate, severe). 
6.3.7 Study Time: Additional Assessments at 24 hours (±15 Minutes) 
1. Record OSS (after VFS is obtained). 
2. Set timer for 60 minutes. 
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6.3.8 Study Time: 48 hours (±15 Minutes) 
1. Record pain intensity (PI-NRS). 
2. Record NS. 
3. Record VFS 
4. Record OSS. 
5. Record temperature (aural), pulse, respiratory rate, blood pressure (after semi-
recumbent for 5 minutes). 
6. Record use(s) of supplemental/rescue medication(s). 
7. Evaluate adverse events (ongoing adverse events will be monitored until 
resolution). 
8. Provide discharge instructions for Study Days 3-7: 
• How to use the Outpatient Diary every day 
• Directions for taking/recording each use of study medication (every 4-6 hours 
as needed for pain, up to 6 doses per 24-hour period) 
• Directions for recording use of supplemental analgesic and/or anti- emetic 
medications 
• Directions for recording symptoms/adverse experiences 
• Explain study conditions for Days 3-7. 
The patient will be reminded that s/he is in a clinical trial and must remain awake until 
his/her usual bedtime, staying alert in order to record all uses of study medication and 
rescue medications, if needed, and to document all adverse events on Days 3 - 7. 
The patient will be instructed that no caffeine-containing beverage, alcohol, chocolate or 
nicotine-containing product may be used during the 7-day study period.  
The patient will also be reminded that no other treatments for pain (including topical 
treatments) and no other medications (except the supplemental analgesic prescribed by 
the Investigator, ibuprofen 400 mg) may be taken if needed for pain. 
The patient will be given a prescription for the anti-emetic of the Investigator’s choice 
according to local medical practice, with instructions to how to use this medication for 
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nausea/vomiting, if needed. 
The patient will also be instructed how to document the names and use of these 
supplemental analgesic and anti-emetic medications, per Section 5.5, above, including 
the requirement to complete all entries in the Outpatient Diary for 7 days. 
The patient will be advised which ongoing medications (e.g. antihypertensive 
medications) are permitted during the study period and which medications (per exclusion 
criterion #4) are not permitted. 
The patient will also be informed that the Study Coordinator will contact the patient by 
phone approximately 24 hours after discharge from Visit 2 (or up to 2 days later, to 
account for weekends) to ask how the patient is feeling, adverse events, and any 
medications taken, to see how s/he is doing post-op and monitor his/her use of the 
outpatient diary. 
The patient will be discharged from Visit 2 with a bottle containing the remaining study 
medication capsules, a bottle containing ibuprofen 200 mg tablets (to be used if needed), 
and a prescription for an anti-emetic(to be used if needed). 
The patient will be released from the research facility only when his/her pre- arranged 
(adult) transportation and escort have arrived. 
Patient status and findings will be recorded in the source and eCRF. 
6.3.9 Outpatient Activities:  Day 3 through Day 7 
1. Record the date and times of taking study medication at each time dosed. 
2. Record the date and times of taking supplemental analgesic and anti-emetic 
medication(s) at the time(s) used every day. 
3. Record all symptoms (adverse events) experienced over the past 24 hours (even if 
the patient did not take any study medication on a particular day). 
6.3.10 Follow-Up Telephone Call:  approximately 24 hours after discharge (+2 days, 
to account for weekends) 
The Study Coordinator will telephone the patient approximately 24 hours after discharge 
(or up to 2 days after discharge if over a weekend) to inquire about the patient’s post-op 
status (e.g., pain, bleeding, fever, nausea, vomiting, side effects) and uses of medications. 
Adverse events and concomitant medications will be recorded in the eCRF. 
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6.3.11 Follow-Up Visit 3 on Day 8 (± 2 days) 
The following procedures will be completed at the follow-up visit: 
1. Vital signs (aural temperature, pulse, respiratory rate) and blood pressure (semi-
recumbent for 5 minutes) will be measured. 
2. Retrieve Outpatient Diary, study medication bottle, supplemental pain and anti-
emetic medication bottles. 
3. Count remaining study medication capsules, account for the number of study 
medication capsules used and compliance. 
4. Evaluate adverse events (ongoing adverse events will be monitored until 
resolved, per Section 9.1, below). 
5. Review use of supplemental/rescue medication(s). 
6. Review and document all concomitant medications. 
7. Perform urine pregnancy test on all female patients. 
8. Perform urine cotinine test on all patients 
9. Discharge patient from study with instructions for routine post-op care. 
10. For any continuing side effects, the Study Coordinator will call the patient every 
48 hours (or routine follow-up) until the resolution of the side effect. 
6.4 
Concomitant Therapy 
Any concomitant medication used (e.g., antihypertensive, contraceptive) must be entered into 
the eCRF.   
6.5 
Assignment of Numbers 
Each patient who has signed an informed consent form in the study will be assigned in sequence 
the lowest available (3-digit) screening number.  
Patients assigned a screening number but who do not meet inclusion/ exclusion criteria (e.g., do 
not have at least moderate pain on the PI-CAT and PI-NRS) will have the reasons for screen 
failure entered into the eCRF.  
Patients who meet inclusion/exclusion criteria and qualify to receive study medication will be 
assigned the next available 4-digit randomization number in ascending sequential order at the 
investigative site.  Each randomization number assigns treatment according to an independent 
computer-generated randomization schedule. 
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6.6 
Treatment 
Patients will be randomized to receive over-encapsulated CL-108 5 mg, hydrocodone 5 mg/ 
APAP 325 mg, or placebo.  The randomization number for a bottle of study drug will 
correspond to the double-blind assignment of study drug assigned for an individual patient.  
6.7 
Clinical Adverse Events 
All adverse events reported until Visit 3 must be recorded in the case report form according to 
Section 9.1 of this protocol.  All Adverse Events will be followed until resolution or clinical 
stability. 
6.8 
Risks/Precautions 
Hydrocodone combined with acetaminophen is a Schedule II controlled substance that can 
produce drug dependence of the opioid type.  Like other opioids, respiratory depression has been 
associated with hydrocodone.  Deaths have also been reported in association with concomitant 
administration of hydrocodone with other depressants such as alcohol or other opioids.  Patients 
should be warned of the potential danger of the self-administration of benzodiazepines or other 
depressants while under treatment with hydrocodone. 
Opioid analgesics impair the mental and/or physical ability required for the performance of 
potentially dangerous tasks (e. g., driving a car or operating machinery).  Patients should be 
warned of these dangers and counseled accordingly.  Patients in the study will not be released 
from the facility unless their prearranged transportation has arrived.  
Promethazine is a phenothiazine.  Like other phenothiazines, respiratory depression, seizures, 
and sedation have been associated with promethazine.  Dyskinetic reactions may occur in 
patients with previous dyskinetic reactions to acute or chronic anti-emetic or antipsychotic 
medications. Because phenothiazines impair the mental and/or physical ability required for the 
performance of potentially dangerous tasks (e. g. driving a car or operating machinery), patients 
should be warned of these dangers and counseled accordingly.   
Short-term use of acetaminophen at therapeutic doses is rarely associated with side effects, 
although nausea and vomiting have been reported with its use.  Patients who are alcoholics are 
susceptible to hepatotoxicity, even liver failure, if they consume more than 4 grams of 
acetaminophen per day. 
6.9 
Overdosage 
The manifestations of overdosage with hydrocodone and promethazine are similar, with the 
most serious effects being respiratory depression and hypoventilation.  
Immediate management of opioid overdose includes ensuring a patent airway, physical and 
verbal stimulation of the patient, and assessment of level of consciousness, ventilatory and 
circulatory status. 
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In the case of overdose, the primary management should be the re-establishment of adequate 
ventilation with mechanical assistance of respiration, if required.  Naloxone may be 
administered, if necessary, to reverse opioid-induced respiratory depression.  In the presence of 
hypo-ventilation or apnea, ventilation should be assisted or controlled and oxygen administered 
as indicated. 
Acetaminophen overdosage can result in hepatotoxicity and acute liver failure.  Treatment is 
aimed at removing the acetaminophen from the body and replacing glutathione. Activated 
charcoal can be used to decrease absorption of acetaminophen if the patient presents for 
treatment soon after the overdose. The specific antidote for acetaminophen overdosage, 
acetylcysteine, (also called N-acetylcysteine or NAC) acts as a precursor for glutathione, helping 
the body regenerate enough to prevent permanent damage to the liver which, if extensive, may 
require liver transplantation. 
7 
Data Collection and Analysis  
7.1 
Recording of Data 
Data will be recorded from clinical source records and patient diaries into electronic case report 
forms (eCRFs) by site personnel.  
All missing data must be accounted for. If a space is blank because the item was not completed, 
if the item is unknown, or if the item is not applicable to an individual case the computer will 
flag the blank and the site personnel must add an explanation why the space is blank.  If an entry 
error has been made, the original entry must be corrected.  The computer will record the date of 
the change and the identity of the person making the change. 
All patients signing an informed consent form who fail screening or who withdraw before 
randomization must have the reason(s) entered in the eCRF.  All patients who are randomized 
will have all data entered in the eCRF. 
7.2 
Control Methods 
Patients will be randomly assigned to receive one of three treatments: CL-108 5 mg, 
hydrocodone 5 mg/APAP 325 mg, or placebo. In case of an emergency the Investigator should 
treat the patient assuming he/she received hydrocodone/acetaminophen/ promethazine.  In an 
unusual event where the safety of a patient is at risk and unblinding is necessary to treat the 
patient, the bottom (scratch-off) portion of the tear-off label may be accessed.  Diligent attempts 
should be made to contact the Medical Monitor and sponsor prior to unblinding.  The reason for 
unblinding, the time of sponsor contact, and unblinding procedures followed should be carefully 
documented.   
7.3 
Safety Assessments 
Verbatim adverse event terms will be coded into standardized system organ classes and 
preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA). Because 
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sleep disturbance and opioid-related adverse events contributing to it are of special interest, 
sleep disturbance, nausea, retching, vomiting, and headache will be summarized and analyzed 
for CL-108 5 mg, hydrocodone 5 mg/APAP 325 mg, and placebo.  
Adverse events will be summarized for CL-108 5 mg, hydrocodone 5 mg/ APAP 325 mg, and 
placebo. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD). 
7.4 
Statistical Analysis 
7.4.1 Primary Hypotheses 
This study will test two co-primary null hypotheses: 
• That CL-108 5 mg has the same occurrence of vomiting and use of anti-emetic(s) 
as hydrocodone 5 mg/APAP 325 mg 
• That CL-108 5 mg has the same analgesic effect as placebo 
This study uses two co-primary endpoints, one for the assessment of opioid-induced 
nausea and vomiting (OINV) and one for the assessment of pain. Both endpoints are 
defined over the initial 48 hours following randomization 
Co-Primary OINV Endpoint: 
The co-primary OINV endpoint is a binary assessment of response/no response to a 
composite index consisting of any vomiting or use of anti-emetic medication (indicative 
of nausea) over 48 hours, comparing CL-108 5 mg to hydrocodone 5 mg/ APAP 325 mg   
Co-Primary Analgesia Endpoint: 
The co-primary analgesia endpoint is the time-weighted sum of pain intensity differences 
over 48 hours (SPID48), comparing CL-108 5 mg to placebo 
The SPID48 endpoint is calculated from the PI-NRS values at baseline, every 30 minutes 
until hour 12, then every hour (when awake) until hour    48 as follows: 
• Each subsequent PI-NRS value is subtracted from the baseline PI-NRS value. 
• Each difference is weighted by the elapsed time from the previous PI-NRS value 
to the current one 
• The weighed differences are summed to yield the SPID48 
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7.4.2 Sample Size Justification 
A sample size of 300 completed patients is planned for analysis: 120 patients in the CL-
108 5 mg treatment group, 120 patients in the hydrocodone 5 mg/APAP 325 mg 
treatment group, 60 patients in the placebo treatment group. 
The rates of observed OINV (any vomiting or use of anti-emetic) were 11.9% and 45.2% 
for CL-108 7.5 mg and hydrocodone 7.5 mg/APAP 325 mg, respectively, in a previous 
48-hour bunionectomy study (CLCT-003). Based on a reduced per dose exposure to 
hydrocodone in the present study (CLCT-018), the expected incidence of OINV in the 
control group (Norco 5 mg) is estimated to be approximately 30% (vs 45% for Norco 7.5 
mg in CLCT-003).  With an absolute delta of .20, the estimated incidence of OINV in the 
CL-108 5 mg treatment group is 10%.  With a power of 96.4% and a 2-sided 2-sample 
chi-square test with an alpha of 0.05, approximately 110 patients would be required in 
each active treatment group. 
The observed means of SPID48 in CLCT-003 were 118.4 and 53.1 for CL-108 7.5 mg 
and placebo, respectively, and the pooled standard deviation was 75. Based on a 
reduction of hydrocodone exposure (from 7.5 to 5 mg per dose), the estimated SPID48 is 
one-third lower for CL-108 5 mg.  For SPID48, a sample size of 110 patients in the CL-
108 5mg treatment group and 55 in the placebo group provides 93.7% power using a 2-
sided 2-sample t-test with an alpha of 0.05 for a delta of 43.5 (96.6 vs 53.2) and SD of 
75. 
The overall power is 90% for the analyses of these 2 co-primary endpoints. Based on the 
number of patients who do not qualify (eg, because of admission criteria such as low 
baseline pain) or patients who enroll but do not complete the study, the plan is to enroll 
approximately 330 patients in order to be able to analyze a total sample size of 300 
patients who complete the study.  
7.4.3 Key Secondary Endpoints 
1. Percentage of patients with complete absence of OINV (no nausea, no vomiting, 
and no use of anti-emetic medication) over 48 hours, comparing CL-108 5 mg to 
hydrocodone 5 mg/APAP 325 mg 
2. Percentage of patients with any vomiting over 48 hours, comparing CL-108 5 mg 
to hydrocodone 5 mg/APAP 325 mg  
3. Percentage of patients with any nausea over 48 hours, comparing CL-108 5 mg to 
hydrocodone 5 mg/APAP 325 mg 
4. Percentage of patients with any nausea or vomiting over 48 hours, comparing 
CL-108 5 mg to hydrocodone 5 mg/APAP 325 mg    
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5. Percentage of patients with Post-Discharge Nausea and Vomiting (PDNV) over 
days 3-7 
 
6. Number of doses of study medication taken over days 3-7 
 
7. Number of doses of study medication taken per day over days 3-7 
 
 
7.4.4 Labeling Endpoints 
Specific endpoints will be presented in sequence to support a label stating that: 
1.  CL-108 5 mg relieves moderate to severe pain 
2.  CL-108 5 mg prevents opioid-induced nausea and vomiting (OINV) 
3.  More patients treated with CL-108 5 mg experience complete absence of OINV 
than patients treated with a comparable product containing hydrocodone 5 mg/ 
acetaminophen 325 mg 
4.  Patients treated with CL-108 5 mg experience less vomiting than patients treated 
with a comparable product containing hydrocodone 5 mg/ acetaminophen 325 mg 
5. Patients treated with CL-108 5 mg experience less nausea than patients treated 
with a comparable product containing hydrocodone 5 mg/acetaminophen 325 mg 
6. Patients treated with CL-108 5 mg experience less nausea and vomiting than 
patients treated with a comparable product containing hydrocodone 5 
mg/acetaminophen 325 mg 
7. Patients treated with CL-108 5 mg experience less nausea and vomiting after 
discharge following surgery than patients treated with a comparable product 
containing hydrocodone 5 mg/acetaminophen 325 mg  
 
8. Patients treated with CL-108 5 mg take more doses over days 3-7 and have 
greater reduction in pain and less OINV after discharge following surgery than 
patients treated with a comparable product containing hydrocodone 5 mg/ 
acetaminophen 325 mg  
 
9. Patients treated with CL-108 5 mg take more doses each day over days 3-7 and 
have greater reduction in pain and less OINV after discharge following surgery 
than patients treated with a comparable product containing hydrocodone 5 mg/ 
acetaminophen 325 mg. 
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These labelling endpoints are supported by the co-primary and key secondary endpoints. 
7.4.5 Study Populations 
Three datasets will be used for analysis: safety, intent-to-treat, and per protocol.   
The definition of these populations follows: 
• Safety Population:  All randomized patients who received at least one dose of 
study medication comprise the Safety Population. 
• Intent-to-Treat (ITT) Population:  All randomized patients who took at least one 
dose of study medication comprise the Intent-to-Treat Population.  The ITT 
Population is the same as the Safety Population. 
 Per-Protocol Population:  All ITT patients without major protocol violations that 
significantly affect the efficacy analyses.  (Major and minor protocol violations 
will be defined in the SAP.) 
Safety will be analyzed based on the safety population. Efficacy will be analyzed based 
on the ITT and Per-Protocol populations. 
7.4.6 Predefined Subgroups 
Analgesia (SPID24, SPID48) will be analyzed in the subgroups of patients with moderate 
pain and patients with severe pain. No other subgroup analyses are planned.  
7.4.7 Missing Data Conventions 
Missing data for PI-NRS, NS, VFS and OSS will be imputed on a patient-by-patient 
basis as specified in the Statistical Analysis Plan. 
7.4.8 Use of Supplemental Medication 
After each use of the supplemental medication for pain (ibuprofen) during the 48-hour 
period of the primary outcome measures, a baseline observation carried forward (BOCF) 
method will be used to impute PI-NRS and a worst observation carried forward (WOCF) 
method will be used to impute NS, VFS, and OSS values for the next 6 hours (the 
duration of action on the label for ibuprofen 400 mg). After the first use of anti-emetic 
medication, a worst observation carried forward (WOCF) method will be used to impute 
NS, VFS, and OSS values (because any use of an anti-emetic indicates the presence of 
OINV, i.e., non-response), and a baseline observation carried forward (BOCF) method 
will be used to impute PI-NRS values until the next scheduled assessment following the 
duration of action of the anti-emetic medication.5,9 
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7.4.9 Statistical Analysis 
All analyses will follow a prospectively approved statistical analysis plan (SAP). The 
SAP will be approved before data lock and before any looks at the data. The SAP will 
include the details of all analyses, all database specifications and conventions, and all 
tables, listings and figures.  
All analyses will be conducted using two-sided tests with a type I error of 0.05. 
7.4.10 Descriptive Statistics: 
Continuous variables will be summarized as n, mean, standard deviation, minimum, 
median, and maximum. Asymptotic 95% confidence intervals for means and for mean 
differences will be provided as specified in the SAP. For variables expected to be 
skewed, transformations such as log may be specified in the SAP. 
Categorical and binary variables will be summarized as percentages, noting the 
numerator and denominator of the percentage. 
7.4.11 Analysis of the OINV Co-Primary Endpoint: 
The OINV endpoint will be tested using a logistic regression model with treatment, 
gender, and investigator as main effects. Treatment will be tested using a type III 
likelihood ratio test. The test will be performed on the ITT population. 
7.4.12 Analysis of Analgesia Co-Primary Endpoint: 
The analgesia endpoint will be tested using a general linear model with treatment, 
investigator and gender as main effects. Treatment will be tested using a type III test. The 
test will be performed on the ITT population. 
The mean difference between treatment groups will be calculated using least squares 
means, and 95% confidence interval will be calculated. 
7.4.13 Sensitivity Analysis of Primary Endpoints 
The missing data imputation method has little impact on the event driven OINV 
endpoint. Therefore, no sensitivity analysis will be performed for the OINV endpoint.  
Two sensitivity analyses will be performed on SPID48 to evaluate the robustness of the 
co-primary analgesic efficacy analysis and the impact of missing data on the results for 
the ITT population. 
In the first sensitivity analysis, the method of multiple imputations (MI)10 will be used to 
impute post-dose missing pain intensity differences over 48 hours (either due to early 
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09-Nov-2018
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Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
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discontinuation, no valid data entry, or use of supplemental medication for pain or use of 
anti-emetics for the duration of their dosing interval during which the medications were 
administered) by using Markov chain Monte Carlo (MCMC) method for the non-
monotone missing pattern values and then the sample mean pain intensity difference for 
patients with available data within that treatment group at that time point for the 
monotone missing pattern values. The method of multiple imputations uses SAS PROC 
MI to generate multiple complete datasets for the calculation of SPID48, and PROC 
MIXED and MIANALYZE to analyze and combine the results from them. To ensure 
robustness of results 10 complete datasets will be created with the initial seed value set at 
‘123’. The same general linear model for the co-primary efficacy endpoint will be carried 
out for the above datasets. 
In the second sensitivity analysis, a Pattern Mixture Model,11 which is based upon an 
assumption of Missing Not at Random (MNAR) with an approach similar to above 
multiple imputations, will be used with missing data for Patients at each time point 
imputed using the available data for Placebo Patients at that time point. 
7.4.14 Analyses of Key Secondary Endpoints: 
The details of key secondary endpoint analyses will be specified in the SAP.   
7.4.15 Statistical Significance: 
The two co-primary endpoints will each be tested at the 0.05 using a two-sided test using 
the ITT population. Both co-primary endpoints must be statistically significant so that no 
adjustment for multiple comparisons is required.  
If both co-primary nausea and pain endpoints are significant, the key secondary 
endpoints will be tested using Hochberg step-up test procedure for controlling family-
wise type 1 error on the ITT population at the 0.05 level. This sequential testing 
procedure preserves the overall type I error so that no adjustment for multiple tests is 
required.   
7.4.16 Safety 
Adverse events will be summarized for each treatment group. Tabulations and listings of 
values and/or parameters will be presented for the incidence and severity of adverse 
events (and, separately, for the incidence and severity of nausea, retching, vomiting, 
emetic episodes, sleep disturbance, headache).   
7.4.17 Interim Analyses 
An independent Data Monitoring Committee (DMC) will meet to review efficacy and 
safety endpoints. The DMC will operate under a charter and will make recommendations 
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to the sponsor. An interim analysis will be performed by the DMC after approximately 
66% of the subjects have completed the 300-subject study and there is adequate 
representation from each of the investigative sites (i.e., approximately 30 completed 
subjects per site).  If it is judged impossible to achieve this de minimis representation at a 
particular site or sites, the interim analysis will be conducted on the total number of 
subjects completed (i.e., approximately 200 subjects). Since the DMC will review 
efficacy data, formal sequential boundaries for efficacy and futility will be declared in the 
DMC’s Statistical Analysis Plan.  
7.4.18 Protocol Deviations 
No patients will be excluded from the Safety or Intent-to-Treat populations because of 
protocol violations. Patients who do not meet admission criteria prior to dosing or who 
have major protocol violations after dosing that could significantly affect efficacy results 
(e.g., a missed dose of study medication) will be excluded from the Per Protocol 
population.  
Minor protocol deviations that do not bias efficacy results (such as assessments not 
obtained at scheduled time points during the 48-hour primary treatment evaluation 
period) will not be noted as deviations. 
8 
Clinical Supplies  
8.1 
Packaging 
Double-blinded study medication will be provided in 100-mL HDPE bottles, each 
containing 45 capsules of study medication. 
8.2 
Label 
On the outer cover of each bottle will appear: 
Subject Initials/Subject Screening Number:           ___ ___ ___ /___ ___ ___ 
Date Dispensed: 
___ ___ ___  
 
Protocol Number:   
CLCT-018 
 
Directions:     
Take one capsule every 4-6 hours for pain.   
 
  
Do not exceed 6 capsules in a 24-hour period.   
  
 
  
Keep this out of the sight and reach of children. 
 
Contents: 
  
45 green capsules   
 
  
Store at 20o to 25oC (680 to 770F) 
 
 
Manufactured for: 
Charleston Laboratories 
 
  
1001 North US Highway 1 
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Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
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Jupiter, FL 33477 
 
Date of Manufacture: MM-DD-YYYY 
 
Lot #:  
  
vvvvvvv 
 
Caution:  
 
New Drug Limited by Federal Law to Investigational Use 
Only Federal law prohibits the transfer of this drug to any 
person other than the patient for whom it was prescribed.  
Investigational Drug to be used by a Qualified Investigator 
Only. 
 
Study Medication #:  XXXX 
 
A tear-off label will also be attached to the outer cover of each bottle and will be placed in the 
source documents.  The top section of the tear-off label is open-label: 
 
Subject Initials  
___ ___ ___  
Subject Screen # 
___ ___ ___ 
Date 
___ ___ ___ 
Study Medication # 
XXXX  
 
The bottom portion of the tear-off label is scratch-off (blinded, identifying the Study Medication 
# and the Treatment Group). 
 
9 
Investigator Obligations 
9.1 
Adverse Event Reporting Obligations 
An important objective of this study is to assess the safety and tolerability of the drug.  
Therefore, the Investigator is responsible for recording and reporting adverse events observed 
during and after study drug treatment. 
9.1.1 Definition of an Adverse Event 
An adverse event is any reaction, side effect, or other untoward event, regardless of 
relationship to study drug, including death, experienced by a patient.   An adverse event 
may consist of a disease, an exacerbation of a pre-existing illness, or condition, a 
recurrence of an intermittent illness or condition, a set of related signs or symptoms, or a 
single sign or symptom. 
Serious and non-serious events occurring after the ICF is signed, but prior to first dose of 
study drug, will be collected as part of the medical history. Adverse events noted or 
reported from the first administration of investigational product to Visit 3 will be 
followed until resolution. 
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A treatment-emergent adverse event (TEAE) is defined as: 
1. Any new medical occurrence not seen before initial study drug administration. 
2. A pre-existing medical condition which recurs with increased intensity or 
increased frequency subsequent to initial study drug administration. 
3. A medical condition which is present at the time of study drug administration 
which exacerbates at any time following initial study drug administration. 
A pre-existing condition or signs or symptoms present at the time of study drug 
administration are not considered an adverse event unless criterion #2 or #3 above 
applies.  Signs or symptoms associated with the disease or medical condition being 
evaluated (e.g., pain) should not be recorded as adverse events. 
Standard symptoms expected in patients who have recently undergone first metatarsal 
bunionectomy will not be recorded as adverse events unless they are of greater severity 
and/or intensity than would be expected.  The events considered standard in this study 
are:  pain, erythema, numbness, swelling, bruising, bleeding, and decreased range of 
motion of the affected foot.  Investigators will use their clinical judgment in determining 
whether these symptoms are of greater severity than usual.    
9.1.2 Definition of a Serious Adverse Event (SAE) 
Each of the following adverse events is defined as serious: 
1. Death 
2. Life-threatening event 
A "life-threatening" event is present when the patient was, in the view of the 
Investigator, at immediate risk of death from the event as it occurred.  Note that 
this definition does not include an event that, had it occurred in a more serious 
form, might have caused death. 
3. Inpatient hospitalization or prolongation of existing hospitalization 
Note that elective hospitalization for treatment of a pre-existing condition that did 
not worsen/exacerbate during the study is not considered a serious adverse event.  
Complications, which occur during any hospitalization, are adverse events and if 
such complication(s) prolongs the hospitalization, the event is a serious adverse 
event.  These conditions should be recorded on the physical examination section 
of the eCRF. 
4. A persistent or significant disability / incapacity 
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5. Any congenital anomaly / birth defect  
6. Important medical events that may not be immediately life-threatening or result 
in death or hospitalization may be considered a serious adverse event (SAE) 
when, based upon appropriate medical judgment, they may jeopardize the patient 
or may require medical or surgical intervention to prevent one of the outcomes 
listed in the definition of SAE above.   
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias, or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
9.1.3 Recording and Documenting Adverse Events 
Patient-reported adverse events will be captured from the initial time of dosing with study 
medication, through the time of discharge from the study. Serious adverse events will be 
captured from the initial time of dosing with study medication until 30 days after the last 
time of dosing with study medication.    
Each adverse event must be promptly recorded and sufficiently documented by the 
Investigator in the source document as well as the eCRF, even if the adverse event is 
assessed by the Investigator as unlikely to be causally related to therapy with study drug.  
The Investigator should attempt, if possible, to establish a diagnosis based on the 
presenting signs and symptoms.   
If the adverse event meets the definition of an SAE, in addition to being documented on 
the AE page of the eCRF, the SAE form must also be completed. The completeness and 
accuracy of these forms will be monitored. 
When a patient spontaneously mentions any problems or an adverse event is observed, the 
duration and intensity of each adverse event will be documented as well as any action 
taken and treatment administered. The investigator will evaluate the adverse event and 
determine the severity and relationship to (association with) study medication.   
Recurrent symptoms of a chronic pre-existing condition are not considered adverse events 
unless they occur in a worse or unexpected pattern during study drug administration. 
9.1.4 Intensity of Adverse Events 
The intensity (or severity) of adverse events is characterized as mild, moderate, or 
severe: 
• Mild adverse events are usually transient, do not interfere with the patient’s daily 
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activities, and often respond to symptomatic therapy (e.g. rest or distraction). 
• Moderate adverse events introduce some level of inconvenience or concern to 
the patient and may interfere with daily activities, but are usually ameliorated by 
simple therapeutic measures (e.g. medication to treat the symptom). 
• Severe adverse events significantly interrupt a patient’s usual daily activity and 
often are not ameliorated by therapeutic drug therapy or other treatment.  In 
addition, the adverse event may require discontinuing or reducing the dose of 
study medication administration.  
When the intensity of an adverse event changes more frequently than once daily, the 
maximum intensity for the event is recorded.  If the intensity changes after a number of 
days, then these sub-events or changes are recorded separately (i.e., with distinct onset 
and stop dates). 
9.1.5 Relationship to Study Medication 
The degree of “relatedness” of the adverse event to the study drug may be described 
using the following scale:   
• Not related indicates that the adverse event is definitely not related to the 
study drug. 
• Unlikely related indicates that there are other, more likely causes and study 
drug is not suspected as a cause. 
• Possibly related indicates that a direct cause and effect relationship between 
study drug and the adverse event has not been demonstrated but there is a 
reasonable possibility that the event was caused by the study drug. 
• Probably related indicates that there probably is a direct cause and effect 
relationship between the adverse event and the study drug. 
It is the sponsor’s policy to consider “Probable” and “Possible” causality assessments as 
positive causality and to consider “Not” and “Unlikely” causality assessments as 
negative causality. 
Assessments will be recorded on the eCRF.  The date and time of the last dose of study 
medication will be recorded on the AE page of the eCRF. 
9.1.6 Therapeutic Failure as an Adverse Event 
Reports of therapeutic failure need not be recorded or processed as adverse events.  
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Protocol No. CLCT-018 
 
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9.1.9 Other Investigations 
The Investigator and supporting personnel responsible for patient care should institute 
any supplementary investigations of serious adverse events based on their clinical 
judgment of the likely causative factors.  This may include seeking a consult by an 
appropriate specialist.  Charleston Laboratories may also request extra tests or follow-up 
assessment.  If a patient dies, any post-mortem findings (including histopathology) must 
be provided to Charleston Laboratories. 
9.1.10 Ethics Committee Notification 
The Investigator is responsible for promptly notifying the ethics committee (Institutional 
Review Board) of all serious adverse events, including any significant follow-up 
information. 
9.1.11 Post-study Serious Adverse Events 
The Investigator should notify Charleston Laboratories of any new serious adverse event 
that occurs within 30 days following the last dose of study drug.   
Investigators should notify Charleston Laboratories, or designee, if they become aware 
of a study participant who is one of the parents of a subsequently conceived child with a 
congenital anomaly. 
9.1.12 Regulatory Aspects 
In agreeing to the provisions of this protocol, the legal responsibilities for prompt 
notification of serious adverse events are accepted by the Investigator. 
9.2 
Drug Accountability 
9.2.1 Storage of Investigational Drug 
All study medication for this study must be stored under ambient temperature conditions 
in a locked area suitable for schedule II controlled substances. The area must also be free 
of environmental extremes and with a limited access.  Before any agreements are 
concluded between the Principal Investigator and Charleston Laboratories, the drug 
storage area will be inspected and the drug accountability system discussed. 
9.2.2 Receipt of Drug Shipment 
No study drug will be shipped prior to receipt of a valid DEA Form 222 by the clinical 
trial supplier. The Principal Investigator or designee, upon receipt of the drug supplies 
and accompanying packing list, will conduct an inventory and sign the pro forma invoice 
and manufacturer shipping checklist and forward one copy to the manufacturer and one 
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copy to Charleston Laboratories.  One copy of all documents contained with the drug 
supplies must be retained in the Investigator's records. 
9.2.3 Materials Control 
The Principal Investigator, or his designee, shall record the dispensing of the clinical 
drug supply to patients and any subsequent returns.  These records will be made 
available to clinical monitoring personnel for the purpose of accounting for the clinical 
drug supply.  A drug supply inspection for inventory purposes and assurance of proper 
storage will be conducted no less than every 6-8 weeks throughout the clinical 
investigation.  Any significant discrepancy and/or deficiency is to be recorded and 
immediately reported to Charleston Laboratories and the DEA (according to 
requirements), and a plan for resolution is to be documented. 
Clinical trial material must not be loaned or dispensed by the Principal Investigator to 
another Investigator or site.  Only patients in this clinical trial and eligible for treatment 
are to receive this clinical trial material. 
9.2.4 Return of Drug to Sponsor 
At the end of the study, a final inventory will be performed by the Study Monitor and the 
Principal Investigator or designee.  If any supplies are missing, this must be indicated on 
the Drug Accountability Form together with an explanation of the discrepancy.  The 
Principal Investigator will be instructed to return all unused medication to the 
manufacturer along with a DEA 222 Form and to return a copy of the Clinical Supplies 
Return Form to Charleston Laboratories or designee.  The Principal Investigator must 
retain a copy of the Clinical Supplies Return Form and the original Drug Accountability 
Form.  A copy of the Drug Accountability Form must be returned to the Study 
Monitor/Charleston Laboratories. 
9.3 
Deviations from Protocol 
The Investigator is not permitted to deviate from the protocol.  Apart from the regulatory 
requirements, it is vital to the success of the study that the Investigator adheres to the details of 
the protocol and thus holds to a minimum the number of cases later classified as "incomplete," 
"unusable," or "not evaluable." 
Charleston Laboratories will not compensate the Investigator for evaluation of cases in which 
the procedures and evaluations are not conducted as specified in the protocol. 
9.4 
Disclosure of Data 
9.4.1 Confidentiality 
The Principal Investigator and all of the Principal Investigator's employees or agents 
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involved with this study shall not disclose or use for any purposes (other than 
performance of the Study) any data, records, or other information (hereinafter 
collectively "Information") disclosed to the Principal Investigator or his employees or 
agents.  Such Information shall remain the confidential and proprietary property of 
Charleston Laboratories, and shall be disclosed only to the Principal Investigator or his 
employees or agents.   
The obligation of non-disclosure shall not apply to the following: 
a. Information after such time that it is or becomes publicly available through no 
fault of the Principal Investigator or his employees or agents; 
b. Information after such time that it is disclosed to the Principal Investigator by a 
third party entitled to disclose such information; or 
c. Information that is already known to the Principal Investigator as shown by his 
prior written records provided the Principal Investigator so advises Charleston 
Laboratories within twenty (20) days after disclosure of the Information to the 
Principal Investigator by Charleston Laboratories. 
9.4.2 Publication 
All data resulting from this study remain property of Charleston Laboratories. 
Publication of trial results is discussed in the Clinical Trial Agreement. 
9.5 
Study Records and Source Documents 
Federal regulations and Charleston Laboratories policy require that, following completion of a 
clinical study, a copy of all records of that study be maintained by the Principal Investigator for 
at least the shorter of the following two time periods: 
• Two years after FDA approval of the drug for the indication for which it was 
investigated; or 
• In situations where no application is to be filed or an application is not approved for 
such indication, two years after the IND is discontinued and the FDA is notified. 
Current electronic data collection should be maintained throughout the conduct of the study.  
The Investigator must maintain an electronic copy (e. g CDROM) of all data collected for each 
patient screened and treated.  Charleston Laboratories or its representative will provide the 
electronic copy of the data; paper copies of the completed eCRFs for each patient are not 
required. 
In order to assure the accuracy of data collected in the eCRFs, it is mandatory that 
representatives of Charleston Laboratories, as well as representatives of the Food and Drug 
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Administration, have access to original source documents (e.g., patient records, patient charts, 
and laboratory reports).  During the review of these documents, the anonymity of the patient will 
be respected with strict adherence to professional standards of confidentiality. 
Charleston Laboratories reserves the right to terminate the study for refusal of the Investigator to 
supply source documentation of work performed in this clinical trial. 
9.6 
Investigator Documentation 
9.6.1 Patient Consent 
Written informed consent of the patient to participate in the study must be obtained in 
accordance with the Declaration of Helsinki and in accordance with the FDA 
Regulations set forth in Part 50 of Title 21 of the Code of Federal Regulations. 
9.6.2 Ethics Committee Review 
This protocol, the Informed Consent Form, and any relevant supporting information must 
be submitted to the ethics committee (IRB) for review and must be approved before the 
study is initiated. In addition, all advertising materials must be approved by the IRB. The 
study will be conducted in accordance with FDA Regulations, applicable national and 
local health authority, and IRB requirements.  
The Principal Investigator is responsible for keeping the IRB apprised of the progress of 
the study and of any changes made to the protocol as deemed appropriate.  
The Principal Investigator must also keep the IRB informed of any significant adverse 
events.  
Investigators are required to promptly notify their respective IRB of all adverse drug 
reactions that are both serious and unexpected. This generally refers to SAEs that are not 
already identified in the Investigator Brochure and that are considered by the Investigator 
to be possibly or probably related to the study drug. Some IRBs may have other specific 
adverse event requirements to which Investigators are expected to adhere. Investigators 
must immediately forward to their IRB any written safety report or update provided by 
Charleston Laboratories (e.g. IND safety report, Investigator Brochure, safety 
amendments and updates, etc.). 
The Principal Investigator will forward to Charleston Laboratories a copy of the ethics 
committee approval of this protocol, amendments, informed consent form and any 
changes to the informed consent form.  A copy of the IRB membership list is to be 
provided to Charleston Laboratories.   
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9.6.3 Curriculum Vitae and FDA Form 1572 
The Principal Investigator must provide Charleston Laboratories with his/her own 
current curriculum vitae, a current curriculum vita for each sub-Investigator, and a 
completed and signed FDA Form 1572. 
9.6.4 Financial Disclosure   
The Investigator is required to provide Financial Disclosure for each person listed on 
Form FDA 1572 relating to financial interests held. 
9.6.5 Tax ID No. and Form W-9 
Prior to payments from any grant-in-aid, Charleston Laboratories must be provided the 
tax identification number for each grant payee and a completed Form W-9.  In addition, 
the Investigator is required to provide Financial Disclosure for each person listed on 
Form FDA 1572 relating to financial interests held. 
9.6.6 Laboratory Certification and Normal Values 
(Not applicable.)  
9.6.7 Final Report to the IRB 
After completion of the clinical trial, the Investigator will submit a Study Close-Out 
Report to the IRB. 
10 
Termination of Study 
Charleston Laboratories reserves the right to discontinue this study for administrative reasons at any 
time.  Investigators will be compensated for reasonable expenses incurred, if it is necessary to 
terminate the study.  Charleston Laboratories will not compensate the Investigator for evaluation of 
cases in which the procedures and evaluations are conducted in a manner other than that specified 
by the protocol. 
11 
Investigator's Protocol Agreement 
The Investigator's Protocol Agreement (last page of this protocol) must be signed by the Principal 
Investigator.  The original or a copy must be kept on file at Charleston Laboratories or designee, and 
the Investigator must retain the original or a copy.  The completed Investigator's Protocol 
Agreement signifies review and acceptance of the protocol by the Principal Investigator prior to 
initiation of the study. 
 
 
 
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12 
References  
1. 
Apfel CC, Greim CA, Haubitz I et al. A risk score to predict the probability of 
postoperative vomiting in adults.  Acta Anaesthesiol Scand 1998;42:495-501. 
2. 
Apfel CC, Laara E, Koivuranta M, et al. A simplified risk score for predicting 
postoperative nausea and vomiting.  Anesthesiology 1999;91:693-700. 
3. 
Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the 
prevention of postoperative nausea and vomiting. NEJM 2004 June 10;350 (24):2441-
51. 
4. 
Apfelbaum JL, Gan TJ, Zhao S, Hanna DB, Chen C. Reliability and validity of the 
perioperative opioid-related symptom distress scale. Anesth Analg 2004;99:699-709. 
5. 
Center for Drug Evaluation and Research, US Food and Drug Administration. Guidance 
for Industry. Analgesic Indications: Developing Drug and Biological Products. 2014. 
6. 
Gan T, Meyer T, Apfel C, et al. Consensus guidelines for the management of 
postoperative nausea and vomiting. Anesth Analg 2003;97:62–71. 
7. 
Gan TJ. Risk factors for postoperative nausea and vomiting. Anesth Analg 
2006;102:1884-98.20. 
8. 
Gan TJ, Meyer T, PONV Consensus Panel: Christian A, Chung F, Davis P, Eubanks S, 
Kovac A, Philips B, Sessler D, Temo J, Tramer M, Watcha M. A consensus panel 
identification of risk factors for PONV.  Anesth 2002; 97:A19. 
9. 
Panel on Handling Missing Data in Clinical Trials; National Research Council. The 
Prevention and Treatment of Missing Data in Clinical Trials. National Academies Press. 
2010. 
10. Ratitch B and O’Kelly M. Implementation of Pattern Mixture Models Using Standard 
SAS/STAT Procedures. PharmaSug 2011 paper SP04. 
11. Little RJA. Pattern-Mixture Models for Multivariate Incomplete Data with Covariates. 
Biometrics, Vol. 52, No. 1 (Mar., 1996), 98-111 
 
 
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13 
Appendices 
13.1 Appendix 1. Analgesic Rating Scales 
 
Numerical Pain Intensity Scale (PI-NRS) 
 
 
 
On a scale of 0 to 10, where 0 is “no pain” and 10 is “severe pain,”  circle 
the number that best describes your pain now. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
Categorical Pain Intensity Scale (PI-CAT) 
 
 
 
How would you describe your pain now? 
 
 (circle one) 
 
NO 
MILD 
MODERATE 
SEVERE 
PAIN 
PAIN 
PAIN 
PAIN 
 
 
 
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13.2  Appendix 2: Nausea/Vomiting Rating Scales 
 
Nausea Scale (NS) 
 
 
 
Over the past half-hour (over the past hour), 
have you had any nausea  
(feeling like you wanted to throw up)?  
 
(circle one) 
 
NO NAUSEA  
 
NAUSEA 
 
 
Vomiting Frequency Scale (VFS) 
 
    
  
  
How often did you vomit (throw up) over the past hour? 
 
  (Circle one) 
 
  
NOT         
 
ONE        
  
TWO   
 
THREE OR 
AT ALL     
TIME       
 
TIMES        
 
MORE TIMES 
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13.3 Appendix 3: Opioid Symptoms Scales (OSS) 
 
 
For each symptom you’ve had over the past 24 hours,  
circle the number that describes how severe it was for you: 
 
 
 
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13.4 Appendix 4.  Nausea Prone Questionnaire (called “Health Questionnaire” in the CRF) 
 
1. What medications have you used over the past week? 
 
Any antihistamines (e.g., Benadryl, Claritin)? Any cough-cold products (e.g., Sudafed, 
Tussionex)? Any antibiotics (e.g., Cipro, tetracycline)? Any vitamins or nutritional 
supplements (e.g., vitamin E, calcium)?  Any prescription medicines? 
 
List all medications used over the past week: 
 
 
 
 
 
2. Did you have any side effects from any of these medicines? NONE 
N/A 
 
(Circle all that apply) 
 
 
a) Nausea 
b) Vomiting 
 
c)  Problems with urination 
d) Diarrhea 
 
e)  Constipation 
f) Itchy skin 
 
g)  Dizziness (light-headed) 
h) Difficulty concentrating 
 
i) Feeling confused 
j) Drowsiness (difficulty staying awake) 
 
k)  Lack of energy (fatigue, weakness) 
l) Dry mouth 
 
m) Headache 
n) Hives 
 
o) Other:    
 
 
p) Other:    
 
 
 
 
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Considering medications you have used in the past (e.g., antihistamines, cough medicines, 
cold products, antibiotics, nutritional supplements, prescription medicines), have you ever 
had any side effects from any medicines?                         NONE 
 
(Circle all that apply) 
 
a) Nausea 
b) Vomiting 
 
c)   Problems with urination 
d) Diarrhea 
 
e)  Constipation 
f) Itchy skin 
 
g)  Dizziness (light-headed) 
h) Difficulty concentrating 
 
i) Feeling confused 
j)  Drowsiness (difficulty staying awake) 
 
k)   Lack of energy (fatigue, weakness) 
l) Dry mouth 
 
m) Headache 
n) Hives 
 
o) Other:    
 
 
p) Other:    
 
 
 
Write the medicine(s) beside each side effect: 
For example:  Drowsiness – Benadryl, Tylenol with codeine, Vicodin. 
 
 
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3. Have you ever used a strong pain-killer, a prescription drug 
NO 
YES 
such as Vicodin, Oxycontin, Norco, Tylenol with codeine, morphine, 
Demerol, hydrocodone, Lortab, cough medicine containing codeine, 
Tussionex? 
 
Which medicine(s)?   
 
 
 
 
4. Have you ever had any allergies or side effects from any of these medicines?   NONE N/A 
 
(Circle all that apply) 
 
a) Nausea 
b) Vomiting 
 
c)   Problems with urination 
d) Diarrhea 
 
e)  Constipation 
f) Itchy skin 
 
g)  Dizziness (light-headed) 
h) Difficulty concentrating 
 
i) Feeling confused 
j) Drowsiness (difficulty staying awake) 
 
k)   Lack of energy (fatigue, weakness) 
l) Dry mouth 
 
m) Headache 
n) Hives 
 
o)  Other:    
 
 
 
 
Write in the medicine(s) beside each side effect: 
For example:  Drowsiness – Tylenol with codeine, Lortab, Vicodin. 
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6. 
Have you ever had an operation or surgical procedure? 
If yes, type of operation or surgical procedure (e.g., stitches): 
NO 
YES  
 
7. 
Were you ever nauseous after taking any medication after the 
surgery or procedure? 
 
NO 
 
YES 
 
N/A 
8. 
Did you vomit after taking any medication after the surgery or 
procedure? 
NO 
YES 
N/A 
9. 
Do you have anemia or bleeding problems? 
If yes, medications you are taking: 
NO 
YES  
 
10. Do you have heart disease or high blood pressure? 
If yes, medications you are taking: 
 
NO 
 
YES 
 
 
11. Do you have asthma? 
If yes, medications you are taking: 
 
NO 
 
YES 
 
 
12. Do you have any gastro-intestinal disorders (ulcer, colitis, etc.)? 
If yes, medications you are taking: 
 
NO 
 
YES 
 
 
13. Do you have arthritis? 
If yes, medications you are taking: 
 
NO 
 
YES 
 
 
14. Do you have any endocrine disorder (thyroid disease, diabetes)? 
If yes, medications you are taking: 
 
NO 
 
YES 
 
 
15. Do you have any neurologic disease (seizure disorder)? 
If yes, medications you are taking: 
 
NO 
 
YES 
 
 
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16. Do you ever get “vertigo” (a sense of motion when 
you’re not moving, a sense of things moving around you, 
with dizziness, lightheadedness, or loss of balance)? 
NO 
YES 
17. Do you have “Meniere’s Disease” (a sense of the room spinning 
around you, ringing in the ears, hearing loss, ear fullness, 
with recurrent bouts of dizziness, loss of balance, or unsteadiness)? 
NO 
YES 
18. Are you ever nauseous when you have a Meniere’s attack? 
NO 
YES 
N/A 
19. Do you get “migraine headaches”? 
NO 
YES 
If yes, medications you are taking:    
 
 
 
 
20. 
Do you ever get headaches that are associated with nausea 
NO 
YES      N/A 
or vomiting? 
 
21. 
Do you ever get nauseous? 
NO 
YES 
If yes, when?  
 
 
 
 
22. Do you ever get “a knot in your stomach” when you’re nervous 
NO 
YES  
or afraid or very worried about something? 
 
23. Did this “knot in your stomach” ever make you feel nauseous? 
 
 
NO 
 
 
YES 
 
 
N/A 
24. Did this “knot in your stomach” ever make you vomit? 
NO 
YES 
N/A 
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Following are questions about different situations where some people tend to be nauseous or 
vomit: 
 
25. Do you walk slowly or turn slowly to avoid losing your balance? 
NO 
YES 
26. Do you get “car sick”? 
NO 
YES 
27. Do you need to have the window open when riding in a car? 
NO 
YES 
28. Do you get “sea sick”? 
NO 
YES 
29. Do you get sick to your stomach or nauseous or even vomit 
when you gag on something? 
NO 
YES 
30. Do you get sick to your stomach or nauseous or even vomit 
when riding backwards on a train? 
NO 
YES 
31. Do you get sick to your stomach or nauseous or even vomit 
when riding on a plane during turbulence or a sudden turn? 
NO 
YES 
32. Do you get sick to your stomach or nauseous or even vomit 
on roller coasters or other amusement park rides? 
NO 
YES 
33. Do you get sick to your stomach or nauseous or even vomit 
from spinning around? 
NO 
YES 
34. Do you get sick to your stomach, nauseous, or vomit sometimes 
when you bend over? 
NO 
YES 
35. Do you get sick to your stomach or nauseous or even vomit 
from seeing a frightening movie? 
NO 
YES 
36. Do you get sick to your stomach or nauseous or even vomit 
from seeing blood? 
NO 
YES 
37. Do you get sick to your stomach or nauseous or even vomit 
from seeing body parts (such as seeing a horrible accident)? 
NO 
YES 
38. Do you get sick to your stomach or nauseous or even vomit 
from seeing severe malnutrition (such as starving children)? 
NO 
YES 
39. Do you get sick to your stomach or nauseous or even vomit 
from smelling a very bad smell (such as vomit)? 
NO 
YES 
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40. Do you get sick to your stomach or nauseous or even vomit 
from seeing someone throw up? 
NO 
YES 
 
41. Do you get sick to your stomach or nauseous or even vomit 
after eating certain foods? 
NO 
YES 
42. Do you get sick to your stomach or nauseous or even vomit 
just thinking about getting nauseous? 
NO 
YES 
 
43. 
Think of situations where you tend to get sick to your stomach, nauseous or vomit 
 
--- such as taking a strong pain-killer or a cough medicine with codeine, gagging, 
riding a roller coaster, spinning around, turning around suddenly, riding in a car, 
sitting backwards on a train, riding in a boat, seeing blood, smelling a bad smell. 
 
In general: 
 
Do you consider yourself prone (likely) to get nauseous? 
 
(Circle one number) 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
NOT 
VERY 
LIKELY 
LIKELY 
 
 
 
44. 
Is there anyone in your family who has a tendency to get nauseous easily? NONE 
 
Circle all relatives who are likely to get nauseous: 
 
FATHER 
MOTHER 
SISTER 
BROTHER 
TWIN 
UNCLE 
AUNT 
COUSIN 
45. 
Is there anyone in your family who gets nauseous after taking a strong pain killer 
(a prescription drug such as Vicodin, OxyContin, Tylenol with codeine, 
morphine, 
hydrocodone, Norco, Lortab, cough medicine containing codeine, Tussionex)? 
 NONE 
 
Circle all relatives who are prone to get nauseous after taking a strong pain killer: 
 
FATHER 
MOTHER 
SISTER 
BROTHER 
TWIN 
UNCLE 
AUNT 
COUSIN 
 
 
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14 
INVESTIGATOR'S PROTOCOL AGREEMENT 
 
 
PROTOCOL NUMBER 
CLCT-018 (Version 3.0) 
PROTOCOL TITLE 
A Randomized, Double-Blind, Placebo- and Active-
Controlled Study to Determine the Efficacy and Safety of 
CL-108 5 mg (Hydrocodone 5 mg/Acetaminophen 325 
mg/Promethazine 12.5 mg) as a Treatment for Moderate-
to-Severe Pain and the Prevention of Opioid-Induced 
Nausea and Vomiting (OINV) following Orthopedic 
Surgery 
 
 
By my signature, I confirm that my staff and I have carefully read and understand this 
protocol, and agree to comply with the conduct and terms of the study specified herein.  In 
particular, I/we have agreed to: 
 
1. Maintain confidentiality and assure security of Charleston Laboratories, Inc. confidential 
documents such as the protocol, case report form, Investigator's Brochure, final study reports, 
manuscript drafts, unpublished data, correspondence, etc. 
 
2. Assure access by Charleston Laboratories, Inc. monitors to original source documents. 
 
3. Retain IRB approval of study, any amendments to the study, and periodic re-approval as 
required. 
 
4. Keep the IRB informed of serious adverse events.  A copy of the Study Close-Out Report 
will be sent to the IRB upon completion of the study. 
 
5. Obtain written informed consent from each participant or their legal representative. 
 
6.  Make prompt reports of serious adverse events to Charleston Laboratories, Inc.  
 
7. Cooperate fully with any study-related GCP audit as performed by the sponsor's quality 
assurance group. 
 
8. Abide by stipulations in the Disclosure of Data section. 
 
9. Abide by manuscript preparation/authorship guidelines established at the outset of the 
study. 
 
 
 
 
 
Principal Investigator 
 
Date 
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15 
Protocol Amendment 1: Table of Changes  
Section Updated 
Original Text/Content 
Updated Text/Content 
Title Page and Footers 
Dates and Version # 
Original Text 
Version 1.0, May 10, 2017 
Updated Text:  
Version 2.0, June 16, 2017 
Retching Vomiting Index 
(RVI) Replaced with 
Vomiting Frequency Scale 
((VFS) 
Page 5: Abbreviations  
Page 8 and 9: Section 1.3, 
Study Design 
Page 11: Section 1.8, Study 
Flow Chart  
Page 15-17: Section 4.2, 
Visit 2 
Page 22: Section 5.5 Use of 
Supplemental (Rescue) 
Medications, Paragraphs 6-
9. 
Page 23: Section 5.6, 
Withdrawal 
Page 26: Section 6.2.4, 
Retching and Vomiting 
Index (entire section 
replaced) 
Page 32: Section 6.3.4, 
Post-Surgical Eligibility 
Assessments and Dosing, 
#2  
Page 32-33: Sections 6.3.5, 
6.3.6, 6.3.7, 6.3.8 (Time 
Point Assessments) 
Page 43: Section 7.4.7, 
Missing Data 
Page 43: Section 7.4.8, Use 
of Supplemental 
Medications  
Page 62: Section 13.2, 
Nausea/Vomiting Rating 
Scales 
Original Scale 
Retching 
Vomiting 
Index 
(RVI) 
Section 5.6 Original Text 
For the RVI - Did you have 
these stomach symptoms over 
the past hour? 
 
Deleted Scale 
RVI in all relative locations. 
Added Scale  
Vomiting Frequency Scale 
(VFS) 
General Changes 
-The entire RVI scale was 
replace with the VFS scale in all 
referenced sections.   
-The Acronym “RVI” was 
replaced with “VFS” in all 
referenced areas of the protocol. 
-Timing of assessments of the 
new VFS scale will occur at the 
same time points specified for 
RVI in the original protocol. 
Section 5.6 Updated Text 
For the RVFSI – How many 
times did you vomit (throw 
up) over the past hour? Did 
you 
have 
these 
stomach 
symptoms over the past hour? 
 
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Section Updated 
Original Text/Content 
Updated Text/Content 
Nausea Intensity Scale 
Page 5: Abbreviations  
Page 7 and 8: Section 1.3, 
Study Design 
Page 11: Section 1.8, Study 
Flow Chart  
Page 15-17: Section 4.2, 
Visit 2 
Page 22: Section 5.5, Use 
of Supplemental (Rescue) 
Medications, Paragraphs 6-
9. 
Page 23: Section 5.6, 
Withdrawal 
Page 26: Section 6.2.3: 
Nausea Intensity Scale  
Page 32: Section 6.3.4: 
Post-Surgical Eligibility 
Assessments and Dosing, 
#2 
Page 36-38: Sections 6.3.5, 
6.3.6, 6.3.7 and 6.3.8 
(Assessment Time points) 
Page 59: Section 13.2 
Nausea/Vomiting Rating 
Scales 
Original Name 
Nausea Intensity Scale (NIS) 
Original Definition 
Nausea Intensity Scale (NIS), 
a 0-10 Likert scale derived 
from the Edmonton Symptom 
Assessment Scales,5,7 to assess 
the intensity of nausea 
Section 5.6 Wording 
For the NIS - On a scale of 0 
to 10, where 0 is “no nausea” 
and 10 is “severe nausea,” 
circle the number that best 
describes the worst nausea 
you’ve had over the past half 
hour. 
 
Update Name of Scale: 
Nausea Intensity Scale (NIS) 
Updated Definition:  
Nausea Intensity Scale (NIS), a 
0-10 Likert binary scale derived 
from the Edmonton Symptom 
Assessment Scales,5,7 to assess 
the intensity presence/absence of 
nausea 
Reference #5 and 7 in original 
protocol now deleted. 
 
Section 5.6 Updated Language 
For the NS - For the NIS - On a 
scale of 0 to 10, where 0 is “no 
nausea” and 10 is “severe 
nausea,” circle the number that 
best describes the worst nausea 
you’ve had Over the past half-
hour, have you had any nausea 
(feeling like you wanted to 
throw up)? 
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Section Updated 
Original Text/Content 
Updated Text/Content 
Secondary Endpoints 
Page 9: Section 1.4.2 Key 
Secondary Endpoints 
Original Text 
1) Severity of opioid-induced 
nausea over 48 hours, 
comparing CL-108 5 mg 
to hydrocodone 5 
mg/APAP 325 mg 
Updated Text: 
1) Absence of any Severity of 
opioid-induced nausea or 
any use of anti-emetic 
medication over 48 hours, 
(complete absence of 
OINV), comparing CL-108 5 
mg to hydrocodone 5 
mg/APAP 325 mg 
Added Secondary End Point 
#3:  
Percentage of patients without 
any nausea over 48 hours, 
comparing CL-108 5 mg to 
hydrocodone 5 mg/APAP 325 
mg  
Added Secondary End Point #4 
Percentage of patients without 
any nausea or vomiting 48 
hours, comparing CL-108 5 mg 
to hydrocodone 5 mg/APAP 
325 mg  
Secondary Endpoints 
Page 42:  Section 7.4.3 Key 
Secondary Endpoints 
Original Text 
1. Severity of opioid-
induced nausea over 48 
hours, comparing CL-108 
5 mg to hydrocodone 5 
mg/APAP 325 mg 
2. Percentage of patients 
with any vomiting over 
48 hours, comparing CL-
108 5 mg to hydrocodone 
%5 mg/APAP 325 mg  
Updated Text 
1. Percentage of patients with 
complete absence Severity of 
OINV (no nausea, no vomiting, 
and no use of anti-emetic 
medication) opioid induced 
nausea over 48 hours, 
comparing CL-108 5 mg to 
hydrocodone 5 mg/APAP 325 
mg 
2. Percentage of patients 
without any vomiting over 48 
hours, comparing CL-108 5 mg 
to hydrocodone 5 mg/APAP 
325 mg  
ADDED #3 
Percentage of patients without 
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Section Updated 
Original Text/Content 
Updated Text/Content 
any nausea over 48 hours, 
comparing CL-108 5 mg to 
hydrocodone 5 mg/APAP 325 
mg  
ADDED #4 
Percentage of patients without any 
nausea or vomiting 48 hours, 
comparing CL-108 5 mg to 
hydrocodone 5 mg/APAP 325 mg  
Rescue Medication 
Clarification 
 
Page 16: Section 4.2: Visit 
2 
 
Page17: Section 4.3: 
Outpatient 
Original Text 
Section 4.2: NA 
 
 
 
Added Text 
Section 4.2 
All patients will receive a bottle 
of ibuprofen tablets (analgesic 
rescue medication) and a 
prescription for an anti-emetic 
of the investigator’s choice 
(anti-emetic rescue medication) 
to be used as needed during 
Study Days 3-7. 
Section:  
The patient will be discharged 
from Visit 2 with a bottle 
containing the remaining study 
medication capsules, a bottle 
containing ibuprofen 200 mg 
tablets (to be used if needed), 
and a prescription for an anti-
emetic(to be used if needed). 
 
Page 17: Section 4.3: 
Outpatient 
Original Text 
to document any symptoms 
(adverse events) they 
experienced and any cigarettes 
smoked over the past 24 
hours. 
Deleted Text 
to document any symptoms 
(adverse events) they 
experienced and any cigarettes 
smoked over the past 24 
hours. 
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Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
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Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 74 of 86 
 
Section Updated 
Original Text/Content 
Updated Text/Content 
Page 12: Section 2: 
Background and Rationale  
Original Text:  
… the occurrence of any 
vomiting or use of anti-emetic 
medication (indicative of 
nausea) over 48 hours. 
… 48 hours (SPID48) will be 
compared for patients treated 
with CL-108 5 mg and those 
treated with placebo.   
Opioid Symptoms Scales 
(OSS), derived from the 
Symptom Distress Scale to 
identify other opioid effects,4  
 
Added Text: 
….the occurrence of any 
vomiting or use of anti-emetic 
medication (indicative of nausea) 
over 48 hours.  The occurrence 
and frequency of vomiting will 
be measured on a 0-3 Vomiting 
Frequency Scale, the 
occurrence of nausea will be 
measured on a binary Nausea 
Scale, and the use of anti-emetic 
medication will be documented 
in diaries.  
…. 48 hours (SPID48) will be 
compared for patients treated 
with CL-108 5 mg and those 
treated with placebo.  Pain 
intensity will be measured on a 
0-10 Pain Intensity Numerical 
Rating Scale. 
Opioid Symptoms Scales (OSS), 
derived 
from 
the 
Symptom 
Distress Scale to identify other 
opioid effects,4 which were used 
in CLCT-002 and CLCT-003 
Page 18:  Inclusion 
Criteria, #2 
Original Text 
…condom, abstinence or 
surgical sterilization)… 
Updated Text 
…condom, abstinence abstain 
from heterosexual sex, or 
surgical sterilization)… 
Opioid Symptom Scale 
Page 27: Section 6.2.5: 
(OSS) (from the Symptom 
Distress Scale)4  
 
Page 32: Section 6.3.4, 
Post-Surgical Eligibility 
Assessments and Dosing, 
#2, c  
 
Original Text: 
Page 29: NA 
 
Page 34: Opioid symptoms 
Scales (OSS) over past 24 
hours 
 
Clarification Added:  
Page 29:  
The Opioid Symptom Scales are 
measurement instruments for 
documenting the occurrence 
and severity of each other 
opioid-related symptom, as in 
CLCT-002 and CLCT-003. 
Page 34: Opioid symptoms 
Scales (OSS) over past 24 hours 
PI-CAT Scale 
Page 25:  Section 6.1, 
Original Text 
Pain Assessments:  
Deleted Text 
Pain Assessments  
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Protocol Number: CLCT-018
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Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 75 of 86 
 
Section Updated 
Original Text/Content 
Updated Text/Content 
Evaluations of Safety and 
Eligibility, Pain 
Assessments  
Page 25: Section 6.2.1 
Categorical Pain Intensity 
Scale (PI-CAT)  
Page 61: Appendix 13.1 
… categorical pain intensity 
scale, or PI-CAT (which is 
called a “Pain Severity Scale” 
in the patient diary).  Only 
patients with moderate or 
severe pain ratings (2 or 3) are 
eligible for the trial. 
… categorical pain intensity 
scale, or PI-CAT (which is called 
a “Pain Severity Scale” in the 
patient diary).  Only patients 
with moderate or severe pain 
ratings (2 or 3)…  
 
Section 6.2.1 Updated  
…(called “Pain” in the Clinic 
Diary) 
Adverse Event Reporting 
of Opioid –related Events 
Page 8: Section 1.3: Study 
Design, Paragraph 13 
Page 25:  Section 6.1, 
Evaluations of Safety and 
Eligibility, Clinical Adverse 
Event Assessment 
 
Original Text: 
Section 1.3: Study Design 
The Investigator will rate the 
severity of these other (i.e., not 
opioid-related) side effects on 
a 3-category severity scale 
 
Section 6.1: Adverse event 
assessment:  
All adverse events except for 
those evaluated by the patient 
on the NIS, RVI and OSS will 
be recorded by the Study 
Coordinator or designee in the 
electronic case report form 
(eCRF) according to Section 
9.1 of this protocol. 
Updated Text:  
Section 1.3: Study Design 
The Investigator will rate the 
severity of all these other (i.e., 
not opioid-related) side effects 
on a 3-category severity scale 
 
Section 6.1: Clinical adverse 
event assessment:  
All adverse events except for 
those evaluated by the patient on 
the NIS, RVI and OSS will be 
recorded by the Study 
Coordinator or designee in the 
electronic case report form 
(eCRF) according to Section 9.1 
of this protocol. 
Adverse Event Reporting 
of Opioid –related Events 
Page 27: Section 6.2.8, 
Patients Reports of Adverse 
Events (Elicited and 
Volunteered.) 
Original Text: Section 6.2.8  
The Investigator will rate each 
non-opioid-related side effect 
on a 1-3 scale (mild, moderate, 
severe)… 
To avoid duplication of AE 
data entry, the following 
opioid-related adverse events 
will not be reported as AEs 
during the primary 48-hour 
treatment evaluation period: 
nausea, retching and vomiting 
(which are measured as 
endpoints on the NIS and RVI) 
and dizziness, drowsiness, 
constipation, difficulty 
Deleted Text: Section 6.2.8 
The Investigator will rate each 
non-opioid-related side effect on 
a 1-3 scale (mild, moderate, 
severe)… 
To avoid duplication of AE data 
entry, the following opioid-
related adverse events will not be 
reported as AEs during the 
primary 48-hour treatment 
evaluation period: nausea, 
retching and vomiting (which are 
measured as endpoints on the 
NIS and RVI) and dizziness, 
drowsiness, constipation, 
difficulty voiding, confusion, 
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Protocol Number: CLCT-018
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Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 76 of 86 
 
Section Updated 
Original Text/Content 
Updated Text/Content 
voiding, confusion, headache, 
itch, difficulty concentrating, 
and dry mouth (which are 9 
other opioid-related side 
effects measured on the OSS). 
Observed and reported 
episodes of retching will be 
entered on the Adverse Events 
page of the eCRF.  
headache, itch, difficulty 
concentrating, and dry mouth 
(which are 9 other opioid-related 
side effects measured on the 
OSS). Observed and reported 
episodes of retching will be 
entered on the Adverse Events 
page of the eCRF.  
Adverse Event Reporting 
and Opioid Symptoms 
 
Page 48, Section 9.1.1 
Definition of Adverse Event 
 
Original Text 
Because nausea, retching and 
vomiting are measured as 
endpoints on the NIS, WNS 
and RVI and because 9 other 
opioid-related symptoms 
(dizziness, drowsiness, 
constipation, difficulty voiding, 
etc.) are measured on the OSS 
as secondary endpoints, these 
12 opioid-related symptoms 
will not be duplicated as AEs. 
Deleted Text 
Because nausea, retching and 
vomiting are measured as 
endpoints on the NIS, WNS and 
RVI and because 9 other opioid-
related symptoms (dizziness, 
drowsiness, constipation, 
difficulty voiding, etc.) are 
measured on the OSS as 
secondary endpoints, these 12 
opioid-related symptoms will not 
be duplicated as AEs. 
Adverse Event Reporting 
and Opioid Symptoms 
 
Page 50: Section 9.1.5, 
Treatment Period 
Original Text 
Adverse events occurring 
from the initial study drug 
administration to the follow-
up Visit 3 discharge should be 
recorded as adverse events in 
the eCRF.  However, nausea, 
retching, vomiting, other 
opioid symptoms (on the 
OSS) and the usual post-
surgical outcomes of 
bunionectomy should not be 
recorded as adverse events. 
Deleted Text 
Adverse events occurring from 
the initial study drug 
administration to the follow-up 
Visit 3 discharge should be 
recorded as adverse events in the 
eCRF.  However, nausea, 
retching, vomiting, other opioid 
symptoms (on the OSS) and the 
usual post-surgical outcomes of 
bunionectomy should not be 
recorded as adverse events. 
 
 
 
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Protocol Number: CLCT-018
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09-Nov-2018
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Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 77 of 86 
 
Section Updated 
Original Text/Content 
Updated Text/Content 
NPR Scale 
 
Page 26, Section 6.2.2, 
Numerical Pain Intensity 
Rating Scale (PI-NRS)   
 
Page 58: Appendix 13.1 
Original Text 
Numerical Pain Intensity 
Rating Scale (PI-NRS)   
(called “Pain Severity Scale” 
in the Clinic Diary) 
Patients will be asked at 
baseline and at every post 
treatment assessment time… 
This is the measurement 
instrument for the co-primary 
analgesia endpoint. 
 
Original Text 
Numerical Pain Intensity Rating 
Scale (PI-NRS)   
(called “Pain Severity Scale” in 
the Clinic Diary) 
The patients will be asked at 
baseline and at every post 
treatment assessment time …  
The Numerical Pain Intensity 
Rating Scale is the measurement 
instrument for the co-primary 
analgesia endpoint. 
Page 28: Section 6.3.2 
Screening Procedures 
Original Text 
Criterion D:  If Criteria A-C 
do not qualify a patient… 
“clinical judgment” to admit 
up to ca. 10% …. 
Updated Text 
Criterion D:  If Criteria A-C 
does not qualify a patient... 
“clinical judgment” to admit up 
to approximately 10% …. 
Surgical Clarification 
 
Page 32: Section 6.3.3 
Surgical Day (Visit 2) 
Original Text 
…and for observation for up 
to 9 hours to observe if the 
patient develops moderate-to-
severe pain.  During this 
period, the patient will be 
instructed how to use the 
rating scales in the Diary. 
 
Added Text 
…and for observation for up to 
9 hours to observe if the patient 
develops moderate-to-severe 
pain after the PSP is 
discontinued. During this 
period, the patient will be 
instructed how to use the rating 
scales in the Diary. 
Page 32: Section 6.3.4: 
Post-Surgical Eligibility 
Original Text 
During the post-surgical 
period until 10 minutes pre-
dosing, patients may consume 
non-caffeinated liquids and 
soft foods (no chocolate) 
served at room temperature.  
No other treatment is 
permitted.    
… If 9 hours have transpired 
since surgery ended and the 
patient does not indicate… 
Updated Text 
During the post-surgical period 
until 10 minutes pre-dosing, 
patients may consume non-
caffeinated liquids andsoft food 
(no chocolate) served at room 
temperature.  No other 
treatment is permitted.    
… If 9 hours have transpired 
since the popliteal sciatic block 
was discontinued ended and the 
patient does not indicate… 
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Protocol Number: CLCT-018
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09-Nov-2018
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Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 78 of 86 
 
Section Updated 
Original Text/Content 
Updated Text/Content 
Vital Sign Measurements 
 
Page 32: Section 6.3.4, 
Post-Surgical Eligibility 
Original Text 
NA 
Added Text 
Patients are to be in a semi-
recumbent position at least 15 
minutes prior to each scheduled 
assessment time. 
Smoking Exclusions 
 
Page 38: Section 6.4 
Concomitant Medications 
 
Original Text 
Any concomitant medication 
used (e.g., antihypertensive, 
contraceptive) including 
cigarettes smoked during the 
study must be entered into the 
eCRF. 
Deleted Text 
Any concomitant medication 
used (e.g., antihypertensive, 
contraceptive) including 
cigarettes smoked during the 
study must be entered into the 
eCRF. 
Page 42, Section 7.3.4 
Key Secondary Endpoints 
Original Text 
#2 Percentage of patients 
without any vomiting over 48 
hours, comparing CL-108 5 mg 
to hydrocodone 5 mg/APAP 
325 mg  
 
#3 Percentage of patients 
without any nausea over 48 
hours, comparing CL-108 5 mg 
to hydrocodone 5 mg/APAP 
325 mg 
 
#4 Percentage of patients 
without any nausea or 
vomiting over 48 hours, 
comparing CL-108 5 mg to 
hydrocodone 5 mg/APAP 325 
mg    
Updated and Added Text 
#2 Percentage of patients without 
any vomiting over 48 hours, 
comparing CL-108 5 mg to 
hydrocodone 5 mg/APAP 325 
mg  
 
#3 Percentage of patients without 
any nausea over 48 hours, 
comparing CL-108 5 mg to 
hydrocodone 5 mg/APAP 325 
mg 
 
#4 Percentage of patients 
without any nausea or vomiting 
over 48 hours, comparing CL-
108 5 mg to hydrocodone 5 
mg/APAP 325 mg  
 
#5 Percentage of patients with 
Post-Discharge Nausea and 
Vomiting (PDNV) over days 3-7 
 
#6 Number of doses of study 
medication taken over days 3-7 
 
#7 Number of doses of study 
medication taken per day over 
days 3-7 
   
Labeling Endpoints 
 
Page 42-43: 7.4.4 Labeling 
Endpoints 
Original Text:  
Number 3: 
Patients treated with CL-108 5 
mg experience less nausea 
Updated Text 
Number 3: 
More pPatients treated with CL-
108 5 mg experience complete 
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Protocol Number: CLCT-018
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 79 of 86 
 
Section Updated 
Original Text/Content 
Updated Text/Content 
 
than patients treated with a 
comparable product 
containing hydrocodone 5 mg/ 
acetaminophen 325 mg 
 
absence of OINV less nausea 
than patients treated with a 
comparable product containing 
hydrocodone 5 mg/ 
acetaminophen 325 mg 
Added # 5 and #6 
#5: Patients treated with CL-108 
5 mg experience less nausea 
than patients treated with a 
comparable product containing 
hydrocodone 5 
mg/acetaminophen 325 mg 
#6: Patients treated with CL-108 
5 mg experience less nausea and 
vomiting than patients treated 
with a comparable product 
containing hydrocodone 5 
mg/acetaminophen 325 mg 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
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09-Nov-2018
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 80 of 86 
 
Section Updated 
Original Text/Content 
Updated Text/Content 
Page 45: Section 7.4.16 
Safety 
 
Original Text 
…nausea, retching, vomiting, 
emetic episodes).   
 
Updated Text 
…nausea, retching, vomiting, 
emetic episodes, sleep 
disturbance, headache).   
 
Page 46: Section 7.4.18, 
Protocol Deviations 
Original Text 
…could significantly affect 
efficacy will be excluded… 
Updated Text:  
…could significantly affect 
efficacy results (e.g., a missed 
dose of study medication) will 
be excluded 
Urine Cotinine Test 
Added to the Protocol 
 
Page 6-9: Section 1.3, 
Study Design, Paragraphs 2, 
3 
 
Page 11: Section 1.8, Study 
Flow Chart: Line for Urine 
Cotinine Added 
 
Page 13-18: Section 4.1, 
Visit 1, 4.2: Visit 2 and 4.4: 
Visit 3 
 
Page 19: Section 5.2, 
Exclusion Criteria, #4 
Confounding and 
Contraindicated Drugs 
 
Page 23: Section 5.6.1, 
Investigator’s Reason for 
Withdrawal 
 
Page 25: Section 6.1: 
Evaluations of Efficacy and 
Safety 
 
Page 30: Section 6.3.3: 
Screening Procedures (Visit 
1) and 6.3.3: Surgery Day 
(Visit 2): 
 
 
Original Text 
Cotinine not included in the 
original protocol. 
Added Text:  
Section 1.3:  Paragraph 2: 
…collected (for drug screening 
and cotinine on all patients)… 
 
Section 1.3 Paragraph 3; 
…and urine drug screening tests 
and urine cotinine test will be 
performed 
 
Section 4.1, 4.2 and 4.4: 
…and urine cotinine test will be 
performed… 
 
Section 5.2:  
…oxycodone, cotinine at 
screening…. 
 
Section 5.6: 
…pregnancy test, cotinine test, 
or drug screening… 
 
Section 6.1 
Cotinine Test:  A urine cotinine 
test will be performed on each 
patient at the Screening Visit 
and on the morning before 
surgery. A positive result will 
exclude the patient from 
participating in the trial. A 
urine cotinine test will also be 
performed at Visit 3.  A positive 
result will indicate that the 
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09-Nov-2018
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17 August 2017 
CONFIDENTIAL 
Page 81 of 86 
 
Section Updated 
Original Text/Content 
Updated Text/Content 
 
 
patient used nicotine during the 
trial. 
 
Section 6.3.2 and 6.3.3 
• Urine cotinine test… 
General Updates 
 
General grammatical errors were 
updated throughout the 
document. 
 
 
 
Page 6: Section 1.3: Study 
Design 
 
Original Text:  
 
Visit 2. After sedation 
(midazolam and/or propofol) 
is achieved, regional 
anesthesia will be established 
with a popliteal sciatic nerve 
block (PSB) using ropivacaine 
initially, then mepivacaine, 
after which patients will 
undergo primary… 
Updated Text:  
 
Visit 2. After sedation 
(midazolam and/or propofol) is 
achieved, regional anesthesia 
will be established with a 
popliteal sciatic nerve block 
(PSB),using ropivacaine, initially 
then mepivacaine, after which 
patients will undergo primary… 
Page 19: Section 5.2: 
Exclusion Criteria: #3: 
Drug Allergy 
 
Original Text:  
 
…NSAID (such as ibuprofen 
or 
aspirin), 
midazolam, 
propofol or ketorolac… 
Added Text:  
 
NSAID (such as ibuprofen or 
aspirin), midazolam, propofol, 
mepivacaine, ropivacaine or 
ketorolac 
Page 31: Section 6.3.3: 
Surgery Day (Visit 2) 
 
Original Text:  
 
Postoperative pain will be 
controlled by a continuous 
anesthetic infusion through the 
catheter 
previously 
placed 
adjacent to the popliteal sciatic 
nerve.   Mepivacaine 0.5%... 
 
 
All use of mepivacaine will be 
discontinued at approximately 
3 am. 
 
 
Added Text:  
 
Postoperative pain will be 
controlled by a continuous 
anesthetic infusion through the 
catheter previously placed 
adjacent to the popliteal sciatic 
nerve.  Two methods of 
continuous anesthetic infusion 
are permitted. Mepivacaine 
0.5%... 
 
All use of mepivacaine will be 
discontinued at approximately 3 
am on the morning following 
surgery. 
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 82 of 86 
 
Section Updated 
Original Text/Content 
Updated Text/Content 
 
 
 
Page 31: Section 6.3.3: 
Surgery Day (Visit 2) 
 
Original Text:  
 
All use of ketorolac will be 
discontinued at 1:30 am. 
Added Text:  
 
All use of ketorolac will be 
discontinued at 1:30 am on the 
morning following surgery. 
Page 31: Section 6.3.3: 
Surgery Day (Visit 2) 
 
Original Text:  
 
New text 
Added Text:  
 
Alternatively, postoperative pain 
will be controlled by a 
continuous ropivacaine 0.2%  
infusion through the catheter 
previously placed adjacent to 
the popliteal sciatic nerve.  
Ropivacaine 0.2 % will be 
infused starting at 1-2 mL per 
hour and titrating the rate of 
infusion as needed up to a 
maximum rate of 10 mL per 
hour. All use of ropivacaine will 
be discontinued at 
approximately 3 am on the 
morning following surgery. 
During this continuous infusion 
period, patients may receive 
supplemental analgesia for 
breakthrough pain (patients less 
than 65 years of age and greater 
than 50 kg:  ketorolac 30 mg IM 
or IV every 6 hours as needed 
with a maximum daily dose of 
120 mg; patients greater than or 
equal to 65 years of age or less 
than 50 kg: ketorolac 15 mg IM 
or IV every 6 hours as needed 
with a maximum daily dose of 
60 mg).  All use of ketorolac will 
be discontinued at 1:30 am on 
the morning following surgery. 
 
 
 
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Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 83 of 86 
 
16 
Protocol Amendment 2: Table of Changes 
Section Updated 
Original Text/Content 
Updated Text/Content 
Title Page and Footers 
Dates and Version # 
Original Text 
Version 2.0, June 16, 2017 
Updated Text: 
Version 3.0, 13 August 2017 
Clarifying that positive 
urine drug screen will 
result is screen failure of 
subject. 
 
Page 11: Section 1.8,  
Study Flow Chart: Urine 
Drug Screen Footnote 
Original Text: None 
Added Text:  
11 A positive urine drug screen 
will exclude the patient from 
participating in the study. 
Clarifying to awake 
subjects for scheduled 
dosing. 
 
Page 7 and 8,  Section 1.3,  
Study Design 
 
Page 16, Section 4.2, 
Paragraph 14, 
Visit 2 
 
Page 35, Section 6.3.4, 
Post-Surgical Eligibility 
Assessment and Dosing, 
 
Page 37, Section 6.3.6, #6b 
Study Times: 12 Hours 
Post-Initial Dose through 48 
Hours 
Original Text:  
None 
Added Text:   
Subjects should be awoken for 
dosing, as needed to remain on 
the dosing schedule. 
Clarifying % Lidocaine 
Page 14, Section 4.2 
Visit 2 
 
Page 30, Section 6.3.3  
Surgery Day (Visit 2) 
Original Text 
Section 4.2: …short-acting 
lidocaine 1% (plain). 
 
Section 6.3.3, Paragraph 4: 
inject approximately 5 mL 
lidocaine 2% (plain) locally… 
 
 
Section 6.3.3, Paragraph 5: 
… using short-acting lidocaine 
2% (plain, without 
epinephrine)… 
 
 
Updated Text 
Section 4.2: …short-acting 
lidocaine 1% or 2% (plain). 
 
Section 6.3.3, Paragraph 4: 
inject approximately 5 mL 
lidocaine 1% or 2% (plain) 
locally… 
 
Section 6.3.3 Paragraph 5: … 
using short-acting lidocaine 1% 
or 2% (plain, without 
epinephrine)… 
Page 28, Section 6.3.2, 
Original Text 
Updated Text 
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Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 84 of 86 
 
Section Updated 
Original Text/Content 
Updated Text/Content 
Screening Procedures (Visit 
1), Criterion B 
Criterion B: If a patient has at 
least one of the following 5 
responses to Questions 26-27, 30, 
32-34, or 39 (relating to motion 
sickness) on the NPQ 
Criterion B: If a patient has at 
least one of the following 5 
responses to Questions 26-27, 
30, 32-34, or 39 (relating to 
motion sickness) on the NPQ 
Page 30, Section 6.3.3, 
Surgery Day (Visit 2) 
Original Text 
Alternatively, postoperative 
pain will be controlled by a 
continuous ropivacaine 0.2% 
infusion through the catheter 
previously placed adjacent to 
the popliteal sciatic nerve.  
Ropivacaine 0.2 % will be 
infused starting at 1-2 mL per 
hour and titrating the rate of 
infusion as needed up to a 
maximum rate of 10 mL per 
hour.  
 
Updated Text 
Alternatively, postoperative pain 
will be controlled by a 
continuous ropivacaine 0.2% 
infusion through the catheter 
previously placed adjacent to 
the popliteal sciatic nerve.  via 
PSB catheter on a PCA pump at 
a continuous rate of 1 ml/hr.  
Up to two, 3 ml boluses of 
Ropivacaine 0.2% may be given 
per hr.  If pain is not adequately 
controlled after two boluses, 
infusion may be increased by 
2ml/hr. Ropivacaine 0.2 % will 
be infused starting at 1-2 mL 
per hour and titrating the rate 
of infusion as needed up to a 
maximum rate of 10 mL per 
hour.  
Page 42, Section 7.3.4 
Key Secondary Endpoints 
Original Text 
#2 Percentage of patients 
without any vomiting over 48 
hours, comparing CL-108 5 mg 
to hydrocodone 5 mg/APAP 
325 mg  
 
#3 Percentage of patients 
without any nausea over 48 
hours, comparing CL-108 5 mg 
to hydrocodone 5 mg/APAP 
325 mg 
 
#4 Percentage of patients 
without any nausea or 
vomiting over 48 hours, 
comparing CL-108 5 mg 
to 
hydrocodone 
5 
mg/APAP 325 mg    
Updated and Added Text 
#2 Percentage of patients 
without any vomiting over 48 
hours, comparing CL-108 5 mg 
to hydrocodone 5 mg/APAP 325 
mg  
 
#3 Percentage of patients 
without any nausea over 48 
hours, comparing CL-108 5 mg 
to hydrocodone 5 mg/APAP 325 
mg 
 
#4 Percentage of patients 
without any nausea or vomiting 
over 48 hours, comparing CL-
108 5 mg to hydrocodone 5 
mg/APAP 325 mg  
 
#5 Percentage of patients with 
Post-Discharge Nausea and 
Vomiting (PDNV) over days 3-7 
 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 85 of 86 
 
Section Updated 
Original Text/Content 
Updated Text/Content 
#6 Number of doses of study 
medication taken over days 3-7 
 
#7 Number of doses of study 
medication taken per day over 
days 3-7 
   
Page 43, Section 7.4.4 
Labeling Endpoints 
Original Text 
No #7-#9 
Added Text 
#7. Patients treated with CL-108 
5 mg experience less nausea and 
vomiting after discharge 
following surgery than patients 
treated with a comparable 
product containing hydrocodone 
5 mg/acetaminophen 325 mg  
 
#8 Patients treated with CL-108 
5 mg take more doses over days 
3-7 and have greater reduction 
in pain and less OINV after 
discharge following surgery 
than patients treated with a 
comparable product containing 
hydrocodone 5 mg/ 
acetaminophen 325 mg  
 
#9.  Patients treated with CL-
108 5 mg take more doses each 
day over days 3-7 and have 
greater reduction in pain and 
less OINV after discharge 
following surgery than patients 
treated with a comparable 
product containing 
hydrocodone 5 mg/ 
acetaminophen 325 mg. 
Page 46, Section 7.4.17 
Interim Analysis 
Original Text 
No Interim Analysis is 
planned. 
Added Text 
No Interim Analysis is 
planned.  An independent Data 
Monitoring Committee (DMC) 
will meet to review efficacy and 
safety endpoints. The DMC will 
operate under a charter and will 
make recommendations to the 
sponsor. An interim analysis 
will be performed by the DMC 
after approximately 66% of the 
subjects have completed the 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
Page 86 of 87
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CHARLESTON LABORATORIES, INC. 
Protocol No. CLCT-018 
 
17 August 2017 
CONFIDENTIAL 
Page 86 of 86 
 
Section Updated 
Original Text/Content 
Updated Text/Content 
300-subject study and there is 
adequate representation from 
each of the investigative sites 
(i.e., approximately 30 
completed subjects per site).  If 
it is judged impossible to 
achieve this deminimis 
representation at a particular 
site or sites, the interim analysis 
will be conducted on the total 
number of subjects completed 
(i.e., approximately 200 
subjects). Since the DMC will 
review efficacy data, formal 
sequential boundaries for 
efficacy and futility will be 
declared in the DMC’s 
Statistical Analysis Plan. 
Page 62 , Section 13.4 
Appendix 3, Nausea Prone 
Questionnaire 
Original Text 
#20, Responses “Yes” and 
“No” 
 
Updated Text 
#20, Responses, “Yes”, “No” 
and “NA” 
Page 71, Appendix 14 
Protocol Agreement 
Original Text 
Version 2.0 
Updated Text 
Version 3.0 
 
 
Charleston Laboratories, Inc. 
Protocol Number: CLCT-018
Clinical Study Report, Final 
09-Nov-2018
Confidential
Page 87 of 87
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