Clinical trial NCT03028870
Conditions: Osteo Arthritis Knee
Keywords: Osteoarthritis Pain Osteoarthritis Knee
Sponsor: Purdue Pharma LP
Start date: 2017-03-14; Completion date: 2017-11-21
Enrollment: 291 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the analgesic efficacy of V120083 twice daily compared to placebo in subjects with moderate to severe chronic pain due to OA of the knee.

Detailed description:

Arms: arm 1: V120083 30-mg capsules taken orally twice daily arm 2: V120083 60-mg (2 x 30 mg) capsules taken orally twice daily arm 3: Naproxen 500-mg capsules taken orally twice daily arm 4: Capsules to match V120083 and/or naproxen taken orally twice daily
Interventions: intervention 1: V120083 intervention 2: Naproxen intervention 3: Placebo
Intervention descriptions: intervention 1: Capsules intervention 2: Capsules intervention 3: Capsules to match V120083 and/or naproxen

Protocol documents:
Prot_000.pdf: 
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1 
TITLE PAGE 
Protocol Number: 
VAN2001 
 
 
Title: 
A Phase 2a, Multicenter, Randomized, Double-blind, 
Placebo-controlled and Active-controlled, Parallel-group Study 
Evaluating the Analgesic Efficacy and Safety of V120083 in Subjects 
with Moderate to Severe Chronic Pain Due to Osteoarthritis of the 
Knee 
 
 
Sponsor: 
Purdue Pharma L.P.  
One Stamford Forum  
Stamford, CT 06901-3431  
USA  
 
 
Test Drug: 
V120083 
 
 
Phase: 
Phase 2a 
 
 
Version Date: 
Version 2, 17-Feb-2017 
 
 
Approval Date: 
16-Feb-2017 
 
 
GCP Statement: 
This study is to be performed in compliance with the International 
Council for Harmonisation (ICH) and all applicable Good Clinical 
Practices (GCPs) and federal and local regulations.   
 
 
 
Confidentiality: 
This document is confidential.  It contains proprietary information of 
Purdue Pharma L.P.  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor (or designee) is 
strictly prohibited.  Such information may be used solely for the 
purpose of reviewing or performing this study. 
 
 
 


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2 
SYNOPSIS  
Synopsis 
Name of Company: 
Purdue Pharma LP 
 
Protocol Number: 
VAN2001 
Name of Finished Product: 
V120083 capsules  
Name of Active Ingredient: 
V120083 
US IND/EUDRACT No.: 
 
 
 
Full Title of the Study: 
A Phase 2a, Multicenter, Randomized, Double-blind, Placebo-controlled and Active-controlled, Parallel-group 
Study Evaluating the Analgesic Efficacy and Safety of V120083 in Subjects with Moderate to Severe Chronic 
Pain Due to Osteoarthritis of the Knee 
Investigator(s)/Center(s): 
Approximately 30 
Planned First Subject First Visit:  
Q1 2017 
Phase of Development: 
Phase 2a 
Objectives:  
Primary: 
• 
The primary objective of this study is to evaluate the analgesic efficacy of V120083 twice daily (bid) 
compared to placebo in subjects with moderate to severe chronic pain due to osteoarthritis of the knee 
using the “average pain over the last 24 hours” score from the modified Brief Pain Inventory – short form 
(mBPI-SF) pain severity subscale at week 4 of the double-blind period. 
Secondary: 
The secondary objectives of this study are to: 
x 
Evaluate the safety and tolerability (including adverse event [AE] reporting, clinical laboratory 
parameters, and physical examination) of 2 dose levels of V120083 
x 
Evaluate the efficacy of V120083 on pain, stiffness, physical function, and overall disability using the 
Western Ontario and McMaster Osteoarthritis Index (WOMAC) subscale and total scores  
x 
Evaluate the efficacy of V120083 on pain intensity due to OA using numerical rating scale (NRS) pain 
scores from the mBPI-SF pain severity subscale  
x 
Evaluate the impact of V120083 on pain-related quality of life/function using the mBPI-SF pain 
interference subscale  
x 
Evaluate the effect of V120083 on pain severity and pain interference overall using the mBPI-SF total 
score  
x 
Evaluate the impact of V120083 on subjects’ health state (as defined by mobility, self-care, daily 
activities, pain/discomfort, and anxiety/depression) using the EuroQol-5D (EQ-5D)  
x 
Evaluate the impact of V120083 on subjects’ functional health and well-being using the Medical 
Outcomes Study 36-Item Short Form Health Survey (SF-36)  
x 
Evaluate subject global impression of treatments using the Patient Global Impression of Change (PGIC) 
questionnaire  
x 
Evaluate the impact of V120083 on mood (anxiety and depression) using the Hospital Anxiety and 
Depression Scale (HADS) 


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x 
Evaluate the efficacy of naproxen vs. placebo for assay sensitivity using the primary and secondary 
endpoints indicated above. 
x 
Determine plasma levels of V120083 in subjects under clinical use conditions.  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
x 
Evaluate supplemental analgesic medication use 
x 
Evaluate treatment response 
x 
Evaluate the occurrence of treatment-emergent suicidal ideation or behavior using the Columbia – 
Suicide Severity Rating Scale (C-SSRS) 
Study Design (Methodology): 
This is a phase 2a, double-blind, double-dummy, placebo- and active-controlled, parallel-group, multicenter study 
to evaluate the analgesic efficacy and safety of V120083 vs placebo in subjects with moderate to severe chronic 
pain due to osteoarthritis (OA) of the knee (Figure 1). The total duration of the study for a given subject is up to 
56 days, inclusive of a 21 day screening period; a 28 day double blind treatment period; and a 7 day follow up 
period. Naproxen 500 mg bid will be used as an active control to determine the assay sensitivity of the study. 
During the screening period, subjects will be assessed for their eligibility and those who are qualified to continue 
in the study will be randomized at visit 2 in equal ratios to receive 1 of the following 4 treatments in the 
double-blind period: V120083 30 mg bid, V120083 60 mg bid, naproxen 500 mg bid, or placebo. Clinic visits 
during the double-blind period will occur at week 1 (visit 3), week 2 (visit 4), and week 4 (visit 5/end-of-study 
visit).   
Blood samples for pharmacokinetic (PK) analysis will be collected at visits 2, 3, 4, and 5. The PK evaluation will 
involve two components: intense PK sampling and sparse PK sampling.  Sparse PK sampling will be conducted 
for all subjects enrolled (276 subjects), with samples collected at visits 3 (predose, 1 and 2 hours postdose), 
4 (predose or postdose), and 5 (predose or postdose) during the treatment period. Intense PK sampling will be 
conducted for 24 subjects, consisting of the sparse PK schedule and visit 2 predose sample and postdose 
sampling at 1, 2, 4, 6, and 8 hours (day 1 of dosing). The study will include pharmacogenomics (PG) sampling 
that will be optional for all subjects. 
Starting at screening, subjects may take their own supplemental analgesic medication, ie, 500 mg 
acetaminophen (APAP) which can be taken as needed up to 2 g/ 24 hours for breakthrough pain, but is not to be 
taken within 24 hours of visit 2. Acetaminophen 500 mg will be provided as supplemental analgesic medication 
during the double-blind period. Subjects may take no more than 4 tablets of APAP/acetaminophen 500 mg per 
24 hours (ie, no more than 2 g/24 hours) and no more than 2 tablets of APAP/acetaminophen 500 mg at any one 
time for breakthrough pain.  All subjects must refrain from taking any supplemental analgesic medications for at 
least 24 hours prior to the clinic visits during the double-blind period (ie, no supplemental analgesic medication is 
allowed during the 24 hour period before the week 1 [visit 3], week 2 [visit 4], and week 4 [visit 5] visits during the 
double-blind period). 
An interim analysis may be performed for futility when approximately 50% of randomized subjects have 
completed the study. An independent Data Monitoring Committee (DMC) will review all unblinded safety and 
efficacy data from the analysis and make recommendations, as necessary, for plans for additional studies in the 
clinical program.  




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Criteria for Inclusion/Exclusion: 
Inclusion Criteria: 
1. Males and females  40 and  80 years of age with moderate to severe chronic OA pain of the knee (lasting 
several hours daily) as their predominant pain condition for at least 6 months prior to screening; 
2. Diagnostic criteria for primary pain condition (American College of Rheumatology [ACR] clinical and 
radiographic criteria):  
x 
At least 1 of the following in addition to knee pain: age >50, morning stiffness <30 min, crepitus on active 
motion, and  
x 
Kellgren-Lawrence (K-L) grade 2 or 3 radiographic evidence at the screening visit as determined by a 
local radiologist or rheumatologist. If a radiograph is not available, one must be taken and the diagnostic 
criteria must be confirmed before visit 2. Note that K-L grades 2-3 require the presence of osteophytes, 
which is required to meet ACR clinical and radiographic criteria for knee OA; 
3. Subjects with body mass index (BMI) ranging from 18.0 to 38.0 (kg/m2), inclusive; 
4. Subjects whose OA pain of the index knee is not adequately treated prior to the screening visit: 
x 
Subjects must have a self-reported average pain intensity rating of moderate or severe on a verbal 
rating scale (ie none, mild, moderate, and severe) over the 7 days prior to the screening visit 
5. The subjects must have “average pain over the last 24 hours” scores  4 and  9 on an 11-point NRS for the 
index knee on > 3 consecutive days during the pain assessment period and come in for visit 2 within 96 
hours after the latest qualifying pain score entry 
6. For subjects receiving adjunct therapy for chronic pain, such as physical therapy, exercise, chiropractic 
therapy, acupuncture therapy, TENS unit, or herbal and other complementary therapy, such treatment 
should be either stopped at screening or remain unchanged during the entire study; Adjunct therapies, 
glucosamine and chondroitin initiated at least 1 month before screening can be continued at stable 
dose/regimen (should not be initiated during the study); elastic support and other braces applied to either 
knee should be used during the study in the same manner as at screening; 
7. If either female of childbearing potential (ie, not medically or surgically sterilized or not postmenopausal more 
than 1 year) or non-surgically sterilized male with sexual partner of childbearing potential, be willing to use 
adequate and reliable contraception throughout the study (eg, abstinence or barrier with additional 
spermicidal foam or jelly, or the use of intrauterine device or hormonal contraception by female subjects and 
partners of male subjects); 
8. Subjects who are willing and able to stop taking any/all analgesic medications, including over-the-counter 
pain medications, opioids, marijuana, and topical analgesics for OA pain for the duration of the study, with 
the exception of study-specific rescue medication; 
9. Subjects who are willing and able to be compliant with the protocol, are capable of subjective evaluation, are 
able to read and understand questionnaires, and are able to read, understand, and sign the written informed 
consent. 
Exclusion Criteria: 
1. Subjects with radiographic evidence of OA with Kellgren-Lawrence (K-L) grade 0, 1 or 4; 
2. Females who are pregnant (positive serum/urine test) or lactating or planning to become pregnant during the 
study; 
3. Subjects with chronic pain conditions other than OA of the knee as their predominant pain condition, 
including gout, pseudogout, psoriatic arthritis, active Lyme disease, rheumatoid arthritis or any other 
inflammatory arthritis, fibromyalgia, neuropathic pain conditions, bursitis, or acute injury or signs of active 
infection in the target pain area; 
4. Subjects scheduled for surgical interventions of the disease site or any other major surgery during the study 
conduct period; 


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5. Subjects with a history of a prior joint replacement of the index knee; 
6. Subjects who have had arthroscopy on either knee or hip within 6 months of entering the study, or open 
surgery on either knee or hip within 12 months of entering the study; 
7. Subjects with a palpable effusion in either knee; 
8. Subjects with a history of significant trauma to a knee, hip or shoulder within the previous year; 
9. Subjects who have significant pain, other than or more than knee pain, including significant hip, back pain, 
that may confound the analgesic efficacy assessments of this study; 
10. Subjects who used immunosuppressive drugs, anti-depressants other than Selective Serotonin Reuptake 
Inhibitors (SSRls for depression), warfarin or anticoagulants, cyclosporine (except ophthalmic emulsion), 
aspirin except for 81 mg daily dose for cardiovascular prophylaxis, diuretics with unstable cardiac diseases, 
or methotrexate within 30 days of study randomization;  
11. Subjects who initiated, or received an increase in the dose of, oral corticosteroids within 6 weeks prior to 
entering the study or who anticipate a change in oral corticosteroid therapy during the study period; 
12. Subjects who have used any investigational medication within 30 days or five half-lives, whichever is longer, 
prior to the first dose of study medication; 
13. Subjects with a history of seizures within the past 5 years; 
14. Subjects with evidence of current major depression or other clinically significant psychiatric disorder that in 
the opinion of the investigator would interfere with the subject’s ability to participate in the study.  Subjects 
with history of a psychotic disorder or psychosis, bipolar disorder, or post-traumatic stress disorder should be 
excluded.  Subjects with major depression in remission or other psychiatric disorder must be on a stable 
medication (SSRI) for > 3 months to participate in the study;   
15. Subjects with HADS score over 10 on either subscale at visit 1; 
16. Subject answers “yes” to “suicidal ideation” in prior 24 months to any items 1 through 5 on the C-SSRS; 
17. Subject answers “yes” to any lifetime “suicidal behavior” item on the C-SSRS; 
18. Subjects with any history of alcohol or other substance abuse or addiction within the past 5 years; 
19. Subjects who use immediate release/short-acting opioids at a daily dose exceeding 15mg daily morphine 
equivalent more than 4 days per week; 
20. Subjects who have used any extended-release/long acting opioids in the 30 days prior to screening; 
21. Subjects who have a positive urine drug test for illicit drugs, cannabinoids, non-prescribed opioids; 
22. Subjects taking strong CYP3A inhibitors, inducers, sensitive substrates, substrates with narrow therapeutic 
range, or p-gp substrates (see Appendix Q);  
23. Subjects taking moderate CYP3A inhibitors if the dose has not been stable for at least 1 month prior to start 
of study drug dosing (see Appendix Q);  
24. Subjects for whom it is anticipated that therapy with a moderate to strong CYP3A inhibitor, or CYP3A 
inducers, sensitive substrates, substrates with narrow therapeutic range, or P-gp substrates will be initiated 
during the study, after the screening visit; 
25. Subjects with clinically unstable medical conditions, including cardiac disease (unstable atrial fibrillation, any 
symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia), uncontrolled 
hypertension, respiratory disease, biliary tract disease, hypothyroidism, renal disease, adrenal cortical 
insufficiency, or any other medical condition that, in the investigator’s opinion, is inadequately treated and 
precludes entry into the study; 
26. Subjects with myocardial infarction, stroke, or other thrombotic events in the past 5 years; and/or any history 
of coronary artery bypass graft;  


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27. Subjects with a screening electrocardiogram (ECG) showing a QTcF value (QT data corrected for heart rate 
using the Fridericia formula) of  470 milliseconds (msec) or other ECG findings that, in the investigator’s 
opinion, would preclude participation in the study; 
28. Subjects with any clinically significant abnormal laboratory value, including evidence of impaired liver 
function (values  3 times the upper limit of normal for aspartate transaminase [AST/SGOT] or alanine 
transaminase [ALT/SGPT], or bilirubin  1.5 mg/dL), or impaired kidney function (eGFR < 60 mL/min); 
29. Subjects with positive hepatitis B, hepatitis C or HIV test results indicative of current infection; 
30. Subjects with a history of malignancy within the past 5 years, with exception of basal cell carcinoma that has 
been successfully treated; 
31. Subjects with an ongoing or resolved worker’s compensation claim and/or litigation related to their pain 
disorder; 
32. Subjects who, in the opinion of the investigator, are unsuitable to participate in this study for any other 
reason; 
33. Pain-condition-specific exclusions: Subjects who received local pain-control procedures, including 
intra-articular steroid injection in the index knee or intramuscular steroid injection at any site, joint lavage, or 
other invasive therapies within 6 weeks of entering the study or hyaluronate injection in the index knee within 
12 weeks of entering the study, or for whom such therapies are planned within the study period.  
34. Subjects with a history of bleeding disorders or history of documented gastrointestinal ulcer disease. 
35. Subjects who are allergic to or cannot tolerate aspirin, other NSAIDS (including naproxen),  or 
acetaminophen, including history of NSAID-induced asthma, or nasal polyps 
36. Subjects who have received TRPV1 antagonist previously 
Test Treatment, Dose, and Mode of Administration: 
x 
V120083 30 mg, bid, po: supplied as blinded capsules with each capsule containing 30 mg V120083.   
x 
Subjects assigned to V120083 30 mg will take 1 capsule containing V120083 30 mg, 
1-V120083 placebo capsule, and 1 active comparator placebo capsule. 
x 
V120083 60 mg, bid, po supplied as blinded capsules with each capsule containing 30 mg V120083.    
 
x 
Subjects assigned to V120083 60 mg will take 2 capsules containing V120083 30 mg and 
1 active comparator placebo capsule. 
During the double-blind treatment period (days 1 through 28), subjects will self-administer orally (po) study drug 
bid, except on the first day of the double-blind treatment period, when the study personnel will provide the first 
dose at the site. Supplemental analgesic medication should not be taken during the 24 hours prior to clinic visits. 
Study drugs will be supplied in blister packages to be provided to subjects at each clinic visit.  All subjects will 
take 3 capsules bid as outlined in the synopsis and Section 9.4. 
Reference Treatment, Dose, and Mode of Administration: 
x 
Active comparator, bid, po: Naproxen supplied as blinded capsules with each dose consisting of one 
500-mg capsule.  
x 
Subjects assigned to naproxen 500 mg bid will take 1 capsule containing naproxen 500 mg and 
2 capsules containing V120083 placebo 
 
x 
V120083 placebo, bid, po: Capsules that match both 30- and 60-mg doses supplied as blinded capsules; to 
be taken po bid by subject’s assigned to 30 mg V120083, active comparator, or placebo.  
x 
Subjects assigned to placebo will take two V120083 placebo capsules and 1 active comparator placebo 
 
x 
Active comparator placebo, bid, po: Capsules that match active comparator supplied as blinded capsules; 
to be taken by subjects assigned to V120083 (30 or 60 mg) or placebo.


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Supplemental Medication: 
Supplemental analgesic medication is acetaminophen (APAP) 500 mg.  No more than 4 tablets per 24 hours (ie, 
no more than 2 g per 24 hours), and no more than 2 tablets (1 g) per dose, as needed, will be permitted during 
the double-blind period.  All subjects will be instructed to refrain from taking any supplemental analgesic 
medication for at least 24 hours prior to the weeks 1, 2, and 4 visits (visits 3, 4, and 5, respectively) of the 
double-blind period. 
Concomitant Medication: 
All medications used for chronic pain, other than the study drugs and supplemental analgesic medication, are 
prohibited during the study.  Medication used for chronic pain includes opioids, NSAIDs (other than the study 
drug), cyclooxygenase-2 (COX-2) inhibitors, aspirin, gabapentin, antiepileptics, and antidepressants (eg, 
tricyclics and selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors).  
Other prohibited concomitant treatments include benzodiazepines, monoclonal antibodies for osteoporosis, 
methotrexate, any local OA treatments for the knee(s), including topical anesthetics or NSAIDs; topical, 
intra-articular, or systemic corticosteroids; or any OA injection in the knee(s), anti-depressants (other than SSRIs, 
serotonin norepinephrine reuptake inhibitors [SNRIs] for depression), warfarin or anti-coagulants, and 
cyclosporine (except ophthalmic emulsion). 
Based on in vitro data, V120083 is a CYP3A4/5 substrate and has the potential to inhibit P-gp and 
CYP3A4/5.  Concomitant administration of CYP3A inhibitors, inducers, substrates, and P-gp substrates are 
restricted as follows: 
x 
Subjects taking strong CYP3A inhibitors will be excluded from the study due to potential increases in 
plasma levels of V120083 when co-administered with V120083.  Subjects who initiate these medications 
during the study will be discontinued from the study. 
x 
Subjects taking moderate CYP3A inhibitors will be excluded if the dose has not been stable for at least 
one month prior to start of study drug dosing (see Appendix Q for a representative list of moderate and 
strong CYP3A inhibitors). Subjects who discontinue therapy with moderate CYP3A inhibitors during the 
study will be permitted to continue on the study 
x 
If the subject is taking multiple moderate CYP3A inhibitor(s) or the category is unknown, the investigator 
should contact the medical monitor and subjects are to be carefully monitored. 
x 
Subjects taking CYP3A Inducers will be excluded from the study due to potential decrease in plasma 
levels of V120083. Subjects who initiate these medications during the study will be discontinued  from 
the study. 
x 
Subjects taking CYP3A sensitive substrates and substrates with narrow therapeutic range, or P-gp 
substrates will be excluded from the study due to potential increases in plasma levels of such 
medications when co-administered with V120083. Subjects who initiate these medications during the 
study will be discontinued from the study.  (See Appendix Q for a list of inducers and substrates)
APAP/acetaminophen may be used intermittently for headache, fever, or acute pain up to the 2 g per 24 hour 
maximum amount; low-dose aspirin (81mg daily) for cardiovascular disease prophylaxis is allowed. Note: 
Subjects will be requested not to take any APAP/acetaminophen for at least 24 hours before each clinic visit. 
Duration of Treatment and Study Duration 
Total study duration is up to 56 days. 
The screening period is up to 21 days; the double-blind period is 4 weeks; the follow-up period is 7 days. 
Study Procedures: 
Screening Period (up to 21 days) 
Visit 1  


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At visit 1, after written informed consent is obtained, the subject will undergo a complete evaluation for study 
eligibility. To qualify for the study, subjects must meet all initial study entry criteria, including a self-reported 
average pain intensity rating of moderate or severe on a verbal rating scale (ie, none, mild, moderate, severe) 
over the 7 days prior to the screening visit.  For subjects with OA pain at both knees, the investigator will identify 
the more painful knee joint to serve as the index knee for the study. Subjects will be instructed to record all pain 
assessments based on the index knee.  
Telephone Contact and Washout Period   
As soon as the laboratory results, ECG results, and radiograph results are available, the site staff will contact the 
subjects by telephone to inform them of the results and whether they are qualified to continue in the study. 
Subjects who do not meet the initial entry criteria will be considered screen failures. For subjects who meet the 
initial entry criteria and: 
x 
Who do not take any analgesic medications for their pain, the site staff will instruct them to record in the 
diary their “average pain over the last 24 hours” scores for their index knee at approximately 8 PM every 
evening for 3 to 7 days.  These subjects may return to the study clinic for visit 2 as soon as they have 
“average pain over the last 24 hours” scores  4 and  9 for  3 consecutive days. All subjects must 
return to the study clinic for visit 2 within 96 hours of the latest qualifying pain score entry within the pain 
assessment period.  
x 
Who are on topical and/or oral analgesics (including NSAIDs, opioids, antidepressants, anticonvulsants, 
or other medications for OA), the site staff will instruct them to discontinue from these medications in 
accordance with accepted medical practice. Once all medications used for pain have been discontinued, 
the subjects will undergo an analgesic washout period of up to 9 days. During this period, the subjects 
will record in the diary their “average pain over the last 24 hours” scores for the index knee at 
approximately 8 PM every evening for 3 to 9 days.  These subjects may return to the study clinic for visit 
2 as soon as they reported “average pain over the last 24 hours” scores of  4 and  9 for  3 
consecutive days. All subjects must return to the study clinic for visit 2 within 96 hours of the latest 
qualifying pain score entry within the pain assessment period.  
x 
Subject’s own supplemental analgesic medication, ie, APAP/acetaminophen, is permitted to be taken 
during the washout period as needed (PRN) up to 2 g/24 hours. Supplemental analgesic medication is 
not to be taken within 24 hours of visit 2. 
Concomitant medications and AEs will be documented during this telephone contact. 
Rescreening of subjects who previously failed screening is allowed only with the permission of the medical 
monitor on a case by case basis.  
Subjects may be considered for rescreening if they failed screening previously due to eligibility criteria that are 
now allowed under the current amended protocol; delay of acquiring records; out of window issues (eg, lost or 
delayed labs); timing of exclusionary procedures; or other reasons approved by the medical monitor.   
Subjects with positive hepatitis B, hepatitis C, or human immunodeficiency results, subjects with a positive urine 
drug test (UDT) for illicit drugs or non-prescribed opioids; and/or subjects who previously received study drug in a 
V120083 trial will not be permitted to be rescreened.  
X-rays for rescreened subjects do not need to be repeated provided they were originally collected as part of this 
study and occurred within 1 month of rescreening. 
All rescreening must be approved in advance by the medical monitor. 


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Double-blind Period (4 weeks) 
The double-blind period is 4 weeks. 
Prior to entering the double-blind period, the subjects’ “average pain over the last 24 hours” scores will be 
assessed to determine the subjects’ eligibility to continue in the double-blind period. To qualify for entry into the 
double-blind period, subjects must have “average pain over the last 24 hours” scores of  4 and  9 for  3 
consecutive days during the pain assessment period. Subjects who do not qualify for the double-blind period will 
be discontinued from the study as screen failures. 
Subjects who are eligible for the double-blind period will have visit 2 (Day 1) scheduled in the morning.  At this 
visit, all qualified subjects will be randomized to receive the double-blind treatments. The first dose of study drug 
will be administered at the study clinic.  For subjects in the intensive PK subgroup, blood samples for 
pharmacokinetic (PK) analysis will be collected predose and postdose at 1, 2, 4, 6, and 8 hours. These subjects 
will remain at the study clinic until the PK samples are collected. 
Clinic visits during the double-blind period will occur at week 1 (visit 3), week 2 (visit 4), and week 4 (visit 5) 
visits. All clinic visits should occur in the morning. During these visits, PK samples will be collected at visits 3 
(predose, 1 and 2 hours postdose), 4 (predose or postdose), and 5 (predose or postdose) during the treatment 
period. Supplemental analgesic medication is APAP/acetaminophen 500 mg.  No more than 4 tablets/24 hours 
(ie, no more than 2 g/24 hours), as needed, will be permitted during the double-blind period.  All subjects will be 
instructed to refrain from taking any supplemental analgesic medication for at least 24 hours prior to the weeks 1, 
2, and 4 visits (visits 3, 4, and 5, respectively) of the double-blind period and to refrain from taking study drug 
dose on the morning of clinic visits to allow for predose PK sampling. 
Subjects are allowed a ±1 day window for visit 3, and a ±2 day window for visits 4 and 5. All scheduled visits in 
the double-blind period will be anchored to the day of randomization (visit 2).  Subjects who discontinued 
treatment early will be instructed to return to study clinic for an early discontinuation visit (visit 5).  After the end 
of the study or early discontinuation, subjects will be converted to a pain regimen as deemed medically 
appropriate by the investigator/designee.   
 
Follow-up Period (7 days) 
Subjects will receive a telephone call approximately 1 week after the end-of-study visit to assess subject status 
and documentation of AEs and concomitant medications. 
Criteria and Methods for Evaluation:  
Efficacy Variables/Endpoints: 
Primary Efficacy Variable: 
The primary efficacy variable in this study is the “average pain over the last 24 hours” score from the mBPI-SF 
pain severity subscale at week 4 of the double-blind period. 
Secondary Efficacy Variables/Endpoints: 
The secondary efficacy variable/endpoints are: 
x 
Weekly “average pain over the last 24 hours” collected by e-diary 
x 
Average daily “pain right now” collected by e-diary 
x 
WOMAC total scores 
x 
WOMAC pain subscale 
x 
WOMAC physical function subscale  
x 
WOMAC stiffness subscale  
x 
mBPI-SF total scores (all parts of question 6) 
x 
mBPI-SF pain severity subscale 
x 
mBPI-SF pain interference subscale  
x 
Responder to treatment  
x 
SF-36 


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x 
EQ-5D 
x 
PGIC at the end of double-blind period (week 4) 
x 
Supplemental analgesic medication use   
x 
Evaluate the occurrence of treatment-emergent suicidal ideation or behavior using the Columbia – 
Suicide Severity Rating Scale (C-SSRS) 
 
Other Variables 
Evaluation of taste disturbance using the Chemotherapy-induced Taste Alteration Scale (CiTAS) will be 
performed at prespecified times. 
Drug Concentration Measurements: 
Blood samples for pharmacokinetic (PK) analysis will be collected at visits 2, 3, 4, and 5. The PK evaluation will 
involve two components: intense PK sampling and sparse PK sampling.  Sparse PK sampling will be conducted 
for all subjects enrolled (276 subjects), with samples collected at visits 3 (predose, 1 and 2 hours postdose), 
4 (predose or postdose), and 5 (predose or postdose) during the treatment period. Intense PK sampling will be 
conducted for 24 subjects, consisting of the sparse PK schedule and visit 2 predose sample and postdose 
sampling at 1, 2, 4, 6, and 8 hours (day 1 of dosing). A single sample of blood (6 mL) will be taken for each time 
point. The date and time of dosing and sampling will be documented on the case report forms (CRFs).  
Analytical Methodology: 
Plasma concentrations of V120083 and possibly its metabolites will be quantified by a validated bioanalytical 
method. 
Safety Variables: 
Safety will be assessed using adverse events (including SAEs), clinical laboratory results, vital sign 
measurements, physical examinations, ECGs, C-SSRS, and results from the Hospital Anxiety and Depression 
Scale (HADS) 
Pharmacogenomic Sampling:  
The study will include PGx sampling that will be optional for all subjects. 
Statistical Methods: 
Analysis Populations: 
The enrolled population consists of all individuals who sign the informed consent form. 
The safety population is the group of subjects who are randomized and receive at least 1 dose of the 
double-blind study drug. 
The full analysis population (FAP) is the group of subjects who are randomized, receive at least 1 dose of 
double- blind study drug, and have at least 1 efficacy assessment. 
The per-protocol population is a subset of the full analysis population and consists of all subjects in the full 
analysis population (FAP) who do not have major protocol violations. 
The Pharmacokinetics (PK) population consists of all individuals who are randomized and receive at least 1 dose 
of the V120083 and have at least 1 valid, quantifiable PK blood sample 
Efficacy Analysis: 
Primary efficacy analysis is based on the “average pain over 24 hours” score in the mBPI-SF pain severity 
subscale at week 4 and the analysis will be performed using a mixed-effect general linear model with repeated 
measures (MMRM). The MMRM will include treatment (4 levels: V120083 30 mg bid, V120083 60 mg bid, 
naproxen 500 mg bid, and placebo) and time (3 levels for weeks 1, 2 and 4) as fixed effects; the baseline pain 
subscale will be incorporated as fixed covariates, and subject will be a random effect. Restricted maximum 
likelihood (REML) will be used to estimate the parameters in the model. While data from the entire double-blind 
period will be used to fit the linear model to get a better estimate of the variance-covariance matrix, the primary 


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comparison between groups will be based on estimates/contrasts for the pain score over the last 24 hours at 
week 4 means. 
Secondary Efficacy Analysis: 
The PGIC rating score (obtained at the week 4 or end-of-study visit) will be measured on a 7-point scale in which 
1 = very much improved and 7 = very much worse. The categories will be compared between treatment group 
and placebo using the Chi-squared test. Further analysis will be conducted on collapsed categories (very much 
improved/much improved vs improved/no change/worse/much worse/very much worse) using Fisher’s exact test. 
Other continuous longitudinal variables will be analyzed similarly to the primary efficacy method, using an 
MMRM. 
All hypothesis tests will be 1-sided and conducted at the 5% level of significance. 
Pharmacokinetic Analyses: 
Pharmacokinetic parameters of V120083 will be calculated based on the plasma concentrations of V120083 by 
using non-compartmental analysis for intense PK sampling component. 
A population PK analysis may be performed and will be reported in a separate report from the clinical study 
report. 
Interim Analysis: 
All interim analysis may be performed by the independent statistician/independent programmer and 
communicated to the independent (DMC. At the interim analysis, the following procedures will be performed: 
x 
Safety evaluation for early termination may be performed when 50% of subjects have completed the 
study. The independent statistician /programmer will provide safety data listings and summary tables by 
unblinded treatment arms. The DMC members will review the safety data, including AEs and clinical 
laboratory values. The decision to stop 1 or more treatment arms due to safety issues will be made 
based on clinical judgment. The arm will be stopped if there is significant physical toxicity or evidence of 
impending risk of physiologic harm or extremely abnormal laboratory findings related to treatment.  
x 
Efficacy evaluation for V120083 treatment arms may be performed by the independent 
statistician/programmer when 50% of subjects have completed the study. The 50% interim analysis will 
be performed to evaluate the efficacy of each dose of study drug in the study population. The DMC will 
review the results of the analysis and make recommendations, as appropriate, regarding plans for 
further studies.  
Lan et al (1982) introduced stochastic curtailment to stop a trial if, given current data, it is likely to predict the 
outcome of the trial with high probability. 32The conditional power at the scheduled end of the study, given 
the observed data at the interim evaluation, will be calculated with a stochastic curtailment approach to 
support the decision of early stop for futility. The conditional power is based on the formula given by Cui et al 
(1999, p. 854) and Emerson et al (2005, p. 13). 33,34  
Safety Analysis: 
Safety analyses will include vital signs, physical examinations, clinical laboratory parameters, AEs, ECGs, and 
C-SSRS results. AEs will be displayed by body system and preferred term using the Medical Dictionary for 
Regulatory Activities®, and summarized in terms of severity and relationship to study drug. Vital signs analysis 
will include the mean, standard deviation, and range at baseline and at the end of the double-blind treatment 
period, and the change from baseline to the end of the double-blind treatment period. Laboratory parameters will 
be summarized for the randomized safety population by presenting summary statistics (n, mean, standard 
deviation, median, and range) at the baseline and end of double-blind treatment, and change from baseline 
values to end of double-blind treatment for each treatment group. Within-treatment comparisons during the 
double-blind period will be based on shift tables (3 by 3: low, normal, high classification [LNH]) for a particular 
laboratory test and will compare the baseline LNH to the end-of-double-blind LNH. ECG findings at each time 
point will be tabulated.  
 
 


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3 
TABLE OF CONTENTS 
1
TITLE PAGE ...................................................................................................................... 2
2
SYNOPSIS ......................................................................................................................... 3
3
TABLE OF CONTENTS ................................................................................................... 14
4
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 20
5
ETHICS ............................................................................................................................ 23
5.1
Institutional Review Board or Independent Ethics Committee ...................................... 23
5.2
Ethical Conduct of the Study ........................................................................................ 23
5.3
Subject Information and Consent ................................................................................. 23
6
INVESTIGATORS AND STUDY PERSONNEL ............................................................... 23
7
INTRODUCTION .............................................................................................................. 24
7.1
Potential Risks and Benefits ......................................................................................... 27
8
STUDY OBJECTIVES ...................................................................................................... 28
9
INVESTIGATIONAL PLAN ............................................................................................... 29
9.1
Overall Study Design and Plan Description .................................................................. 29
9.2
Discussion of Study Design, Including the Choice of Control Groups .......................... 32
9.3
Selection of Study Population ....................................................................................... 33
9.3.1
Inclusion Criteria .................................................................................................... 33
9.3.2
Exclusion Criteria .................................................................................................. 34
9.3.3
Removal of Subjects from Study Participation ...................................................... 36
9.4
Treatments ................................................................................................................... 38
9.4.1
Treatments administered ....................................................................................... 38
9.4.2
Identity of Investigational Product(s) ..................................................................... 38
9.4.3
Drug Accountability ............................................................................................... 40
9.4.4
Method of Assigning Subjects to Treatment Groups ............................................. 41


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9.4.5
Selection of Doses in the Study ............................................................................ 41
9.4.6
Selection and Timing of Dose for Each Patient ..................................................... 41
9.4.7
Blinding .................................................................................................................. 41
9.4.8
Prior and Concomitant Therapy ............................................................................ 42
9.4.9
Treatment Compliance .......................................................................................... 43
9.5
Study Procedures ......................................................................................................... 44
9.5.1
Schedule of Activities ............................................................................................ 44
9.5.2
Screening .............................................................................................................. 48
9.5.2.1
Visit 1 (Screening Visit) .................................................................................. 48
9.5.2.2
Telephone Contact/Washout Period .............................................................. 50
9.5.3
Visit 2 – Randomization ......................................................................................... 52
9.5.4
Visits 3 (week 1) and 4 (week 2) - Double-blind Period......................................... 54
9.5.5
Visit 5 - End of Study or Early Discontinuation ...................................................... 56
9.5.6
Unscheduled Visits ................................................................................................ 58
9.5.7
Follow-up ............................................................................................................... 58
9.6
Efficacy Variables, Drug Concentration, Safety and Other Variables ........................... 59
9.6.1
Appropriateness of Measurements ....................................................................... 59
9.6.2
Efficacy Variables .................................................................................................. 61
9.6.2.1
Primary Efficacy Variable ............................................................................... 61
9.6.2.2
Secondary Efficacy Variable(s) ...................................................................... 61
9.6.3
Drug Concentration Measurements ...................................................................... 61
9.6.3.1
Analytical Methodology .................................................................................. 62
9.6.4
Safety Variable(s) .................................................................................................. 62
9.6.4.1
Adverse Events (AEs) .................................................................................... 62
9.6.4.2
Clinical Laboratory Evaluations ...................................................................... 62
9.6.4.3
Vital Signs ...................................................................................................... 62
9.6.4.4
Electrocardiograms (ECGs) ........................................................................... 63


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9.6.4.5
Physical Examination ..................................................................................... 64
9.6.4.6
Other Safety Variables ................................................................................... 64
9.6.5
Other Variables ..................................................................................................... 64
9.6.5.1
Chemotherapy-induced Taste Alteration Scale (CiTAS) ................................ 64
9.6.5.2
Pharmacogenomics ....................................................................................... 64
9.6.6
Clinical Supplies Product Complaints .................................................................... 65
9.6.6.1
Types of CSPCs ............................................................................................. 65
9.6.6.2
Reporting of CSPCs to Sponsor or Designee ................................................ 65
9.6.7
Subject Drug Discrepancies .................................................................................. 66
9.6.8
Quality Assurance ................................................................................................. 66
9.6.9
Data Collection ...................................................................................................... 66
9.6.10
Clinical Data Management .................................................................................... 67
9.6.11
Data Quality Assurance ......................................................................................... 67
9.7
Statistical Methods Planned in the Protocol and Determination of Sample Size .......... 67
9.7.1
Analysis Populations ............................................................................................. 67
9.7.2
Summary of Study Population Characteristics ...................................................... 68
9.7.2.1
Demographics and Baseline Characteristics ................................................. 68
9.7.2.2
Subject Disposition ......................................................................................... 68
9.7.2.3
Dosing and Extent of Exposure ...................................................................... 68
9.7.2.4
Prior and Concomitant Therapy ..................................................................... 68
9.7.2.5
Medical History ............................................................................................... 69
9.7.3
Efficacy Analysis ................................................................................................... 69
9.7.3.1
Primary Efficacy Variable(s) ........................................................................... 69
9.7.3.2
Secondary Efficacy Variable(s) ...................................................................... 69
9.7.4
Pharmacokinetic Analysis ..................................................................................... 72
9.7.4.1
Pharmacokinetic Variable(s) .......................................................................... 72
9.7.4.2
Pharmacokinetic Statistical Analysis .............................................................. 72


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9.7.5
Statistical / Analytical Issues ................................................................................. 72
9.7.5.1
Adjustments for Covariates ............................................................................ 72
9.7.5.2
Handling of Dropouts or Missing Data ........................................................... 72
9.7.5.3
Interim Analyses and Data Monitoring ........................................................... 73
9.7.5.4
Homogeneity Across Clinical Sites ................................................................ 74
9.7.5.5
Multiple Comparisons / Multiplicity ................................................................. 74
9.7.5.6
Examination of Subgroups ............................................................................. 74
9.7.6
Safety Analyses ..................................................................................................... 74
9.7.6.1
Adverse Events (AEs) .................................................................................... 74
9.7.6.2
Laboratory Values .......................................................................................... 75
9.7.6.3
Vital Signs ...................................................................................................... 77
9.7.6.4
Electrocardiograms ........................................................................................ 77
9.7.6.5
Physical Examination ..................................................................................... 79
9.7.6.6
Other Safety Variables ................................................................................... 79
9.7.7
Other variable analysis .......................................................................................... 79
9.7.8
Other Analyses ...................................................................................................... 80
9.7.9
Determination of sample size ................................................................................ 80
10
Adverse Events ................................................................................................................ 80
10.1
Definition ....................................................................................................................... 80
10.2
Assessment .................................................................................................................. 81
10.2.1
Criteria for Assessing Severity .............................................................................. 81
10.2.2
Criteria for Assessing Causality ............................................................................ 81
10.2.3
Criteria for Assessing Seriousness ....................................................................... 82
10.3
Adverse Events – Reporting ......................................................................................... 83
10.3.1
Additional Reporting Requirements for Pregnancies ............................................ 83
10.3.2
Additional Reporting Requirements for Adverse Events of Special Interest.......... 84
10.3.3
Additional Reporting Requirements for Serious Adverse Events .......................... 84


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11
ADMINISTRATIVE ASPECTS ......................................................................................... 85
11.1
Changes to Protocol ..................................................................................................... 85
11.2
Discontinuation of Study ............................................................................................... 86
11.3
Disclosure and Confidentiality ...................................................................................... 86
11.4
Monitoring Procedures ................................................................................................. 86
11.5
Records Retention ........................................................................................................ 87
11.6
Inspection Procedures .................................................................................................. 87
11.7
Publication of Results ................................................................................................... 87
12
SIGNATURE PAGE FOR INVESTIGATORS................................................................... 88
13
REFERENCE LIST .......................................................................................................... 89
14
APPENDICES .................................................................................................................. 92
Appendix A: Clinical Laboratory Evaluations ........................................................................... 92
Appendix B: Critical Alert Laboratory Values .......................................................................... 93
Appendix C: Pharmacokinetic Sample Collection, Processing, Storage, and Shipment ......... 94
Appendix D: Naproxen Capsules 500 mg Comparator Product Formulations ........................ 95
Appendix E: Naproxen Product Information ............................................................................ 96
Appendix F: Average Pain Intensity over the Last 7 Days .................................................... 128
Appendix G: Kellgren - Lawrence Classification ................................................................... 129
Appendix H: Hospital Anxiety and Depression Scale (HADS) .............................................. 130
Appendix I: Modified Brief Pain Inventory-Short Form (mBPI-SF) ........................................ 133
Appendix J: Western Ontario and McMaster OA Index (WOMAC) ....................................... 136
Appendix K: EQ-5D ............................................................................................................... 142
Appendix L: Medical Outcomes Study 36-item Short-Form (SF-36) ..................................... 144
Appendix M: Patient Global Impression of Change (PGIC) .................................................. 149
Appendix N: Pain Numerical Rating Scale ............................................................................ 150
Appendix O: Columbia Suicide Severity Rating Scale (C-SSRS) ......................................... 151
Appendix P: Chemotherapy-induced Taste Alteration Scale (CiTAS) ................................... 154


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Appendix Q: List of Prohibited Medications and Classification ............................................. 155
Appendix R: Amendment 1 Summary of Changes ................................................................ 158
LIST OF TABLES 
Table 1 
Test Treatment .......................................................................................................... 38
Table 2 
Reference Treatments .............................................................................................. 39
Table 3
Schedule of Activities ................................................................................................ 44
Table 4 
Reference Range for Vital Sign Values .................................................................... 63
Table 5 
Criteria Used to Identify Clinically Notable Vital Sign Abnormalities ......................... 63
Table 6 
Criteria Used to Identify Clinically Notable ECG Values ........................................... 64
Table 7  
Laboratory Ranges Used to Identify Markedly Abnormal Laboratory Values ........... 76
Table 8 
Categories for Shift Analysis of AST, ALT, and Total Bilirubin ................................. 77
 
LIST OF FIGURES 
Figure 1    Study Design………………………………………………………..………………………29 
 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
μ 
mu (also symbol for micro) 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALT 
alanine aminotransferase (alanine transaminase; also SGPT) 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
APAP 
acetaminophen 
AST 
aspartate aminotransferase (aspartate transaminase; also SGOT) 
ATC 
anatomical therapeutic chemical 
AUC 
area under the plasma concentration-time curve 
bid 
twice daily 
BMI 
body mass index 
BP 
bodily pain 
Bpm 
beats per minute 
C 
Celsius or centigrade 
CFR 
Code of Federal Regulations 
CiTAS 
Chemotherapy-induced Taste Alteration Scale 
Cmax 
Maximum Concentration 
COX-2 
cyclo-oxygenase 2 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CSPC 
clinical supply product complaint 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
dL 
deciliter 
DMC 
data monitoring committee 
DO 
Doctor of Osteopathic Medicine 
ECG 
electrocardiogram 
EQ-5D 
EuroQol-5D 
EQ-5D-5L 
F 
5-level scale EQ-5D 
Fahrenheit 
FAP 
full analysis population 
FDA 
Food and Drug Administration 
g 
gram 
GCP(s) 
Good Clinical Practice(s) 
GEE 
generalized estimating equation 
GGT 
gamma-glutamyltransferase 
GH 
general health 
HADS 
Hospital Anxiety and Depression Scale 
HBV 
hepatitis B 


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HCV 
hepatitis C 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethic Committee 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
Kg 
kilogram 
K-L 
Kellgren-Lawrence 
L 
liter 
L.P. 
Limited Partnership 
LAH 
left anterior hemiblock 
LBBB 
left bundle branch block 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LLN 
lower limit of the laboratory reference range 
LNH 
low, normal, high (relative to the laboratory reference range) 
MAD 
multiple ascending dose 
mBPI-SF 
modified Brief Pain Inventory – Short Form 
MedDRA 
Medical Dictionary for Regulatory Activities 
mEq 
milliequivalent 
mg 
milligram 
MH 
mental health 
MI 
myocardial infarction 
mL 
milliliter 
mm 
millimeter 
mm Hg 
millimeters of mercury 
MMRM 
mixed-effect general linear model with repeated measures 
mmol 
millimole 
msec 
millisecond 
NP 
Nurse Practitioner 
NOAEL 
no-observed-adverse-event-level 
NRS 
numerical rating scale 
NSAID 
nonsteroidal anti-inflammatory drug 
OA 
Osteoarthritis 
PA 
Physician Assistant 
PF 
physical functioning 
PG 
pharmacogenomics 
PGIC 
Patient Global Impression of Change 


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PI 
principal investigator 
PK 
pharmacokinetic(s) 
po 
oral route of administration 
PP 
per-protocol population 
PPLP 
Purdue Pharma Limited Partnership 
PR 
PR interval (ECG) 
QRS 
QRS interval (ECG) 
QT 
QT interval (ECG) 
QTc 
QT data corrected for heart rate 
QTcB 
QT data corrected for heart rate using the Bazett formula 
QTcF 
QT data corrected for heart rate using the Fridericia formula 
RBC 
red blood cell (count) 
RE 
role-emotional 
RP 
role-physical 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SF 
social functioning 
SF-36 
Medical Outcomes Study 36-Item Short Form Health Survey 
SGOT 
serum glutamic-oxaloacetic transaminase (also AST) 
SGPT 
serum glutamate pyruvate transaminase (also ALT) 
SI 
international system of units for clinical laboratory values 
SOC 
System Organ Class 
SOP 
standard operating procedure 
SSRI 
selective serotonin reuptake inhibitors  
SNRI 
serotonin norepinephrine reuptake inhibitors 
ST 
ST interval (ECG) 
TEAE 
treatment-emergent adverse event 
TENS 
Transcutaneous Electrical Nerve Stimulation 
TESS 
treatment-emergent sign or symptom 
Tmax 
time to maximum  plasma concentration 
TRPV1 
transient receptor potential vanilloid subfamily, member 1 
UA 
urinalysis 
ULN 
upper limit of the laboratory reference range 
US 
United States 
v 
versus 
VAS 
ED-5Q visual analogue scale 
VT 
vitality 
WBC 
white blood cell (count) 
WOMAC 
Western Ontario and McMaster Osteoarthritis Index 
 
 


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5 
ETHICS 
5.1 
Institutional Review Board or Independent Ethics Committee 
The protocol, any protocol amendments, and the informed consent form (ICF) will be reviewed 
and approved by each study center’s Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) before subjects are screened for entry.  Verification of the IRB’s/IEC’s 
unconditional approval of the protocol will be transmitted to the sponsor (or designee) prior to 
the site(s) being initiated.  The investigator(s) will submit, depending on local regulations, 
periodic reports and inform the IRB/IEC of any reportable adverse events (AEs) per 
International Council for Harmonisation (ICH) guidelines and local IRB standards of practice. 
A list of IRB(s)/IEC(s) that approved this study will be included in the clinical study report. 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating practices (SOPs) of the 
sponsor (or designee) to ensure adherence to Good Clinical Practice (GCP) guidelines as 
required by the following: 
x 
Declaration of Helsinki, 1964 (“Recommendations Guiding Physicians in Biomedical 
Research Involving Human Subjects”), and all its accepted amendments to date 
concerning medical research in humans 
x 
ICH E6 Guideline for Good Clinical Practice (CPMP/ICH/135/95) of the European 
Agency for the Evaluation of Medicinal Products, Committee for Proprietary 
Medicinal Products, and ICH of Pharmaceuticals for Human Use 
x 
US Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR, 
including, but not limited to, parts 11, 50, 54, 56, and 312 concerning electronic 
records/signatures, Informed Consent, Financial Disclosures, IRB/IEC and 
Investigational New Drug Application regulations). 
5.3 
Subject Information and Consent 
The principal investigator (or designee) will explain the nature of the study and the action of the 
test product.  The subjects will be informed that participation is voluntary and that they can 
withdraw from the study at any time.   
In accordance with ICH E6 (section 4.8) and 21 CFR 50, informed consent shall be documented 
by the use of a written ICF approved by the IRB prior to protocol-specific procedures being 
performed. 
The subject or their guardians/legally authorized representatives will be given a signed copy of 
the consent, and the original will be maintained with the subject’s records. 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Purdue Pharma 
Limited Partnership (PPLP) at multiple sites in the United States. 


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The contract research organization (CRO) 
 has been retained by PPLP to implement 
and manage the study, including management of subcontracted vendors, and is referred to 
henceforth in this protocol as the sponsor’s designee.   
The name of the Medical Monitor, along with the telephone and fax numbers of the other 
contact persons at the CRO, will be listed in the regulatory binder provided to each site. 
The names of clinical site personnel trained for this study must appear on the delegation log. 
7 
INTRODUCTION 
Chronic pain is estimated to affect approximately 100 million adults in the United States (US) 
alone.1  Osteoarthritis (OA), a common form of joint disease, results in long-term pain and 
prolonged disability.  In the US, OA affects approximately 27 million patients of all ages.2  Pain, 
joint stiffness, and reduced motion lead to disability and loss of independence among patients 
with OA.  An effective cure for OA remains elusive and analgesics provide the primary 
treatments.  Current standard of care therapies for OA pain include use of traditional 
nonsteroidal anti-inflammatory drugs (NSAIDs), which can cause serious and sometimes 
life-threatening adverse effects associated with long-term use.  Management of chronic pain, 
especially for OA patients, is in need of novel therapeutic options. 
 
Purdue Pharma, L.P. is developing V120083 for the management of pain due to OA.  V120083 
is a potent and selective TRPV1 receptor antagonist which was discovered in the collaborative 
research 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
. 
 
TRPV1 (transient receptor potential vanilloid subfamily, member 1) is an ion channel located 
mainly on peripheral sensory neurons.  TRPV1 plays a significant and unique role in the pain 
pathway because it is a polymodal initiator of pain signaling.  Direct blockade of this channel is 
expected to interrupt the start of neuronal transmission of pain producing signals.  TRPV1 is 
activated by a broad range of mechanical, thermal, or chemical stimuli including factors often 
associated with infection, inflammation or ischemia such as heat, low pH, nitric oxide, and 
lipoxygenase metabolite formation3, 4.  TRPV1 expression on sensory neurons is also known to 
be increased in the presence of persistent inflammation.  The hyperalgesia associated with the 
inflammatory process is related to this increase.  The ultimate result is channel sensitization, 
which manifests as a potentiation of thermal, capsaicin, and pH responses in  
TRPV1 channels.3, 4  
There are many published examples of novel TRPV1 antagonists that produce significant 
antihyperalgesia against thermal and mechanical endpoints in standard models of pain-like 
behavior in rodents.  A number of these TRPV1 antagonists are currently in various stages of 
clinical development.  Contact activation, tissue and/or cellular injury, and inflammation are each 
capable of direct and indirect modulation of the TRPV1 channel via multiple mechanisms.  The 
mechanistic convergence of initiators and potentiators of the TRPV1 channel provide the 
conceptual basis for believing that TRPV1 antagonism might be an effective approach to 
treating pain associated with inflammation and nerve injury 3, 4. 
 


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V120083 has an analgesic effect, not only in rodent inflammatory pain models but also in rodent 
neuropathic pain models.  These pharmacological profiles suggest an analgesic effect on 
chronic pain and various other pain mechanisms.  
 
In metabolism studies, in vivo metabolites in rats, dogs and humans and in vitro metabolites in 
cryopreserved human hepatocytes were identified.  In rat and dog studies, V120083 mainly 
existed in an unchanged form in the plasma and the majority of V120083 was excreted as 
metabolites in the urine, the feces, and in bile.  The major metabolic pathway of V120083 in the 
human plasma and cryopreserved human hepatocytes appears to be oxidation followed by 
glucuronidation and the formation of 5-methyl-2-oxoimidazolidinyl acetic acid (OAA), 2-
oxoimidazolidinyl propanoic acid (OPA). 
 
In the 1 month repeated dose toxicity study in dogs, vomiting and low body weight accompanied 
with decreased food consumption were observed in both sexes treated at 600 mg/kg/day during 
dosing period.  In the 3 month repeated dose toxicity study in dogs, these findings were also 
noted at the high dose of 500 mg/kg/day. 
 
In both the dog 3 month and rat 6 month repeat dose toxicology studies, the presence of study 
test article (V120083) manifested as crystal formation and deposition was observed in the 
lamina propria of the small intestine and/or mesenteric lymph node in the majority of animals in 
the high dose group in rats (1,000 mg/kg/day) and dogs (500 mg/kg/day).  Crystals were also 
observed in mandibular lymph nodes and the lamina propria of several other organs in a smaller 
number of rats in the high dose group. The crystal deposition was identified as unchanged 
V120083 based on analytical identification and likely related to limitation in the solubility in body 
fluid including plasma.   
 
V120083 was negative in the following genotoxicity studies: in vitro bacterial reverse mutation 
test, mouse lymphoma assay, and in vivo micronucleus test with rat bone marrow cells.  
Potential genotoxicity of S189A6, an impurity of V120083, has been also evaluated.  S189A6 
was negative in in vitro micronucleus test and in vivo combination study of micronucleus and 
comet assays in rats, while S189A6 was concluded to be positive in the reverse mutation test 
with bacteria. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Some investigational TRPV1 antagonists have demonstrated deficits in thermosensory function, 
placing patients at risk for inadvertent cutaneous and oral burns6. These issues have not been 
seen in prior studies with V120083.  Subjects will receive additional instructions on how to avoid 
thermal injury.  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
This present study, VAN2001, is the first efficacy study planned for V120083. Osteoarthritis 
(OA) has been chosen as a chronic pain model of choice to demonstrate efficacy. OA is a 
leading cause of pain, loss of function, and disability in Western populations, and radiographic 
evidence of OA is present in the majority of adults by the age of 65 years 7. Nonsteroidal 
anti-inflammatory drugs (NSAIDs), such as naproxen, are the most frequently used analgesics 
for the treatment of mild to moderate OA pain 8, and thus naproxen is being used in this study 
as a positive control. 
Although efficacious, NSAIDs are associated with significant gastrointestinal side effects and a 
potential increased risk of adverse cardiovascular events. Therefore, alternatives for the chronic 
treatment of OA pain are needed.  
Expression of the TRPV1 receptor is upregulated in animal models of OA9. In patients with OA, 
injection of the TRPV1 agonist capsaicin into affected joints relieves pain, presumably by 
desensitizing the TRPV1 receptor10. Thus, antagonism of the TRPV1 receptor may be useful in 
the treatment of OA pain.  
Additional information pertaining to V120083, including its physicochemical properties in in vitro 
and in vivo nonclinical studies specifically its pharmacology, pharmacokinetics, and toxicology, 
are presented in the Investigator’s Brochure 5. 
 
Refer to the V120083 Investigator’s Brochure for additional product information.  Refer to 
Appendix E for naproxen product information. 


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7.1 
Potential Risks and Benefits 
The safety assessments of V120083 rely on data accumulated during product development and 
data on other drugs in the class.  Based on the preclinical and clinical data available to date, the 
conduct of the trial is regarded as justifiable at the planned doses and duration. 
V120083 is being considered as a new option for the treatment of pain due to osteoarthritis of 
the knee.  No identified risks or new potential risks have emerged from the phase I clinical 
studies performed.  V120083 was safe and generally well tolerated by healthy human 
volunteers at single doses up to 1000 mg and at multiple doses up to 300 mg bid administered 
for up to 14 days. The dose of V120083 (30 mg or 60 mg) selected for the proposed trial is 
within the dose ranges studied in the phase I trials. 
 
Important potential risks to subjects are based on nonclinical safety data of V120083 and the 
phase 1 clinical studies.  The most common TEAEs reported in the MAD study were feeling cold 
and feeling hot, reported in subjects receiving higher doses (100 mg and 300 mg) of V120083. 
No subjects in the 30 mg dose group experienced these events and only 1 AE each of feeling 
cold and feeling hot were reported by placebo-treated subjects. These AEs were expected due 
to the mechanism of action of V120083; no clinically significant changes in body temperature 
were observed.  
 
One subject, who received multiple doses of 300 mg V120083, experienced an SAE of pleural 
effusion. This SAE was considered not related to study drug.  
 
V120083, like other TRPV1 antagonists, may attenuate response to noxious heat stimuli. 
Therefore, subjects receiving V120083 should be cautioned to take measures to avoid the 
occurrence of burn injury. Such measures include keeping the hot water thermostat 
 120 degrees Fahrenheit (F), checking water temperature, using potholders or oven mitts when 
handling cookware, and taking care when eating hot foods or drinking hot beverages.  
Risk minimization measures include a data monitoring committee (DMC) to review available 
safety and tolerability data and will be mandated to make decisions regarding the conduct of the 
trial according to the DMC charter and interim analysis criteria.  Additionally, the sponsor or 
representatives will review blinded safety data throughout the trial.  The DMC members will 
review the safety data, including but not limited to AEs and clinical laboratory values.  The DMC 
recommendations will include: 1) Continue the study without modification; 2) Continue the study 
and amend the protocol, as specified; 3) Pause enrollment, pending resolution of a specified 
issue; 4) Terminate the study. 
 
The decision to stop 1 or more treatment groups due to safety issues will be made based on 
review and recommendation by the DMC. 
Placebos are used in this trial to conceal whether a treatment is being given or not and hence to 
control for the psychosomatic effects of offering treatment.  Randomization will be used in this 
trial to avoid bias in the assignment of subjects to treatment, to increase the likelihood that 
known and unknown patient attributes (eg, demographics and baseline characteristics) are 
evenly balanced across treatment groups.  Blinded treatment will be used to reduce potential 
bias during data collection and evaluation of endpoints. 
Taking the above information into account, benefit-risk considerations support conduct of the 
proposed clinical trial VAN2001 in patients with OA pain of the knee. 


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For full details, refer to the latest IB for further information about the nonclinical and clinical 
programs and Guidance for the Investigator. 
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP 
guidelines, and any additional applicable regulatory requirements. 
8 
STUDY OBJECTIVES 
The primary objective of this study is: 
x 
To evaluate the analgesic efficacy of V120083 bid compared with placebo in subjects 
with moderate to severe chronic pain due to OA of the knee using the “average pain 
over the last 24 hours” score from the modified Brief Pain Inventory – short form 
(mBPI-SF) pain severity subscale at week 4 of the double blind period.  
The secondary objectives of this study are: 
x 
Evaluate the safety and tolerability (including adverse event [AE] reporting, clinical 
laboratory parameters, and physical examination) of 2 dose levels of V120083 
x 
Evaluate the efficacy of V120083 on pain, stiffness, physical function, and overall 
disability using the Western Ontario and McMaster Osteoarthritis Index (WOMAC) 
subscale and total scores  
x 
Evaluate the efficacy of V120083 on pain intensity due to OA using numerical rating 
scale (NRS) pain scores from the mBPI-SF pain severity subscale  
x 
Evaluate the impact of V120083 on pain-related quality of life/function using the 
mBPI-SF pain interference subscale  
x 
Evaluate the effect of V120083 on pain severity and pain interference overall using the 
mBPI-SF total score  
x 
Evaluate the impact of V120083 on subjects’ health state (as defined by mobility, 
self-care, daily activities, pain/discomfort, and anxiety/depression) using the EuroQol-5D 
(EQ-5D)  
x 
Evaluate the impact of V120083 on subjects’ functional health and well-being using the 
Medical Outcomes Study 36-Item Short Form Health Survey (SF-36)  
x 
Evaluate subject global impression of treatments using the Patient Global Impression of 
Change (PGIC) questionnaire  
x 
Evaluate the impact of V120083 on mood (anxiety and depression) using the Hospital 
Anxiety and Depression Scale (HADS) 
x 
Evaluate the efficacy of naproxen vs. placebo for assay sensitivity using the primary and 
secondary endpoints indicated above. 
x 
Determine plasma levels of V120083 in subjects under clinical use conditions.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
x 
Evaluate supplemental analgesic medication use 




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Efficacy and safety evaluation for V120083 treatment groups may be performed by the DMC when 50% 
of subjects have completed the study.   
The total duration of the study for a given subject is up to 56 days, inclusive of a 21-day 
screening period; a 28-day double-blind treatment period; and a 7-day follow-up period.  
Naproxen 500 mg bid will be used as an active control to determine the assay sensitivity of the 
study.  
During the screening period, subjects will be assessed to determine eligibility for enrollment into 
the trial.  As soon as the laboratory, ECG, and radiograph results are available, the site staff will 
contact the subjects by telephone to inform them of the results and whether they are qualified to 
continue in the study.  Subjects who do not meet the initial entry criteria will be considered 
screen failures.  For subjects who meet the initial entry criteria and:  
x 
Who do not take any analgesic medications for their pain, the site staff will instruct them 
to record in the diary their “average pain over the last 24 hours” scores (Appendix N) for 
their index knee at approximately 8 PM every day for 3 to 7 days; these subjects may 
return to the study clinic for visit 2 as soon as they have “average pain over the last 
24 hours” scores  4 and  9 for  3 consecutive days. All subjects must return to the 
study clinic for visit 2 within 96 hours of the latest qualifying pain score entry within the 
pain assessment period. 
x 
Who take medication for their chronic pain (including any topical and/or oral analgesics, 
antidepressants, anticonvulsant, and other medication used for pain), the site staff 
instruct them to: 
 
Discontinue use of all medication for pain (including any topical and/or oral 
analgesics, antidepressants, anticonvulsant and other medication used for pain) in 
accordance with accepted medical practice and,  
 
As soon as all medication used for pain is stopped, record in the diary their “average 
pain over the last 24 hours” scores for their index knee at approximately 8 PM every 
day for 3 to 9 days; these subjects may return to the study clinic for visit 2 as soon as 
they reported “average pain over the last 24 hours” scores of  4 and  9 for 
 3 consecutive days.  All subjects must return to the study clinic for visit 2 within 
96 hours of the latest qualifying pain score entry within the pain assessment period. 
Prior to entering the double-blind period, the subjects’ “average pain over the last 24 hours” 
scores will be assessed to determine the subjects’ eligibility to continue in the double-blind 
period.  To qualify for entry into the double-blind period, subjects must have “average pain over 
the last 24 hours” scores of  4 and  9 for  3 consecutive days during the pain assessment 
period.  Subjects who do not qualify for the double-blind period will be discontinued from the 
study as screening failures.  
Rescreening of subjects who previously failed screening is allowed only with the permission of 
the medical monitor on a case by case basis.  
Subjects may be considered for rescreening if they failed screening previously due to eligibility 
criteria that are now allowed under the current amended protocol; delay of acquiring records; 
out of window issues (eg, lost or delayed labs); timing of exclusionary procedures; or other 
reasons approved by the medical monitor.   


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Subjects with positive hepatitis B, hepatitis C, or human immunodeficiency results, subjects with 
a positive urine drug test (UDT) for illicit drugs or non-prescribed opioids; and/or subjects who 
previously received study drug in a V120083 trial will not be permitted to be rescreened.  
X-rays for rescreened subjects do not need to be repeated provided they were originally 
collected as part of this study and occurred within 1 month of rescreening. 
All rescreening must be approved in advance by the medical monitor. 
Subjects who are eligible for the double-blind period will have visit 2 scheduled in the morning.   
After meeting eligibility requirements, approximately 276 subjects will be stratified for 
randomization in a 1:1:1:1 fashion according to the baseline severity of pain score (mBPI-SF 
average pain) and study site at visit 2 to receive 1 of the following 4 treatments in the double 
blind period: V120083 30 mg bid, V120083 60 mg bid, naproxen 500 mg bid, or placebo.  The 
first dose of study drug will be administered at the study clinic.  
Blood samples for pharmacokinetic (PK) analysis will be collected at visits 2, 3, 4, and 5. The 
PK evaluation will involve two components: intense PK sampling and sparse PK sampling.  
Sparse PK sampling will be conducted for all subjects enrolled (276 subjects), with samples 
collected at visits 3 (predose, 1 and 2 hours postdose), 4 (predose or postdose), and 5 (predose 
or postdose) during the treatment period. Intense PK sampling will be conducted for 
24 subjects, consisting of the sparse PK schedule and visit 2 predose sample and postdose 
sampling at 1, 2, 4, 6, and 8 hours (day 1 of dosing). The study will include pharmacogenomics 
(PG) sampling that will be optional for all subjects. 
Clinic visits during the double-blind period will occur at week 1 (visit 3), week 2 (visit 4), and 
week 4 (visit 5).  All clinic visits must occur in the morning.  During these visits, blood samples 
for PK analysis will be collected as outlined in the Schedule of Activities (Table 3).  The study 
will also include pharmacogenomics (PG) sampling that will be optional for all subjects. 
Starting at screening phone call visit, subjects may take their own supplemental analgesic 
medication, ie, 500 mg acetaminophen (APAP), which can be taken as needed up to 
2 g/24 hours  for breakthrough pain, but it is not to be taken within 24 hours of visit 2.  
Supplemental analgesic medication, APAP/acetaminophen 500 mg, will be provided during the 
double-blind period.  No more than 4 tablets/24 hours (ie, no more than 2 g/24 hours), as 
needed, will be permitted during the double-blind period.  All subjects will be instructed to refrain 
from taking any supplemental analgesic medication for at least 24 hours prior to the weeks 1, 2, 
and 4 (visits 3, 4, and 5, respectively) of the double-blind period.  
Subjects are allowed a ±1 day window for visit 3, and a ±2 day window for visits 4 and 5, from 
baseline.  All scheduled visits will be anchored to the day of randomization (visit 2).  Subjects 
who discontinued treatment early will be instructed to return to study clinic for an early 
discontinuation visit (visit 5).  After the end of the study/early discontinuation visit, all subjects 
will be converted to a pain regimen as deemed medically appropriate by the 
investigator/designee. 
An interim analysis may be performed for futility when approximately 50% of randomized 
subjects have completed the study.  An independent DMC will review all unblinded safety and 
efficacy data from the interim analysis and make recommendations as necessary. 


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Follow-up Period (7  days) 
Subjects will receive a telephone call approximately 7 days after the end of the study/ study 
discontinuation visit to assess subject status and documentation of AEs and concomitant 
medications. 
A study flow chart describing the schedule of activities for this study is presented in Table 3. 
9.2 
Discussion of Study Design, Including the Choice of Control Groups 
The analgesic effect of V120083 is currently unknown.  This is a proof-of-concept study 
designed to evaluate the efficacy of V120083 30 mg bid and 60 mg bid compared with placebo 
in subjects with chronic moderate to severe OA pain of the knee.  
This study will employ a double-blind, parallel-group design.  This method is selected because it 
is the most efficient and nonbiased design to demonstrate the efficacy and safety of V120083 
versus (v) placebo.  The duration of the double-blind period will be 28 days.  This treatment 
duration was selected as this length of time was sufficient to demonstrate the onset of analgesic 
activity for a drug that may require repeated use for efficacy and for establishing maintenance of 
analgesic activity for chronic pain conditions such as OA.   
Naproxen 500 mg bid will be used in this study as active control.  Naproxen is selected for this 
study because it has shown to be efficacious in treating subjects with OA pain of the knee in 
previous proof-of-concept studies conducted by PPLP.  In this study, naproxen will be used to 
determine assay sensitivity for a successful study regardless of efficacy of the study drug. 
The purpose of the placebo group is to account for the placebo effect, that is, effects from 
treatment that do not depend on the treatment itself.  Such factors include knowing one is 
receiving a treatment, attention from health care professionals, and the expectations of a 
treatment's effectiveness by those running the research study.  Without a placebo group to 
compare against, it is not possible to know whether the treatment itself had any effect. 
The study population was chosen for study as it represents significant numbers of subjects who 
are suboptimally treated with currently available standard-of-care therapies.  Only those 
subjects who meet protocol-specified criteria for inadequate analgesia will be eligible to enter 
the double-blind period.  During the study, subjects will be asked to stop all incoming analgesic 
medications and other medications used for chronic pain and instead receive only the study 
drugs to manage their OA pain of the knee.  Subjects are permitted to take supplemental 
analgesic medication throughout the double-blind period in order to maintain subjects in the 
study for the 4-week time course (except for 24 hours prior to the weeks 1, 2, and 4 visits).   
Randomization will be used in this study to avoid bias in the assignment of subjects to study 
treatments, to increase the likelihood that known and unknown subject attributes 
(eg, demographics and baseline characteristics) are evenly balanced across treatment groups, 
and to enhance the validity of statistical comparisons across treatment groups.  Blinded 
treatment will be used to reduce potential bias during data collection and evaluation of 
endpoints. 


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9.3 
Selection of Study Population 
Subjects meeting all the inclusion criteria and none of the exclusion criteria may be entered into 
the study.  Subjects who do not fulfill the inclusion or exclusion criteria may be allowed to enter 
the study only after discussion with the sponsor (or designee).  In such instances, 
documentation will be filed at the clinical site and with the sponsor (or designee). 
9.3.1 Inclusion Criteria 
Subjects who meet the following criteria will be included in the study: 
1. Males and females  40 and  80 years of age with moderate to severe chronic OA pain of 
the knee (lasting several hours daily) as their predominant pain condition for at least 6 
months prior to screening; 
2. Diagnostic criteria for primary pain condition (American College of Rheumatology [ACR] 
clinical and radiographic criteria):  
x 
At least 1 of the following in addition to knee pain: age > 50, morning stiffness < 30 min, 
crepitus on active motion, and  
x 
Kellgren-Lawrence (K-L) grade 2 or 3 radiographic evidence at the screening visit as 
determined by a local radiologist or rheumatologist. If a radiograph is not available, one 
must be taken and the diagnostic criteria must be confirmed before visit 2. Note that K-L 
grades 2-3 require the presence of osteophytes, which is required to meet ACR clinical 
and radiographic criteria for knee OA; 
3. Subjects with body mass index (BMI) ranging from 18.0 to 38.0 (kg/m2), inclusive; 
4. Subjects whose OA pain of the index knee is not adequately treated prior to the screening 
visit: 
x 
Subjects must have a self-reported average pain intensity rating of moderate or 
severe on a verbal rating scale (ie none, mild, moderate, and severe) over the 7 days 
prior to the screening visit 
5. The subjects must have “average pain over the last 24 hours” scores  4 and  9 on an 
11-point NRS for the index knee on > 3 consecutive days during the pain assessment period 
and come in for visit 2 within 96 hours after the latest qualifying pain score entry. 
6. For subjects receiving adjunct therapy for chronic pain, such as physical therapy, exercise, 
chiropractic therapy, acupuncture therapy, TENS unit, or herbal and other complementary 
therapy, such treatment should be either stopped at screening or remain unchanged during 
the entire study; Adjunct therapies, glucosamine and chondroitin initiated at least 1 month 
before screening can be continued at stable dose/regimen (should not be initiated during the 
study); elastic support and other braces applied to either knee should be used during the 
study in the same manner as at screening; 
7. If either female of childbearing potential (ie, not medically or surgically sterilized or not 
postmenopausal more than 1 year) or non-surgically sterilized male with sexual partner of 
childbearing potential, be willing to use adequate and reliable contraception throughout the 
study (eg, abstinence or barrier with additional spermicidal foam or jelly, or the use of 
intrauterine device or hormonal contraception by female subjects and partners of male 
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8. Subjects who are willing and able to stop taking any/all analgesic medications, including 
over-the-counter pain medications, opioids, marijuana, and topical analgesics for OA pain 
for the duration of the study, with the exception of study-specific rescue medication; 
9. Subjects who are willing and able to be compliant with the protocol, are capable of 
subjective evaluation, are able to read and understand questionnaires, and are able to read, 
understand, and sign the written informed consent. 
9.3.2 Exclusion Criteria 
1. Subjects with radiographic evidence of OA with Kellgren-Lawrence (K-L) grade 0, 1 or 4; 
2. Females who are pregnant (positive serum/urine test) or lactating or planning to become 
pregnant during the study; 
3. Subjects with chronic pain conditions other than OA of the knee as their predominant pain 
condition, including gout, pseudogout, psoriatic arthritis, active Lyme disease, rheumatoid 
arthritis or any other inflammatory arthritis, fibromyalgia, neuropathic pain conditions, 
bursitis, or acute injury or signs of active infection in the target pain area; 
4. Subjects scheduled for surgical interventions of the disease site or any other major surgery 
during the study conduct period; 
5. Subjects with a history of a prior joint replacement of the index knee; 
6. Subjects who have had arthroscopy on either knee or hip within 6 months of entering the 
study, or open surgery on either knee or hip within 12 months of entering the study; 
7. Subjects with a palpable effusion in either knee; 
8. Subjects with a history of significant trauma to a knee, hip or shoulder within the previous 
year; 
9. Subjects who have significant pain, other than or more than knee pain, including significant 
hip, back pain, that may confound the analgesic efficacy assessments of this study; 
10. Subjects who used immunosuppressive drugs, anti-depressants other than Selective 
Serotonin Reuptake Inhibitors (SSRls for depression), warfarin or anticoagulants, 
cyclosporine (except ophthalmic emulsion), aspirin except for 81 mg daily dose for 
cardiovascular prophylaxis, diuretics with unstable cardiac diseases, or methotrexate within 
30 days of study randomization;  
11. Subjects who initiated, or received an increase in the dose of, oral corticosteroids within 
6 weeks prior to entering the study or who anticipate a change in oral corticosteroid therapy 
during the study period; 
12. Subjects who have used any investigational medication within 30 days or five half-lives, 
whichever is longer, prior to the first dose of study medication; 
13. Subjects with a history of seizures within the past 5 years; 
14. Subjects with evidence of current major depression or other clinically significant psychiatric 
disorder that in the opinion of the investigator would interfere with the subject’s ability to 
participate in the study.  Subjects with history of a psychotic disorder or psychosis, bipolar 
disorder, or post-traumatic stress disorder should be excluded.  Subjects with major 
depression in remission or other psychiatric disorder must be on a stable medication (SSRI) 
for > 3 months to participate in the study;   


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15. Subjects with HADS score over 10 on either subscale at visit 1; 
16. Subject answers “yes” to “suicidal ideation” in prior 24 months to any items 1 through 5 on 
the C-SSRS; 
17. Subject answers “yes” to any lifetime “suicidal behavior” item on the C-SSRS; 
18. Subjects with any history of alcohol or other substance abuse or addiction within the past 
5 years; 
19. Subjects who use immediate release/short acting opioids at a daily dose exceeding 15 mg 
daily morphine equivalent more than 4 days per week; 
20. Subjects who have used any extended-release/long acting opioids in the 30 days prior to the 
screening visit; 
21. Subjects who have a positive urine drug test for illicit drugs, cannabinoids, or non-prescribed 
opioids; 
22. Subjects taking strong CYP3A inhibitors, inducers, sensitive substrates, substrates with 
narrow therapeutic range, or P-gp substrates (see Appendix Q); 
23. Subjects taking moderate CYP3A inhibitors if the dose has not been stable for at least 
1 month prior to start of study drug dosing (see Appendix Q);  
24. Subjects for whom it is anticipated that therapy with a moderate to strong CYP3A inhibitor, 
or CYP3A inducers, sensitive substrates, substrates with narrow therapeutic range, or P-gp 
substrates will be initiated during the study, after the screening visit; 
25. Subjects with clinically unstable medical conditions, including cardiac disease (unstable 
atrial fibrillation, any symptomatic bradycardia, unstable congestive heart failure, or active 
myocardial ischemia), uncontrolled hypertension, respiratory disease, biliary tract disease, 
hypothyroidism, renal disease, adrenal cortical insufficiency, or any other medical condition 
that, in the investigator’s opinion, is inadequately treated and precludes entry into the study; 
26. Subjects with myocardial infarction, stroke, or other thrombotic events in the past 5 years; 
and/or any history of coronary artery bypass graft;  
27. Subjects with a screening ECG showing a QTcF value (QT data corrected for heart rate 
using the Fridericia formula) of  470 msec or other ECG findings that, in the investigator’s 
opinion, would preclude participation in the study; 
28. Subjects with any clinically significant abnormal laboratory value, including evidence of 
impaired liver function (values  3 times the upper limit of normal for aspartate transaminase 
[AST/SGOT] or alanine transaminase [ALT/SGPT], or bilirubin  1.5 mg/dL), or impaired 
kidney function (eGFR < 60 mL/min); 
29. Subjects with positive hepatitis B, hepatitis C or HIV test results indicative of current 
infection; 
30. Subjects with a history of malignancy within the past 5 years, with exception of basal cell 
carcinoma that has been successfully treated; 
31. Subjects with an ongoing or resolved worker’s compensation claim and/or litigation related 
to their pain disorder; 


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32. Subjects who, in the opinion of the investigator, are unsuitable to participate in this study for 
any other reason; 
33. Pain-condition-specific exclusions:  
o Subjects who received local pain-control procedures, including intra-articular steroid 
injection in the index knee or intramuscular steroid injection at any site, joint lavage, or 
other invasive therapies within 6 weeks of entering the study or hyaluronate injection in 
the index knee within 12 weeks of entering the study, or for whom such therapies are 
planned within the study period;  
34. Subjects with a history of bleeding disorders or history of documented gastrointestinal ulcer 
disease; 
35. Subjects who are allergic to or cannot tolerate aspirin, other NSAIDS (including naproxen), 
or acetaminophen, including history of NSAID-induced asthma, or nasal polyps; 
36. Subjects who have received TRPV1 antagonist previously. 
9.3.3 Removal of Subjects from Study Participation 
Subjects will be informed that they are free to discontinue from the study at any time and for any 
reason.  The investigator may remove a subject from the study if, in the investigator's opinion, it 
is not in the best interest of the subject to continue in the study.  Subjects may be discontinued 
due to a change in compliance with inclusion/exclusion criteria that is clinically relevant and 
affects subject safety, occurrence of AEs, or ingestion of protocol-prohibited concomitant 
medication that might affect subject safety or study assessments/objectives.  In case of 
premature discontinuation of study participation, every effort will be made to perform all 
end-of-study assessments.  All subjects who prematurely discontinue will be followed for 
ongoing and newly occurring AEs as described in section 10. 
For subjects who discontinue the study prematurely due to an AE, per FDA’s Guidance for 
Industry - Premarketing Risk Assessment (March 2005)11, copies of relevant hospital records, 
autopsy reports, biopsy reports and radiological reports related to the event should be obtained, 
when feasible. 
Reasons for screen/randomization failure consist of the following: 
x 
The subject does not meet all the inclusion or meets any exclusion criteria – the criteria 
will be recorded; or 
x 
Subject’s choice (the subject chooses for personal reasons to withdraw from the study, 
eg, family emergency precluding the subject from continuing in the study, relocation of 
the subject, or a new work schedule which precludes the subject from further study 
participation); or 
x 
Lost-to-follow-up (the study clinic personnel lose contact with the subject); or 
x 
AE or SAE, (if an AE or SAE causes a subject to withdraw from the study); or 
x 
Administrative reason (the subject discontinues from the study early for any logistical, 
nonmedical reason that is associated with either the clinical site or sponsor, eg, the 
sponsor stops the study or the clinical site is no longer able or is no longer approved to 
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Reasons for discontinuation from the study and study drug at the same time during the 
double-blind period consist of the following: 
x 
Adverse event  (if an AE causes a subject to withdraw from the study), 
 
Note:  worsening of the condition for which the subject qualifies for study entry (ie, 
OA pain in the index knee) will not be considered an AE; for these subjects, the 
reason for discontinuation should be recorded as lack of therapeutic effect (see 
below), or 
x 
Subject’s choice (the subject chooses for personal reasons, to withdraw from the study, 
eg, family emergency precluding the subject from continuing in the study, relocation of 
the subject, or a new work schedule which precludes the subject from further study 
participation), or 
x 
Lost-to-follow-up (the study clinic personnel lose contact with the subject).  Once 
suspecting the subject is lost-to-follow-up, the study clinic must attempt to contact the 
subject by phone, making at least 3 documented attempts, each at least 1 week apart.  
Additionally, 1 registered letter must have been sent with a copy on file.  The study clinic 
should only deem the subject as lost-to-follow-up no less than 30 days following the first 
documented phone call attempt, unless circumstances preclude this (eg, phone service 
has been discontinued, or there is other evidence that contact is not feasible), or 
x 
Lack of therapeutic effect (the subject chooses to withdraw from the study because 
he/she does not feel the study drug is effectively treating his/her condition under study or 
the investigator/medically qualified designee chooses to discontinue the subject from the 
study because, in his/her opinion, the study drug is not effectively treating the subject’s 
condition under study.  The study clinic should confirm that worsening of OA pain in the 
index knee, not worsening of other pain, is in fact the cause for discontinuation, or 
x 
Confirmed or suspected diversion, or 
x 
Administrative reason (the subject discontinues from study early for any logistical, 
nonmedical reason that is associated with either the clinical site or sponsor, eg, the 
sponsor stops the study or the clinical site is no longer able or no longer approved to 
conduct the study). 
If the subject discontinues due to subject’s choice, administrative, or lost to follow-up reasons, 
the specific circumstances surrounding the discontinuation must be recorded.   
The investigator/designee should document instances of inability to tolerate treatment as 
discontinuations due to AE and record the specific symptom(s) and/or sign(s) (eg, nausea, 
vomiting).  Instances of inadequate pain control in the index knee should be documented as 
lack of therapeutic effect. 
Dosing must be permanently discontinued for a study subject if he/she develops any of the 
following: 
1. QTcF values > 500 msec or > 480 msec with a concurrent increase in QTcF 
> 60 msec from the mean screening value
2. Answers “yes” to “suicidal ideation” to items 1 through 5 or “yes” to any “suicidal 
behavior” on the C-SSRS


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9.4 
Treatments 
9.4.1 Treatments administered 
The first dose of the study drug will be administered by study personnel at the study clinic.   
For the remainder of the double-blind treatment period, subjects will self-administer the study 
drugs orally bid, in the morning and evening at consistent time intervals.  
Between the screening phone call visit and visit 2, subjects may take their own supplemental 
analgesic medication, ie, APAP/acetaminophen, which can be taken as needed up to 2 g/day 
for breakthrough pain, but it is not to be taken within 24 hours of visit 2.  Acetaminophen 500 mg 
will be provided in bottles to subjects at visits 2, 3, and 4 of the study, as needed.  The 
supplemental medication is to be taken only, as needed, for breakthrough pain. Subjects are 
permitted to take one to two 500 mg tablets of acetaminophen at a time  as needed for 
breakthrough pain, not to exceed 2 grams total in 24 hours. Subjects will be instructed that no 
more than 4 tablets of APAP/acetaminophen 500 mg per 24 hours (ie, no more than 
2 g/24 hours) are allowed.  All subjects will be instructed to refrain from taking any supplemental 
analgesic medication for at least 24 hours prior to each scheduled visit. 
At visit 5, study drugs and supplemental medication will not be dispensed to subjects, and 
subjects will be instructed to return to taking their prestudy medications.  
9.4.2 Identity of Investigational Product(s) 
Study drugs will be supplied as blinded materials in blister cards and dispensed to subjects at 
visits 2 through 4 during the study.  Each subject will take 3 capsules at each dosing time po, 
bid. 
All study drugs should be stored at 25°C (77°F); excursions permitted between 15°to 30°C 
(59°to 86°F) and protected from light. 
All study drug will be labeled as V120083 30 mg, naproxen 500 mg and/or placebo capsules.   
The sponsor (or designee) will provide the principal investigator (PI) with study drugs according 
to Table 1 and Table 2. 
Table 1  
Test Treatment 
 
Name 
V120083 
Dosage Form 
Capsules 
Dosage Regimen 
bid  
Route 
Oral 
Strength 
30 mg  
Supplier 
Purdue Pharma L.P. 
bid=twice daily, L.P.=limited partnership 


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Table 2  
Reference Treatments 
 
Name 
Naproxen 
V120083 Placebo 
Active Comparator Placebo 
Dosage Form 
Capsules 
Capsules 
Capsules 
Dosage 
Regimen 
bid  
bid  
bid 
Route 
Oral 
Oral 
oral 
Strength 
500 mg 
n/a 
n/a 
Supplier 
Purdue Pharma L.P. 
Purdue Pharma L.P. 
Purdue Pharma L.P. 
Refer to Appendix D for naproxen comparator product formulations. 
bid=twice daily, L.P.=limited partnership, n/a=not applicable 
 
Dosage and Administration:  
x 
V120083 30 mg, bid, po, supplied as blinded capsules with each capsule containing 
30 mg V120083.  Subjects assigned to V120083 30 mg will take 1 capsule containing 
V120083 30 mg, 1 V120083 placebo capsule, and 1 active comparator placebo capsule 
bid during the double blind period (days 1 to 28). 
x 
V120083 60 mg, bid, po supplied as blinded capsules with each capsule containing 
30 mg V120083.  Subjects assigned to V120083 60 mg will take 2 capsules containing 
V120083 30 mg and 1 active comparator placebo capsule bid during the double blind 
period (days 1 to 28). 
 
x 
Active comparator, Naproxen, bid, po, supplied as blinded capsules with each dose 
consisting of one 500-mg capsule. Subjects assigned to naproxen 500 mg bid will take 
1 capsule containing naproxen 500 mg and 2 capsules containing V120083 placebo bid 
during the double blind period (days 1 to 28). 
 
x 
V120083 placebo, bid, po: Capsules that match both 30- and 60-mg doses supplied as 
blinded capsules; to be taken po bid by subjects assigned to 30 mg V120083 active 
comparator or placebo during the double blind period (days 1 to 28). Subjects assigned 
to placebo will take two V120083 placebo capsules and 1 active comparator placebo bid 
during the double blind period (days 1 to 28). 
 
x 
Active comparator placebo, bid, po: Capsules that match active comparator supplied 
as blinded capsules; to be taken po bid by subjects assigned V120083 (30 or 60 mg) or 
placebo during the double blind period (days 1 to 28). 
 


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Supplemental Analgesic Medication: 
Between the screening phone call visit and visit 2, subjects may take their own supplemental 
analgesic medication, 500 mg APAP/acetaminophen, which can be taken as needed up to 
2 g/24 hours for breakthrough pain, but is not to be taken within 24 hours of visit 2.  
Supplemental analgesic medication (subject’s own) will be recorded in the subject diary.  The 
sites may dispense 500 mg APAP/acetaminophen at the screening visit as needed. 
Acetaminophen, 500 mg, will be procured by the sites and provided to subjects at 
visits 2, 3, and 4, as needed.  
Dosage and Administration:  
Subjects will be instructed to take supplemental medication, as needed, for breakthrough pain 
only, no more than 2 tablets at a time (ie, no more than 1000 mg/dose) and no more than 
4 tablets per 24 hours (ie, no more than 2 g/24 hours).  Subjects will also be instructed not to 
take any supplemental medication for at least 24 hours before any scheduled clinic visit during 
the double-blind period.  Supplemental medication is not considered a concomitant medication 
and will be recorded separately from concomitant medications. 
Drug Supplies Instructions: 
Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored 
according to the conditions specified on the drug labels.  All other protocol-required treatments 
as identified in Table 1 and Table 2 and acetaminophen are not considered concomitant 
medications and will be recorded separately from concomitant medications. 
The study drug identification numbers (Med identification #) will be provided to the clinical site 
on the packing list with the study drug shipment. 
9.4.3 Drug Accountability 
The PI and study staff will be responsible for the accountability of all clinical supplies 
(dispensing, inventory, and record keeping) following sponsor (or designee) instructions and 
adhering to GCP guidelines as well as municipal, state, and federal regulations.   
Under no circumstances will the PI and study staff allow the study drug to be used other than as 
directed by this protocol.  Clinical supplies will not be dispensed to any individual who is not 
enrolled in the study. 
An accurate and timely record of clinical supplies must be maintained.  This includes, but may 
not be limited to: (a) documentation of receipt and condition of clinical supplies, (b) 
documentation of study drug dispensing/return, (c) documentation of clinical supply product 
complaints, if any, (section 9.6.6 Clinical Supplies Product Complaints), (d) documentation of 
return of clinical supplies to sponsor (or designee), and (e) all shipping service receipts.  All 
forms will be provided by the sponsor (or designee).  The clinical site may use comparable 
forms to comply with any institutional SOPs. 
The supplies and inventory records must be made available, upon request, for inspection by 
designated representatives of the sponsor (or designee), representatives of the FDA, and 
representatives of US (including state or local) or international health authorities.  All 


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undispensed study drug and empty containers are to be returned by the PI and/or study staff 
and ultimately to the sponsor (or designee) at the conclusion of the study, unless provision is 
made by the sponsor (or designee).  Upon completion of drug accountability and reconciliation 
procedures by clinical site personnel and by sponsor (or designee) personnel, study drug that is 
to be returned to the sponsor (or designee) must be sealed with tamper-evident seals and 
shipped back to the sponsor (or designee) following all local regulatory and shipment laws. 
9.4.4 Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized at visit 2 by Interactive Web Response System/Interactive Voice 
Response System (IWRS/IVRS) to receive 1 of the 4 treatment groups according to a 
randomization schedule generated by sponsor (or designee) and will be assigned a unique 
randomization number. 
9.4.5 Selection of Doses in the Study  
The doses selected for this study are based on the safety, tolerability, and PK profiles 
established from two phase 1 studies in healthy human subjects.  In these studies, single doses 
of V120083 up to 1000mg and multiple doses up to 300mg bid for up to 14 days were safe and 
generally well tolerated. 
In this phase 2a, proof-of-concept study, the near maximal safe and tolerated dose of V120083 
60 mg bid was selected as the highest dose level to maximize the chances to demonstrate 
efficacy.  Additionally, V120083 30 mg bid will be evaluated to establish the therapeutic dose 
range of the study drug. 
9.4.6 Selection and Timing of Dose for Each Patient 
The dosing frequency of bid dosing for this study was selected on the basis of multiple-dose PK 
data generated in a phase 1 clinical study.  For the doses selected in this study, bid 
administration of V120083 is estimated to provide plasma concentrations sufficient to achieve 
efficacy for subjects in studies and is expected to yield a trough concentration at 12 hours after 
V120083 dosing higher than the trough observed for nonclinical efficacious dose. 
9.4.7 Blinding 
During the double-blind period of the study, the subject and all personnel involved with the 
conduct, analysis, and the interpretation of the study, including the investigators, clinical site 
personnel, and the sponsor (or designee) staff, will be blinded to the medication codes. 
The randomization schedule will be kept strictly confidential, filed securely by the sponsor (or 
designee), and accessible only to authorized persons per sponsor’s (or designee)’s SOPs until 
the time of unblinding.   
Unblinding a subject should only be done in emergency situations for reasons of subject safety.   
At the initiation of the study, the clinical sites will receive instructions for unblinding a subject.   
In the event that an emergency unblinding is required, the investigator/medically qualified 
designee should make every attempt to contact the sponsor’s Medical Monitor or designee 
before breaking the blind.   


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When the blinding code is broken, the date, time of unblinding, and reason(s) must be fully 
documented in the source documentation.  If not already done, the sponsor’s Medical Monitor or 
designee must be contacted as soon as possible to notify him/her of the unblinding and to 
discuss the reason(s) for unblinding. 
In the event that an emergency unblinding is required, authorized IWRS users at the clinical 
sites and the sponsor or designee, will have the ability to retrieve the subject’s treatment group 
assignment through IVRS/IWRS. 
If not already done, the sponsor’s Medical Monitor or designee must be contacted as soon as 
possible to notify him/her of the unblinding and to discuss the reason(s) for unblinding. 
9.4.8 Prior and Concomitant Therapy 
At the screening visit, study staff will record all medications, including analgesics, used by the 
subject during the 30 days prior to screening.  At all subsequent visits, including the 
post-treatment follow-up period, study staff will record concomitant therapy taken by a subject 
during the study; the reason for its use will be recorded. 
Prior and concomitant therapy is defined to include all medications (over-the-counter and/or 
prescription, including analgesics), procedures, and significant nonpharmacological therapies 
that are used to treat the subject, including those used in response to an AE/SAE, during the 
time periods relevant to study conduct. 
Prohibited concomitant medications: 
All medications used for chronic pain, other than the study drugs and supplemental analgesic 
medication, are prohibited during the study.  Prohibited medication used for chronic pain 
includes all opioids, NSAIDs (other than the study drug), cyclooxygenase-2 (COX-2) inhibitors, 
aspirin, gabapentin, antiepileptics, and antidepressants used for chronic pain (eg, tricyclics, 
selective serotonin /norepinephrine re-uptake inhibitors [SSRIs,SNRIs]) 
Muscle relaxants (eg cyclobenzaprine, methocarbamol) are prohibited. Muscle relaxants cannot 
be initiated during the study. 
Other prohibited concomitant treatments include benzodiazepines, monoclonal antibodies for 
osteoporosis, methotrexate, any local OA treatments for the knee(s), including topical 
anesthetics or NSAIDs; topical, intra-articular, or systemic corticosteroids (other than inhalers); 
or any OA injection in the knee(s), antidepressants (other than SSRIs used for depression), 
warfarin or anticoagulants, cyclosporine (except ophthalmic emulsion), and marijuana. 
Based on in vitro data, V120083 is a CYP3A4/5 substrate and has the potential to inhibit P-gp 
and CYP3A4/5.  Concomitant administration of CYP3A inhibitors, inducers, substrates, and P-
gp substrates are restricted as follows: 
x 
Subjects taking strong CYP3A inhibitors will be excluded from the study due to potential 
increases in plasma levels of V120083 when co-administered with V120083.  Subjects 
who initiate these medications during the study will be discontinued from the study. 
x 
Subjects taking moderate CYP3A inhibitors will be excluded if the dose has not been 
stable for at least one month prior to start of study drug dosing. See Appendix Q for a 


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representative list of moderate and strong CYP3A inhibitors). Subjects who discontinue 
therapy with moderate CYP3A inhibitors during the study will be permitted to continue on 
the study 
x 
If the subject is taking multiple moderate CYP3A inhibitor(s) or the category is unknown, 
the investigator should contact the medical monitor and subjects are to be carefully 
monitored. 
x 
Subjects taking CYP3A inducers will be excluded from the study due to potential 
decrease in plasma levels of V120083. Subjects who initiate these medications during 
the study will be discontinued from the study. 
x 
Subjects taking CYP3A sensitive substrates and substrates with narrow therapeutic 
range, or P-gp substrates will be excluded from the study due to potential increases in 
plasma levels of such medications when co-administered with V120083. Subjects who 
initiate these medications during the study will be discontinued from the study.  (See 
Appendix Q for a representative list of inducers and substrates). 
x 
The investigator should contact the medical monitor if there are any questions or 
concerns. 
APAP/acetaminophen may be used intermittently for headache, fever, or acute pain up to the 
1 gram maximum per dose and 2 g per 24 hour maximum amount; low-dose aspirin (81 mg 
daily) for cardiovascular disease prophylaxis is allowed. Note: Subjects will be requested not to 
take any APAP/acetaminophen for at least 24 hours before each clinic visit. 
Aspirin dose of 81 mg per day is allowed to be taken for cardiovascular disease prophylaxis.  
9.4.9 Treatment Compliance 
Records of study drug and doses administered, including supplemental analgesic medication 
(ie, acetaminophen), will be kept during the study.  The site monitor will review drug 
accountability records during site visits and at the completion of the study. 
Site personnel will evaluate clinical supplies returned and acetaminophen at each subject visit in 
accordance with section 9.4.3.  In addition, as each subject completes the study, site personnel 
will review the records of all clinical supplies returned by the subject (including evaluation for 
possible trends, eg, 5% of drug missing at 3 subject visits) in accordance with section 9.4.3.  


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9.5 
Study Procedures 
9.5.1 Schedule of Activities 
The Schedule of Activities for the study is presented in Table 3. 
Table 3 
Schedule of Activities 
Protocol Activity 
Screening 
Double-blind Period
Follow-up
 
Visit 1  
Phone 
Call  
Pain 
Assessment 
/Washouta 
Visit 2 
(Rand) 
Visit 3
Visit 4 
Visit 5 or 
discontinuation 
(EOS)
Phone Call or 
Clinic Visit 
Study day 
Days -21 to -1 
Day 1 
Week 1 Week 2
Week 4 
7 after the last 
dose
Days from Baseline 
- 
- 
6-8 
12-16 
25-31 
 
Informed consent form (ICF)  
X
 
Contact IVRS/IWRS 
X
Xb 
X 
X
X
X
Inclusion/exclusion criteria 
X
X 
Demography  
X
 
Medical history and current medical 
condition 
X 
 
 
 
 
 
 
 
Pain history/ACR criteria 
X 
 
 
 
 
 
 
 
Vital Signs 
X
X 
X
X
X
HADS 
X
 
X
Columbia-Suicide Severity Rating Scale 
(C-SSRS)o 
X 
 
 
X 
X 
X 
X 
X p 
Physical examination  
X 
 
 
X 
X 
 
X
X 
 
Height, weight, and BMId 
X
 
X
Bilateral X-ray of the knees 
X
 
X
Kellgren-Lawrence classificationq 
X
 
X
Identify index knee 
X
 
Average pain over the last 7 days 
X
 
Electrocardiograme 
X
 
X
X
Xr
Virus screen (HBV, HCV, and HIV) 
X
 


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Protocol Activity 
Screening 
Double-blind Period
Follow-up
 
Visit 1  
Phone 
Call  
Pain 
Assessment 
/Washouta 
Visit 2 
(Rand) 
Visit 3
Visit 4 
Visit 5 or 
discontinuation 
(EOS)
Phone Call or 
Clinic Visit 
Study day 
Days -21 to -1 
Day 1 
Week 1 Week 2
Week 4 
7 after the last 
dose
Days from Baseline 
- 
- 
6-8 
12-16 
25-31 
 
Laboratory evaluations (chemistry, 
hematology, and urinalysis) 
X 
 
 
 
 
X 
X 
Xr 
Serum pregnancy testf 
X
 
X
Urine pregnancy test 
X 
X
X
Urine drug test 
X
 
Chemotherapy-induced Taste Alteration 
Scale (CiTAS) 
 
 
 
X 
X 
X 
X 
 
mBPI-SF – entire scale 
X 
X
X
X
WOMAC  
X 
X
X
X
EQ-5D 
X 
X
X
X
SF-36 
X 
X
X
X
PGIC  
 
X
Randomization 
X 
Dispense study drug as instructed by 
IWRS 
 
 
 
X 
X 
X 
 
 
Dispense supplemental analgesic 
medication 
Xg 
 
 
X 
Xh 
Xh 
 
 
Adverse events  
Prior and concomitant therapies  
Distribute subject diary  
X
 
Collect subject diary 
Xb
Xc
 
Xi
Review subject's diary  
X 
X
X
Xi
Diary entries 
Study medication dosing  information 
(date/time/amount taken)  
 
 
 
 
 
Indicate if meal eaten within 
± 2 hours of dosing 
 
 
 
 
 
Supplemental analgesic use 
(time/date/amount taken)  
 
 
 
 


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Protocol Activity 
Screening 
Double-blind Period
Follow-up
 
Visit 1  
Phone 
Call  
Pain 
Assessment 
/Washouta 
Visit 2 
(Rand) 
Visit 3
Visit 4 
Visit 5 or 
discontinuation 
(EOS)
Phone Call or 
Clinic Visit 
Study day 
Days -21 to -1 
Day 1 
Week 1 Week 2
Week 4 
7 after the last 
dose
Days from Baseline 
- 
- 
6-8 
12-16 
25-31 
 
“Pain right now” scores 
Daily “average pain over the last 24 
hours” scores 
 
 
 
 
Collect unused study drug and conduct 
drug accountability 
 
 
 
 
X 
X 
X 
 
Washout of prohibited analgesics 
X
 
Collect sample(s) for PK analysis 
Xj 
Xk 
Xk
Xk
Collect sample for PG analysisl 
X 
X
Telephone contacts 
Xm 
Xm 
Xm 
Xm 
Xn
 
 
Abbreviations: ACR = American College of Rheumatology, BMI = body mass index; C-SSRS = Columbia-Suicide Severity Rating Scale; EQ-5D = EuroQol-5D; HADS = Hospital 
Anxiety and Depression Scale; HBV = hepatitis B; HCV = hepatitis C; HIV = human immunodeficiency virus; ICF = informed consent form; IVRS/IWRS = interactive voice response 
system/interactive web response system; mBPI-SF = Modified Brief Pain Inventory – Short Form; PG = pharmacogenomics; PGIC = Patient Global Impression of Change; PK = 
pharmacokinetic; Rand = randomization; SF-36 = Medical Outcomes Study 36-Item Short Form Health Survey; WOMAC = Western Ontario and McMaster Osteoarthritis Index.  
 
a The washout period is required only for subjects who take analgesic medications for pain. Subjects who do not take any medications for pain will record their “average pain over last 
24 hours” scores for 3 to 7 days. Subjects who take medications for pain will record their “average pain over last 24 hours” scores for at least 3 days once all medication used for pain 
has been discontinued in accordance with acceptable medical practice. Subjects may return to the study clinic for visit 2 as soon as they recorded “average pain over last 24 hours” 
scores  4 and  9 for  3 consecutive days. All subjects must return to the study clinic for visit 2 within 96 hours of the latest qualifying pain score entry within the pain assessment 
period. 
b Applicable only to screen failure subjects who do NOT meet the study inclusion criteria or who meet ANY of the exclusion criteria for clinical laboratory results, radiograph results, 
and/or ECG results.  
c Applicable only to randomization failure subjects who do NOT meet the randomization criteria, the subject diary will be collected at the end of the pain assessment visit.  
d Body weight and BMI will be assessed at screening and visit 5 (end-of-study). Height will be assessed at screening only.  
e Subjects with a screening ECG showing a QTcF value (QT data corrected for heart rate using the Fridericia formula) of  470 msec or other ECG findings that, in the investigator’s 
opinion, would preclude participation in the study.  If subsequent QTcF values exceed 500 msec or 480 msec with a concurrent QTcF change of > 60 msec from baseline, the subject 
must discontinue study drug and the reason for study drug discontinuation will be recorded as AE (see section 10).  
f Serum pregnancy test to be included for female subjects who are premenopausal or postmenopausal for less than 1 year and who are not surgically sterile.  
g Supplemental analgesic medication is to be dispensed as needed at the screening visit 
h Supplemental analgesic medication will be dispensed at visits 2, 3, and 4 of the study, as needed.  
I Subject diary will be collected at last visit.  
J For subjects in the intense PK sampling population, PK samples will be collected at Visit 2 (6 time points; predose and 1, 2 [+/- 10 min], 4, 6 and 8 hrs [+/- 20 min] postdose).  The 
actual time of dosing and sampling should be recorded. 
k  For all subjects, PK samples will be collected at visit 3 (predose, 1 and 2 hours postdose); visit 4 (predose or postdose) and 5 (predose or postdose). The actual time of dosing and 
sampling should be recorded.   


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l PG samples will be collected for DNA and  protein at visit 2 predose and at visit 5 postdose.  
m At approximately 1 to 2 days prior to each scheduled visits, the site personnel will contact the subject to remind subjects to:  
Refrain from taking any supplemental analgesic medications for at least 24 hours prior to the clinic visit (applicable to visits 3, 4 and 5 only) and to hold morning dose of study drug on 
the day of the clinic visit for predose PK sampling 
n Follow-up visit could be by telephone contact or by a clinic visit.  
o At screening visit, use C-SSRS Baseline/Screening Assessment. For randomization visit and subsequent scheduled or unscheduled visits, use C-SSRS Since Last Visit Assessment. 
Positive scores on the C-SSRS may result in discontinuation and/or referral to a specialist for evaluation as outlined in the protocol  
p C-SSRS should be completed at all visits that include clinical assessments  
q K-L grade should be determined by a local radiologist or rheumatologist.  
r Subjects who require follow-up of clinical laboratory or ECG assessments must return to the clinical site for this visit. 
 


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9.5.2 Screening  
9.5.2.1 Visit 1 (Screening Visit) 
Each subject will be assigned a unique subject number at screening.  Subject numbers will be 
used on all study documentation. 
The following information will be obtained and procedures performed for all potential subjects at 
a screening visit conducted within 7 to 14 days after the ICF is signed: 
x 
Obtain ICF 
x 
Obtain PG consent form (optional) 
x 
Obtain intense PK consent form (optional) 
x 
Contact IVRS/IWRS to obtain subject number which will be retained throughout the 
study.  Instructions for contacting the IWRS are provided in the study manual 
x 
Review inclusion/exclusion criteria 
x 
Record the subject’s demographic information 
x 
Record the subject’s medical history and current medical conditions 
If the subject is a referral, the site should make every effort (eg, collect medical records 
released at screening visits and make at least 2 attempts) to obtain subject’s medical 
records to verify eligibility. 
x 
Record the subject's pain history/ACR criteria 
x 
Collect any spontaneously reported AEs/SAEs prior to recording vital sign 
measurements 
x 
Record the subject’s vital signs as outlined in section 9.6.4.3 (sitting after 5 minutes’ 
rest) 
x 
Administer the HADS questionnaire 
Note: Subjects with HADS score over 10 on either subscale will be excluded from the 
study. 
x 
Administer C-SSRS Baseline/Screening questionnaire 
o Note: Subjects who answer “yes” to “suicidal ideation” to any item 1 through 5 
(past 24 months) or “yes” to any suicidal behavior, current or history of, will be 
excluded from the study. The Principal Investigator must evaluate positive 
responses on the C-SSRS and take appropriate action in consideration of 
medical judgement and the training and certification process for administering the 
test.  It is the responsibility of the PI to review the results in all subjects and 
determine if any result constitutes an adverse event and/or requires evaluation 
by a mental health professional.  
x 
Perform a physical examination (including  measurement of height, weight, and BMI) 
and examination of the index knee 
x 
Perform X-ray of both knees in standing position 


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x 
K-L grade 
x 
Identify the index knee 
o Note: The Investigator or his/her staff must identify and record which knee is 
chosen as the primary OA site (index knee).  The same site must be used for all 
pain assessments throughout the study. 
x 
Have the subject record his/her ‘average pain over the last 7 days’ for the index knee on 
the verbal rating scale 
x 
Record all prior medications, including the subject’s incoming analgesic medications and 
other medications used for chronic pain (if applicable), and non-drug therapies used over 
the last 30 days 
x 
Collect any AEs that occur during the visit 
For subjects NOT meeting inclusion/exclusion criteria evaluated at the screening visit, complete 
the following screen failure procedures: 
x 
Discontinue the subject 
x 
Record reason for discontinuation 
x 
Provide each subject with post-study instructions as deemed medically appropriate 
x 
Contact IWRS to indicate that the subject discontinued from the study. 
For subjects meeting all Inclusion/Exclusion Criteria evaluated at the screening visit, the visit 
continues as follows: 
x 
Perform a 12-lead ECG after 5 minutes’ rest, and verify QTcF value.  
Note: Subjects with any clinically significant findings as well as QTcF > 470 msec will be 
excluded from the study. 
 
Transmit all electronic ECG data immediately to the central ECG provider for 
interpretation.  Retain a copy of all electronic ECG data obtained during the study in 
the subject’s file; 
x 
ECG reports from the central ECG provider will be sent to the clinical site within 72 hours 
of receipt of ECG transmission.  The investigator/designee must review and sign the 
ECG report from the central ECG provider. 
 
Note: to be eligible for this study, the Fridericia-Corrected QT (QTcF) value must be 
 470 msec.  Subjects will proceed with the screening visit if the ECG readings at the 
clinical site meet these criteria.  However, a confirmation from the central ECG provider 
is needed before the subject is permitted to continue in the double-blind period.  The 
subject will be discontinued if the QTcF value is > 470 msec (based on reports 
generated by the central ECG provider). 
x 
Collect samples for clinical laboratory tests (hematology, chemistry, and urinalysis) 
x 
Collect samples for viral serology (hepatitis B and C and HIV) 


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x 
Collect sample for serum pregnancy test to be included for female subjects who are 
premenopausal or postmenopausal for less than 1 year and who are not surgically 
sterile 
x 
Collect sample for a urine drug test 
x 
Dispense subject diary and provide instructions for diary completion 
x 
As needed, dispense supplemental analgesic medication: 
 
Instruct the subject to take supplemental analgesic medication (acetaminophen 
500 mg), as needed, for OA pain of the knee only.  No more than 1000 mg (ie, 1- 2 
tablets) at a time and no more than 2 g (ie, 4 tablets) per 24 hours is allowed 
 
Instruct the subject to refrain from taking any supplemental analgesic medication for 
at least 24 hours prior to the next scheduled visit. 
 
Instruct the subject to avoid other acetaminophen-containing over the counter 
products (eg, cold and flu products). Subject should consult with investigator if there 
is any question or doubt as to whether an over-the-counter medication contains 
acetaminophen labelled for uses other than pain (eg, cold and flu remedies/products) 
x 
The Investigator or a medically qualified designee will discuss with the subject which 
pain medications will need to be discontinued when he/she is contacted by telephone. 
Rescreening of subjects who previously failed screening is allowed only with the permission of 
the medical monitor on a case by case basis.  
Subjects may be considered for rescreening if they failed screening previously due to eligibility 
criteria that are now allowed under the current amended protocol; delay of acquiring records; 
out of window issues (eg, lost or delayed labs); timing of exclusionary procedures; or other 
reasons approved by the medical monitor. 
Subjects with a positive hepatitis B, hepatitis C, or human immunodeficiency virus test results; 
subjects with positive urine drug test (UDT) for illicit drugs or non-prescribed opioids and/or 
subjects who previously received study drug in a V120083 trial will not be permitted to be 
rescreened.  
All rescreening must be approved in advance by the medical monitor. 
9.5.2.2 Telephone Contact/Washout Period 
When results for laboratory assessments (eg, pregnancy tests, hematology, serum chemistry, 
and urinalysis, urine drug screen), ECG, and radiograph results are available: 
x 
The investigator/medically qualified designee  will review the results against all relevant 
inclusion/exclusion criteria to determine whether it is appropriate for the subject to enter 
into the double-blind period 
 
All results must be signed by the investigator/medically qualified designee upon 
review 
x 
The clinical site personnel will contact subjects by telephone to inform them of the 
results and whether they qualify to continue in the study.  


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If results from the central ECG provider, radiograph, and/or clinical laboratory assessment do 
not meet the study entry criteria: 
x 
Record reason for discontinuation 
x 
Provide each subject with post-study instructions as deemed medically appropriate 
x 
Contact the IWRS to indicate the subject is a screen failure. 
If the subject’s results from the central ECG provider, clinical laboratory assessment and 
radiograph all meet the study entry criteria: 
x 
Record AEs 
x 
Record concomitant medication and therapies 
x 
If the subject is taking medications for pain - instruct subjects to discontinue all analgesic 
medications (with the exception of supplemental analgesic medication) in accordance 
with accepted medical practice 
x 
Subject’s own supplemental analgesic medication, ie, APAP, is permitted to be taken as 
needed up to 2 g/day (limited to maximum of 1g/dose). Supplemental analgesic 
medication is not to be taken within 24 hours of visit 2/randomization. 
x 
Instruct the subject to record his/her daily "average pain over the last 24 hours" scores 
for the index knee at approximately 8 PM every day for: 
 
Up to 7 days (or until instructed to stop) if the subject is not taking any medications 
for pain 
 
Up to 9 days (or until instructed to stop) after all analgesic medications have been 
discontinued (applicable only to subjects taking medications for pain) 
x 
During the remaining screening period, the site personnel will monitor daily the subjects' 
daily "average pain over the last 24 hours" scores in the diaries.  The subjects may 
return to the study clinic as soon as he/she recorded "average pain over the last 24 
hours" scores of  4 and  9 for  3 consecutive days or until the pain score recording 
period (7 days for subjects not taking any medications; 9 days for subjects who were on 
pain medication prior to screening) is completed.  All subjects must return for visit 2 
within 96 hours of the latest qualifying pain score entry within the pain assessment 
period. 
If the subject’s daily “average pain over the last 24 hours” scores do not meet the study entry 
criteria (see sections 9.3.1 and 9.3.2) – contact the subject via telephone to: 
x 
Discontinue the subject  
x 
Instruct the subject to return his/her diary to the study clinic 
x 
Record reason for discontinuation 
x 
Provide each subject with poststudy instructions as deemed medically appropriate 
x 
Contact the IWRS/IVRS to indicate the subject is a screen failure. 
If the subject’s daily “average pain over the last 24 hours” scores do meet the study entry 
criteria (see sections 9.3.1 and 9.3.2) – contact the subject via telephone to: 


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x 
Record AEs 
x 
Record concomitant medication 
x 
Schedule visit 2 to occur in the morning as soon as possible (within 96 hours of the 
latest qualifying score within the pain assessment period) 
x 
Instruct the subject to refrain from taking any medications used for chronic pain 
 
9.5.3 Visit 2 – Randomization 
At approximately 1 to 2 days before visit 2, the study clinic personnel will contact the subjects to: 
x 
Instruct the subject to keep refraining from taking any medications used for chronic pain 
 
The following procedures will be performed at visit 2: 
x 
Record AEs 
x 
Perform a physical examination and examination of the index knee 
x 
Record concomitant medication and therapies 
x 
Record the subject’s vital signs (to be performed prior to any venipuncture/blood testing) 
as outlined in section 9.6.4.3 
x 
Administer C-SSRS Since Last Visit questionnaire 
o Note: Subjects who answer “yes” to “suicidal ideation” to any item 1 through 5 or 
“yes” to any suicidal behavior must be discontinued from the study. The Principal 
Investigator must evaluate positive responses on the C-SSRS and take 
appropriate action in consideration of medical judgement and the training and 
certification process for administering the test.  It is the responsibility of the PI to 
review the results in all subjects and determine if any result constitutes an 
adverse event and/or requires evaluation by a mental health professional. Any 
new suicidal ideation or behavior must be discussed with the Medical Monitor.  
x 
For women of childbearing potential, conduct urine pregnancy test 
Note: Subjects with a positive urine pregnancy test will be discontinued from the study. 
x 
Review the subject diary 
x 
Review subject eligibility for randomization 
 
Subjects are eligible to be randomized if he/she: 
x 
Reported "average pain over the last 24 hours" scores of  4 or  9 for  3 consecutive 
days 
x 
Continues to forgo all incoming analgesic medications, and other medications used for 
chronic pain (if applicable) 
x 
Does not use any concomitant medication prohibited by the protocol 


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x 
Continues to meet all criteria for study continuation 
x 
Has a negative urine pregnancy test (applicable only to women of childbearing potential) 
The following randomization failure procedures will be performed for subjects who do not qualify 
for continuing in the study: 
x 
Record reason for discontinuation 
x 
Provide each subject with post-study instructions as deemed medically appropriate 
x 
Contact the IWRS to indicate the subject is a randomization failure. 
 
The following procedures will be performed for subjects who are eligible for randomization: 
x 
Contact IVRS/IWRS to indicate that the subject is entering the double-blind period.  
x 
Have the subject record his/her responses to the mBPI-SF WOMAC, EQ-5D, and SF-36  
x 
Perform CiTAS rating 
x 
Collect optional PG sample (for subjects who provide additional consent) 
x 
Collect optional PK sample (for subject who provide additional consent) 
x 
Dispense study drug as instructed by IWRS   
x 
Instruct the subject to take the first dose of the study drug at the study clinic 
x 
For subsequent doses, instruct the subject to take 3 capsules bid  
x 
Instruct the subject to record the following information in the diary during the study: 
 
Study drug dosing information (date/time/amount taken) 
 
Supplemental analgesic medication dosing information (date/time/amount taken) 
 
Indicate if meal eaten within ± 2 hours of dosing 
 
The "pain right now" scores for the index knee immediately prior to taking 
supplemental analgesic medication (Appendix N). 
x 
Dispense supplemental analgesic medication 
 
Instruct the subject to take supplemental analgesic medication (acetaminophen 
500 mg), as needed, for OA pain of the knee only.  No more than 1000 mg (ie, 1-
2 tablets) at a time and no more than 2 g (ie, 4 tablets) per 24 hours is allowed 
 
Instruct the subject to refrain from taking any supplemental analgesic medication for 
at least 24 hours prior to the next scheduled visit. 
 
Instruct the subject to avoid other acetaminophen-containing over the counter 
products (eg, cold and flu products). Subject should consult with investigator if there 
is any question or doubt as to whether an over-the-counter medication contains 
acetaminophen labelled for uses other than pain (eg, cold and flu remedies/products) 


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x 
Instruct the subject to record his/her daily "average pain over the last 24 hours" scores 
for the index knee at approximately 8 PM every day 
x 
For subjects in the intensive PK subgroup, collect PK blood samples for pharmacokinetic 
(PK) analysis at the following time points and record time of collection: 
o Predose and 1, 2, 4, 6, and 8 hours after the first dose of the study drug 
x 
Schedule the next visit to occur in the morning approximately 1 week later 
x 
Telephone contact 1 to 2 days prior to next scheduled visit for reminders. 
9.5.4 Visits 3 (week 1) and 4 (week 2) - Double-blind Period 
At approximately 1 to 2 days before the scheduled clinic visits, the site personnel will contact the 
subject to remind subjects to refrain from taking any supplemental analgesic medications for at 
least 24 hours prior to the clinic visit. Remind subject to hold morning dose of study drug to 
allow for predose PK sampling during clinic visits. 
The following procedures will be performed at visit 3 (week 1) and 4 (week 2): 
x 
Administer C-SSRS Since Last Visit questionnaire 
o Note: Subjects who answer “yes” to “suicidal ideation” to any item 1 through 5 or 
“yes” to any suicidal behavior must be discontinued from the study. The Principal 
Investigator must evaluate positive responses on the C-SSRS and take 
appropriate action in consideration of medical judgement and the training and 
certification process for administering the test.  It is the responsibility of the PI to 
review the results in all subjects and determine if any result constitutes an 
adverse event and/or requires evaluation by a mental health professional. Any 
new suicidal ideation or behavior must be discussed with the Medical Monitor.  
x 
Have the subject record his/her responses to the mBPI-SF, WOMAC, EQ-5D, and SF-36  
x 
Perform CiTAS rating 
x 
Record AEs 
x 
Record the subject’s vital signs (to be performed prior to any venipuncture/blood testing) 
as outlined in section 9.6.4.3 
x 
Perform a physical examination and examination of the index knee 
x 
Record concomitant medication and therapies 
x 
For women of childbearing potential, conduct urine pregnancy test 
o Note: Subjects with a positive urine pregnancy test will be discontinued from the 
study. 
 
x 
At visit 4 only,  
o Perform a 12-lead ECG after 5 minutes’ rest [prior to predose or postdose PK 
sampling] 


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 
Transmit all electronic ECG data immediately to the central ECG 
provider for interpretation.  Retain a copy of all electronic ECG 
data obtained during the study in the subject’s file.  ECG reports 
from the central ECG provider will be sent to the clinical site within 
72 hours of receipt of ECG transmission 
 
The investigator/designee must review and sign the ECG report 
from the central ECG provider 
 
For any subjects with any QTcF values > 500 msec or > 480 msec 
with a concurrent increase in QTcF > 60 msec from the mean 
screening value, record an AE as "QTcF prolonged (QTcF values 
> 500 msec)” or "QTcF prolonged > 480 msec with a concurrent 
increase in QTcF value > 60 msec)”, and instruct the subject to 
return to the clinical site at the follow-up visit for a repeat ECG. 
x 
At visit 4 only,  
o Collect samples for clinical laboratory tests (hematology, chemistry, and 
urinalysis) 
x 
Collect predose PK sample at visit 3, noting time of sample collection [at visit 4, conduct 
the ECG prior to any PK sampling and PK sample could be pre- or postdose] 
x 
Advise subject to take morning dose of study drug at the study clinic 
o Record the study drug dosing information in the diary 
x 
Collect all unused double-blind medication and supplemental analgesic medication, as 
required 
x 
Review subject diary for the following information to ensure continual compliance.  
Educate the subject as necessary: 
 
Double-blind study medication dosing information (time/date/amount of taken) 
 
Supplemental pain medication dosing information (time/date/amount of taken) with 
corresponding "pain right now" scores. 
 
Instruct the subject to complete last missed diary(ies) if not completed.   
x 
Perform drug accountability review 
x 
Dispense study drug as instructed by IWRS 
 
Remind the subject to take 3 capsules bid  
x 
Dispense supplemental analgesic medication; 
 
Instruct the subject to take supplemental analgesic medication (acetaminophen 
500 mg), as needed, for OA pain of the knee only.  No more than 1000 mg 
(ie, 1-2 tablets) at a time and no more than 2 g (ie, 4 tablets) per 24 hours is allowed 
 
Instruct the subject to refrain from taking any supplemental analgesic medication for 
at least 24 hours prior to the next scheduled visit. 


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 
Instruct the subject to avoid other acetaminophen-containing over the counter 
products (eg, cold and flu products). Subject should consult with investigator if there 
is any question or doubt as to whether an over-the-counter medication contains 
acetaminophen labelled for uses other than pain (eg, cold and flu remedies/products) 
x 
Remind the subject to record the following information in the diary: 
 
Study drug dosing information (date/time/amount taken) 
 
Supplemental analgesic medication dosing information (date/time/amount taken) 
 
Indicate if meal eaten within ± 2 hours of dosing 
 
The "pain right now" scores for the index knee immediately prior to taking 
supplemental analgesic medication (Appendix N) 
x 
Instruct the subject to record his/her daily "average pain over the last 24 hours" scores 
for the index knee at approximately 8 PM every day 
x 
At visit 3 only, collect PK blood sample at predose and at 1 and 2 hours postdose, noting 
time of sample collection.  Collect pre- or postdose sample at visit 4. 
x 
Schedule the next visit 
x 
Telephone contact 1 to 2 days prior to next scheduled visit for reminders. 
9.5.5 Visit 5 - End of Study or Early Discontinuation 
At approximately 1 to 2 days before the scheduled clinic visits, the site personnel will contact the 
subject to remind subjects to refrain from taking any supplemental analgesic medications for at 
least 24 hours prior to the clinic visit. Remind subject to hold morning dose of study drug to 
allow for predose PK sampling during clinic visit (if taking pre-dose sample). 
The following procedures will be performed at the clinical site for all subjects at the end of study 
or early discontinuation visit: 
x 
Record AEs 
x 
Administer C-SSRS Since Last Visit questionnaire 
o Note: Subjects who answer “yes” to “suicidal ideation” to any item 1 through 5 or 
“yes” to any suicidal behavior must be discontinued from the study. The Principal 
Investigator must evaluate positive responses on the C-SSRS and take 
appropriate action in consideration of medical judgement and the training and 
certification process for administering the test.  It is the responsibility of the PI to 
review the results in all subjects and determine if any result constitutes an 
adverse event and/or requires evaluation by a mental health professional. Any 
new suicidal ideation or behavior must be discussed with the Medical Monitor.  
x 
Have the subject record his/her responses to the mBPI-SF, WOMAC, EQ-5D, SF-36,  
HADS, and Patient’s Global Impression of Change (PGIC)  
x 
Perform CiTAS rating 
x 
Record the subject’s vital sign measurements 


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x 
Record concomitant medication and therapies 
x 
Collect samples for clinical laboratory tests (hematology, chemistry, and urinalysis) 
x 
Collect predose or postdose PK blood sample and record time of collection 
x 
Collect optional PG sample (for subjects who provide additional consent) 
x 
Collect sample for serum pregnancy test to be included for female subjects who are 
premenopausal or postmenopausal for less than 1 year and who are not surgically 
sterile 
x 
Instruct subject to take study drug at the study clinic (if taking predose PK); 
o Record the study drug dosing information in the diary 
x 
Collect all unused double-blind medication and supplemental analgesics medication 
x 
Collect subject diary 
x 
Review subject diary for the following information to ensure continual compliance.   
 
Double-blind study medication dosing information (time/date/amount of taken) 
 
Indicate if meal eaten within ± 2 hours of dosing 
 
Supplemental pain medication dosing information (time/date/amount of taken) with 
corresponding "pain right now" scores 
 
Instruct the subject to complete last missed diary(ies) if not completed.   
x 
Perform drug accountability review 
x 
Perform X-ray of both knees in standing position 
x 
K-L grade 
x 
Perform a physical examination (measurements for weight and BMI) and examination of 
the index knee.   
x 
Perform a 12-lead ECG after 5 minutes’ rest 
 
Transmit all electronic ECG data immediately to the central ECG provider for 
interpretation.  Retain a copy of all electronic ECG data obtained during the study in 
the subject’s file.  ECG reports from the central ECG provider will be sent to the 
clinical site within 72 hours of receipt of ECG transmission 
 
The investigator/designee must review and sign the ECG report from the central 
ECG provider 
 
For any subjects with any QTcF values > 500 msec or > 480 msec with a concurrent 
increase in QTcF > 60 msec from the mean screening value, record an AE as "QTcF 
prolonged (QTcF values > 500 msec)” or "QTcF prolonged > 480 msec with a 
concurrent increase in QTcF value > 60 msec)”, and instruct the subject to return to 
the clinical site at the follow-up visit for a repeat ECG. 
x 
Discontinue the subject 


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x 
Confirm that the subject has completed the double-blind period or record the reason for 
discontinuation from the double-blind period 
x 
Convert the subject to his/her own pain regimen and provide poststudy instructions as 
deemed medically appropriate 
Note: Before releasing the subject from the clinical site, it is the responsibility of the 
investigator/designee (medically qualified designee) to use his/her clinical judgment to assess 
the subject’s continuing pain medication needs. 
x 
Contact IWRS to indicate that the subject has completed/discontinued from the 
double-blind period  
x 
Schedule a telephone contact or clinic visit to occur in 7 days for the follow-up visit 
Schedule the follow-up telephone contact or visit 
x 
Telephone contact 1 to 2 days prior to next scheduled visit for reminders (for subjects 
required to visit study site for follow-up visit) 
x 
The investigator/medically qualified designee  will review and sign upon receipt, all 
radiograph results, all clinical laboratory results from the central laboratory, and all ECG 
reports from the central ECG provider 
o For any subjects with any QTcF values > 500 msec or an QTcF > 480 msec with a 
concurrent increase in QTcF value > 60 msec from the mean screening value, 
instruct the subject to return to the clinical site for a follow-up ECG during the 
follow-up visit 
o For subjects with abnormal clinical laboratory assessments that require further 
follow-up, instruct the subject to return to the clinical site for a follow-up assessment 
during the follow-up visit. 
9.5.6 Unscheduled Visits 
At the investigator’s discretion, a subject may have an unscheduled visit, eg, to discuss safety.  
If any clinical assessments are performed during an unscheduled visit, the C-SSRS Since Last 
Visit questionnaire should be administered. 
 
9.5.7 Follow-up 
The follow-up phase is designed to evaluate the proper conversion from the study drug to the 
subject's individual pain regimen upon completion of or discontinuation from the study drug.   
The follow-up evaluation is performed 7 days after the last dose via a telephone call or at the 
study clinic by the investigator/designee if the investigator deems necessary.  However, 
subjects who require follow-up clinical laboratory or ECG assessments must return to the 
clinical site for this visit. The C-SSRS should be administered if any clinical assessments are 
conducted. 
The following procedures will be performed for all subjects via telephone contact or at the study 
clinic: 
x 
Record information for all concomitant medications and nondrug therapies 


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x 
Record all adverse events, including outcomes of previously reported unresolved 
adverse events 
x 
If any SAEs or AESIs are reported at 7 days follow-up, a clinical visit must be scheduled 
and the full AE assessment must be performed; If the subject has their 7 day 
assessment at the clinic and an SAE or AESI is reported, the full AE assessment must 
be performed. 
9.6 
Efficacy Variables, Drug Concentration, Safety and Other Variables 
9.6.1 Appropriateness of Measurements 
All assessments are standard, widely used, and generally recognized as reliable, accurate, and 
relevant.  
x 
Kellgren-Lawrence Classification 
The K-L criteria are the most widely used method of classifying the severity of knee 
osteoarthritis (OA; Appendix G).  It consists of 5 grades (ranging from grade 0 = no radiographic 
features of OA to grade 4 = severe OA with large osteophytes, marked narrowing of the joint 
space, severe sclerosis, and definite deformity of the bone ends).12  According to a review 
conducted by Schiphof et al, a cutoff of  2 is sufficient to distinguish definite/mild osteoarthritis 
from none/possible osteoarthritis.13 The K-L criteria will be used to evaluate subjects at the 
screening visit.  Subjects meeting K-L criteria 0, 1, or 4 do not qualify for this study. 
x 
Columbia-Suicide Severity Rating Score (C-SSRS) 
Suicidality will be monitored throughout the study using the C-SSRS (Appendix O). The 
C-SSRS scale consists of a baseline/screening evaluation that assesses the lifetime and prior 
24 month experience of the subject with suicide events and suicidal ideation and a post 
baseline/”Since Last Visit” evaluation that focuses on suicidality since the last study visit. The 
C-SSRS is a prospective assessment instrument that directly classifies suicidal ideation and 
behavior into categories. The C-SSRS involves a series of probing questions to inquire about 
possible suicidal thinking and behavior.  
Hospital Anxiety and Depression Scale (HADS) 
The HADS is a self-screening questionnaire that is commonly used by physicians and therapists 
to assess levels of anxiety and depression (Appendix H).  The HADS is a self-reported 14-item 
instrument that measures the presence and severity of anxiety and depression based on the 
subject’s experience over the past week.14 It consists of 2 subscales, each having 7 items: an 
anxiety subscale (HADS-A) and a depression subscale (HADS-D).  The 2 subscales, anxiety 
and depression, have been found to be independent measures.  The score for each subscale 
ranges from 0 (no anxiety or depression) to 21, with a score of 11 or higher indicating the 
probable presence of the mood disorder.  The questionnaire will be administered at visit 1 
(screening) and visit 5 (end-of-study/study discontinuation).   
Subjects with scores > 10 at the screening visit do not qualify for this study. 
x 
Modified Brief Pain Inventory-Short Form (mBPI-SF) 
The mBPI-SF is a self-administered questionnaire used to assess the severity of pain, and the 
interference of pain on daily functions (Appendix I).  It has been validated in numerous trials and 


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for use in patients with OA.17 It consists of 6 questions: 4 questions ask the subjects to rate their 
pain on a 0 to 10 NRS for worst pain, average pain, least pain, and current pain; 1 question 
asks subjects to rate their pain relief over the past 24 hours; 1 question with 7 parts that ask 
subjects to rate the impact of their pain on mood and everyday activities.  The mBPI-SF 
questionnaire will be completed at each clinic visit from visit 2 to the last visit during the 
double-blind period.  The questionnaire takes less than 5 minutes to complete. 
The question daily “average pain over the last 24 hours” scores will be administered daily during 
the screening visits (Appendix N).  The full questionnaire will be administered at 
visits 2 through 5 (end of study/early discontinuation). 
x 
Western Ontario and McMaster OA Index (WOMAC) 
The WOMAC is a self-administered questionnaire used to assess subjects with OA of the hip or 
knee (see Appendix J).  The WOMAC was validated in 1988 and is the leading outcome 
measure in clinical trials for knee and hip OA.18-23  The 24-hour, 0 to 4 categorical version 
(LK3.1) will be administered at each visit (excluding the follow-up visit), and it will be used to 
monitor the course of the disease or to determine the effectiveness of medications.  The 
following 3 subscales will be calculated and analyzed:  
Pain Subscale (5 items: walking; stair climbing; nocturnal; at rest; weight bearing): the pain 
subscale score can be 0 to 20. 
Stiffness Subscale (2 items: morning stiffness; stiffness occurring later in the day): the stiffness 
subscale score can be 0 to 8. 
Physical Function Subscale (17 items: descending stairs; ascending stairs; rising from sitting; 
standing; bending to floor; walking on flat surface; getting into or out of car; going shopping; 
putting on socks; rising from bed; taking off socks; lying in bed; sitting; getting into or out of the 
bathtub; getting on or off the toilet; heavy domestic duties; light domestic duties): the physical 
function subscale score can be 0 to 68. 
The questionnaire will be administered at visits 2 through 5 (end of study/early discontinuation). 
x 
EQ-5D 
EQ-5D is a standardized generic measure of health status for clinical and economic appraisal 
(see Appendix K).24-29 It is based on a descriptive system that defines health in terms of 
5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  
Each dimension has 5 levels of severity (no problems, slight problems, moderate problems, 
severe problems, and extreme problems/unable to).  It is a valid, reliable, and widely used 
instrument.  The questionnaire will be administered at visits 2 through 5 (end of study/early 
discontinuation).  It takes a few minutes to complete.  
x 
Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) 
The SF-36 is a generic health survey with 36 items that measure functional health and 
well-being from the subject's perspective (Appendix L).28  The 36 questions are grouped into 
11 sections.  Some of the sections consist of multiple questions.  The survey is summarized into 
8 dimensions/scales: physical functioning (PF), role-physical (RP), bodily pain (BP), general 
health (GH), vitality (VT), social functioning (SF), role-emotional (RE), and mental health (MH).  
From the 8 health dimensions, a physical component summary and mental component 


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summary measure are derived.  The questionnaire will be administered at visits 2 through 5 
(end of study/early discontinuation).  The SF-36 questionnaire takes 5 to 10 minutes to 
complete. 
x 
Patient Global Impression of Change (PGIC)  
The Patient Global Impression of Change (PGIC; Appendix M) is an ordinal scale of global 
evaluation which assesses the change in overall status relative to the start of the study. The 
scale has only1 item that measures global change of overall status (improvement or worsening) 
by the subject on a 7-point scale from 1 to 7, where 1 = very much improved and 7 = very much 
worse.  It is a valid, reliable, and widely used instrument and has shown a high degree of 
correlation with a subject’s self-reported pain score.  The PGIC will be administered at visit 5 
(end-of-study/early discontinuation).  
9.6.2 Efficacy Variables 
9.6.2.1 Primary Efficacy Variable 
The primary efficacy assessment is the daily "average pain over the last 24 hours” score (on an 
11-point NRS scale where 0 = no pain, 10 = pain as bad as you can imagine) from the mBPI-SF 
pain severity subscale at week 4 of the double-blind period. 
9.6.2.2 Secondary Efficacy Variable(s) 
x 
Weekly “average pain over the last 24 hours” collected by e-Diary 
x 
Average daily “pain right now” collected by e-Diary 
x 
WOMAC total scores 
x 
WOMAC pain severity subscale 
x 
WOMAC physical function subscale  
x 
WOMAC stiffness subscale  
x 
mBPI-SF total scores (all parts of 6 questions) 
x 
mBPI-SF pain severity subscale 
x 
mBPI-SF pain interference subscale  
x 
SF-36 
x 
EQ-5D  
x 
PGIC at the end of double-blind period (week 4) 
x 
Supplemental analgesic medication use 
x 
Responder to treatment 
 
9.6.3 Drug Concentration Measurements 
Samples of blood will be taken to determine plasma concentrations of V120083 in this study. 
For subjects in the intensive PK subgroup, blood samples will be collected at visit 2 (day 1 of 


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dosing) predose and postdose at 1, 2, 4, 6, and 8 hours.  All subjects will have PK samples 
collected a visit 3 (week 1; predose, 1 and 2 hours postdose); visit 4 (week 2; predose or 
postdose); and visit 5 (week 4; predose or postdose).  The site will obtain one (6 mL) blood 
sample during the visit and confirm the time of the subject’s last 2 doses of study drug.  The 
actual time when the samples are taken should be recorded.  See Appendix C for information 
on collection, processing, storage, and shipment of PK samples. 
9.6.3.1 Analytical Methodology 
Plasma concentrations of V120083 will be quantified by a validated liquid chromatography 
tandem mass spectrometric method. 
9.6.4 Safety Variable(s) 
9.6.4.1 Adverse Events (AEs) 
AEs will be collected as described in the schedule of assessments in section 9.5.1.  Details of 
AE data collection are described in section 10. 
9.6.4.2 Clinical Laboratory Evaluations 
Blood and urine samples will be collected for chemistry, hematology, and urinalysis evaluation 
(Appendix A).  The clinical laboratory evaluations will be conducted by a central laboratory. 
Some of blood/plasma and urine samples collected during the study may be used for future 
exploratory investigative studies, if and as necessary. 
A serum pregnancy test will be performed for female subjects who are premenopausal or 
postmenopausal for less than 1 year and who are not surgically sterile at screening, and at end 
of study or early discontinuation as applicable.  A urine pregnancy test will be performed for all 
female subjects of childbearing potential prior to the first dose of the study drug and as indicated 
in Table 3. 
Laboratory results will be evaluated.  The investigator will assess whether any values reflect 
AEs and if so, report them as described in section 10. 
Appendix B represents the criteria (ie, upper limit, lower limit criteria for each laboratory 
parameter) that will be used to identify subjects with alert laboratory values. 
The Schedule of Activities (section 9.5.1) shows the time points at which blood will be collected 
for clinical laboratory tests, and urine will be collected for urinalysis.   
9.6.4.3 Vital Signs 
Height, weight, and BMI will be measured at visit 1. 
Vital signs will be collected at the visits designated on the Schedule of Activities (section 9.5.1).   
Vital signs to be collected are the following: systolic/diastolic blood pressure, heart rate, 
respiration rate (after subject has been seated for at least 5 minutes), and temperature. When 
vital signs are scheduled at the same time that blood samples are obtained, the vital signs will 
be obtained before and as close to the scheduled blood sample as possible. 


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All vital sign abnormalities, including clinically notable vital sign abnormalities (Table 5), will be 
evaluated using appropriate medical judgment to determine whether they represent AEs.  Vital 
sign abnormalities that require medical intervention (beyond confirmatory vital sign collection) 
are AEs.  
Reference ranges for the vital sign values are presented in Table 4.  For values outside the 
reference range, the measurements will be repeated at the investigator’s discretion. 
Table 4  
Reference Range for Vital Sign Values   
Vital Sign Parameter 
Range 
Systolic blood pressure 
100–140 mm Hg 
Diastolic blood pressure 
60–90 mm Hg 
Heart Rate 
60–100 bpm 
Respiratory rate 
12–20 breaths per minute 
Temperature 
36.8°C–38.3°C 
 
Table 5  
Criteria Used to Identify Clinically Notable Vital Sign Abnormalities  
Vital Sign Parameter 
Value 
Change From Baselinea 
Systolic blood pressure 
 180 mm Hg 
Increase of  20 mm Hg 
 
 90 mm Hg 
Decrease of  20 mm Hg 
Diastolic blood pressure 
 105 mm Hg 
Increase of  15 mm Hg 
 
 50 mm Hg 
Decrease of  15 mm Hg 
Heart rate 
 120 bpm 
Increase of  15 bpm 
 
 50 bpm 
Decrease of  15 bpm 
Respiratory rate 
< 12 breaths per minute 
— 
 
> 20 breaths per minute 
— 
a Both value and change from baseline criteria must be met to qualify as a clinically notable abnormality. 
 
9.6.4.4 Electrocardiograms (ECGs) 
ECG results from 12-lead ECG will be transmitted to the central ECG provider for interpretation 
and will be evaluated by the investigator for clinical significance.  The investigator will assess 
whether any findings reflect AEs and if so, report them as described in section 10, Adverse 
Events. 
In order for subjects to enter the study, the baseline QTcF value obtained at the screening visit 
(visit 1) should not exceed 470 msec.  To remain in the study, QTcF values for ECG tracings in 
each visit subsequent to screening should not exceed 500 msec or 480 msec with a concurrent 
QTcF change of > 60 msec from baseline.  If QTcF values exceed 500 msec or 480 msec with a 
concurrent QTcF change of > 60 msec from baseline, the subject must discontinue study drug 
and the reason for study drug discontinuation will be recorded as AE (section 10). 


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All ECG abnormalities, including clinically notable abnormalities ( 
Table 6), will be evaluated using appropriate medical judgment to determine whether they 
represent AEs.  Abnormalities that require medical intervention are AEs.  
Table 6  
Criteria Used to Identify Clinically Notable ECG Values 
ECG Parameter 
Value 
Change From Baselinea 
Heart rate 
 100 bpm 
Increase of  15 bpm 
 
 50 bpm 
Decrease of  15 bpm 
QTcF – Screening 
> 470  
 
QTcF – During study 
> 480 
With increase of 60 msec from 
baseline 
a Value or change from baseline criteria may be met to qualify as a clinically notable abnormality. 
 
9.6.4.5 Physical Examination 
The physical examination must be performed by the investigator or a medically qualified 
designee (MD, DO, PA, NP).   
Findings from physical examinations will be evaluated by the investigator.  Findings at the 
screening visit will be considered medical history.  The investigator will assess whether any 
changes from the baseline physical examination reflect AEs and if so, report them as described 
in section 10, Adverse Events. 
9.6.4.6 Other Safety Variables 
Other safety variables will include: 
x 
HADS scores 
x 
C-SSRS 
x 
K-L scores 
9.6.5 Other Variables 
9.6.5.1 Chemotherapy-induced Taste Alteration Scale (CiTAS) 
Subjects will be asked to rate their evaluation of taste alterations for the 18 items and 
5 subscales on the CiTAS, a 5-point Likert-type scale.31  All results will be reviewed by the staff 
for accuracy and completeness at the time the questionnaire is administered (Appendix P). 
9.6.5.2 Pharmacogenomics 
Subjects will be asked if they are interested in participating in an optional exploratory 
pharmacogenomic portion of the study following their written informed consent for the trial.  Not 
participating in this exploratory PG portion of the study will not affect their participation in the 
trial.  This will involve collecting additional blood samples which may be used for future 
exploratory PG analysis.  In general, collection of these additional blood samples will be 
scheduled to occur at times when blood samples are already being collected for the study. 


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Three samples of blood, totaling approximately 20 mL, will be collected from each subject 
during the treatment period: 
o 1 sample for DNA at visit 2 predose 
o 2 samples for protein: 1 sample at visit 2 predose, and 1 sample at visit 5. 
Pharmacogenomic Samples 
Informed consent specific for PG sampling, must be obtained prior to blood collection.  
To obtain sufficient DNA for PG studies, a single blood sample will be drawn at the time point 
specified in Table 3 into the appropriate tubes provided by the sponsor 
 
 
 
 
 
 
 
. 
Privacy of information collected from samples obtained for storage and future analysis will be 
maintained.  PPLP has developed secure policies and procedures to maintain subject privacy.  
At the clinical site, unique codes will be placed on each PG blood sample for transfer to the 
sponsor designated/approved storage facility.  Each code is a unique random number used only 
to identify each biosample of each subject.   
Subjects may withdraw consent for banking samples at any time by contacting the investigator 
responsible for administering their initial informed consent.  After withdrawal of consent, no 
future samples will be collected and any samples with subject identification will be removed from 
the biorepository and their destruction documented in the repository database.  Any analyses 
performed or data obtained from the samples prior to the subject withdrawing consent will not 
be deleted. 
Data generated from processed samples remain confidential and will be retained by PPLP for 
an indefinite period.  Specimens will be maintained for potential analysis for up to approximately 
20 years following their acquisition.  Samples will be destroyed according to PPLP policies and 
procedures and this destruction will be documented in the repository database. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.6.6 Clinical Supplies Product Complaints 
9.6.6.1 Types of CSPCs 
Clinical Supplies Product Complaints (CSPCs) of study drug(s) consist of any issues involving: 
x 
Supply quality, quantity, packaging 
x 
Supply shipping 
x 
Supply storage 
x 
Suspected or known theft or diversion by non-subjects 
9.6.6.2 Reporting of CSPCs to Sponsor or Designee 
All CSPCs must be reported to the sponsor (or designee) by completing the CSPC Report Form 
and faxing within 24 hours of first knowledge of the issue.  Follow-up information, or new 


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information available after the initial report, should be actively sought and reported by faxed 
follow-up reports to the sponsor (or designee) as it becomes available.  In cases of confirmed or 
suspected diversion, the signature of the investigator / medically qualified designee is required 
on the CSPC Report Form. 
9.6.7 Subject Drug Discrepancies 
Site personnel will evaluate the study drugs dispensed / used by each subject at each visit and 
upon subject completion or discontinuation of the subject for any reason.  All study drugs should 
be accounted for.  Site personnel will consult the subject regarding any discrepancies of what is 
expected to be returned vs. what is actually returned.  This discussion and its outcome should 
be documented in the source on the individual subject.  Questions regarding the event may be 
referred to the Medical Monitor. 
Any study drug discrepancy will be reported in the Electronic Data Capture system.  The 
discrepancy may be categorized into the following:  
x 
Subject lost drug 
x 
Subject’s drug was stolen 
x 
Subject took more than expected 
x 
Other (subject related) (any other situation which does not fall into the above 
categories). 
9.6.8 
Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
working practice documents, and applicable regulations and guidelines.  Clinical site audits will 
be conducted periodically by the sponsor’s (or designee’s) qualified compliance auditing team, 
which is an independent function from the study conduct team. 
9.6.9 Data Collection 
Electronic Data Capture will be used to record case report form (CRF) data.  
Electronic diaries will be used for this study.  
Investigators/designees will enter the information required by the protocol onto the appropriate 
source documents, and in CRFs in accordance with the accompanying CRF completion 
instructions.  The CRFs will be reviewed for completeness and accuracy against the source 
documents by the CRAs who will periodically visit each clinical site.  Any discrepancies found 
between the source documents and the completed CRFs will be noted, and the CRAs will 
ensure that appropriate clinical site personnel address the discrepancies.     
The investigator/medically qualified designee must verify that the data are complete and 
accurate via signature in the CRF as required. 
Subjects will enter self-reported information into their diaries and/or directly into an electronic 
device or on paper at the clinical site.  Investigators/designees will review the diary data on an 
ongoing basis and periodically with the subject. 


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9.6.10 Clinical Data Management 
Clinical data will be entered into the clinical database in accordance with data management 
procedures.  Programmed and manual review of the clinical database will be performed 
according to data validation procedures.  Clinical sites will be notified of any discrepancies and 
will be requested to address them.  The database will be ‘locked’ by clinical data management 
once the database has been appropriately updated in accordance with the clinical site 
responses. 
CRF data will be stored in a clinical database as specified in data management processes.  
External data (eg, laboratory data, diary, and ECG data) will be received from third party 
vendors and processed per the data management procedures.  Quality control and data 
validation procedures will be applied to ensure the validity and accuracy of the clinical database. 
9.6.11 Data Quality Assurance 
In accordance with the data management plan, the clinical database will be reviewed and 
checked for omissions, apparent errors, and values requiring further clarification using 
computerized and manual procedures.  Data queries requiring clarification will be documented 
and sent to the clinical site for resolution.  Only authorized personnel will make corrections to 
the clinical database, and all corrections will be documented in an audit trail.  Quality checks will 
be performed per the data management procedures.  
9.7 
Statistical Methods Planned in the Protocol and Determination of Sample 
Size 
All data analyses will be performed by sponsor’s (or designee’s) statistical and programming 
personnel.  Statistical programming and analyses will be performed using SAS® and/or other 
validated statistical software as required. 
This section describes the statistical analyses of safety, efficacy, and other data collected.  The 
statistical analyses described in this section will be performed as further outlined in the 
statistical analysis plan (SAP).  The final SAP will take into account any amendment to the 
protocol. 
The data described in the sections below will be listed by subject. 
9.7.1 Analysis Populations 
The enrolled population consists of all individuals who sign the ICF. 
The safety population is the group of subjects who are randomized and receive at least 1 dose 
of the double-blind study drug. 
The full analysis population (FAP) is the group of subjects who are randomized, receive at 
least 1 dose of double-blind study drug, and have at least 1 efficacy assessment. 
The per-protocol population (PP) is a subset of the full analysis population and consists of all 
subjects in the full analysis population who do not have major protocol violations. 
The pharmacokinetics (PK) population consists of all individuals who are randomized and 
receive at least 1 dose of V120083 and have at least 1 valid, quantifiable PK blood sample. 


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9.7.2 Summary of Study Population Characteristics 
9.7.2.1 Demographics and Baseline Characteristics 
The continuous demographic/baseline variables (eg, age [years], weight), will be summarized 
using mean, standard deviation (SD), minimum, and maximum values.  For categorical 
(nominal) variables (eg, gender, race), the number and percentage of subjects will be used.  
Demographic/baseline variables will be summarized for all subjects in the safety population.  
A listing will be provided for the enrolled population and the safety population.  
9.7.2.2 Subject Disposition 
Subject disposition will be summarized by treatment groups for the double-blind period.  The 
number and percent of subjects who completed and the number and percent of subjects who 
discontinued along with the distribution of the reasons for discontinuation will be presented.  The 
number and percent of subjects in each analysis population will be presented.  Subject 
disposition and reasons for discontinuation during screening period will be presented for the 
enrolled population. A listing will be provided for the enrolled population and the safety 
population. 
 
9.7.2.3 Dosing and Extent of Exposure 
Dosing and extent of exposure will be summarized by treatment groups for the double-blind 
period. 
The double-blind period begins on the day the first double-blind study drug is administered.  The 
number and percentage of subjects exposed to double-blind treatment for overlapping time 
intervals (eg, any exposure,  1 week,  2 weeks,  4 weeks) in the double-blind period will be 
calculated by treatment group for the safety population.  Descriptive statistics (mean, 
SD/standard error, median, minimum, and maximum) will be provided to summarize the length 
of exposure (in days) to each treatment. 
A data listing of the study drug dosage administered to each subject during the double-blind 
period will be provided. 
9.7.2.4 Prior and Concomitant Therapy 
Prior and concomitant therapies will be coded to World Health Organization Drug Dictionary 
terms.  A dictionary listing of all unique concomitant medications used in the study will be 
provided, sorting medications by drug class and preferred drug name. 
Concomitant therapy use during the double-blind period will be summarized by treatment group 
for the safety population.  In each of these summary tables, the number of subjects taking each 
therapy will be presented by anatomical therapeutic chemical (ATC) codes (levels 1, 2, and 3).  
In addition, prior medications used for OA will be summarized using ATC codes by treatment 
group for the safety population. 
A data listing for all prior and concomitant therapy will be provided for the safety population. 


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9.7.2.5 Medical History 
Medical history will be coded to Medical Dictionary for Regulatory Activities Terminology 
(MedDRA) terms.  Coded medical history terms will be summarized for all subjects in the safety 
population. 
9.7.3 Efficacy Analysis 
All efficacy analyses will be conducted on the full analysis population.  An analysis of the 
primary efficacy variable for the per-protocol population may be performed if more than 20% of 
the subjects in the FAP have major protocol deviations that would affect the evaluation of 
efficacy.  The primary hypothesis test will be 1 sided with a 5% significance level.  For each of 
the following primary and secondary analyses, the primary contrasts will be those between 
placebo and each dose of study drug.  The placebo and the active control will be compared to 
assess assay sensitivity. 
9.7.3.1 Primary Efficacy Variable(s) 
Primary efficacy analysis is based on the daily “average pain over the last 24 hours” score from 
the mBPI-SF pain severity subscale at week 4 of the double-blind period.  The analysis will be 
performed using a mixed-effect general linear model with repeated measures (MMRM).  The 
MMRM will include treatment (4 levels: 60 mg bid or 30 mg bid of V120083, 500 mg bid 
naproxen, and placebo) and time (3 levels for weeks, 1, 2, and 4) as fixed effects; the baseline 
pain scale will be incorporated as fixed covariates, and subject will be a random effect.  The 
treatment by time interaction effect will also be investigated. The restricted maximum likelihood 
approach will be used to estimate the parameters in the model.  While data from the entire 
double-blind period will be used to fit the linear model to get a better estimate of the 
variance-covariance matrix (based on Akaike information criteria), the primary comparison 
between groups will be based on estimates/contrasts for the week 4 means. Reported results of 
primary analysis from MMRM will include least-squares mean (LSM) estimates, standard errors 
for each treatment group, the p-value for testing the differences between placebo/naproxen and 
each dose of V120083, and the corresponding confidence interval (90% and 95%) for the 
difference in LSMs. 
 
9.7.3.2 Secondary Efficacy Variable(s) 
Weekly “average pain over the last 24 hours” collected by e-Diary 
The weekly “average pain over the last 24 hours” collected by e-Diary will be analyzed in a 
similar manner as for the primary endpoint. 
Average daily “pain right now” collected by e-Diary 
Summary statistics (mean, SD, median, and range) for the average daily “pain right now” scores 
will be provided by weeks and treatment group for all subjects in the full analysis population.  
The weekly average of daily “pain right now” scores will be defined as the sum of nonmissing 
daily “pain right now” scores reported during that week (days 1 to 7, days 8 to 14, days 15 to 21, 
and days 21 to 28) divided by the number of days with nonmissing scores for that week.  If a 
subject reports fewer than 3 days of pain scores during a week, the weekly mean “pain right 


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now” score will be set to missing.  If there are > 1 “pain right now” scores reported on the same 
day, then the average “pain right now” score on the day will be used to calculate weekly mean 
“pain right now” scores.  All observed data will be used.  Associated 95% CIs for the treatment 
group means will be calculated and presented. 
WOMAC 
The WOMAC total score, pain subscale, stiffness subscale and physical function subscale will 
be analyzed in a similar manner as for the primary endpoint. 
mBPI-SF 
The 2 components (severity and interference of pain) of the mBPI-SF will be analyzed in a 
similar manner as for the primary endpoint. 
SF-36 
There are 8 dimensions/scales:  physical functioning (PF), role-physical (RP), bodily pain (BP), 
general health (GH), vitality (VT), social functioning (SF), role-emotional (RE), and mental health 
(MH).  Special transformations are applied to the sum of the scores for a dimension in order to 
standardize the scales.  The detailed algorithm for computing the scores for the scales will be 
described in the Statistical Analysis Plan for the study.  
In addition to the 8 scales, 2 summary measures will be derived: 
Physical component summary (PCS) measure (aggregate of PF, RP, BP, and GH scales); and  
Mental component summary (MCS) measure (aggregate of VT, SF, RE, and MH scales). 
EQ-5D 
The 5-level scale EQ-5D (EQ-5D-5L) is a generic instrument that can be used in the clinical and 
economic evaluation of health care, and to collect data on quality of life and preferences/utility.  
The instrument comprises questions on mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, and a visual analogue scale (VAS) from 0 (“Worst imaginable health state”) 
to 100 (“Best imaginable health state”). 
The U.S. population-based index values based on crosswalk value sets for EQ-5D-5L 
developed by EuroQoL Research Fundation (van Hout B et al. 2012) and VAS will be analyzed 
in a similar manner as for the primary endpoint. In addition, responses from each of 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) will 
be converted into binary outcomes (‘No problems’ vs ‘Problems’) based on EQ-5D-5L User 
Guide and the binary outcomes from each of 5 dimensions will be analyzed using a generalized 
estimating equation (GEE). 
Responder to treatment 
A subject’s response to treatment will be defined as the percentage reduction from the baseline 
mean “average pain over the last 24 hours” score to the week 4 pain score from the mBPI-SF 
pain severity subscale.  For each subject, percentage reduction in pain from baseline through 
double-blind treatment will be calculated as: 


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% reduction = 100* (bslpain – wk4) / bslpain, 
Where, bslpain = baseline mean pain score 
wk4 = week 4 pain intensity score. 
All subjects who discontinue study drug prior to week 4 will be considered nonresponders and 
will be assigned a 0% reduction in pain. 
The proportion of subjects with a response to treatment at week 4 will be compared using a 
logistic regression model with “responder” (yes/no) as dependent variable, treatment and 
screening mean pain score as covariate.  
A graph of the observed cumulative percentage of subjects v percentage reduction in pain from 
screening mean pain score will be generated by treatment group.  Based on this graph, 
estimates of percentage of responders for the following cutoffs: (<0, 0, > 0, t 10%, t 20%, 
t 30%, t 40%, t 50%, t 60%, t 70%, t 80%, t 90%, and = 100%) for each treatment group will 
be computed and graphed. 
PGIC 
The PGIC rating score obtained at week 4 or end-of-study visit of the double-blind period will be 
measured on a 7-point scale in which 1 = very much improved and 7 = very much worse.  The 
categories will be compared between treatment group and placebo using the Chi-Squared test.  
Further analysis will be conducted on collapsed categories (very much improved/much 
improved v minimally improved/no change/minimally worse/much worse/very much worse) 
using Fisher’s exact test.  Changes from baseline values will be analyzed by treatment group 
separately using analysis of covariance (ANCOVA), with baseline adjusted as a covariate. 
Supplemental Medication 
The percentage of subjects who require no supplemental analgesic medication usage will be 
calculated for each treatment group.  Ninety-five percent confidence intervals for the proportion 
of subjects in each treatment group who do not require any supplemental analgesic medication 
will be constructed using the normal approximation to the binomial distribution and a correction 
for continuity.  The average daily number of supplemental acetaminophen 500 mg will be 
summarized for each treatment group weekly and over 28 days.  For each visit (time point), the 
total number of tablets taken will be calculated as the number of tablets given minus the number 
of tablets returned.  The average daily number of tablets will be calculated by dividing the total 
number of tablets taken during the time interval by the number of days in the interval. 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) will be presented by 
treatment group. Due to the nature of the data, supplemental pain medication for OA tends to 
have a large proportion of zeros (contributed by subjects who do not take any supplemental 
pain medication) followed by continuous distribution of nonzero values. Therefore, the 
supplemental pain medication for OA will also be summarized categorically. Preliminarily, the 
categories will be (1) no supplemental acetaminophen tablets, (2) 0 to  0.5 tablets, (3) > 0.5 to 
 1.0 tablets, (4) > 1.0 to  2.0 tablets, and (5) > 2.0 tablets.  Upon review of the blinded data 
prior to database lock, the categories will be reviewed and if any adjustments to the categories 
are deemed necessary, the rationale and new categories will be documented in the SAP prior to 
database lock.  


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Other continuous secondary variables (see section 9.6.2.2) will be analyzed similarly to the 
primary efficacy method, using an MMRM.  
9.7.4 Pharmacokinetic Analysis 
9.7.4.1 Pharmacokinetic Variable(s) 
Plasma V120083 concentrations, sampling times, dosing histories, and individual-specific 
demographics, including age and weight, will be collected. For intense PK sampling component, 
time to maximum plasma concentration (Tmax), maximum observed plasma concentration 
(Cmax), and area under the plasma concentration-time curve from time zero to the time of the 
last sampling after dosing (AUC0-8) will be calculated. 
9.7.4.2 Pharmacokinetic Statistical Analysis 
All individual subject plasma concentration data will be listed. 
Descriptive statistics (mean, standard deviation, coefficient of variation, geometric mean, 
coefficient of variation for geometric mean, median, minimum, and maximum) will be tabulated 
by treatment and visit for predose individual plasma concentrations (troughs), which are 
sampled at 12 ± 1 hours postdose at visit 3, 4, and 5. 
For intense PK sampling component, descriptive statistics for plasma concentrations at visit 2 
will be tabulated by treatment and nominal sampling time. The time course of individual and 
mean plasma concentrations will be graphically presented. Pharmacokinetic parameters of 
V120083 will be calculated based on the plasma concentrations of V120083 by using 
non-compartmental analysis for intense PK sampling component. The actual elapsed sampling 
times will be used in the PK metrics calculations. Descriptive statistics for PK metrics will be 
tabulated by treatment. 
A population PK analysis may be performed and will be reported in a separate report from the 
clinical study report. 
9.7.5 Statistical / Analytical Issues 
9.7.5.1 Adjustments for Covariates 
Details of adjustments for covariates for the efficacy variables and the definition of these 
covariates are contained in section 9.7.3.  For each primary and secondary efficacy variable 
analyzed using MMRM, the baseline values will be included as covariate in the model. 
Exploratory/subgroup analyses with adjustment for covariates may be performed for further 
scientific interest in order to look for explanatory variables related to the occurrence of primary 
safety and efficacy endpoints.  Models predicting study endpoints may be developed with 
potential covariates inclusion in the analysis.  The covariates will be chosen and pre-specified 
from among the baseline and demographic variables. 
9.7.5.2 Handling of Dropouts or Missing Data 
The distribution of prognostic factors between subjects with complete data and those who 
discontinue study drug early will be examined to evaluate any potential sources of bias.  In the 


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absence of any apparent systematic loss, data will be analyzed assuming that these 
observations are missing at random. 
mBPI-SF 
If more than half of the items in either the severity of pain subscale or the interference of pain 
subscale are missing, then the resulting subscale score will be treated as missing.  Otherwise, if 
half the items or less in a particular subscale are missing, then for the purpose of computing the 
subscale score, the item’s scoring value will be imputed by the mean score from the other items 
within the subscale. 
WOMAC 
The pain subscale of the WOMAC at week 4, will be obtained by adding the responses to 
questions 1 through 5.  A mean score will also be computed for the 3 subscales and composite 
scale by averaging the response to the questions instead of summing them. 
x 
Pain Subscale: calculated by averaging items 1 to 5.  If 2 or more pain scores are 
missing, then the pain subscale will be set to missing; otherwise, the average of the 
nonmissing pain scores will be used for the missing pain scores. 
x 
Stiffness Subscale: calculated by averaging items 6 to 7.  If both stiffness scores are 
missing, then the stiffness subscale will be set to missing.  If 1 stiffness score is missing, 
then the nonmissing stiffness score will be used in the analysis. 
x 
Physical Function Subscale: calculated by averaging items 8 to 24.  If 4 or more physical 
functioning scores are missing, then the physical functioning subscale will be set to 
missing; otherwise, the average of the nonmissing physical function scores will be used 
for the missing physical functioning scores. 
x 
Composite Scale: calculated by averaging 3 subscale averages: (pain subscale + 
stiffness subscale + physical functioning subscales)/3.  If 1 or more of the subscales is 
missing, then the composite scale will be set to missing. 
PGIC and other efficacy endpoints 
No imputation will be done for the PGIC or other efficacy endpoints.  
9.7.5.3 Interim Analyses and Data Monitoring 
An interim analysis may be conducted when approximately 50% of randomized subjects have 
completed the end-of-study visit.  The unblinded interim analyses and data review will be 
performed by an independent committee consisting of a statistician, clinician, and programmer 
not associated with the study team.  Additional data reviews may be conducted as deemed 
necessary. The sponsor may request additional (ad hoc) DMC recommendations throughout the 
study.  Details will be further pre-specified in the DMC and corresponding interim analysis 
statistical analysis plan documents.   
At the interim analysis, the following procedures will be performed: 
x 
Safety evaluation for early termination will be performed when 50% of subjects have 
completed the study.  The independent statistician/programmer will provide safety data 
listing and summary tables by unblinded treatment groups.  The DMC members will 
review the safety data, including but not limited to AEs and clinical laboratory values.  


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The decision to stop 1 or more treatment groups due to safety issues will be made 
based on clinical judgment.  The arm will be stopped if there is significant physical 
toxicity or evidence of impending risk of physiologic harm or extremely abnormal 
laboratory findings related to treatment.  
x 
Efficacy evaluation for V120083 treatment groups may be performed by the independent 
statistician/programmer when 50% of subjects have completed the study.  The 50% 
interim analysis may be performed to evaluate the efficacy of each dose of study drug in 
the study population.  The DMC will review the results of the analysis and make 
recommendations, as appropriate, regarding plans for further studies.  
Lan et al32 introduce stochastic curtailment to stop a trial if, given current data, it is likely to 
predict the outcome of the trial with high probability.  The conditional power at the scheduled 
end of the study, given the observed data at the interim evaluation, will be calculated with a 
stochastic curtailment approach to support the decision of early termination for futility.  
SAS 9.2 PROC SEQTEST will be used to calculate the conditional power based on the formula 
given by Cui et al33 and Emerson et al34Additional info will be pre-specified in the DMC charter. 
9.7.5.4 Homogeneity Across Clinical Sites 
Although subjects will be assigned unique subject numbers sequentially within sites, there is no 
plan currently to include site as a factor in the statistical models as a main effect because of the 
large number of sites that are expected to be used for the study.  In addition, enrollment at 
some sites will be very small.  Per ICH guidance (E9 section 3.2), a graphical exploration of the 
homogeneity of treatment effects across sites will be provided for the primary efficacy variable if 
appropriate.   
9.7.5.5 Multiple Comparisons / Multiplicity 
No multiplicity adjustment will be performed for this study. 
9.7.5.6 Examination of Subgroups 
No formal subgroup analyses are planned for efficacy and safety variables. 
9.7.6 Safety Analyses 
Evaluation of safety will be performed for all subjects in the safety population.   
9.7.6.1 Adverse Events (AEs) 
AEs will be coded to MedDRA terms (version 18.1).  A listing sorted by MedDRA System Organ 
Class (SOC) and Preferred Term will include all lower level terms and verbatim descriptions 
associated with the Preferred Terms. 
Data for AEs will be analyzed using the treatment-emergent signs and symptoms (TESS) 
philosophy.  Treatment-emergent signs and symptoms are defined as AEs that: 
x 
Emerge during treatment, having been absent at pretreatment; or  
x 
Re-emerge during treatment, having been present at pretreatment but stopped prior to 
treatment; or  
x 
Worsen in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 


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Treatment emergent AEs (TEAEs) will be assigned to study drug according to their onset date.  
AEs that start after a subject’s last dose but within 7 days of dosing will be considered TEAEs 
and will be assigned to the last treatment administered.  AEs that start more than 7 days after 
the last dose of study drug will be considered non-TEAEs. 
Only TEAEs will be included in summary tables.  However, all AEs will be included in a 
by-subject AE listing.  The incidence of TEAEs will be summarized by SOC, MedDRA Preferred 
Term and treatment (if appropriate) by presenting the number and percentage of subjects with 
an AE.  A subject will be counted only once in the incidence count for a specific MedDRA 
Preferred Term, although a MedDRA Preferred Term might be reported more than once for a 
particular subject.  Separate summaries will be provided for TEAEs by maximum severity (mild, 
moderate, severe) and relationship (yes, no) to study drug.  A TEAE will be considered related 
to study drug if the investigator reported the event to be “definitely, probably, possibly, or 
unlikely” related to treatment.  In addition, a table of TEAEs occurring in  5% of the subjects in 
at least 1 treatment group will be presented. 
x 
Individual subject listings of AEs that resulted in death, of other SAEs and of AEs that 
led to treatment discontinuation, dose interruption, or dose reduction will be generated.  
These listings will include the treatment group and dose (if applicable) at the time of AE 
onset, start and stop dates of the AE, days on study, and days on treatment.  Summary 
tables (eg, incidence of TEAEs leading to treatment discontinuation) may be generated 
depending upon the incidence of these significant AEs.   
x 
Summaries of TEAEs occurring in the double-blind period will be generated by treatment 
group for subjects in the safety population.  
Adverse events of special interest (AESIs) will be summarized as well.  A list of AESIs are 
defined in section 10.3.2. 
9.7.6.2 Laboratory Values 
Clinical laboratory values will be evaluated for each laboratory parameter by subject.  For each 
laboratory test, abnormal values will be identified as those outside (above or below) the 
reference range, and will be flagged in the by-subject listings.   
Reference (normal) ranges for laboratory parameters will be included in the clinical study report 
for this protocol. 
Laboratory test results will be assigned an LNH classification according to whether the value is 
below (L), within (N), or above (H) the laboratory parameter’s reference range.  Within treatment 
comparisons during the double-blind period will be based on 3 by 3 tables (shift tables) that, for 
a particular laboratory test, compare the prerandomization LNH classification to the LNH 
classification at the end of double-blind treatment.   
Summary statistics (n, mean, SD, minimum, maximum, and median values) for end of 
double-blind (EODB) and change from baseline to EODB values of continuous laboratory 
parameters will be produced by treatment group for subjects in the safety population.  
All clinical laboratory results will be evaluated for markedly abnormal values, see Table 7.  A 
listing of all subjects in the safety population with at least 1 markedly abnormal laboratory value 
will be prepared; for a given subject, in addition to the flagged markedly abnormal laboratory 
parameters, the listing will present the results of all scheduled and unscheduled study 
evaluations of the same laboratory parameter whether or not they are markedly abnormal.  The 
incidence of markedly abnormal laboratory tests will be summarized by treatment group for 
subjects in the safety population.  For these calculations, each subject may be counted once in 


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the laboratory parameter value high and in the laboratory parameter low categories, as 
applicable.  
Table 7   
Laboratory Ranges Used to Identify Markedly Abnormal Laboratory Values 
 
Markedly Abnormal Rangea 
Laboratory Parameter 
Lower Limita 
Upper Limita 
Hematology 
 
 
Hemoglobin 
< 10 g/dL or 100 g/L 
—–– 
Platelets 
< 75.0 × 109/L or < 75000/mm3 
—–– 
Leukocytes 
< 3.0 × 109/L or < 3000/mm3 
—–– 
Lymphocytes 
<800/mm3 or <0.8 × 109/L 
—–– 
Neutrophils 
< 1500 × 106/L or < 1500/mm3 
—–– 
Clinical Chemistry 
Electrolytes 
 
 
Sodium 
< LLN 
> 150 mmol/L 
Potassium 
< LLN 
> 5.5 mmol/L 
Bicarbonate (HCO3) 
<16 mmol/L or <16 mEq/dLb 
—–– 
Liver Function Tests  
 
 
Alkaline phosphatase 
—–– 
>2.5 × ULN 
Aspartate aminotransferase (AST) 
—–– 
> 3 × ULN 
Alanine aminotransferase (ALT) 
—–– 
> 3 × ULN 
Gamma glutamyl transferase (GGTP) 
—–– 
> 2.5 × ULN  
Total bilirubin 
—–– 
> 1.5 × ULN 
Renal Function Tests 
 
 
Creatinine 
—–– 
> 1.5 × baseline or > 1.5 × ULN 
eGFR 
 59 ml/min/1.73 m2 
 
Other Chemistry 
 
 
Calcium corrected 
< 8 mg/dL or < 2.0 mmol/L 
> 11.5 mg/dL or > 2.9 mmol/L 
Phosphorus 
< 2.5 mg/dL or < 0.8 mmol/L 
— 
Glucose 
< 55 mg/dL or < 3.0 mmol/L 
Fasted > 160 mg/dL or 
> 8.9 mmol/L 
Uric acid 
—–– 
> ULN 
Cholesterol 
—–– 
> 300 mg/dL or > 7.75 mmol/L 
Triglycerides 
—–– 
> 2.5 × ULN 
Albumin 
< 3 g/dL or 30 g/L 
—–– 
Abbreviations: LLN = lower limit of the laboratory reference (normal) range; ULN = upper limit of the laboratory 
reference (normal) range.  
a Common Terminology Criteria for Adverse Events  version 4.03 June 2010, Grade 2 limits , unless otherwise 
specified. 
b Common Terminology Criteria for Adverse Events  version 3.0 Aug 2006, Grade 2 limit. 
 
Additional analyses of liver function tests (AST, ALT, and total bilirubin) will be conducted by 
generating shift tables using the categories presented in Table 8 below.  


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For liver function tests, shift summaries will be generated comparing screening values to end of 
double-blind values. 
Table 8  
Categories for Shift Analysis of AST, ALT, and Total Bilirubin 
AST/ALT 
Total Bilirubin 
 1 × ULN 
1 × ULN 
> 1 -  3 × ULN 
> 1 – 1.5 × ULN 
> 3 -  5 × ULN 
> 1.5 – 2.0 × ULN  
> 5 -  10 × ULN 
> 2.0 × ULN 
> 10 -  20 × ULN 
— 
> 20 × ULN 
— 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; ULN = upper limit of the laboratory reference (normal) 
range. 
A listing of all subjects in the safety population with liver function test results for AST and 
ALT >3 × ULN or total bilirubin > 1.5 × ULN will be generated: 
For all laboratory listings and summaries described in this section, the following definitions will 
be applied to each laboratory test: 
Screening value = the last scheduled or unscheduled (repeat) test result obtained prior to the 
first dose of study drug in the double-blind period.  
End of double-blind value = the last scheduled test result obtained during treatment with 
double-blind study drug.  
Laboratory evaluations occurring  7 days after the last dose of study drug will not be included 
in the calculations listed above. 
All laboratory test results will be reported in SI units. 
9.7.6.3 Vital Signs 
Vital sign listings will include all subjects in the safety population.  Vital sign summary tables will 
be presented by treatment group for subjects in the safety population. 
Vital sign values will be evaluated on an individual basis by subject.  Abnormal vital sign values 
will be identified as those outside (above or below) the reference ranges defined in Table 4.   
For each continuous vital sign parameter descriptive summary statistics (n, mean, standard 
deviation/standard error, median, and range) will be prepared for values observed.  Summary 
statistics for the change from baseline to the end of the double-blind will also be presented. 
Vital sign abnormalities that meet or exceed the “clinically notable vital sign” values (Table 5) 
will be listed.  The incidence of clinically notable vital signs during the double-blind period will be 
presented by treatment for all subjects in the safety population.  
9.7.6.4 Electrocardiograms 
ECG parameters collected include: heart rate (bpm), PR interval (msec), RR interval (msec), 
QRS interval (msec), uncorrected QT interval (msec), QTcB (Bazett’s correction) interval 
(msec), and QTcF (Fridericia’s correction) interval (msec). 


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All summaries described in this section will be generated by period.  Summaries of ECG 
evaluations performed during the double-blind period will be generated by randomized 
treatment group for subjects in the safety population.  In addition, certain summary tables may 
be generated for ECGs collected during exposure to the study drugs across the double-blind 
period. 
The following listings and summary tables will be generated: 
1. Summary statistics (n, mean, SD, minimum, and maximum) of the baseline value, the value 
at each scheduled evaluation, and the corresponding change from baseline for each 
continuous ECG parameter. 
2. Count (%) of subjects with a change from baseline in QT, QTcB, or QTcF intervals > 30 but 
 60 milliseconds, and with a change > 60 milliseconds at each scheduled postbaseline 
evaluation. 
3. Listing of subjects with a change from baseline in QT, QTcB, or QTcF intervals > 30 but 
 60 milliseconds, and with a change > 60 milliseconds at each scheduled postbaseline 
evaluation. 
4. Count (%) of subjects, for each ECG parameter, with at least 1 outlier value observed during 
the phase or period of interest. 
5. Listing of subjects with at least 1 outlier ECG parameter postbaseline 
6. For each selected ECG morphology finding, the count (%) of subjects with the specific 
finding absent or present at baseline vs. end of phase (eg, end of run-in period, end of 
double-blind period). 
7. Listing of subjects with treatment-emergent ECG morphology findings. 
For these analyses, the following rules will apply: 
o The baseline value of each ECG parameter will be defined as the average of all 
ECG values collected prior to the start of study drug.  
o In listings summaries 1 through 3 above, the value of the ECG parameters at each 
scheduled post-baseline evaluation will be calculated as the average of the tracing 
results collected at that time.   
o For listings 4 through 7, every ECG tracing will be evaluated (ie, no average will 
be calculated).  
o For listings 6 and 7, a subject will be categorized as having a specific morphology 
finding present at baseline if the finding is observed in at least 1 ECG tracing 
obtained prior to the start of study drug.  A specific ECG morphology finding will 
be considered present at the end of a phase/period if it is observed in at least 
1 ECG tracing collected during that phase/period.  
o For listing 7, an ECG morphology finding will be considered treatment emergent if 
it is observed in at least 1 postbaseline ECG tracing but is absent from all screening 
baseline tracings. 
Outliers (display 5 above) are defined as follows: 
o Heart rate: a value for a subject is considered to be an outlier at a postscreening 
time point if the heart rate measurement at that time point is < 50 bpm and at least 
a 25% decrease from the subject’s baseline mean heart rate (ie, a bradycardia 


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event), or if the heart rate measurement at the postscreening time point is > 100 
bpm and at least a 25% increase from the baseline mean heart rate (ie, a 
tachycardia event). 
o PR interval: a value for a subject is considered to be an outlier at a postscreening 
time point if the PR interval from the ECG at the postscreening time point is > 200 
msec and at least a 25% increase from the subject’s baseline mean PR interval. 
o QRS interval: a value for a subject is considered to be an outlier at a postscreening 
time point if the QRS interval from the ECG at the postscreening time point is > 
100 msec and at least a 25% increase from the subject’s baseline mean QRS 
interval. 
o QT interval: a value for a subject is considered to be an outlier at a postscreening 
time point if the QT interval from the ECG at the postscreening time point is 
> 450 msec, and the subject’s baseline mean QT interval is > 450 msec. 
o QTcF: a value for a subject is considered to be an outlier at a postscreening time 
point if the QTcF interval from the ECG at the postscreening time point is 
> 450 msec, and the subject’s baseline mean QTcF interval is  450 msec. 
For display 7 listed above, the specific ECG morphology findings consist of the following: 
o Abnormal U wave 
o Atrial fibrillation 
o Right bundle branch block (RBBB) 
o Left bundle branch block (LBBB) 
o Left anterior hemiblock (LAH) 
o Myocardial infarction (MI) 
o ST depression 
o T wave (biphasic and/or inverted). 
For each of the of the findings  listed above, a subject will be categorized as having the specific 
treatment-emergent ECG abnormality if it is observed in at least 1 postscreening period ECG 
morphologic determination, but is absent from all screening baseline results.  The final list of 
abnormalities will be defined in the statistical analysis plan based on a blinded data review. 
9.7.6.5 Physical Examination 
Any observed changes in physical examinations from before treatment to after treatment will be 
listed and described. 
9.7.6.6 Other Safety Variables 
Descriptive statistics will be presented by treatment group for the HADS, C-SSRS, and K-L 
scores using the safety population.  Changes from baseline values will be analyzed by 
treatment group separately for both the anxiety and depression scores using ANCOVA, with 
baseline adjusted as a covariate.   
9.7.7 Other variable analysis 
CiTAS scores will be listed and summarized descriptively using the safety population.  


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For the assessment of the CiTAS, scores received from each subscale will be evaluated rather 
than the total score received from the entire scale. The subscale scores will be obtained by 
dividing the number of the items into the sum of scores of those items as follows: 
x 
Decline in basic taste: Add up score from question 2 to question 6, and divide it by 5. 
x 
Discomfort: Add up score from question 13 to question 18, and divide it by 6. 
x 
Phantogeusia and parageusia: Add up score from question 10 to question 12, and divide 
it by 3. 
x 
General taste alterations: Add up score from question 1 and question 7 to question 9, 
and divide it by 4. 
The maximum score is 5 points, whereas the minimum score is 1 point that can be received 
from subscales. 
9.7.8 Other Analyses 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
    
9.7.9 Determination of sample size 
A total of up to 276 subjects is planned to be randomized to the double-blind period of this study 
using a 1:1:1:1 randomization ratio; ie, approximately 69 subjects are to be randomized to each 
of the 4 treatment groups (V120083 [60 mg or 30 mg], naproxen [active comparator], or 
placebo).  The actual number of subjects treated will depend on the outcome of the interim 
analysis.  
The analgesic effect size of V120083 is unknown. Therefore, the sample size calculation is 
based on a clinically important difference for OA pain reduction of 1 unit on an 11-point NRS 
(0 to 10). 
 
 
 
 
 
 
  
 
 
 
 
 This study may provide appropriate information for the data variability in the sample 
size calculations. The standard deviation (SD) for average pain over last the 24 hours, an 
individual question of the Summary of Modified Brief Pain Inventory Short Form (mBPI-SF) at 
week 4, was approximately 2.34. With a fixed sample size study design, the sample size 
needed for 80% power to detect this difference with a significance level of 0.05 (1-sided) is 
69 subjects per arm, assuming a 1:1 randomization ratio of each active arm to placebo. The 
sample size calculation was performed with nQuery+nTerim 3.0. 
10 ADVERSE EVENTS  
10.1 Definition 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject, regardless of whether administered any pharmaceutical product or placebo.  An AE 
does not necessarily have a causal relationship with treatment.  


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An AE can be: 
x 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the investigational product. 
x 
Any new disease or exacerbation of an existing disease. 
x 
Recurrence of an intermittent medical condition (eg, headache) not present at baseline. 
x 
Any case of abuse of alcohol, illicit drugs, or prescription drugs; abuse of study drug(s) 
or protocol -specified drug(s); addiction.  
x 
A pregnancy that occurs or becomes confirmed during a clinical study (see 
section 10.3.1). 
x 
Abnormal laboratory values or other clinical tests (eg, ECG or X-ray) that results in 
symptoms, a change in treatment, discontinuation from study drug, or are considered to 
be medically significant. 
o All laboratory abnormalities should be evaluated by the investigator to determine if 
indicative of an adverse event. 
10.2 Assessment 
10.2.1 Criteria for Assessing Severity 
The investigator/medically qualified designee will evaluate the comments of the subject and the 
response to treatment in order that he/she may judge the true nature and severity of the AE.  
Severity refers to the accumulated intensity of discomfort / impairment of health since the last 
recording of AEs and will be assessed according to the following criteria: 
Mild: Awareness of sign, symptom, or event, but easily tolerated. 
Moderate: Enough discomfort to interfere with usual activity and may warrant intervention. 
Severe: Incapacitating with inability to do usual activities or significantly affects clinical status 
and warrants intervention. 
The criteria for assessing severity are different from those used for seriousness (see 
section 10.2.3 for the definition of SAE). 
10.2.2 Criteria for Assessing Causality  
The question of the relationship of an AE to study drug should be determined by the 
investigator/medically qualified designee after thorough consideration of all facts that are 
available.   
Assessment of causality is based on considering associative connections (time or place), 
pharmacological explanations, previous knowledge of the drug, presence of characteristic 
clinical or pathological phenomena, exclusion of other causes, and/or absence of alternative 
explanations.  The causal relationship of an AE to study drug will be assessed according to the 
following criteria: 


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Reasonable possibility: There is evidence to suggest a causal relationship between 
the drug and the adverse event [21CFR312.32]. 
No reasonable possibility: The evidence does not suggest a causal relationship 
between the drug and the adverse event.   
10.2.3 Criteria for Assessing Seriousness 
All AEs must be evaluated as potential SAEs.  An SAE is any untoward medical occurrence that 
at any dose: 
x 
Results in a fatality 
x 
Is life-threatening, ie, the subject was at immediate risk of fatality from the AE as it 
occurred.  (This does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have been fatal.) 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization 
o The following types of hospitalizations are not considered SAEs for regulatory 
reporting purposes:   
 
Hospitalization(s) for planned (pre-scheduled) medical procedures 
known at the time of screening  
 
Protocol-specific hospital admission  
 
Respite care  
 
Admission for the treatment of pre-existing condition (known at the 
time of screening) not associated with the development of a new 
adverse event or with the worsening of the pre-existing condition 
 
Observation/same day/ambulatory procedures. 
x 
Results in persistent or significant disability/incapacity 
x 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)  
x 
Is a medically important event or reaction.  
o Other important medical events that may not be immediately life-threatening or 
result in fatality or hospitalization but may, based on appropriate medical 
judgment, jeopardize the subject or require intervention to prevent one of the 
outcomes in the definition of SAE listed above, should also be considered SAEs.  
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.   
Cases of abuse, addiction, or substance dependence involving study drug(s) or 
protocol-specified drug(s) AND cases of abuse, addiction, or substance dependence involving 
alcohol or other drug(s) occurring after the initiation of protocol-specified drug(s) or study 
drug(s) for which there is no relevant history must be reported as SAEs (see section 10.3.3).  
Subjects involved in suspected or known abuse must be discontinued from the study. 


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10.3 Adverse Events – Reporting 
All AEs will be reported starting from the time informed consent for study participation is 
provided.  
A cluster of signs and symptoms that results from a single cause should be reported as a single 
AE (eg, fever, elevated white blood cell count, cough, abnormal chest X-ray, etc. can all be 
reported as “pneumonia”). 
AEs assessed as non-serious will be reported through the 7 days following the subject’s last 
study drug dose or until the last study visit, whichever is later.  Nonserious AEs that are ongoing 
at the subject’s last study visit must be followed until resolution or for 30 days after the subject’s 
last study drug dose, whichever comes first. 
AEs assessed as SAEs will be reported as per section 10.3.3.  
10.3.1 Additional Reporting Requirements for Pregnancies 
A pregnancy is not by definition an AE, but it is handled as an AE because it is not a condition 
that should occur during the clinical trial, requires the subject to be discontinued from the study, 
and requires ongoing monitoring of the pregnancy by the investigator.  A pregnancy that occurs 
or becomes confirmed during a clinical study must be recorded as an AE on the AE CRF and 
submitted electronically to the sponsor.  The pregnancy must also be reported to the sponsor 
(or designee) using the Notification of Pregnancy Form within 24 hours of first knowledge of the 
pregnancy to Sponsor. 
x 
The investigator/medically qualified designee should discuss every pregnancy (either 
subject or subject’s partner) with the Medical Monitor. 
x 
The investigator/medically qualified designee will follow up with the subject or subject’s 
partner every 3 months throughout the pregnancy and report to the sponsor (or 
designee) using the Notification of Pregnancy Form. 
x 
Following the estimated date of delivery, the investigator/medically qualified designee 
will follow up with the subject or subject’s partner and report to the sponsor (or designee) 
using the Pregnancy Outcome Questionnaire. 
While pregnancy itself is not considered an SAE, any SAEs related to the pregnancy of the 
subject (see below) or occurring in a subject during the subject’s pregnancy or after delivery, 
must be documented using the SAE CRF.  SAEs occurring in the child (ie, congenital anomalies 
or other conditions present at birth, whether genetically inherited or occurring in utero) must be 
documented and reported to the sponsor (or designee) on a separate SAE CRF (see 
section 10.3.3 for SAE reporting procedures). 
Reportable SAEs associated with pregnancy include, but are not limited to: 
x 
Pregnancy losses (eg, spontaneous abortion, late fetal fatality, elective termination) 
x 
Life-threatening developments (eg, placental abruption, fetal distress) 
x 
Congenital anomalies 
x 
Neonatal fatality, or 
x 
Any event resulting in maternal hospitalization/prolonged hospitalization or maternal 
fatality. 


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10.3.2 Additional Reporting Requirements for Adverse Events of Special Interest   
The following AESIs will be recorded and reported via the AE of Special Interest Notification 
Form: 
x 
Disturbances in thermal sensation, which may include: 
o inhibition of thermal sensation and associated AEs such as thermal burns  
o heat sensitivity 
x 
Taste disturbance 
AESIs must be reported to the sponsor (or designee) as soon as possible of first knowledge.  
AESIs that also meet criteria of SAEs (see section 10.2.3) must additionally be reported via the 
SAE CRF Data Form (see section 10.3.3). 
Criteria for placing the study on clinical hold and temporarily halting dosing is outlined in section 
7.1 Potential Risks and Benefits. 
10.3.3 Additional Reporting Requirements for Serious Adverse Events  
Additional Reporting Requirements for Serious Adverse Events  
All SAEs must be reported starting from the time informed consent for study participation is 
provided.  If the investigator becomes aware of an SAE within 30 days after the subject’s last 
dose of study drug, or protocol-specified drug, or standard treatment, or within 30 days after the 
last study visit or follow-up phone call, the SAE must be reported.  SAEs must be followed until 
the event resolves, the event or sequelae stabilize, or it is unlikely that additional information 
can be obtained after demonstration of due diligence with follow-up efforts (ie, the subject or 
health care practitioner is unable to provide additional information, or the subject is lost to 
follow-up).    
All SAEs must be reported to the sponsor (or designee) within 24 hours of first knowledge of the 
SAE following the SAE CRF Completion Instructions.  In the initial report, all available 
information should be provided.  The SAE CRF must be signed by the investigator/medically 
qualified designee (must be MD or DO).  The investigator or sponsor (or designee), depending 
on local regulations, must inform the IRB about such AEs in accordance with ICH guidelines 
and the practices of the governing IRBs.  Follow-up information, or new information available 
after the initial report, should be actively sought and reported to the sponsor (or designee) as it 
becomes available following the SAE CRF Completion Instructions    
SAE CRFs should contain the following information, at a minimum:   
x 
The reportable event 
x 
Study drug (if known) 
x 
Protocol number 
x 
Subject number 
x 
Investigator name 


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x 
Investigator/medically qualified designee (must be MD or DO) causality assessment for 
each SAE. 
All documents that will be submitted to the sponsor (or designee) that contain information 
regarding the SAE (including but not limited to, ancillary source document(s), medical or 
hospital charts, notes) must be redacted (blacked out) for protected health information, including 
subject initials.  The assigned subject number should be recorded on each of the documents 
submitted to the sponsor.  These documents should be faxed to 
. 
The investigator/medically qualified designee (must be MD or DO) must notify the sponsor’s (or 
designee’s) medical monitor by telephone immediately if: 
x 
The SAE CRFs cannot be completed to meet the 24-hour reporting requirement due to 
business hours (or other plausible reason) or,  
x 
An SAE is being reported during weekend hours (beginning at 5 PM Eastern Time Friday 
through 12 AM Eastern Time Monday) or, 
x 
An SAE is reported on a holiday (beginning at 5 PM Eastern Time of the business day 
before the holiday through 12 AM Eastern Time of the next business day). 
All available information should be provided in the phone contact including: 
x 
Protocol number. 
x 
Investigator name.  
x 
Subject number. 
x 
AE with serious criterion. 
x 
Investigator/medically qualified designee (must be MD or DO) causality assessment(s) 
for each SAE. 
The SAE must be reported to the sponsor (or designee) as soon as possible upon reopening for 
business following the SAE Case Report Form Completion Instructions. 
See section 9.4.7 for description of the emergency unblinding procedure. 
11 ADMINISTRATIVE ASPECTS 
11.1 Changes to Protocol 
Any change to the protocol will be in the form of a written protocol amendment or administrative 
change document that will be issued by the sponsor or designee.   
Amendments specifically affecting the safety of subjects, the scope of the investigation, or the 
scientific quality of the study require additional approval by the applicable IRB(s)/IEC(s) of all 
clinical sites. 
The protocol requirements should in no way prevent any immediate action from being taken by 
the investigator/medically qualified designee, or by the sponsor (or designee), in the interest of 
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is deemed by the investigator /medically qualified designee to be necessary for safety reasons, 
the sponsor’s Medical Monitor (or designee) must be notified promptly and the IRB/IEC for the 
site must be informed according to the IRBs/IECs documented process. 
Changes affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC approval, but the IRB/IEC must be kept informed of such changes.  
Therefore the clinical site will send the administrative change document to the IRB/IEC 
according to the IRBs/IECs documented process. 
11.2 Discontinuation of Study 
The sponsor reserves the right to discontinue the study for safety or administrative reasons at 
any time.  A written statement fully documenting the reasons for discontinuing the study will be 
provided to the clinical site(s) and IRB/IEC.   
Criteria for placing the study on clinical hold and temporarily halting dosing is outlined in section 
7.1 Potential Risks and Benefits. If, in the opinion of the investigator, the clinical observations in 
the study suggest that it may be unwise to continue, the investigator may discontinue their 
participation in the study or part of the study.  A written statement fully documenting the reasons 
for discontinuation will be provided to the sponsor (or designee) and IRB.   
11.3 Disclosure and Confidentiality 
This protocol will be registered and maintained on ClinicalTrials.gov in accordance with federal 
and local regulations. 
The contents of this protocol and any amendments and results obtained during the course of 
this study will be kept confidential by the investigator, the investigator’s staff, and IRB/IEC and 
will not be disclosed in whole or in part to others or used for any purpose other than reviewing or 
performing the study without the written consent of the sponsor.  Accordingly, the investigator is 
prohibited from publishing any data collected or results obtained during the course of this study 
without the prior written approval of the sponsor.  These obligations of confidentiality and 
nonuse shall in no way diminish such obligations as set forth in the Confidentiality Agreement 
between the sponsor and the investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in the Confidentiality Agreement between the investigator 
and sponsor or designee. 
11.4 Monitoring Procedures 
The CRA will visit the study clinic at suitable intervals and be in frequent contact with the site 
through verbal and written communication.  The investigator will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP.  The investigator 
and staff are expected to cooperate with the CRA, to be available during a portion of the 
monitoring visit to answer questions, and to provide any missing information.   
It is essential that the CRA have access to all study and subject related documents at any time 
these are requested.  The CRFs and corresponding original subject source documents are to be 
fully available for review by the CRA to verify data accuracy and adherence to study protocol.  
The CRA will adhere to all requirements for subject confidentiality.   


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11.5 Records Retention 
The investigator has the responsibility to retain all study documents, including but not limited to 
the protocol, site source documents, copies of CRFs, Investigator's Brochure, regulatory 
documents (eg, FDA 1572 form, ICFs, and IRB/IEC correspondence)  in accordance with 
ICH E6 (4.9.5) and 21 CFR 312.62(c). 
In addition, if applicable the sponsor (or designee) will send a list of treatment codes by study 
subject to the investigator after the clinical database for this study has been unblinded.  The 
clinical site should plan on retaining study documents per the site contract. 
11.6 Inspection Procedures 
A government regulatory authority may conduct an inspection during the study or after its 
completion.  If an inspection is requested by a regulatory authority the investigator or designee 
must immediately inform the sponsor that a request has been made. 
11.7 Publication of Results 
Any formal presentation or publication of data collected as a direct or indirect result of this trial 
will be considered as a joint publication by the investigator(s) and the appropriate personnel at 
the sponsor’s site.  Authorship will be determined by mutual agreement.  For multicenter 
studies, it is mandatory that the first publication is based on data obtained from all analyzed 
subjects as stipulated in the protocol by the sponsor’s statisticians, and not by the investigators 
themselves.  Investigators participating in multicenter studies must agree not to present data 
gathered individually or by a subgroup of centers prior to the full, initial publication, unless this 
has been agreed to by all other investigators and the sponsor. 
The sponsor must receive copies of any intended communication at least 30 working days in 
advance for an abstract or oral presentation and 60 days in advance for a manuscript.  This is to 
allow the sponsor to review the communication for accuracy (thus avoiding potential 
discrepancies with submissions to regulatory authorities), to verify that confidential information 
is not being inadvertently divulged, to allow for the filing of additional patent protection, to 
provide any relevant supplementary information, and to allow establishment of co-authorship.  
The authorship of communications arising from pooled data will include selected members from 
clinical sites as well as sponsor personnel. 
 


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12 SIGNATURE PAGE FOR INVESTIGATORS 
 
Protocol Number: 
VAN2001 
 
 
Version: 
Version 2, 17-Feb-2017 
 
 
Title: 
A Phase 2a, Multicenter, Randomized, Double-blind, Placebo-
controlled and Active-controlled, Parallel-group Study Evaluating the 
Analgesic Efficacy and Safety of V120083 in Subjects with Moderate 
to Severe Chronic Pain Due to Osteoarthritis of the Knee 
 
 
Test Drug: 
V120083  
 
 
I have read this protocol and agree to conduct this trial in accordance with the protocol and in 
accordance with ICH and Good Clinical Practices and local and federal regulations.  It will be 
conducted in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki and relevant amendments to date. 
 
 
 
 
 
 
Investigator 
 
Signature 
 
Date 





 
 


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13 REFERENCE LIST 
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2015;16(8):769-80. 
2. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the 
prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis 
Rheum. 2008;58(1):26-35. 
3. Patapoutian A, Tate S, Woolf CJ. Transient receptor potential channels: targeting pain at the 
source. Nat Rev Drug Discov 2009; 8(1): 55–68. 
4. Moran MM, McAlexander MA, Biro T, Szallasi A. Transient receptor potential channels as 
therapeutic targets. Nat Rev Drug Discov 2011; 10(8): 601–20. 
5. V120083 Investigators Brochure. Purdue Pharma L.P. Stamford, CT. 
6. Rowbotham MC, Nothaft W, Duan WR, Wang Y, Faltynek C, McGaraughty S, Chu KL, 
Svensson P. Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by 
ABT-102 in a randomized healthy volunteer trial. Pain. 2011; 152(5):1192-200. 
7. Arden N, Nevitt MC. Osteoarthritis: epidemiology. Best Pract Res Clin Rheumatol. 2006: 
20(1):3-25. 
8. Hungin AP, Kean WF. Nonsteroidal anti-inflammatory drugs: overused or underused in 
osteoarthritis? Am J Med. 2001; 110(1A): 8S-11S. 
9. Fernihough J, Gentry C, Bevan S, Winter J. Regulation of calcitonin gene-related peptide 
and TRPV1 in a rat model of osteoarthritis. Neurosci Lett. 2005; 388(2): 75-80. 
10. Remadevi R, Szallisi AA. ALGRX-4975, an injectable capsaicin (TRPV1 receptor agonist) 
formulation for longlasting pain relief. IDrugs. 2008; 11(2):120-32. 
11. U.S. Department of Health and Human Services Food and Drug Administration. FDA’s 
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http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126958.pdf. 
Accessed Nov 13, 2015. 
12. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 
1957 Dec;16(4):494-502. 
13. Schiphof D, de Klerk BM, Kerkhof HJ, Hofman A, Koes BW, Boers M, Bierma-Zeinstra SM. 
Impact of different descriptions of the Kellgren and Lawrence classification criteria on the 
diagnosis of knee osteoarthritis. Ann Rheum Dis. 2011;70(8):1422-7. 
14. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 
1983;67(6):361-70. 
15. Dagnan D, Chadwick P, Trower P. Psychometric properties of the Hospital Anxiety and 
Depression Scale with a population of members of a depression self-help group. Br J Med 
Psychol. 2000;73 ( Pt 1):129-37. 
16. Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and 
Depression Scale. An updated literature review. J Psychosom Res. 2002 Feb;52(2):69-77. 
17. Mendoza T, Mayne T, Rublee D, Cleeland C. Reliability and validity of a modified Brief Pain 
Inventory short form in patients with osteoarthritis. Eur J Pain. 2006 May;10(4):353-61. 
18. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of 
WOMAC: a health status instrument for measuring clinically important patient relevant 


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outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. 
J Rheumatol. 1988;15(12):1833-40. 
19. Bellamy N. Pain assessment in osteoarthritis. Experience with the WOMAC osteoarthritis 
index. Semin Arthritis Rheum. 1989;18(4 suppl 2):14-17. 
20. Bellamy N, Kean WF, Buchanan WW, Gerecz-Simon E, Campbell J. Double-blind 
randomized controlled trial of sodium meclofenamate (Meclomen) and diclofenac sodium 
(Voltaren): Post validation reapplication of the WOMAC osteoarthritis index. J Rheumatol. 
1992;19(1):153-9. 
21. Hawker G, Melfi C, et al. Comparison of a generic (SF-36) and a disease specific (WOMAC) 
(Western Ontario and McMaster Universities Osteoarthritis Index) instrument in the 
measurement of outcomes after knee replacement surgery. J Rheumatol. 1995;22:1193-96. 
22. Lequesne M. Indices of severity and disease activity for osteoarthritis. Semin Arthritis 
Rheum. 1991;20(6 suppl 2):48-54. 
23. Stucki G, Sangha O, Stucki S, Michel BA, Tyndall A, Dick W, Theiler R. Comparison of the 
WOMAC (Western Ontario and McMaster Universities) osteoarthritis index and a self-report 
format of the self-administered Lequesne-Algofunctional index in patients with knee and hip 
osteoarthritis. Osteoarthritis Cartilage. 1998:6(2):79-86. 
24. The EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16(3):199-208. 
25. Brooks R. EuroQol: the current state of play. Health Policy. 1996;37(1):53-72. 
26. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X.  
Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). 
Qual Life Res. 2011 Dec;20(10):1727-36. 
27. Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, Swinburn P, 
Busschbach J. Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across 
eight patient groups: a multi-country study. Qual Life Res. 2013;22(7):1717-27. 
28. van Hout B, Janssen MF, et al. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to 
EQ-5D-3L value sets. Value in Health  2012;15(5):708-15 
29. Mandy van R., Bas J. EQ-5D-5L User Guide: Basic information on how to use the EQ-5D-5L 
instrument, V2.1. Retrieved from http://www.euroqol.org/about-eq-5d/publications/user-
guide.html 
30. Ware JE.  SF-36 health survey update. Spine. 2000;25(24):3130–39. 
31. Kano T, Kanda K. Development and validation of a chemotherapy induced taste alteration 
scale. Oncol Nurs Forum 2013; 40(2):E79-85.
32. Lan KKG, Simon R, and Halperin M. Stochastically curtailed tests in long-term clinical trials. 
Communications in Statistics 1982;C1, 207-19.  
33. Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999;55(3):853-7.  
34. Emerson SS, Kittelson JM, Gillen DL. On the Use of Stochastic Curtailment in Group 
Sequential Clinical Trials. UW Biostatistics Working Paper Series. 2005. University of 
Washington,13. 


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35. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM.  Clinical importance of changes 
in chronic pain intensity measured on an 11-point numerical pain rating scale.  Pain. 2001; 
94(2):149-158. 
 
 


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14 APPENDICES 
 
Appendix A: Clinical Laboratory Evaluations 
Category 
Parameters 
Hematology 
RBC counts, Hemoglobin, Hematocrit, Platelets, and WBC count with 
differential (Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils) in 
percentages (%) and absolute counts 
Clinical Chemistry 
 
Electrolytes 
Sodium, Potassium, Chloride, Calcium Corrected, Magnesium, Bicarbonate 
Liver function tests 
Alkaline Phosphatase, Aspartate Aminotransferase (AST/SGOT), Alanine 
Aminotransferase (ALT/SGPT), Total Bilirubin, Direct Bilirubin, gamma-
glutamyl transferase (GGT) 
Renal function 
parameters 
Blood Urea/Blood Urea Nitrogen, Creatinine, eGFR 
Other 
Glucose, Albumin, Cholesterol, Triglycerides, Phosphorus, Lactate 
Dehydrogenase (LDH), Total Protein, Globulin, Uric Acid 
Urinalysis 
pH, Protein, Glucose, Ketone, Occult Blood, RBC, WBC, Epithelial Cells, 
Bacteria, Casts, Crystals, Specific Gravity  
Urine drug test 
Urine screen includes: Amphetamines, Cannabinoids, Opiates, Cocaine 
Metabolites, Benzodiazepines, Barbiturates; Phencyclidine, Methadone, 
Propoxphene 
Serum pregnancy test 
Human Chorionic Gonadotropin (Choriogonadotropin Beta) 
Urine pregnancy test 
Human Chorionic Gonadotropin (Choriogonadotropin Beta) 
Virus screen  Hepatitis B, Hepatitis C, Human Immunodeficiency Virus 
RBC = red blood cells, WBC = white blood cells 


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Appendix B: Critical Alert Laboratory Values 
Critical Laboratory Ranges Used to Identify Alert Range Values 
 
 
Alert Laboratory Rangea 
Laboratory Parameter 
Low 
High 
Hematology 
 
 
 
 
Hemoglobin 
< 8.0 g/dL or < 80 g/L  
—–– 
 
Platelets 
< 50,000mm3 or < 50 × 109/L 
—–– 
 
Leukocytes (total WBC) 
< 2,000/mm3 or < 2.0 × 109/L 
—–– 
 
Absolute Neutrophil Count 
< 1,000/mm3 or < 1.0 × 109/L 
—–– 
Chemistry 
 
 
 
Electrolytes 
 
 
 
Sodium 
< 130 mmol/L 
> 155 mmol/L 
 
Potassium 
< 3.0 mmol/L 
> 6.0 mmol/L 
 
Magnesium 
< 0.9 mg/dL or < 0.4 mmol/L 
> 3.0 mg/dL or > 1.23 mmol/L
 
Bicarbonate (HCO3) 
<11 mEq/dL or < 11 mmol/Lb 
—–– 
Liver Function 
 
 
 
Alkaline phosphatase 
—–– 
> 5 × ULN 
 
Aspartate aminotransferase (AST)
—–– 
> 5 × ULN 
 
Alanine aminotransferase (ALT) 
—–– 
>5 × ULN 
 
Total Bilirubin 
—–– 
>3 × ULN 
 
Total Bilirubin (Screening only) 
—–– 
>ULN c 
Renal Function 
 
 
 
Creatinine 
—–– 
> 3 × baseline or > 3 × ULN 
 
eGFR 
<29 ml/min/1.73m2 
 
Other Chemistry 
 
 
 
Calcium Corrected 
< 7.0 mg/dL or < 1.75 mmol/L 
> 12.5 mg/dL or > 3.1 mmol/L
 
Glucose 
< 40 mg/dL or < 2.2 mmol/L 
> 250 mg/dL or> 13.9 mmol/L
 
Albumin 
< 2 g/dL or < 20 g/L 
—–– 
 
Bilirubin and Liver Function Test  
—–– 
Bilirubin > 34 μmol/L and 
any LFT > 3.0 × ULNd 
ULN = upper limit of the laboratory reference (normal) range; WBC = white blood cells (count). 
a Common Terminology Criteria for Adverse Events version 4.03 June 2010, Grade 3 limits, unless otherwise specified.
b Common Terminology Criteria for Adverse Events version 3.0 Aug 2006, Grade 3 limit. 
c Common Terminology Criteria for Adverse Events version 4.03 June 2010, Grade 1 limit. 
d Sponsor defined alert value, based on Hy’s Law. 


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Appendix C: Pharmacokinetic Sample Collection, Processing, Storage, and 
Shipment 
Detailed instructions are provided in the study-specific Pharmacokinetic Sample Collection 
Manual (PK Manual) which will be provided separately to the clinical site. 
Collect PK blood samples to analyze V120083 concentrations in plasma using labeled 
4 mL-draw K2EDTA Vacutainer® evacuated collection tubes. 
After obtaining the PK blood sample, mix collection tube thoroughly by slowly inverting the 
collection tube several times. 
Place the collection tube in an ice/water bath immediately after collection and inversion. 
Within 30 minutes of blood sample collection, centrifuge the blood samples in a refrigerated 
centrifuge set at approximately 3000 rpm for 15 minutes at approximately 4°C. 
Transfer clear supernatant (plasma), using clean disposable pipettes, split equally into 
appropriately prelabeled cryotubes (primary and back-up). 
Within 60 minutes of blood sample collection, store plasma samples in a freezer set to maintain 
a temperature of -20°C. 
At times agreed upon by the sponsor and the clinical site, one set of samples (primary) will be 
packed in sufficient dry ice and shipped to the sponsor designated bioanalytical laboratory as 
per the Sample Shipment schedule.  The second set (back-up samples) will be shipped 
separately to the sponsor designated bioanalytical laboratory as per the Sample Shipment 
schedule. 
On the day of shipment, clinical site staff will notify (via telephone or email) the contact person 
at the bioanalytical laboratory about the shipment and provide the tracking number of the 
pending shipment. 


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Appendix D: Naproxen Capsules 500 mg Comparator Product Formulations 
 
Description:  
Commercially available naproxen 500 mg tablets will be over-encapsulated with Swedish 
Orange opaque gelatin capsules (Double-blind Size 00) so they cannot be identified.  
Route of Administration: 
The intended route of administration is oral. 


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Appendix E: Naproxen Product Information 
 
Full product prescribing information available at 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017581s112,018164s062,020067s0
19lbl.pdf 


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Appendix F: Average Pain Intensity over the Last 7 Days 
Please describe your average pain intensity over the last 7 days: 
o 0=None 
o 1=Mild 
o 2=Moderate 
o 3=Severe 


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Appendix G: Kellgren - Lawrence Classification 
 
Grade 
Description 
0: No osteoarthritis  
No osteroarthritis 
1: Doubtful 
Doubtful narrowing of the joint space and 
possible osteophytic tipping 
2: Mild 
Definite osteophytes, possible narrowing of 
the joint space  
3: Moderate 
Multiple osteophytes, definite narrowing of 
the joint space, and some sclerosis and 
possible deformity of bone ends 
4: Severe 
Large osteophytes, marked narrowing of the 
joint space, severe sclerosis, and definite 
deformity of the bone ends 
 
 


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Appendix H: Hospital Anxiety and Depression Scale (HADS) 
Hospital Anxiety and Depression Scale (HADS)  
This questionnaire is designed to help your doctor to know how you feel. Read each item and 
check off the box opposite the reply that comes closest to how you have been feeling in the past 
week. 
Don’t take too long on your replies; your immediate reaction to each item will probably be more 
accurate than a long-thought-out response. 
 
 
Patient 
Response 
Anxiety 
Score 
Depression 
Score 
1. 
I feel tense or “wound-up” 
 
 
Most of the time 
A lot of the time 
From time to time, occasionally 
Never 
 
 
 
 
(3) 
(2) 
(1) 
(0) 
 
2. 
I enjoy the things I used to enjoy 
 
 
Definitely as much 
Not quite so much 
Only a little 
Hardly at all 
 
 
 
 
 
(0) 
(1) 
(2) 
(3) 
3. 
I get a sort of frightened feeling as if something 
awful is about to happen 
 
 
Very definitely and fairly badly 
Yes, but not too badly 
 
Sometimes, but it doesn’t worry me 
Never 
 
 
 
 
(3) 
(2) 
(1) 
(0) 
 
4. 
I can laugh and see the funny side of things 
 
 
 
 
As much as I always could 
Not quite so much now 
Definitely not so much now 
Never 
 
 
 
 
 
(0) 
(1) 
(2) 
(3) 


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5. 
Worrying thoughts go through my mind 
 
 
 
 
A great deal of the time 
A lot of the time 
Not too often 
Almost never 
 
 
 
 
(3) 
(2) 
(1) 
(0) 
 
 
 
6. 
I feel cheerful 
 
 
 
 
Never  
Not often 
Sometimes 
Most of the time 
 
 
 
 
 
(3) 
(2) 
(1) 
(0) 
7. 
I can sit at ease and feel relaxed 
 
 
 
 
Always 
Usually 
Not often 
Never 
 
 
 
 
(0) 
(1) 
(2) 
(3) 
 
8. 
I feel as if I am slowed down 
 
 
 
Nearly all the time 
Very often 
Sometimes 
Never 
 
 
 
 
 
(3) 
(2) 
(1) 
(0) 
9. 
I get a sort of anxious feeling like “butterflies” in 
the stomach 
 
 
Never 
Occasionally 
Often 
Very often 
 
 
 
 
(0) 
(1) 
(2) 
(3) 
 
10. I have lost interest in my appearance 
 
 
 
 
Definitely 
Often I don’t take as much care as I should 
Sometimes I don’t take as much care as I should 
I take just as much care as ever 
 
 
 
 
 
(3) 
(2) 
(1) 
(0) 
 
 


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11. I feel restless as if I have to be on the move 
 
 
 
 
Definitely 
Quite a lot 
Not very much 
Never 
 
 
 
 
(3) 
(2) 
(1) 
(0) 
 
12. I look forward with enjoyment to things 
 
 
 
 
As much as I ever have  
Somewhat less than I used to 
Much less than I used to 
Rarely 
 
 
 
 
 
(0) 
(1) 
(2) 
(3) 
13. I get sudden feelings of panic 
 
 
 
 
Very often  
Often 
Not very often 
Never 
 
 
 
 
(3) 
(2) 
(1) 
(0) 
 
14. I can enjoy a good book, radio or television 
program 
 
 
Often 
Sometimes 
Not often 
Very seldom 
 
 
 
 
 
(0) 
(1) 
(2) 
(3) 
Now check that you have answered all questions:   
 
 
 
(Note: Subjects do not see scoring.)  
 
HADS Scoring 
 
1. Add up all the odd-numbered questions for the total anxiety score.  
2. Add up all the even-numbered questions, for the total depression score. 
 


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Appendix I: Modified Brief Pain Inventory-Short Form (mBPI-SF) 
1. Please rate your pain by circling the one number that best describes your pain at its WORST in 
the last 24 hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Pain 
 
 
 
 
 
 
 
 
 
As bad as 
you can 
imagine 
2. Please rate your pain by circling the one number that best describes your pain at its LEAST in 
the last 24 hours 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
pain 
 
 
 
 
 
 
 
 
 
As bad as 
you can 
imagine 
3. Please rate your pain by circling the one number that best describes your pain on the 
AVERAGE in the last 24 hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
pain 
 
 
 
 
 
 
 
 
 
As bad as 
you can 
imagine 
4. Please rate your pain by circling the one number that tells how much pain you have right now. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
pain 
 
 
 
 
 
 
 
 
 
As bad as 
you can 
imagine 
5. In the last 24 hours, how much relief have pain treatments or medications provided? Please 
circle the one percentage that most shows how much relief you have received. 
0% 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
100% 
No 
relief 
 
 
 
 
 
 
 
 
 
Complete 
relief 
6. Circle the one number that describes how, during the past 24 hours, pain has interfered with 
your: 


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A. General activity 
    0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does 
not 
interfere 
 
 
 
 
 
 
 
 
 
Completely 
interferes 
B. Mood 
    0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does 
not 
interfere 
 
 
 
 
 
 
 
 
 
Completely 
interferes 
C. Walking ability 
    0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does 
not 
interfere 
 
 
 
 
 
 
 
 
 
Completely 
interferes 
D. Normal work (includes both work outside the home and housework) 
    0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does 
not 
interfere 
 
 
 
 
 
 
 
 
 
Completely 
interferes 
E. Relations with other people  
    0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does 
not 
interfere 
 
 
 
 
 
 
 
 
 
Completely 
interferes 
F. Sleep  
    0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does 
not 
interfere 
 
 
 
 
 
 
 
 
 
Completely 
interferes 


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G. Enjoyment of life 
    0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Does 
not 
interfere 
 
 
 
 
 
 
 
 
 
Completely 
interferes 


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Appendix J: Western Ontario and McMaster OA Index (WOMAC) 


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Appendix K: EQ-5D 


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Appendix L: Medical Outcomes Study 36-item Short-Form (SF-36) 


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Appendix M: Patient Global Impression of Change (PGIC) 
Since the start of the study, my overall status is: (Please check only 1 choice) 
1. Very much improved 
2. Much improved 
3. Minimally improved 
4. No change 
5. Minimally worse 
6. Much worse 
7. Very much worse 


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Appendix N: Pain Numerical Rating Scale 
 
Daily Average Pain Over the Last 24 Hours 
Choose 1 number that best describes your average pain in the last 24 hours. 
0 
1 
2 
3 
4 
5
6
7
8
9
10 
No 
Pain 
 
 
 
 
 
 
 
 
 
Pain as bad as 
you can 
imagine 
 
Pain Right Now (assessments taken before taking supplemental pain medications) 
Choose 1 number that best describes the pain you have right now. 
0 
1 
2 
3 
4 
5
6
7
8
9
10 
No 
Pain 
 
 
 
 
 
 
 
 
 
Pain as bad as 
you can 
imagine 
 


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Appendix O: Columbia Suicide Severity Rating Scale (C-SSRS)    
Sample  “Baseline/Screening” below: 
 


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 Version 1/14/09  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; Burke, A.; 
Oquendo, M.; Mann, J. 
 


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Sample “Since Last Visit” Questionnaire: 
 
Version 1/14/09  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; Burke, A.; 
Oquendo, M.; Mann, J. 
 
 


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Appendix P: Chemotherapy-induced Taste Alteration Scale (CiTAS) 
The following scale will be administered for each subject.31 
 
 
 
 


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Appendix Q: List of Prohibited Medications and Classification 
Source:  FDA Guidance: Drug Interaction Studies-Study Design, Data Analysis, and Implications for 
Dosing and Labeling 
If it's unknown whether the medication the patient is taking a moderate to strong CYP3A inhibitor, please 
contact the medical monitor. 
This is a representative list.  Please contact the medical monitor if there are any questions. 
Medication 
Category 
Protocol guidance 
alfentanil 
CYP3A - narrow range
Excluded
aliskiren 
P-gp substrate
Excluded
ambrisentan 
P-gp substrate
Excluded
amprenavir 
CYP3A Moderate inhibitor
Allowed if on stable dose for 
1 month prior to start of study drug 
dosing
aprepitant 
CYP3A Sensitive substrate
Excluded
atazanavir 
CYP3A Moderate inhibitor
Allowed if on stable dose for 
1 month prior to start of study drug 
dosing
atorvastatin 
P-gp substrate
Excluded
avanafil 
CYP3A Sensitive substrate
Excluded
azithromycin 
P-gp substrate
Excluded
boceprevir 
CYP3A Strong inhibitor
Excluded
Bosentan 
CYP3A Sensitive substrate
Excluded
budesonide 
CYP3A Sensitive substrate
Excluded
Buspirone 
CYP3A Sensitive substrate
Excluded
carbamazepine 
Strong CYP3A inducer
Excluded
cerivastatin 
P-gp substrate
Excluded
chloramphenicol 
CYP3A Strong inhibitor
Excluded
ciprofloxacin 
CYP3A Moderate inhibitor
Allowed if on stable dose for 
1 month prior to start of study drug 
dosing
clarithromycin 
CYP3A Strong inhibitor
Excluded
colchicine 
P-gp substrate
Excluded
conivaptan 
CYP3A Sensitive substrate & Strong 
inhibitor 
Excluded
cyclosporine 
CYP3A - narrow range & P-gp 
substrate 
Excluded
dabigatran 
P-gp substrate
Excluded
darifenacin 
CYP3A Sensitive substrates
Excluded
darunavir 
CYP3A Sensitive substrates
Excluded
darunavir/ritonavir 
CYP3A Moderate inhibitor
Allowed if on stable dose for 
1 month prior to start of study drug 
dosing
digoxin 
P-gp substrate
Excluded


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dihydroergotamine 
CYP3A - narrow range
Excluded
diltiazem 
CYP3A Moderate inhibitor
Allowed if on stable dose for 
1 month prior to start of study drug 
dosing
domperidone 
P-gp substrate
Excluded
dronedarone 
CYP3A Sensitive substrates
Excluded
eletriptan 
CYP3A Sensitive substrates
Excluded
eplerenone 
CYP3A Sensitive substrates
Excluded
ergotamine 
CYP3A - narrow range
Excluded
erythromycin 
CYP3A Moderate inhibitor
Allowed if on stable dose for 
1 month prior to start of study drug 
dosing
everolimus 
CYP3A Sensitive  & P-gp substrate
Excluded
felodipine 
CYP3A Sensitive substrates
Excluded
fentanyl 
CYP3A - narrow range & P-gp 
substrate 
Excluded
fexofenadine 
P-gp substrate
Excluded
fluconazole 
CYP3A Moderate inhibitor
Allowed if on stable dose for 
1 month prior to start of study drug 
dosing
fluticasone 
CYP3A Sensitive substrates
Excluded
grapefruit juice 
CYP3A Strong inhibitor
Excluded
indinavir 
CYP3A Sensitive substrate & Strong 
inhibitor 
Excluded
itraconazole 
CYP3A Strong inhibitor
Excluded
ketoconazole 
CYP3A Strong inhibitor
Excluded
linezolid 
P-gp substrate
Excluded
lomitapide 
CYP3A Sensitive substrates
Excluded
loperamide 
P-gp substrate
Excluded
lopinavir 
CYP3A Sensitive substrates
Excluded
lopinavir/ritonavir 
CYP3A Strong inhibitor
Excluded
lovastatin 
CYP3A Sensitive substrates
Excluded
lurasidone 
CYP3A Sensitive substrates
Excluded
midazolam 
CYP3A Sensitive substrates
Excluded
nefazodone 
CYP3A Strong inhibitor
Excluded
nelfinavir 
CYP3A Strong inhibitor
Excluded
nisoldipine 
CYP3A Sensitive substrates
Excluded
phenytoin 
Strong CYP3A inducer
Excluded
pimozide 
CYP3A - narrow range
Excluded
posaconazole 
CYP3A Strong inhibitor & P-gp 
subsrate 
Excluded
quetiapine 
CYP3A Sensitive substrates
Excluded


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quinidine 
CYP3A - narrow range & P-gp 
substrate 
Excluded
ranolazine 
P-gp substrate
Excluded
rifampin 
Strong CYP3A inducer
Excluded
riociguat 
P-gp substrate
Excluded
ritonavir 
CYP3A Strong inhibitor & P-gp 
subsrate 
Excluded
rivaroxaban 
P-gp substrate
Excluded
saquinavir 
CYP3A Sensitive substrates, strong 
inhibitor, p-gp substrate
Excluded
saxagliptin 
P-gp substrate
Excluded
sildenafil 
CYP3A Sensitive substrates
Excluded
simvastatin 
CYP3A Sensitive substrates & p-gp 
substrate 
Excluded
sirolimus 
CYP3A - narrow range, sensitive 
substrate, & P-gp substrate
Excluded
sitagliptin 
P-gp substrate
Excluded
sofosbuvir 
P-gp substrate
Excluded
St. John's wort 
Strong CYP3A inducer
Excluded
tacrolimus 
CYP3A - narrow range & P-gp 
substrate 
Excluded
talinolol 
P-gp substrate
Excluded
telaprevir 
CYP3A Strong inhibitor
Excluded
telithromycin 
CYP3A Strong inhibitor
Excluded
ticagrelor 
P-gp substrate
Excluded
tipranavir 
CYP3A Sensitive substrates
Excluded
tolvaptan 
CYP3A Sensitive substrate & P-gp 
substrate 
Excluded 
triazolam 
CYP3A Sensitive substrates
Excluded
vardenafil 
CYP3A Sensitive substrates
Excluded
verapamil 
CYP3A Moderate inhibitor
Allowed if on stable dose for 
1 month prior to start of study drug 
dosing
voriconazole 
CYP3A Strong inhibitor
Excluded
 


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Appendix R: Amendment 1 Summary of Changes 
VAN2001 
Amendment No. 1 
Summary of Changes 
1. Date of Amendment: 17-February-2017 
2. Replaces Protocol VAN2001 Version 1, dated 14-October-2016 
3. The overall rationale for the content changes in Amendment 1 is summarized as follows: 
a. To revise the protocol to align with standard medical practice 
x 
Increased allowed BMI to 38.0 kg/m2 
x 
Excluded monoclonal antibodies for osteoporosis as a concomitant 
medication 
x 
Excluded benzodiazepines as concomitant medications 
b. To further clarify protocol requirements 
x 
Rescreening allowed within certain parameters 
x 
Clarification to indicate if a meal had been eaten within 2 hours of dosing 
x 
Extended pain assessment period 
x 
Clarification of timing of visit 2 related to pain score qualification 
x 
Clarified Kellgren-Lawrence grade scale 
x 
Extended period for central ECG provider to report ECG data rate 
x 
Added predose PK sampling at visit 2 for intensive sampling patients and 
removed requirement for predose sample at visits 4 and 5  
x 
Clarified definition of AESI  
c. To correct lettering of appendices to be in sequence 
d. To correct minor typos, formatting errors and inconsistencies 
 
4. Changes, additions, and deletions are described below, with in-text changes 
represented in red.  Changes that appear in more than 1 section of the protocol are 
presented as a single entry with references to the other sections where the changes 
occur.  When the changed text affects multiple sections, the wording may be slightly 
different depending on the context, eg, the visit.  Those sentences and paragraphs that 
do not have design changes, but rather have only minor stylistic changes, eg, changing 


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“Visit” to “visit” and adding periods, will not be presented in this summary of changes 
document. The list of abbreviations was updated when needed. 
 
5. Summary of changes, additions, and deletions 
 
 
a. Synopsis and Section 9.1, Study Design schematic 
 
i. Footnote b 
Changed from: 
69 subjects/treatment arm 
[…] 
Subjects who do not take any medications for pain will record their “average pain 
over last 24 hours” scores for 3 to 5 days.  Subjects who take medications for 
pain will record their “average pain over last 24 hours” scores for 3 to 7 days after 
all incoming pain medications have been stopped.  All subjects may return to the 
study clinic for visit 2 as soon as they recorded “average pain over last 24 hours” 
scores  4 for 3 consecutive days. 
 
Changed to: 
Approximately 69 subjects/treatment arm 
[…] 
Subjects who do not take any medications for pain will record their “average pain 
over last 24 hours” scores for 3 to 7 days.  Subjects who take medications for 
pain will record their “average pain over last 24 hours” scores for 3 to 9 days after 
all incoming pain medications have been stopped.  All subjects may return to the 
study clinic for visit 2 as soon as they recorded “average pain over last 24 hours” 
scores  4 and  9 for  3 consecutive days.  All subjects must return to the study 
clinic for visit 2 within 96 hours of the latest qualifying pain score entry within the 
pain assessment period.  
 
b. Synopsis and Section 9.3.1, Inclusion criteria 
i. Inclusion criteria #3, revised to increase BMI range 
Changed from:  
Subjects with body mass index ranging from 18 to 34 (kg/m2), inclusive 
 
Changed to: 
Subjects with body mass index ranging from 18.0 to 38.0 (kg/m2) 
 
ii. Inclusion criteria #5, revised to allow patients to come in for 
randomization/visit 2 within 96 hours after qualification met 
Changed from:  
The subjects must have “average pain over the last 24 hours” scores  4 and  9 
on an 11-point NRS for the index knee on  3 consecutive days during the 


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screening period and come in for randomization within 96 hours after qualification 
is met. 
 
Changed to: 
The subjects must have “average pain over the last 24 hours” scores  4 and  9 
on an 11-point NRS for the index knee on  3 consecutive days during the pain 
assessment period and come in for visit 2 within 96 hours after the latest 
qualifying pain score entry. 
 
c. Synopsis and Section 9.3.2, Exclusion criteria  
i. Exclusion criteria #1, clarified Kellgren-Lawrence grade scale 
Changed from: 
Subjects with radiographic evidence of OA with Kellgren-Lawrence (K-L) grade 1 
or 4; 
 
Changed to: 
Subjects with radiographic evidence of OA with Kellgren-Lawrence (K-L) grade 0, 
1 or 4; 
 
ii. Exclusion criteria #22 & 23, added reference to appendix 
Changed from: 
Subjects taking strong CYP3A inhibitors, inducers, sensitive substrates, 
substrates with narrow therapeutic range, or P-gp substrates;  
 
Subjects taking moderate CYP3A inhibitors if the dose has not been stable for at 
least 1 month prior to start of study drug dosing; 
 
Changed to: 
Subjects taking strong CYP3A inhibitors, inducers, sensitive substrates, 
substrates with narrow therapeutic range, or P-gp substrates (see Appendix Q); 
 
Subjects taking moderate CYP3A inhibitors if the dose has not been stable for at 
least 1 month prior to start of study drug dosing (see Appendix Q); 
 
d. Synopsis and Section 9.4.8 Concomitant Medication: 
i. Added restriction of benzodiazepines and monoclonal antibodies for 
osteoporosis 
 
Changed from: 
Other prohibited concomitant treatments include methotrexate, any local OA 
treatments for the knee(s), including topical anesthetics or NSAIDs; topical, 
intra-articular, or systemic corticosteroids; or any OA injection in the knee(s), 
antidepressants (other than SSRIs), warfarin or anticoagulants, and cyclosporine 
(except ophthalmic emulsion). 
 
Changed to: 


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Other prohibited concomitant treatments include benzodiazepines, monoclonal 
antibodies for osteoporosis, methotrexate, any local OA treatments for the 
knee(s), including topical anesthetics or NSAIDs; topical, intra-articular, or 
systemic corticosteroids; or any OA injection in the knee(s), antidepressants 
(other than SSRIs), warfarin or anticoagulants, and cyclosporine (except 
ophthalmic emulsion). 
 
e. Synopsis and Section 9.1, Study Procedures: 
i. Revised washout period 
Changed from: 
Telephone Contact and Washout Period   
As soon as the laboratory results, ECG results, and radiograph results are 
available, the site staff will contact the subjects by telephone to inform them of 
the results and whether they are qualified to continue in the study.  Subjects who 
do not meet the initial entry criteria will be considered screen failures.  For 
subjects who meet the initial entry criteria and: 
 
 
Who do not take any analgesic medications for their pain, the site 
staff will instruct them to record in the diary their “average pain 
over the last 24 hours” scores for their index knee at 
approximately 8 PM every day for 3 to 5 days; these subjects will 
return to the study clinic for visit 2 as soon as they have “average 
pain over the last 24 hours” scores  4 for 3 consecutive days. 
 
Who are on topical and/or oral analgesics (including opioids, 
antidepressants, anticonvulsants, or other medications for OA), 
the site staff will instruct them to discontinue from these 
medications in accordance with accepted medical practice.  Once 
all medications used for pain have been discontinued, the subjects 
will undergo an analgesic washout period of up to 7 days.  During 
this period, the subjects will record in the diary their “average pain 
over the last 24 hours” scores for the index knee at approximately 
8 PM every day.  These subjects will return to the study clinic for 
visit 2 as soon as they reported “average pain over the last 
24 hours” scores of  4 for 3 consecutive days.   
Changed to: 
Telephone Contact and Washout Period   
As soon as the laboratory results, ECG results, and radiograph results are 
available, the site staff will contact the subjects by telephone to inform them of 
the results and whether they are qualified to continue in the study.  Subjects who 
do not meet the initial entry criteria will be considered screen failures.  For 
subjects who meet the initial entry criteria and: 
 
 
Who do not take any analgesic medications for their pain, the site 
staff will instruct them to record in the diary their “average pain 
over the last 24 hours” scores for their index knee at 
approximately 8 PM every evening for 3 to 7 days; these subjects 
may return to the study clinic for visit 2 as soon as they have 


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“average pain over the last 24 hours” scores  4 and  9 for 
 3 consecutive days. All subjects must return to the study clinic 
for visit 2 within 96 hours of the latest qualifying pain score entry 
within the pain assessment period. 
x 
Who are on topical and/or oral analgesics (including opioids, 
antidepressants, anticonvulsants, or other medications for OA), 
the site staff will instruct them to discontinue from these 
medications in accordance with accepted medical practice.  Once 
all medications used for pain have been discontinued, the subjects 
will undergo an analgesic washout period of up to 9 days.  During 
this period, the subjects will record in the diary their “average pain 
over the last 24 hours” scores for the index knee at approximately 
8 PM every evening for 3 to 9 days.  These subjects may return to 
the study clinic for visit 2 as soon as they have “average pain over 
the last 24 hours” scores  4 and  9 for  3 consecutive days. All 
subjects must return to the study clinic for visit 2 within 96 hours of 
the latest qualifying pain score entry within the pain assessment 
period. 
  
f. 
Synopsis and Section 9.1 Overall Study Design  
i. Rescreening language added  
Rescreening of subjects who previously failed screening is allowed only with the 
permission of the medical monitor on a case by case basis.  
Subjects may be considered for rescreening if they failed screening previously 
due to eligibility criteria that are now allowed under the current amended 
protocol; delay of acquiring records; out of window issues (eg, lost or delayed 
labs); timing of exclusionary procedures; or other reasons approved by the 
medical monitor. 
 
Subjects with positive hepatitis B, hepatitis C, or human immunodeficiency 
results, subjects with a positive urine drug test (UDT) for illicit drugs or 
non-prescribed opioids; and/or subjects who previously received study drug in a 
V120083 trial will not be permitted to be rescreened. 
 
X-rays for rescreened subjects do not need to be repeated provided they were 
originally collected as part of this study and occurred within 1 month of 
rescreening. 
 
All rescreening must be approved in advance by the medical monitor.  
 
g. Synopsis and Section 9.1 Overall Study Design and Plan Description 
i. Clarified period when eligibility is assessed and clarified PK sampling  
 
Changed from: 
Prior to entering the double-blind period, the subjects’ “average pain over the last 
24 hours” scores will be assessed to determine the subjects’ eligibility to continue 
in the double-blind period. To qualify for entry into the double-blind period, 
subjects must have “average pain over the last 24 hours” scores of  4 and  9 


Clinical Protocol 
 
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Protocol: VAN2001  
Protocol Amendment 1 
 
Page 163 of 173 
for  3 consecutive days during the screening. Subjects who do not qualify for the 
double-blind period will be discontinued from the study as screen failures. 
 
Subjects who are eligible for the double-blind period will have visit 2 (Day 1) 
scheduled in the morning.  At this visit, all qualified subjects will be randomized to 
receive the double-blind treatments. The first dose of study drug will be 
administered at the study clinic.  For subjects in the intensive PK subgroup, blood 
samples for pharmacokinetic (PK) analysis will be collected postdose at 1, 2, 4, 
6, and 8 hours. These subjects will remain at the study clinic until the PK 
samples are collected. 
Clinic visits during the double-blind period will occur at week 1 (visit 3), week 2 
(visit 4), and week 4 (visit 5) visits. All clinic visits should occur in the morning. 
During these visits, PK samples will be collected at visits 3 (predose, 1 and 2 
hours postdose), 4 (predose), and 5 (predose) during the treatment period. 
Supplemental analgesic medication is APAP/acetaminophen 500 mg.  No more 
than 4 tablets/24 hours (ie, no more than 2 g/24 hours), as needed, will be 
permitted during the double-blind period.  All subjects will be instructed to refrain 
from taking any supplemental analgesic medication for at least 24 hours prior to 
the weeks 1, 2, and 4 visits (visits 3, 4, and 5, respectively) of the double-blind 
period and to refrain from taking study drug dose on the morning of clinic visits to 
allow for predose PK sampling. 
 
Changed to: 
Prior to entering the double-blind period, the subjects’ “average pain over the last 
24 hours” scores will be assessed to determine the subjects’ eligibility to continue 
in the double-blind period. To qualify for entry into the double-blind period, 
subjects must have “average pain over the last 24 hours” scores of  4 and  9 
for  3 consecutive days during the pain assessment period. Subjects who do not 
qualify for the double-blind period will be discontinued from the study as screen 
failures. 
Subjects who are eligible for the double-blind period will have visit 2 (Day 1) 
scheduled in the morning.  At this visit, all qualified subjects will be randomized to 
receive the double-blind treatments. The first dose of study drug will be 
administered at the study clinic.  For subjects in the intensive PK subgroup, blood 
samples for pharmacokinetic (PK) analysis will be collected predose and 
postdose at 1, 2, 4, 6, and 8 hours. These subjects will remain at the study clinic 
until the PK samples are collected. 
Clinic visits during the double-blind period will occur at week 1 (visit 3), week 2 
(visit 4), and week 4 (visit 5) visits. All clinic visits should occur in the morning. 
During these visits, PK samples will be collected at visits 3 (predose, 1 and 2 
hours postdose), 4 (predose or postdose), and 5 (predose or postdose) during 
the treatment period. Supplemental analgesic medication is 
APAP/acetaminophen 500 mg.  No more than 4 tablets/24 hours (ie, no more 
than 2 g/24 hours), as needed, will be permitted during the double-blind period.  
All subjects will be instructed to refrain from taking any supplemental analgesic 
medication for at least 24 hours prior to the weeks 1, 2, and 4 visits (visits 3, 4, 
and 5, respectively) of the double-blind period and to refrain from taking study 
drug dose on the morning of clinic visits to allow for predose PK sampling. 
 


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Protocol: VAN2001  
Protocol Amendment 1 
 
Page 164 of 173 
h. Synopsis – Study design section and Drug Concentration Measurements and 
Section 9.1 Overall Study Design 
i. Clarified PK sampling  
 
Changed from: 
Blood samples for pharmacokinetic (PK) analysis will be collected at visits 2, 3, 4, 
and 5. The PK evaluation will involve two components: intense PK sampling and 
sparse PK sampling.  Sparse PK sampling will be conducted for all subjects 
enrolled (276 subjects), with samples collected at visits 3 (predose, 1 and 2 
hours postdose), 4 (predose), and 5 (predose) during the treatment period. 
Intense PK sampling will be conducted for 24 subjects, consisting of the sparse 
PK schedule and visit 2 postdose sampling at 1, 2, 4, 6, and 8 hours (day 1 of 
dosing). A single sample of blood (6 mL) will be taken for each time point. The 
date and time of dosing and sampling will be documented on the case report 
forms (CRFs). 
 
Changed to: 
Blood samples for pharmacokinetic (PK) analysis will be collected at visits 2, 3, 4, 
and 5. The PK evaluation will involve two components: intense PK sampling and 
sparse PK sampling.  Sparse PK sampling will be conducted for all subjects 
enrolled (276 subjects), with samples collected at visits 3 (predose, 1 and 2 
hours postdose), 4 (predose or postdose), and 5 (predose or postdose) during 
the treatment period. Intense PK sampling will be conducted for 24 subjects, 
consisting of the sparse PK schedule and visit 2 predose sample and postdose 
sampling at 1, 2, 4, 6, and 8 hours (day 1 of dosing). A single sample of blood (6 
mL) will be taken for each time point. The date and time of dosing and sampling 
will be documented on the case report forms (CRFs). 
 
 
i. 
Section 9.4.8 Prior and Concomitant Therapy  
 
 
i. Addition of text directing investigator to contact the medical monitor with 
questions or concerns 
x 
The investigator should contact the medical monitor if there are any 
questions or concerns. 
 
ii. Clarified the language for inclusion of aspirin 
Changed from: 
Aspirin is permitted only for conditions other than chronic pain, including 
headache, fever, and cardiovascular disease prophylaxis. Aspirin dose of 81 mg 
per day is allowed to be taken for cardiovascular disease prophylaxis. Note: 
Subjects will be requested not to take any aspirin for at least 24 hours before 
each clinic visit. 
 
Changed to: 


Clinical Protocol 
 
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Protocol: VAN2001  
Protocol Amendment 1 
 
Page 165 of 173 
Aspirin dose of 81 mg per day is allowed to be taken for cardiovascular disease 
prophylaxis. 
 
j. 
Section 9.5.1 Schedule of activities,  
 
i. Footnote a revised 
 
Changed from: 
a The washout period (at least 3 days) is required only for subjects who take 
analgesic medications for pain.  Subjects who do not take any medications for 
pain will record their “average pain over last 24 hours” scores for 3 to 5 days.  
Subjects who take medications for pain will record their “average pain over last 
24 hours” scores for at least 3 days once all medication used for pain has been 
discontinued in accordance with acceptable medical practice.  Subjects may 
return to the study clinic for visit 2 as soon as they recorded “average pain over 
last 24 hours” scores  4 and  9 for  3 consecutive days. 
 
Changed to: 
a The washout period is required only for subjects who take analgesic 
medications for pain.  Subjects who do not take any medications for pain will 
record their “average pain over last 24 hours” scores for 3 to 7 days.  Subjects 
who take medications for pain will record their “average pain over last 24 hours” 
scores for at least 3 days once all medication used for pain has been 
discontinued in accordance with acceptable medical practice.  Subjects may 
return to the study clinic for visit 2 as soon as they recorded “average pain over 
last 24 hours” scores  4 and  9 for  3 consecutive days.  All subjects must 
return to the study clinic for visit 2 within 96 hours of the latest qualifying pain 
score entry within the pain assessment period. 
  
ii. Footnote j and k - revised to clarify PK sampling time points and remove 
recording of food intake 
 
Changed from: 
J For subjects in the intense PK sampling population, PK samples will be collected at Visit 2 
(5 time points; 1, 2 [+/- 10 min], 4, 6 and 8 hrs [+/- 20 min] postdose).  The actual time of food 
intake, dosing and sampling should be recorded. 
k  For all subjects, PK samples will be collected at visit 3 (predose, 1 and 2 hours post-dose); 
visit 4 (predose) and 5 (predose). The actual time of dosing and sampling should be recorded.  
Visit 3 sample must contain a predose PK sample collection.  If the subject took a morning dose 
of study medication at home on day of visit 3, subject should be instructed to return the following 
day. 
Changed to: 
J For subjects in the intense PK sampling population, PK samples will be collected at Visit 2 
(6 time points; predose and 1, 2 [+/- 10 min], 4, 6 and 8 hrs [+/- 20 min] postdose).  The actual 
time of dosing and sampling should be recorded. 


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Protocol: VAN2001  
Protocol Amendment 1 
 
Page 166 of 173 
k  For all subjects, PK samples will be collected at visit 3 (predose, 1 and 2 hours postdose); 
visit 4 (predose or postdose) and 5 (predose or postdose).  The actual time of dosing and 
sampling should be recorded.   
 
k. Sections 9.5.2.1 – Visit 1 (screening) 
 
i. Clarified consent for PK sampling 
 
Changed from: 
The following information will be obtained and procedures performed for all potential subjects at 
a screening visit conducted within 7 to 14 days after the ICF is signed: 
• 
Obtain ICF 
• 
Obtain PG consent form (optional) 
• 
Contact IVRS/IWRS to obtain subject number which will be retained throughout the 
study.  Instructions for contacting the IWRS are provided in the study manual 
Changed to: 
The following information will be obtained and procedures performed for all potential subjects at 
a screening visit conducted within 7 to 14 days after the ICF is signed: 
• 
Obtain ICF 
• 
Obtain PG consent form (optional) 
• 
Obtain intense PK consent form (optional) 
• 
Contact IVRS/IWRS to obtain subject number which will be retained throughout the 
study.  Instructions for contacting the IWRS are provided in the study manual 
 
l. 
Sections 9.5.2.1, 9.5.4 and 9.5.5 
 
i. 
Extended period for central ECG provider to provide data to site 
 
Changed from: 
ECG reports from the central ECG provider will be sent to the clinical site within 
24 hours of receipt of ECG transmission.  The investigator/designee must review 
and sign the ECG report from the central ECG provider. 
 
Changed to: 
ECG reports from the central ECG provider will be sent to the clinical site within 
72 hours of receipt of ECG transmission.  The investigator/designee must review 
and sign the ECG report from the central ECG provider. 


Clinical Protocol 
 
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Protocol: VAN2001  
Protocol Amendment 1 
 
Page 167 of 173 
 
m. Section 9.5.2.1 Rescreening language added: 
Rescreening of subjects who previously failed screening is allowed only with the 
permission of the medical monitor on a case by case basis. 
 
Subjects may be considered for rescreening if they failed screening previously 
due to eligibility criteria that are now allowed under the current amended 
protocol; delay of acquiring records; out of window issues (eg, lost or delayed 
labs); timing of exclusionary procedures; or other reasons approved by the 
medical monitor.   
 
Subjects with a positive hepatitis B, hepatitis C, or human immunodeficiency 
virus test results; subjects with positive urine drug test (UDT) for illicit drugs or 
non-prescribed opioids and/or subjects who previously received study drug in a 
V120083 trial will not be permitted to be rescreened.  
 
All rescreening must be approved in advance by the medical monitor.  
 
n. Section 9.5.2.2. Telephone Contact/ Washout Period 
i. Changed from: 
 
Instruct the subject to record his/her daily "average pain over the last 
24 hours" scores for the index knee at approximately 8 PM every day 
for: 
x 
Up to 5 days (or until instructed to stop) if the subject is not 
taking any medications for pain 
x 
Up to 7 days (or until instructed to stop) after all analgesic 
medications have been discontinued (applicable only to 
subjects taking medications for pain) 
During the remaining screening period, the site personnel will monitor daily the 
subjects' daily "average pain over the last 24 hours" scores in the diaries.  The 
subjects may return to the study clinic as soon as he/she recorded "average pain 
over the last 24 hours" scores of  4 and  9 for  3 consecutive days or until the 
pain score recording period (5 days for subjects not taking any medications; 7 days 
for subjects who were on pain medication prior to screening) is completed.  
[…] 
• 
Schedule visit 2 to occur in the morning as soon as possible 
Changed to: 
 
Instruct the subject to record his/her daily "average pain over the last 
24 hours" scores for the index knee at approximately 8 PM every day 
for: 
x 
Up to 7 days (or until instructed to stop) if the subject is not 
taking any medications for pain 


Clinical Protocol 
 
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Protocol: VAN2001  
Protocol Amendment 1 
 
Page 168 of 173 
x 
Up to 9 days (or until instructed to stop) after all analgesic 
medications have been discontinued (applicable only to 
subjects taking medications for pain) 
During the remaining screening period, the site personnel will monitor daily the 
subjects' daily "average pain over the last 24 hours" scores in the diaries.  The 
subjects may return to the study clinic as soon as he/she recorded "average pain 
over the last 24 hours" scores of  4 and  9 for  3 consecutive days or until the 
pain score recording period (7 days for subjects not taking any medications; 9 days 
for subjects who were on pain medication prior to screening) is completed. The 
subjects must return for visit 2 within 96 hours of the latest qualifying pain score entry 
within the pain assessment period.
[…] 
• 
Schedule visit 2 to occur in the morning as soon as possible (within 96 hours of 
the latest qualifying score within the pain assessment period) 
 
o. Section 9.5.3 Visit 2 – Randomization 
i. Clarified consent for PK sampling 
Changed from: 
The following procedures will be performed for subjects who are eligible for 
randomization: 
• 
Contact IVRS/IWRS to indicate that the subject is entering the double-blind 
period.  
• 
Have the subject record his/her responses to the mBPI-SF WOMAC, EQ-5D, and 
SF-36  
• 
Perform CiTAS rating 
• 
Collect optional PG sample (for subjects who provide additional consent) 
• 
Dispense study drug as instructed by IWRS   
ii. Changed to: 
The following procedures will be performed for subjects who are eligible for 
randomization: 
• 
Contact IVRS/IWRS to indicate that the subject is entering the double-blind 
period.  
• 
Have the subject record his/her responses to the mBPI-SF WOMAC, EQ-5D, and 
SF-36  
• 
Perform CiTAS rating 
• 
Collect optional PG sample (for subjects who provide additional consent) 


Clinical Protocol 
 
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Protocol: VAN2001  
Protocol Amendment 1 
 
Page 169 of 173 
• 
Collect optional PK sample (for subject who provide additional consent) 
• 
Dispense study drug as instructed by IWRS   
 
 
 
p. Section 9.5.3 Visit 2 – Randomization and Section 9.5.4 Visits 3 (week 1) and 4 
(week 2) – Double-blind Period 
i. Revised requirement for recording of date/time of meals to indication if a 
meal had been eaten within 2 hours of dosing. 
 
Changed from: 
 
Supplemental analgesic medication dosing information (date/time/amount 
taken) 
 
Date/time of meals 
 
The "pain right now" scores for the index knee immediately prior to taking 
supplemental analgesic medication (Appendix P). 
Changed to: 
 
Supplemental analgesic medication dosing information (date/time/amount 
taken) 
 
Indicate if meal eaten within ± 2 hours of dosing 
 
The "pain right now" scores for the index knee immediately prior to taking 
supplemental analgesic medication (Appendix N). 
Note: Updated assessment in Table 3 to reflect this change. 
 
q. Section 9.5.3 Visit 2 – Randomization 
i. Clarified time points for PK sampling 
Changed from: 
• 
For subjects in the intensive PK subgroup, collect PK blood samples for 
pharmacokinetic (PK) analysis at the following time points and record time of 
collection: 
x 
1, 2, 4, 6, and 8 hours after the first dose of the study drug 
• 
Schedule the next visit to occur in the morning approximately 1 week later 
Changed to: 
• 
For subjects in the intensive PK subgroup, collect PK blood samples for 
pharmacokinetic (PK) analysis at the following time points and record time of 
collection: 


Clinical Protocol 
 
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Protocol: VAN2001  
Protocol Amendment 1 
 
Page 170 of 173 
x 
Predose and 1, 2, 4, 6, and 8 hours after the first dose of the 
study drug 
• 
Schedule the next visit to occur in the morning approximately 1 week later 
r. Section 9.5.4 Visits 3 (week 1) and 4 (week 2) – Double-blind Period and Section 
9.5.5 Visit 5- End of Study or Early Discontinuation 
i. Clarified time points for PK sampling 
Changed from: 
 
• 
Collect pre-dose PK sample, noting time of sample collection [at visit 4, conduct 
the ECG prior to any PK sampling] 
[…] 
• 
Instruct the subject to record his/her daily "average pain over the last 24 hours" 
scores for the index knee at approximately 8 PM every day 
• 
At visit 3 only, collect PK blood sample 1 and 2 hours post-dose, noting time of 
sample collection.   
[…] 
9.5.5 
Visit 5 - End of Study or Early Discontinuation 
At approximately 1 to 2 days before the scheduled clinic visits, the site personnel will 
contact the subject to remind subjects to refrain from taking any supplemental 
analgesic medications for at least 24 hours prior to the clinic visit. Remind subject to 
hold morning dose of study drug to allow for pre-dose PK sampling during clinic visit. 
[…] 
• 
Collect predose PK blood sample and record time of collection 
Changed to: 
• 
Collect pre-dose PK sample at visit 3, noting time of sample collection [at visit 4, 
conduct the ECG prior to any PK sampling and PK sample could be pre- or 
postdose] 
[…] 
• 
At visit 3 only, collect PK blood sample at predose and at 1 and 2 hours 
postdose, noting time of sample collection.  Collect pre- and postdose sample at 
visit 4. 
[…] 
9.5.5 
Visit 5 - End of Study or Early Discontinuation 
At approximately 1 to 2 days before the scheduled clinic visits, the site personnel will 
contact the subject to remind subjects to refrain from taking any supplemental 


Clinical Protocol 
 
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Protocol: VAN2001  
Protocol Amendment 1 
 
Page 171 of 173 
analgesic medications for at least 24 hours prior to the clinic visit. Remind subject to 
hold morning dose of study drug to allow for predose PK sampling during clinic visit. 
[…] 
• 
Collect predose or postdose PK blood sample and record time of collection 
 
s. Section 9.5.7 Follow-up 
 
i. Clarified the recording of adverse events 
Changed from 
 
Record all adverse events 
Changed to 
 
Record all adverse events, including outcomes of previously reported 
unresolved adverse events  
 
t. 
Section 9.5.4 Visit 3 (week 1) and 4 (week 2) - Double-blind Period 
i. Clarified PK sampling relative to ECG measurements 
Changed from: 
x 
At visit 4 only,  
o Perform a 12-lead ECG after 5 minutes’ rest [prior to predose PK 
sampling] 
 
Changed to: 
x 
At visit 4 only,  
o Perform a 12-lead ECG after 5 minutes’ rest [prior to predose or 
postdose PK sampling] 
 
u. Section 9.5.4 Visit 3 (week 1) and 4 (week 2) - Double-blind Period and Section 
9.5.5 Visit 5 - End of Study or Early Discontinuation 
i. Added text regarding missing subject diary entries 
 
Instruct the subject to complete last missed diary(ies) if not completed.   
 
v. Section 9.5.5 Visit 5 - End of Study or Early Discontinuation 
i. Revised requirement for recording of date/time of meals to indication if a 
meal had been eaten within 2 hours of dosing. 
 
Changed from: 
 
Supplemental analgesic medication dosing information 
(date/time/amount taken) 
 
Date/time of meals 
Changed to: 


Clinical Protocol 
 
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Protocol: VAN2001  
Protocol Amendment 1 
 
Page 172 of 173 
 
Supplemental analgesic medication dosing information 
(date/time/amount taken) 
 
Indicate if meal eaten within ± 2 hours of dosing 
 
w. Section 9.6.3 Drug Concentration Measurements 
i. Clarified PK sampling 
 
Changed from: 
Samples of blood will be taken to determine plasma concentrations of V120083 
in this study. For subjects in the intensive PK subgroup, blood samples will be 
collected at visit 2 (day 1 of dosing) postdose at 1, 2, 4, 6, and 8 hours.  All 
subjects will have PK samples collected a visit 3 (week 1; predose, 1 and 2 hours 
postdose); visit 4 (week 2; predose); and visit 5 (week 4; predose).  The site will 
obtain one (6 mL) blood sample during the visit and confirm the time of the 
subject’s last 2 doses of study drug.  The actual time when the samples are 
taken should be recorded.  See Appendix C for information on collection, 
processing, storage, and shipment of PK samples. 
 
Changed to: 
Samples of blood will be taken to determine plasma concentrations of V120083 
in this study. For subjects in the intensive PK subgroup, blood samples will be 
collected at visit 2 (day 1 of dosing) predose and postdose at 1, 2, 4, 6, and 8 
hours.  All subjects will have PK samples collected a visit 3 (week 1; predose, 1 
and 2 hours postdose); visit 4 (week 2; predose or postdose); and visit 5 (week 4; 
predose or postdose).  The site will obtain one (6 mL) blood sample during the 
visit and confirm the time of the subject’s last 2 doses of study drug.  The actual 
time when the samples are taken should be recorded.  See Appendix C for 
information on collection, processing, storage, and shipment of PK samples. 
 
x. Section 9.6.5.2. Pharmacogenomics 
i. Clarified pharmacogenomics sampling schedule at visit 5 
Changed from: 
Three samples of blood, totaling approximately 20 mL, will be collected from 
each subject during the treatment period: 
o 1 sample for DNA at visit 2 predose 
o 2 samples for protein: 1 sample at visit 2 predose, and 1 sample 
at visit 5 postdose. 
 
Changed to: 
Three samples of blood, totaling approximately 20 mL, will be collected from 
each subject during the treatment period: 
o 1 sample for DNA at visit 2 predose 


Clinical Protocol 
 
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Protocol: VAN2001  
Protocol Amendment 1 
 
Page 173 of 173 
o 2 samples for protein: 1 sample at visit 2 predose, and 1 sample 
at visit 5. 
 
y. Section 10.3.2 Additional Reporting Requirements for Adverse Events of Special 
Interest 
 
i. Clarified description of AESI  
Changed from: 
Thermal burns/heat sensitivity Inhibition of thermal sensation and associated AEs  
Taste disturbance (as evaluated by the CiTAS) 
 
Changed to: 
x 
Disturbances in thermal sensation, which may include: 
o inhibition of thermal sensation and associated AEs such as 
thermal burns  
o heat sensitivity  
x 
Taste disturbance 
 
 
z. Appendices  
i. Re-lettered or corrected formatting of appendices titles so falls 
sequentially.  Corrected in-text references accordingly. 
ii. Appendix Q - List of Prohibited Medications and Classification 
Add the following language for clarity. 
This is a representative list.  Please contact the medical monitor if there 
are any questions. 

SAP_001.pdf: 
PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 1 of 80
VersionDate: 12JAN2018
 
 
 
 
TITLE PAGE 
DOCUMENT: 
STATISTICAL ANALYSIS PLAN 
PROTOCOL 
NUMBER: 
VAN2001 
 
 
TITLE: 
A Phase 2a, Multicenter, Randomized, Double-blind, 
Placebo-controlled and Active-controlled, Parallel-group 
Study Evaluating the Analgesic Efficacy and Safety of 
V120083 in Subjects with Moderate to Severe Chronic 
Pain Due to Osteoarthritis of the Knee. 
 
 
DATE: 
17-FEB-2017 (amendment 1) 
SAP STATUS 
SAP2, Final 1.0 
 
SAP VERSION DATE 
12JAN2018 
 
 
SPONSOR: 
Purdue Pharma L.P. 
One Stamford Forum 
Stamford, CT 06901-3431 
USA 
PREPARED BY: 
 
 
 
 
 
 
 
 
 




PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 3 of 80
VersionDate: 12JAN2018
TABLEOFCONTENTS
1. LISTOFABBREVIATIONS...................................................................................................9
2. INTRODUCTION..............................................................................................................12
3. STUDYOBJECTIVES.........................................................................................................12
3.1. PRIMARYOBJECTIVE..........................................................................................................12
3.2. SECONDARYOBJECTIVE......................................................................................................12
4. STUDYDESIGN................................................................................................................14
4.1. GENERALSTUDYDESIGNANDPLAN......................................................................................14
4.2. STUDYPOPULATION..........................................................................................................16
4.3. RANDOMIZATIONANDBLINDING..........................................................................................17
4.4. STUDYASSESSMENTS.........................................................................................................18
5. STUDYVARIABLESANDDEFINITIONS.............................................................................22
5.1. EFFICACYVARIABLES..........................................................................................................22
5.1.1. PrimaryEfficacyVariable................................................................................................22
5.1.2. SecondaryEfficacyVariables..........................................................................................22
 





5.2. SAFETYVARIABLES............................................................................................................29


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 4 of 80
VersionDate: 12JAN2018
5.2.1. AdverseEvents................................................................................................................29
5.2.2. ClinicalLaboratoryEvaluations......................................................................................31
5.2.3. VitalSigns........................................................................................................................35
5.2.4. ECGs................................................................................................................................36
5.2.5. PhysicalExamination......................................................................................................39
5.2.6. OtherSafetyAssessments..............................................................................................39
5.3. ADDITIONALVARIABLES.....................................................................................................40
5.3.1. PKandPGVariables........................................................................................................40
5.3.2. ChemotherapyͲinducedTasteAlterationScale(CiTAS).................................................40
6. SAMPLESIZEDETERMINATION.......................................................................................41
7. ANALYSISPOPULATIONS................................................................................................41
7.1. ENROLLEDPOPULATION.....................................................................................................41
7.2. SAFETYPOPULATION.........................................................................................................41
7.3. FULLANALYSISPOPULATION...............................................................................................42
7.4. PERPROTOCOLPOPULATION...............................................................................................42
7.5. PROTOCOLDEVIATIONS.......................................................................................................42
8. GENERALSTATISTICALCONSIDERATIONS.......................................................................43
8.1. ADJUSTMENTSFORCOVARIATES.........................................................................................43


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 5 of 80
VersionDate: 12JAN2018
8.2. HANDLINGOFDROPOUTSORMISSINGDATA.........................................................................44
8.3. INTERIMANALYSESANDDATAMONITORING..........................................................................45
8.4. MULTIͲCENTERSTUDIES...................................................................................................47
8.5. MULTIPLECOMPARISONS/MULTIPLICITY..............................................................................48
8.6. EXAMINATIONOFSUBGROUPS.............................................................................................48
9. STUDYPOPULATIONCHARACTERISTICS.........................................................................48
9.1. SUBJECTDISPOSITION........................................................................................................48
9.2. MAJORPROTOCOLDEVIATIONS...........................................................................................48
9.3. DEMOGRAPHICSANDBASELINECHARACTERISTICS....................................................................49
9.4. DOSINGANDEXTENTOFEXPOSURE......................................................................................49
9.5. PRIORANDCONCOMITANTMEDICATIONANDTHERAPIES..........................................................50
9.6. MEDICALHISTORY.............................................................................................................51
9.7. KELLGRENͲLAWRENCE........................................................................................................51
10. EFFICACYANALYSES......................................................................................................51
10.1. PRIMARYEFFICACYVARIABLE(S)........................................................................................52
10.1.1. AnalysisforPrimaryEfficacyEndpoint.........................................................................52
10.1.2. Hypothesis Testing for the Primary Efficacy Endpoint........................................54


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SAP2FinalV1.0
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10.2. SECONDARYEFFICACYVARIABLE(S)....................................................................................54
10.2.1. Weekly “average pain over the last 24 hours” collected by e-Dairy.................54
10.2.2. Average daily “pain right now” collected by e-Dairy..........................................54
10.2.3. WOMAC total score..................................................................................................55
10.2.4. WOMAC pain severity subscale...........................................................................55
10.2.5. WOMAC physical function subscale......................................................................55
10.2.6. WOMAC stiffness subscale...................................................................................56
10.2.7. mBPI-SF total scores (all parts of the 6 questions)...........................................56
10.2.8. mBPI-SF pain severity subscale...........................................................................56
10.2.9. mBPI-SF pain interference subscale.....................................................................56
10.2.10. SF-36.........................................................................................................................57
10.2.11. EQ-5D-5L..................................................................................................................57
10.2.12. PGIC at the end of double-blind period (week 4).............................................58
10.2.13. Supplemental analgesic medication use...........................................................58
10.2.14. Responder to treatment..........................................................................................58
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
10.3.1. “Worst Pain over the last 24 hours” collected by mBPI-SF..............................59
11. SAFETYANALYSES.........................................................................................................59
11.1. ADVERSEEVENTS..........................................................................................................60
11.2. CLINICALLABORATORYEVALUATIONS..................................................................................61


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SAP2FinalV1.0
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11.3. VITALSIGNS..................................................................................................................62
11.4. ECGS........................................................................................................................63
11.5. ABUSEORDIVERSIONOFSTUDYDRUG..............................................................................64
11.6. PHYSICALEXAMINATION.................................................................................................64
11.7. OTHERSAFETYMEASURES................................................................................................64
11.7.1. HADS...........................................................................................................................64
11.7.2. C-SSRS.......................................................................................................................65
11.7.3. CiTAS scores...........................................................................................................65
12. OTHERANALYSES.........................................................................................................65
12.1. PKANDPGANALYSES.....................................................................................................65
13. SUMMARYOFCHANGESFROMPROTOCOLͲSPECIFIEDANALYSES...............................65
14. REPORTINGCONVENTIONS.........................................................................................66
15. REFERENCES..................................................................................................................68
16. TABLES,FIGURES,LISTINGSANDOUTPUT....................................................................68
16.1. TABLES.......................................................................................................................68
16.2. FIGURES.......................................................................................................................68
16.3. DATALISTINGSFORAPPENDIX16.2...................................................................................69


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Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
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VersionDate: 12JAN2018
17. ATTACHMENTS.............................................................................................................69
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18. APPENDIX.....................................................................................................................79


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Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
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VersionDate: 12JAN2018
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
1.
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase (alanine transaminase; also SGPT) 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase (aspartate transaminase; also SGOT) 
ATC 
anatomical therapeutic chemical 
BUN 
blood urea nitrogen 
bid 
twice daily 
BMI 
body mass index 
bpm 
beats per minute 
CRF 
case report form 
CSR 
Clinical study report 
C-SSRS 
columbia-suicide severity rating scale 
dL 
deciliter 
DMC 
data monitoring committee 
DO 
Doctor of Osteopathic Medicine 
ECG 
electrocardiogram 
EQ-5D-5L 
EuroQol-5D 
FAP 
full analysis population 
FDA 
Food and Drug Administration 
g 
gram 
GGT 
gamma-glutamyltransferase 
GH 
general health 
HADS 
Hospital Anxiety and Depression Scale 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 


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Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
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VersionDate: 12JAN2018
 
 
 
kg 
kilogram 
K-L 
Kellgren-Lawrence 
L 
liter 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LLN 
lower limit of the laboratory reference range 
LNH 
low, normal, high (relative to the laboratory reference range) 
mBPI-SF 
modified Brief Pain Inventory – Short Form 
MedDRA 
Medical Dictionary for Regulatory Activities 
mEq 
milliequivalent 
mg 
milligram 
MH 
mental health 
MI 
myocardial infarction 
mL 
milliliter 
mm 
millimeter 
mm Hg 
millimeters of mercury 
MMRM 
mixed-effect general linear model with repeated measures 
mmol 
millimole 
msec 
millisecond 
NRS 
numerical rating scale 
OA 
osteoarthritis 
MD 
Medical doctor 
PF 
physical functioning 
PG 
pharmacogenomics 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetic(s) 
po 
oral route of administration 
PP 
per-protocol population 
PR 
PR interval (ECG) 
QRS 
QRS interval (ECG) 
QT 
QT interval (ECG) 
QTc 
QT data corrected for heart rate 


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Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
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VersionDate: 12JAN2018
 
 
 
QTcB 
QT data corrected for heart rate using the Bazett formula 
QTcF 
QT data corrected for heart rate using the Fridericia formula 
RBC 
red blood cell (count) 
RE 
role-emotional 
RP 
role-physical 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SF 
social functioning 
SF-36 
Medical Outcomes Study 36-Item Short Form Health Survey 
SGOT 
serum glutamic-oxaloacetic transaminase (also AST) 
SGPT 
serum glutamate pyruvate transaminase (also ALT) 
SI 
international system of units for clinical laboratory values 
SOC 
System Organ Class 
SOP 
standard operating procedure 
SSRI 
selective serotonin reuptake inhibitor 
ST 
ST interval (ECG) 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of the laboratory reference range 
US 
United States 
v
versus 
VT 
vitality 
WBC 
white blood cell (count) 
WOMAC 
Western Ontario and McMaster Osteoarthritis Index 


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 12 of 80
VersionDate: 12JAN2018
 
 
 
2.
INTRODUCTION 
This Statistical Analysis Plan (SAP) summarizes the planned presentation and analysis of the 
clinical data from Purdue Pharma L.P. Protocol VAN2001  
 
 
 
 
 a 
Phase 2a, multicenter, randomized, double-blind, placebo-controlled and active-controlled, 
parallel-group study evaluating the analgesic efficacy and safety of V120083 in subjects with 
moderate to severe chronic pain due to osteoarthritis (OA) of the knee. 
 
Study measurements and assessments, planned statistical analysis methods, and planned 
tables, listings and graphs are specified in this plan. 
The final version of the SAP will be developed in two stages. At the first stage, SAP1 will be 
developed and initial approval by Purdue will be obtained prior to commencing the programming 
activities.  All changes introduced during the second stage following the initial approval of SAP1 
will be tracked and a final version of the SAP, known as SAP2, will be issued for Purdue’s final 
approval prior to database lock and study unblinding. 
 
 
3.
STUDY OBJECTIVES 
3.1.
PRIMARY OBJECTIVE 
The primary objective of this study is: 
 
x 
To evaluate the analgesic efficacy of V120083 twice daily (bid) compared with placebo in 
subjects with moderate to severe chronic pain due to OA of the knee using the “average 
pain over the last 24 hours” score from the modified Brief Pain Inventory – short form 
(mBPI-SF) pain severity subscale at week 4 of the double blind period. 
 
3.2.
SECONDARY OBJECTIVE 
The secondary objectives of this study are: 
 
x 
Evaluate the safety and tolerability (including adverse event [AE] reporting, clinical 
laboratory parameters, and physical examination) of 2 dose levels of V120083. 


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 13 of 80
VersionDate: 12JAN2018
 
 
 
x 
Evaluate the efficacy of V120083 on pain, stiffness, physical function, and overall 
disability using the Western Ontario and McMaster Osteoarthritis Index (WOMAC) 
subscale and total scores. 
 
x 
Evaluate the efficacy of V120083 on pain intensity due to OA using numerical rating 
scale (NRS) pain scores from the mBPI-SF pain severity subscale. 
 
x 
Evaluate the impact of V120083 on pain-related quality of life/function using the mBPI- 
SF pain interference subscale. 
 
x 
Evaluate the effect of V120083 on pain severity and pain interference overall using the 
mBPI-SF total score. 
 
x 
Evaluate the impact of V120083 on subjects’ health state (as defined by mobility, self- 
care, daily activities, pain/discomfort, and anxiety/depression) using the EuroQol-5D 
(EQ-5D-5L). 
 
x 
Evaluate the impact of V120083 on subjects’ functional health and well-being using the 
Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). 
 
x 
Evaluate subject global impression of treatments using the Patient Global Impression of 
Change (PGIC) questionnaire. 
 
x 
Evaluate the impact of V120083 on mood (anxiety and depression) using the Hospital 
Anxiety and Depression Scale (HADS). 
 
x 
Evaluate the efficacy of naproxen vs. placebo for assay sensitivity using the primary and 
secondary endpoints indicated above. 
 
x 
Determine plasma levels of V120083 in subjects under clinical use conditions. 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
x 
Evaluate supplemental analgesic medication use. 
 
x 
Evaluate treatment response. 


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 14 of 80
VersionDate: 12JAN2018
 
 
 
x 
Evaluate the occurrence of treatment-emergent suicidal ideation or behavior using the 
Columbia-Suicide Severity Rating Scale (C-SSRS). 
 
4.
STUDY DESIGN 
4.1.
GENERAL STUDY DESIGN AND PLAN 
The study consists of 3 periods: 1) the screening period (within 21 days of baseline); 2) the 
double-blind period, which consists of 4 weeks of treatment (28 days); and 3) the follow-up 
period, during which a telephone contact is made approximately 7 days after the end of 
study/study discontinuation visit.  Subjects may withdraw from the study at any time and for any 
reason. The reasons for screen failure, baseline failure and discontinuation from the double- 
blind period are summarized in section 9.3.3 of the protocol. 
 
It is planned that up to 276 subjects, in approximately 30 sites in the United States, will be 
randomly assigned to one of the 4 treatments in the double-blind period: V120083 30 mg bid, 
V120083 60 mg bid, naproxen 500 mg bid, or placebo. Naproxen 500 mg bid will be used as an 
active control to determine the assay sensitivity of the study. 
 
Figure 1 Study Plan 
 
TC
Visit2
Week 1 
Visit 3 
Week2
Visit4
Week4
Visit5
Follow-up 
 
 
 
Stopincoming
analgesics
Placebo

Pain
Assessmentb
Washout


V12008330mgbid



V12008360mgbid
Period





Randomization
Naproxen500mgbid

EndofStudy
ScreeningPeriod
(ч21days)
DoubleͲblind Period
(28 days)
FollowͲup Period
(7days)


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
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VersionDate: 12JAN2018
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

During the screening period, subjects will be assessed to determine eligibility for enrollment into 
the trial.  Subjects who do not meet the initial entry criteria will be considered screen failures. 
For subjects who meet the intital entry criteria and: 
 
x 
Who do not take any analgesic medications for their pain, the site staff will instruct them 
to record in the diary their “average pain over the last 24 hours” scores (Appendix N) for 
their index knee at approximately 8 PM every day for 3 to 7 days; these subjects may 
return to the study clinic for visit 2 as soon as they have “average pain over the last 
24 hours” scores  4 and  9 for  3 consecutive days. All subjects must return to the 
study clinic for visit 2 within 96 hours of the latest qualifying pain score entry within the 
pain assessment period. 
x 
Who take medication for their chronic pain (including any topical and/or oral analgesics, 
antidepressants, anticonvulsant, and other medication used for pain), the site staff will 
instruct them to: 
y 
Discontinue use of all medication for pain (including any topical and/or oral 
analgesics, antidepressants, anticonvulsant and other medication used for pain) in 
accordance with accepted medical practice and, 
 
o
As soon as all medication used for pain is stopped, record in the diary their 
“average pain over the last 24 hours” scores for their index knee at approximately 
8 PM every day for 3 to 9 days; these subjects may return to the study clinic for 
visit 2 as soon as they reported “average pain over the last 24 hours” scores of 
 4 and  9 for  3 consecutive days. All subjects must return to the study clinic 
for visit 2 within 96 hours of the latest qualifying pain score entry within the pain 
assessment period. 
 
Subjects who are eligible for the double-blind period will have visit 2 scheduled in the morning. 
After meeting eligibility requirements, approximately 276 subjects will be stratified for 
randomization in a 1:1:1:1 fashion according to the baseline severity of pain score (mBPI-SF 
average pain) and study site at visit 2 to receive 1 of the following 4 treatments in the double- 
blind period: V120083 30 mg bid, V120083 60 mg bid, naproxen 500 mg bid, or placebo. The 
first dose of study drug will be administered at the study clinic. 
 
Clinic visits during the double-blind period will occur at week 1 (visit 3), week 2 (visit 4), and 
week 4 (visit 5).  All clinic visits should occur in the morning. During these visits, blood samples 
for PK analysis will be collected as outlined in the Schedule of Activities (Table 1). The study 
will also include pharmacogenomics (PG) sampling that will be optional for all subjects. 


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
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VersionDate: 12JAN2018
 
 
 
Starting at the screening phone call visit, subjects may take their own supplemental analgesic 
medication, ie, 500 mg acetaminophen (APAP), which can be taken as needed up to 2 g/24 
hours for breakthrough pain, but it is not be be taken within 24 hours of visit 2. Supplemental 
analysis medication, APAP/acetaminophen 500 mg, will be provided during the double-blind 
period. No more than 4 tablets/24 hours (ie, no more than 2 g/24 hours, and no more than 2 
tablets of APAP/acetaminophen 500 mg at any one time), as needed, will be permitted during 
the double-blind period. All subjects will be instructed to refrain from taking any supplemental 
analgesic medication for at least 24 hours prior to the weeks, 1, 2, and 4 (visits 3, 4, and 5, 
respectively) of the double-blind period. 
 
Subjects are allowed a ±1 day window for visit 3, and a ± 2 day window for visits 4 and 5, from 
baseline.  All scheduled visits will be anchored to the day of randomization (visit 2). Subjects 
who discontinued treatment early will be instructed to return to study clinic for an early 
discontinuation visit (visit 5). After the end of the study/early discontinuation visit, all subjects 
will be converted to a pain regimen as deemed medically appropriate by the 
investigator/designee. 
 
During the follow-up period, subjects will receive a telephone call approximately 7 days after the 
end of the study/study discontinuation visit to assess subject status and documentation of AEs 
and concomitant medications. 
 
An interim analysis will be performed for futility when approximately 50% of randomized 
subjects have completed the study. An independent data monitoring committee (DMC) will 
review all unblinded safety and efficacy data from the analysis and make recommendations. 
 
4.2.
STUDYPOPULATION 
The subject population will consist of males and females  40 and  80 years of age with 
moderate to severe chronic OA pain of the knee as their predominant pain condition for at least 
6 months prior to screening. 
Subjects meeting all the inclusion criteria per section 9.3.1 of the protocol, and none of the 
exclusion criteria per section 9.3.2 of the protocol may be enrolled in the study. 
Approximately 276 subjects will be stratified for randomization in a 1:1:1:1 fashion according to 
the baseline severity of pain score (mBPI-SF average pain) and study site at visit 2 to receive 1 
of the following 4 treatments in the double blind period: V120083 30 mg bid, V120083 60 mg bid, 
naproxen 500 mg bid, or placebo. The actual number of subjects treated will depend on the 
outcome of the interim analyses. 


PurduePharmaLP
Protocol:VAN2001
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SAP2FinalV1.0
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4.3.
RANDOMIZATION AND BLINDING 
Subjects will be randomized at visit 2 by Interactive Web Response System/Interactive Voice 
Response System (IWRS/IVRS) to receive 1 of the 4 treatment groups according to a 
randomization schedule generated by 
 and will be assigned a unique randomization 
number. 
 
The subject number will be recorded on all clinical investigation documentation (e.g, case report 
forms, clinical drug supply labels, laboratory kits, ECGs, etc.).  During the double-blind period of 
the study, the subject and all personnel involved with the conduct, analysis, and the 
interpretation of the study, including the investigators, clinical site personnel, and the sponsor  
(or designee) staff, will be blinded to the study drug codes. 
 
The randomization schedule will be kept strickly confidential, filed securely by the sponsor (or 
designee), and accessible only to authorized persons per sponsor’s (or designee’s) SOPs until 
the time of unblinding. 
 
Unblinding a subject should only be done in emergency situations for reasons of subject’s 
safety. 
 
In the event that an emergency unblinding is required, the investigator/medically qualified 
designee (must be a MD or a DO) should make every attempt to contact the sponsor’s medical 
monitor or designee before breaking the blind. 
 
When the blinding code is broken, the date, time of unblinding, and reason(s) must be fully 
documented in the source documentation. If not already done, the sponsor’s medical monitor or 
designee must be contacted as soon as possible to notify him/her of the unblinding and to 
discuss the reason(s) for unblinding. 
 
In the event that an emergency unblinding is required, authorized IWRS users at the clinical 
sites and the sponsor or designee, will have the ability to retrieve the subject’s treatment group 
assignment through IVRS/IWRS. 
 
This study includes an interim analysis for safety and efficacy (for futility) when 50% of the 
subjects have completed the end-of-study visit.  The treatment assignment for the subset of 
subjects included in the interim analyses will be released to the interim analysis team through 


PurduePharmaLP
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StatisticalAnalysis Plan 2
SAP2FinalV1.0
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the IVRS system and will be kept strictly confidential in a secure location. The unblinded interim 
analysis team will consist of a statistician and programmer not associated with the study team. 
 
 
 
4.4.
STUDY ASSESSMENTS 
Table 1 summarizes the schedule of expected visits and procedures of the study, including 
clinical evaluations and clinical laboratory test measurements. 


PurduePharmaLP
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StatisticalAnalysis Plan 2
SAP2FinalV1.0
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Table 1 
Schedule of Activities 
Protocol Activity
Screening
Double-blind Period
Follow-up
Visit 1 Phone
Call
Pain
Assessment
/Washouta
Visit 2
(Rand)
Visit
3
Visit 4
Visit 5 or
discontinuation
(EOS)
Phone Call
or Clinic
Visit
Study day
Days -21 to -1
Day 1 Week
1
Week 
2
Week 4
7 after the 
last dose
Days from Baseline
-
-
6-8
12-16
26-30
Informed consent form (ICF)
X
Contact IVRS/IWRS
X
Xb
X
X
X
X
Inclusion/exclusion criteria
X
X
Demography
X
Medical history and current 
medical condition
X
 
 
 
 
 
 
 
Pain history/ACR criteria
X
 
 
 
 
 
 
 
Vital Signs
X
X
X
X
X
HADS
X
X
Columbia-Suicide Severity 
Rating Scale (C-SSRS)o
X
X
X
X
X
X p
Physical examination
X
X
X
X
X
Height, weight, and BMId
X
X
Bilateral X-ray of the knees
X
X
Kellgren-Lawrence 
classificationq
X
 
 
 
 
 
X
Identify index knee
X
Average pain over the last 
7 days
X
 
 
 
 
 
 
 
Electrocardiograme
X
X
X
Xr
Virus screen (HBV, HCV, and 
HIV)
X
 
 
 
 
 
 
 
Laboratory evaluations 
(chemistry, hematology, and 
urinalysis)
X
 
 
 
 
X
X
Xr
Serum pregnancy testf
X
X
Urine pregnancy test
X
X
X


PurduePharmaLP
Protocol:VAN2001
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SAP2FinalV1.0
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Protocol Activity
Screening
Double-blind Period
Follow-up
Visit 1 Phone
Call
Pain
Assessment
/Washouta
Visit 2
(Rand)
Visit
3
Visit 4
Visit 5 or
discontinuation
(EOS)
Phone Call
or Clinic
Visit
Study day
Days -21 to -1
Day 1 Week
1
Week 
2
Week 4
7 after the 
last dose
Days from Baseline
-
-
6-8
12-16
26-30
Urine drug test
X
Chemotherapy-induced Taste 
Alteration Scale (CiTAS)
 
 
 
X
X
X
X
mBPI-SF – entire scale
X
X
X
X
WOMAC
X
X
X
X
EQ-5D
X
X
X
X
SF-36
X
X
X
X
PGIC
X
Randomization
X
Dispense study drug as 
instructed by IWRS
 
 
 
X
X
X
Dispense supplemental 
analgesic medication
Xg
X
Xh
Xh
Adverse events
Prior and concomitant 
therapies
Distribute subject diary
X
Collect subject diary
Xb
Xc 
Xi
Review subject's diary
X 
X 
X 
Xi
Diary entries
Study medication dosing 
information 
(date/time/amount taken)
 
 
 
 
 
Indicateifmealeaten
within±2hoursofdosing
 
 
 
 
 
Supplemental analgesic 
use (time/date/amount 
taken)
 
 
 
 
“Pain right now” scores
Daily “average pain over 
the last 24 hours” scores
 
 
 
 


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 21 of 80
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Protocol Activity
Screening
Double-blind Period
Follow-up
Visit 1 Phone
Call
Pain
Assessment
/Washouta
Visit 2
(Rand)
Visit
3
Visit 4
Visit 5 or
discontinuation
(EOS)
Phone Call
or Clinic
Visit
Study day
Days -21 to -1
Day 1 Week
1
Week 
2
Week 4
7 after the 
last dose
Days from Baseline
-
-
6-8
12-16
26-30
Collect unused study drug 
and conduct drug 
accountability
 
 
 
 
X
X
X
Washout of prohibited 
analgesics
X
 
 
 
 
 
Collect sample(s) for PK 
analysis
 
 
 
Xj
Xk
Xk
Xk
Collect sample for PG 
analysisl
 
 
 
X
X
Telephone contacts
Xm
Xm
Xm
Xm
Xn
 
 
 
Abbreviations: ACR = American College of Rheumatology, BMI = body mass index; C-SSRS = Columbia-Suicide Severity Rating 
Scale; EQ-5D = EuroQol-5D; HADS = Hospital Anxiety and Depression Scale; HBV = hepatitis B; HCV = hepatitis C; HIV = human 
immunodeficiency virus; ICF = informed consent form; IVRS/IWRS = interactive voice response system/interactive web response 
system; mBPI-SF = Modified Brief Pain Inventory – Short Form; PG = pharmacogenomics; PGIC = Patient Global Impression of 
Change; PK = pharmacokinetic; Rand = randomization; SF-36 = Medical Outcomes Study 36-Item Short Form Health Survey; 
WOMAC = Western Ontario and McMaster Osteoarthritis Index. 
 
a The washout period is required only for subjects who take analgesic medications for pain. Subjects who do not take any medications for 
pain will record their “average pain over last 24 hours” scores for 3 to 7  days. Subjects who take medications for pain will record their 
“average pain over last 24 hours” scores for at least 3 days once all medication used for pain has been discontinued in accordance with 
acceptable medical practice. Subjects may return to the study clinic for visit 2 as soon as they recorded “average pain over last 24 hours” 
scores  4 and  9 for  3 consecutive days. Allsubjectsmustreturntothestudyclinicforvisit2within96hoursofthelatestqualifyingpain
scoreentrywithinthepainassessmentperiod.
b Applicable only to screen failure subjects who do NOT meet the study inclusion criteria or who meet ANY of the exclusion criteria 
for clinical laboratory results, radiograph results, and/or ECG results. 
c Applicable only to randomization failure subjects who do NOT meet the randomization criteria, the subject diary will be collected at 
the end of the pain assessment visit. 
d Body weight and BMI will be assessed at screening and visit 5 (end-of-study). Height will be assessed at screening only. 
e Subjects with a screening ECG showing a QTcF value (QT data corrected for heart rate using the Fridericia formula) of  470 msec 
or other ECG findings that, in the investigator’s opinion, would preclude participation in the study. If subsequent QTcF values exceed 
500 msec or 480 msec with a concurrent QTcF change of > 60 msec from baseline, the subject must discontinue study drug and the 
reason for study drug discontinuation will be recorded as AE (see section 10). 
f Serum pregnancy test to be included for female subjects who are premenopausal or postmenopausal for less than 1 year and who 
are not surgically sterile. 
g Supplemental analgesic medication is to be dispensed as needed at the screening visit 
h Supplemental analgesic medication will be dispensed at visits 2, 3, and 4 of the study, as needed. 
I Subject diary will be collected at last visit. 


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J For subjects in the intense PK sampling population, PK samples will be collected at Visit 2 (6 timepoints; predose, 1, 2 [+/- 10 min], 
4, 6 and 8 hrs [+/- 20min] postdose)  The actual time of dosing and sampling should be recorded. 
k  For all subjects, PK samples will be collected at visit 3 (predose, 1 and 2 hours post-dose); visit 4 (predose or post  dose) and 5 
(predose or post dose). The actual time of dosing and sampling should be recorded. 
l PG samples will be collected for DNA and  protein at visit 2 predose and at visit 5 postdose. 
m At approximately 1 to 2 days prior to each scheduled visits, the site personnel will contact the subject to remind subjects to:  
Refrain from taking any supplemental analgesic medications for at least 24 hours prior to the clinic visit (applicable to visits 3, 4 and 
5 only)  and to hold morning dose of study drug on the day of the clinic visit for predose PK sampling 
n Follow-up visit could be by telephone contact or by a clinic visit. 
o At screening visit, use C-SSRS Baseline/Screening Assessment. For randomization visit and subsequent scheduled or 
unscheduled visits, use C-SSRS Since Last Visit Assessment. Positive scores on the C-SSRS may result in discontinuation and/or 
referral to a specialist for evaluation as outlined in the protocol 
p C-SSRS should be completed at all visits that include clinical assessments 
q K-L grade should be determined by a local radiologist or rheumatologist. 
r Subjects who require follow-up of clinical laboratory or ECG assessments must return to the clinical site for this visit. 
 
 
5.
STUDY VARIABLES AND DEFINITIONS 
5.1.
EFFICACY VARIABLES 
5.1.1.
Primary Efficacy Variable 
The primary efficacy assessment is the “average pain over the last 24 hours” score (on an 11- 
point NRS scale where 0=no pain, 10=pain as bad as you can imagine) from the mBPI-SF pain 
severity subscale at week 4 of the double-blind period. 
 
The baseline score will be the value collected the day of randomization (Visit 2). 
No missing data will be imputed for the primary efficacy variable. 
5.1.2.
Secondary Efficacy Variables 
The secondary efficacy variables are: 
 
x 
Weekly “average pain over the last 24 hours” collected by e-Diary 
 
x 
Average daily “pain right now” collected by e-Diary 
 
x 
WOMAC total scores 
 
x 
WOMAC pain severity subscales 
 
x 
WOMAC physical function subscale 


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x 
WOMAC stiffness subscale 
 
x 
mBPI-SF total scores (all parts of 6 questions) 
 
x 
mBPI-SF pain severity subscale 
 
x 
mBPI-SF interference subscale 
 
x
SF-36 
 
x 
EQ-5D-5L 
 
x 
PGIC at the end of double-blind period (week 4) 
 
x 
Supplemental analgesic medication use 
 
x 
Responder to treatment 
 
x 
Evaluate the occurrence of treatment-emergent suicidal ideation or behavior using the 
Columbia – Suicide Severity Rating Scale (C-SSRS) 
 
 
Weekly “average pain over the last 24 hours” collected by e-Dairy 
 
The question daily “average pain over the last 24 hours” scores is administered daily during the 
screening visits and at visits 2 through 5 (end of study/early discontinuation). 
 
For the purposes of defining weekly averages, weeks will be defined as 7X24 hours intervals 
starting on the date/time when the first dose of double-blind medication was taken. 
 
A minimum of 4 non-missing scores are required in order to compute the average for any given 
week. 
 
The baseline score will be the average of non-missing observations taken over the 7 days prior 
to first dose date. 
 
Handling of missing data is described in detail in Section 8.2. 


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Average daily “pain right now” collected by e-Diary 
 
The average daily “pain right now” scores (see Appendix P of the protocol) will be defined as the 
sum of nonmissing daily “pain right now” scores reported during that week (days 1 to 7, days 8 
to 14, days 15 to 21, and days 22 to 28) divided by the number of days with nonmissing scores 
for that week.  If a subject reports fewer than 3 days of pain scores during a week, the weekly 
mean “pain right now” score will be set to missing. If there are >1 “pain right now” scores 
reported on the same day, then the average score on the day will be used to calculate weekly 
mean scores. 
 
The baseline score will be the average of non-missing observations taken over the 7 days prior 
to first dose date. 
 
Handling of missing data is described in detail in Section 8.2. 
 
WOMAC: The WOMAC is a self-administered questionnaire used to assess subjects with OA of 
the hip or knee. The 24-hour, 0-4 categorical version (see Appendix J of the protocol) will be 
administered at each clinic visit (excluding the follow-up visit), and it will be used to monitor the 
course of the disease or to determine the effectiveness of medications. The following 3 
subscales will be calculated and analyzed: 
 
x 
Pain Subscale (5 items: walking; stair climbing; nocturnal; at rest; weight bearing).  The 
pain subscale score will be obtained by adding the responses to questions 1-5. The 
score can range from 0-20. 
 
x 
Stiffness Subscale (2 items: morning stiffness; stiffness occurring later in the day). The 
stiffness subscale score will be obtained by adding the responses to questions 6-7. The 
score can range from 0-8. 
 
x 
Physical Function Subscale (17 items: descending stairs; ascending stairs; rising from 
sitting; standing; bending to floor; walking on flat; getting into or out of car; going 
shopping; putting on socks; rising from bed; taking off socks; lying in bed; sitting; getting 
into or out of the bathtub; getting on or off the toilet; heavy domestic duties; light 
domestic duties). The physical function subscale score will be obtained by adding the 
responses to questions 8-24. The score can range from 0-68. 
 
x 
Total score (24 items from pain, stiffness and physical function subscales).  The total 
score will be obtained by adding the response to questions 1 to 24. 


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A mean score will also be computed for the 3 subscales/scale by averaging the response to 
questions instead of summing them. 
 
The questionnaire will be administered at visits 2 through 5. 
 
The baseline subscales/scale will be defined as the score obtained at the randomization Visit 2 
(day 1) prior to the first dose of the study drug. 
 
Handling of missing data is described in detail in Section 8.2. 
mBPI-SF Scores 
The mBPI-SF (see protocol Appendix I) is a self-administered questionnaire used to assess the 
severity of pain, and the interference of pain on daily functions. It consists of 6 questions. 
Questions 1-4 ask the subjects to rate their severity of pain on a 0-10 numerical rating scale 
(NRS) for worst pain, least pain, average pain, and current pain. Question 5 asks subjects to 
rate their pain relief over the past 24 hours. Question 6 has 7 parts, all of which ask the 
subjects to rate the impact/interference of their pain on various functions, ie, general activity, 
mood, walking, normal work, relations with others, sleep, and enjoyment of life. 
 
The severity of pain subscale will be computed as the mean of items 1-4. The interference of 
pain subscale will be computed as the mean of the sub-questions of item 6. Question 5, relief 
from pain, will be analyzed on its own. 
 
The questionnaire will be administered at visits 2 through 5. 
 
The baseline pain score will be defined as the score obtained at the randomization visit 2 (day 
1) prior to the first dose of the study drug. 
 
Handling of missing data is described in detail in Section 8.2. 
Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) 
The SF-36 is a generic health survey with 36 items that measure functional health and well- 
being from the subject’s perspective (see Appendix L of the protocol). The 36 questions are 
grouped into 11 sections. Some of the sections consist of multiple questions. The survey is 
summarized into 8 dimensions/scales on a 0-100 scale: 
 
x 
Physical Functioning (PF) 
x 
Role Physical (RP) 


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x 
Bodily Pain (BP) 
x 
General Health (GH) 
x 
Vitality (VT) 
x 
Social Functioning (SF) 
x 
Role Emotional (RE) 
x 
Mental Health (MH) 
 
 
From these 8 dimensions, 2 components will be derived: 
 
x 
Physical component score 
x 
Mental component score 
The questionnaire will be administered visits 2 through 5. 
 
 
The baseline dimension/scale will be defined as the score obtained at the randomization Visit 2 
(day 1) prior to the first dose of the study drug. 
 
 
 
 
 
 
 
 
 
 
  
  
 
. 
 
EQ-5D-5L 
 
EQ-5D-5L is a standardized generic measure of health status for clinical and economic 
appraisal (see Appendix K of the protocol). It is based on a descriptive system that defines 
health in terms of 5 dimensions who have 5 levels of severity (no problems, slight problems, 
moderate problems, severe problems, and extreme problems/unable to): 
 
x 
Mobility 
x 
Self-care 
x 
Usual activities 
x 
Pain/discomfort 
x 
Anxiety/Depression 
It also includes a visual analogue scale (VAS) from 0 (“worst imaginable health state”) to 100 
(“best imaginable health state”). 
 
For each of the dimension the scores will be dichotomized into “no problems” (i.e. level 1) and 
“problems” (i.e. levels 2 to 5). 


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The U.S. population-based indez values based on crosswal value sets for EQ-5D-5L developed 
by EuroQoL Research Funcation (van Hout B et al. 2012) will be derived. 
 
The baseline subscales will be defined as the score obtained at the randomization Visit 2 (day 
1) prior to the first dose of the study drug. 
 
The questionnaire will be administered visits 2 through 5. 
Missing data will not be imputed. 
PGIC Score 
 
The PGIC (see protocol Appendix M) is a self-administered questionnaire which assesses the 
subject’s change in the overall status relative to the start of treatment. The scale has only 1 
item, which measures global change of overall status (improvement or worsening) as evaluated 
by the subject on a 7-point scale from 1 to 7 (lower scores represent better outcomes).  PGIC 
will be assessed at visit 5 (end of study/early discontinuation). 
 
Missing data will not be imputed. 
Supplemental Analgesic Medication Use 
Commercially available APAP/acetaminophen 500mg, will be provided to subjects in bottles 
starting at visit 1. Prior to visit 1, subjects will provide their own supplemental analgesic 
medication (APAP). 
 
For each visit (timepoint), starting at randomization visit 2, the total number of tablets taken will 
be calculated as the number of tablets given minus the number of tablets returned. The 
average daily number of tablets will be calculated by dividing the total number of tablets taken 
during the time interval by the number of days in the interval. 
 
Due to the nature of the data, supplemental analgesic medication for OA tends to have a large 
proportion of zeros (contributed by subjects who do not take any supplemental analgesic 
medication) followed by continuous distribution of nonzero values. Therefore, the supplemental 
analgesic medication for OA will also be summarized categorically during the double-blind 
period.  Preliminarily, the categories will be: 
 
x 
No supplemental actetaminophen tablets, 
x 
0 to  0.5 tablet, 


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x
> 0.5 to  1.0 tablet, 
x 
>1.0 to  2.0 tablets, 
x 
> 2.0 tablets. 
 
Upon review of the blinded data prior to database lock, the categories will be reviewed and if 
any adjustments to the categories are deemed necessary, the rational and new categories will 
be documented in the SAP prior to database lock. 
 
Missing supplemental medication data will not be imputed. 
 
 
Responder to treatment 
 
A subject’s response to treatment is defined as the percentage reduction from the the baseline 
“average pain over the last 24 hours” score to the week 4 pain score from the mBPI-SF pain 
severity subscale.  For each subject, percentage reduction in pain from baseline through 
double-blind treatment will be calculated as: 
 
%reduction = 100 * (baseline pain score – week 4 pain intensity score) / baseline pain score, 
 
If a subject’s week 4 “average pain over the last 24 hours” score is greater than the baseline 
score, the subject will be assigned a 0% reduction in pain. 
 
All subjects who discontinue study drug prior to week 4 will be considered nonresponders and 
will be assigned a 0% reduction in pain. 
 
Responder analysis will be performed based on different cutoffs (<0, 0, >0, 10%, 20%, 30%, 
40%, 50%, 60%, 70%, 80%, 90%, and =100%) for the percent reduction.  Responders 
are defined as having >0 % reduction, non-responders are defined as having <=0% reduction. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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5.2.
SAFETY VARIABLES 
5.2.1.
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject, regardless of whether administered any pharmaceutical product or 
placebo.  An AE does not necessarily have a causal relationship with treatment. 
 
Severity of AEs and will be described using the following categories: mild, moderate, and 
severe. 
 
The relationship of an AE to study drug will be determined by the investigator/medically qualified 
designee (must be MD or DO) after thorough consideration of all facts that are available, and will 
be reported using the following categories: reasonable possibility and no reasonable possibility. 
 
All AEs will be reported starting from the time an informed consent for study participation is 
provided. 
 
AEs assessed as non-serious will be reported through the 7 days following the subject’s last 
study drug dose or until the last study visit, whichever is later.  Non-serious AEs that are 
ongoing at the subject’s last study visit must be followed until resolution or for 30 days after the 
subject’s last study drug dose, whichever comes first. 
 
All AEs must be evaluated as potential Serious Adverse Events (SAEs).  A SAE is any untoward 
medical occurrence that at any dose: 
 
x 
Results in a fatality 
 
x 
Is life-threatening (i.e., the subject was at immediate risk of fatality from the AE as it 
occurred. (This does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death). 
 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
x 
Results in persistent or significant disability/incapacity 
 
x 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) or 


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x 
Is a medically important event or reaction. 
 
All SAEs must be reported starting from the time an informed consent for study participation is 
provided.  If the Investigator becomes aware of an SAE within 30 days after the subject’s last 
study drug dose or study drug, or protocol-specified drug, or standard treatment, or within 30 
days after the last study visit or follow-up phone call, the SAE must be reported.  SAEs must be 
followed until the event resolves, the event or sequelae stabilize, or it is unlikely that additional 
information can be obtained after demonstration of due diligence with follow-up efforts (i.e., the 
subject or health care practioner is unable to provide additional information, or the subject is lost 
to follow up). 
 
Treatment-emergent adverse events (TEAEs) will be assigned to study drug according to their 
onset date. TEAEs are defined as any sign or symptom that emerges during treatment, having 
been absent at pretreatment; or re-emerges during treatment, having been present at 
pretreatment but stopped prior to treatment; or worsens in severity during treatment relative to 
the pretreatment state, when the AE is continuous. In summary, adverse events that started on 
or after the first dose of double-blind study medication up to 7 days (30 days for SAE) after 
subject’s last dose are considered treatment-emergent.  AEs that start more than 7 days (30 
days for SAE) after the last dose of study drug will be considered non-TEAEs. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
. Details on 
summarizing treatment emergent and non-treatment emergent AEs are provided in Section 
11.1. 
 
For analysis purposes, a TEAE will be considered related to study drug if the investigator 
assess the relationship to study drug as a reasonable possibility. 
 
Adverse events of special interest (AESI) will be recorded and reported on the AE of Special 
Interest Notifical Form. The following AESI will be considered: 
 
x 
Disturbances in thermal sensation, which may include: 
o inhibition of thermal sensation and associated AEs such as thermal burns 
o heat sensitivity 
x 
Taste disturbance. 


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5.2.2.
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for chemistry, hematology, and urinalysis evaluation at 
Visit 1, 4, and 5. The clinical laboratory evaluations will be conducted by a central laboratory. 
 
Some of blood/plasma and urine samples collected during the study may be used for future 
exploratory investigative studies, if and as necessary. 
 
A serum pregnancy test will be performed for all female subjects at screening, and at end of 
study or early discontinuation as applicable. A urine pregnancy test will be performed for all 
female subjects prior to the first dose of the study drug and at each study visit. 
 
A list of clinical laboratory evaluations planned for this study is presented in Table 2 (as per 
protocol Appendix A). 
 
 
Table 2 Clinical Laboratory Evaluations 
 
Category 
Parameters 
Hematology 
RBC counts, Hemoglobin, Hematocrit, Platelets, and WBC count with 
differential (Neutrophils, Bands, Lymphocytes, Monocytes, Eosinophils,
Basophils) in percentages (%) and absolute counts
Clinical Chemistry 
Electrolytes 
Sodium, Potassium, Chloride, Calcium Corrected, Magnesium, Bicarbonate
Liver function tests 
Alkaline Phosphatase, Aspartate Aminotransferase (AST/SGOT), Alanine 
Aminotransferase (ALT/SGPT), Total Bilirubin, Direct Bilirubin, Gamma- 
glutamyl transferase (GGTP) 
Renal function 
Blood Urea/Blood Urea Nitrogen, Creatinine, eGFR. 
parameters 
Other 
Urinalysis 
Urine drug test 
Glucose, Albumin, Cholesterol, Triglycerides, Phosphorus, Lactate 
Dehydrogenase (LDH), Total Protein, Globulin, Uric Acid 
pH, Protein, Glucose, Ketone, Occult Blood, RBC, WBC, Epithelial Cells,
Bacteria, Casts, Crystals, Specific Gravity 
Urine screen includes: Amphetamines, Cannabinoids, Opiates, Cocaine
Metabolites, Benzodiazepines, Barbiturates; Phencyclidine, Methadone,
Propoxphene


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Serum pregnancy test
Human Chorionic Gonadotropin (Choriogonadotropin Beta)
Category
Parameters
Urine pregnancy test
Human Chorionic Gonadotropin (Choriogonadotropin Beta)
Virus screen
Hepatitis B, Hepatitis C, Human Immunodeficiency Virus
Subject laboratory values will be classified as low, normal, or high (LNH) according to whether 
the value was below (low), within (normal) or above (high) the laboratory parameter’s reference 
range provided by the central lab. 
 
All clinical laboratory results will also be evaluated for markedly abnormal values according to 
the criteria listed in Table 3 (as per protocol Section 9.7.6.2). 
 
 
Table 3 Laboratory Ranges Used to Identify Markedly Abnormal Laboratory 
Values 
Laboratory Parameter
Markedly Abnormal Rangea
Lower Limita
Upper Limita
Hematology
< 10 g/dL or 100 g/L
—––
Hemoglobin
Platelets
< 75.0 x 109/L or < 75000/mm3
—––
Leukocytes
< 3.0 x 109/L or < 3000/mm3
—––
Lymphocytes
< 0.8 x 109/L or < 800/mm3
—––
Neutrophils
< 1500 x 106/L or < 1500/mm3
—––
Clinical Chemistry
Electrolytes
Sodium
< LLN
> 150 mmol/L
Potassium
< LLN
> 5.5 mmol/L
Bicarbonate (HCO3)
<= 16 mEq/dL or <= 16 mmol/Lb
—––
Liver Function Tests
Alkaline phosphatase
—––
> 2.5 x ULN c
Aspartate aminotransferase (AST)
—––
> 3 x ULN


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Laboratory Parameter
Markedly Abnormal Rangea
Lower Limita
Upper Limita
Alanine aminotransferase (ALT)
—––
> 3 x ULN
Gamme glutamyl transferase (GGTP)
—––
> 2.5 x ULN c
Total bilirubin
—––
> 1.5 x ULN
Renal Function Tests
Creatinine
—––
> 1.5 x ULN or > 1.5 x baseline
eGFR
<=59 ml/min/1.73 m2
Other Chemistry
Calcium corrected
< 8 mg/dL or < 2.0 mmol/L
> 11.5 mg/dL or > 2.9 mmol/L
Phosphorus
< 2.5 mg/dL or < 0.8 mmol/L
—
Fasted > 160 mg/dL or > 8.9
Glucose
< 55 mg/dL or < 3.0 mmol/L
mmol/L
Uric acid
—––
> ULN
Cholesterol
—––
> 300 mg/dL or > 7.75 mmol/L
Triglycerides
—––
> 2.5 x ULN c
Albumin
< 3 g/dL or 30g/L
—––
Abbreviations:LLN=lowerlimitofthelaboratoryreference(normal)range;ULN=upperlimitofthelaboratoryreference
(normal)range.
a Common Terminology Criteria for Adverse Events version 4.03 June 2010, Grade 2 limits (Grade 1 limit if Grade 2 
limit missing), unless otherwise specified. 
b Common Terminology Criteria for Adverse Events version 3.0 Aug 2006, Grade 2 limit. 
c Sponsor defined value. 
 
 
All clinical laboratory results will also be evaluated for critical alert laboratory values according to 
the criteria listed in Table 4 (as per protocol Appendix B). 
 
Table 4 Laboratory Ranges Used to Identify Alert Range Values 
Laboratory Parameter
Alert Laboratory Rangea
Low
High
Hematology 
Hemoglobin
<8.0 g/dL or < 80 g/L
—––


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Chemistry 
Electrolytes 
Platelets 
<50,000mm3 or < 50 x 109/L 
—–– 
Leukocytes (total WBC) 
< 2,000/mm3 or < 2.0 x 109/L 
—–– 
Absolute Neutrophil Count 
< 1,000/mm3 or < 1.0 x 109/L 
—–– 
 
Sodium
< 130 mmol/L
> 155 mmol/L
Potassium
< 3.0 mmol/L
> 6.0 mmol/L
Magnesium 
Bicarbonate (HCO3)
< 0.9 mg/dL or < 0.4 mmol/L 
<=11 mEq/dL or <= 11 mmol/Lb
> 3.0 mg/dL or > 1.23 mmol/L
—––
Liver Function 
Alkaline phosphatase
—––
> 5 x ULN
Aspartate aminotransferase (AST)
—––
> 5 x ULN
Alanine aminotransferase (ALT)
—––
>5 x ULN
Total Bilirubin 
Total Bilirubin (Screening only)
—–– 
—––
> 3 x ULN
>ULNc
Renal Function 
Creatinine 
eGFR
—–– 
<29 ml/min/1.732
> 3 x baseline or >3 x ULN 
—––
Other Chemistry
Calcium Corrected
< 7.0 mg/dL or < 1.75 mmol/L
> 12.5 mg/dL or > 3.1 mmol/L
Glucose
< 40 mg/dL or < 2.2 mmol/L
> 250 mg/dL or> 13.9 mmol/L
Albumin
< 2 g/dL or < 20 g/L
—––
Bilirubin and Liver Function Test
—––
Bilirubin > 34 ȝmol/L and 
any LFT > 3.0 x ULNd
ULN = upper limit of the laboratory reference (normal) range; WBC = white blood cells (count). 
a Common Terminology Criteria for Adverse Events version 4.03 June 2010, Grade 3 limits, unless otherwise specified. 
b Common Terminology Criteria for Adverse Events version 3.0 Aug 2006, Grade 3 limit. 
c Common Terminology Criteria for Adverse Events version 4.03 June 2010, Grade 1 limit. 
d Sponsor defined alert value, based on Hy’s Law. 


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Liver function tests (aspartate aminotransferase, alanine aminotransferase, and total bilirubin) 
results will be categorized according to the criteria listed in Table 5 (as per protocol Section 
9.7.6.2). 
 
Table 5 
Categories for Shift Analysis of AST, ALT, and Total Bilirubin 
AST/ALT
Total Bilirubin
 1 x ULN 
1 x ULN 
> 1 -  3 x ULN 
> 1 – 1.5 x ULN 
> 3 -  5 x ULN 
> 1.5 – 2.0 x ULN 
> 5 -  10 x ULN 
> 2.0 x ULN 
> 10 -  20 x ULN 
— 
> 20 x ULN 
—
Abbreviations: ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; ULN = upper limit of the laboratory reference (normal) range. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  All 
laboratory test results will be reported in SI units. Details on statistical summaries of laboratory 
data by treatment group can be found in Section 11.2. 
 
5.2.3.
Vital Signs 
Vital signs will be collected at planned study visits 1, 2, 3, 4, 5, and may be collected at 
unscheduled study visits.  Vital signs to be collected are the following:  systolic/diastolic blood 
pressure, heart rate, respiration rate (after subject has been seated for at least 5 minutes), and 
temperature. Weight will be obtained at visit 1 and 5, and height will be obtained at visit 1 only. 
When vital signs are scheduled at the same visits as blood samples are obtained, the vital signs 
will be obtained before and as close to the scheduled blood sample as possible. 
 
Abnormal vital sign values will be identified as those outside (above or below) the reference 
ranges defined in Table 6 (as per protocol Section 9.6.4.3). If values outside the normal range 
are observed, the measurements may be repeated at the investigator’s discretion. 


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Table  6 
Reference Range for Vital Sign Values Measured in Supine Position 
 
All vital sign assessments will be evaluated for clinically notable abnormalities as defined in 
Table 7 (as per protocol Section 9.6.4.3). 
 
Table 7 
Criteria Used to Identify Clinically Notable Vital Sign Abnormalities 
Measured in Supine Position 
Vital Sign Parameter
Value
Change From Baselinea
Systolic blood pressure
 180 mm Hg
Increase of  20 mm Hg
 90 mm Hg
Decrease of  20 mm Hg
Diastolic blood pressure
 105 mm Hg
Increase of  15 mm Hg
 50 mm Hg
Decrease of  15 mm Hg
Heart rate
 120 bpm
Increase of 15 bpm
 50 bpm
Decrease of  15 bpm
Respiratory rate
< 12 breaths per minute
—
> 20 breaths per minute
—
a Both value and change from baseline criteria must be met to qualify as a clinically notable abnormality. 
 
 
 
 
5.2.4.
ECGs 
ECG data will be obtained at visits 1 (screening), visit 4 (week 2), and visit 5 (week4). ECG 
parameters include heart rate (bpm), PR interval (msec), RR interval (msec), QRS interval 
Vital Sign Parameter 
Range 
Systolic blood pressure 
100–140 mm Hg 
Diastolic blood pressure 
60–90 mm Hg 
Heart Rate 
60–100 bpm 
Respiratory rate 
12–20 breaths per minute 
Temperature 
36.8°C–38.3°C 


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(msec), uncorrected QT interval (msec), QTcB (Bazett’s correction) interval (msec), and QTcF 
(Fridericia’s correction) interval (msec).  The results of the 12-lead ECG will be transmitted to 
the central ECG provided for interpretation and will be evaluated by the investigator for clinical 
significance. 
 
In order for subjects to enter the study, the baseline QTcF value obtained at the screening visit 
(visit 1) should not exceed 470 msec. To remain in the study, QTcF values for ECG tracings in 
each visit subsequent to screening should not exceed 500 msec or 480 msec with a concurrent 
QTcF change of > 60 msec from baseline. If QTcF values exceed 500 msec or 480 msec with a 
concurrent QTcF change of > 60 msec from baseline, the subject must discontinue study drug 
and the reason for study drug discontinuation will be recorded as AE (protocol section 10). 
 
All ECG abnormalities, including clinically notable abnormalities (Table 8), will be evaluated 
using appropriate medical judgment to determine whether they represent AEs.  Abnormalities 
that require medication intervention are AEs. 
 
 
Table 8 
Criteria Used to Identify Clinically Notable ECG Values 
ECG Parameter
Value
Change From Baselinea
Heart Rate
 100 bpm
Increase of  15 bpm
 50 bpm
Decrease of  15 bpm
QTcF- Screening
> 470
QTcF- During study
> 480
With increase if 60 msec from 
baseline
a Value or change from baseline criteria may be met to qualify as a clinically notable abnormality. 
 
 
For each ECG parameter, subjects will be categorized as having or not at least 1 outlier value 
observed during each period. Outliers are defined as follows (based on mean tracings at each 
visit or over a period): 
 
x 
Heart Rate:  a value for a subject is considered to be an outlier at a postscreening time point 
if the heart rate measurement at that time point is < 50bpm and at least a 25% decrease 
from the subject’s baseline mean heart rate (i.e., a bradycardia event), or if the heart rate 


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measurement at the postscreening time point is > 100 bpm and at least a 25% increase 
from the baseline mean heart rate (i.e., a tachycardia event). 
x 
PR interval: a value for a subject is considered to be an outlier at a postscreening time point 
if the PR interval from the ECG at the postscreening time point is > 200 msec and at least a 
25% increase from the subject’s baseline mean PR interval. 
x 
QRS interval: a value for a subject is considered to be an outlier at a postscreening time 
point if the QRS interval from the ECG at the postscreening time point is > 100 msec and at 
least a 25% increase from the subject’s baseline mean QRS interval. 
x 
QT interval: a value for a subject is considered to be an outlier at a postscreening time point 
if the QT interval from the ECG at the postscreening time point is > 450 msec, and the 
subject’s baseline mean QT interval is > 450 msec. 
x 
QTcF: a value for a subject is considered to be an outlier at a postscreening time point if the 
QTcF interval from the ECG at the postscreening time point is > 450 msec, and the subject’s 
baseline mean QTcF interval is  450 msec. 
 
ECG morphology findings consist of the following: 
x 
Abnormal U wave 
x 
Atrial fibrillation 
x 
Right bundle branch block (RBBB) 
x 
Left bundle branch block (LBBB) 
x 
Left anterior hemiblock (LAH) 
x 
Myocardial infarction (MI) 
x 
ST depression 
x 
T wave (biphasic and/or inverted). 
 
For each of the of the findings listed above, a subject will be categorized as having the specific 
treatment-emergent ECG abnormality if it is observed in at least 1 postscreening period ECG 
morphologic determination, but is absent from all screening baseline results. 


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5.2.5.
Physical Examination 
Physical examination will be performed at visit 1 (screening), visit 2 (Day 1), visit 3 (week 1), 
visit 4 (week 2), and visit 5 (week 4). 
 
5.2.6.
Other Safety Assessments 
HADS questionnaire 
The HADS (see protocol Appendix H) is a self-screening questionnaire that is commonly used by 
physicians and therapists to assess levels of anxiety and depression. The HADS is a self- 
reported 14-item instrument that measures the presence and severity of anxiety and depression 
based on the subject’s experience over the past week. It consists of 2 subscales, each having 7 
items (range 0-3): an anxiety subscale (HADS-A) and a depression subscale (HADS-D). The 2 
subscales, anxiety and depression, have been found to be independent measures.  The score 
for each subscale ranges from 0 (no anxiety or depression) to 21, with a score of 12 or higher 
indicating the probable presence of the mood disorder. Subjects with score > 12 at screening 
visit do not qualify for this study. 
 
The HADS questionnaire will be administered at visit 1 (screening) as well as visit 5 (week 4). 
 
To obtain the anxiety score at a given visit add up all the answers to the odd-numbered 
questions, wheareas to obtain the depression score add up all the answers to the even- 
numbered questions.  Since questions are asked in a positive/negative way, see Protocol 
Appendix H for the scoring of each item as the first answer may be worth 0, 1, 2 or 3 points. 
Missing scores will be imputed as described in Section 8.2. 
 
Kellgren-Lawrence (K-L) 
The K-L criteria (see protocol Appendix G) are used to classify the severity of knee 
osteoarthritis.  It consists of 5 grades (ranging from grade 0 = no radiographic features of OA to 
grade 4= severe OA with large osteophytes, marked narrowing of the joint space, severe 
sclerosis, and definite deformity of the bone ends). The K-L will be performed at visit 1 
(screening) and visit 5 (week 4).  Subjects meeting K-L criteria 0, 1, or 4 do not qualify for this 
study. 
 
Since the goal of using this scale is to distinguish definite mild/moderate OA (K-L grades  2) 
from none, the original version (Kellgren & Lawrence 1957) will be used in this study. 


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Columbia-Suicide Severity Rating Score (C-SSRS) 
The C-SSRS scale (Protocol Appendix O) consists of a baseline/screening evaluation that 
assessed the lifetime and prior 24 month experience of the subject with suicide events and 
suicidal ideation and a post baseline ”Since Last Visit” evaluation that focuses on suicidality 
since the last study visit. The C-SSRS is a prospective assessment instrument that directly 
classifies suicidal ideation and behavior into categories. The C-SSRS involves a series of 
probing questions to inquire about possible suicidal thinking and behavior. 
 
5.3.
ADDITIONAL VARIABLES 
5.3.1.
PK and PG Variables 
PK and PG analyses will be described in separate documents and will be presented in separate 
reports. 
 
5.3.2.
Chemotherapy-induced Taste Alteration Scale (CiTAS) 
Subjects will rate their evaluation of taste alterations for the 18 items and 5 subscales on the 
CiTAS, a 5-point Likert-type scale (Protocol Appendix P). The scores received from each 
subscale will be evaluated rather than the total score received from the entire scale. The 
subscale scores will be obtained by dividing the number of the items into the sum of scores of 
those items as follows: 
 
x 
Decline in basic taste: add up score from question 2 to question 6, and divite it by 5. 
 
x 
Discomfort: add up score from question 13 to question 18, and divide it by 6. 
 
x 
Phantogeusia and parageusia:  add up score from question 10 to question 12, and 
divide it by 3. 
 
x 
General taste alterations:  add up score from question 1 and question 7 to question 9, 
and divide it by 4. 
 
The maximum score is 5 ppints, whereas the minimum score is 1 point that can be received 
from subscales. 


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6.
SAMPLE SIZE DETERMINATION 
A total of up to 276 subjects is planned to be randomized to the double-blind period of this study 
using a 1:1:1:1 randomization ratio; ie, approximately 69 subjects are to be randomized to each 
of the 4 treatment groups (V120083 [60 mg or 30 mg], naproxen [active comparator], or 
placebo). The actual number of subjects treated will depend on the outcome of the interim 
analysis. 
 
The analgesic effect size of V120083 is unknown.  Therefore, the sample size calculation is 
based on a clinically important difference for OA pain reduction of 1 unit on an 11-point NRS (0 
to 10). 
 
 
 
 
 
 
  
 
 
 
 
 This study may provide appropriate information for the data variability in the sample 
size calculations.  The SD for average pain over the last 24 hours, an individual question of the 
mBPI-SF at week 4 was approximately 2.34. With a fixed sample size study design, the sample 
size needed for 80% power to detect this difference with a significance level of 0.05 (1-sided) is 
69 subjects per arm, assuming a 1:1 randomization ratio of each active arm to placebo. The 
sample size calculation was performed in nQuery+nTerim 3.0. 
 
7.
ANALYSIS POPULATIONS 
If there is at least one subject for whom planned/randomized treatment is not the same as the 
actual treatment received, all safety displays will use the actual treatment received, and all 
efficacy displays will use the planned/randomized treatment. 
 
7.1.
ENROLLEDPOPULATION 
The enrolled population consists of all subjects who signed the informed consent form. 
 
7.2.
SAFETY POPULATION 
The safety population consists of subjects who were randomized and received at least 1 dose of 
the double-blind study drug. Subjects will be analyzed according to the treatment they received. 
The safety population will be used to analyze all safety endpoints. 


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7.3.
FULL ANALYSIS POPULATION 
The full analysis population consists of subjects who were randomized and received at least 1 
dose of the double-blind study drug, and have at least 1 efficacy assessment. This population 
will be used to analyze all efficacy endpoints, unless otherwise stated. Following the intention- 
to-treat principle, data from subjects in this population will be analyzed according to their 
randomized treatment. 
 
7.4.
PER PROTOCOL POPULATION 
The per protocol population consists of subjects in the full analysis population without any major 
protocol deviations. Major protocol deviations will be defined prior to database lock.  Per 
protocol population will be used for supportive analysis to assess robustness of the primary 
analysis. 
 
7.5.
PROTOCOL DEVIATIONS 
Protocol deviations will be identified in two ways: programmatically and through monitoring 
reviews.  The deviations identified through monitoring are classified according to the 9 
categories listed below and will be assigned a severity flag (major/minor) according to pre- 
specified rules. 
 
1. Informed consent 
2. Eligibility and Entry Criteria 
3. Prohibited Medication 
4. Laboratory Assessment Criteria 
5. Study procedure Criteria 
6. Visit Scheduled Criteria 
7. IP Compliance 
8. Rescue Medication 
9. Other Criteria 
 
 
 
Some of these deviations are considered major from an operations perspective but may not 
affect the efficacy evaluations. Therefore, for purposes of analysis, the monitoring flag will not 


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be used, although the classification of deviations as major or minor will be retained in the 
listings. All programmed deviations defined below, are affecting the efficacy evaluations and 
therefore lead to the exclusion of subjects from the per-protocol population: 
 
1) Known protocol deviations identified from the subject qualification CRF and/or 
inclusion/exclusion entry criteria. 
 
2) Non-randomized subject who received study medication or subject who received wrong 
study medication, as per the randomization list. 
 
3) Subjects who discontinued before the end of the study. Even if protocol allows for early 
discontinuation, this has a major impact on the primary efficacy endpoint (“average pain 
over the last 24 hours” at week 4). 
 
4) Prohibited prior, concomitant, or supplemental medication deviations. 
 
5) Overall study drug compliance < 80% or >120% for the active treatment or for both 
tablets and capsules for the placebo group. 
 
6) Missing “average pain over the last 24 hours”  at week 4. 
 
8.
GENERAL STATISTICAL CONSIDERATIONS 
8.1.
ADJUSTMENTS FOR COVARIATES 
Details of adjustments for covariates for the efficacy variables and the definition of these 
covariates are detailed in Sections 10.1 and 10.2. For each primary and secondary efficacy 
variable analyzed using MMRM, the baseline values will be included as covariates in the model. 
 
Exploratory/subgroup analyses with adjustment for covariates may be performed for further 
scientific interest in order to look for explanatory variables related to the occurrence of primary 
safety and efficacy endpoints.  Models predicting study endpoints may be developed with 
potential covariates inclusion in the analysis.  The covariates will be chosen and pre-specified 
from among the baseline and demographic variables. 


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8.2.
HANDLING OF DROPOUTS OR MISSING DATA 
Weekly “average pain over the last 24 hours”: 
If more than 3 scores are missing in the “average pain over the last 24-hours” then the resulting 
average will be treated as missing. 
 
Weekly average “daily pain right now”: 
If more than 3 scores are missing in the “pain right now” then the resulting average will be 
treated as missing. 
 
WOMAC: 
x 
Pain subscale: Calculated by summing items 1-5.  If 2 or more pain scores are missing, 
then the pain subscale will be set to missing; otherwise, the average multiplied by 5 of 
the nonmissing pain scores will be used for the missing pain scores. 
x 
Stiffness Subscale:  Calculated by summing items 6-7.  If both stiffness scores are 
missing, then the stiffness subscale will be set to missing. If 1 stiffness score is missing, 
then the nonmissing stiffness score will be multiplied by 2 for the analysis. 
x 
Physical Function Subscale: This scale is calculated by summing items 8-24.  If 4 or 
more physical functioning scores are missing, then the physical functioning subscale will 
be set to missing; otherwise, the average multiplied by 17of the nonmissing physical 
function scores will be used for the missing physical functioning scores. 
x 
Composite Scale: Calculated by summing 3 subscales: (pain subscale + stiffness 
subscale + physical functioning subscales). If 1 or more of the subscales is missing, 
then the composite scale will be set to missing. 
x 
The mean subscales/scale will be imputed the same way as the sum subscales/scale. 
 
mBPI-SF: 
If more than half of the items in either the severity of pain subscale (3) or the interference of 
pain subscale (4) are missing, then the resulting subscale score will be treated as missing. 
Otherwise, if half the items or less in a particular subscale are missing, then for the purpose of 


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computing the subscale score, the item’s scoring value will be imputed by the mean score from 
the other items within the subscale. 
 
 
 
PGIC: 
No imputation will be done for the PGIC. 
 
 
 
Supplemental Medication use: 
No imputation will be done for the analysis of supplemental medication use. 
 
 
 
HADS: 
If more than 1 item in either the anxiety subscale or the depression subscale are missing, then 
the resulting subscale score will be treated as missing. Otherwise, if 1 item or less in a 
particular subscale is missing, then for the purpose of computing the subscale score, the item’s 
scoring value will be imputed by the mean score from the other items within the subscale. 
 
 
Columbia-Suicide Severity Rating Score (C-SSRS): 
No imputation will be done for the C-SSRS. 
 
8.3.
INTERIM ANALYSES AND DATA MONITORING 
An interim analysis may be conducted when approximately 50% of randomized subjects have 
completed the end-of-study visit.  The unblinded interim analyses will be performed by an 
unblinded statistical team, which includes a statistician and programmers not associated with 
the study team.  The unblinded statistical team will provide partially unblinded tables to the 
reviewers, by partially unblinded tables it is meant that instead of having the treatment names 
on each column, it will be presented as “Treatment A”, “Treatment B”, etc. The unblinded 


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statistician will provide the unblinded treatment information to the DMC members only if 
requested. The data review will be performed by an independent data monitoring committee. 
Additional data reviews may be conducted as deemed necessary. The sponsor may request 
additional (ad hoc) DMC recommendations throughout the study. 
 
At the interim analysis, the following procedures will be performed: 
 
1) Safety evaluation for early termination will be performed when 50% of subjects have 
completed the study. The independent statistician/programmer will provide safety data 
listing and summary tables by partially unblinded treatment groups. The DMC members 
will review the safety data, including but not limited to AEs, clinical laboratory values, C- 
SSRS listing, ECGs and Chemotherapy-induced Taste Alteration Scale (CiTAS). The 
decision to stop 1 or more treatment groups due to safety issues will be made based on 
clinical judgment. The arm will be stopped if there is significant physical toxicity or 
evidence of impending risk of physiologic harm or extremely abnormal laboratory 
findings related to treatment. 
 
2) Futility evaluation for V120083 treatment arms will be performed by the independent 
statistician/programmer when 50% of subjects have completed the study. The 50% 
interim analysis will be performed to evaluate the futility of each dose of study drug in the 
study population on the primary efficacy parameter. The DMC will review the results of 
the analysis and make recommendations, based on the pre-specified futility stopping 
criteria, regarding plans for further studies. The unblinded biostatistician will also pass 
unblinded conditional powers and relevant efficacy summary outputs to Internal DMC 
members for reviewing the results of futility analysis. Only the conditional power will be 
provided, no p-values, no confidence intervals will be presented for the primary efficacy 
parameter. No summaries on other efficacy parameters will be provided.  Please refer to 
DMC charter for the appointed internal DMC members and the procedures to ensure    
the integrity of blinding. 
 
3) Futility stopping criteria: Stop the trial if the conditional powers of both V120083 30 mg 
BID and 60 mg BID groups fall below the value of 0.2. The conditional power is based on 
one-sided test (Type I Error Rate = 10%). 
 
Lan et all (1982) introduced stochastic curtailment to stop a trial if, given current data, it is likely 
to predict the outcome of the trial with high probability.  The conditional power at the scheduled 
end of the study, given the observed data at the interim evaluation, will be calculated with a 
stochastic curtailment approach to support the decision of early termination for futility.  SAS 9.2 


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PROC SEQTEST will be used to calculate the conditional power based on the formula given by 
Cui et al and Emerson et al (2005, p.13).. 
 
An external data monitoring board will be used for this study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  An Interim 
Analysis charter, including more administrative details, will be written and approved before the 
interim analysis. 
 
 
 
8.4.
MULTI-CENTER STUDIES 
All investigative sites within a US census region (West, Midwest, Northeast and South) with 
fewer than 8 randomized subjects will be combined into a single pooled site for analysis 
purposes. If a resulting pooled site still has fewer than 8 randomized subjects, then this pooled 
site will be further combined with the smallest unpooled site within that region. If there is not 
another unpooled site within that region, then the pooled site will be combined with the smallest 
pooled site from another region. This pooling process will continue until there are at least 8 
randomized subjects in each pooled site. 
 
Detailed steps: 
1. All sites within a US census region with fewer than 8 subjects will be combined into a 
single pooled site. If a resulting pooled site still has fewer than 8 subjects, then 
proceed to the next step. 
2. The pooled site (<8) will be further combined with the smallest unpooled site within 
that region. If there is not another unpooled site within that region, then proceed to 
the next step. 
a. If several unpooled sites within the region have the smallest subjects (tie), the 
preference is to select the unpooled site that is the closest to the site in 
distance. 
b. If there are still more than one unpooled site within the region after evaluating 
the distance, an unpooled site will be selected randomly to combine with the 
pooled site (<8) from step 1. 
3. The pooled site will be combined with the smallest pooled site from another region. 


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If some sites are very small, per ICH guidance (E9 section 3.2), a graphical exploration of the 
homogeneity of treatment effects across sites will be provided for the primary efficacy variable if 
appropriate. 
 
 
8.5.
MULTIPLE COMPARISONS / MULTIPLICITY 
No multiplicity adjustment will be performed for this study. 
 
8.6.
EXAMINATION OF SUBGROUPS 
No formal subgroup analyses are planned for efficacy and safety variables. 
 
9.
STUDY POPULATION CHARACTERISTICS 
9.1.
SUBJECT DISPOSITION 
Subject disposition will be summarized for the screening period for all subjects in the enrolled 
population and by treatment groups for the double-blind period in the safety population. 
 
The number and percentage of subjects who completed, and the number and percentage of 
subjects who discontinued, along with the distribution of the reasons for discontinuation will be 
presented for all enrolled subjects during the screening period and for all randomized subjects in 
the safety population. Additionally, there will be a cumulative display of subject disposition and 
reason for discontinuation of the study drug by double-blind visit for the safety population. 
 
The number and percent of subjects in each analysis population will be presented. All 
disposition data will be presented in data listings. 
 
9.2.
MAJOR PROTOCOL DEVIATIONS 
All protocol deviations (see section 7.5) will be listed. The listing will include an indicator for 
major/minor deviations. 
 
Major protocol deviations will be summarized using counts and percentages for the safety 
population during the double-blind period. 


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9.3.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
The continuous demographic/baseline variables (e.g.: age, weight, height, BMI, “average pain 
over the last 24 hours” (baseline value and screening value that qualifies subject), and WOMAC 
[pain subscale, stiffness subscale, physical function subscale, and composite scale]) will be 
summarized using mean, median, standard deviation, minimum, and maximum values.  For 
categorical (nominal) variables (e.g., age group, gender, race, ethnicity, stratified baseline pan 
score [moderate or severe], and Kellgren-Lawrence grade), the number and percentage of 
subjects will be used. 
BMI (kg/cm2) will be calculated as baseline (weight (kg)/[screening height(cm)/100]2). 
Demographic/baseline variables will be summarized by treatment group for the subjects in the 
safety population.  Demographic/baseline variables will also be summarized by subjects who 
completed the study and those who discontinued for the safety population.  All demographic and 
baseline characteristic data will be listed. 
 
9.4.
DOSING AND EXTENT OF EXPOSURE 
The double-blind period begins on the day the fist double-blind study drug is administered. The 
number and percentage of subjects exposed to double-blind treatment for overlapping time 
intervals (e.g.: any exposure,  1 week,  2 weeks,  4 weeks) in the double-blind period will be 
calculated by treatment group for the safety population.  Descriptive statistics (mean, standard 
error, median, minimum, and maximum) will be provided to summarize the length of exposure 
(in days) to each treatment . 
 
Exposure (days) = last dose date minus first dose date of study medication + 1 
 
A data listing of the study drug dosage administered to each subject during the double-blind 
period as well as the number of capsules dispensed and returned for each patient and visit will 
be provided. 
 
Time to discontinuation of double-blind study drug is equal to the exposure (days) defined 
above.  Subjects who completed the study are censored at the time of their last dose.  A figure 
using the Kaplan-Meier method will be used to estimate the distribution of the time to 
discontinuation. 
 
Compliance will be calculated using this formula: 


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(Total number of capsules dispensed – total number of capsules returned) X 100 
Expected number of capsules to be taken 
 
The expected number of capsules to be taken is based on the exposure (as defined above) 
times 6 (as subjects are expected to take 6 capsules per day). 
 
Subjects will be considered non-compliant if their overall compliance during the double-blind 
period is not within 80% to 120% (inclusive) for the active drug (V120083 or Naproxen). The 
count and percentage of subjects compliant and non-compliant with study drug during the 
double-blind period will be summarized by treatment group using the following categories: 
<80%, 80%-120%, and >120%. 
 
 
9.5.
PRIOR AND CONCOMITANT MEDICATION AND THERAPIES 
Prior and concomitant therapy includes all medications (over-the-counter (OTC) and/or 
prescription, including analgesics except sponsor-provided supplemental analgesic medication), 
procedures, and significant nonpharmacological therapies that are used to treat the subject, 
including those used in response to an AE/SAE, during the time periods relevant to study 
conduct. 
 
Any prior (within 30 days of screening) and concomitant therapy taken by a subject during the 
course of the study and the reason for its use will be documented. 
 
Medications and therapies that the subject received within 30 days of screening and stopped on 
or before the date of the first dose of double-blind study medication will be considered as prior. 
All medications and therapies that the subject received on or after the date of the first dose of 
double-blind study medication up until 7 days after the last dose of study medication will be 
considered as concomitant. 
 
Medications stopped on the day of the first double-blind dose will be considered as both prior 
and concomitant. 
 
 
 
 
 
 
 
  
  
 
 
 
Prior and concomitant medications and therapies will be coded to World Health Organization 
Drug Dictionary (WHO DD enhanced) version 01SEP2016 terms. A dictionary listing of all 
unique concomitant medications used in the study will be provided, sorting medications by drug 
class and preferred drug name. 


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Prior medication/therapy will be summarized by treatment group for the safety population. 
 
Concomitant medication/therapy will be summarized similarly. In each of the above summary 
tables, the number of subjects taking each medication/therapy will be presented by anatomical 
therapeutic chemical (ATC) names (levels 1, 2, 3). Each subject taking the same therapy more 
than once will be counted once within each ATC code level. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
All prior and concomitant therapies as well as supplemental analgesic medications used during 
the study will be presented in data listings. 
 
9.6.
MEDICAL HISTORY 
Medical history will be coded to Medical History Dictionary for Regulatory Activites Terminology 
(MedDRA, version 19.1 terms.  Coded medical history terms will be summarized by System 
Organ Class and Preferred Term for the safety population by treatment group. 
 
Multiple entries for an individual subject under the same System Organ Class/Preferred Term 
will only be counted once. 
 
9.7.
KELLGREN-LAWRENCE 
The total number of subjects responding to each grade (no OA, doubtful, mild, moderate, 
severe) will be summarized descriptively (number of subjects and percentages) for each 
treatment group. The mean of the grades will also be summarized for each treatment group. 
 
10.
EFFICACY ANALYSES 
All efficacy analyses will be conducted on the full analysis population.  An analysis of the  
primary efficacy variable on the per-protocol population will also be performed. Primary 
hypothesis test will be one-sided with a 5% significance level.  For each of the following primary, 
secondary, and 
 
 the primary contrast will be those between placebo and 
each dose of study drug. The placebo and the active control will be compared to assess assay 
sensitivity. 
 
All efficacy data will be listed by investigator, subject and treatment group. 


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Descriptive statistics for a continuous variable will include mean, standard deviation, median, 
minimum, and maximum.  Descriptive statistics for a categorical variable will include count and 
percent. 
 
10.1.
PRIMARY EFFICACY VARIABLE(S) 
The primary efficacy variable is defined in Section 5.1.1. 
 
 
 
10.1.1. Analysis for Primary Efficacy Endpoint 
Descriptive Summaries 
For the primary efficacy endpoint, the “average pain over the last 24 hours” score from the 
mBPI-SF pain severity subscale at week 4 of the double-blind period, descriptive statistics will 
be tabulated by treatment and by timepoint (baseline and double-blind weeks 1, 2 and 4). 
Change from baseline to post-baseline timepoints will also be presented. 
 
 
 
 
Statistical Analysis 
Primary Statistical Analysis Model 
The primary efficacy analysis of the “average pain over the last 24 hours” score at week 4 
comparing the two levels of the study drug vs. placebo will be performed using a mixed-effects 
general linear model with repeated measures (MMRM).  The model will include treatment (4 
levels: 60 mg bid or 30 mg bid of V120083, 500mg bid naproxen, and placebo), and time (3 
levels: end of week 1 (visit 3), end of week 2 (visit 4), and end of week 4 (visit 5 end of study)) 
as fixed effects, and treatment by time interaction; the baseline score as fixed covariate, and 
subjet as random effect. The pooled sites (based on US census regions) and disease status 
(moderate, severe) will also be included in the model if they are not causing issues in the model 
convergence, otherwise they will be removed.  Restricted maximum likelihood (REML) will be 
used to estimate the parameters in the model. The “average pain over the last 24 hours” score 
will be modeled as a dependent variable with repeated measures within subject. 




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10.1.2. Hypothesis Testing for the Primary Efficacy Endpoint 
The null hypothesis corresponding to the primary efficacy comparisons (each dose of V120083 
versus placebo) will be considered as distinct. 
 
The null hypothesis to be tested is: 
H0: ȝ30 = ȝ60 = ȝp 
The (1-sided) alternative hypothesis is: 
 
H1: (ȝ30 or ȝ60) - ȝp < 0 
Where ȝp, ȝ30 and ȝ60 are the treatment effect of Placebo, V120083 30mg and V120083 60mg, 
respectively. 
 
Both hypothesis (V120083 30mg or 60mg bid versus placebo) will be tested simultaneously, 
without order or alpha level adjustment strategy. 
 
10.2. SECONDARY EFFICACY VARIABLE(S) 
All secondary efficacy variables are defined in Section 5.1.2. The analyses of the secondary 
efficacy variables will be carried out for the FAP by treatment group. 
 
10.2.1. Weekly “average pain over the last 24 hours” collected by e-Dairy 
The weekly “average pain over the last 24 hours” collected by e-Dairy will be analyzed in a 
similar manner as for the primary endpoint. 
 
Descriptive statistics will be tabulated by treatment and by timepoint (baseline and double-blind 
weeks 1, 2 and 4).  Change from baseline to post-baseline timepoints will also be presented. 
 
Estimates of the means, LSMeans (95% CI) at each visit during the double-blind period will be 
presented graphically. 
 
10.2.2. Average daily “pain right now” collected by e-Dairy 
Summary statistics (mean, SD, median, and range) for the average daily “pain right now” scores 
will be provided by weeks and treatment group for all subjects in the full analysis population. 


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Estimates of the means, LSMeans (95% Cis) at each visit during the double-blind period will be 
presented graphically. 
 
10.2.3. WOMAC total score 
The WOMAC total score, will be analyzed using the same MMRM model as the primary efficacy 
variable. 
 
Descriptive statistics will be tabulated for the total score by treatment and timepoint (baseline, 
weeks 1, 2 and 4).  Change from baseline to post-baseline timepoints will also be presented. 
 
Estimates of the means, LSMeans (95% CIs) at each Visit during the double-blind period will be 
presented graphically. 
 
The WOMAC mean score will be summarized similarly. 
 
10.2.4. WOMAC pain severity subscale 
The WOMAC pain severity subscale (total score and mean score), will be analyzed using the 
same MMRM model as the primary efficacy variable. 
 
Descriptive statistics will be tabulated for the pain subscale by treatment and timepoint 
(baseline, weeks 1, 2 and 4).  Change from baseline to post-baseline timepoints will also be 
presented. 
 
Estimates of the means, LSMeans (95% CIs) at each Visit during the double-blind period will be 
presented graphically. 
 
10.2.5. WOMAC physical function subscale 
The WOMAC physical function subscale (total score and mean score), will be analyzed using 
the same MMRM model as the primary efficacy variable. 
 
Descriptive statistics will be tabulated for the physical function subscale by treatment and 
timepoint (screening, baseline, weeks 1, 2 and 4). Change from baseline to post-baseline 
timepoints will also be presented. 
 
Estimates of the means, LSMeans (95% CIs)at each Visit during the Double-Blind Period will be 
presented graphically. 


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10.2.6. WOMAC stiffness subscale 
The WOMAC stiffness subscale (total score and mean score),  will be analyzed using the same 
MMRM model as the primary efficacy variable. 
 
Descriptive statistics will be tabulated for the stiffness subscale by treatment and timepoint 
(baseline, weeks 1, 2 and 4).  Change from baseline to post-baseline timepoints will also be 
presented. 
 
Estimates of the means, LSMeans (95% CIs) at each Visit during the Double-Blind Period will 
be presented graphically. 
 
10.2.7. mBPI-SF total scores (all parts of the 6 questions) 
The mBPI-SF individual questions, will be analyzed using the same MMRM model as the 
primary efficacy variable. 
 
Descriptive statistics (mean, standard deviation, median, minimum, and maximum) will be 
generated by treatment group and visit will be tabulated. Change from baseline to post-baseline 
timepoints will also be presented. 
 
10.2.8. mBPI-SF pain severity subscale 
The mBPI-SF severity of pain subscale, will be analyzed using the same MMRM model as the 
primary efficacy variable. 
 
Descriptive statistics will be tabulated for pain subscale by treatment  and by timepoint.  Change 
from baseline to post-baseline timepoints will also be presented. Decrease in % change from 
baseline >30% or >50% will be presented for mBPI-SF question 3 (average pain in the last 24 
hours). 
 
Estimates of the means, LSMeans (95% CIs) at each Visit during the double-blind period will be 
presented graphically. 
 
10.2.9. mBPI-SF pain interference subscale 
The mBPI-SF pain interference subscale, will be analyzed using the same MMRM model as the 
primary efficacy variable. 
 
Descriptive statistics will be tabulated for pain interference by treatment  and by timepoint. 
Change from baseline to post-baseline timepoints will also be presented. Decrease in % 


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change from baseline >30% or >50% will be presented for mBPI-SF question 3 (average pain in 
the last 24 hours). 
 
Estimates of the means, LSMeans (95% CIs) as well as treatment difference (versus Placebo) 
at each Visit during the double-blind period will be presented graphically. 
 
10.2.10. SF-36 
There are 8 dimensions/scales: physical functioning (PF), role-physical (RP), bodily pain (BP), 
general health (GH), vitality (VT), social functioning (SF), role-emotional (RE), and mental health 
(MH).  In addition to the 8 scales, 2 summary measures will be derived: 
 
Physical component summary (PCS) measure (aggregate of PF, RP, BP, and GH scales); and 
Mental component summary (MCS) measure (aggregate of VT, SF, RE, and MH scales). 
 
 
 
 
 
 
 
 
  
  
 
. 
 
The PCS and MCS measures will be analyzed using the same MMRM model as the primary 
efficacy variable. 
 
Descriptive statistics (mean, standard deviation, median, minimum, and maximum) will be 
generated by treatment group and visit for the Physical Health Component Measure and Mental 
Health Component Measure (see Section 5.1.2). 
 
10.2.11. EQ-5D-5L 
The same MMRM model as the primary efficacy variable will be used for the VAS score (how 
good or bad is your health today (0-100)). 
 
Descriptive statistics will be tabulated by treatment and by timepoint.  Change from baseline to 
post-baseline timepoints will also be presented. 
 
The proportions (n, %) of subjects with no problems (includes dimension 1)/problems (includes 
dimension 2, 3, 4, 5) will be summarized descriptively for the five dimensions (mobility, self- 
care, usual activities, pain/discomfort, anxiety/depression). 
 
Fisher’s exact test will be used for comparison between the treatment groups, and a generalized 
estimating equation (GEE) wll be used for the analysis over time. 


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10.2.12. PGIC at the end of double-blind period (week 4) 
Descriptive statistics will be reported for the PGIC score at the end of study visit by treatment. 
The categories will be compared between treatment group and placebo using the Chi-Squared 
test. 
 
Further dichotomous analysis will be conducted on collapsed categories (very much 
improved/much improved vs minimally improved/no change/minimally worse/much worse/very 
much worse) using Fisher’s exact test. 
 
Mean of PGIC scores for each treatment, 95% CI for difference from placebo and associated p- 
values will be based on an ANOVA model with treatment (4 levels) as fixed effect. All 
comparisons versus placebo will be performed. 
 
10.2.13. Supplemental analgesic medication use 
The percentage of subjects who require no supplemental APAP during the double-blind period 
will be reported for each treatment group separately and 95% binomial confidence intervals with 
normal approximation with a correction for continuity will be constructed for each proportion. 
 
In addition, the average daily number of supplemental acetaminophen 500mg, as detailed in 
Section 5.1.2, will be summarized descriptively by treatment groups for double-blind week 1, 
week 2, week 4 and overall for the double-blind period. 
 
The average daily number of supplemental acetaminophen 500mg for each timepoint will also 
be reported using the categories defined in Section 5.1.2. 
 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) will be presented by 
treatment group. Due to the nature of the data, supplemental pain medication for OA tends to 
have a large proportion of zeros (contributed by subjects who do not take any supplemental 
pain medication) followed by continuous distribution of nonzero values.  Therefore, the 
supplemental pain medication for OA will also be summarized categorically.  Preliminarily, the 
categories will be (1) no supplemental acetaminophen tables, (2) 0 to 0.5 tables, (3) >0.5 to 1 
tablets, (4) >1.0 to 2.0 tablets, and (5) >2.0 tablets.  Upon review of the blinded data prior to 
database lock, the categories will be reviewed. 
 
10.2.14. Responder to treatment 
The definition of responder to treatment is defined in Section 5.1.2. The number and 
percentage of subjects with a response to treatment will be summarized by treatment group. 


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The proportion of subjects with a response (>0% reduction) to treatment at week 4 will be 
compared using a logistic regression model with “responder” (yes/no) as dependent variable, 
treatment and baseline pain score as covariate. 
 
A graph of the observed cumulative percentage of subjects vs percentage reduction in pain from 
screening pain score will be generated by treatment group. Based on this graph, estimates of 
percentage of responders for the following cutoffs: (<0, 0, >0, 10%, 20%, 30%, 40%, 
50%, 60%, 70%, 80%, 90%, and =100%) for each treatment group will be computed and 
graphed. 
 
The same analyses will also be performed on the responders based on the weekly “average 
pain at week 4” collected by e-diary. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.
SAFETY ANALYSES 
Evaluation of safety will be performed for all subjects in the safety populations, unless stated 
otherwise. 


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11.1.
ADVERSE EVENTS 
AEs will be coded to MedDRA terms using MedDRA version 19.1. An adverse event dictionary 
listing will be produced presenting by MedDRA System Organ Class, Preferred Term and all 
lower level terms and verbatim descriptions associated with the Preferred Terms. This listing 
will be sorted by MedDRA System Organ Class and Preferred Term. 
 
The definition of TEAEs used in this study is provided in Section 5.2.1. Only TEAEs will be 
included in summary tables. 
 
The incidence of TEAEs and of AESIs will be summarized by System Organ Class, MedDRA 
Preferred Term and treatment (if appropriate) by presenting the number and percentage of 
subjects with an AE.  A subject will be counted only once in the incidence count for a specific 
MedDRA Preferred Term, although a MedDRA Preferred Term might be recorded more than 
once for a particular subject. 
 
Separate summaries will be provided for TEAEs by maximum severity (mild, moderate, severe), 
relationship (yes, no) to study drug, TEAE leading to study drug discontinuation and TEAE 
leading to study discontinuation. A TEAE will be considered related to study drug if the 
investigator reported the event to be a reasonable possibility (if reported as definitely, probably 
or possibly) that it is related to treatment. 
 
In addition, a table of TEAEs occurring in 5% of the subjects in at least 1 treatment group will 
be presented. 
 
Individual subject listings of AEs that resulted in death, or other SAEs, and of AES that led to 
treatment discontinuation, dose interruption, or dose reduction, and AESIs will be generated. 
These listings will include the treatment group and dose (if applicable) at the time of AE onset, 
start and stop dates of the AE, days on study, and days on treatment. 
 
Summaries of TEAEs occurring in the double-blind period will be generated by treatment group 
and for all subjects who received V120083 (30 and 60mg) for subjects in the safety population. 


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11.2.
CLINICAL LABORATORY EVALUATIONS 
For each laboratory test, abnormal values will be identified as those outside (above or below) 
the reference range and will be flagged in the by-subject listings. Laboratory test results will be 
assigned a LNH classification according to whether the value is below (L), within (N), or above 
(H) the laboratory parameter’s reference range (as defined in Section 5.2.2). 
 
Within treatment comparisons during the double-blind phase will be based on 3-by-3 tables 
(shift tables) that, for a particular laboratory test, compare the baseline LNH classification to the 
LNH classification at the end of double-blind treatment for the safety population. 
 
Similar shift tables will be produced for urinalysis test (pH and specific gravity) results. 
 
Summary statistics (n, mean, standard deviation, median, minimum, and maximum) for 
baseline, end of double-blind and change from baseline to end of double-blind values of 
continuous laboratory parameters will be produced by treatment group for subjects in the safety 
population. 
 
All clinical laboratory results will be evaluated for markedly abnormal values, as defined in 
Section 5.2.2.  A listing of all subjects in the safety population with at least 1 markedly abnormal 
laboratory value will be prepared; for a given subject, in addition to the flagged markedly 
abnormal laboratory parameters, the listing will present the results of all scheduled and 
unscheduled study evaluations of the same laboratory parameter whether or not they are 
markedly abnormal. The incidence of markedly abnormal laboratory tests will be summarized by 
treatment group for all subjects in the safety population.  For these calculations, each subject 
may be counted once in the laboratory parameter high and in the laboratory parameter low 
categories as applicable.  A similar summary table and listing will be provided for alert   
laboratory values, as defined in Section 5.2.2. 
 
Additional analyses of liver function tests (AST, ALT, and total bilirubin) will be conducted by 
generating shift tables using the categories presented in Section 5.2.2, Table 5.   Shift 
summaries will be generated comparing baseline values to end of double-blind values. 
 
A listing of all subjects in the safety population with liver function test results for AST and ALT > 
3 X ULN or total bilirubin > 1.5 X ULN will be generated. 


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All laboratory test results will be reported in SI units.  Laboratory tests to be summarized are 
specified in Appendix. 
 
A listing of the reference (normal) ranges for laboratory parameters will be included in the 
clinical study report for this protocol. 
 
Urine drug test and urine/serum pregnancy test results will be listed only. 
 
 
11.3.
VITAL SIGNS 
Vital sign listings will be provided for the safety population.  Vital sign (systolic blood pressure 
[mmHg], diastolic blood pressure [mmHg], pulse rate [beats/min], respiratory rate [breaths/min], 
and temperature [C]) summary tables will be presented by treatment group for subjects in the 
safety population. 
 
Abnormal vital sign values will be identified as those outside (above or below) the reference 
ranges defined in Section 5.2.3, Table 6. The incidence of abnormal vital sign values during the 
double-blind phase will be presented by treatment for subjects in the safety population. 
 
For each continuous vital sign parameter, descriptive summary statistics (n, mean, and standard 
deviation/standard error, median, and range) will be calculated for values observed during the 
double-blind period, including end of double-blind (see Section 5.2.3).  Summary statistics for the 
change from baseline to each post-randomization visit, including end of double-blind 
assessment, will be presented. 
 
Vital sign abnormalities that meet or exceed the “clinical notable vital sign” values (see Section 
5.2.3, table 7) will be listed. The incidence of clinically notable vital signs during the double- 
blind period will be presented by treatment for subjects in the safety population. 


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11.4.
ECGS 
Summaries of ECG evaluations performed at the end of double-blind period will be compared to 
baseline values (see Section 5.2.4) and generated by randomization treatment group for the 
subjects in the safety population.  In addition, summary tables may be generated for ECGs 
collected during exposure to the study drugs across the double-blind period. 
 
The following listings and summary tables will be generated: 
 
1. Summary statistics (n, mean, standard deviation, minimum, and maximum) of the 
baseline value and each scheduled evaluation, and the corresponding change from 
baseline for each continuous ECG parameter (heart rate [beats/min], PR interval [msec], 
QRS duration [msec], QT interval [msec], QTcB [msec], and QTcF[msec]). 
 
2. Count (%) of subjects with a change from baseline in QT, QTcB, or QTcF intervals >30 
but <=60 miliseconds, and with a change >60 miliseconds at each scheduled 
postbaseline evaluation. 
 
3. Listing of subjects with a change from baseline in QT, QTcB, or QTcF intervals >30 but 
<=60 miliseconds, and with a change >60 miliseconds at each scheduled postbaseline 
evaluation. 
 
4. Count (%) of subjects, for each ECG parameter, with at least 1 outlier* value observed 
during the phase or period of interest. 
 
5. Listing of subjects with at least 1 outlier* ECG tracing parameter postbaseline. 
 
6. For each selected ECG morphology finding, the count (%) of subjects with the specific 
finding absent or present at baseline versus end of double-blind period. 
 
7. Listing of subjects with treatment-emergent ECG morphology findings. 
 
*Outliers are defined in section 5.2.4. 
 
For these analyses, the following rules will apply: 
 
x 
The baseline value of each ECG parameter will be defined as the average of all ECG 
values collected prior to the start of study drug. 


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x 
In listings summaries 1 through 3 above, the value of the ECG parameters at each 
scheduled post-baseline evaluation will be calculated as the average of the tracing 
results collected at that time. 
 
x 
For listings 4 through 7, every ECG tracing will be evaluated (ie, no average will be 
calculated). 
 
x 
For listings 6 and 7, a subject will be categorized as having a specific morphology finding 
present at baseline if the finding is observed in at least 1 ECG tracing obtained prior to 
the start of study drug. A specific ECG morphology finding will be considered present at 
the end of a phase/period if it is observed in at least 1 ECG tracing collected during that 
phase/period. 
 
x 
For listing 7, an ECG morphology finding will be considered treatment emergent if it is 
observed in a least 1 postbaseline ECG tracing but is absent from all screening baseline 
tracings. 
 
 
 
11.5.
ABUSE OR DIVERSION OF STUDY DRUG 
A listing will be provided on the abuse or diversion of study drug data. 
 
11.6.
PHYSICAL EXAMINATION 
Any observed changes in physical and neurologic examinations from before treatment to after 
treatment will be listed and described. 
 
 
 
11.7.
OTHER SAFETY MEASURES 
Descriptive statistics will be presented by treatment group for the HADS, C-SSRS, and K-L 
scores using the safety population. 
 
11.7.1. HADS 
The change from baseline to end of double-blind (week 4) for both subjects HADS-A and 
HADS-D as defined in Section 5.2.7 will be analyzed using an ANCOVA model including 


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treatment group (4 levels) and baseline as covariate.  All comparisons versus placebo will be 
performed. 
 
11.7.2. C-SSRS 
Summaries (number of subjects and percentages) will be presented for each question within the 
following categories: suicidal ideation, suicidal behavior, and self-injurious behavior without 
suicidal intent, that occurred during the double-blind period. 
 
11.7.3. CiTAS scores 
The CiTAS scores as defined in section 5.3.2 will be listed and summarized descriptively (n, 
mean, standard deviation, median, and range), for each of the following scores: 
 
- 
Decline in basic taste 
 
- 
Discomfort 
 
- 
Phantogeusia and parageusia 
 
- 
General taste alterations. 
 
 
 
12.
OTHER ANALYSES 
12.1.
PK AND PG ANALYSES 
PK and PG analyses will be described in separate documents and will be presented in separate 
reports.  Due to the exploratory nature of the PG, all summaries and analyses related to PG, if 
conducted, will be documented separately and will not be included in the CSR (clinical study 
report). 
 
13.
SUMMARY OF CHANGES FROM PROTOCOL-SPECIFIED ANALYSES 
No changes are planned/were made to the planned analyses. 


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14.
REPORTING CONVENTIONS 
Page Layout 
x 
The Section 14 tables and Appendix 16 listings should be in landscape orientation by 
default. 
 
x 
The output in Section 14 and Appendix 16 will be in RTF file format using Courier New 
font with 8 point size. 
 
x 
Output should adhere to US/ICH margins requirement. A page in landscape orientation 
requires a margin of ¾ of an inch at the top. Header and footer information should 
appear within these same margins. 
 
x 
Category labels in the left most columns of all tables and listings will be left justified. 
 
x 
A blank row will separate the header from the content of the table listing. 
 
Summary Tables 
In the summary tables for the double-blind period, the defaut order for treatment groups will be 
Placebo, naproxen, V120083 30mg and V120083 60mg. In the summary tables for the pre- 
randomization period, the default order for treatment groups will be Nonrandomized and 
Randomized. 
 
Subject Listings 
Subject listings, unless specified otherwise, should use Country, Investigator Name/Number, 
Subject Number, and Treatment as the “Sort Order”. 
 
Statistical Considerations 
The Standard TLFs adhere to the following statistical conventions: 
 
x 
The subject percentages (%) should be rounded to a whole number, with SAS rounding 
options used to obtain the values. 
 
x 
Percentages for values in the tables that are less than <1 should be presented as “<1”. 


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x 
If “%” is part of the column heading, do not repeat the “%” sign in the body of the table. 
 
x 
If a value is zero (0), then do not use 0% and leave the corresponding percentage blank. 
 
x 
The format for range should always be “Min, Max”. 
 
x 
If there are missing data, then a missing row will be added to keep track of all subjects. 
If no missing data, then delete the missing row. Percentages will not be presented on 
the row missing category. 
 
x 
Standard Deviation should be abbreviated as “SD”, and Standard Error should be 
abbreviated as “SE”; it is presented within parenthesis next to the mean value, without 
any +/- sign. The Standard Deviation or Standard Error should have one additional 
decimal point beyond that of the mean (for example, if the mean has one decimal point, 
SD/SE should have two decimal points).  Mean should have one additional decimal point 
beyond that of the data being summarized. 
 
x 
“N” will represented the entire treatment group, while “n” will represent a subset of the 
treatment group. For tables with population designated as a row heading, “N” should be 
used (i.e. tables where all the participant data is not available for every variable within a 
treatment group).  As a guideline, if the number is used in denominator that it should be 
presented as “N”.  If the number is used in numerator then it should be presented as “n”. 
 
Column Heading Alignment 
x 
Two solid lines should bind the column headings for the tables. 
 
x 
A solid line should be at the end of the table or at the bottom of the page (if table 
extends to more than one page). 
 
x 
Footnote should start after the bottom solid line.  In the event of lengthy footnotes, 
they will only be presented on the last page of the table (as endnote). 
 
 
Directory Patch and Page Numbers 
x 
Page number on the tables should be displayed at the bottom right of the table heading 
for all tables. 


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x 
Format of the page numbers should be: Page X of Y. 
 
x 
Name of the SAS Program and the date/time of the TLFs was run should be displayed 
on the output as the last footnotes. 
 
Cross-References 
x 
All in-text tables should be cross-referenced to a table in Section 14. 
 
x 
All Section 14 tables should be cross-referenced to a listing in Appendix 16. 
 
15.
REFERENCES 
1. Cui L, Hung HMJ, Wang SJ. (1999) Modification of sample size in group sequential 
trials.  Biometrics.  55: 853-857. 
 
2. Emerson SS, Kittelson JM, Gillen DL. (2005) On the use of stochastic curtailment in 
group sequential clinical trials. University of Washington Department of Biostatistics 
Technical Report. 
3. Lan KKG, Simon R, and Halperin M. (1982). Stochastically curtailed tests in long-term 
clinical trials.  Comm Statist, C (Sequentia1 Analysis).  1:207-219. 
 
 
 
16.
TABLES, FIGURES, LISTINGS AND OUTPUT 
16.1.
TABLES 
See separate document for table shells. 
 
16.2.
FIGURES 
See separate document for figure shells. 


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16.3.
DATA LISTINGS FOR APPENDIX 16.2 
See separate document for listing shells. 
 
17.
ATTACHMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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VersionDate: 12JAN2018
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
  
 
  
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
  
 
  
  
  
 
 
 
 
 
    
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
   
   
   
   
   
   
   
   
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 71 of 80
VersionDate: 12JAN2018
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 72 of 80
VersionDate: 12JAN2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 








PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 76 of 80
VersionDate: 12JAN2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
 
  
  
  
 
  
  
  
 
 
 
  
  
  
 


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 77 of 80
VersionDate: 12JAN2018
 
 
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 78 of 80
VersionDate: 12JAN2018
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 79 of 80
VersionDate: 12JAN2018
 
 
 
18.
APPENDIX 
Appendix A – Laboratory Tests 
 
Hematology: RBC counts, Hemoglobin, Hematocrit, Platelets, and WBC count with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils) in percentages (%) and absolute 
counts. 
 
Clinical Chemistry: 
 
Electrolytes: Sodium, Potassium, Chloride, Calcium Corrected, Magnesium, Bicarbonate 
 
Liver function tests: Alkaline Phosphatase, Asparate Aminotransferase (AST/SGOT), Alanine 
Aminotransferase (ALT/SGPT), Total Bilirubin, gamma-glutamyl transferase (GGT). 
 
Renal function parameters: Blood Urea/Blood Urea Nitrogen, Creatinine, eGFR 
 
Other: Glucose, Albumin, Cholesterol, Triglycerides, Phosphorus, Lactate Dehydrogenase 
(LDH), Total Protein, Globulin, Uric Acid. 
 
Urinalysis: pH, Protein, Glucose, Ketone, Occult Blood, RBC, WBC, Epithelial Cells, Bacteria, 
Casts, Crystals, Specific Gravity. 
 
Urine drug test: Amphetamines, Cannabinoids, Opiates, Cocaine Metabolites, Benzodiazepines, 
Barbiturates, phencyclidine, methadone, propoxphene. 
 
Serum pregnancy test: Human Chorionic Gonadotropin (Choriogonadotropin Beta). 
Urine pregnancy test: Human Chorionic Gonadotropin (Choriogonadotropin Beta). 
Virus screen: Hepatitis B, Hepatitis C, Human Immunodeficiency Virus. 


PurduePharmaLP
Protocol:VAN2001
StatisticalAnalysis Plan 2
SAP2FinalV1.0
Page 80 of 80
VersionDate: 12JAN2018
 
 
 
 
 
DOCUMENTHISTORY
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ModifiedBy
SummaryofChanges