Clinical trial NCT03108482
Conditions: Acute Post-surgical Pain
Keywords: Acute Pain Post-surgical Pain Bunionectomy Co-crystal Tramadol Celecoxib
Sponsor: Laboratorios del Dr. Esteve, S.A.
Start date: 2017-03-14; Completion date: 2017-11-28
Enrollment: 637 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, randomized, double-blind, controlled, parallel-group, multicenter clinical trial with co-crystal E-58425 compared to tramadol, to celecoxib, and to placebo. The primary objective of the trial is to establish the analgesic efficacy of co-crystal E-58425 by demonstrating a superior effect compared to tramadol and to celecoxib for the management of moderate to severe acute post-operative pain for 48 hours after bunionectomy.

Detailed description:

Arms: arm 1: Co-crystal E-58425 (Tramadol/Celecoxib): Two tablets of 100 mg every 12 hours. The total daily dose will be 400 mg of Co-crystal E-58425. arm 2: Tramadol: One tablet of 50 mg every 6 hours. The total daily dose will be 200 mg of tramadol. arm 3: Celecoxib: One capsule of 100 mg every 12 hours. The total daily dose will be 200 mg of celecoxib. arm 4: Placebo: One or two tablets of 100 mg every 6 hours.
Interventions: intervention 1: Co-crystal E-58425 (Tramadol/Celecoxib) intervention 2: Tramadol (Ultram®) intervention 3: Celecoxib (Celebrex®) intervention 4: Placebo
Intervention descriptions: intervention 1: Co-crystal E-58425 (Tramadol/Celecoxib): Two immediate release oral over-encapsulated tablets of 100 mg, every 12 hours for 48 hours. intervention 2: Tramadol: One immediate release oral over-encapsulated tablet of 50 mg, every 6 hours for 48 hours. intervention 3: Celecoxib: One immediate release oral over-encapsulated capsule of 100 mg, every 12 hours for 48 hours. intervention 4: Placebo 100 mg or 200 mg oral over-encapsulated tablets every 6 hours for 48 hours.

Protocol documents:
Prot_000.pdf: 
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AMENDED PROTOCOL  
 
PRODUCT NAME/NUMBER: 
CO-CRYSTAL E-58425 (tramadol-celecoxib) 
PROTOCOL NUMBER: 
ESTEVE-SUSA-301 
IND NUMBER: 
128177 
DEVELOPMENT PHASE: 
3 
PROTOCOL TITLE: 
A Randomized, Double-blind, Active- (Tramadol and Celecoxib) and 
Placebo-controlled, Parallel Groups, Phase 3 Clinical Trial to 
Establish the Efficacy of Co-crystal E-58425 for the Management of 
Moderate to Severe Post-surgical Pain after Bunionectomy 
PROTOCOL DATE: 
Final Version 1.0; 06 Jul 2016 
 
Final Version 1.1; 26 Aug 2016 (including FDA requested changes) 
 
Final Version 2.0; 09 Nov 2016 
 
Final Version 3.0; 15 Feb 2017 
 
Final Version 4.0; 20 Jul 2017 
AMENDMENT 1 DATE: 
Final Version 1.0; 09 Nov 2016 
AMENDMENT 2 DATE 
Final Version 1.0; 15 Feb 2017 
AMENDMENT 3 DATE 
Final Version 1.0; 20 Jul 2017 
SPONSORED BY: 
Laboratorios del Dr. ESTEVE, S. A. U. 
Avda. Mare de Déu de Montserrat, 221 
08041 Barcelona (Spain) 
Tel: 
 
CONTRACT RESEARCH 
ORGANIZATION: 
Premier Research  
One Park Drive, STE 150 
Durham, NC 27709 
Tel: 
 
This study will be performed in compliance with Good Clinical Practices (GCP) and applicable regulatory 
requirements, including the archiving of essential documents. Information contained in this protocol is 
confidential in nature, and may not be used, divulged, published or otherwise disclosed to others except to the 
extent necessary to obtain approval of the Institutional Review Board, or as required by law. Persons to whom 
this information is disclosed should be informed that this information is confidential and may not be further 
disclosed without the express permission of Laboratorios del Dr. ESTEVE, S. A. U. 
 


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1.
APPROVAL SIGNATURES
PROTOCOL NUMBER: 
ESTEVE-SUSA-301 
PROTOCOL TITLE: 
A Randomized, Double-blind, Active- (Tramadol and Celecoxib) and 
Placebo-controlled, Parallel Groups, Phase 3 Clinical Trial to Establish the 
Efficacy of Co-crystal E-58425 for the Management of Moderate to Severe 
Post-surgical Pain after Bunionectomy 
PROTOCOL DATE: 
Final Version 4.0, 20 Jul 2017 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it accurately describes 
the planned conduct of the study. 
 
 
Laboratorios del Dr. ESTEVE, S.A.U. 
Date 
 
 
 
Premier Research 
Date 
 
 
Premier Research 
Date 
 
 
 
Premier Research 
Date 


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2. SYNOPSIS 
PRODUCT 
NAME/NUMBER 
CO-CRYSTAL E-58425 (racemic tramadol hydrochloride and celecoxib) 
PROTOCOL NUMBER 
ESTEVE-SUSA-301 
IND NUMBER 
128177 
DEVELOPMENT 
PHASE 
3 
PROTOCOL TITLE 
A Randomized, Double-blind, Active- (Tramadol and Celecoxib) and Placebo-controlled, Parallel-
groups, Phase III Clinical Trial to Establish the Efficacy of Co-Crystal E 58425 for the Management 
of Moderate to Severe Post-surgical Pain after Bunionectomy 
INDICATION 
Moderate to severe post-surgical pain after bunionectomy 
OBJECTIVES 
Primary:  
• 
To establish the analgesic efficacy of co-crystal E-58425 compared to tramadol and to 
celecoxib for the management of moderate to severe post-operative pain for 48 hours after 
bunionectomy by using assessments of pain intensity 
Secondary:  
• 
To assess the analgesic efficacy of co-crystal E-58425 compared to tramadol and to celecoxib 
for the management of moderate to severe post-operative pain at various time points after 
bunionectomy by using assessments of pain intensity 
• 
To assess the analgesic efficacy of co-crystal E-58425 by means of responder rates, use of 
rescue medication, time to onset of analgesia, time to perceptible and meaningful pain relief, 
time to onset of pain intensity decrease, peak pain relief and time to peak pain relief, and the 
subjects’ overall assessment of the study medication 
• 
To assess the absolute analgesic efficacy of co-crystal E-58425 compared to placebo for the 
treatment of moderate to severe post-operative pain for 48 hours at various time points after 
bunionectomy by using assessments of pain intensity 
• 
To assess the safety and tolerability of the co-crystal E-58425  
STUDY DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is a Phase 3, randomized, double-blind, active- and placebo-controlled, parallel-group, 
multicenter clinical trial with co-crystal E-58425 compared to tramadol, to celecoxib, and to placebo.  
Eligible subjects will complete all screening procedures within 28 days before the surgery. At 
Screening, subjects will provide written informed consent to participate in the study before any 
protocol specified procedures or assessments are conducted. 
Subjects will be admitted to the study center on the morning of the scheduled surgery (Day -1), will 
remain at the study center until post-operative Day 3 (a total of 3 nights at the study center), and will 
return for the Follow-up Visit, which will occur 5 to 9 days after surgery. 
On Day -1, regional anesthesia will be established using a popliteal sciatic nerve block (PSB) after 
which subjects will undergo primary, unilateral, first metatarsal osteotomy with internal fixation with 
no additional collateral procedure. The regional anesthesia will be continued postoperatively via a 
continuous anesthetic infusion. Subjects may receive supplemental analgesia with ketorolac 30 mg 
intravenously during the continuous infusion period and up until 1:00 A.M to help control 
breakthrough pain if the regional anesthetic infusion appears to be ineffective in the investigator’s 
opinion up until 1:00 A.M. If the regional anesthetic infusion and supplemental analgesia do not 
effectively control the subject’s postoperative pain prior to the 3:00 A.M. anesthetic infusion 
discontinuation time, the subject will not be eligible to be considered for the study. 
On Day 1, after regional anesthetic infusion is discontinued between 3:00 and 4:00 A.M, study staff 
will contact interactive response technology (IRT) system to obtain the moderate and severe pain box 
numbers for the subject and will retrieve the study medication boxes from stock, 1 for moderate pain 
and 1 for severe pain. The subject will be instructed to notify a member of the study staff and request 
treatment when he or she experiences a level of pain that requires medication. When the subject 


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requests pain medication, they will be asked to rate their pain intensity (PI) using the Numerical Pain 
Rating Scale (NPRS) assessment, a scale marked from zero to 10 on which subjects circle a single 
number to indicate their current pain level, with zero representing "No Pain" and 10 representing 
"Worst Possible Pain."  
Subjects with a score ≥5 and ≤9 on the 0-10 NPRS will be randomized into the study and stratified by 
Baseline pain score (moderate [NPRS 5-6], severe [7-9]) using IRT and the appropriate pain level box 
will be used. Subjects will be randomly assigned in a ratio of 2:2:2:1 to 1 of 4 treatment groups, 
respectively: 
 
Posology 
TOTAL DAILY DOSE 
Tramadol 
Celecoxib 
ARM-1 
Co-crystal 
E-58425 
200 mg bid 
176 mg 
224 mg 
ARM-2 
Tramadol 
50 mg qid 
200 mg 
0 
ARM-3 
Celecoxib 
100 mg bid 
0 
200 mg 
ARM-4 
Placebo 
0 mg qid 
0 
0 
bid = twice daily (every 12 hours); qid = four times daily (every 6 hours) 
Subjects with a NPRS score <5 will be asked if they can wait for treatment. If they cannot, they will 
be dropped from the study and treated according to the standard of care. If they agree to wait, they will 
be requested to notify a member of the study staff when their pain intensity has increased; NPRS will 
be readministered at that time. If the subject’s pain intensity ratings do not meet the minimum entry 
criteria within 8 hours of discontinuation of the regional anesthesia, or if they have a PI >9, subjects 
will not be eligible for randomization and will receive routine postoperative care at the investigator’s 
discretion.  
The NPRS pain intensity assessments made just before randomization will serve as the Baseline PI to 
which all subsequent PI assessments will be compared. Time 0 will be defined as the time of the first 
dose of study medication. Pain intensity (NPRS) and pain relief (5-point categorical scale) 
assessments will be recorded in the subject diary at scheduled times during the 48-hour period after 
Time 0 (15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 14, 18, 22, 24, 26, 
28, 30, 32, 34, 36, 38, 42, 46, and 48 hours) and immediately before each use of rescue medication. 
During the night, subject will be wakened to administer the study medication. Pain assessments will 
be performed during the night only if the subject is awake. Time to perceptible and meaningful pain 
relief will be evaluated using the 2 stopwatch method. Pain intensity and pain relief assessments will 
also be recorded before premature study termination. Subjects will complete a patient’s global 
evaluation of the study medication at the end of the Double-blind Treatment Period (Day 3) before 
discharge from the study center.  
Intravenous (IV) acetaminophen 1 g will be supplied to the subject by the study staff every 4 to 
6 hours as needed as rescue medication after treatment with the study medication has been initiated 
(ie, the double-blind phase) up to a total of 4 g per 24 hours. If subjects are unable to tolerate IV 
acetaminophen or if there is insufficient pain relief, then oxycodone hydrochloride 5 mg Immediate 
Release (IR) tablets will be allowed every 4 to 6 hours if needed, up to a total of 30 mg/24 hours. 
After randomization, subjects will be encouraged to wait for at least 1 hour after the first dose of study 
medication before receiving rescue medication to allow time for the study medication to exert its 
pharmacologic effect. 
After randomization, subjects whose pain cannot be adequately managed by a combination of study 
medication and rescue medication, or who develop unacceptable side effects during the study will be 
discontinued from study medication or from further study participation. Their pain will be managed 
conventionally at the investigator’s discretion. All end-of-study assessments should be performed for 
subjects who discontinue from the study, if possible. Pain measurements affected by use of rescue 
medication will be replaced with pre-rescue pain measurements. 


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Before discharge from the study center on Day 3, study personnel will dispense a prescription for pain 
medication (if not already dispensed) and an outpatient subject diary in which subjects will record 
concomitant medications taken and adverse events (AEs) experienced after discharge. Subjects will 
also be instructed to return the outpatient subject diary to study personnel at the Follow-up Visit. 
PLANNED NUMBER 
OF SUBJECTS 
The planned total number of subjects to be randomized into the study is 630, divided into the 
treatment groups as follows: 
Treatment group 
Number of subjects 
Co-crystal E-58425 
180 
Tramadol 
180 
Celecoxib 
180 
Placebo 
90 
It is anticipated that this will provide a sample size of at least 142 subjects per group (71 for the 
placebo group) in the Per Protocol Analysis Set. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria: 
1. Subject must have signed consent before study entry. 
2. Subject must be at least 18 years old, scheduled to undergo primary unilateral first metatarsal 
osteotomy with internal fixation with no additional collateral procedure. 
3. Male and female subjects are eligible. If female, subject must be either not of childbearing 
potential (defined as postmenopausal for at least 1 year or surgically sterile [bilateral tubal 
ligation, bilateral oophorectomy, or hysterectomy]) or practicing 1 of the following effective 
methods of birth control: 
o 
Hormonal methods such as oral, implantable, injectable, vaginal ring, or 
transdermal contraceptives. 
o 
Total abstinence from sexual intercourse since the last menses before study 
medication administration. 
o 
Intrauterine device  
o 
Double-barrier method (condoms, sponge, or diaphragm with spermicidal jellies 
or cream). 
Women must use effective methods of birth control from Screening until 4 weeks after the last 
administration. 
4. If female and of childbearing potential, subject must be non-lactating and non-pregnant (has 
negative serum pregnancy test results at Screening and negative urine test on the day of 
surgery prior to surgery). 
5. Subject must have a body weight of 45 kg or more and a body mass index (BMI) of 40 kg/m2 
or less. 
6. Subject must have a qualifying pain score of ≥5 and <9 on the 0-10 NPRS at rest as a result 
of turning off the popliteal sciatic block for bunionectomy to be eligible for randomization. 
7. Subject must be in good physical health in the investigator’s judgment. 
8. Subject must be sufficiently alert to understand and communicate intelligibly with the study 
observer. 
 
Exclusion criteria: 
1. Subject’s Baseline pain is <5 or >9 on a 0-10 NPRS. 
2. Subject received any analgesic medication other than short-acting pre-operative or intra-
operative anesthetic agents before the end of bunionectomy surgical procedure. Subjects who 
received any analgesic medication immediately after the bunionectomy surgical procedure 
was completed and before study medication is administered will also be excluded, with the 


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exception of ketorolac 30 mg intravenously as supplemental analgesia during the continuous 
infusion period and up until 1:00 A.M. 
3. Subject has a history of seizures or alcohol abuse (eg, drinks >4 units of alcohol per day, a 
unit being equal to 8 oz. beer, 3 oz. wine, 1 oz. spirits) within the past 5 years, has a history 
of prescription/illicit drug abuse within 6 months before dosing with study medication, or has 
positive results on the urine drug screen or alcohol breath test indicative of illicit drug or 
alcohol abuse. 
4. Subject has a history of or positive test results for human immunodeficiency virus or hepatitis 
B or C. 
5. Subject has an active malignancy of any type, or has been diagnosed with cancer within 5 years 
before Screening (excluding successfully treated squamous or basal cell carcinoma of the skin). 
6. Subject is currently receiving anticoagulants (eg, heparin or warfarin) or antiplatelets (except 
aspirin ≤325 mg/day). 
7. Subject has received a course of systemic (either oral or parenteral) or intra-articular 
corticosteroids within 3 months before Screening (inhaled nasal steroids and topical 
corticosteroids are allowed). 
8. Subject has any ongoing condition, other than one associated with the current primary, 
unilateral, first metatarsal bunionectomy, that, in the investigator’s opinion, could generate 
levels of pain sufficient to confound assessments of post-operative pain (eg, severe 
osteoarthritis of the target joint or extremity, fibromyalgia, rheumatoid arthritis, moderate to 
severe headache, diabetic foot pain or neuropathy). 
9. Subject has been receiving or has received chronic (defined as daily use for >2 weeks) opioid 
(oral codeine, dextromoramide, dihydrocodeine, oxycodone, or morphine-like anti-tussive) 
therapy defined as >15 morphine equivalents units per day for more than 3 out of 7 days per 
week over a 1-month period within 12 months of surgery, or has been treated chronically 
with opioid analgesic (buprenorphine, nalbuphine, or pentazocine) or NSAIDs within 30 days 
before Screening. 
10. Subject received a long-acting Non-Steroidal Anti-Inflammatory Drug (NSAID) within 
4 days before initiation of study medication (except aspirin ≤325 mg/day), or a short-acting 
NSAID within 1 day, with the exception of ketorolac 30 mg intravenously as supplemental 
analgesia during the continuous infusion period. 
11. Subject is under long-term treatment with opioid agonist-antagonists.  
12. Subject has used drugs with enzyme-inducing properties, such as rifampicin and St. John’s 
Wort, or any drug known to be a strong inhibitor or inducer of CYP3A4, CYP2C9, or 
CYP2D6 within 3 weeks before surgery. 
13. Subject is pregnant or lactating.  
14. Subject had any complication during primary bunionectomy surgery. 
15. Subject has received monoamine oxidase inhibitors, tricyclic antidepressants, neuroleptics, or 
other drugs that reduce the seizure threshold within 4 weeks of study entry. 
16. Subject has a history or evidence of a clinically significant (in the investigator’s opinion) 
gastrointestinal (GI) event within 6 months before Screening or has any history of peptic or 
gastric ulcers or GI bleeding. 
17. Subject has clinically significant renal or hepatic disease, as indicated by clinical laboratory 
assessment (results ≥3 times the upper limit of normal for any liver function test, including 
aspartate aminotransferase, alanine aminotransferase, bilirubin, and lactate dehydrogenase, or 
creatinine ≥1.5 times the upper limit of normal). Laboratory tests may be repeated once at 
Screening to rule out laboratory error. 
18. Subject has any clinically significant laboratory or 12-lead electrocardiogram (ECG) finding 
at Screening that, in the opinion of the investigator, contraindicates study participation (eg, 
QTc >450 msec [male] or >470 msec [female]). 
19. Subject has a known history of allergic reaction or clinically significant intolerance to 
acetaminophen, aspirin, opioids, or any NSAIDs; history of NSAID-induced bronchospasm 
(subjects with the triad of asthma, nasal polyps, and chronic rhinitis are at greater risk for 


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bronchospasm and should be considered carefully) or to the ingredients of the study 
medication, or any other drugs used in the study, including anesthetics and antibiotics that 
may be required on the day of surgery.  
20. Subject has received anti-depressive medication with serotonin–norepinephrine reuptake 
inhibitors (SNRIs; milnaciprin, duloxetine, venlafaxine), diet pills (including fenfluramine 
and phentermine) or methylphenidate (Ritalin®), or other similar medications for ADHD 
within 4 weeks of study entry. Subjects receiving selective serotonin reuptake inhibitors 
(SSRIs) may be included provided they have been on a stable dose for 60 days prior to study 
participation and plan to remain on that dose throughout the study. 
21. Subject is, in the investigator’s judgment, at risk in terms of precautions, warnings, and 
contraindications in the package insert for Ultram® (tramadol hydrochloride) or Celebrex® 
(celecoxib). Specifically, in situations where participation is contraindicated per the package 
insert the subject should be excluded. However, in situations where medications or medical 
conditions listed in the precautions and warnings are present the physician should evaluate 
the subject’s history, physical examination results, laboratory analysis, and ECG carefully 
and use his/her discretion as to whether the subject is suitable for participation. 
22. Subject has a known coagulation disorder. 
23. Subject has history of or current medical, surgical, post-surgical, or psychiatric condition that 
would confound interpretation of safety, tolerability, or efficacy, (eg, uncontrolled diabetes 
mellitus, uncontrolled hypertension, hemodynamic instability, or respiratory insufficiency, 
cancer or palliative care). 
24. Subject received an experimental drug or used an experimental medical device within 
30 days prior to Screening or has previously participated in this trial. 
25. Subject is unable to comply with the requirements of the study or, in the investigator’s 
opinion, should not participate in the study. 
26. Subject is undergoing concomitant surgical procedure(s) in addition to primary 
bunionectomy. 
INVESTIGATIONAL 
PRODUCT 
Name: Co-crystal E-58425 (tramadol 88 mg/celecoxib 112 mg) 
Dose, route, frequency: over encapsulated 200-mg immediate-release oral tablet; every 12 hours  
REFERENCE 
PRODUCT(S) 
Name: Ultram® (tramadol)  
Dose, route, frequency: 50-mg immediate-release oral tablet (manufactured by Janssen Ortho; LLC, 
Gurabo, Puerto Rico 00778) every 6 hours, over encapsulated by ESTEVE 
Name: Celebrex® (celecoxib) 
Dose, route, frequency: 100-mg immediate-release oral capsules (Marketing Authorization Holder GD 
Searle) every 12 hours, over encapsulated by ESTEVE 
Name: Placebo  
Dose, route, frequency: matching over encapsulated capsules 
RESCUE 
MEDICATION: 
Acetaminophen 1 g IV every 4 to 6 hours, up to 4 g/24 hours, or oxycodone hydrochloride 5 mg 
Immediate Release (IR) tablet every 4 to 6 hours if needed, up to a total of 30 mg/24 hours. 
TREATMENT 
REGIMENS 
After the entry criteria are met, subjects will be randomly assigned in a ratio of 2:2:2:1 to 1 of the 4 
treatment groups (Co-crystal E-58425, tramadol, celecoxib, or placebo). After Randomization, 
subjects will be encouraged to wait for at least 1 hour after the first dose of study medication before 
receiving rescue medication to allow time for the study medication to exert its pharmacologic effect. 
Subjects will take study medication 4 times daily, in a blinded manner according to their random 
treatment arm assignment. All study medications will be over encapsulated to maintain the blind. 
Study medication will be administered in a predefined manner to ensure adequate blinding and 
appropriate dosing regimens for active medication and placebo. Study medication will be administered 
for up to 48 hours after the first dose of study medication. 
PLANNED STUDY 
CENTERS 
Approximately 5 to 6 study centers in the United States. 


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CRITERIA FOR 
EVALUATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy endpoints:  
Primary efficacy endpoint: 
The primary efficacy variable will be the Pain Intensity (PI) measured by Numerical Pain Rating 
Scale (NPRS). The primary analysis endpoint will be the Sum of Pain Intensity Differences (SPID) 
from 0-48 hours defined as follows. 
 
PIDt = Pain Intensity Differences = PIt - PI0 where  
PI0 = Pain Intensity (PI) at time t = 0h on NPRS 
PIt = Pain Intensity on NPRS at specific time points 
 
The NPRS summed pain intensity difference (SPID) is calculated as a time-weighted sum of the pain 
intensity difference values at each follow-up time point (difference between the starting pain 
intensity and the pain intensity at the given assessment time) multiplied by the amount of time (in 
hours) since the prior assessment.  
Negative values of PID will correspond to an amelioration of pain, while positive values will 
correspond to a recrudescence of pain. 
Secondary efficacy endpoints 
Secondary efficacy parameters will be the following: 
• 
SPID (0-4 hours), SPID (0-6 hours), SPID (0-12 hours), and SPID (0-24 hours) as defined in 
previous section 
• 
PIDt at each time point 
• 
Pain intensity at each time point 
• 
Pain Relief (PARt) = pain relief at each time point 
• 
Total Pain Relief (TOTPAR) for time intervals (t=15 minutes – t=4 hours), (t=15 minutes 
– t=6 hours), (t=15 minutes – t=12 hours), (t=15 minutes – t=24 hours), and (t=15 minutes 
– t=48 hours)  
o 
TOTPAR is the time-weighted sum of the Pain Relief (PAR) at each time point 
• 
Peak pain relief and time to peak pain relief 
• 
Stop watches: Time to onset of analgesia, time to perceptible pain relief and time to 
meaningful pain relief 
• 
Time to onset of pain intensity decrease 
• 
Overall assessment of study medication 
• 
Rescue medication: 
o 
Proportion of subjects who take of at least 1 dose of rescue medication up to 4, up to 
6, up to 12, up to 24, and up to 48 hours after study medication administration; total 
amount of rescue medication for the same time intervals 
o 
Time to first use of rescue medication. 
o 
To avoid interference in efficacy measures (pain intensity assessments, PARt, PIDt, 
and SPID calculations) at scheduled time points because of use of rescue 
medication, additional pain assessments will be made just before each 
administration of rescue medication, asking subjects to report their pain intensity at 
the current time. These data will be carried over for the duration of effect of the 
rescue medication taken. 


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• 
Proportions of Responders, defined as follows:  
o 
Subject who reaches a 50% reduction in pain intensity from baseline sustained until 
the end of the 48-hour observation period; 
o 
Subject who reaches a 30% reduction in pain intensity from baseline sustained until 
the end of the 48-hour observation period; 
o 
Subject who reaches a pain intensity below 4 on NPRS sustained until the end of the 
48-hour observation period; 
o 
Subject who reaches a 50% reduction in pain intensity as compared to baseline and a 
pain intensity below 4 on NPRS sustained until the end of the 48-hour observation 
period; 
o 
Subject who reaches a 30% reduction in pain intensity as compared to baseline and a 
pain intensity below 4 on NPRS sustained until the end of the 48-hour observation 
period. 
• 
Time-to-response will also be analyzed as time-to-event data, using the first time at which 
each response criterion was reached by each subject. 
Cumulative proportion of responders analysis plot. 
 
Safety endpoints: 
• 
Clinical laboratory test results will be marked whether the result is below, within, or above the 
respective reference range and whether it is clinically significant. The number of such values 
will be counted and tabulated. 
• 
For electrocardiogram (ECG) and vital signs parameters, the values that are below, within, or 
above a defined normal range and the values that are clinically significant may be counted and 
tabulated by the number and percentage of subjects with such values. 
• 
Adverse events will be tabulated by system organ class (SOC) and preferred term (PT) using 
the Medical Dictionary for Regulatory Activities (MedDRA). 
• 
An overview of AEs will be prepared showing the number of AEs and the number of subjects 
with any AEs, treatment-emergent AEs, treatment-related AEs, serious AEs (SAEs), 
treatment-related SAEs, severity of AEs, AEs leading to withdrawal, and AEs of special 
interest.  
• 
Various summary tables showing the number of subjects with at least 1 AE and event count by 
SOC (System Organ Class) and PT (Preferred Term) will be prepared. 
Additional safety data will be tabulated for each treatment group. 
STATISTICAL 
METHODS 
Analysis Sets 
The primary statistical analysis will be based on the Full Analysis Set (FAS), defined as all 
randomized subjects. The Per-Protocol Analysis Set (PPAS), defined as all subjects with no major 
protocol deviations, will be used for sensitivity analyses. Safety analyses will use the Safety Analysis 
Set (SAS), defined as all subjects who receive at least 1 dose of study medication. The Completers 
Analysis Set (CAS) will be a subset of the PPAS that includes all subjects who have pain assessments 
up to 48 hours after first dose of study medication. 
Subject Characteristics and Disposition 
Subject characteristics and disposition data will be presented using descriptive statistics only. 
Efficacy Analyses  
The primary efficacy analysis will compare treatment groups for the SPID from Time 0 to 48 hours. 
This will be tested using an analysis of covariance model adjusting for center and baseline pain 
intensity.  
To account for the use of rescue medication, any pain measurements taken during a period of time in 
which rescue medication is active will be replaced by the last pain measurement before rescue 
medication was taken.   
Additional sensitivity analyses assessing the impact of rescue use and missing data due to study 
discontinuation will be performed. Efficacy analyses will be also performed by subgroups defined by 
moderate or severe baseline pain. Other subgroup analyses may also be done and will be specified in 
the statistical analysis plan (SAP). 


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Primary efficacy analyses will be based on the FAS. The PPAS and the CAS will be used for 
sensitivity analysis for some efficacy endpoints. Safety analyses will be based on the safety set. 
All subjects who signed informed consent will be considered study participants. 
Secondary efficacy outcome measures will be analyzed using similar methods. 
All statistical methods will be described in full in the SAP that will be prepared before the study is 
unblinded.  
Safety Analyses 
Data listings will be provided for protocol-specified safety data. The number and percentage of 
subjects with AEs will be displayed for each treatment group by SOC and PT. Summaries of AEs by 
severity and relationship to study medication will also be provided. Serious adverse events, AEs 
resulting in discontinuation of study medication and AEs of special interest will be summarized 
separately in a similar manner. Comparisons between treatment groups for incidence of AEs, AEs of 
special interest, and significant AEs may be performed. For clinical laboratory, ECG, and/or vital sign 
variables, the values that are below, within, or above a defined normal range and the values that are 
clinically significant will be counted and tabulated by the number and percentage of subjects with 
such values may be performed if required. Any comparisons of safety analyses will be described in 
detail in the SAP. 
SAMPLE SIZE 
DETERMINATION 
The primary outcome measure is SPID (NPRS) up to 48 hours post-dose (SPID-48h). The study is 
powered to detect differences between the co-crystal E-58425 and each of the 2 active control groups 
if they exist. Since co-crystal E-58425 must show superiority over both tramadol and celecoxib, the 
power is set at 90%, which will maintain an overall study power at 81%. 
To detect a difference of 48 with a Standard Deviation (SD) of 124 at an alpha level of 0.05 and a 
power of 90% requires 142 subjects per group (71 for the placebo group since a 2:2:2:1 randomization 
scheme is being used). It is assumed that the comparison versus placebo will be adequately powered 
since the difference versus placebo will be larger than that for the active comparators. Allowing for 
approximately a 20% rate of non-evaluable subjects (ie, those not included in the PPAS), a sample 
size of 180 subjects per group (90 for the placebo group) will be required to achieve 81% overall 
power and therefore a total of 630 subjects will be randomized. 
A blinded sample size calculation will be repeated during a blinded interim analysis conducted when 
approximately 50% of subjects have completed the study using the actual SD of the SPID-48 hours 
calculated on pooled data. The sample size will not be reduced as a result of this re-estimation. Details 
will be presented in the SAP. 
STUDY AND 
TREATMENT 
DURATION 
The overall study duration is expected to be 10 months (6 months of active enrollment and 4 months 
of data management, statistical analyses and reporting). 
The estimated duration of the study for each subject is approximately 6 weeks, which includes up to a 
4-week Screening Period, a 3-day treatment period (72 hours of confinement with 48 hours of 
treatment), and a post-treatment follow-up visit approximately 1 week after surgery. 
The maximum study duration for each subject is approximately 40 days. 
The maximum treatment duration for each subject is 2 days. 
 
 
 
 


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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES .....................................................................................................................2 
2. 
SYNOPSIS .................................................................................................................................................3 
3. 
TABLE OF CONTENTS .........................................................................................................................11 
3.1. LIST OF TABLES ..........................................................................................................................14 
4. 
LIST OF ABBREVIATIONS...................................................................................................................15 
5. 
INTRODUCTION ....................................................................................................................................17 
5.1. Background and Rationale ..............................................................................................................17 
5.2. Clinical Experience .........................................................................................................................18 
5.3. Summary of Potential Risks and Benefits .......................................................................................19 
6. 
OBJECTIVES ...........................................................................................................................................20 
6.1. Primary Objective ...........................................................................................................................20 
6.2. Secondary Objectives ......................................................................................................................20 
7. 
STUDY DESIGN .....................................................................................................................................20 
7.1. Overall Study Design and Plan .......................................................................................................20 
7.2. Discussion of Study Design ............................................................................................................22 
7.3. Study Center(s) ...............................................................................................................................22 
8. 
SUBJECT POPULATION .......................................................................................................................22 
8.1. Selection of Study Population .........................................................................................................22 
8.2. Study Entry Criteria ........................................................................................................................22 
8.2.1 Inclusion Criteria .................................................................................................................22 
8.2.2 Exclusion Criteria ................................................................................................................23 
8.3. Premature Subject Withdrawal .......................................................................................................24 
9. 
TREATMENTS ........................................................................................................................................25 
9.1. Identification of Investigational Product(s) ....................................................................................25 
9.2. Labeling and Packaging ..................................................................................................................25 
9.2.1 Labeling ...............................................................................................................................25 
9.2.2 Packaging ............................................................................................................................26 
9.3. Treatments Administered ................................................................................................................26 
9.4. Dispensing and Storage ...................................................................................................................27 
9.5. Method of Assigning Subjects to Treatment Groups ......................................................................27 
9.6. Blinding and Unblinding Treatment Assignment ...........................................................................27 
9.7. Selection of Doses in the Study ......................................................................................................28 
9.8. Selection of Timing of Dose for Each Subject................................................................................28 
9.9. Dose Adjustment Criteria ................................................................................................................28 
9.10. Drug Accountability ........................................................................................................................28 
9.11. Treatment Compliance ....................................................................................................................29 
9.12. Concomitant Therapies ...................................................................................................................29 


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9.13. Other Restrictions............................................................................................................................30 
9.14. Rescue Medication ..........................................................................................................................30 
9.15. Treatment after End of Study ..........................................................................................................30 
10. STUDY PROCEDURES ..........................................................................................................................30 
10.1. Screening .........................................................................................................................................30 
10.2. Day of Surgery (Day -1) .................................................................................................................31 
10.2.1 Preoperative .........................................................................................................................31 
10.2.2 Surgery and Standardized Regional Anesthesia ..................................................................32 
10.2.3 Postoperative Regional Anesthesia .....................................................................................32 
10.3. Day 1 (Pretreatment/Randomization) .............................................................................................32 
10.4. Treatment Period (Day 1 through Day 3) .......................................................................................33 
10.4.1 First Dose (Time 0 through Hour 6) ....................................................................................33 
10.4.2 Subsequent Doses ................................................................................................................34 
10.4.3 Duration of Treatment .........................................................................................................34 
10.5. Follow-Up (Day 7 ± 2 days) Visit...................................................................................................34 
10.6. Study Duration ................................................................................................................................35 
10.7. Efficacy Assessments ......................................................................................................................35 
10.7.1 Pain Intensity .......................................................................................................................35 
10.7.2 Pain Relief ...........................................................................................................................35 
10.7.3 Stopwatch Assessment ........................................................................................................36 
10.7.4 Patient’s Global Evaluation of Study Medication ...............................................................36 
10.8. Safety Evaluations ...........................................................................................................................36 
10.8.1 Physical Examination ..........................................................................................................36 
10.8.2 Vital Signs ...........................................................................................................................36 
10.8.3 Electrocardiograms ..............................................................................................................36 
10.8.4 Clinical Laboratory Tests ....................................................................................................37 
11. ADVERSE EVENTS................................................................................................................................37 
11.1. Definitions .......................................................................................................................................37 
11.1.1 Definition of Adverse Events ..............................................................................................37 
11.1.2 Definition of Serious Adverse Events .................................................................................38 
11.1.3 Significant Adverse Events .................................................................................................38 
11.1.4 Definition of Severity ..........................................................................................................38 
11.1.5 Definition of Start Date, Stop Date, and Duration ..............................................................38 
11.1.6 Action(s) Taken ...................................................................................................................39 
11.1.7 Definition of Expectedness .................................................................................................39 
11.1.8 Definition of Relationship to Study Medication(s) .............................................................39 
11.1.9 Definition of Outcome at the Time of Last Observation .....................................................39 
11.2. Management of Adverse Events .....................................................................................................40 


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11.2.1 Documentation of Adverse Events ......................................................................................40 
11.2.2 Follow-up of Subjects with an Adverse Event ....................................................................40 
11.2.3 Treatment of Adverse Events ..............................................................................................40 
11.2.4 Reporting of Serious Adverse Events .................................................................................40 
11.2.5 Adverse Events of Special Interest ......................................................................................41 
11.2.6 Pregnancy ............................................................................................................................42 
12. DATA SAFETY MONITORING BOARD .............................................................................................42 
13. STATISTICS ............................................................................................................................................42 
13.1. Primary Endpoint ............................................................................................................................42 
13.1.1 Secondary Endpoints ...........................................................................................................43 
13.2. Sample Size Determination .............................................................................................................44 
13.3. Analysis Sets ...................................................................................................................................44 
13.4. Statistical Analyses .........................................................................................................................45 
13.4.1 Disposition ...........................................................................................................................45 
13.4.1.1 Protocol Deviations .................................................................................................45 
13.4.2 Subject Characteristics ........................................................................................................45 
13.4.3 Efficacy ...............................................................................................................................45 
13.4.3.1 Primary Analysis .....................................................................................................45 
13.4.3.2 Secondary Analyses ................................................................................................46 
13.4.4 Exposure ..............................................................................................................................46 
13.4.5 Safety Analyses ...................................................................................................................46 
13.4.6 Interim Analysis ..................................................................................................................47 
14. STUDY CONDUCT .................................................................................................................................47 
14.1. Sponsor and Investigator Responsibilities ......................................................................................48 
14.1.1 Sponsor Responsibilities .....................................................................................................48 
14.1.2 Investigator Responsibilities ...............................................................................................48 
14.2. Center Initiation ..............................................................................................................................48 
14.3. Screen Failures ................................................................................................................................48 
14.4. Study Documents ............................................................................................................................49 
14.4.1 Investigator’s Regulatory Documents .................................................................................49 
14.4.2 Case Report Forms ..............................................................................................................49 
14.4.3 Source Documents ...............................................................................................................49 
14.4.4 Data Quality Control ...........................................................................................................49 
14.4.5 Monitoring Procedures ........................................................................................................50 
14.4.6 Data Management ................................................................................................................50 
14.4.7 Quality Assurance/Audit .....................................................................................................50 
14.5. Study Termination ...........................................................................................................................51 
14.6. Study Center Closure ......................................................................................................................51 


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14.6.1 Record Retention .................................................................................................................51 
14.7. Changes to the Protocol ..................................................................................................................51 
14.8. Use of Information and Publication ................................................................................................52 
15. ETHICAL AND LEGAL CONSIDERATIONS ......................................................................................52 
15.1. Declaration of Helsinki and Good Clinical Practice .......................................................................52 
15.2. Subject Information and Informed Consent ....................................................................................52 
15.3. Approval by Institutional Review Board ........................................................................................52 
15.4. Finance and Insurance .....................................................................................................................53 
16. REFERENCES .........................................................................................................................................54 
17. ATTACHMENTS .....................................................................................................................................55 
17.1. Schedule of Events ..........................................................................................................................55 
17.2. Investigator’s Agreement ................................................................................................................57 
APPENDICES .................................................................................................................................................58 
A. 
Address List ....................................................................................................................................59 
1. 
Sponsor ................................................................................................................................59 
2. 
Clinical Research Organization ...........................................................................................59 
3. 
Drug Safety ..........................................................................................................................59 
4. 
Monitor ................................................................................................................................60 
5. 
Coordinating/Principal Investigator ....................................................................................60 
6. 
Laboratories .........................................................................................................................61 
B. 
Regulations and Good Clinical Practice Guidelines .......................................................................62 
1. 
Regulations ..........................................................................................................................62 
2. 
Good Clinical Practice Guidelines ......................................................................................62 
 
3.1. LIST OF TABLES 
Table 1: 
Study Treatment Arms ....................................................................................................... 26 
Table 2: 
Dosing Scheme ................................................................................................................... 28 
 
 
 
 


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4. LIST OF ABBREVIATIONS 
AE 
adverse event 
API 
active pharmaceutical ingredient 
ASA 
American Society of Anesthesiologists 
BID 
twice daily 
BMI 
body mass index 
BOCF 
baseline-observation-carried-forward 
CAS 
Completers Analysis Set 
CFR 
Code of Federal Regulations 
COX 
cyclooxygenase 
CRA 
Clinical research associate 
CS 
clinically significant 
ECG 
electrocardiogram 
eCRF 
electronic case report form  
EDC 
electronic data capture 
ESTEVE 
Laboratorios del Dr. ESTEVE, S. A. U. 
FAS 
full analysis set 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
IRT 
interactive response technology 
IUD 
intrauterine device  
IV 
intravenous 
LOCF 
last-observation-carried-forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEQ 
morphine equivalents units 
NCS 
not clinically significant 
NPRS 
Numerical pain rating scale 
NPRS PID 
NPRS pain intensity difference 
NPRS SPID 
NPRS summed pain intensity difference 
NPRS SPID-4 
NPRS SPID over 0 to 4 hours 
NPRS SPID-6 
NPRS SPID over 0 to 6 hours 


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NPRS SPID-12 
NPRS SPID over 0 to 12 hours 
NPRS SPID-24 
NPRS SPID over 0 to 24 hours 
NPRS SPID-48 
NPRS SPID over 0 to 48 hours 
NSAID 
nonsteroidal anti-inflammatory drug 
PARt 
pain relief at each time point 
PI 
pain intensity 
PID 
paint intensity difference 
PK 
pharmacokinetic 
PP 
per-protocol 
PPAS 
Per-protocol Analysis Set 
Premier Research 
Premier Research Group Limited 
PSB 
popliteal sciatic nerve block 
PT 
preferred term 
QID 
4 times daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SD 
standard deviation 
SOC 
system organ class 
SOP 
Standard Operating Procedure 
SPID 
sum of pain intensity differences 
TEAE 
treatment-emergent AE 
TOTPAR 
total pain relief 
Tramadol HCl 
Tramadol hydrochloride 
US 
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5. INTRODUCTION 
5.1. Background and Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.3. Summary of Potential Risks and Benefits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6. OBJECTIVES 
6.1. Primary Objective 
The primary objective of this study is to establish the analgesic efficacy of co-crystal E-58425 compared to 
tramadol and to celecoxib for the management of moderate to severe post-operative pain for 48 hours after 
bunionectomy by using assessments of pain intensity. 
6.2. Secondary Objectives 
Secondary objectives are as follow: 
• To assess the analgesic efficacy of co-crystal E-58425 compared to tramadol and to celecoxib for the 
management of moderate to severe post-operative pain at various time points after bunionectomy by using 
assessments of pain intensity 
• To assess the analgesic efficacy of co-crystal E-58425 by means of responder rates, use of rescue 
medication, time to onset of analgesia, time to perceptible and meaningful pain relief, time to onset of 
pain intensity decrease, peak pain relief and time to peak pain relief, and the subjects’ overall assessment 
of the study medication 
• To assess the absolute analgesic efficacy of co-crystal E-58425 compared to placebo for the treatment of 
moderate to severe post-operative pain for 48 hours at various time points after bunionectomy by using 
assessments of pain intensity 
• To assess the safety and tolerability of the co-crystal E-58425 
7. STUDY DESIGN 
7.1. Overall Study Design and Plan 
This phase 3, randomized, double-blind, active- and placebo-controlled, parallel group, multicenter clinical trial 
will compare co-crystal E-58425 to tramadol, to celecoxib, and to placebo. Approximately 630 male and female 
subjects will be randomized. Subjects must be at least 18 years of age and scheduled to undergo primary unilateral 
first metatarsal osteotomy with internal fixation with no additional collateral procedure. Efforts will be made to 
enroll subjects ≥65 years old. 
Eligible subjects will complete all screening procedures within 28 days before the surgery. At Screening, subjects 
will provide written informed consent to participate in the study before any protocol specified procedures or 
assessments are conducted. 
Subjects will be admitted to the study center on the morning of the scheduled surgery (Day -1), will remain at the 
study center until postoperative Day 3 (a total of 3 nights at the study center), and will return for the Follow up 
Visit, which occurs 5 to 9 days after surgery. 
On Day -1, regional anesthesia will be established using a popliteal sciatic nerve block (PSB) after which subjects 
will undergo primary, unilateral, first metatarsal osteotomy with internal fixation with no additional collateral 
procedure. The regional anesthesia will be continued postoperatively via a continuous anesthetic infusion. 
Subjects may receive supplemental analgesia with ketorolac 30 mg intravenously during the continuous infusion 
period and up until 1:00 A.M. to help control breakthrough pain if the regional anesthetic infusion appears to be 
ineffective in the investigator’s opinion up until 1:00 A.M. If the regional anesthetic infusion and supplemental 
analgesia do not effectively control the subject’s postoperative pain prior to the 3:00 A.M. anesthetic infusion 
discontinuation time, the subject will not be eligible to be considered for the study. 


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On Day 1, after regional anesthetic infusion is discontinued between 3:00 and 4:00 A.M., study staff will contact 
interactive response technology (IRT) system to obtain the moderate and severe pain box numbers for the subject 
and will retrieve the study medication boxes from stock, 1 for moderate pain and 1 for severe pain. The subject 
will be instructed to notify a member of the study staff and request treatment when he or she experiences a level 
of pain that requires medication. When the subject requests pain medication, they will be asked to rate their pain 
intensity (PI) using the Numerical Pain Rating Scale (NPRS) assessment, a scale marked from zero to 10 on which 
subjects circle a single number to indicate their current pain level, with zero representing "No Pain" and 
10 representing "Worst Possible Pain." 
Subjects with a score ≥5 and ≤9 on the 0-10 NPRS will be randomized into the study and stratified by Baseline 
pain score (moderate [NPRS 5-6], severe [7-9] using interactive response technology (IRT) and the appropriate 
pain level box will be used. Subjects will be randomly assigned in a ratio of 2:2:2:1 to 1 of the 4 treatment groups, 
respectively: Co-crystal R-58425 200 mg twice daily (bid; every 12 hours), tramadol 50 mg 4 times daily (qid; 
every 6 hours), celecoxib 100 mg bid, or placebo qid, respectively (see Table 1). 
Subjects with a NPRS score <5 will be asked if they can wait for treatment. If they cannot, they will be dropped 
from the study and treated according to the standard of care. If they agree to wait, they will be requested to notify 
a member of the study staff when their pain intensity has increased; NPRS will be readministered at that time. If 
the subject’s pain intensity ratings do not meet the minimum entry criteria within 8 hours of discontinuation of 
the regional anesthesia, or if they have a PI >9, subjects will not be eligible for randomization and will receive 
routine postoperative care at the investigator’s discretion.  
The NPRS pain intensity assessments made just before randomization will serve as the Baseline PI to which all 
subsequent PI assessments will be compared. Time 0 will be defined as the time of the first dose of study 
medication. Pain intensity (NPRS) and pain relief (5-point categorical scale) assessments will be recorded in the 
subject diary at scheduled times during the 48 hour period after Time 0 (15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 
2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, 38, 42, 46, and 48 hours) and immediately 
before each use of rescue medication. During the night, subject will be wakened to administer the study 
medication. Pain assessments will be performed during the night only if the subject is awake. Time to perceptible 
and meaningful pain relief will be evaluated using the 2 stopwatch method starting at Time 0. Pain intensity and 
pain relief assessments will also be recorded before premature study termination. Subjects will complete a 
patient’s global evaluation of the study medication at the end of the Double-blind Treatment Period (Day 3) before 
discharge from the study center.  
After randomization, subjects will be encouraged to wait for at least 1 hour after the first dose of study medication 
before receiving first rescue medication to allow time for the study medication to exert its pharmacologic effect. 
Subjects may be given acetaminophen 1 g IV every 4 to 6 hours, up to 4 g/24 hours, for pain as rescue medication 
after the anesthetic infusion is discontinued and treatment with study medication has been initiated. If subjects 
are unable to tolerate IV acetaminophen or have insufficient pain relief with acetaminophen 1 g IV every 4 to 6 
hours, then oxycodone hydrochloride 5 mg Immediate Release (IR) tablets can be administered every 4 to 6 hours 
as needed for pain, up to a total of 30 mg/24 hours.  
Subjects whose pain cannot be adequately managed by a combination of study medication and rescue medication, 
or who develop unacceptable side effects during the study, will be discontinued from study medication or from 
further study participation. Their pain will be managed conventionally at the investigator’s discretion. All end-
of-study assessments should be performed for subjects who discontinue from the study, if possible. Side effects 
will be managed with pharmacologic and non-pharmacologic methods at the investigator’s discretion.  
Before discharge from the study center on Day 3, study personnel will dispense a prescription for pain medication 
(if not already dispensed) and an outpatient subject diary. Subjects will be instructed to record concomitant 


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medications taken and adverse events (AEs) experienced after discharge in their outpatient subject diary. Subjects 
will also be instructed to return the outpatient subject diary to study personnel at the Follow-up Visit.  
7.2. Discussion of Study Design 
The postsurgical bunionectomy pain model was selected for this study as the acute pain model based on its record 
of assay sensitivity and reproducibility in evaluating putative analgesic agents.2,3 Studies have demonstrated that 
subjects given nonsteroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenases (COX)-2 inhibitors 
for the treatment of pain have had clinically significant reductions in their pain scores and statistically significant 
differences from placebo.4,5 This study includes a placebo control group to evaluate whether active treatment is 
superior to placebo for the efficacy assessments. The pain intensity NPRS to be used in this study is a widely 
accepted tool to measure a subject’s perception of pain.  
7.3. Study Center(s) 
The study will take place at approximately 5 to 6 centers in the United States. Each center is anticipated to screen 
a sufficient number of subjects to be able to randomize approximately 630 subjects in total. A study center with 
a high recruitment rate may be allowed to recruit more subjects if other centers have slow enrollment. 
8. SUBJECT POPULATION 
8.1. Selection of Study Population  
A screening log of potential study candidates and an enrollment log of randomized subjects must be maintained 
at each study center. 
8.2. Study Entry Criteria 
8.2.1 Inclusion Criteria 
A subject will be eligible for study participation if the subject meets all of the following criteria: 
1. Subject must have signed consent before study entry. 
2. Subject must be at least 18 years old, scheduled to undergo primary unilateral first metatarsal osteotomy 
with internal fixation with no additional collateral procedure. 
3. Male and female subjects are eligible. If female, subject must be either not of childbearing potential 
(defined as postmenopausal for at least 1 year or surgically sterile [bilateral tubal ligation, bilateral 
oophorectomy, or hysterectomy]) or practicing 1 of the following effective methods of birth control : 
o Hormonal methods such as oral, implantable, injectable, vaginal ring, or transdermal 
contraceptives  
o Total abstinence from sexual intercourse since the last menses before study medication 
administration 
o Intrauterine device 
o Double-barrier method (condoms, sponge, or diaphragm with spermicidal jellies or cream) 
Women must use effective methods of birth control from Screening until 4 weeks after the last 
administration. 
4. If female and of childbearing potential, subject must be non-lactating and non-pregnant (has negative 
serum pregnancy test results at Screening and negative urine test on the day of surgery prior to surgery). 
5. Subject must have a body weight of 45 kg or more and a body mass index (BMI) of 40 kg/m2 or less. 


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6. Subject must have a qualifying pain score of ≥5 and ≤9 on the 0-10 NPRS at rest as a result of turning off 
the popliteal sciatic block for bunionectomy to be eligible for randomization. 
7. Subject must be in good physical health in the investigator’s judgment. 
8. Subject must be sufficiently alert to understand and communicate intelligibly with the study observer. 
8.2.2 Exclusion Criteria 
A subject will be excluded from the study if the subject meets any of the following criteria: 
1. Subject’s Baseline pain is <5 or >9 on a 0-10 NPRS. 
2. Subject received any analgesic medication other than short-acting pre-operative or intra-operative 
anesthetic agents before the end of bunionectomy surgical procedure. Subjects who received any analgesic 
medication immediately after the bunionectomy surgical procedure was completed and before study 
medication is administered will also be excluded, with the exception of ketorolac 30 mg intravenously as 
supplemental analgesia during the continuous infusion period and up until 1:00 A.M. 
3. Subject has a history of seizures or alcohol abuse (eg, drinks >4 units of alcohol per day, a unit being equal 
to 8 oz. beer, 3 oz. wine, 1 oz. spirits) within the past 5 years, has a history of prescription/illicit drug 
abuse within 6 months before dosing with study medication, or has positive results on the urine drug 
screen or alcohol breath test indicative of illicit drug or alcohol abuse. 
4. Subject has a history of or positive test results for human immunodeficiency virus or hepatitis B or C. 
5. Subject has an active malignancy of any type, or has been diagnosed with cancer within 5 years before 
Screening (excluding successfully treated squamous or basal cell carcinoma of the skin). 
6. Subject is currently receiving anticoagulants (eg, heparin or warfarin) or antiplatelets (except aspirin 
≤325 mg/day). 
7. Subject has received a course of systemic (either oral or parenteral) or intra-articular corticosteroids within 
3 months before Screening (inhaled nasal steroids and topical corticosteroids are allowed). 
8. Subject has any ongoing condition, other than one associated with the current primary, unilateral, first 
metatarsal bunionectomy, that, in the investigator’s opinion, could generate levels of pain sufficient to 
confound assessments of post-operative pain (eg, severe osteoarthritis of the target joint or extremity, 
fibromyalgia, rheumatoid arthritis, moderate to severe headache, diabetic foot pain or neuropathy). 
9. Subject has been receiving or has received chronic (defined as daily use for >2 weeks) opioid (oral 
codeine, dextromoramide, dihydrocodeine, oxycodone, or morphine-like anti-tussive) therapy defined as 
>15 morphine equivalents units per day for more than 3 out of 7 days per week over a 1-month period 
within 12 months of surgery, or has been treated chronically with opioid analgesic (buprenorphine, 
nalbuphine, or pentazocine) or Non-Steroidal Anti-Inflammatory Drug (NSAID)within 30 days before 
Screening. 
10. Subject received a long-acting NSAID within 4 days before initiation of study medication (except aspirin 
≤325 mg/day), or a short-acting NSAID within 1 day, with the exception of ketorolac 30 mg intravenously 
as supplemental analgesia during the continuous infusion period. 
11. Subject is under long-term treatment with opioid agonist-antagonists.  
12. Subject has used drugs with enzyme-inducing properties, such as rifampicin and St. John’s Wort, or any 
drug known to be a strong inhibitor or inducer of CYP3A4, CYP2C9, or CYP2D6 within 3 weeks before 
surgery.  
13. Subject is pregnant or lactating.  
14. Subject had any complication during primary bunionectomy surgery. 
15. Subject has received monoamine oxidase inhibitors, tricyclic antidepressants, neuroleptics, or other drugs 
that reduce the seizure threshold within 4 weeks of study entry. 


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16. Subject has a history or evidence of a clinically significant (in the investigator’s opinion) gastrointestinal 
(GI) event within 6 months before Screening or has any history of peptic or gastric ulcers or GI bleeding. 
17. Subject has clinically significant renal or hepatic disease, as indicated by clinical laboratory assessment 
(results ≥3 times the upper limit of normal for any liver function test, including aspartate aminotransferase, 
alanine aminotransferase, bilirubin, and lactate dehydrogenase, or creatinine ≥1.5 times the upper limit of 
normal). Laboratory tests may be repeated once at Screening to rule out laboratory error. 
18. Subject has any clinically significant laboratory or 12-lead electrocardiogram (ECG) finding at Screening 
that, in the opinion of the investigator, contraindicates study participation (eg, QTc >450 msec [male] or 
>470 msec [female]). 
19. Subject has a known history of allergic reaction or clinically significant intolerance to acetaminophen, 
aspirin, opioids, or any NSAIDs; history of NSAID induced bronchospasm (subjects with the triad of 
asthma, nasal polyps, and chronic rhinitis are at greater risk for bronchospasm and should be considered 
carefully) or to the ingredients of the study medication, or any other drugs used in the study, including 
anesthetics and antibiotics that may be required on the day of surgery.  
20. Subject has received anti-depressive medication with serotonin–norepinephrine reuptake inhibitors 
(SNRIs; milnaciprin, duloxetine, venlafaxine), diet pills (including fenfluramine and phentermine) or 
methylphenidate (Ritalin®), or other similar medications for ADHD within 4 weeks of study entry. 
Subjects receiving selective serotonin reuptake inhibitors (SSRIs) may be included provided they have 
been on a stable dose for 60 days prior to study participation and plan to remain on that dose throughout 
the study. 
21. Subject is, in the investigator’s judgment, at risk in terms of precautions, warnings, and 
contraindications in the package insert for Ultram® (tramadol hydrochloride) or Celebrex® (celecoxib). 
Specifically, in situations where participation is contraindicated per the package insert the subject should 
be excluded. However, in situations where medications or medical conditions listed in the precautions 
and warnings are present the physician should evaluate the subject’s history, physical examination 
results, laboratory analysis, and ECG carefully and use his/her discretion as to whether the subject is 
suitable for participation. 
22. Subject has a known coagulation disorder.  
23. Subject has history of or current medical, surgical, post-surgical, or psychiatric condition that would 
confound interpretation of safety, tolerability, or efficacy, (eg, uncontrolled diabetes mellitus, 
uncontrolled hypertension, hemodynamic instability, or respiratory insufficiency, cancer or palliative 
care). 
24. Subject received an experimental drug or used an experimental medical device within 30 days prior to 
Screening or has previously participated in this trial. 
25. Subject is unable to comply with the requirements of the study or, in the investigator’s opinion, should 
not participate in the study. 
26. Subject is undergoing concomitant surgical procedure(s) in addition to primary bunionectomy. 
8.3. Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any time, for any 
reason, and without prejudice. Every reasonable attempt should be made by the investigator to keep subjects in 
the study; however, subjects must be withdrawn from the study if they withdraw consent to participate. 
Investigators must attempt to exclude the possibility of an AE being the cause of withdrawal. Should this be the 
cause, the AE must be documented, reported, and followed as described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or other reasons. 


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The investigator also has the right to withdraw subjects from the study at any time for lack of therapeutic effect 
that is intolerable or otherwise unacceptable to the subject, for intolerable or unacceptable AEs, intercurrent 
illness, noncompliance with study procedures, administrative reasons, or in the investigator’s opinion, to protect 
the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of discontinuation 
will be recorded on the appropriate page of the electronic case report form (eCRF). Whenever possible and 
reasonable, the evaluations that were to be conducted at the completion of the study should be performed at the 
time of premature discontinuation, unless the subject withdraws consent. Whenever possible and reasonable, 
when study medication is discontinued efforts will be made to collect all study assessments as scheduled up to 
the completion of the study, unless the subject withdraws consent. 
Subject Replacement Criteria 
Withdrawn subjects will not be replaced. If a substantial number of subjects are withdrawn from the study, the 
sponsor will evaluate the need for developing replacement criteria. 
Enrolled subjects withdrawn from the study may not reenter. The subject number for a withdrawn subject will 
not be reassigned to another subject. 
9. TREATMENTS 
9.1. Identification of Investigational Product(s) 
Co-crystal E-58425 will be provided in the form of over encapsulated 100-mg oral tablets. 
Co-crystal E-58425 tablets will be supplied as by ESTEVE (manufactured by Esteve, Martorelles, Barcelona, 
Spain). 
Ultram (tramadol) will be supplied as 50-mg, immediate-release, oral tablets (manufactured by 
 
), over encapsulated by ESTEVE. 
Celebrex (celecoxib) 100-mg, immediate-release, oral capsules (Marketing Authorization Holder 
), 
over encapsulated by ESTEVE. 
Placebo will be provided in the form of over encapsulated 100-mg oral tablets. Placebo tablets will be supplied 
by ESTEVE (manufactured by Esteve, Martorelles, BARCELONA [SPAIN]). All study medications will be over 
encapsulated to match. 
9.2. Labeling and Packaging 
Labeling and packaging of Co-crystal E-58425 will be performed by 
 
). 
9.2.1 Labeling 
Each container of study medication will be labeled with study specific information meeting all the applicable 
regulatory requirements. 
Carton label text:  
• Protocol Code 
• Treatment number 
• “For oral administration only” 
• Quantity of bottles 
• Directions for use 


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• Caution: “New Drug – Limited by Federal Law to Investigational Use” and “Keep out of the sight and 
reach of children” 
• Storage instructions 
 
Bottle label text: 
• Protocol code 
• Treatment number 
• Bottle number 
• “For oral administration only” 
• Directions for use 
• Package contents (quantity) 
• Storage instructions 
• Caution: “New Drug – Limited by Federal Law to Investigational Use” and “Keep out of the sight and 
reach of children” 
 
9.2.2 Packaging 
Study treatments will shipped in boxes to the centers, each holding 8 bottles, containing 1 capsule per bottle for 
Bottles 2, 4, 6 and 8 and 2 capsules per bottle per Bottles 1, 3, 5 and 7. Each bottle will be labeled, “Bottle 1-
0h”, “Bottle 2-6h”, etc. All pills will be over-encapsulated, and will all look the same (all capsules will have the 
same organoleptic characteristics), to maintain blinding. 
The boxes will have consecutive numbers and will be distributed per the randomization by IRT, stratified by 
Baseline pain score (moderate [NPRS 5-6] or severe [NPRS 7-9]). 
9.3. Treatments Administered 
Subjects will be randomly assigned in a ratio of 2:2:2:1 to 1 of 4 treatment groups as in Table 1. Study medication 
and/or placebo will be administered 4 times daily for a maximum of 2 days. Study medication will be 
administered with 8 ounces of water. 
 
Table 1: 
Study Treatment Arms 
 
Posology 
TOTAL DAILY DOSE 
Tramadol 
Celecoxib 
ARM-1 
Co-crystal E-58425 
200 mg bid 
176 mg 
224 mg 
ARM-2 
Tramadol 
50 mg qid 
200 mg 
0 
ARM-3 
Celecoxib 
100 mg bid 
0 
200 mg 
ARM-4 
Placebo 
0 mg qid 
0 
0 
Abbreviations: bid = twice daily (every 12 hours); qid = four times daily (every 6 hours) 
 
All subjects will be dosed every 6 hours, (ie, 4 times daily) as displayed in Table 2: 


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• Co-crystal: the total daily dose will be 400 mg (200 mg every 12 hours):  
400 mg of co-crystal corresponds to 176 mg of tramadol and 224 mg of celecoxib. 
• Tramadol: the total daily dose will be 200 mg (50 mg every 6 hours) 
• Celecoxib: the total daily dose will be 200 mg (100 mg every 12 hours) 
9.4. Dispensing and Storage 
The study medication supplied by ESTEVE is to be used exclusively in the clinical study according to the 
instructions of this protocol. The investigator is responsible for dispensing the study medication according to the 
dosage scheme and for ensuring proper storage of the study medication. 
Until the study medication is dispensed to the subjects, it must be stored at 68°F-77°F (20°C-25°C). Store in 
accordance with controlled drug regulations, in a securely locked area that is not generally accessible. The key to 
the storage area is to be kept by the investigator or designee responsible for the IP. The store will be accessible 
only to those persons authorized by the investigator to dispense the study medication. 
9.5. Method of Assigning Subjects to Treatment Groups 
In this parallel-group randomized study, subjects who meet study entry criteria will be randomly assigned in a 
2:2:2:1 ratio to co-crystal E-58425, tramadol, celecoxib, or placebo. The randomization schedule will be computer 
generated and will randomly allocate study medication to randomization numbers.  
The randomization numbers will be assigned sequentially through central IRT as subjects are entered into the 
study. The randomization schedule will be stratified by center and baseline pain score (moderate [NPRS 5-6] or 
severe [NPRS 7-9]).1 
The randomization schedule will be prepared by Premier Research before the start of the study. No one involved 
in the study performance will have access to the randomization schedule before official unblinding of treatment 
assignment. No subject will be randomized into this study more than once. 
9.6. Blinding and Unblinding Treatment Assignment 
All subjects, investigators, and study personnel involved in the conduct of the study, including data management, 
will be blinded to treatment assignment.  
Study personnel will endeavor to safeguard the integrity of the study blind to minimize bias in the conduct of the 
study. Treatment unblinding is discouraged if knowledge of the treatment assignment will not materially change 
the planned management of a medical emergency. Unblinding will be permitted in a medical emergency that 
requires immediate knowledge of the subject’s treatment assignment. 
Unblinding should be discussed in advance with the medical monitor if possible. For emergency unblinding, study 
personnel will use the IRT. If the investigator is not able to discuss treatment unblinding in advance, then he or 
she must notify the medical monitor as soon as possible about the unblinding incident without revealing the 
subject’s treatment assignment.   
The investigator or designee must record the date and reason for study discontinuation on the appropriate case 
report form (CRF) for that subject. In all cases that are not emergencies, the investigator must discuss the event 
with the medical monitor prior to unblinding the subject’s treatment assignment. 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of that subject’s 
treatment assignment without unblinding the treatment assignments for the remaining subjects in the study. Thus, 
the overall study blind will not be compromised. If a subject’s treatment assignment is unblinded, he/she may or 
may not be asked to withdraw from the study. The investigator will make this decision after consultation with the 
medical monitor. 


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9.7. Selection of Doses in the Study 
The analgesic activity of the co-crystal E-58425 is expected to be superior to the activity predicted by the sum of 
the individual components.1 This synergistic pharmacological activity of the co-crystal E-58425 would result 
from the recruitment of 4 relevant molecular mechanisms of action: μ-opioid receptor agonism, inhibition of the 
neuronal reuptake of norepinephrine and serotonin, and COX-2 inhibition. In the same way, the dissociation of 
the co-crystal E-58425 favors a concomitant action of tramadol and celecoxib, with potential implications for the 
onset, magnitude, duration and consistency of efficacy. On this basis, low doses of the co-crystal E-58425 could 
achieve a similar efficacy to that of the therapeutic doses of tramadol (eg, 200 mg).  
The efficacy of the co-crystal E-58425 due to tramadol and celecoxib will be achieved with lower plasma levels 
of the current use of each.  
9.8. Selection of Timing of Dose for Each Subject 
Subjects will receive assigned treatment of study medication after reaching a minimum designated level of 
postoperative pain intensity. Study medication will be administered in a qid regimen for 48 hours after the first 
dose, with a maximum of 4 doses (active and/or placebo) in a 24-hour period. The timing of study medication 
dosing is based on the current dosage and administration recommendations for tramadol and for celecoxib. 
Table 2 describes treatment administration. 
 
Table 2: 
Dosing Scheme 
Treatment Group 
DAY 2 
DAY 3 
Dose 1 
(0 h) 
Dose 2 
(6 h) 
Dose 3 
(12 h) 
Dose 4 
(18 h) 
Dose 5 
(24 h) 
Dose 6 
(30 h) 
Dose 7 
(36 h) 
Dose 8 
(42 h) 
Co-crystal E-58425 
200 mg 
P  
200 mg 
P 
200 mg 
P  
200 mg 
P 
Tramadol 
50 mg 
50 mg 
50 mg 
50 mg 
50 mg 
50 mg 
50 mg 
50 mg 
Celecoxib 
100 mg 
P 
100 mg 
P 
100 mg 
P 
100 mg 
P 
Placebo 
P 
P 
P 
P 
P 
P 
P 
P 
Abbreviations: h = hour; P = placebo 
 
9.9. Dose Adjustment Criteria 
Dose adjustment is not allowed in this study. 
The regional anesthesia will be continued postoperatively via a continuous anesthetic infusion. Subjects may 
receive supplemental analgesia with ketorolac 30 mg IV during the continuous infusion period until 1:00 A.M to 
help control breakthrough pain if the regional anesthetic infusion appears, in the investigator’s opinion, to be 
ineffective. If the regional anesthetic infusion and supplemental analgesia do not effectively control the subject’s 
postoperative pain prior to the 3:00 A.M. anesthetic infusion discontinuation time, the subject will not be eligible 
to be considered for the study. 
9.10. Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other disposition of 
the study medication including the date, quantity, batch or code number, and identification of subjects (subject 
number) who received the study medication. The investigator will not supply the study medication to any person 


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except those named as subinvestigators on the FDA 1572, designated staff, and subjects in this study. The 
investigator will not dispense the study medication from any centers other than those listed on the FDA 1572. 
Study medications may not be relabeled or reassigned for use by other subjects. 
Upon completion of the study, unused supplies of the study medication will be returned to sponsor or destroyed 
as directed. 
9.11. Treatment Compliance 
All subjects will receive the study medication at the study center under the surveillance of appropriate study 
personnel. Study medication administration details will be recorded in the subject’s CRF. 
9.12. Concomitant Therapies 
Treatment with the following medications and therapies before study entry (see Section 8.2) or during the study 
is not allowed: 
• 
All medications (except hormonal contraceptives and vitamins) will be prohibited within 5 half-lives 
of the prohibited medication (or, if half-life is unknown, within 48 hours) before dosing with study 
medication until discharge from the study center on Day 3. Exceptions include study-designated rescue 
medications, anesthetics, antibiotics, and concomitant medication for chronic stable illness, which will 
be permitted according to the judgment of the investigator. 
• 
Analgesic medication other than short-acting pre-operative or intra-operative anesthetic agents before 
the popliteal sciatic block for bunionectomy is removed, ie, before taking study medication, is 
prohibited. All analgesic medication taken immediately after the bunionectomy is completed and 
before study medication is administered is excluded, with the exception of ketorolac 30 mg 
intravenously supplemental analgesia during the continuous infusion period and up until 1:00 A.M. 
• 
Chronic (defined as daily use for >2 weeks) opioid (oral codeine, dextromoramide, dihydrocodeine, 
oxycodone, or morphine-like anti-tussive) therapy, defined as >15 morphine equivalent units per day 
for more than 3 out of 7 days per week over a 1-month period within 12 months of surgery. 
• 
Long-acting NSAID within 4 days before initiation of study medication (except aspirin ≤325 mg/day 
for cardiovascular prophylaxis) or short-acting NSAID within 1 day. 
• 
Regular use of opioid analgesic (buprenorphine, nalbuphine, or pentazocine) within 30 days before 
Screening. 
• 
Long-term use of opioid agonist-antagonists. 
• 
Liver-inducing enzyme cytochrome P450: antiinfectives (eg, rifampicin, rifabutin, nevirapine, 
griseofulvin) or anti-epileptics (phenobarbital, phenytoin). 
• 
Monoamine oxidase inhibitors, tricyclic antidepressants, neuroleptics, or other drugs that reduce the 
seizure threshold within 4 weeks of study entry. 
• 
Serotonin–norepinephrine reuptake inhibitors (milnaciprin, duloxitene, venlafaxine), diet pills 
(including fenfluramine and phentermine), or methylphenidate (Ritalin®), or similar ADHD 
medications within 4 weeks of study entry. 
• 
Any investigational drug or device or investigational therapy will be prohibited within 30 days before 
Screening. 
All concomitant medications used (including over-the-counter medications and herbal supplements) will be 
recorded in the source document and on the appropriate CRF. 


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9.13. Other Restrictions 
Other restrictions include the following: 
• Alcohol use is prohibited from 24 hours before surgery until discharge from the study center on Day 3. 
• No smoking upon admission to the study center until discharge from the study center on Day 3. 
• Nothing by mouth from midnight before surgery until 1 hour after surgery. 
9.14. Rescue Medication 
After randomization, subjects will be encouraged to wait for at least 1 hour after the first dose of study 
medication before receiving first rescue medication to allow time for the study medication to exert its 
pharmacologic effect. Subjects may be given acetaminophen 1 g IV every 4 to 6 hours, up to 4 g/24 hours, for 
pain as rescue medication after the anesthetic infusion is discontinued and treatment with study medication has 
been initiated. If subjects are unable to tolerate IV acetaminophen or have insufficient pain relief with 
acetaminophen 1 g IV every 4 to 6 hours, oxycodone hydrochloride 5 mg Immediate Release (IR) tablets can be 
administered every 4 to 6 hours as needed for pain, up to a total of 30 mg/24 hours 
Acetaminophen has been selected because its mechanism of action differs from tramadol and celecoxib, while 
oxycodone has been chosen as a secondary rescue medication because, although it is contraindicated with other 
NSAIDs, it is expected that secondary rescue medication will be required by few subjects and primarily for 
subjects randomized to the placebo group. 
Subjects whose pain cannot be adequately managed by a combination of study medication and rescue 
medication, or who develop unacceptable side effects during the study, will be discontinued from study 
medication or from further study participation. Their pain will be managed conventionally at the investigator’s 
discretion. All end-of-study assessments should be performed for subjects who discontinue from the study, if 
possible. 
All concomitant medications used will be recorded in the source document and on the case report form. 
9.15. Treatment after End of Study 
After the end of the study, each subject will be treated according to standard clinical practice. 
Subjects will be discharged home with a prescription for pain-relief medication and a subject diary in which to 
record AEs and concomitant medications.  
10. STUDY PROCEDURES 
Subjects must provide written informed consent before any study-related procedures are initiated, including the 
cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the study, refer to the schedule of events (Section 17.1). 
Throughout the study, every reasonable effort should be made by study personnel to follow the timing of 
assessments and procedures in the schedule of events for each subject. If a subject misses a study visit for any 
reason, the visit should be rescheduled as soon as possible. 
10.1. Screening 
Subjects will sign an ICF before any screening-related procedures are performed. Screening assessments must 
be performed within 28 days before the bunionectomy surgery (Day -1). The following procedures will be 
performed at Screening: 


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1. Assign a screening number. 
2. Review inclusion/exclusion criteria. 
3. Record demographics and detailed medical history, including medications taken within 30 days before 
Screening. 
4. Perform a complete physical examination (excluding genitourinary examination) with review of body 
systems and include classification of ASA physical status classification. 
5. Record vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) after the subject 
has been in a resting position for 5 minutes. 
6. Record any AEs and concomitant medications. 
7. Measure height and weight and calculate body mass index (BMI). 
8. Record 12-lead electrocardiogram (ECG). 
9. Collect blood and urine samples for clinical laboratory tests (hematology, chemistry, and urinalysis; see 
Section 10.8.4 for a complete list of required laboratory tests). 
10. Collect a blood sample for serum pregnancy test from female subjects of childbearing potential. 
11. Collect a urine sample for the drug screen. 
12. Perform podiatric examination and obtain radiograph (a radiograph taken within the previous 6 months will 
be acceptable). 
13. Remind the subject not to use prohibited concomitant medications (see Section 9.12) and to comply with all 
study restrictions, including nothing by mouth starting from midnight before surgery. 
14. Train the subject on the use of self-assessment measures. 
10.2. Day of Surgery (Day -1) 
The day of surgery (Day -1) is defined as a time period that includes the time of surgery (primary, unilateral, 
first metatarsal osteotomy with internal fixation with no additional collateral procedure) and the immediate 
postoperative period of up to 24 hours. During this period, the following events will occur: 
10.2.1 Preoperative 
1. Review inclusion and exclusion criteria and verify that the subject continues to meet all study entry criteria. 
2. Update medical history (including adverse reactions experienced and concomitant medications taken, if 
applicable, since Screening). 
3. Record vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) after the subject 
has been in a resting position for 5 minutes. 
4. Perform a physical examination.  
5. Collect a urine sample for the pregnancy test from female subjects of childbearing potential. 
6. Collect a urine sample for the drug screen. 
7. Perform alcohol breathalyzer test. 
8. Train the subject on how to assess their pain level after surgery.  
Subjects who are deemed ineligible for study participation before surgery will be considered screen failures. 


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10.2.2 Surgery and Standardized Regional Anesthesia 
Subjects who continue to meet all study entry criteria will undergo standard first metatarsal bunionectomy 
procedure under a standardized regimen of regional anesthesia. The local anesthetic technique to be used for 
this surgery comprises a combination of a PSB to establish and maintain surgical field anesthesia and a 
continuous sciatic infusion to provide an effective method of controlling pain in the immediate postoperative 
period. 
The PSB will be administered using modifications of the Singelyn technique.6 Subjects will receive midazolam 
and/or propofol for initial sedation at the anesthesiologist’s discretion. After adequate sedation is achieved, the 
anesthesiologist will inject approximately 5 mL lidocaine 1% (plain) (or suitable short acting local anesthetic 
without epinephrine) locally to anesthetize the skin, and will determine the location of the sciatic nerve for the 
PSB. Once the appropriate location is determined, the anesthesiologist will inject 40 mL of ropivacaine 0.5% to 
establish the PSB. Subsequently a catheter will be placed in the proximity of the popliteal sciatic nerve for 
delivery of postoperative anesthesia. If the PSB is not sufficient to provide adequate intraoperative anesthesia, a 
standard Mayo block may be established using lidocaine 2% (plain) not to exceed 25 mL. The time, date, dose, 
and route of all local anesthetics will be recorded in the CRF. (NOTE: While lidocaine 2% plain is the preferred 
local anesthetic to establish the Mayo block, an alternative plain short-acting local anesthetic or plain 
combination of 2 local anesthetics may be substituted if necessary. If mepivacaine is used for the Mayo block, 
the amount of mepivacaine should be added to the amount of mepivacaine used postoperatively for the popliteal 
block in order not to exceed maximum allowed daily dose of 1000 mg). 
10.2.3 Postoperative Regional Anesthesia 
Postoperative pain will be managed using a continuous anesthetic infusion through the catheter previously 
placed adjacent to the popliteal sciatic nerve in a manner adapted from the method described by Singelyn et al 
(1997) and Zetlaoui and Bouaziz (1998).8,9 Mepivacaine 0.5% (plain) will be infused starting at 8 mL per hour 
and not to exceed 14 mL per hour. Alternatively, ropivacaine 0.2% (ropivacaine 0.5% diluted with saline to a 
final concentration of 0.2%) may be substituted and infused starting at 1 - 8 mL per hour, not to exceed 8 mL 
per hour. Maintenance of the block may require additional procedures such as periodic boluses of the anesthetic 
through the catheter or an increase in the rate of infusion of the anesthetic.  
Additionally, subjects may receive supplemental analgesia with ketorolac 30 mg IV during the continuous 
infusion period up until 1:00 A.M to help control breakthrough pain if the regional anesthetic infusion is 
ineffective in the investigator’s opinion.  
All subjects’ continuous anesthetic infusion will be discontinued between 3:00 and 4:00 A.M. the morning after 
surgery. 
The time, date, dose, and route of all local anesthetics and systemic medications used in the postoperative 
period will be recorded in the eCRF. 
10.3. Day 1 (Pretreatment/Randomization) 
The following study procedures will occur on the day after surgery and before dosing on Day 1: 
1. Discontinue regional anesthetic infusion between 3:00 and 4:00 A.M. An IV catheter should have been 
placed for delivery of postoperative analgesia or other required medication and will be maintained until 
discharge.  
2. Contact IRT to obtain the moderate and severe pain box numbers for the subject. Retrieve the study 
medication boxes from stock, 1 for moderate pain and 1 for severe pain. 


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3. Record vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) after the subject 
has been in a resting position for 5 minutes. 
4. Review the NPRS assessment training with the subject and instruct the subject to notify a member of the 
study staff and request treatment when he or she experiences a level of pain that they feel requires 
medication.  
5. Prior to the first dose of study medication, perform clinical laboratory tests. 
6. Prior to the first dose of study medication, perform a 12-lead ECG. 
7. When the subject requests pain medication, administer the NPRS pain intensity assessment; subjects with a 
score ≥5 and ≤9 on the 0-10 NPRS will be eligible for randomization into the study.  
8. Assign the corresponding study medication box; subjects with a score ≥5 and ≤9 on the 0-10 NPRS will be 
randomized and stratified by Baseline pain level (moderate [NPRS 5-6] or severe [7-9]) using IRT, and 
assigned the appropriate pain level treatment box. The qualifying NPR pain assessment will serve as 
Baseline. 
9. Subjects with a NPRS score <5 will be asked if they can wait for treatment. If they cannot, they will be 
dropped from the study and treated according to the standard of care. If they agree to wait, they will be 
requested to notify a member of the study staff when their pain intensity has increased. If the subject’s pain 
intensity ratings do not meet the minimum entry criteria within 8 hours of discontinuation of the regional 
anesthesia, subjects will not be eligible for randomization and will receive routine postoperative care at the 
investigator’s discretion. 
10. Subjects with a NPRS score >9 will be dropped from the study and treated according to the standard of care. 
11. Record and review concomitant medications. 
12. Record AEs. 
10.4. Treatment Period (Day 1 through Day 3) 
Once the pain intensity entry criteria are met and the subject is randomized, the first dose of study medication 
will be administered by study personnel with 8 ounces of water. After first dose (defined as Time 0), the subject 
will remain at the study center for subsequent dosing and completion of efficacy and safety assessments. Study 
medication will be administered in a qid regimen for 48 hours after the first dose, with a maximum of 4 doses 
(active and/or placebo) in a 24-hour period. 
10.4.1 First Dose (Time 0 through Hour 6) 
The following events will be completed between first dose (Time 0) and Hour 6: 
1. Administer first dose of study medication – see Table 2 (Time 0). 
2. Start 2 stopwatches and instruct the subjects to stop the first stopwatch when they experience perceptible 
pain relief and the second stopwatch when they experience meaningful pain relief. 
3. Continue to record pain intensity (NPRS) assessments first and pain relief (5-point categorical scale) 
assessments second at 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, and 6 hours after Time 0, 
and immediately before each use of rescue analgesia. During the night, subject will be wakened to 
administer the study medication. Pain assessments will be performed during the night only if the subject is 
awake. 
4. Record vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature), after the subject 
has been in a resting position for 5 minutes, immediately before and 1 hour after each dose of study 
medication. 


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5. Encourage subjects to wait for at least 1 hour after the first dose of study medication before receiving first 
rescue medication to allow time for the study medication to exert its pharmacologic effect. 
6. Record and review concomitant medications. 
7. Record AEs. 
10.4.2 Subsequent Doses 
The following procedures and assessments will be completed during the Double-blind Treatment Period when 
subsequent doses of study medication will be administered: 
1. Administer study medication in a QID regimen for 48 hours after the first dose, with a maximum of 4 doses 
(active and/or placebo – see Table 2) in a 24-hour period. Subjects are to be wakened during the night to 
administer study medication. 
2. Administer pain intensity (NPRS) assessments first and pain relief (5-point categorical scale) assessments 
second at 7, 8 10, 12, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, 38, 42, 46, and 48 hours and immediately prior 
to administration of any rescue medication. During the night, the subject will be wakened to administer the 
study medication. Pain assessments will be performed during the night only if the subject is awake. 
3. Record vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature after the subject 
has been in a resting position for 5 minutes) immediately before and 1 hour after each study medication 
administration each day. 
4. Record concomitant medications. 
5. Record AEs. 
6. Administer the patient’s global evaluation of study medication at the end of the treatment period (Day 3) 
before discharge from the study center. 
7. Conduct clinical laboratory tests and a 12-lead ECG before discharge from the study center on Day 3. 
8. Dispense prescription for postoperative pain medications and outpatient subject diary before discharge from 
the study center on Day 3. 
9. Discharge subject from study center on Day 3. 
10.4.3 Duration of Treatment 
The total treatment period is 48 hours. 
10.5. Follow-Up (Day 7 ± 2 days) Visit 
The subject will be instructed to return to the study center for the Follow-up Visit 5 to 9 days after surgery 
(Day 7 ± 2 days). At the Follow-up Visit, the following procedures will be performed: 
1. Perform a targeted physical examination, and record any changes from previous visit. 
2. Perform X-ray and examination of the foot. 
3. Record vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) after the subject 
has been in a resting position for 5 minutes. 
4. Record concomitant medications taken since discharge from the study center. 
5. Record AEs occurring since discharge from the study center. 
6. Collect and review subject diary. 
7. Perform serum pregnancy test for female subjects of childbearing potential. 


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8. Collect blood and urine samples for routine laboratory tests. 
9. Perform 12-lead ECG. 
10.6. Study Duration 
The overall study duration is expected to be 10 months (6 months of active enrollment and 4 months of data 
management, statistical analyses and reporting). 
The estimated duration of the study for each subject is approximately 6 weeks, which includes up to a 4-week 
Screening Period, a 3-day treatment period (72 hours of confinement with 48 hours of treatment), and a 
post-treatment follow-up visit approximately 1 week after surgery. 
The maximum study duration for each subject is approximately 40 days. 
10.7. Efficacy Assessments 
At assessment time points throughout the study, the pain intensity assessment will be completed first and the pain 
relief assessment will be completed second. Subjects will not be permitted to compare their responses with their 
previous responses. Efforts should be made to perform the assessments at the scheduled times. The actual 
assessments time must always be recorded. 
10.7.1 Pain Intensity 
Subjects will assess their current pain intensity using a 0-10 NPRS. The NPRS is a scale numbered zero to 10 
with “No Pain” as the left anchor (0) and “Worst Possible Pain” as the right anchor (10). Each subject will be 
instructed to circle a single number on the line to indicate his or her current pain intensity. Pain intensity will be 
assessed before Time 0, at 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 14, 18, 
22, 24, 26, 28, 30, 32, 34, 36, 38, 42, 46, and 48 hours after Time 0, and immediately before each use of rescue 
analgesia. During the night, subject will be wakened to administer the study medication. Pain assessments will 
be performed during the night only if the subject is awake. 
10.7.2 Pain Relief 
Subjects will assess their pain relief relative to Time 0 using a 5-point categorical scale. Subjects will be asked 
“How much relief have you had since your starting pain?” with response choices of none = 0, a little = 1, 
some = 2, a lot = 3, and complete = 4. Pain relief will be assessed at 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 
2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, 38, 42, 46, and 48 hours after Time 0, and 
immediately before each use of rescue analgesia. During the night, subject will be wakened to administer the 
study medication. Pain assessments will be performed during the night only if the subject is awake. 


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10.7.3 Stopwatch Assessment 
Two stopwatches will be started immediately after the subject has swallowed the last tablet of the first dose of 
study medication with 8 ounces of water. Each subject will be instructed, “Stop the first stopwatch when you 
first feel any pain relief whatsoever. This does not mean you feel completely better, although you might, but 
when you first feel any relief in the pain you have now” (perceptible pain relief). The subject will also be 
instructed, “Stop the second stopwatch when you feel the pain relief is meaningful to you” (meaningful pain 
relief). If the subject does not press the stopwatches within 8 hours after Time 0, the subject will discontinue use 
of the stopwatches. 
10.7.4 Patient’s Global Evaluation of Study Medication 
For the patient’s global evaluation of study medication, the subject will be asked “How effective do you think 
the study medication is as a treatment for pain?” with response choices of 0 = poor, 1 = fair, 2 = good, 3 = very 
good, or 4 = excellent. The subject will complete the patient’s global evaluation of study medication at the end 
of the treatment period (Day 3) before discharge from the study center. 
10.8. Safety Evaluations 
Safety will be evaluated by the incidence of treatment-emergent AEs (TEAEs), physical examination findings, 
clinical laboratory test results, and changes in vital sign and ECG measurements. 
10.8.1 Physical Examination 
A complete physical examination (excluding the genitourinary exam) will be performed at Screening and before 
surgery on Day -1. A targeted physical examination, including an examination of the subject’s surgical center, 
will be performed before discharge from the study center and at the Follow-up Visit. 
10.8.2  Vital Signs 
Vital signs, including blood pressure, heart rate, respiratory rate, and oral body temperature, will be measured 
after the subject has been in a resting position for 5 minutes. Vital signs will be measured at Screening and 
before surgery on Day -1. From Day 1 through discharge from the study center, vital signs will be measured 
immediately before and 1 hour after each dose of study medication each day. Vital signs will also be measured 
at the Follow-up Visit. 
10.8.3 Electrocardiograms 
A 12-lead ECG will be performed at Screening, on Day 1 before the first dose of study medication, before 
discharge from the study center, and at the Follow-up Visit. 


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10.8.4  Clinical Laboratory Tests 
The following clinical laboratory tests will be performed at Screening, before the first dose of study medication 
on Day 1, before discharge from the study center, and at Follow-up. 
Hematology: 
hemoglobin, hematocrit, platelet count (or estimate), red blood cell 
count, white blood cell count (including differential) 
Serum Chemistry: 
glucose, blood urea nitrogen, creatinine, total bilirubin, alkaline 
phosphatase, alanine aminotransferase, aspartate aminotransferase, 
gamma-glutamyl transferase, sodium, potassium, calcium, chloride, 
bicarbonate, lactate dehydrogenase, albumin 
Urinalysis 
(dipstick): 
pH, specific gravity, blood, glucose, protein, ketones, nitrate, 
leukocytes 
The following laboratory tests will also be performed: 
• Alcohol breathalyzer test will be performed before surgery on Day -1. 
• Urine drug screen samples will be collected at Screening and before surgery on Day -1 to test for 
amphetamines, barbiturates, benzodiazepines, cocaine, methamphetamines, opiates, phencyclidine, and 
tetrahydrocannabinol. 
• For female subjects of childbearing potential, a blood sample for the serum pregnancy test will be collected 
at Screening and at Follow-up; a urine pregnancy test sample will be collected before surgery on Day -1.  
Blood and urine samples for hematology, serum chemistry, and urinalysis will be prepared using standard 
procedures and will be sent to a central laboratory for analyses. 
Dipstick determination of pH, specific gravity, blood, glucose, protein, ketones, and nitrate will be tested locally 
at each center. If a dipstick test result is abnormal, a biochemistry urinalysis and a microbiology analysis will be 
performed, if needed.  
11. ADVERSE EVENTS 
Adverse events will be collected from the time of signing of the ICF through to the completion of the clinical 
study (including the Follow-up Visit) or premature subject discontinuation from the clinical study.  
11.1. Definitions 
11.1.1 Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product that does not necessarily have a causal relationship with the product. An AE can 
therefore be any unfavorable and unintended sign (including a new, clinically important abnormal laboratory 
finding), symptom, or disease, temporally associated with the product, whether or not related to the product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the frequency or 
severity, or a change in the quality, of the disease or condition.  
An AE is defined as treatment emergent if the first onset or worsening is after the first administration of study 
medication and not more than 7 days after the last administration of study medication. 


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11.1.2 Definition of Serious Adverse Events 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event 
Medical and scientific judgment should be exercised in deciding whether it is appropriate to consider other 
situations serious, such as important medical events that may not be immediately life threatening or result in 
death or hospitalization but may jeopardize the subject or may require intervention to prevent another of the 
outcomes listed in the definition above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
An elective hospital admission to treat a condition present before exposure to the study medication, or a hospital 
admission for a diagnostic evaluation of an AE, does not qualify the condition or event as an SAE. 
A newly diagnosed pregnancy in a subject that has received a study medication is not considered as an SAE 
unless it is suspected that the study medication(s) interacted with a contraceptive method and led to the 
pregnancy. A congenital anomaly in an infant born to a mother who was exposed to the study medication during 
pregnancy is an SAE. 
11.1.3 Significant Adverse Events 
All laboratory results will be reviewed by the investigator and any that are deemed clinically significant will be 
recorded as AEs. Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, including withdrawal 
of study medication or significant additional concomitant therapy.  
11.1.4 Definition of Severity 
The clinical “severity” of an AE will be classified as: 
Mild: 
Causes no limitation of usual activities  
Moderate: 
Causes some limitation of usual activities  
Severe: 
Prevents or severely limits usual activities  
 
11.1.5 Definition of Start Date, Stop Date, and Duration 
Start Date and Time: 
The date at which the AE is first noted  
Stop Date and Time: 
The date at which the AE is known to be resolved. If it is not known to 
have stopped, then indicate “ongoing.” 
Duration: 
A time in days, hours, or minutes.  


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11.1.6 Action(s) Taken 
Action(s) taken with study medication as a result of an AE may consist of the following: 
• Dose not changed 
• Drug withdrawn 
11.1.7 Definition of Expectedness 
An AE is expected when its nature or severity is consistent with the known AE profile of the product. For a 
study medication, the known information is contained in the IB. For a marketed product, the known information 
is contained in the current package insert for the product. 
An AE is unexpected when its specificity or severity is not consistent with the current IB. For example, hepatic 
necrosis would be unexpected (greater severity) if the IB only listed elevated hepatic enzymes or hepatitis. 
Likewise, cerebral thromboembolism and cerebral vasculitis would be unexpected (greater specificity) if the IB 
only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already documented 
adverse reaction constitute unexpected events. Examples would be (a) acute renal failure as an expected adverse 
reaction with a subsequent new occurrence of interstitial nephritis and (b) hepatitis with a first occurrence of 
fulminate hepatitis. 
11.1.8 Definition of Relationship to Study Medication(s) 
The categories for classifying the investigator’s opinion regarding the relationship of an AE to study 
medication(s) are listed below.  
Related 
A reasonable possibility exists of a relationship between the AE and the study 
medication. 
Not related 
No reasonable possibility exists of a relationship between the AE and study medication. 
In situations where causality is unassessable, the AE will be considered related. 
11.1.9 Definition of Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as follows: 
• Resolved 
• Resolved with sequelae 
• Ongoing 
• Death 
• Unknown 
Death should only be selected as an outcome when the AE resulted in death. If more than 1 AE is possibly 
related to the subject’s death, the outcome of death should be indicated for each such AE. Although “death” is 
usually an event outcome, events such as sudden death or unexplained death should be reported as SAEs. 


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11.2. Management of Adverse Events 
11.2.1 Documentation of Adverse Events 
The investigator is responsible for the detection and documentation of any clinically relevant observations 
meeting the criteria and definition of an AE or SAE. The subject will be allowed to spontaneously report any 
issues since the evaluation; then the investigator will then monitor and/or ask about or evaluate AEs using 
non-leading questions, such as “How are you feeling?” 
All AEs will be documented in the CRF with the following information, where appropriate: 
• AE name or term 
• When the AE first occurred (start date) 
• When the AE stopped (stop date), or an indication of “ongoing” 
• How long the AE persisted (optional) 
• Severity of the AE 
• Seriousness 
• Actions taken 
• Outcome 
• Investigator opinion regarding the relationship of AE to the study medication(s) 
 
11.2.2  Follow-up of Subjects with an Adverse Event 
Any AE will be followed to a satisfactory resolution until it becomes stable or until it can be explained by 
another known cause(s) (ie, concurrent condition or medication) and clinical judgment indicates that further 
evaluation is not warranted. All findings relevant to the final outcome of an AE must be reported in the 
subject’s medical record. 
11.2.3  Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards of care. If 
pharmacologic treatment is given, it must be documented in the CRF. The decision about whether the subject may 
continue in the study will be made by the investigator after consultation with the sponsor and/or medical monitor. 
If AEs occur in a subject that are not tolerable despite conventional treatment, the investigator must decide 
whether to stop the subject’s involvement in the study. 
For double- or triple-blinded studies, it is not necessary to unblind a subject’s treatment assignment in most 
circumstances, even if an SAE has occurred. If unblinding is necessary, see Section 9.6 for a description of the 
unblinding procedures. 
11.2.4 Reporting of Serious Adverse Events 
The investigator or designee must report all SAEs promptly to Premier Research Pharmacovigilance within 
24 hours of first becoming aware of the event.  The investigator or designee must complete and date the Serious 
Adverse Event Report Form, verifying the accuracy of the information recorded in the form with the source 
documents and CRF, and sending the SAE form to the Premier Research via one of the following methods:  
Email: 
 
Fax number:
 


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For questions regarding the reporting of SAEs, investigators should contact the Medical Monitor, 
 
. 
The written report should be submitted on the SAE form provided for this purpose. At the time of first notification, 
the investigator or designee must provide the following information, if available: 
• Reporter (study center and investigator) 
• Subject’s study number  
• Subject’s year of birth  
• Subject’s gender 
• Date of first dose of study medication(s) (if available) 
• Date of last dose of study medication(s), if applicable and available 
• Adverse event term 
• Investigator’s opinion of the relationship to study medication(s). (“Is there a reasonable possibility that the 
study medication caused the SAE? Yes or No?”) 
• Date of occurrence of the event (if available) 
• A brief description of the event, outcome to date, and any actions taken (if available) 
• The seriousness criteria(on) that were met (if available) 
• Concomitant medication at onset of the event (if available) 
• Relevant medical history information (if available) 
• Relevant laboratory test findings (if available) 
• Whether and when the investigator was unblinded as to the subject’s treatment assignment (if available) 
Any missing or additional relevant information concerning the SAE should be provided to the recipient(s) of the 
initial information as soon as possible on a follow-up SAE Report Form, together with the following information 
(adverse event, date of occurrence, subject ID, study ID, study medication, and center number); this will allow 
the follow-up information to be linked to the initial SAE report.  
The investigator is required to comply with applicable regulations (including local laws and guidances) regarding 
the notification of his/her health authorities, IRB, principal and coordinating investigators, study investigators, 
and institutions.  
Originals SAE Forms are to be kept by the investigator in the Investigator’s File. 
The investigator shall be nullify by forwarding a follow up report an event reported to Premier that does not meet 
the SAE criteria or should not have been reported because it is a protocol exemption. 
Serious AEs will be collected and reported up to 2 weeks after the subject’s last study visit if the investigator 
considers the SAE is related to the study medication or the clinical study procedures. 
11.2.5 Adverse Events of Special Interest 
Adverse events of special interest comprise the most common AEs observed with tramadol use (ie, cumulative 
incidence of adverse reactions observed in ≥10% of subjects who used Ultram for up to 7 days in chronic trials 
of nonmalignant pain (N=427): dizziness/vertigo (26%); nausea (24%); constipation (24%); headache (18%); 
and somnolence (16%).11 The following will be also considered as adverse events of special interest, since they 
are typically related to opioids administration: fatigue, inability to concentrate, itching, difficulty with urination, 
confusion, dry mouth and vomiting/retching.12 All episodes of post-operative vomiting and any anti-emetic drug 


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use will be properly documented and analyzed. The details of the analysis will be included in the statistical 
analysis plan (SAP). 
11.2.6 Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the need to practice 
adequate birth control and on the importance of avoiding pregnancy during study participation. Women should 
be instructed to contact the investigator or study staff immediately if pregnancy occurs or is suspected. 
Pregnancy testing will be conducted prior to administration of study medication on every woman of childbearing 
potential. A woman who is found to be pregnant at the Screening Visit will be excluded from the study and 
considered to be a screening failure. 
The investigator must report any pregnancy within 24 hours of first becoming aware of the event by completing 
a pregnancy report form and faxing it to Premier Research Pharmacovigilance 
 or email to 
 
12. DATA SAFETY MONITORING BOARD 
A Data Safety Monitoring Board (DSMB) will not be used in this study. 
13. STATISTICS 
This section presents a summary of the planned statistical analyses. A statistical analysis plan (SAP) that describes 
the details of the analyses to be conducted will be written prior to database lock; the SAP will include any 
specifications of subgroup analyses for selected efficacy and safety variables.  
Each efficacy and safety endpoint will be summarized descriptively by treatment group. Summary statistics will 
be provided for all demographic, efficacy, and safety parameters listed below. Unless otherwise indicated, all 
statistical tests will be 2 sided and differences will be considered statistically significant if P ≤0.05. 
To avoid interference in efficacy measures (pain intensity assessments, pain relief at each time point [PARt], pain 
intensity differences [PIDt], and Sum of Pain Intensity Differences [SPID] calculations) at scheduled time points 
because of use of rescue medication, additional assessments will be made just before each administration of rescue 
medication, asking subjects to report their pain intensity/pain relief at the current time. These data will be carried 
over for the duration of effect of the rescue medication taken (4 hours for acetaminophen and 4 hours for 
oxycodone hydrochloride). 
13.1. Primary Endpoint 
The primary efficacy variable will be the pain intensity (PI) measured by NPRS.  
The primary analysis endpoint will be the SPID from 0-48 hours defined as follows. 
• PIDt = Pain Intensity Differences = PIt - PI0 where  
• PI0 = PI at time t = 0h on NPRS 
• PIt = Pain Intensity on NPRS at specific time points 
 
The SPID is calculated as a time-weighted sum of the pain intensity difference values at each follow-up time 
point (difference between the starting pain intensity and the pain intensity at the given assessment time) multiplied 
by the amount of time (in hours) since the last, non-missing assessment.  
Negative values of PID will correspond to an amelioration of pain, while positive values will correspond to a 
recrudescence of pain. 


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13.1.1 Secondary Endpoints 
The secondary endpoints are the following: 
• SPID (0-4 hours), SPID (0-6 hours), SPID (0-12 hours), and SPID (0-24 hours) as defined in previous 
section 
• PIDt at each time point 
• Pain intensity at each time point 
• Pain Relief (PARt) = pain relief at each time point 
• Total Pain Relief (TOTPAR) for time intervals (t=15 minutes – t=4 hours), (t=15 minutes – t=6 hours), 
(t=15 minutes – t=12 hours), (t=15 minutes – t=24 hours), and (t=15 minutes – t=48 hours)  
o TOTPAR is the time-weighted sum of the Pain Relief (PAR) at each time point 
The summed time-weighted 
pain relief score over 0 hour to 
the x-hour period after Time 0 
TOTPAR_x = PR_t1*(t1 ─ 0) + PR_t2*(t2 ─ t1) +   …   + 
PR_n*(t[n] ─ t[n ─ 1]), where PR_t[m] is pain relief score at mth time 
point, and x is the nth time point;  x = 6, 12, 24, 48 
Where PR measured as 5-point categorical scale: 0 = None; 1 = A little; 2 = Some; 3 = A lot; 
4 = Complete. 
• Peak pain relief and time to peak pain relief 
• Stop watches: time to onset of analgesia, time to perceptible pain relief, and time to meaningful pain relief 
• Time to onset of pain intensity decrease 
• Subject’s overall assessment of study medication 
• Rescue medication: 
- 
Proportion of subjects who take of at least 1 dose of rescue medication up to 4, up to 6, up to 12, up 
to 24, and up to 48 hours after first dose of study medication; number of doses of rescue medication 
for the same time intervals 
- 
Time to first use of rescue medication. 
• Proportion of Responders, where Responders are:  
- 
Subject who reaches a 50% reduction in pain intensity from baseline sustained until the end of the 
48-hour observation period; 
- 
Subject who reaches a 30% reduction in pain intensity from baseline sustained until the end of the 
48-hour observation period; 
- 
Subject who reaches a pain intensity below 4 on NPRS sustained until the end of the 48-hour 
observation period; 
- 
Subject who reaches a 50% reduction in pain intensity as compared to baseline and a pain intensity 
below 4 on NPRS sustained until the end of the 48-hour observation period; 
- 
Subject who reaches a 30% reduction in pain intensity as compared to baseline and a pain intensity 
below 4 on NPRS sustained until the end of the 48-hour observation period. 
• Time-to-first-response will also be analyzed as time-to-event data, using the first time at which each 
response criterion was reached by each subject. 
• Cumulative proportion of responders analysis plot 


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13.2. Sample Size Determination 
The primary outcome measure is SPID (NPRS) up to 48 hours post dose (SPID-48h). The study is powered to 
detect the superiority of co-crystal E-58425 to each of the 2 active control groups.  
A difference in pain intensity of 1 on a 0-10 NPRS is considered to be the minimum detectable change for an 
individual time point. Since SPID is the time-weighted average of pain intensity over a 48-hour period, the 
minimum detectable change of 10 mm from a single measurement must be multiplied by 48 hours. Therefore, the 
minimum detectable change in the primary outcome measure of SPID-48 hours is considered to be 48. 
Data from another bunionectomy study that used SPID-48 hours as a primary endpoint to compare two doses of 
tapentadol with placebo (ClinicalTrials.gov identifier NCT01516008) was used to estimate the expected SD in 
SPID-48 hours for the present study. In that study, the SD of the SPID-48 hours ranged from 107 to 124. 
Therefore, conservatively, the SD of SPID-48 hours for the present study is assumed to be 124. 
Since co-crystal E-58425 must show superiority over both tramadol and celecoxib, the power of each individual 
comparison is set at 90%, which will maintain an overall study power at 81%. 
To detect a difference of 48 with an SD of 124 at an alpha level of 0.05 with a power of 90% requires 142 subjects 
per group (71 for the placebo group since a 2:2:2:1 randomization scheme is being used). It is assumed that the 
comparison versus placebo will be adequately powered since the difference versus placebo is believed to be larger 
than that of the active comparators. 
Allowing for approximately a 20% rate of non-evaluable subjects (ie, those not included in the PPAS), a total of 
630 subjects, 180 subjects per active group and 90 subjects for the placebo group will be randomized. 
A blinded sample size re-estimation will be conducted when approximately 50% of subjects have completed the 
study and the actual pooled SD of the SPID-48 will be calculated on blinded/pooled data (see Section 13.4.6). 
The sample size will not be reduced as a result of this re-estimation. The exact time when this procedure will be 
made will be decided based on the observed actual accrual rate and it will be specified in the SAP. 
13.3. Analysis Sets 
The following 3 analysis populations are planned for this study:  
• Safety Set: all subjects who receive at least 1 dose of study medication. 
• Full Analysis Set (FAS): all randomized subjects  
• Per-protocol Analysis Set (PPAS): all subjects in the Full Analysis Set with no major protocol deviations 
• Completers Analysis Set (CAS): A subset of the PP set that includes all subjects who have pain assessments 
up to 48 hours after first dose of study medication 
Inclusion in the analysis sets will be determined prior to database lock and prior to unblinding the treatment 
assignments. 
If a subject is randomized incorrectly or is administered the incorrect study medication, analyses of the Full 
Analysis Set will be based on the assigned treatment whereas all other analyses will be based on the actual 
treatment. 
Primary efficacy analyses will be based on the FAS. The PP Set and the CAS will be used for sensitivity 
analysis for some efficacy endpoints. Safety analyses will be based on the Safety Set. 
 
All subjects who signed informed consent will be considered study participants. 


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13.4. Statistical Analyses 
This section presents a summary of the planned statistical analyses.  
Unless otherwise indicated, all testing of statistical significance will be two-sided, and a difference resulting in a 
P value of ≤0.05 will be considered statistically significant. To declare the study successful, co-crystal E-58425 
will need to show a statistically significant advantage over each comparator (tramadol and celecoxib). Moreover, 
a comparison with placebo will be performed to assess the co-crystal E-58425 absolute efficacy. Because all 
3 comparisons must be statistically significant to declare the study successful, no formal adjustment for multiple 
comparisons is needed.  
For analyses involving study center, if the number of subjects per center is small, centers may be pooled for 
analysis, or omitted from statistical models. The final determination will be made prior to database lock.  
For continuous variables, summary statistics will typically include the number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum. For categorical variables, summary statistics will typically 
include the number and percentage of subjects in each category. 
13.4.1 Disposition 
The numbers of subjects randomized, completing, and withdrawing, along with reasons for withdrawal, will be 
tabulated overall and by treatment group. The number of subjects in each analysis population will be reported. 
This analysis will be based on all study participants. 
13.4.1.1 Protocol Deviations 
Protocol deviations will be collected ongoing through the study.  Protocol deviations excluding subjects from 
the PP analysis set will be agreed and signed off by the sponsor prior to database lock and unblinding. 
13.4.2 Subject Characteristics 
Demographic variables will include age, gender, race, weight, height, and BMI. Baseline subject characteristics 
will include surgery duration and other surgery characteristics. 
Medical history and study medication administration will be summarized descriptively by treatment group and 
presented in listings. 
Prior and concomitant medications will be summarized by treatment group and by the number and percentage 
of subjects taking each medication, classified using World Health Organization Drug Dictionary Anatomical 
Therapeutic Chemical classes and preferred terms. 
The remaining subject characteristic variables will be summarized descriptively by treatment group and overall. 
No formal statistical analyses will be performed. 
These analyses will be conducted for the Safety Set. 
13.4.3 Efficacy 
13.4.3.1 Primary Analysis 
The primary efficacy analysis will compare treatment groups for the SPID from time 0 to 48 hours. This will be 
tested using an analysis of covariance model adjusting for center and baseline pain intensity. In addition, 95% 
confidence intervals for pairwise differences between treatments will be estimated. 
To account for the use of rescue medication, any pain measurements taken during a period of time in which 
rescue medication is active will be replaced by the last pain measurement before rescue medication was taken. 


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Additional sensitivity analyses assessing the impact of rescue use and missing data due to study discontinuation 
will be performed.  
The details of the sensitivity analyses and handling of missing data will be described in the SAP written prior to 
database lock. 
13.4.3.2 Secondary Analyses 
Each efficacy endpoint will be summarized descriptively by treatment group. 
Continuous secondary endpoints will be analyzed similarly to the primary endpoint.  
For ordinal secondary endpoints such as pain relief score at each scheduled time point, peak pain relief (ie, the 
lowest value of the PID), and patient’s global evaluation of study medication, descriptive summaries include the 
number and percentage of subjects within each category for each treatment group. Nominal P values from 
ordinal logistic regression, adjusting for baseline pain intensity and center, as appropriate comparing the 
placebo group with other treatment groups will be provided, but no formal statistical inferences will be drawn 
on the basis of these tests. 
For each time-to-event endpoint, the Kaplan-Meier method will be used to evaluate the treatment effect. Time 
to peak pain relief will be taken as the time to the lowest value of the NPRS after baseline, provided that the 
lowest value after baseline is lower than the baseline value. Time to onset of pain intensity decrease will be 
measured as the time at which the difference from baseline pain intensity (PID) is decreased ≥1 point in NPRS 
for the first time after the first study medication intake. Time to perceptible pain relief confirmed by meaningful 
pain relief will be based on data collected using the 2-stopwatch method following the first dose of study 
medication. In addition to the raw data from the stopwatches, a derived measure “time to onset of analgesia” 
will be defined as the time to perceptible pain relief if subsequently confirmed by meaningful pain relief. The 4 
time-to-event variables will be right censored at 8 hours for subjects who reach the event during the 8-hour 
interval after Time 0, or those who require rescue medication before achieving the event. The summary table 
will provide the number of subjects analyzed, the number of subjects censored, estimates for the quartiles, and 
95% confidence intervals for the estimated median. P values from log-rank tests will also be used to examine 
treatment effect. Cox proportional hazard models may be used to further explore such potential covariates as 
gender, baseline pain intensity, and center.  
For the proportion of subjects using rescue medication, a logistic regression model that adjusts for baseline pain 
intensity and center will be used to evaluate the treatment effect. 
Efficacy analyses will be also performed by subgroups defined by moderate or severe baseline pain. 
13.4.4 Exposure  
Investigational product administration will be summarized in terms of each subject’s mean, mode, and final dose, 
and in terms of duration of exposure. Descriptive statistics for these quantities, including the mean, median, SD, 
minimum, maximum, and quartiles, will be provided by treatment group.  
13.4.5 Safety Analyses 
The safety endpoints are the incidence of TEAEs, physical examination findings, and changes in ECG and vital 
sign measurements.  
Data listings will be provided for protocol-specified safety data. The Medical Dictionary for Regulatory 
Activities (Version 19.0 or higher) will be used to classify all AEs with respect to system organ class and 
preferred term. The number and percentage of subjects with AEs will be displayed for each treatment group by 


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SOC and PT. Summaries of AEs by severity and relationship to study medication will also be provided. Serious 
adverse events, AEs resulting in discontinuation of study medication and AEs of special interest will be 
summarized separately in a similar manner. Subject listings of AEs, SAEs and AEs causing discontinuation of 
study medication will be produced. Comparisons between treatment groups for incidence of AEs, AEs of 
special interest may be performed. Any comparisons of safety analyses will be described in detail in the SAP. 
For vital sign measurements and ECG parameters, descriptive statistics will be provided at each scheduled time 
point for each treatment group. Changes from Baseline for vital signs and ECG parameters will be calculated 
for each subject, and descriptive statistics will be provided on changes in vital signs from Baseline for each 
treatment group at each scheduled time point after Baseline. No formal statistical tests will be performed. For 
clinical laboratory, ECG, and vital sign variables, the values that are below, within, or above a defined normal 
range and the values that are clinically significant will be counted and tabulated by the number and percentage 
of subjects with such values and will be tabulated showing change from baseline (shift tables). 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values and changes 
from baseline values will be presented for clinical laboratory values for each treatment group at each time point. 
The number of subjects with clinical laboratory values categorized as below, within, or above normal ranges, [or 
other specific ranges of interest] will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory analyte by treatment group and by time. Pre- and post-treatment values will also be presented with an 
analysis of mean changes from baseline.  
Laboratory values, vital sign measurements and ECG measurements that are outside the normal range will also 
be flagged in the data listings, along with corresponding normal ranges, if provided. Any out-of-range values that 
are identified by the investigator as being clinically significant will also be shown in a data listing. For laboratory 
values, vital sign measurements and ECG parameters individual data and mean values by treatment groups will 
also be shown in graphical displays. 
The number and percentage of subjects with normal and abnormal findings in the complete physical 
examination will be displayed for each treatment group. 
The results of the safety analyses described in this section are to be taken as descriptive measures of differences 
among treatment groups, and not as formal statistical hypothesis tests or indicators of important clinical 
differences. 
Safety analyses will be conducted for the safety analysis population. 
13.4.6 Interim Analysis 
An interim analysis is planned. A blinded sample size re-estimation following the methodology described in 
Keiser and Friede10 will be conducted when approximately 50% of subjects have completed the study and the 
actual pooled SD of the SPID-48 will be calculated on blinded/pooled data. If that SD is >124, the sample size 
will be increased accordingly to maintain an overall study power of at least 81%, up to a maximum of 900 subjects. 
The sample size will not be reduced if the SD is smaller. The exact time when this procedure will be made will 
be decided based on the observed actual accrual rate and it will be specified in the SAP. 
14. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators and appropriate 
study centers, review of protocol procedures with the investigator and associated personnel before the study, 
periodic monitoring visits, and meticulous data management. 


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14.1. Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles (Section 15). The sponsor 
reserves the right to withdraw a subject from the study (Section 8.3), to terminate participation of a study center 
at any time (Section 14.6), and/or to discontinue the study (Section 14.5). 
ESTEVE agrees to provide the investigator with sufficient material and support to permit the investigator to 
conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 17.2), the investigator indicates that he/she has carefully read 
the protocol, fully understands the requirements, and agrees to conduct the study in accordance with the 
procedures and requirements described in this protocol. 
The investigator also agrees to conduct this study in accordance with all laws, regulations, and guidelines of the 
pertinent regulatory authorities, including the April 1996 ICH Guidance for Industry E6 GCP, and in agreement 
with the 2013 version of the Declaration of Helsinki. While delegation of certain aspects of the study to 
subinvestigators and study coordinators is appropriate, the investigator will remain personally accountable for 
closely overseeing the study and for ensuring compliance with the protocol and all applicable regulations and 
guidelines. The investigator is responsible for maintaining a list of all persons that have been delegated 
study-related responsibilities (eg, subinvestigators and study coordinators) and their specific study-related duties. 
Investigators should ensure that all persons who have been delegated study-related responsibilities are adequately 
qualified and informed about the protocol, study medications, and their specific duties within the context of the 
study. Investigators are responsible for providing ESTEVE with documentation of the qualifications, GCP 
training, and research experience for themselves and their staff as required by the sponsor and the relevant 
governing authorities. 
To ensure compliance with the guidelines, the study may be audited/inspected by an independent 
person/regulatory body. The investigator agrees, by written consent to this protocol, to cooperate fully with 
compliance checks by allowing access to all study documentation by authorized individuals. 
14.2. Center Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification from the sponsor 
or its designee that the study can be initiated at the study center. The study center will not be authorized for study 
initiation until: 
1. The study center has received the appropriate IRB/IEC approval for the protocol and the appropriate ICF. 
2. All regulatory documents have been submitted to and approved by the sponsor or its designee. 
3. The study center has a Clinical Trial Agreement in place. 
4. Study center personnel, including the investigator, have participated in a study initiation meeting. 
14.3. Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study. Subjects may only be 
rescreened once 30 days or more after the original Screening Visit. If a subject is eligible to enter the study after 
having previously failed screening, the subject will be assigned a new subject identification number. 


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14.4. Study Documents 
All documentation and material provided by ESTEVE for this study are to be retained in a secure location and 
treated as confidential material. 
14.4.1 Investigator’s Regulatory Documents 
The regulatory documents are listed in the Study Manual. 
The regulatory documents must be received from the investigator and reviewed and approved by ESTEVE or its 
designee before the study center can initiate the study and before Premier will authorize shipment of study 
medication to the study center. Copies of the investigator’s regulatory documents must be retained at the study 
center in a secure location. Additional documents, including a copy of the protocol and applicable amendment(s), 
the co-crystal E-58425 IB, electronic case report form (eCRF) completion guidelines, copies of regulatory 
references, copies of IRB correspondence, and study medication accountability records should also be retained as 
part of the investigator’s regulatory documents. It is the investigator’s responsibility to ensure that copies of all 
required regulatory documents are organized, current, and available for inspection. 
14.4.2 Case Report Forms 
The study data will be recorded by the investigators in an electronic CRF (eCRF) built using 
. 
By signing the Investigator’s Agreement (Section 17.2), the investigator agrees to maintain accurate eCRFs and 
source documentation as part of the case histories for all subjects who sign an ICF. 
Case report forms are considered confidential documents and should be handled and stored accordingly. The 
sponsor or its designee will provide the necessary training on the use of the specific eCRF system used during the 
study to ensure that the study information is captured accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as possible after 
the visit. All requested information must be entered in the electronic data capture (EDC) system according to the 
completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a subinvestigator. These signatures serve to attest that the 
information contained in the eCRF is accurate and true. 
Subject assessments during hospitalization will be performed on paper subject diary, and assessments made after 
discharge will be done on a paper subject diary. 
14.4.3 Source Documents 
Information recorded in the EDC system should be supported by corresponding source documentation. Examples 
of acceptable source documentation include, but are not limited to hospital records, clinic and office charts, 
laboratory notes, and recorded data from automated instruments, memoranda, and pharmacy dispensing records. 
Clinical laboratory data required by the protocol will be electronically transferred from the central/local laboratory 
to the sponsor or its designee. An anonymized paper copy of the laboratory results will be provided to the study 
center and should be retained with each subject’s source data.  
14.4.4 Data Quality Control 
Steps to assure the accuracy and reliability of data include the selection of qualified investigators and appropriate 
study centers, review of protocol procedures with the investigator and associated personnel prior to the study, and 
periodic monitoring visits by Premier Research. Data will be reviewed for accuracy and completeness by Premier 
Research during and after center monitoring visits, and any discrepancies will be resolved with the investigator 
or designees as appropriate. 


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14.4.5 Monitoring Procedures 
ESTEVE or its designee will conduct center visits to monitor the study and ensure compliance with the protocol, 
ICH Guidance for Industry E6 Good Clinical Practice (GCP), and applicable regulations and guidelines. The 
assigned clinical research associate(s) (CRA[s]) will visit the investigator and study center at periodic intervals 
and maintain periodic communication. The investigator agrees to allow the CRA(s) and other authorized [sponsor] 
personnel access. The CRA(s) will maintain current personal knowledge of the study through observation, review 
of study records and source documentation, and discussion of the conduct of the study with the investigator and 
staff. While on center, the CRA(s) will review:  
• regulatory documents, directly comparing entries in the EDC system with the source documents 
• consenting procedures 
• AE procedures 
• storage and accountability of study medication and study materials 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for correcting eCRF 
are described in the study manual. As representatives of the sponsor, CRAs are responsible for notifying project 
management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 17.2), the investigator agrees to meet with the CRA(s) during 
study center visits; to ensure that study staff is available to the CRA(s) as needed; to provide the CRA(s) access 
to all study documentation, to the clinical supplies dispensing and storage area; and to assist the monitors in their 
activities, if requested. Further, the investigator agrees to allow ESTEVE or designee auditors or inspectors from 
regulatory agencies to review records, and to assist the inspectors in their duties, if requested.  
14.4.6 Data Management 
Premier Research will be responsible for activities associated with the data management of this study using 
 The standard procedures for handling and processing records will be followed per GCP and 
Premier Research’s standard operating procedures (SOPs). A comprehensive data management plan (DMP) will 
be developed including a data management overview, description of database contents, annotated CRF, pre-entry 
review list, self-evident correction conventions, query contacts, and consistency checks. 
Study center personnel will be responsible for providing resolutions to all data queries. The investigator will be 
required to document electronic data review to ensure the accuracy of the corrected and/or clarified data. 
Procedures for soliciting and documenting resolution to data queries are described in the study manual. 
14.4.7 Quality Assurance/Audit 
This study will be subject to audit by ESTEVE or its designee. Audits may be undertaken to check compliance 
with GCP guidelines, and can include the following: 
• center audits 
• TMF audits 
• database audits 
• document audits (eg, protocol and/or CSR) 
ESTEVE or its designee may conduct additional audits on a selection of study centers, requiring access to subject 
notes, study documentation, and facilities or laboratories used for the study. 
The study center, facilities, all data (including source data), and documentation will be made available for audit 
by quality assurance auditors and for IRB or regulatory authorities according to GCP guidelines. The investigator 


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agrees to cooperate with the auditor during the visit and will be available to supply the auditor with CRFs or other 
files necessary to conduct that audit. Any findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the investigator shall 
notify ESTEVE immediately. 
14.5. Study Termination 
The study may be terminated at ESTEVE’s discretion at any time and for any reason The Independent Ethics 
Committee(s) (IECs) and Competent Authority(ies) (CAs) should be informed promptly should that occur.  
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled in the study, or 
potential study subjects 
• A decision on the part of ESTEVE to suspend or discontinue development of the study medication 
• If the CA obtains information that raises doubts about the safety or scientific validity of the clinical study, the 
CA can suspend or prohibit the study (Code of Federal Regulations Title 21, Part 312, Subpart C, 
Section 312.44). 
• Should the study be prematurely terminated or suspended for any reason, the Investigator/institution must 
promptly inform the study subjects and assure appropriate therapy and follow-up for the subjects 
14.6. Study Center Closure 
At the end of the study, all study centers will be closed. ESTEVE may terminate participation of a study center at 
any time. Examples of conditions that may require premature termination of a study center include, but are not 
limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate subject enrollment 
14.6.1  Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the study, specifically 
including, but not limited to, those defined by GCP as essential until:  
• At least 2 years after the last marketing authorization for the study medication has been approved or the 
sponsor has discontinued its research with the study medication, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of the study medication 
These documents should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of her/his intent to destroy all such 
material. The sponsor shall have 30 days to respond to the investigator’s notice, and the sponsor shall have a 
further opportunity to retain such materials at the sponsor’s expense. 
14.7. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which requires the 
written approval of ESTEVE. The protocol amendment must be signed by the investigator and approved by the 
IRB before it may be implemented. Protocol amendments will be filed with the appropriate regulatory agency(s) 
having jurisdiction over the conduct of the study. 


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14.8. Use of Information and Publication 
After completion of the study, a clinical study report will be prepared according to the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3) by Premier Research in close collaboration with the Investigators 
and ESTEVE. All publications and presentations must be based upon the clinical study report.  
ESTEVE will retain ownership of all data. 
ESTEVE is committed to communicate the results of the study, positive or negative, in media of public access, 
and will particularly enforce the publication of the results in scientific publications, playing an active role in the 
preparation of the paper, in agreement with the principal investigator and participating in the submission to the 
corresponding editors. The manuscript should mention the Ethics Committee involved. 
If an Investigator wishes to publish results from this clinical study, written permission to publish must be obtained 
from ESTEVE in advance. As some of the information regarding the study medication and development activities 
at ESTEVE may be of a strictly confidential nature, ESTEVE keeps the right to review the manuscript before its 
submission to journals, meetings or conferences. 
ESTEVE may choose to publish or present data from this study. If an Investigator is offered first authorship, 
he/she will be asked to critically review the article for important intellectual content and approve the version to 
be published. ESTEVE has the right to use the results for registration and internal presentation and for promotion 
of the ESTEVE’s commercial interests. 
15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1. Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry E6 GCP (including 
archiving of essential study documents), the 2013 version of the Declaration of Helsinki, and the applicable 
regulations of the country(ies) in which the study is conducted. 
15.2. Subject Information and Informed Consent 
A properly constituted, valid IRB must review and approve the protocol, the investigator’s informed consent 
document, and related subject information and recruitment materials before the start of the study. 
All subjects will receive written and oral information regarding the study at an interview prior to joining the study. 
The information will emphasize that participation in the study is voluntary and that the subject may withdraw 
from the study at any time and for any reason. The information must be written in a language that is understandable 
to the subject. All subjects will be given the opportunity to ask questions about the study and will be given 
sufficient time to decide whether to participate in the study. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from the subject 
before any activity or procedure is undertaken that is not part of routine care. A copy of the subject information 
including the signed consent form will be provided to the subject. 
15.3. Approval by Institutional Review Board  
For Investigational New Drug (IND) studies, the minimum standards of conduct and requirements for informed 
consent are defined in the FDA regulations. 
A valid IRB must review and approve this protocol before study initiation. Written notification of approval is to 
be provided by the investigator to the sponsor’s monitor/project manager before shipment of investigational drug 
supplies, and will include the date of the committee’s approval and the chairperson’s signature. This written 


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approval must consist of a completed sponsor form, IRB Approval Form or written documentation from the IRB 
containing the same information. 
Until written approval by the IRB has been received by the investigator, no subject may undergo any procedure 
not part of routine care for the subject’s condition. 
Protocol amendments must also be reviewed and approved by the IRB. Written approval from the IRB, or a 
designee, must be received by ESTEVE before implementation. This written approval will consist of a completed 
IRB Approval form or written documentation from the IRB containing the same information. 
15.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator and the 
sponsor. 


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16. REFERENCES 
1. ESTEVE Investigator’s Brochure CO-CRYSTAL E-58425 / MR308. Edition Number: 7.0; Release Date: 02-
May-2016.  
2. Desjardins PJ, Shu VS, Recker DP, Verburg KM, Woolf CJ. A single preoperative oral dose of valdecoxib, a 
new cyclooxygenase 2 specific inhibitor, relieves post oral surgery or bunionectomy pain. Anesthesiology. 
2002;97(3):565 573. 
3. Desjardins PJ, Traylor L, Hubbard RC. Analgesic efficacy of preoperative parecoxib sodium in an orthopedic 
pain model. J Am Podiatr Med Assoc. 2004;94(3):305 314. 
4. Reinhart DJ, Wang W, Stagg KS, Walker KG, Bailey PL, Walker EB, Zaugg SE. Postoperative analgesia 
after peripheral nerve block for podiatric surgery: clinical efficacy and chemical stability of lidocaine alone 
versus lidocaine plus clonidine. Anesth Analg. 1996;83(4):760-765. 
5. Max MB, Laska EM. Single-dose analgesic comparisons. In: Max MB, Portenoy RK, Laska EM, eds. 
Advances in Pain Research and Therapy, The Design of Analgesic Clinical Trials. Vol 18.New York: Raven 
Press;1991: Chapter 4. 
6. Singelyn FJ. Single-injection applications for foot and ankle surgery. Best Pract Res Clin Anaesthesiol. 
2002;16(2):247-254. 
7.  McCaffery M, Beebe A. Pain: Clinical Manual for Nursing Practice. St. Louis: CV Mosby, 1989. 
8. Singelyn FJ, Aye F, Gouverneur JM. Continuous popliteal sciatic nerve block: an original technique to provide 
postoperative analgesia after foot surgery. Anesth Analg. 1997;84(2):383-386. 
9. Zetlaoui PJ, Bouaziz H. Lateral approach to the sciatic nerve in the popliteal fossa. Anesth Analg. 
1998;87(1):79-82. 
10. Kaiser M, Friedd T. Blinded Sample Size Reestimation in Multiarmed Clinical Trials. Drug Information 
Journal. 2000;34:455-460. 
11. Ultram (tramadol hydrochloride) Tablets package insert. OMP Division ORTHO-McNEIL Pharmaceutical, 
Inc. Raritan, NJ. Revised March 2008. 
12. Apfelbaum JL, Gan TJ, Zhao S, Hanna DB, Chen C. Reliability and validity of the perioperative opioid-
related symptom distress scale. Anesth Analg. 2004 Sep;99(3):699-709. 
 


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17. ATTACHMENTS 
17.1. Schedule of Events 
 
Screening 
(-28 days 
to -1 day 
before 
surgery) 
Surgery 
Day -1 
Day 1 
(before 
dosing) 
Treatment Period 
Day 1 through Day 3 
Follow-up 
Day 7 ± 2 days 
(5 to 9 days 
after surgery) 
or ET 
First dose 
(Time 0) 
Subsequent 
doses 
Written informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X (update) 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
X (update) 
 
 
 
 
Physical examinationa 
X 
X 
 
 
 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
Height, weight, and BMI 
X 
 
 
 
 
 
12-lead electrocardiogram 
X 
 
X 
 
Xc 
X 
Clinical laboratory tests (hematology, chemistry, urinalysis) 
X 
 
X 
 
Xd 
X 
Pregnancy test for female subjectse 
X 
X 
 
 
 
X 
Urine drug screenf 
X 
X 
 
 
 
 
Alcohol breathalyzer test 
 
X 
 
 
 
 
X-ray and podiatric examinationg 
Xh 
 
 
 
 
X 
First metatarsal bunionectomy procedurei 
 
X 
 
 
 
 
Discontinue anesthetic block between 3:00 and 4:00 AMj 
 
 
X 
 
 
 
Assign randomization number 
 
 
Xk 
 
 
 
Subject training on self-assessments measures  
X 
X 
X 
 
 
 
Pain intensity and relief assessmentsl 
 
 
X 
X 
X 
 
Administer study medicationm 
 
 
 
X 
X 
 
Start stopwatches for perceptible and meaningful pain reliefn 
 
 
 
X 
 
 
Patient’s global evaluation of study medicationo 
 
 
 
 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Dispense postoperative pain medication and outpatient subject 
diaryp 
 
 
 
 
X 
 
Discharge subject from the study centerq 
 
 
 
 
X 
 
Collect and review diary for completion 
 
 
 
 
 
X 
 
 
 
 
 
 
Continued 


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Abbreviations: BMI = body mass index; ET = early termination; NPRS = numerical pain rating scale. 
a 
A complete physical examination (excluding the genitourinary examination) will be performed at Screening and before surgery on Day -1. A targeted 
physical examination, including an examination of the subject’s surgical site, will be performed at the Follow-up Visit. 
b 
Vital signs, including blood pressure, heart rate, respiratory rate, and oral body temperature, will be measured after the subject has been in a resting 
position for 5 minutes. Vital signs will be measured at Screening and before surgery on Day -1. From Day 1 through discharge from the study center, vital 
signs will be measured immediately before and 1 hour after each dose of study medication each day. Vital signs will also be measured before study 
termination. 
c 
A 12-lead ECG to be administered before discharge on Day 3. 
d 
Clinical laboratory tests to be performed before discharge on Day 3. 
e 
Serum pregnancy test at Screening and at Follow-up and urine pregnancy test before surgery on Day -1. Test results must be negative for the subject to 
continue in the study. 
f 
Collected at Screening and before surgery on Day -1. Test results must be negative for the subject to continue in the study except in cases where a valid 
physician’s prescription can be verified. 
g 
Radiographs taken within 6 months before Screening will be acceptable. X-ray and podiatric examination will be performed at the Follow-up Visit. 
h 
X-ray and podiatric examination only. 
i 
Primary unilateral first metatarsal osteotomy with internal fixation with no additional collateral procedure. 
j 
Immediately after the block is discontinued, study staff will pull 2 random study medication kits, 1 for moderate pain and 1 for severe pain. Subjects will 
be instructed to request pain medication when they experience pain. 
k 
When a subject requests pain medication, the Pain intensity (NPRS) assessment will be conducted and the qualifying pain score must be ≥5  and ≤9; 
subjects will be randomized into the study and stratified by Baseline pain score (moderate [NPRS 5-6], severe [7-9], using interactive response technology 
and the appropriate pain level kit will be used. 
l 
Pain intensity (NPRS) assessments will be recorded by the subject in the inpatient subject diary; the qualifying pain score serves as the Baseline pain 
score before the first dose of study medication (Day 1/Time 0). Pain intensity (NPRS) and pain relief (5-point categorical scale) assessments will be 
recorded at the following time points: 
• 
First dose: to 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, and 6 7, 8 hours after Time 0, and immediately before the use of rescue 
analgesia  
• 
Subsequent doses: 7, 8, 10, 12, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, 38, 42, 46, and 48 hours after Time 0 and immediately before each use of rescue 
analgesia. 
• 
Before premature study termination. 
m The first dose of study medication will be administered within 8 hours after the anesthetic block has been discontinued when pain intensity is ≥5 and ≤9 
on the NPRS. Study medication will be administered from Day 1 through Day 3 for a total of 48 hours. 
n 
Start stopwatches as soon as the first dose of study medication is administered. 
o 
Subjects will complete a patient’s global evaluation of study medication at the end of the treatment period (Day 3) before discharge from the study center. 
p 
Before discharge from the study center on Day 3. 
q 
On Day 3 
 
 


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17.2. Investigator’s Agreement 
PROTOCOL NUMBER: ESTEVE-SUSA-301 
PROTOCOL TITLE: 
A Randomized, Double-blind, Active- (Tramadol and Celecoxib) and 
Placebo-controlled, Parallel-groups, Phase 3 Clinical Trial to Establish the 
Efficacy of Co-Crystal E-58425 for the Management of Moderate to Severe 
Post-surgical Pain after Bunionectomy 
FINAL PROTOCOL: 
Final Version 4.0, 20 Jul 2017 
AMENDMENT 1 
Final Version 1.0, 09 Nov 2016 
AMENDMENT 2 
Final Version 1.0, 15 Feb 2017 
AMENDMENT 3 
Final Version 1.0, 20 Jul 2017 
I have read this protocol and agree to conduct this clinical trial as outlined herein. I will ensure that all 
subinvestigators and other study staff members have read and understand all aspects of this protocol. I agree to 
cooperate fully with ESTEVE and Premier Research during the study. I will adhere to all FDA, ICH, and other 
applicable regulations and guidelines regarding clinical trials on a study medication during and after study 
completion. 
Principal Investigator: 
 
 
Printed Name: 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
Date: 
 
 
 


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APPENDICES 
A. Address List 
B. Study Specific Requirements 
C. Regulations and Good Clinical Practice Guidelines 
 


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A. Address List 
1. Sponsor 
Sponsor 
Name: 
Laboratorios del Dr. ESTEVE, S. A. U. 
Address: 
Avda. Mare de Déu de Montserrat, 221 
 
08041 Barcelona (Spain) 
Phone: 
 
Project Manager: 
 
2. Clinical Research Organization 
Name: 
Premier Research  
Address: 
One Park Drive, Suite 150 
 
Durham, NC 27709 
Phone: 
 
Fax: 
 
Project Manager: 
 
Study Statistician: 
 
3. Drug Safety 
Medical Monitor 
Name: 
 
Address: 
Premier Research  
 
One Park Drive, Suite 150 
 
Durham, NC 27709 
Phone: 
 
Fax: 
 
 


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Pharmacovigilance 
Name: 
 
Address: 
1st Floor, Rubra 2 
Mulberry Business Park 
Fishponds Road 
 
Wokingham, RG41 2GY United Kingdom 
Phone: 
 
Fax: 
 
4. Monitor 
Name: 
  
Address: 
One Park Drive, Suite 150 
 
Durham, NC 27709 
Phone: 
 
Fax: 
 
5. Coordinating/Principal Investigator 
Name: 
 
Address: 
 
 
 
Phone: 
 
 


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6. Laboratories 
Central Laboratory 
Name: 
 
Address: 
 
 
 
Phone: 
 
Fax: 
 
 


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B. Regulations and Good Clinical Practice Guidelines 
1. Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
2. Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf 
 
 

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Statistical Analysis Plan 
 
Protocol Title: A Randomized, Double-blind, Active- (Tramadol and Celecoxib) and 
Placebo-controlled, Parallel Groups, Phase 3 Clinical Trial to Establish the 
Efficacy of Co-crystal E 58425 for the Management of Moderate to Severe 
Post-surgical Pain after Bunionectomy 
Protocol Number: ESTEVE SUSA-301 (Amendment 3, 30 June 2017) 
Compound: Co-crystal E 58425 
Phase: 3 
Sponsor: Laboratorios del Dr ESTEVE, S. A. U. 
Avda. Mare de Déu de Montserrat, 221 
08041 Barcelona (Spain) 
 
SAP Author: 
 
 
 
 
 
 
 
 
 
SAP Version: FINAL Version 3.0 
SAP Date: 13 December 2017 
CONFIDENTIAL 


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DOCUMENT HISTORY 
Version 
Date 
Author 
Description 
1.0 
11 November 2016 
 
First final version 
2.0 
09 June 2017 
 
Revised version following 
protocol amendment 2 and FDA 
feedback on version 1 
3.0 
13 December 2017 
 
Updated to clarify some minor 
ambiguities and inconsistencies 
with the protocol and incorporate 
some decisions made at the 
blinded data review meeting 
 


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SIGNATURE PAGE AND APPROVALS 
 
 
 
 
 
 
Premier Research 
Date 
 
 
 
 
 
 
 
Laboratorios del Dr Esteve 
 
Date 


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TABLE OF CONTENTS 
DOCUMENT HISTORY ..................................................................................................2 
SIGNATURE PAGE AND APPROVALS .......................................................................3 
TABLE OF CONTENTS ..................................................................................................4 
LIST OF TABLES .............................................................................................................6 
ABBREVIATIONS ............................................................................................................7 
1. 
OVERVIEW ...........................................................................................................8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................9 
2.1 
Study Objectives ..........................................................................................9 
2.1.1 Primary Objective ............................................................................9 
2.1.2 Secondary Objectives .......................................................................9 
2.2 
Efficacy and Safety Endpoints (Target Variables) ......................................9 
2.2.1 Efficacy Variables ............................................................................9 
2.2.2 Safety Variables .............................................................................10 
3. 
OVERALL STUDY DESIGN AND PLAN .......................................................11 
4. 
ANALYSIS AND REPORTING ........................................................................12 
4.1 
Interim Analysis .........................................................................................12 
4.2 
Final Analysis ............................................................................................12 
5. 
ANALYSIS SETS.................................................................................................13 
6. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ..................................15 
6.1 
General Statistical Methodology................................................................15 
6.1.1 Handling of Missing Data ..............................................................15 
6.1.2 Adjustment of Pain Scores for Rescue Medication Use ................16 
6.1.3 Pooling of Centres..........................................................................16 
6.1.4 Visit Windows ...............................................................................16 
6.2 
Details of Original Efficacy Variables .......................................................17 
6.2.1 Pain Intensity .................................................................................17 
6.2.2 Pain Relief ......................................................................................17 
6.2.3 Stopwatch Assessment ...................................................................17 
6.2.4 Patient’s Global Evaluation of Study Medication .........................17 
6.3 
Derived and Computed Variables ..............................................................18 
7. 
STUDY SUBJECTS AND DEMOGRAPHICS.................................................22 
7.1 
Disposition of Subjects and Withdrawals ..................................................22 
7.2 
Protocol Violations and Deviations ...........................................................22 
7.3 
Demographics and Other Baseline Characteristics ....................................22 


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8. 
EFFICACY ANALYSIS ......................................................................................23 
8.1 
Primary Efficacy Variable Analysis ..........................................................23 
8.1.1 Sensitivity Analyses of the Primary Efficacy Variable .................23 
8.2 
Secondary Efficacy Variable Analysis ......................................................25 
8.3 
Subgroup Analysis of Efficacy Variables ..................................................28 
9. 
SAFETY AND TOLERABILITY ANALYSIS .................................................29 
9.1 
Adverse Events ..........................................................................................29 
9.1.1 Adverse Events Leading to Withdrawal ........................................30 
9.1.2 Serious Adverse Events .................................................................30 
9.1.3 TEAEs of special interest ...............................................................31 
9.2 
Clinical Laboratory Test Results ...............................................................31 
9.3 
Vital Signs ..................................................................................................31 
9.4 
ECGs ..........................................................................................................32 
9.5 
Concomitant Medication ............................................................................32 
9.6 
Exposure and Compliance .........................................................................33 
10. 
CHANGES FROM PLANNED ANALYSIS .....................................................34 
11. 
OTHER PLANNED ANALYSIS ........................................................................35 
12. 
REFERENCES .....................................................................................................36 
13. 
TABLES, LISTINGS, AND FIGURES .............................................................37 
13.1 
Planned Table Descriptions .......................................................................37 
13.2 
Planned Listing Descriptions .....................................................................41 
13.3 
Planned Figure Descriptions ......................................................................43 
14. 
TABLE SHELLS .................................................................................................45 
 


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LIST OF TABLES 
Table 1: Derived and Computed Variables .............................................................................. 18 
Table 2: Imputation schemes ................................................................................................... 24 
Table 3: Normal ranges for vital signs ..................................................................................... 32 
Table 4: Normal ranges for ECG ............................................................................................. 32 
 
 


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ABBREVIATIONS 
ABBREVIATION DEFINITION OR DESCRIPTION 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BOCF 
Baseline Observation Carried Forward 
CAS 
Completers Analysis Set 
CRF 
Case Report Form 
CPMP 
Committee for Proprietary Medicinal Products 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FAS 
Full Analysis Set 
FCS 
Full Conditional Specification 
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonisation 
LOCF 
Last Observation Carried Forward 
MAR 
Missing At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not At Random 
NPRS 
Numeric Pain Rating Scale 
PPAS 
Per Protocol Analysis Set 
QTC 
QT-interval for ECG corrected for heart rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPID 
Sum of Pain Intensity Differences 
TEAE 
Treatment-emergent Adverse Event 
TOTPAR 
Total Pain Relief 
TTOA 
Time To Onset of Analgesia 
TTPPR 
Time To Peak Pain Relief 
WHO 
World Health Organization 
WOCF 
Worst Observation Carried Forward 
 


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1. OVERVIEW 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for 
Laboratorios del Dr Esteve protocol ESTEVE-SUSA-301 (A Randomized, Double-blind, 
Active- (Tramadol and Celecoxib) and Placebo-controlled, Parallel Groups, Phase 3 Clinical 
Trial to Establish the Efficacy of Co-crystal E-58425 for the Management of Moderate to 
Severe Post-surgical Pain after Bunionectomy), Amendment 1, dated 9 November 2016, 
Protocol Version 4. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in 
Clinical Trials[1]. All work planned and reported for this SAP will follow internationally 
accepted guidelines, published by the American Statistical Association[2] and the Royal 
Statistical Society[3], for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-
hoc, or unplanned, exploratory analysis will be clearly identified as such in the final CSR. 
In addition to the study protocol, the following documents were reviewed in preparation of 
this SAP: 
 ICH Guidance on Statistical Principles for Clinical Trials (E9) 
The reader of this SAP is encouraged to also read the clinical protocol, and other identified 
documents, for details on the planned conduct of this study. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless 
relevant to the planned analysis. 


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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective of this study is to establish the analgesic efficacy of co-crystal 
E-58425 compared to tramadol and to celecoxib for the management of moderate to severe 
post-operative pain for 48 hours after bunionectomy by using assessments of pain intensity. 
2.1.2 Secondary Objectives 
The secondary objectives are as follows: 
 To assess the analgesic efficacy of co-crystal E-58425 compared to tramadol and 
to celecoxib for the management of moderate to severe post-operative pain at 
various time points after bunionectomy by using assessments of pain intensity 
 To assess the analgesic efficacy of co-crystal E-58425 by means of responder 
rates, use of rescue medication, time to onset of analgesia, time to perceptible and 
meaningful pain relief, time to onset of pain intensity decrease, peak pain relief, 
and time to peak pain relief and the subjects’ overall assessment of the study 
medication 
 To assess the absolute analgesic efficacy of co-crystal E-58425 compared to 
placebo for the treatment of moderate to severe post-operative pain in the first 
48 hours and at various time points after bunionectomy by using assessments of 
pain intensity 
 To assess the safety and tolerability of co-crystal E-58425 
2.2 
Efficacy and Safety Endpoints (Target Variables) 
2.2.1 Efficacy Variables 
The primary efficacy variable is the sum of pain intensity differences (SPID) up to 48 hours 
(SPID-48), calculated as described in Section 6.3. 
The secondary efficacy variables are as follows: 
 SPID up to 4, 6, 12, and 24 hours (SPID-4, SPID-6, SPID-12, and SPID-24)  
 Pain intensity at each time point 
 Pain intensity difference from baseline at each time point 
 Pain Relief (PARt) = pain relief at each time point 
 Total Pain Relief (TOTPAR) for time intervals (t=15 minutes – t=4 hours), (t=15 
minutes – t=6 hours), (t=15 minutes – t=12 hours), (t=15 minutes – t=24 hours), 
and (t=15 minutes – t=48 hours), calculated as described in Section 6.3 
 Peak pain relief and time to peak pain relief 
 Stop watches: time to onset of analgesia, time to perceptible pain relief and time 
to meaningful pain relief 
 Time to onset of pain intensity decrease 


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 Subject’s overall assessment of study medication 
 Rescue medication: 
 Proportion of subjects who take of at least 1 dose of rescue medication up to 4, 
up to 6, up to 12, up to 24, and up to 48 hours after first dose of study 
medication; number of doses of rescue medication for the same time intervals 
 Time to first use of rescue medication 
 Proportion of responders, where responders are:  
 Subject who reaches a 50% reduction in pain intensity from baseline sustained 
until the end of the 48-hour observation period 
 Subject who reaches a 30% reduction in pain intensity from baseline sustained 
until the end of the 48-hour observation period 
 Subject who reaches a pain intensity below 4 on the numeric pain rating scale 
(NPRS) sustained until the end of the 48-hour observation period 
 Subject who reaches a 50% reduction in pain intensity as compared to baseline 
and a pain intensity below 4 on NPRS sustained until the end of the 48-hour 
observation period 
 Subject who reaches a 30% reduction in pain intensity as compared to baseline 
and a pain intensity below 4 on NPRS sustained until the end of the 48-hour 
observation period 
 Time-to-first-response will also be analysed as time-to-event data, using the first 
time at which each response criterion was reached by each subject 
2.2.2 Safety Variables 
The safety variables are as follows: 
 Incidence of treatment emergent adverse events (TEAEs) 
 Electrocardiogram (ECG) variables 
 Vital signs measurements 
 Laboratory safety variables 
 Concomitant medication 
 Medication exposure 


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3. OVERALL STUDY DESIGN AND PLAN 
This is a randomized, double-blind, placebo and active controlled phase 3 study of co-crystal 
E-58425. Subjects are eligible for the study if they have pain in the range 5–9 inclusive on an 
11-point numeric pain rating scale (NPRS) after bunionectomy. 
Subjects will be randomized in a 2:2:2:1 ratio to co-crystal E-58425, tramadol, celecoxib, or 
placebo. Randomization will be stratified according to whether subjects have a baseline 
NPRS pain score in the moderate (5–6) or severe (7–9) range. The randomization process 
proceeds in 2 steps: in the first step, subjects are assigned to 2 possible treatments depending 
on the stratum for which they qualify based on their baseline pain score, and in the second 
step, they are assigned to a specific stratum and therefore to a unique treatment arm, once 
their baseline pain score is known. 
Subjects will complete the NPRS at various timepoints up to 48 hours after dosing (15, 30, 
and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 14, 18, 22, 24, 26, 28, 
30, 32, 34, 36, 38, 42, 46, and 48 hours and immediately before each use of rescue 
medication). Subjects whose pain is not sufficiently managed by the study medication will be 
able to take rescue medication (either IV acetaminophen or oral oxycodone). 
Subjects will be discharged from the study centre on day 3 of the study, after the 48-hour 
efficacy assessments and the end-of-treatment period safety assessments have been done. 
Subjects will return to the study on day 7 for follow-up safety assessments, which represents 
the end of study for each subject. 
Whenever possible and reasonable, when study medication is discontinued efforts will be 
made to collect all study assessments as scheduled up to the completion of the study, unless 
the subject withdraws consent. 
For full details of the study design, please see the protocol. 


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4. ANALYSIS AND REPORTING 
4.1 Interim Analysis 
A blinded interim analysis will be done after approximately half the subjects have been 
recruited, for the purpose of sample size re-estimation. 
To that end, the variance of the primary outcome measure will be calculated from blinded 
data. Variance estimates of unblinded data can be inflated in the presence of treatment 
effects, although Friede and Kieser have shown that ignoring the treatment effects and using 
a naïve pooled estimate of the variance is often the preferred strategy[4]. Nonetheless, 
simulations have been done to determine the effect of different strategies for estimating the 
variance from the unblinded data, and those simulations have shown that using the naïve 
pooled estimate is indeed the preferred strategy for this study. 
Details of the simulations results and the detailed rationale for using the naïve pooled 
estimate for calculating the variance are described in a separate interim analysis plan. 
Once the variance has been estimated, that will be used to recalculate the sample size for the 
study, using the same inputs as the original calculation apart from the new variance. If the 
new calculation shows that a greater sample size is required, then the sample size will be 
increased to either the new sample size required or to 900, whichever is the smaller. 
If the new calculation shows that a smaller sample size is required than originally estimated, 
then the study will continue to its original sample size. The sample size will not be reduced. 
Full details are specified in the separate interim analysis plan dated 20 January 2017. 
4.2 Final Analysis 
All final, planned analyses identified in the protocol and in this SAP will be done after the 
last subject has completed the follow-up assessments on day 7, and all relevant study data 
have been processed and integrated into the analysis data base, data have been reviewed at a 
blinded data review meeting, and the database has been locked. Any post-hoc, exploratory 
analysis that were not identified in this SAP to support planned study analyses will be 
documented and reported in appendices to the CSR. Any results from unplanned analyses 
(post-hoc) will also be clearly identified in the text of the CSR. 


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5. ANALYSIS SETS 
The following analysis sets are planned for this study:  
 Safety Set: The safety set includes all subjects who receive at least 1 dose of study 
medication 
 All Enrolled Patients Set (ALL): The ALL set includes all subjects who are entered 
into the interactive randomisation system and receive the initial assignment to two 
possible treatment arms, depending on the stratification according to the pain score at 
baseline will be, irrespective of whether they are subsequently assigned to a specific 
randomisation stratum and to a unique treatment arm (and to a unique box of study 
medication) 
 Full Analysis Set (FAS): The FAS includes all subjects who undergo both steps of 
the randomization process and so are assigned to a specific randomisation stratum and 
to a unique treatment arm, irrespective of whether they actually receive any dose of 
study medication 
 Per Protocol Analysis Set (PPAS): The PPAS set includes all subjects in the FAS 
with no major protocol deviations 
 Completers Analysis Set (CAS): A subset of the PPAS that includes all subjects who 
have pain assessments up to 48 hours after first dose of study medication (Note: if few 
patients in the PPAS are excluded from the CAS, no CAS will be defined. This 
decision will be taken in the blinded data review meeting.) 
Inclusion in the analysis sets will be determined at a blinded data review meeting before 
database lock and before unblinding the treatment assignments. 
The following protocol deviations may be considered as major and will lead to an exclusion 
of subjects form the PPAS: 
 Not receiving any dose of study medication 
 Lack of any pain intensity assessment following study medication intake and before 
intake of rescue medication during the first 4 hours after the first study medication 
intake 
 Receiving rescue medication during the first hour after the first study medication 
intake 
 Age < 18 years 
 Baseline pain intensity <5 or > 9 
 Deviation from the standard surgical or anaesthesia procedures which could interfere 
with post-surgical pain 
 Use of prohibited concomitant medication or non-pharmacological therapies 
 Insufficient treatment compliance (less that 6 out of the 8 scheduled doses) 
 Insufficient pain intensity assessment compliance which does not allow to fully 
characterize pain response evolution 
 Time between qualifying pain score and first study medication intake > 30 minutes 
Additional protocol deviations may be considered major at the blinded data review meeting 
and will be documented appropriately. 
If a subject is randomized incorrectly or is administered the incorrect study medication, 
analyses of the FAS will be based on the assigned treatment, whereas all other analyses will 
be based on the actual treatment received. 


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Primary efficacy analyses will be based on the FAS. The PPAS and the CAS will be used for 
sensitivity analysis for some efficacy endpoints. Safety analyses will be based on the safety 
set. The ALL set will be used for analyses of patient disposition, but will not be used for 
efficacy or safety analyses. 
All subjects who signed informed consent will be considered as study participants. 


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6. GENERAL ISSUES FOR STATISTICAL ANALYSIS 
6.1 General Statistical Methodology 
Descriptive summaries will be provided where appropriate for each of the primary and 
secondary variables. In general, tables will summarize data by treatment group.  
Continuous, quantitative, variable summaries will include the number of subjects (N) with 
non-missing values, mean, standard deviation (SD), median, minimum, and maximum, unless 
otherwise specified.  
Categorical, qualitative, variable summaries will include the frequency and percentage of 
subjects in the particular category. In general, the denominator for the percentage calculation 
will be based upon the total number of subjects in the analysis set for the treatment groups, 
unless otherwise specified.  
Statistical analysis models will be used to estimate treatment differences or ratios for the co-
crystal E-58425 compared to tramadol and to celecoxib for the different study endpoints, as 
the study confirmatory analysis. Additionally, the absolute analgesic efficacy of co-crystal E-
58425 will be estimated by comparison to placebo. Comparisons of tramadol and celecoxib to 
placebo will serve to assess the trial assay sensitivity. 
All statistical tests will be based on a 2-sided test at the significance level of 0.05 and 95% 
confidence intervals, unless otherwise specified. 
Graphical presentations will be employed to illustrate results from the statistical analyses. 
All analysis will use SAS® software version 9.3 or later. 
6.1.1 Handling of Missing Data 
If subjects have missing pain data (ie, pain intensity or pain relief scores) within the 48 h 
period for the collection of pain rating data, but nonetheless complete the 48-hour period, 
then any missing timepoints will be replaced by a time-weighted average of the previous and 
the next available values (ie a linear interpolation for missing values) in the SPID or 
TOTPAR calculation. 
If subjects do not complete the pain intensity assessments for the full 48 hours, then in the 
primary analysis, the SPID will be calculated up to the last available timepoint, with no 
imputation for later timepoints. This is equivalent to imputing a value of zero for the change 
from baseline, ie a baseline-observation-carried-forward (BOCF) analysis. As pain is 
expected to decrease after baseline, even without treatment, this is a conservative analysis. A 
similar approach will be used in calculating TOTPAR, which is also conservative, as it 
assumes zero pain relief where values are missing. 
The only exception to the above imputation rule will be for patients who do not complete the 
full 48 h of assessments because the assessment at the 48-h timepoint was recorded early. In 
those cases, a further value at exactly 48 h will be imputed using the same value as recorded 
at the nominal 48-h timepoint, and the SPID will be calculated using both the recorded 
measurement at the nominal 48-h timepoint and the imputed measurement at exactly 48 h 
post-dose. 
If subjects have no post-baseline pain assessments at all, then a value of zero will be imputed 
for the SPID; this is also equivalent to a BOCF analysis. 
In a sensitivity analysis, subjects who drop out of the study early because of a related AE or 
lack of efficacy will have later missing timepoints imputed using a worst-observation-carried-


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forward (WOCF) method, in which their worst observation at baseline or any time thereafter 
is imputed. For subjects dropping out early for any other reason, a last-observation-carried-
forward (LOCF) imputation will be used. 
In a further sensitivity analysis, all subjects who do not have the whole 48 hours of pain data 
will have later missing timepoints imputed using the WOCF method, in which their worst 
observation at baseline or any time thereafter is imputed. This is an even more conservative 
analysis than the BOCF method. 
Additionally, an analysis of the most important efficacy endpoints based on the Completers 
Analysis Set will be performed to further assess the impact of the imputation of missing 
values on the study results. 
As a further sensitivity analysis, a multiple imputation approach will be taken in which 
missing data are imputed. Details of the multiple imputation methods are specified in section 
8.1.1. 
No imputation will be done for missing data on stopwatch assessments of perceptible and 
meaningful pain relief. Instead, if data are missing for those assessments, data will be 
censored as described in section 8.2. 
If the patient’s global evaluation of the study medication is missing, a value of 0 (poor) will 
be imputed. 
6.1.2 Adjustment of Pain Scores for Rescue Medication Use 
If subjects take rescue medication during the 48-hour period of pain assessments, a pain 
assessment will be made immediately before the dose of rescue medication. In the primary 
analysis, that score will be used to impute all scores taken in the 4 hours after the dose of 
rescue medication, even if the next dose of study medication is taken in that 4 hour period. 
Provided that another dose of rescue medication has not been taken in that 4-hour period, 
after the end of the 4-hour period actual pain scores will again be used until either the end of 
the 48-hour period or the next dose of rescue medication, whichever occurs earlier. If 
subsequent rescue medication is given, the score measured at the time of the administration 
of the subsequent rescue medication will continue to be imputed up to 4 hours after that 
rescue medication intake. 
A sensitivity analysis will be done in which that imputation will not be done and all scores 
will be analysed as recorded. 
If patients take other analgesic medication during the study other than allowed rescue 
medication, then all subsequent pain assessments will be treated as missing and handled as 
described in section 6.1.1 above. 
6.1.3 Pooling of Centres  
No pooling of centres is planned. In the unlikely event that any centre recruits too few 
subjects to be analysed as a centre in its own right, a decision will be made about pooling of 
centres at the blinded data review meeting. 
6.1.4 Visit Windows 
As the subjects are confined to the study site for the duration of the efficacy assessment 
period, the question of visit windows is not relevant. 


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6.2 Details of Original Efficacy Variables 
The following efficacy variables will be collected directly, and will be reported in their own 
right and used to calculate the derived variables as described in section 6.3. 
6.2.1 Pain Intensity 
Subjects will assess their current pain intensity using a 0–10 NPRS. The NPRS is a scale 
numbered zero to 10 with “No Pain” as the left anchor (0) and “Worst Possible Pain” as the 
right anchor (10). Each subject will be instructed to circle a single number on the line to 
indicate his or her current pain intensity. Pain intensity will be assessed before Time 0, at 15, 
30, and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 14, 18, 22, 24, 26, 
28, 30, 32, 34, 36, 38, 42, 46, and 48 hours after Time 0, and immediately before each use of 
rescue analgesia. 
If patients assessed their pain intensity at times deviating from the nominal time by more than 
acceptable windows, then their pain intensity scores will still be included in listings, but will 
be excluded from summary statistics of pain scores, calculation of SPID, and MMRM 
analysis of pain by timepoint. 
Acceptable windows will be defined during the blinded data review meeting. 
6.2.2 Pain Relief 
Subjects will assess their pain relief relative to Time 0 using a 5-point categorical scale. 
Subjects will be asked “How much relief have you had since your starting pain?” with 
response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4. Pain relief 
will be assessed at 15, 30, and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 
10, 12, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, 38, 42, 46, and 48 hours after Time 0, , and 
immediately before each use of rescue analgesia. 
If times of assessments differ from nominal times, then values will be excluded from analyses 
as described above for pain intensity. 
6.2.3 Stopwatch Assessment 
Two stopwatches will be started immediately after the subject has swallowed the last tablet of 
the first dose of study medication with 8 ounces of water. Each subject will be instructed, 
“Stop the first stopwatch when you first feel any pain relief whatsoever. This does not mean 
you feel completely better, although you might, but when you first feel any relief in the pain 
you have now” (perceptible pain relief). The subject will also be instructed, “Stop the second 
stopwatch when you feel the pain relief is meaningful to you” (meaningful pain relief). If the 
subject does not press the stopwatches within 8 hours after Time 0, the subject will 
discontinue use of the stopwatches. 
6.2.4 Patient’s Global Evaluation of Study Medication 
For the patient’s global evaluation of study medication, the subject will be asked “How 
effective do you think the study medication is as a treatment for pain?” with response choices 
of 0 = poor, 1 = fair, 2 = good, 3 = very good, or 4 = excellent. The subject will complete the 
patient’s global evaluation of study medication at the end of the treatment period (Day 3) 
before discharge from the study centre. 


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6.3 Derived and Computed Variables 
The following derived and computed variables have been initially identified as important for 
the analysis of efficacy. It is expected that additional variables will be required. The SAP will 
not be amended for additional variables that are not related to the primary target or key 
secondary target variables. Any additional derived or computed variables will be identified 
and documented in the define.xml document that accompanies the analysis datasets. If the 
SAP is not amended, further derivations related to primary and secondary target variables 
will be described in the CSR.  
Table 1: Derived and Computed Variables 
Variable 
Name 
Description 
Computation Methods 
Baseline 
Baseline value (There will be 
different variable names for 
different assessments)  
Baseline is defined as the last measurement taken 
before the first study medication administration 
PID-x 
The pain intensity difference 
over 0 hour to the x- hour 
period after Time 0 
PID-x = PI at x timepoint – PI at baseline 
Note: Negative values of PID correspond to an 
amelioration of pain in the corresponding 
assessment time compared to the initial intensity, 
while positive values correspond to an increase in 
pain.  


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Variable 
Name 
Description 
Computation Methods 
SPID-x 
The summed pain intensity 
difference over 0 hour to the 
x- hour period after Time 0 
SPID-x = PID_t1*(t1 ─ 0) + PID_t2*(t2 ─ t1) + 
… + PID_n*(t[n] ─ t[n ─ 1]), where PID_t[m] is 
(PI at baseline – PI at mth time-point), and x is the 
nth time-point; x=4, 6, 12 24, 48. 
Note: Negative values of SPID correspond to an 
average amelioration of pain up to the 
corresponding assessment time compared to the 
initial intensity, while positive values correspond 
to an increase in pain. 
Actual assessment times will be used for this 
calculation. If the nominal 48-h timepoint is 
measured early, then the remaining time to 48 h 
will be imputed as described in section 6.1.1. If 
the 48 h timepoint is measured late, then the 
SPID-48 will be measured up to an imputed value 
at 48 h based on linear interpolation between the 
48 h timepoint and the previous measurement. 
For SPID up to earlier timepoints, if the final 
timepoint is not taken at exactly the nominal time, 
then a value will be imputed by linear 
interpolation at the final timepoint between the 
previous and following measurements, and the 
SPID calculated up to that timepoint. 
In all SPID calculations, individual values will be 
excluded from analyses if they differ from 
nominal timepoints by more than acceptable 
windows, as described in section 6.2.1. 
TOTPAR-x 
The summed time-weighted 
pain relief score over 0 hour 
to the x-hour period after 
Time 0 
TOTPAR_x= PR_t1*(t1 ─ 0) + PR_t2*(t2 ─ t1) + 
… + PR_x*(t[n] ─ t[n ─ 1]), where PR_t[m] is 
pain relief score at m time-point, and x is the nth 
time-point; x= 6, 12, 24, 48 
Note: TOTPAR can only take positive values, 
corresponding the higher values to higher pain 
relief and a value of 0 to no pain relief compared 
to the initial intensity. 
Actual assessment times will be used for this 
calculation. If the final measurement is not taken 
exactly at the nominal timepoint, then imputations 
will be used as described above for calculation of 
SPID. 
In all TOTPAR calculations, individual values will 
be excluded from analyses if they differ from 
nominal timepoints by more than acceptable 
windows, as described in section 6.2.1. 


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Variable 
Name 
Description 
Computation Methods 
Response-50 
Response (50% pain 
reduction) 
Equals 1 if subjects have a 50% reduction in pain 
intensity from baseline, sustained until the end of 
the 48 h period, otherwise equals 0. If subjects 
drop out before the 48 h assessments, they will be 
considered non-responders. 
Response-30 
Response (30% pain 
reduction) 
Equals 1 if subjects have a 30% reduction in pain 
intensity from baseline, sustained until the end of 
the 48-h period, otherwise equals 0. If subjects 
drop out before the 48-h assessments, they will be 
considered non-responders. 
Response-4 
Response (below 4) 
Equals 1 if subjects have a reduction in pain 
intensity from baseline to below 4 on the NPRS, 
sustained until the end of the 48-h period, 
otherwise equals 0. If subjects drop out before the 
48-h assessments, they will be considered non-
responders. 
Response-4-50 Response (below 4 and 50% 
reduction) 
Equals 1 if subjects have a reduction in pain 
intensity from baseline to below 4 on the NPRS 
and a 50% reduction from baseline, sustained until 
the end of the 48-h period, otherwise equals 0. If 
subjects drop out before the 48-h assessments, 
they will be considered non-responders. 
Response-4-30 Response (below 4 and 30% 
reduction) 
Equals 1 if subjects have a reduction in pain 
intensity from baseline to below 4 on the NPRS 
and a 30% reduction from baseline, sustained until 
the end of the 48-h period, otherwise equals 0. If 
subjects drop out before the 48-h assessments, 
they will be considered non-responders. 
TTOA 
Time to onset of analgesia 
Equal to the time to perceptible pain relief, as 
measured with the first stopwatch, when 
confirmed by achievement of meaningful pain 
relief by the subject (as measured with the second 
stopwatch) within 8 h of dosing. The time will be 
censored at 8 h if perceptible and meaningful pain 
relief have not both been recorded by that time 
point, or at the time of dropout if earlier than 8 h. 
If rescue medication is taken before meaningful 
pain relief is recorded (and before 8 h after 
dosing), then TTOA will be censored at the time 
of rescue medication. 


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Variable 
Name 
Description 
Computation Methods 
TTOPID 
Time to onset of pain 
intensity decrease 
Time to onset of pain intensity decrease will be 
measured as the time at which the difference from 
baseline pain intensity (PID) is decreased ≥1 point 
in NPRS for the first time after the first study 
medication intake. For any patients who do not 
have a decrease in pain intensity, this will be 
censored at 48 h, even for patients who drop out 
before then. 
PPR 
Peak pain relief 
The minimum (ie most negative) difference from 
baseline in pain intensity by NPRS, after 
imputation for any rescue medication (if 
applicable). Note that if patients have increases 
from baseline at all post-baseline timepoints, this 
will be a positive number, and will not actually be 
a relief. 
TTPPR 
Time to peak pain relief 
Time to peak pain relief will be taken as the time 
to the lowest value of the NPRS after baseline, 
provided that the lowest value after baseline is 
lower than the baseline value. Subjects who do not 
experience any pain score lower than baseline will 
have the time censored at the time of the final pain 
assessment (48 h after the first dose or early 
dropout). If a subject records the lowest value of 
the NPRS at more than one timepoint, the first 
such timepoint will be used. 
For the time to event variables TTOPID and TTPPR, the start time will be taken as the time 
of the first dose of study medication for all subjects who are dosed. If a patient is randomised 
in the second step of randomisation but is not then dosed, the start time will be taken as the 
time of the second step of randomisation. 


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7. STUDY SUBJECTS AND DEMOGRAPHICS 
7.1 Disposition of Subjects and Withdrawals 
All subjects who provide informed consent will be accounted for in this study. Descriptive 
summaries of analysis set data will be presented for all subjects unless otherwise specified 
and will include the following: 
 The frequency and percent of subjects in each analysis set, overall and by treatment 
group and centre 
 The disposition of subjects (including number of study participants, number of 
subjects undergoing surgery, screening failures, number of subjects randomized in the 
first randomization step, number of subjects randomized in both randomization steps, 
number of subjects treated, and number of completers), overall and by treatment 
group and centre 
 Patients who discontinue study medication by reason for discontinuation, overall and 
by treatment group 
 Study withdrawals by reason for withdrawal, overall and by treatment group 
In addition, all study withdrawals will be listed. 
7.2 Protocol Violations and Deviations 
Protocol violations and deviations will be categorized as major or minor at the blinded data 
review meeting before defining the analysis sets as described in Section 5. 
Major protocol violations (ie those leading to exclusion from the PPAS) will be summarized 
by type of violation, overall and by treatment group. Individual major and minor protocol 
violations will be listed by subject. 
7.3 Demographics and Other Baseline Characteristics 
Descriptive summaries of the demographic and other baseline characteristics will be 
presented for the safety set. All demographic and baseline characteristics will be presented 
both overall and by treatment group. 
The following demographic and baseline data will be presented: 
 Demographics (age, sex, race, and body weight, height, and BMI) 
 Medical history: number and percentage of subjects with at least one medical history 
item in each System Organ Class (SOC) and preferred term  
 Prior medications (any medications taken before the baseline visit, irrespective of 
whether they were recorded in the prior medications log or the concomitant 
medication log): number and percentage of subjects with at least one drug in each 
Anatomical Therapeutic Chemical (ATC) level 3 group and preferred term 
 Duration of surgery and other surgery characteristics 
Demographic and other baseline data will be presented using descriptive statistics only; no 
hypotheses will be tested. 


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8. EFFICACY ANALYSIS 
This study will examine the efficacy of co-crystal E-58425 in the management of acute pain 
to support registration with regulatory authorities. The analyses described here are intended 
as confirmatory analyses.  
It may be necessary to complete additional exploratory analyses after the planned analyses 
are completed. Full details of additional analyses will be presented in the CSR, and any such 
analyses will be clearly identified as post-hoc. 
All statistical tests will be based on a 2-sided test at the significance level of 0.05, unless 
otherwise specified. 
All efficacy variables will be presented with descriptive statistics, broken down by treatment 
group. In addition, statistical analyses will be presented as described below. 
8.1 Primary Efficacy Variable Analysis 
In the primary efficacy analysis, the SPID-48h will be compared between the treatment 
groups. Three separate null hypotheses will be tested: 
 The mean SPID-48 in the co-crystal E-58425 group is equal to the mean SPID-48 
in the tramadol group 
 The mean SPID-48 in the co-crystal E-58425 group is equal to the mean SPID-48 
in the celecoxib group 
 The mean SPID-48 in the co-crystal E-58425 group is equal to the mean SPID-48 
in the placebo group 
For the study to be declared successful, all 3 of those null hypotheses must be rejected such 
that Co-crystal E-58425 shows superiority over each comparator. Because all 3 null 
hypotheses must be rejected, no adjustment for multiple comparisons is necessary. 
The hypotheses will be tested in an analysis of covariance (ANCOVA) model including 
terms for centre and baseline pain (as a continuous variable). The model will be used to show 
least squares means of the SPID-48 in each treatment group, and to estimate the difference in 
least squares means between the co-crystal E-548425 group and each of the 3 control groups, 
along with 95% confidence intervals and P values associated with those differences. 
The primary efficacy analysis will use the FAS. 
In the primary analysis, SPID-48 will be imputed as described in Section 6.1.1 if any pain 
assessments are missing and as described in Section 6.1.2 if subjects take rescue medication. 
8.1.1 Sensitivity Analyses of the Primary Efficacy Variable 
The primary analysis will be repeated using the PPAS and the CAS as sensitivity analyses. 
Sensitivity analyses will also be done (using both the FAS and PP set) for alternative 
imputation methods for SPID-48 if any pain assessments are missing or if subjects take 
rescue medication. The following imputation schemes will be used: 


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Table 2: Imputation schemes 
Analysis 
number 
Imputation method for 
missing data 
Imputation method if 
rescue medication is taken 
Analysis model 
1 
WOCF for dropouts for AE, 
LOCF otherwise 
Same as primary analysis 
Same as primary 
analysis 
2 
WOCF 
Same as primary analysis 
Same as primary 
analysis 
3 
Same as primary analysis 
Values analysed as 
recorded; no imputation 
Same as primary 
analysis 
4 
Same as primary analysis 
Values analysed as 
recorded; no imputation 
Additional adjustment 
for rescue medication 
use 
5 
Multiple imputation 
Same as primary analysis 
Same as primary 
analysis 
For analysis 4, the ANOVA model will also be adjusted for rescue medication use. This will 
include terms for the number of rescue medication doses taken of each kind (ie one term for 
number of acetaminophen doses taken, and one term for the number of oxycodone doses 
taken), as continuous variables. 
For analysis 5, a jump to control multiple imputation analysis on missing pain scores on the 
ITT population will be done. The analysis has three broad components: i) the multiple 
imputation process for the placebo data; ii) the multiple imputation process for the treated 
patient’s data; and iii) the analysis model that will be used to draw inference regarding the 
primary causal estimand along with the method for combining the results across the multiply 
imputed datasets.  
i. 
The imputation for the placebo group will be carried out in SAS using the full 
conditional specification method (FCS) with a regression model approach.[5] Since the 
method assumes the missing data are missing at random (MAR), the result will be that 
patients will have imputed values that are similar to other patients at that site with 
similar baseline and post-baseline pain scores. The method then repeats the operation 
multiple times to iterate to a stable solution. The algorithm will use 20 burn-in 
iterations before each imputation. The variables included sequentially in the model are 
sex, centre, baseline pain, and then the post-baseline pain. A minimum of 1000 
imputed datasets will be created for the analysis. 
ii. 
The imputation of missing values for treated patients in each individual active 
treatment group assumes the data after withdrawal are missing not at random 
(MNAR) while intermittent missing data up to discontinuation from the study are 
MAR. This imputation process will proceed in a multi-stage fashion. The first stage 
will be to impute only intermittent missing values for the treated patients assuming 
the intermittent missing values are MAR. The second stage will impute missing 
monotone post-withdrawal in a sequential manner using a method proposed by 
Ratitch and O’Kelly.[6] During the second stage, at each timepoint with missing data 
on treated patients, PROC MI will be used with a dataset that contains complete data 
for all placebo patients (observed and imputed under MAR) and the treated patients 
with missing data at that time point. Therefore, the imputation model will be fit based 


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solely on placebo patients and the treated patients will have values imputed as if they 
were placebo patients. The first stage to impute the intermittent missing values will 
proceed as described for the imputation of missing data in the placebo arm using a 
FCS method with a regression model. The algorithm will use 20 burn-in iterations 
before each imputation. The variables included sequentially in the model are sex, 
centre, baseline pain score and then the post-baseline pain scores. A minimum of 
1000 imputed datasets (the number of datasets will match the number of imputed 
datasets for the placebo arm) will be created for the analysis. The post-withdrawal 
values in each of the imputed datasets for the imputed arm will then be set to missing, 
thus leaving a dataset with multiply imputed values and monotone missing data 
patterns due to early termination. The second stage of the imputation procedure will 
handle the MNAR imputation for the monotone missing post-withdrawal data in the 
treated patients. A dataset will then be created with all placebo patients including their 
observed and imputed data. Treated patients will have all post-withdrawal/post-
treatment pain scores set to missing. These groups will then be combined. The second 
stage imputation will be done sequentially by timepoint for each first stage 
imputation. 
iii. 
The analysis model will be an analysis of covariance (ANCOVA) with SPID-48 
(calculated from the imputed data) as the dependent variable, treatment and centre as 
categorical variables and baseline pain as a covariate. The causal estimand will be 
estimated using the difference in the least squares means between the co-crystal 
E-58425 group and the other treatment groups. The ANCOVA results from the 
multiply imputed datasets will be combined using the usual Rubin’s rules for multiple 
imputation[7] (Little and Rubin, 1987) and will be done in SAS using PROC 
MIANALYZE. A significance test of the treatment difference will be tested at the 
two-sided 0.05 level and corresponding 95% confidence intervals will be calculated. 
8.2 Secondary Efficacy Variable Analysis 
No formal statistical inferences will be drawn from secondary efficacy analyses. Any 
P values presented from secondary efficacy analyses will be interpreted in an exploratory 
sense only. 
The following efficacy variables will be analysed in the same manner as the primary analysis, 
but without any sensitivity analyses: 
 SPID-4 
 SPID-6 
 SPID-12 
 SPID-24 
 PID at 4, 6, 12, 24 and 48 hours 
 TOTPAR-4 
 TOTPAR-6 
 TOTPAR-12 
 TOTPAR-24 
 TOTPAR-48 


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 PAR at 4, 6, 12, 24 and 48 hours 
PID at each timepoint and PAR at each timepoint will also be analysed in a mixed model for 
repeated measures (MMRM) ANCOVA analysis. For each variable (PID and PAR), all post-
baseline timepoints will be included in the analysis as dependent variables (except those 
where the time of measurement deviated from the nominal time by more than acceptable 
windows: see section 6.2.1). The model will include treatment, timepoint, treatment by 
timepoint interaction, centre, and baseline as fixed effects, and subject as a random effect. An 
unstructured covariance matrix will be used to model the within-subject correlations by 
timepoint. If the model fails to converge, alternative covariance structures, such as compound 
symmetry, will be tried instead. The model will be used to show estimated treatment effects 
at each timepoint, together with their 95% confidence intervals and P values, for the 
comparison of co-crystal E-58425 against each comparator. 
Peak pain relief will be compared between the treatment groups using an ANCOVA model, 
adjusting for centre and baseline pain. The estimated difference in peak pain relief will be 
presented for co-crystal E-58425 versus each other treatment group, together with its 95% 
confidence interval and P value. 
The following binary variables will be compared between the treatment groups using logistic 
regression, adjusting for centre and baseline pain. The odds ratio for response (or rescue 
medication use) will be presented for co-crystal E-58425 versus each other treatment group, 
together with its 95% confidence interval and P value. 
 Responder (50%) 
 Responder (30%) 
 Responder (score of 4 or less) 
 Responder (score of 4 or less and 50%) 
 Responder (score of 4 or less and 30%) 
 Whether subjects used any rescue medication at any time (yes or no, and by type 
of rescue medication) 
 Whether subjects used any rescue medication in the first 4 hours after dosing (yes 
or no, and by type of rescue medication) 
 Whether subjects used any rescue medication in the first 6 hours after dosing (yes 
or no, and by type of rescue medication) 
 Whether subjects used any rescue medication in the first 12 hours after dosing 
(yes or no, and by type of rescue medication) 
 Whether subjects used any rescue medication in the first 24 hours after dosing 
(yes or no, and by type of rescue medication) 
The number of doses of each kind of rescue medication taken will also be presented with 
descriptive statistics. In addition, the number of doses of rescue medication taken (ignoring 
which kind of rescue medication is used) will be compared between the treatment groups 
using ordinal logistic regression. The model will be used to estimate odds ratios together with 
their 95% confidence intervals for the comparison of co-crystal E-58425 versus each of the 
comparators. If some patients take large number of doses, numbers of doses of rescue 
medication may be combined into categories for the purpose of that analysis; this will be 
decided at the blinded data review meeting. 


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As a sensitivity analysis, the analyses of responders will be repeated for a definition which 
does not include the obligation to have a sustained response up to 48 hours. 
Response will be plotted graphically by showing the cumulative proportion of responders 
over time for each treatment group. Separate graphs will be produced for each of the 5 
definitions of response (but without the sensitivity analysis mentioned above). 
The patients global assessment of study medication will be presented by tabulating the 
number and percentage of patients in each category by treatment group. The global 
assessment will also be compared between treatment groups using ordinal logistic regression. 
The model will be used to estimate odds ratios together with their 95% confidence intervals 
for the comparison of co-crystal E-58425 versus each of the comparators. 
The following time-to-event variables will be compared between the treatment groups using 
Cox proportional hazards regression, adjusting for centre and baseline pain. The hazard ratio 
for response (or rescue medication use) will be presented for co-crystal E-58425 versus each 
other treatment group, together with its 95% confidence interval and P value. The median and 
first and third quartiles of the time to event will also be estimated, together with their 95% 
confidence intervals, and the times to event will be shown graphically with Kaplan-Meier 
graphs. 
 TTOA 
 Time to perceptible pain relief 
 Time to meaningful pain relief 
 Time to onset of pain intensity decrease 
 TTPPR 
 Time to response (50%) 
 Time to response (30%) 
 Time to response (score of 4 or less) 
 Time to response (score of 4 or less and 50%) 
 Time to response (score of 4 or less and 30%) 
 Time to first use of rescue medication 
Calculation of TTOA and TTPPR are described in Section 6.3. Time to perceptible and 
meaningful pain relief are recorded directly in the CRF, and will be censored at 8 h (even in 
the case of early dropout) if a time is not recorded, and will be censored at the time of the 
first rescue medication dose if rescue medication is taken before pain relief is recorded or 
before 8 h, whichever is the earlier. Time to response is the time at which the definition of 
response is first met, or if it is not met, it is censored at 48 hours (even in the case of early 
dropout). Time to first use of rescue medication is also censored at 48 hours or at the time of 
early dropout (or the time of the second randomisation for subjects who are never dosed with 
study medication) for subjects who do not take rescue medication. The start time for those 
time to event variables will be the time of the first dose of study medication, or the time of 
the second randomisation in the case of any patients who undergo both randomisation steps 
but are not dosed with study medication. 
The raw NPRS scores, the change from baseline in NPRS, and the raw pain relief scores at 
each timepoint will be presented with descriptive statistics and graphs. 


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8.3 Subgroup Analysis of Efficacy Variables 
For assessing consistency of efficacy results, the primary and key secondary efficacy 
analyses will be repeated separately for subgroups of subjects defined by: 
 moderate (NPRS = 5 or 6) or severe (NPRS = 7, 8 or 9) baseline pain 
 age => 65 years vs. < 65 years old 
 gender 
 race (if some categories have only few patients, they may be combined into an 
“other” group for this analysis: this will be determined at the blinded data review 
meeting) 
 centre 
For all of these subgroups, primary and key secondary endpoint analysis models will be 
repeated, including subgroup and subgroup*treatment interaction as fixed effects. These 
statistical models will be used to calculate least squares mean estimates for the treatment 
differences or odds ratios, as appropriate, the corresponding two-sided 95% confidence 
intervals and p-values from 2-sided test on no difference between co-crystal E-58425 and 
each of the comparators in each level of the defined subgroup. P-value from the interaction 
test will also be presented. Results will further be illustrated using Forest Plots. 


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9. SAFETY AND TOLERABILITY ANALYSIS 
The analysis of safety assessments in this study will include summaries of the following 
categories of safety and tolerability data collected for each subject: 
 Adverse events 
 Adverse events (AEs), treatment-emergent AEs (TEAEs), and serious adverse 
events (SAEs) 
 AEs leading to withdrawal 
 Any deaths 
 Clinical laboratory test results (chemistry, haematology, urinalysis) 
 Vital signs (blood pressure, heart rate, respiratory rate, body temperature) 
 Electrocardiogram variables (ECG) 
 Concomitant medications 
 Study medication exposure 
All safety analyses will use the safety analysis set. 
9.1 Adverse Events 
All AEs, TEAEs, and SAEs will be coded using the MedDRA dictionary (the most recent 
version before starting the trial will be used).  
An AE is defined as treatment emergent if the first onset or worsening is after the first 
administration of study medication and not more than 7 days after the last administration of 
study medication. 
If the start date and time of an AE are partially or completely missing, the AE will be 
assumed to be treatment-emergent if it cannot be definitely shown that the AE did not occur 
or worsen during the treatment-emergent period (worst case approach). Missing dates and 
times will not be replaced.  
The following are used for guidance for programmers. 
 If the start time of an AE is missing, but the start date is complete, an AE will only 
be excluded from TEAEs if the start day is before the day of first dose of study 
medication or the start day is after the last day of the treatment-emergent period. 
 If the start time and day are missing but the start month is complete, an AE will 
only be excluded from TEAEs if the start month is before the month of the first 
dose of study medication, or the start month is after last month of the treatment-
emergent period, or if the stop date/time is before the first dose of study 
medication. 
 If the start day and months are missing but the start year is complete, an AE will 
only be excluded from TEAEs if the start year is before the year of the first dose 
of study medication, or if the start year is after the last year of the treatment-
emergent period, or if the stop date/time is before the first dose of study 
medication. 
If the start date is completely missing, an AE will not be excluded from TEAEs unless the 
stop date/time is before the first dose of study medication. 


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All AEs will be summarized in a table whose rows give the number and percentage of 
subjects reporting at least one AE and the number of reported AEs for each of the following: 
 Any AE 
 Any TEAE  
 Any serious TEAE 
 Any drug-related serious TEAE 
 Any serious TEAE leading to death 
 Any drug-related TEAE 
 Any severe TEAE 
 Any TEAE requiring additional therapy 
 Any TEAEs leading to discontinuation of study medication 
 Any TEAEs of special interest 
Summaries of incidence rates (frequencies and percentages of subjects reporting at least one 
AE) and the number of reported AEs of individual TEAEs by MedDRA SOC and preferred 
term will be prepared. Such summaries will be displayed for all TEAEs, TEAEs by maximum 
intensity, and TEAEs by strongest relationship to study medication. 
Each subject will be counted only once within each preferred term. If a subject experiences 
more than 1 TEAE within a preferred term, only the TEAE with the strongest relationship or 
the maximum intensity, as appropriate, will be included in the summaries of relationship and 
intensity.  
The most frequent TEAEs, defined as PTs reported in more than 5% of subjects in any 
treatment group will also be summarised. 
The proportion of patients reporting at least one TEAE will be compared pairwise between  
co-crystal E-58425 and each of the comparators using logistic regression, adjusting for 
centre. The adjusted odds ratio for the treatment effect will be presented together with its 
95% confidence interval, as well as the corresponding P value. The same statistical test will 
be used for the comparison between pairwise treatment groups of the proportion of patients 
reporting at least one TEAEs leading to withdrawal of study medication, at least one SAEs, 
and at least one TEAE of special interest, described in the following sections.  
In the AE data listings, all AEs will be displayed. Adverse events that are not treatment-
emergent will be flagged. 
9.1.1 Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages of subjects) and number of 
episodes of TEAEs leading to withdrawal of study medication, by treatment group, SOC, and 
preferred term, will be prepared. 
A data listing of AEs leading to withdrawal of study medication will also be provided, 
displaying details of the event(s) captured on the CRF. 
9.1.2 Serious Adverse Events 
A summary of incidence rates (frequencies and percentages of subjects) and number of 
episodes of SAEs by treatment group, SOC, and preferred term will be prepared.  


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A data listing of SAEs will also be provided, displaying details of the event(s) captured on 
the CRF.  
9.1.3 TEAEs of special interest 
As specified in the protocol, TEAEs of special interest include the following: 
 Common AEs observed with tramadol: dizziness, vertigo, nausea, constipation, 
headache, and somnolence 
 Common AEs observed with opioids: fatigue, inability to concentrate, itching, 
difficulty with urination, confusion, dry mouth, and vomiting 
A summary of incidence rates (frequencies and percentages of subjects) and number of 
episodes of TEAEs of special interest, by treatment group, SOC, and preferred term, will be 
prepared. 
Additional summaries will be provided on TEAEs from each of the following classes: 
 Nausea and vomiting 
 Central nervous system depression such as somnolence, sedation, 
disorientation/confusion and dizziness. 
These lists of preferred terms considered to be of special interest will be checked at the 
blinded data review meeting, which will be held before database lock. 
9.2 Clinical Laboratory Test Results 
Descriptive summaries of absolute values and changes from baseline values will be presented 
for clinical chemistry and haematology tests by treatment and timepoint. 
The number of subjects with clinical laboratory values (chemistry, haematology, and 
urinalysis) categorised as below, within, or above normal ranges (or as either normal or 
abnormal for urinalysis variables that do not have quantitative ranges) and whether they are 
clinically significant or not will be tabulated for each clinical laboratory analyte by treatment 
group and time. 
The number of subjects with clinical laboratory values (chemistry, haematology, and 
urinalysis) categorized as below, within, or above normal ranges (or as either normal or 
abnormal for urinalysis variables that do not have quantitative ranges), will be tabulated 
showing change from baseline (shift tables) for each clinical laboratory analyte by treatment 
group and by time.  
Laboratory values will be displayed in the data listings and those that are outside the normal 
range will be flagged, along with corresponding normal ranges 
9.3 Vital Signs 
Descriptive summaries of absolute values and changes from baseline will be calculated for 
systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), temperature, 
and respiratory rate (RR). These summaries will be presented by treatment and timepoint.  
Summaries of whether vital signs are below, within, or above the normal ranges, and whether 
results are clinically significant, will also be presented by treatment and timepoint. 
Shift tables will be presented for vital signs by treatment and timepoint, showing the number 
of vital sign measurements below, within, or above the normal ranges, and whether any 


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abnormalities are clinically significant. Normal ranges for vital signs are defined in the table 
below (Table 3). 
Table 3: Normal ranges for vital signs 
Vital signs: 
Normal Ranges 
Temperature 
35–37.5ºC 
Respiratory Rate 
12–20 bpm 
Pulse Rate 
40–100 bpm 
Systolic Blood Pressure (Supine) 
80–140 mmHg 
Diastolic Blood Pressure (Supine) 
40–90 mmHg 
 
9.4 ECGs 
Descriptive summaries of absolute values will be presented for ECG measures of PR interval, 
QRS interval, QT interval, QTC interval (as reported by the ECG machine), and HR. These 
summaries will be presented by treatment and timepoint. Summaries of the investigator’s 
overall interpretation will also be presented by treatment and timepoint. 
Summaries of whether ECG are below, within, or above the normal ranges, and whether 
results are clinically significant, will also be presented by treatment and timepoint. 
Shift tables will be presented for ECG variables by treatment and timepoint, showing the 
number of ECG measurements below, within, or above the normal ranges, and whether any 
abnormalities are clinically significant. Normal ranges for ECG variables are shown in the 
table below. 
Table 4: Normal ranges for ECG 
Electrocardiogram (ECG):  
Normal Ranges 
Ventricular Rate (Supine) 
40–100 bpm 
PR interval 
120–200 ms 
QRS duration 
70–120 ms 
QT 
350–450 ms 
QTC 
350–450 ms 
 
9.5 Concomitant Medication 
Concomitant medications will be analysed in the same way as prior medications. 
A concomitant medication is defined as any medication that was administered during the 
treatment period, with the exception of the protocol-specified treatment and rescue 
medication. This includes medications that started before the Treatment Period and continued 


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while on treatment (which may have been recorded in the prior medications log) and 
medications that started during the Treatment Period. The frequency and percentage of 
patients taking each concomitant medications will be summarized by ATC class 3 and 
preferred term for all subjects in the safety set, by treatment group. Moreover a table 
summarizing the patients who take antiemetic concomitant medication will be produced. 
If the start/stop dates of a medication are partially or completely missing, then the medication 
will be assumed to be concomitant if it cannot be definitely shown that it was not 
administered during the treatment period. Missing dates will not be replaced.  
Thus, the following approach will be taken for exclusion from concomitant medications 
because of discontinuation before start of treatment: 
 If the stop day is missing but the month is complete, then the medication will be 
excluded from concomitant medications only if the stop month is before the 
month of the first dose of study medication. 
 If the stop day and month are missing but the year is complete, then the 
medication will be excluded from concomitant medications only if the stop year is 
before the year of the first dose of study medication. 
 If the stop date is completely missing, then the medication will not be excluded. 
For concomitant medication exclusion (because of the late start after the end of the Treatment 
Period): 
 If the start day is missing but the month is complete, then the medication will be 
excluded from concomitant medications only if the start month is after the last 
month of the treatment period. 
 If the start day and month are missing but the year is complete, then the 
medication will be excluded from concomitant medications only if the start year is 
after the year of the treatment period. 
 If the start date is completely missing, then the medication will not be excluded. 
9.6 Exposure and Compliance 
Investigational product administration will be summarized in terms of the number of doses 
received, and in terms of duration of exposure, from first dose to last dose of the study 
treatment. Descriptive statistics for these quantities, including the mean, median, SD, 
minimum, maximum, and quartiles, will be provided by treatment group. 
Compliance will be calculated as the number of doses the subject actually received as a 
percentage of the number of doses the subject would have received if the study were 
completed. 


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10. CHANGES FROM PLANNED ANALYSIS 
No changes from the analyses specified in the protocol are planned. 


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11. OTHER PLANNED ANALYSIS 
No other analyses are planned for this study. 


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12. REFERENCES 
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: 
Food and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, 
Number 179, pages 49583-49598. September 16, 1998. 
2. ASA. (1999) Ethical Guidelines for Statistical Practice. Prepared by the Committee 
on Professional Ethics, August 7, 1999. 
http://www.amstat.org/about/ethicalguidelines.cfm 
3. RSS. (1993) The Royal Statistical Society: Code of Conduct, April 1993. 
http://www.rss.org.uk/main.asp?page=1875. 
4. Friede T, Kieser M, 2013. Blinded sample size re‐estimation in superiority and 
noninferiority trials: bias versus variance in variance estimation. Pharmaceutical 
statistics, 12(3), pp.141-146. 
5. Carpenter, J. R., and Kenward, M. G. (2013), Multiple Imputation and its Application 
(Statistics in Practice), Wiley. 
6. Ratitich, B. and O’Kelly, M. (2011), “Implementation of Pattern-Mixture Models 
Using Standard SAS/STAT Procedures,” PharmaSUG.  Available at 
http://www.pharmasug.org/proceedings/2011/SP/PharmaSUG-2011-SP04.pdf 
7. Little, R. and Rubin, D. (1987), Statistical Analysis with Missing Data, New York: 
Wiley. 
 


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13. TABLES, LISTINGS, AND FIGURES 
The description of the planned tables, listings and figures will be provided in this section in 
the next version of this SAP 
13.1 Planned Table Descriptions 
The following are planned summary tables for the study. The numbering is intended to be 
compatible with the format of clinical study reports as per ICH E3 (ICH, 1995), so tables are 
included in section 14 of the report. 
Tables will be split according to population adding an additional table extension digit, e.g. 
Table 14.1.2.1 will split into 14.1.2.1.1 (FAS), 14.1.2.1.2 (PPAS), 14.1.2.1.3 (CAS), and 
14.1.2.4 (SAS). 
Table 
Number 
Population(s) 
Table Title / Summary 
Supporting 
listing 
14.1 Demographic and baseline tables 
14.1.1 
ALL 
Analysis populations  
16.2.1.1 
14.1.2 
ALL 
Analysis populations by centre 
16.2.1.1 
14.1.3 
ALL 
Disposition of patients 
16.2.1.2 
14.1.4 
ALL 
Disposition of patients by centre 
16.2.1.2 
14.1.5 
All patients not fully 
randomised 
Summary of reasons for screening failure 
16.2.2.2 
14.1.6 
FAS 
Summary of reasons for discontinuation of study 
medication 
16.2.1.3 
14.1.7 
FAS 
Summary of reasons for withdrawal 
16.2.1.3 
14.1.8 
FAS 
Summary of major protocol violations 
16.2.2.1 
14.1.9 
FAS 
Summary of demographic data: age, body weight, 
height, and BMI 
16.2.4.1 
14.1.10 
FAS 
Summary of demographic data: sex, ethnicity, and race 
16.2.4.1 
14.1.11 
FAS 
Medical history by SOC and preferred term 
16.2.4.2 
14.1.12 
FAS 
Prior medication by ATC level 3 and preferred term 
16.2.4.3 
14.1.13 
FAS 
ASA classification 
16.2.4.4 
14.1.14 
FAS 
X-ray and podiatric examination 
16.2.4.5 
14.1.15 
FAS 
Duration of bunionectomy procedure 
16.2.4.6 
14.2 Efficacy tables 
14.2.1 
FAS, PPAS, CAS 
SPID-48: summary statistics 
16.2.6.2 
14.2.2 
FAS, PPAS, CAS 
SPID-48: primary ANCOVA analysis 
16.2.6.2 
14.2.3.1 
FAS, PPAS 
SPID-48: sensitivity analysis 1 (WOCF for dropouts due 
to AEs or lack of efficacy) 
16.2.6.2 
14.2.3.2 
FAS, PPAS 
SPID-48: sensitivity analysis 2 (WOCF imputation for 
all missing data) 
16.2.6.2 
14.2.3.3 
FAS, PPAS 
SPID-48: sensitivity analysis 3 (no imputation for rescue 
medication use) 
16.2.6.2 


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Table 
Number 
Population(s) 
Table Title / Summary 
Supporting 
listing 
14.2.3.4 
FAS, PPAS 
SPID-48: sensitivity analysis 4 (adjusted analysis for 
rescue medication) 
16.2.6.2 
14.2.3.5 
FAS, PPAS 
SPID-48: sensitivity analysis 5 (multiple imputation) 
16.2.6.2 
14.2.4.1 
FAS 
SPID-48: subgroup analysis by baseline pain, summary 
statistics 
16.2.6.2 
14.2.4.2 
FAS 
SPID-48: subgroup analysis by baseline pain, ANCOVA 
analysis 
16.2.6.2 
14.2.4.3 
FAS 
SPID-48: subgroup analysis by age, summary statistics 
16.2.6.2 
14.2.4.4 
FAS 
SPID-48: subgroup analysis by age, ANCOVA analysis 16.2.6.2 
14.2.4.5 
FAS 
SPID-48: subgroup analysis by sex, summary statistics 
16.2.6.2 
14.2.4.6 
FAS 
SPID-48: subgroup analysis by sex, ANCOVA analysis 
16.2.6.2 
14.2.4.7 
FAS 
SPID-48: subgroup analysis by race, summary statistics 
16.2.6.2 
14.2.4.8 
FAS 
SPID-48: subgroup analysis by race, ANCOVA analysis 16.2.6.2 
14.2.4.9 
FAS 
SPID-48: subgroup analysis by centre, summary 
statistics 
16.2.6.2 
14.2.4.10 
FAS 
SPID-48: subgroup analysis by centre, ANCOVA 
analysis 
16.2.6.2 
14.2.5.1 
FAS 
SPID by timepoint: summary statistics 
16.2.6.2 
14.2.5.2 
FAS 
SPID by timepoint: ANCOVA analysis 
16.2.6.2 
14.2.6.1 
FAS 
TOTPAR by timepoint: summary statistics 
16.2.6.4 
14.2.6.2 
FAS 
TOTPAR by timepoint: ANCOVA analysis 
16.2.6.4 
14.2.7.1 
FAS 
TOTPAR-48: subgroup analysis by baseline pain, 
summary statistics 
16.2.6.4 
14.2.7.2 
FAS 
TOTPAR-48: subgroup analysis by baseline pain, 
ANCOVA analysis 
16.2.6.4 
14.2.7.3 
FAS 
TOTPAR-48: subgroup analysis by age, summary 
statistics 
16.2.6.4 
14.2.7.4 
FAS 
TOTPAR-48: subgroup analysis by age, ANCOVA 
analysis 
16.2.6.4 
14.2.7.5 
FAS 
TOTPAR-48: subgroup analysis by sex, summary 
statistics 
16.2.6.4 
14.2.7.6 
FAS 
TOTPAR-48: subgroup analysis by sex, ANCOVA 
analysis 
16.2.6.4 
14.2.7.7 
FAS 
TOTPAR-48: subgroup analysis by race, summary 
statistics 
16.2.6.4 
14.2.7.8 
FAS 
TOTPAR-48: subgroup analysis by race, ANCOVA 
analysis 
16.2.6.4 
14.2.7.9 
FAS 
TOTPAR-48: subgroup analysis by centre, summary 
statistics 
16.2.6.4 
14.2.7.10 
FAS 
TOTPAR-48: subgroup analysis by centre, ANCOVA 
analysis 
16.2.6.4 


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Table 
Number 
Population(s) 
Table Title / Summary 
Supporting 
listing 
14.2.8.1 
FAS 
Pain intensity and pain intensity difference by timepoint: 
summary statistics 
16.2.6.1 
14.2.8.2 
FAS 
Pain intensity difference by timepoint: ANCOVA 
analysis 
16.2.6.1 
14.2.8.3 
FAS 
Pain intensity difference by timepoint: MMRM analysis 16.2.6.1 
14.2.9.1 
FAS 
Pain relief by timepoint: summary statistics 
16.2.6.3 
14.2.9.2 
FAS 
Pain relief by timepoint: ANCOVA analysis 
16.2.6.3 
14.2.9.3 
FAS 
Pain relief by timepoint: MMRM analysis 
16.2.6.3 
14.2.10.1 
FAS 
Peak pain relief: summary statistics 
16.2.6.5 
14.2.10.2 
FAS 
Peak pain relief: ANCOVA analysis 
16.2.6.5 
14.2.11.1 
FAS 
Peak pain relief: subgroup analysis by baseline pain, 
summary statistics 
16.2.6.5 
14.2.11.2 
FAS 
Peak pain relief: subgroup analysis by baseline pain, 
ANCOVA analysis 
16.2.6.5 
14.2.11.3 
FAS 
Peak pain relief: subgroup analysis by age, summary 
statistics 
16.2.6.5 
14.2.11.4 
FAS 
Peak pain relief: subgroup analysis by age, ANCOVA 
analysis 
16.2.6.5 
14.2.11.5 
FAS 
Peak pain relief: subgroup analysis by sex, summary 
statistics 
16.2.6.5 
14.2.11.6 
FAS 
Peak pain relief: subgroup analysis by sex, ANCOVA 
analysis 
16.2.6.5 
14.2.11.7 
FAS 
Peak pain relief: subgroup analysis by race, summary 
statistics 
16.2.6.5 
14.2.11.8 
FAS 
Peak pain relief: subgroup analysis by race, ANCOVA 
analysis 
16.2.6.5 
14.2.11.9 
FAS 
Peak pain relief: subgroup analysis by centre, summary 
statistics 
16.2.6.5 
14.2.11.10 FAS 
Peak pain relief: subgroup analysis by centre, ANCOVA 
analysis 
16.2.6.5 
14.2.12 
FAS 
Responder analysis 
16.2.6.6 
14.2.13 
FAS 
Rescue medication use 
16.2.6.10 
14.2.14.1 
FAS 
Number of doses of rescue mediation: summary 
statistics 
16.2.6.11 
14.2.14.2 
FAS 
Number of doses of rescue medication: ordinal logistic 
regression analysis 
16.2.6.11 
14.2.15.1 
FAS 
Time to onset of analgesia, onset of pain intensity 
decrease, and peak pain relief: quartiles of distribution 
16.2.6.7 
14.2.15.2 
FAS 
Time to onset of analgesia, onset of pain intensity 
decrease, and peak pain relief: Cox regression analysis 
16.2.6.7 
14.2.16.1 
FAS 
Time to response: quartiles of distribution 
16.2.6.8 
14.2.16.2 
FAS 
Time to response: Cox regression analysis 
16.2.6.8 


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Table 
Number 
Population(s) 
Table Title / Summary 
Supporting 
listing 
14.2.17.1 
FAS 
Time to first use of rescue medication: quartiles of 
distribution 
16.2.6.12 
14.2.17.2 
FAS 
Time to first use of rescue medication: Cox regression 
analysis 
16.2.6.12  
14.2.17.3 
FAS 
Patient global evaluation of study drug: summary 
statistics 
16.2.6.13 
14.2.17.4 
FAS 
Patient global evaluation of study drug: ordinal logistic 
regression 
16.2.6.13 
14.3 Safety and tolerability tables 
14.3.1 Displays of adverse events 
14.3.1.1 
SAS 
Summary of all Aes 
16.2.7.1 
14.3.1.2 
SAS 
TEAEs by SOC and preferred term 
16.2.7.1 
14.3.1.3 
SAS 
TEAEs by severity 
16.2.7.1 
14.3.1.4 
SAS 
TEAEs by relationship to study medication 
16.2.7.1 
14.3.2 Displays of serious and other significant adverse events 
14.3.2.1 
SAS 
SAEs by SOC and preferred term 
16.2.7.2 
14.3.2.2 
SAS 
Aes leading to withdrawal from the study by SOC and 
preferred term 
16.2.7.3 
14.3.2.3 
SAS 
TEAEs of special interest by SOC and preferred term 
16.2.7.4 
14.3.2.4 
SAS 
Summary of TEAEs of nausea and vomiting 
16.2.7.4 
14.3.2.5 
SAS 
Summary of TEAEs of central nervous system 
depression 
16.2.7.4 
14.3.3 Laboratory data tables 
14.3.3.1 
SAS 
Clinical chemistry results: absolute values 
16.2.8.1 
14.3.3.2 
SAS 
Clinical chemistry results: change from baseline 
16.2.8.1 
14.3.3.3 
SAS 
Clinical chemistry results: normal range indicators and 
clinical significance by time 
16.2.8.1 
14.3.3.4 
SAS 
Shift tables of clinical chemistry results 
16.2.8.1 
14.3.3.5 
SAS 
Haematology results: absolute values 
16.2.8.2 
14.3.3.6 
SAS 
Haematology results: change from baseline 
16.2.8.2 
14.3.3.7 
SAS 
Haematology results: normal range indicators and 
clinical significance by time 
16.2.8.2 
14.3.3.8 
SAS 
Shift tables of haematology results 
16.2.8.2 
14.3.3.9 
SAS 
Urinalysis results: normal range indicators and clinical 
significance by time 
16.2.8.3 
14.3.3.10 
SAS 
Shift tables of urinalysis results 
16.2.8.3 
14.3.4 Other safety and tolerability tables 
14.3.4.1 
SAS 
Vital signs results: absolute values 
16.2.9.2 


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Table 
Number 
Population(s) 
Table Title / Summary 
Supporting 
listing 
14.3.4.2 
SAS 
Vital signs results: change from baseline 
16.2.9.2 
14.3.4.3 
SAS 
Vital signs results: normal range indicators and clinical 
significance 
16.2.6.2 
14.3.4.4 
SAS 
Shift tables of vital signs results 
16.2.9.2 
14.3.4.5 
SAS 
ECG results: absolute values 
16.2.9.3 
14.3.4.6 
SAS 
ECG results: change from baseline 
16.2.9.3 
14.3.4.7 
SAS 
ECG results: normal range indicators and clinical 
significance 
16.2.9.3 
14.3.4.8 
SAS 
ECG results: investigator’s overall interpretation 
16.2.9.3 
14.3.4.9 
SAS 
Shift tables of ECG results 
16.2.9.3 
14.3.4.10 
SAS 
Summary of concomitant medications by ATC level 3 
and preferred term 
16.2.9.4 
14.3.4.11 
SAS 
Summary of antiemetic medications by preferred term 
16.2.9.4 
14.3.4.12 
SAS 
Summary of exposure and compliance 
16.2.5.2 
 
13.2 Planned Listing Descriptions 
The following are planned data and patient data listings for the study. The numbering is 
intended to be compatible with the format of CSRs as per ICH E3 (ICH, 1995), so listings are 
included in section 16.2 of the report. 
Data Listing 
Number 
Population 
Data Listing Title / Summary 
16.2.1 Patient disposition 
16.2.1.1 
All patients 
Assignment to analysis populations and treatment group 
16.2.1.2 
All patients 
Study completion status 
16.2.1.3 
FAS 
List of reasons for discontinuation of study medication and withdrawal from 
the study 
16.2.1.4 
All patients 
List of visit dates 
16.2.2 Protocol deviations 
16.2.2.1 
All patients 
List of all protocol violations 
16.2.2.2 
All patients 
List of violations of inclusion or exclusion criteria 
16.2.3 Patients excluded from the efficacy analysis 
16.2.3.1 
All patients 
List of patients excluded from the FAS, PPAS, or CAS analysis sets, with 
reasons for exclusion 
16.2.4 Demographic and other baseline characteristics 
16.2.4.1 
FAS 
Demographic data 
16.2.4.2 
FAS 
Medical history 


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Data Listing 
Number 
Population 
Data Listing Title / Summary 
16.2.4.3 
FAS 
Prior medications 
16.2.4.4 
FAS 
ASA classification 
16.2.4.5 
FAS 
X-ray and podiatric examination 
16.2.4.6 
FAS 
Bunionectomy procedure details 
16.2.5 Drug compliance listings 
16.2.5.1 
FAS 
Drug administration data – individual doses 
16.2.5.2 
FAS 
Drug administration data – calculated variables on overall treatment period 
16.2.6 Individual efficacy listings 
16.2.6.1 
FAS 
Pain intensity and pain intensity difference at each timepoint 
16.2.6.2 
FAS 
Sum of pain intensity differences 
16.2.6.3 
FAS 
Pain relief at each timepoint 
16.2.6.4 
FAS 
TOTPAR scores 
16.2.6.5 
FAS 
Peak pain relief 
16.2.6.6 
FAS 
Response classification 
16.2.6.7 
FAS 
Time to onset of analgesia, onset of pain intensity decrease, and peak pain 
relief 
16.2.6.8 
FAS 
Time to response 
16.2.6.9 
FAS 
List of rescue medication 
16.2.6.10 
FAS 
Rescue medication use by time period 
16.2.6.11 
FAS 
Number of doses of rescue medication used 
16.2.6.12 
FAS 
Time to first use of rescue medication 
16.2.6.13 
FAS 
Patient global evaluation of study drug 
16.2.7 Adverse event listings 
16.2.7.1 
SAS 
Listing of all AEs 
16.2.7.2 
SAS 
Listing of SAEs 
16.2.7.3 
SAS 
Listing of AEs leading to withdrawal 
16.2.7.4 
SAS 
Listing of TEAEs of special interest 
16.2.8 Laboratory data listings 
16.2.8.1 
SAS 
Clinical chemistry results 
16.2.8.2 
SAS 
Hematology results 
16.2.8.3 
SAS 
Urinalysis results 
16.2.9 Listings of other clinical observations and measurements 
16.2.9.1 
SAS 
Vital signs results 
16.2.9.2 
SAS 
ECG results 
16.2.9.3 
SAS 
Concomitant medications 


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13.3 Planned Figure Descriptions 
The following are planned summary figures for the study. Figures will numbered according 
to the ICH E3 guidelines CSRs (ICH, 1993), and so will be included in section 14, after the 
tables. 
Figure 
Number 
Population 
Figure Title / Summary 
Supporting 
table or 
listing 
14.4 Efficacy figures 
14.4.1 
FAS 
Pain intensity by timepoint and treatment 
14.2.8.1 
14.4.2 
FAS 
Pain intensity difference by timepoint and treatment 
14.2.8.1 
14.4.3 
FAS 
Pain relief by timepoint and treatment 
14.2.9.1 
14.4.4 
FAS 
Kaplan–Meier graph of TTOA by treatment 
16.2.6.7 
14.4.5 
FAS 
Kaplan–Meier graph of time to perceptible pain relief by treatment 
16.2.6.7 
14.4.6 
FAS 
Kaplan–Meier graph of time to meaningful pain relief by treatment 
16.2.6.7 
14.4.7 
FAS 
Kaplan–Meier graph of time to onset of pain intensity decrease by 
treatment 
16.2.6.7 
14.4.8 
FAS 
Kaplan–Meier graph of TTPPR by treatment 
16.2.6.7 
14.4.9 
FAS 
Kaplan–Meier graph of time to response (50%) by treatment 
16.2.6.8 
14.4.10 
FAS 
Kaplan–Meier graph of time to response (30%) by treatment 
16.2.6.8 
14.4.11 
FAS 
Kaplan–Meier graph of time to response (score of 4 or less) by 
treatment 
16.2.6.8 
14.4.12 
FAS 
Kaplan–Meier graph of time to response (score of 4 or less and 50%) 
by treatment 
16.2.6.8 
14.4.13 
FAS 
Kaplan–Meier graph of time to response (score of 4 or less and 30%) 
by treatment 
16.2.6.8 
14.4.14 
FAS 
Kaplan–Meier graph of time to first use of rescue medication by 
treatment 
16.2.6.12 
14.4.15 
FAS 
Cumulative proportion of response (50%) by treatment 
16.2.6.8 
14.4.16 
FAS 
Cumulative proportion of response (30%) by treatment 
16.2.6.8 
14.4.17 
FAS 
Cumulative proportion of response (score of 4 or less) by treatment 
16.2.6.8 
14.4.18 
FAS 
Cumulative proportion of response (score of 4 or less and 50%) by 
treatment 
16.2.6.8 
14.4.19 
FAS 
Cumulative proportion of response (score of 4 or less and 30%) by 
treatment 
16.2.6.8 
14.4.20 
FAS 
Forest plot of subgroup analyses of SPID-48 
14.2.4.1, 
14.2.4.3, 
14.2.4.5. 
14.2.4.7 


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Figure 
Number 
Population 
Figure Title / Summary 
Supporting 
table or 
listing 
14.4.21 
FAS 
Forest plot of subgroup analyses of TOTPAR-48 
14.2.7.1, 
14.2.7.3, 
14.2.7.5. 
14.2.7.7 
14.4.22 
FAS 
Forest plot of subgroup analyses of peak pain relief 
14.2.11.1, 
14.2.11.3, 
14.2.11.5. 
14.2.11.7 
 
 


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14. 
TABLE SHELLS 
Table shells are provided in a separate document.