Conditions: Acute Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 120
Healthy volunteers: no

Brief summary:
Efficacy, Tolerability, Safety and Pharmacokinetic Study of DFN-15 in Post-Surgical Dental Pain.

Detailed description:
This is a Phase 2, single-center, randomized, double blind, dose-ranging placebo-controlled, clinical study evaluating the efficacy, tolerability, safety, and the pharmacokinetic properties of a known drug (selective COX-2 inhibitor) administered as an alternative formulation/dosage form (DFN-15, a liquid oral formulation) in an accepted model of acute post-operative pain (acute pain following oral surgery for extraction of bilateral impacted mandibular third molar teeth in otherwise healthy subjects).120 female and male healthy subjects scheduled to undergo elective bilateral third molar extraction will be randomized, after they provide informed consent and are confirmed to meet all the study selection criteria, in a 1:1:1:1 ratio to receive a single oral dose of either DFN-15 Dose A DFN-15 Dose B, DFN-15 Dose C or matching placebo.

Subjects will undergo a screening procedure (within 28 days of the scheduled extraction of the impacted third molars) that will involve the collection of demographic information, height, weight and body mass index (BMI), urine pregnancy test (women of child-bearing potential,) medical and medicinal history, physical examination, dental examination, vital signs measurement (blood pressure, pulse rate, respiratory rate), clinical laboratory investigation (hematology,serology, coagulation parameters, serum chemistry and urinalysis),12-lead ECG and a panoramic x-ray to document the impacted mandibular third molar teeth. As a pre-requisite for randomization, subjects will be required to report "moderate" to "severe" baseline pain on the provided paper diary within 6 hours post-surgery (called the 'Baseline' period) as characterized on a 4-point categorical pain intensity (PI) scale (0= none, 1= mild, 2= moderate, 3= severe), and a score of ≥5, on the 11-point Numerical Pain Rating Scale (NPRS) where 0 represents 'no pain' and 10 represents 'worst pain imaginable'. Eligible subjects will be randomized and will receive a single dose of the assigned study treatment. Subjects will be randomized and administered the study medication within 15 minutes of meeting the post-operative inclusion criteria (baseline score).Subjects will be assessed at pre-specified time-points over an observation period of 8 hours from the time of randomization.

Subjects with inadequately controlled pain symptoms may request rescue analgesic medication. Subjects will be encouraged to delay using the rescue medication if their pain is tolerable until 120 minutes post-dose of study medication. A subject who is administered rescue pain medication will continue completing pain assessments until 8 hours after treatment initiation. All randomized subjects will be provided with a paper diary to record pain assessments (Pain Intensity on 11-point NPRS scale, followed by Pain Relief using a 5-point categorical scale \[where 0= no pain relief, 1= little pain relief, 2= some pain relief, 3= a lot of pain relief, 4= complete pain relief\]) At study medication administration, two stopwatches will be started, to measure times to 'perceptible' and 'meaningful' pain-relief. Subjects will be instructed to stop the first stopwatch when they first perceive pain relief to occur (time to perceptible relief). Subjects will be instructed to stop the second stopwatch when they first experience meaningful pain relief (time to meaningful relief). Stopwatch times of perceptible relief and meaningful relief will be recorded using exact stopwatch time displayed.

In addition, at 8 hours post-dose or within 5 minutes prior to first use of rescue medication (whichever is earlier), subjects will be asked to record within the provided patient diary: 'Patient Rating of Treatment Satisfactoriness' using a 5-point verbal rating scale (0 =poor, 1 =fair, 2 =good, 3=very good, 4 =excellent).

Subjects will remain NPO (nothing by mouth), including water, from Check-in (i.e., at least 2 hours before the administration of the dose of study medication to randomized subjects) until 2 hours post-dose, on Day 1 (study day). After 2 hours post-dose, subjects may be permitted to consume water, or gelatin snacks. Subjects are prohibited from ingesting solid foods or carbonated beverages for at least 6 hours post-dose.

12-lead ECG and Vital Signs were performed before surgery, at baseline and at periodic intervals post-dose until 8 hours .At discharge (8 hours post-randomization) from the clinical facility, all AEs reported for the subjects will be reviewed. A physical examination, including evaluation of the incision site for hematomas, and clinical laboratory evaluation (coagulation parameters and specific hematology, serum biochemistry and urinalysis parameters) will be conducted.

All subjects will have blood drawn at specified time points (pre-dose and over the 8 hour observation period) for pharmacokinetic evaluation.

Subjects will return to the research center 7 days (± 3 days) post-surgery for evaluation of their safety and well-being. Any AEs experienced post-surgery will be reviewed. A physical examination, of the subject will be performed, 12-lead ECG, and vital signs parameters will be repeated. Hematology, coagulation parameters, serum biochemistry and urinalysis parameters will be repeated only if there is a clinically significant abnormality or ongoing AE(s). Any changes to the prior and concomitant medication made after discharge will be reviewed and recorded.

Arms:
arm 1: Single dose containing 62.5 mg of celecoxib in 10 ml solution arm 2: Single dose containing 125 mg of celecoxib in 10 ml solution arm 3: Single dose containing 250 mg of celecoxib in 10 ml solution arm 4: Single dose containing 0 mg of celecoxib in 10 ml solution

Interventions: intervention 1: DFN-15 (Celecoxib Oral Solution) 62.5 mg intervention 2: DFN-15 (Celecoxib Oral Solution) 125 mg intervention 3: DFN-15 (Celecoxib Oral Solution) 250 mg intervention 4: Placebo
Intervention descriptions: intervention 1: Oral Solution intervention 2: Oral Solution intervention 3: Oral Solution intervention 4: Oral Solution

Protocol document:
Prot_000.pdf: 
DR. REDDY’S LABORATORIES LIMITED 
 
Final Amended Protocol # DFN-15-CD-010 
 
 
Version 2.0 
CLINICAL PROTOCOL DFN-15-CD-010 
                  
Title:  A Randomized, Double-Blind, Placebo-Controlled, 
Efficacy, Tolerability, Safety and Pharmacokinetic Study 
of Single Doses of DFN-15 in Post-Surgical Dental Pain 
Study Phase:   
2 
IND #:  
138593 
Sponsor:   
Dr. Reddy’s Laboratories Limited 
 
8-2-337, Road No. 3 
 
Banjara Hills 
 
Hyderabad – 500034, Telangana 
 
India 
 
Sponsor Agent:   
Dr. Reddy’s Laboratories, Inc. 
 
107 College Road East 
 
Princeton, NJ  08540 
 
 
Date:    
May 2, 2018      
Version:   
2.0 
 
 
 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are 
privileged or confidential and may not be disclosed unless such disclosure is required by federal or 
state law or regulations.  In any event, persons to whom the information is disclosed must be 
informed that the information is privileged or confidential and may not be disclosed by them.  
These restrictions on disclosure will apply equally to all future information supplied to you, which 
is indicated as privileged or confidential. 


DR. REDDY’S LABORATORIES LIMITED 
 
Final Protocol # DFN-15-CD-010 
 
 
Version 2.0 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 2 of 81 
CONTACT INFORMATION 
 
Study Role 
Name/ Title 
Contact Information 
Sponsor 
Dr. Srinivas Shenoy B., MD 
Principal Scientist-Clinical 
Development 
Proprietary Products R & D 
Dr. Reddy's Laboratories Limited 
107 College Road East, 
Princeton, NJ 08540 
Phone: +1-609-282-1425 (Princeton) 
            +91-40-4434-6126 (Hyderabad) 
Email: srinivasshenoyb@drreddys.com 
Medical Monitor 
Dr. John Ruckle 
Lotus Clinical Research 
 
Phone: 253-448-8690 
Cell: 808-349-9812 
Emergency medical hotline : 877-508-8727 
Email: MedicalMonitorDFN-15-CD-
010@lotuscr.com 
Coordinating 
Investigator 
Dr. Neil Singla 
Lotus Clinical Research 
100 W. California Boulevard 
Unit 25 
Pasadena, CA 91105 
Phone: 626-793-3508 
Email: nsingla@lotuscr.com  
 
 
 
 
 
 


DR. REDDY’S LABORATORIES LIMITED 
 
Final Amended Protocol # DFN-15-CD-010 
 
 
Version 2.0 
SIGNATURE PAGE 
 
Sponsor Representative:  _________ Dr. Srinivas Shenoy B., MD________________ 
(Print Name) 
 
 
Signature:                            ____________________________________________________ 
 
 
Date:                                    ______________________________ (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


DR. REDDY’S LABORATORIES LIMITED 
 
Final Protocol # DFN-15-CD-010 
 
 
Version 2.0 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 4 of 81 
PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE: 
(To be signed by the Principal Investigator at each Clinical Site) 
 
By signing this, the Principal Investigator agrees to conduct the clinical study which is the 
subject of this protocol in accordance with the Clinical Study Agreement, this protocol 
including all Administrative Considerations described therein, all applicable government 
regulations including Part 54 of title 21 of the CFR, and the conditions of approval imposed 
by the reviewing Institutional Review Board. 
Principal Investigator:       __________________________________________________ 
(Print Name) 
 
 
Signature:                            ____________________________________________________ 
 
 
Date:                                     ______________________________ (MM/DD/YYYY) 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 5 of 81 
PROTOCOL SYNOPSIS 
 
Protocol No: 
DFN-15-CD-010 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Efficacy, 
Tolerability, Safety and Pharmacokinetic Study of Single Doses of DFN-
15 in Post-Surgical Dental Pain. 
Study Drug/ 
Investigational 
Product: 
1. DFN-15 (celecoxib oral solution, 25 mg/mL) - Test product 
2. Placebo of DFN-15 (oral solution, 0 mg/mL of celecoxib) 
DFN-15 and placebo will be supplied in bottles containing a deliverable 
volume of 4.8 mL solution. 
Doses of DFN-15 (62.5 mg, 125 mg and 250 mg) and placebo will be 
allocated on site for each subject by drawing the appropriate amounts 
of DFN-15 and/or placebo solutions into syringes, based on each 
subject randomized treatment arm. Regardless of DFN-15 dose, the 
total volume administered to each randomized subject will be the 
same (10 ml) given as a single oral dose to ensure blinding is 
maintained. 
Country: 
United States of America 
Phase: 
2 
Primary Objective: 
To assess the analgesic efficacy of DFN-15 in acute pain (post-
operative pain following extraction of bilateral mandibular third 
molars), when administered as a single dose of 62.5 mg, 125 mg or 
250 mg, as compared to placebo. 
Number of 
Subjects: 
An adequate number of subjects will be screened in order to 
randomize 120 subjects into the study. Subjects who discontinue 
study participation after randomization and prior to completing the 
study will not be replaced. 
Trial Design: 
This is a randomized, double-blind, placebo-controlled parallel design 
study, to be conducted at 1-3 centers in the United States. Male and 
female subjects, 18 to 60 years old (inclusive), who are scheduled to 
undergo elective bilateral lower third molar extraction will be 
enrolled.  Subjects who meet all of the inclusion and none of the 
exclusion criteria in the protocol will be randomized in a 1:1:1:1 ratio 
in a double-blind fashion to receive a single oral dose of either DFN-15 
62.5 mg, DFN-15 125 mg, DFN-15 250 mg or matching placebo.   
Subjects will undergo a screening procedure (within 28 days of the 
scheduled extraction of the impacted third molars) that will involve 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 6 of 81 
the collection of demographic information,  height, weight and body 
mass index (BMI), urine pregnancy test (women of child-bearing 
potential,) medical and medicinal history, physical examination, 
dental examination, vital signs measurement (blood pressure, pulse 
rate, respiratory rate), clinical laboratory investigation (hematology, 
serology, coagulation parameters, serum chemistry and urinalysis), 
12-lead ECG and a panoramic x-ray to document the impacted 
mandibular third molar teeth. 
At screening and upon admission/Check-in (Day 1) to the clinic, prior 
to dental surgery, subjects will be screened for alcohol consumption 
and illicit drug use by alcohol breathalyzer test and urine drug screen, 
respectively. 
As a pre-requisite for randomization, subjects will be required to 
report “moderate” to “severe” baseline pain on the provided paper 
diary within 6 h post-surgery (Baseline period) as characterized on a 
4-point categorical pain intensity (PI) scale (0= none, 1= mild, 2= 
moderate, 3= severe), and a score of ≥5, on the 11-point Numerical 
Pain Rating Scale (NPRS) where 0 represents ‘no pain’ and 10 
represents ‘worst pain imaginable’. Eligible subjects will be 
randomized and will receive a single dose of the assigned study 
treatment (a total volume of 10 mL). The start time of dosing will be 
recorded as T0. Subjects will be randomized and administered the 
study medication within 15 minutes of meeting the post-operative 
inclusion criteria (baseline score).    
Subjects with inadequately controlled pain symptoms may request 
rescue analgesic medication.  The rescue medication for this study will 
be 1-2 oxycodone 5 mg/acetaminophen 325 mg q 4 h PRN. Subjects 
will be encouraged to delay using the rescue medication if their pain is 
tolerable until 120 minutes post-dose of study medication. A subject 
who is administered rescue pain medication will continue completing 
pain assessments until 8 hours after treatment initiation.  The use of 
ice packs will not be allowed in the 8-hour observation period. 
All randomized subjects will be provided with a paper diary to record 
pain assessments. A patient training program will be implemented to 
ensure that all subjects understand the relevant scales and 
assessments prior to study participation. At study medication 
administration, two stopwatches will be started, to measure times to 
‘perceptible’ and ‘meaningful’ pain-relief. Subjects will be instructed to 
stop the first stopwatch when they first perceive pain relief to occur 
(time to perceptible relief). Subjects will be instructed to stop the 
second stopwatch when they first experience meaningful pain relief 
(time to meaningful relief). Stopwatch times of perceptible relief and 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 7 of 81 
meaningful relief will be recorded using exact stopwatch time 
displayed. 
The following efficacy assessments will be completed by the subjects 
at 15, 30, and 45 min and at 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours after 
study medication administration, as well as within 5 minutes prior to  
first use of rescue medication and at early termination from the study, 
if it occurs. Subjects will be asked to record responses for the 
following assessments, in order: 
1. Pain intensity using the 11-point Numerical Pain Rating Scale 
(NPRS).  
Followed by: 
2. Pain relief (PR) using a 5-point categorical scale (where 0= no 
pain relief, 1= little pain relief, 2= some pain relief, 3= a lot of 
pain relief, 4= complete pain relief) 
In addition, at 8 hours post-dose or within 5 minutes prior to first use 
of rescue medication (whichever is earlier), subjects will be asked to 
record within the provided patient diary: 
1. ‘Patient Rating of Treatment Satisfactoriness’ using a 5-point 
verbal rating scale (0 =poor, 1 =fair, 2 =good, 3=very good, 4 
=excellent). 
Subjects will remain NPO (nothing by mouth), including water, from 
Check-in (i.e., at least 2 hours before the administration of the dose of 
study medication to randomized subjects) until 2 hours post-dose, on 
Day 1 (study day). After 2 hours post-dose, subjects may be permitted 
to consume water, or gelatin snacks. Subjects are prohibited from 
ingesting solid foods or carbonated beverages for at least 6 hours 
post-dose.  
12-lead ECGs will be performed before surgery, at baseline (before 
administration of the study treatment) and repeated at 1, 2, 4 and 8 
hours post-dose, with a window period of ± 45 minutes for each 
timepoint. Vital sign parameters (sitting pulse rate, sitting or supine 
blood pressure and respiratory rate) will be measured and recorded 
before surgery, at baseline, 1, 2, 4, and 8 hours (before discharge), 
with a window period of ± 30 minutes for each timepoint. Vital signs 
may be performed concurrently with ECG if supine position is 
performed. Safety vital signs and ECG may be performed prior to 
initiation of efficacy assessments should they coincide, with priority 
designated toward efficacy assessment timepoints. At discharge (8 
hours post-surgery) from the clinical facility, all AEs reported for the 
subjects will be reviewed. A physical examination, including 
evaluation of the incision site for hematomas, and clinical laboratory 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 8 of 81 
evaluation (coagulation parameters and specific hematology, serum 
biochemistry and urinalysis parameters) will be conducted.  
All subjects will have blood drawn at specified time points for 
pharmacokinetic evaluation. Pharmacokinetic blood samples will be 
drawn immediately prior to dosing and at 15 min, 30 min, 45 min, 1.0, 
1.5, 2.0, 2.5, 3.0, 4.0, 6.0 and 8.0 hours post-dose, to estimate the 
concentrations of celecoxib, using a validated LC-MS/MS method. 
Whenever the times of PK blood sample collection coincide with the 
efficacy or safety assessments, the PK sample may be drawn within ± 
5 minutes of the scheduled time in first hour and within ± 10 minutes 
of the scheduled time after the first hour, at each timepoint, 
immediately following the efficacy assessments. The exact clock time 
of sample collection will be recorded and used in the PK analysis. 
Subjects will return to the research center 7 days (± 3 days) post-
surgery for evaluation of their safety and well-being. Any AEs 
experienced post-surgery will be reviewed. A physical examination, of 
the subject will be performed, 12-lead ECG, and vital signs parameters 
will be repeated. Hematology, coagulation parameters, serum 
biochemistry and urinalysis parameters will be repeated only if there 
is a clinically significant abnormality or ongoing AE(s). Any changes to 
the prior and concomitant medication made after discharge will be 
reviewed and recorded. 
Treatment: 
A single dose of total volume of 10 mL of oral solution will be 
administered providing DFN-15 (62.5 mg, 125 mg or 250 mg) or 
placebo. The dose will be prepared by a designated unblinded 
pharmacist at site, as per the randomization schedule. Designated 
blinded study staff will dose subjects and administer study 
assessments. Blinded study staff will remain blinded to the dose 
administered to each subject throughout the study.  
Study Duration: 
The duration of study participation will be approximately 39 days, for 
randomized subjects, including a screening period of approximately 
4 weeks, surgery and treatment period day (subjects will be confined 
within the clinical study facility for at least 8 hours post-dose) and a 
post-surgery/ treatment follow up visit to the research center up to 10 
days post-surgery. 
Study Visits: 
Total number of visits to the clinical facility: 3 
Visit no. 1 (Day -28 to Day -1): Screening 
Visit no. 2 (Day 1): Bilateral mandibular third molar extraction surgery, 
followed by randomization, administration of study treatment and 
observation in the clinical facility for 8 hours post dose. Subjects will be 
confined within the clinical study facility for at least 8 hours post-dose. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 9 of 81 
No overnight stay at the research facility will be required, however if it 
is clinically appropriate to do so, subjects should remain at the research 
center until they are safe to leave. 
Visit no. 3 (Day 4 to Day 10): Follow-Up visit 
Study Population: 
Male and female subjects (approximate ratio of 1:1) who meet all of 
the inclusion criteria (including postoperative inclusion criteria) and 
none of the exclusion criteria below. 
Inclusion Criteria: 
1. Subjects must be scheduled to undergo elective bilateral lower 
(mandibular) third molar extraction under local anesthesia (as 
specified in the anesthetic protocol, Section 5.1.1), with 
mandibular third molars involving a full or partial bony impaction 
confirmed 
by 
radiographic 
evidence 
(panoramic 
x-ray). 
Extraction of 1 or 2 impacted or non-impacted maxillary third 
molars as part of the surgical procedure is permitted but not 
required.  
2. Subjects must voluntarily provide signed, written, and dated 
informed consent prior to any study-specific procedures. 
3. Subjects must be between 18-60 years of age, inclusive, at the time 
of screening. 
4. Subjects must be generally healthy, ambulatory, able to understand 
and willing to comply with study procedures, study restrictions, 
assessments, and requirements per the discretion of the 
investigator. 
5. Subjects must be deemed able to comprehend English and fully 
understand the informed consent form (ICF). 
6. Subjects must have a body mass index (BMI) ≥19.0 to ≤35.0 kg/m2 
7. Women are eligible only if all the following apply: 
a. Not pregnant (women of child bearing potential must have 
negative urine pregnancy tests at screening and prior to 
surgery/ randomization) 
b. Not lactating 
c. Not planning to become pregnant during the study; 
d. Surgically sterile (irreversible surgical sterilization by 
hysterectomy, bilateral oophorectomy, bilateral salpingectomy, 
or tubal occlusion), bilateral tubal ligation, or at least two years 
post-menopausal; 
or 
is 
practicing 
double-barrier 
contraception; or using an insertable, injectable, transdermal, 
or combination oral contraceptive approved by the FDA for 
greater than 2 months prior to screening visits. Commits to the 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 10 of 81 
use of a double-barrier, insertable, injectable, transdermal or 
combination oral contraceptive for the duration of the study 
and for 30 days after the last dose study drug administration. In 
addition, a female subject whose partner has had a vasectomy, 
or who abstains from sex, or who is involved in a same sex 
relationship is eligible. 
Exclusion Criteria: 
1. History of allergy or hypersensitivity to celecoxib and similar 
pharmacological agents including any NSAID (including aspirin), 
or to any pre- and post- operative medications used in this study, 
including lidocaine, oxycodone or acetaminophen, as judged by 
the investigator. Subjects with conditions known to be 
contraindications to NSAIDS (risk of thrombovascular events and 
renal insufficiency.) 
2. Evidence or history of clinically significant hematological, renal, 
endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, 
neurologic diseases, malignancies, or any other clinically 
significant disease or disorder which, in the opinion of the 
investigator, may either put the subject at risk because of 
participation in the study, or influence the results or the subject’s 
ability to participate in the study, including but not limited to: 
a. Any bleeding or blood coagulation disorders 
b. History of an upper GI disorder within 6 months of Screening 
visit (e.g. gastric or duodenal ulcers) 
c. History of gastric bypass within 6 months of screening visit 
d. Dysphagia 
3. History of migraine or frequent headaches, low back pain, or 
other acute or chronic pain conditions that according to the 
investigator’s judgment could interfere with efficacy and safety 
evaluations as required by the protocol. 
4. Acute illness or unresolved local infection prior to surgery that 
can interfere with the conduct of the study, as judged by the 
investigator. 
5. History of previous or ongoing psychiatric disease/condition 
including psychosis, affective disorder, anxiety disorder, 
borderline state and personality disorder according to the criteria 
in the Diagnostic and Statistical Manual of Mental Disorders. The 
following exceptions may be applied: 
a. Subjects with history of mild unipolar depression may be 
included if eligible otherwise, and not currently receiving 
SNRIs and medications referenced in Exclusion 10. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 11 of 81 
b. Subjects with mild ADHD or mild anxiety may be included if 
eligible otherwise, and not currently receiving SNRIs and 
medications referenced in Exclusion 10.  
6. Known or suspected drug (including analgesic drugs or 
tranquilizers) or alcohol abuse or dependence, as defined by 
DSM-IV, and not in full remission, as judged by the investigator, 
or history of alcohol abuse or excessive intake of alcohol, defined 
as regular weekly intake of >15 units for men and >10 units for 
women.  (1 unit = 25 mL spirits, 125 mL wine, 250 mL beer or 
lager). 
7. Any clinically significant abnormalities in clinical chemistry, 
hematology, coagulation parameters, or serology results at 
screening that in the investigator’s judgment puts the subject at 
risk due to study participation.  
8. Any clinically significant 12-lead ECG abnormalities at screening 
according to the judgment of the investigator. 
9. Evidence of any clinically significant vital sign abnormality that in 
the investigator’s opinion significantly increases the risks for 
study participation. 
10. Positive results on urine drug screen or alcohol breath test 
indicative of illicit drug (Cocaine Metabolites, Marijuana (THC), 
MDMA (Ecstasy), and Phencyclidine) or alcohol abuse at 
screening and/or prior to extraction procedure. Positive results 
for prescription, (Amphetamines, Barbiturates, Benzodiazepines, 
Methadone, 
Methamphetamine, 
Opiates, 
Oxycodone, 
and 
Tricyclic Antidepressants.) The following exception may apply: 
a. Over-the-counter medications (non-NSAIDs), multi-vitamins 
and supplements are allowable per the opinion of the 
investigator or sponsor (see Exclusion 13-c).  
11. Frequent use of tobacco (smoking, snuff) or other nicotine-
containing products (nicotine chewing gum, nicotine plaster, or 
other smoking cessation therapy).  Frequent use is defined as 
smoking or consumption/intake of nicotine products more than 
2 days per week during the last 12 weeks prior to enrollment.  
Note: occasional smokers/users of nicotine products (<5 
cigarettes per day, and maximally 2 days per week) may be 
included in the study, provided that they refrain from smoking 
and/or the use of nicotine containing products for at least 10 days 
before administration of investigational product and for the 
duration of the study (through Day 7, ±3 days). 
12. Excessive intake of caffeine-containing foods or beverages (more 
than 5 units or equivalent per day) within 48 hours prior to 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 12 of 81 
surgery.  One caffeine unit is contained in the following items: 1 
cup of coffee, 2 cans of cola, 1 glass of tea, ½ cup of energy drink 
(e.g., Red Bull), or 3 chocolate bars. 
13. Routinely uses pain medication, including any of the following: 
a. Any opioid medication, or combination medication, equivalent 
to 5 mg oral morphine per day for 3 or more days per week 
within 4 weeks before surgery. 
b. Nonsteroidal anti-inflammatory drugs [NSAIDs] or selective 
COX-2 inhibitors more than 5 times per week within 4 weeks 
before surgery. 
c. Cannabinoids use within 4 weeks before surgery. 
14. Currently taking any corticosteroid chronically (except for an 
inhaled steroid for pulmonary disease, and local topical or 
ophthalmic steroid) or has taken systemic corticosteroids within 
4 weeks of the proposed date of surgery. 
15. Currently (within 30 days prior to Screening Visit) taking central 
nervous system (CNS) active drugs such as hypnotics, sedatives, 
monoamine oxidase inhibitors, sympathomimetic amines, 
benzodiazepines, 
tricyclic 
antidepressants, 
or 
serotonin 
norepinephrine reuptake inhibitors (SNRIs), and anticonvulsants 
for pain. The following exception may apply: 
a. Subjects taking a stable dose of selective serotonin reuptake 
inhibitors (SSRIs) to treat mild depression for at least 30 days 
prior to screening may be included if eligible otherwise.   
16. Donated blood products/ blood loss >500 mL 30 days prior to 
Screening or between Screening and surgery. 
17. Member or relative of study staff or the Sponsor directly involved 
in the study. 
18. Previous participation in this study. 
19. Has received another new chemical entity (defined as a 
compound which has not been approved for marketing) or has 
participated in any other clinical study that included drug 
treatment within 30 days prior to the Screening visit. Note: 
subjects consented and screened, but not dosed in such a study, 
are not excluded. 
20. Previous exposure to DFN-15 in a clinical trial. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 13 of 81 
21. Currently receiving or have received within 7 days prior to 
investigational product administration in the study, any drug 
(s) that is metabolized by hepatic microsomal enzyme CYP 2D6. 
For examples of drugs that are metabolized by CYP2D6, please 
refer to Table 3-1 ‘in the FDA’s development resource ‘Drug 
Development and Drug Interactions: Table of Substrates, 
Inhibitors 
and 
Inducers’ 
available 
at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/D
evelopmentResources/DrugInteractionsLabeling/ucm093664.
htm 
Post-Operative 
Inclusion Criteria: 
1. Subjects must report “moderate” to “severe” baseline pain within 6 
hours post-surgery, as characterized on a 4-point categorical pain 
intensity scale (0= none, 1= mild, 2= moderate, 3= severe)  
2. Subjects must report a score of ≥5 on the 11-point Numerical Pain 
Rating Scale (NPRS) within 6 h post-surgery, where 0 represents 
‘No pain’ and 10 represents ‘worst pain imaginable’ at study 
baseline.  
3. Subject has had no evidence of any clinically significant 
abnormality during or following surgery that, in the judgment of 
the investigator, significantly increases the risks due to study 
participation. 
4. In the judgment of the investigator, study participation would not 
put the subject at risk from the specified surgical procedure, 
anesthetic protocol, or specified analgesic regimen.  
Trial Center: 
JBR Clinical Research 
1045 E 3900 S 
Salt Lake City, UT 84124 
 
Additional 1-2 study centers may be included, if deemed necessary, 
during the conduct of the study. 
Primary Endpoint: 
Summed pain intensity difference over the first 6 hours (SPID6) 
between DFN-15 doses and placebo. The comparison of primary 
interest is DFN-15 doses vs. placebo. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 14 of 81 
Key Secondary 
Endpoints: 
• 
Total Pain Relief (TOTPAR) over 2, 4, 6 and 8 hours using a 5-
point categorical scale (TOTPAR2, TOTPAR4, TOTPAR6 and 
TOTPAR8) 
• 
Summed Pain Intensity Differences (SPID) at 2, 4 and 8 hours 
post-dose (SPID2, SPID4 and SPID8) 
• 
Time to perceptible and meaningful pain relief as measured by 
two stopwatch technique 
• 
Proportion of subjects reporting treatment satisfaction 
outcome as either 2 = good, 3 = very good or 4 = excellent, on 
the 5-point categorical scale  
• 
Time to use of rescue medication and percentage of patients 
using rescue medication 
• 
Pain intensity difference at each NPRS time point (15, 30, and 
45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 h) 
• 
Pain relief at each time point (15, 30, and 45 min and 1, 1.5, 2, 
3, 4, 5, 6, 7, and 8 h) 
• 
Characterization of plasma pharmacokinetic profiles of DFN-
15 doses in fasting conditions (using Cmax AUC0-t, Tmax; Other 
pharmacokinetic parameters like AUC0-0.25, AUC0-0.5, AUC0-0.75, 
AUC0-1, AUC0-2, AUC0-3, AUC0-4, AUC0-6 will also be calculated) 
Secondary/ 
Exploratory 
Endpoints: 
Additional analyses may be performed and pre-specified in the SAP 
as appropriate.  
Statistical and PK 
Methods: 
The SAP will supersede the protocol in case of a discrepancy. 
Sample Size:   
120 subjects will be randomized into the study in (1:1:1:1) ratio into 
one of 3 doses of active study medication or placebo.   
All safety and efficacy variables will be summarized using descriptive 
statistics by treatment group and time point. Descriptive statistics will 
include (n, arithmetic mean, standard deviation, median, minimum and 
maximum) for continuous variables, categorical variables will be 
summarized with counts and percentages. 
Analysis Populations:   
• 
Modified Intent-to-Treat (mITT) Population will include all 
subjects who are randomized, take the assigned dose of the study 
medication and complete at least one post-baseline pain 
assessment. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 15 of 81 
• 
Safety Population will include all subjects receiving any amount of 
study medication. 
Primary Efficacy Analysis:  
SPID6 values will be analyzed using an ANCOVA (analysis of 
covariance) model with treatment as the main effect; the baseline pain 
intensity (PI) score will be added to the model as a covariate.  Analgesic 
effect of DFN-15 at each dose level will be evaluated compared to 
placebo using Dunnett’s test.  Imputation methods for rescue use and 
missing data due to early termination will be specified in a statistical 
analysis plan (SAP) prior to database lock. 
Secondary Efficacy Analyses:  
Other SPID and TOTPAR endpoints will be analyzed using similar 
methods as the primary analysis.  Time to meaningful and perceptible 
pain relief and time to rescue will be summarized graphically with 
Kaplan-Meier curves and compared across treatments using the log-
rank test.  Proportion of subjects reporting treatment satisfaction 
outcome will be summarized and treatments compared using Chi-
Square techniques. 
Exploratory Efficacy Analyses:  
Similar analysis methods will be used for any exploratory endpoints. 
Safety:   
All safety parameters and changes from baseline will be summarized 
descriptively by treatment arm and time point. No statistical testing 
will be performed. 
Pharmacokinetics:  
Key pharmacokinetic endpoints will be Cmax, AUC0-t and Tmax. Other 
pharmacokinetic parameters like AUC0-0.25, AUC0-0.5, AUC0-0.75, AUC0-1, 
AUC0-2, AUC0-3, AUC0-4, AUC0-6 will also be calculated. Any other 
additional parameters requiring estimation will be included in the PK 
Analysis Plan. 
 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 16 of 81 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................ 5 
TABLE OF CONTENTS .......................................................................................................... 16 
LIST OF ABBREVIATIONS ................................................................................................... 20 
Amendment 1 - Protocol Changes Log ........................................................................... 23 
1. 
INTRODUCTION ............................................................................................................ 25 
2. 
STUDY OBJECTIVES ..................................................................................................... 26 
3. 
INVESTIGATIONAL PLAN ........................................................................................... 27 
3.1. 
Overall Study Design ...................................................................................................... 27 
3.2. 
Rationale for Study Design and Control Groups ................................................... 29 
4. 
STUDY POPULATION ................................................................................................... 30 
4.1. 
Inclusion Criteria ............................................................................................................. 30 
4.2. 
Exclusion Criteria ............................................................................................................ 30 
4.3. 
Post-Operative Inclusion Criteria .............................................................................. 33 
4.4. 
Discontinuation of Subjects ......................................................................................... 33 
4.4.1. 
Procedures for Withdrawal ............................................................................................. 33 
4.4.2. 
Replacement of Subjects ................................................................................................... 33 
4.5. 
Lifestyle Guidelines ........................................................................................................ 34 
4.5.1. 
Confinement ........................................................................................................................... 34 
4.5.2. 
Diet ............................................................................................................................................. 34 
5. 
TREATMENTS ................................................................................................................ 35 
5.1. 
Surgical Procedure .......................................................................................................... 35 
5.1.1. 
Anesthetic Care ..................................................................................................................... 35 
5.1.2. 
Surgery ..................................................................................................................................... 35 
5.1.3. 
Post-operative Care ............................................................................................................. 35 
5.2. 
Disallowed medications ................................................................................................ 35 
5.3. 
Administration of Study Medication......................................................................... 35 
5.4. 
Identity of Study Medication ....................................................................................... 35 
5.5. 
Method of Assigning Subjects to Treatment Groups ........................................... 36 
5.6. 
Selection of Doses ............................................................................................................ 36 
5.7. 
Selection of Timing of Dose .......................................................................................... 36 
5.8. 
Blinding and Unblinding of Study Medications .................................................... 36 
5.9. 
Treatment Compliance and Safety ............................................................................ 37 
5.10. 
Drug Accountability ........................................................................................................ 37 
5.11. 
Packaging, Labeling, and Storage .............................................................................. 38 
5.12. 
Prior and Concomitant Medications ......................................................................... 38 
5.13. 
Prohibited Medications ................................................................................................. 38 
5.14. 
Concomitant Interventions and Procedures ......................................................... 39 
5.15. 
Rescue Medication .......................................................................................................... 39 
6. 
Study procedures ......................................................................................................... 41 
6.1. 
Order of Study Procedures ........................................................................................... 41 
6.2. 
Pharmacokinetic Assessments ................................................................................... 41 
6.2.1. 
Pharmacokinetic Groups ................................................................................................... 41 
6.2.2. 
Sample Collection ................................................................................................................. 41 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 17 of 81 
6.2.3. 
Processing, Storage, and Shipping of Pharmacokinetic Samples ..................... 41 
6.2.4. 
Bioanalytical Methodology ............................................................................................... 42 
6.3. 
Demographic and Efficacy Assessment ................................................................... 42 
6.3.1. 
Demographics ........................................................................................................................ 42 
6.3.2. 
Medical/Medicinal History ............................................................................................... 42 
6.3.3. 
Physical Examination ......................................................................................................... 42 
6.3.4. 
Dental Examination ............................................................................................................. 43 
6.3.5. 
Pain Intensity: 4-Point Categorical Pain Intensity (PI) and Numerical Pain 
Rating Scale (NPRS) .................................................................................................................................. 43 
6.3.6. 
Pain Relief (PR) ..................................................................................................................... 44 
6.3.7. 
Time to Perceptible Pain Relief and Time to Meaningful Pain Relief ............. 44 
6.3.8. 
Patient Rating of Treatment satisfactoriness ........................................................... 44 
6.4. 
Safety Assessments Description ................................................................................. 44 
6.4.1. 
Clinical Laboratory Tests .................................................................................................. 44 
6.4.2. 
Vital Sign Measurements ................................................................................................... 45 
6.4.3. 
Electrocardiograms ............................................................................................................. 45 
6.5. 
Assessments by Visit ...................................................................................................... 45 
6.5.1. 
Screening Visit ....................................................................................................................... 45 
6.5.2. 
Day 1 (Prior to surgery) .................................................................................................... 46 
6.5.3. 
Day 1 (After surgery/Pre-dose Baseline) ................................................................... 46 
6.5.4. 
Day 1 (Post Dose) ................................................................................................................. 47 
6.5.5. 
End of Study Visit (Day 7 ± 3 days) ............................................................................... 47 
6.6. 
Clinical Stopping Rules .................................................................................................. 48 
7. 
ADVERSE EVENTS ......................................................................................................... 49 
7.1. 
Definition of an Adverse Event ................................................................................... 49 
7.2. 
Definition of a Serious Adverse Event (SAE) .......................................................... 50 
7.2.1. 
SAEs That Occur Before Administration of Study Medication ........................... 50 
7.2.2. 
SAEs That Occur After Study Completion .................................................................. 50 
7.3. 
Definition of a Suspected Adverse Reaction (SAR) .............................................. 51 
7.4. 
Definition of a Serious Suspected Adverse Reaction (SSAR) ........................... 51 
7.5. 
Recording and Evaluating Adverse Events and Serious Adverse Events .... 51 
7.5.1. 
Assessment of Intensity ..................................................................................................... 52 
7.5.2. 
Assessment of Causality .................................................................................................... 52 
7.5.3. 
Assessment of Outcome ..................................................................................................... 53 
7.5.4. 
Assessment of Expectedness ........................................................................................... 53 
7.6. 
Follow-up of Adverse Events and Serious Adverse Events ............................... 54 
7.7. 
Prompt Reporting of Serious Adverse Events to the Sponsor ......................... 54 
7.8. 
Regulatory Reporting Requirements ....................................................................... 55 
7.9. 
Precautions ........................................................................................................................ 56 
8. 
STATISTICAL METHODOLOGY ................................................................................. 57 
8.1. 
Determination of Sample Size ..................................................................................... 57 
8.2. 
Study Endpoints ............................................................................................................... 57 
8.2.1. 
Efficacy Endpoints ............................................................................................................... 57 
8.2.2. 
Pharmacokinetic Endpoints ............................................................................................. 57 
8.2.3. 
Safety Endpoints ................................................................................................................... 58 
8.3. 
General Considerations for Statistical Analysis ................................................... 58 
8.3.1. 
Analysis Datasets .................................................................................................................. 58 
8.3.2. 
Procedures for Handling Missing Data ........................................................................ 58 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 18 of 81 
8.3.3. 
Definitions for Assessment Windows .......................................................................... 59 
8.3.4. 
Derived Variables ................................................................................................................. 59 
8.4. 
Study Population Summaries ...................................................................................... 59 
8.4.1. 
Disposition .............................................................................................................................. 59 
8.4.2. 
Demographics ........................................................................................................................ 59 
8.4.3. 
Protocol Violations .............................................................................................................. 59 
8.4.4. 
Treatment Compliance ....................................................................................................... 59 
8.4.5. 
Prior and Concomitant Medications ............................................................................. 60 
8.5. 
Efficacy Analysis ............................................................................................................... 60 
8.5.1. 
SPID and PID Analyses ....................................................................................................... 60 
8.5.2. 
TOTPAR and Pain Relief Analyses ................................................................................. 60 
8.5.3. 
Time to Event End Points .................................................................................................. 60 
8.5.4. 
Patient Rating of Treatment satisfactoriness ........................................................... 61 
8.5.5. 
Proportion of Subjects Requiring Rescue Medication .......................................... 61 
8.5.6. 
Subgroup Analyses for Efficacy ...................................................................................... 61 
8.6. 
Safety and Tolerability Evaluations .......................................................................... 61 
8.6.1. 
Extent of Exposure ............................................................................................................... 61 
8.6.2. 
Adverse Events ...................................................................................................................... 61 
8.6.3. 
Clinical Laboratory Tests .................................................................................................. 62 
8.6.4. 
Vital Sign Measurements ................................................................................................... 62 
8.6.5. 
Electrocardiograms ............................................................................................................. 62 
8.6.6. 
Subgroup Analyses for Safety Endpoints ................................................................... 62 
8.7. 
Summaries of Pharmacokinetic Endpoints ............................................................ 62 
9. 
STUDY ADMINISTRATION ......................................................................................... 63 
9.1. 
Regulatory and Ethical Considerations ................................................................... 63 
9.1.1. 
Regulatory Authority Approval ...................................................................................... 63 
9.1.2. 
Ethical Conduct of the Study and Ethics Approval ................................................. 63 
9.1.3. 
Informed Consent ................................................................................................................. 64 
9.1.4. 
Investigator Reporting Requirements ......................................................................... 65 
9.2. 
Study Monitoring ............................................................................................................. 65 
9.3. 
Quality Assurance............................................................................................................ 65 
9.4. 
Study and Site Closure ................................................................................................... 65 
9.5. 
Records Retention ........................................................................................................... 66 
9.5.1. 
Health Insurance Portability and Accountability Act of 1996 ........................... 66 
9.5.2. 
Financial Disclosure ............................................................................................................ 66 
9.5.3. 
Access to Original Records ............................................................................................... 66 
9.5.4. 
Archiving of Study-Related Documents ...................................................................... 66 
9.6. 
Provision of Study Results and Information to Investigators ......................... 67 
9.7. 
Information Disclosure and Inventions .................................................................. 67 
9.7.1. 
Ownership ............................................................................................................................... 67 
9.7.2. 
Confidentiality ....................................................................................................................... 67 
9.7.3. 
Publication .............................................................................................................................. 67 
9.7.4. 
Data Management ................................................................................................................ 68 
9.7.5. 
Data Security .......................................................................................................................... 68 
9.8. 
Subject Tracking .............................................................................................................. 68 
10. 
REFERENCES .............................................................................................................. 69 
11. 
APPENDIX A: OVERVIEW OF STUDY SCHEDULE ............................................ 70 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 19 of 81 
12. 
APPENDIX B: STUDY-SPECIFIC INFORMATION ............................................. 75 
12.1. 
Appendix B.1: Pain Intensity Assessment............................................................... 75 
12.2. 
Appendix B.2: 5-Point Categorical Pain Relief Assessment (PR) ................... 76 
12.3. 
Appendix B.3: 5-Point Patient Rating of Treatment Satisfactoriness ........... 76 
13. 
APPENDIX C: PANEL OF CLINICAL LABORATORY TESTS ........................... 77 
14. 
APPENDIX D: INVESTIGATOR OBLIGATIONS ................................................. 80 
 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 20 of 81 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
AUC  
Adverse event 
Area under the concentration-time curve  
BMI 
Body mass index 
BP 
Blood Pressure 
BPM 
Beats Per Minute 
oC 
Degrees Centigrade 
CFR 
(United States) Code of Federal Regulations 
CNS 
Central Nervous System 
COX-2 
Cyclooxygenase-2 
CRF 
Case report form 
DBP 
DSM-IV 
Diastolic Blood Pressure 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
ET 
Early Termination/Early Discontinuation 
ºF 
Degrees Fahrenheit 
GCP 
Good Clinical Practice 
GI 
Gastro-intestinal 
GMP 
Good Manufacturing Practice 
h/ hs 
Hour / hours 
HR 
Heart rate 
ICH 
International Conference on Harmonization 
I/E 
Inclusion/Exclusion Criteria 
IEC 
Independent Ethics Committee  


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 21 of 81 
Abbreviation 
Definition 
IND  
IP 
Investigational New Drug 
Investigational Product 
IRB 
Institutional Review Board 
IV 
Intravenous 
Kg 
Kilogram 
LOCF 
Last Observation Carried Forward 
m2 
Square meters 
MDMA 
Ecstasy 
MAOI 
Mg 
Monoamine oxidase inhibitors  
Milligram 
Min 
Minute 
mITT 
Modified Intent to Treat 
mL 
Milliliter 
mm Hg 
millimeters of mercury 
NPRS 
Numerical Pain Rating Scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
µL 
Micro liter 
NPO 
Nothing by mouth 
PCP 
Phencyclidine 
pH 
Negative log of hydrogen ion concentration 
PI 
Pain Intensity 
PID 
PK 
PO 
Pain Intensity Difference 
Pharmacokinetic 
By mouth  


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 22 of 81 
Abbreviation 
Definition 
PR 
Pain Relief 
Prn 
As needed 
Q 
Every 
SAR 
Suspected adverse reaction 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SPID 
Summed Pain Intensity Difference 
SNRI’s 
SSAR 
SSRI’s 
Serotonin norepinephrine reuptake inhibitors  
Serious suspected adverse reaction 
Selective serotonin reuptake inhibitors  
TCA 
Tricyclic Antidepressants 
THC 
Tetrahydrocannabinol 
TOTPAR 
Total Pain Relief Scores 
US 
United States 
VS  
Vital signs  
WHO 
World Health Organization 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 23 of 81 
AMENDMENT 1 - PROTOCOL CHANGES LOG 
Original Protocol issued dated March 22, 2018, Final Version. 
 
Version 2.0 dated May 2, 2018  
 
Applicable 
section(s) 
Description of Change(s) 
Synopsis 
-  Trial Design 
Clarified that admission to the clinic (Check-in) occurs on Day 1 
and is referred to as Check-in 
 
Synopsis 
-  Trial Design   
Specified dietary conditions prior and subsequent to dosing as 
follows: 
Subjects will remain NPO (nothing by mouth), including water, 
from Check-in (i.e., at least 2 hours before the administration of 
the dose of study medication to randomized subjects until 2 hours 
post-dose on Day 1 (study day).    
Synopsis 
-  Exclusion 
Criteria 
 
Added the following exclusion requirement: 
Currently receiving or have received within 7 days prior to 
investigational product administration in the study, any drug(s) 
that is metabolized by hepatic microsomal enzyme CYP 2D6.  
For examples of drugs that are metabolized by CYP 2D6, please 
refer to Table 3-1 in the FDA’s development resource “Drug 
Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers, available at  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/
DevelopmentResources/DrugInteractionsLabeling/ucm0936
64.htm 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 24 of 81 
Applicable 
section(s) 
Description of Change(s) 
Protocol 
Section 4.2 
Exclusion 
Criteria 
Added the following exclusion requirement: 
Currently receiving or have received within 7 days prior to 
investigational product administration in the study, any drug(s) 
that is metabolized by hepatic microsomal enzyme CYP 2D6.  
For examples of drugs that are metabolized by CYP 2D6, please 
refer to Table 3-1 in the FDA’s development resource “Drug 
Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers, available at  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/
DevelopmentResources/DrugInteractionsLabeling/ucm0936
64.htm 
Protocol 
Section 4.5.2 
Diet 
Specified dietary conditions prior and subsequent to dosing as 
follows: 
Subjects will remain NPO (nothing by mouth), including water, 
from Check-in (i.e., at least 2 hours before the administration of 
the dose of study medication to randomized subjects until 2 hours 
post-dose on Day 1 (study day).    
Protocol 
Section 5.13 
Prohibited 
Medications 
Added the following: 
Currently receiving or have received within 7 days prior to 
investigational product administration in the study, any drug(s) 
that is metabolized by hepatic microsomal enzyme CYP 2D6.  
For examples of drugs that are metabolized by CYP 2D6, please 
refer to Table 3-1 in the FDA’s development resource “Drug 
Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers, available at  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/
DevelopmentResources/DrugInteractionsLabeling/ucm0936
64.htm 
Protocol 
Section 
6.4.1 Clinical 
Laboratory 
Tests 
and Appendix 
A 
Clarified that admission to the clinic (Check-in) occurs on Day 1 
and is referred to as Check-in 
 
Appendix C 
Changed urinalysis testing from bile salts to bilirubin 
 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 25 of 81 
1. 
INTRODUCTION 
Dr. Reddy’s Laboratories, Limited is developing DFN-15, a new formulation of celecoxib 
[p-[5-p-Tolyl-3-(Trifluoromethyl) pyrazol-1-yl] benzene sulfonamide] for the indications 
of: (1) acute treatment of migraine with or without aura, and (2) management of acute pain 
in adults.  This study is designed to evaluate the efficacy, safety, tolerability and 
pharmacokinetic properties of dosing with three doses of DFN-15 (celecoxib; 62.5 mg, 
125 mg, and 250 mg) in a postoperative pain population.  A single-dose, dose ranging 
design using the oral surgery model will be used to provide useful data in terms of 
analgesic onset, single-dose duration of analgesia, and effect size of pain-time curves 
during an 8-hour evaluation period of postoperative pain. Plasma concentrations and 
calculated Pharmacokinetic parameters will be used to determine the concentration-effect 
relationships for efficacy and safety. Efficacy assessments will attempt to identify the time 
to onset of analgesia, the duration of analgesia, and magnitude of analgesic effect in 
comparison with placebo. 
NSAIDs produce meaningful analgesia without opioid associated side effects such as 
sedation, nausea and vomiting1 and they have a low risk of abuse and dependence2.  
NSAIDs, such as celecoxib, that selectively inhibit cyclooxygenase 2 (COX-2) target the 
prostaglandins (synthesized via COX-2) responsible for inflammation and pain while 
sparing the prostaglandins responsible for maintenance and protection of the 
gastrointestinal (GI) tract (synthesized involving COX-1)3. The analgesic efficacy of 
COX-2 selective NSAIDs is similar to nonselective NSAIDs4 but celecoxib has reduced 
incidence of upper GI ulcers and bleeds and less GI upset5,6,7,8. Data suggests that 
selective COX-2 inhibitors may be safer in the immediate pre- and peri-operative 
periods, especially with respect to the incidences of bleeding9,10, incisional wound 
hematomas, gastro-intestinal ulceration11, and they may not impact bone fusion and 
wound healing12. 
DFN-15 (Celecoxib Oral solution) is a new liquid oral formulation of the selective 
inhibitor of the type 2 (inducible) isoform of the enzyme cyclooxygenase, celecoxib. 
Celecoxib is approved as an oral capsule formulation, Celebrex®, for the management of 
acute pain in adults. DFN-15 contains celecoxib in solution at concentration of 25 mg 
per mL, and is formulated using self-micro-emulsifying Drug Delivery System 
(SMEDDS) technology for quicker absorption. In comparative bioavailability studies in 
healthy subjects, Celebrex was seen to reach peak plasma concentrations at 
approximately 3 hours (Tmax)13, whereas, the DFN-15 oral liquid formulation has a more 
rapid celecoxib absorption rate leading to a higher peak plasma concentration within one 
hour. Moreover, DFN-15 provides higher systemic exposure (as determined by the 
calculated partial AUC, AUC 0-2h) than Celebrex®, 400 mg in the first 2 hours after 
dosing (Pharmacokinetic results from studies DFN-15-CD-008, DFN-15-CD-003, as 
presented in DFN-15 Investigator Brochure edition 3.0). On account of the unique 
physico-chemical and pharmacokinetic characteristics of DFN-15, it is expected to 
provide a quicker onset of analgesia and better relief early on in acute pain, such as post-
surgical pain. 
 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 26 of 81 
2. 
STUDY OBJECTIVES 
The primary objective of the study would be to evaluate the analgesic efficacy  of 
celecoxib at three dose levels of DFN-15 (62.5 mg, 125 mg and 250 mg) in comparison 
to placebo and to determine the pharmacokinetics of celecoxib from different doses, in 
acute post-surgical dental pain. 
The secondary objective of the study would be to evaluate the tolerability and safety of 
single doses of DFN-15 when administered to patients experiencing post-surgical dental 
pain. 
Additional analyses may be performed and pre-specified in the SAP as appropriate. 
 
 
 
 
 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 27 of 81 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase 2, randomized, double-blind, parallel group, dose-ranging placebo-
controlled evaluation of the analgesic efficacy, safety, tolerability and pharmacokinetics 
of DFN-15 in adult subjects who experience post-operative pain after undergoing 
bilateral third mandibular molar extraction.  The study will randomize approximately 
120 subjects across 1-3 sites. 
Subjects will be at least 18 years to 60 years of age and will be scheduled to undergo 
elective bilateral mandibular third molar extraction under local anesthesia.  The 
mandibular third molars must involve a full or partial bony impaction confirmed by 
radiographic evidence (panoramic x-ray). 
After signing the informed consent: demographics, medical/medicinal history, physical 
examination (including height, weight and BMI), dental examination, baseline clinical 
laboratory testing, 12-lead electrocardiogram (ECG), vital sign measurements, urine 
pregnancy testing (females of child bearing potential) and urine drug and alcohol screen 
will be completed during the screening visit. 
On the day of surgery (Day 1), prior to surgery, eligibility will be confirmed through 
updating medical/medicinal history, 12-lead electrocardiogram (ECG), vital sign 
measurements, urine pregnancy testing (females of child bearing potential), urine drug 
and alcohol screen, and review of inclusion exclusion criteria.  A patient training 
program will be implemented to ensure that all subjects understand the relevant scales 
and assessments prior to study participation.  Eligible subjects will undergo bilateral 
mandibular third molar extractions.  Subjects who experience acute postoperative pain 
of ‘moderate’ to ‘severe’ intensity, on a 4-point categorical pain intensity scale (0= none, 
1= mild, 2= moderate, 3= severe), within 6 hours following the end of surgery, and a 
pain intensity ≥ 5 on an 11-point numeric pain rating scale (NPRS), will be eligible for 
randomization and will stay at the study center for at least approximately 8 hours after 
treatment initiation. 
Subjects who meet all of the inclusion and none of the exclusion criteria in the protocol 
will be randomized in a 1:1:1:1 ratio to receive a single oral dose of DFN-15 62.5 mg, 
DFN-15 125 mg, DFN-15 250 mg or placebo. The time of the study drug administration 
will be designated as T0. 
Subjects will be domiciled at the research facility during the first 8 hours after initiation 
of study drug treatment. For safety and welfare of the subject, the site may choose to 
have subjects stay overnight at the study center.  An 11-point numerical pain rating scale 
(NPRS) will be used to determine the intensity of pain, 0-10 where 0 is ‘no pain’ and 10 
is ‘worst imaginable pain’.  NPRS 
 
 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 28 of 81 
 assessments will be performed at: baseline, 15, 30, and 45 minutes, and at 1, 1.5, 2, 3, 4, 
5, 6, 7, and 8 hours after study drug administration (T0). Also at these time points, Pain 
Relief (PR) will be assessed using a 5- point categorical scale. (where 0= no pain relief, 
1= little pain relief, 2= some pain relief, 3= a lot of pain relief, 4= complete pain relief). 
Numerical pain rating scale (NPRS) and pain relief (PR) assessments will also be 
completed before taking any dose of rescue medication, and at time of early 
discontinuation (if it occurs).  The time to first perceptible pain relief and time to 
meaningful pain relief will be determined using the ‘two stop watch’ method.  Subjects 
will also complete a Patient Rating of Treatment satisfactoriness at 8 hours after 
treatment initiation (prior to discharge from the clinical research center), or immediately 
prior to the time of first rescue analgesic administration, or at time of early 
discontinuation.  Serial vital signs and 12 lead ECG will be done as indicated in Section 
6.4. 
For time points where several procedures are scheduled, the following sequence will be 
followed: 12-lead ECG, Vital signs, Pain assessments (where applicable), PK blood draw, 
clinical laboratory (where applicable). 
Subjects with inadequately controlled pain symptoms may request 1-2 oxycodone 5 mg/ 
acetaminophen 325 mg q 4 h as needed as rescue analgesic medication.  For subjects 
who require additional analgesia, additional analgesic medication may be administered 
per the surgeon’s standard of care.   
Post rescue analgesic administration, subjects will continue completing pain assessments 
until 8 hours after treatment initiation.  However, these assessments will be disregarded 
in the statistical analysis.  
Subjects should be encouraged to wait at least 2 hours after the first study drug 
administration before utilizing rescue analgesia, if possible.  As much as possible, rescue 
analgesic medication should be administered only if pain intensity (PI) prior to rescue is 
≥4 on the numerical rating scale. 
A maximum of twelve 4 mL blood samples will be taken from each participant at baseline 
and 15, 30, and 45 minutes, and at 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours after study drug 
administration for analysis of plasma celecoxib concentrations. Whenever the times of PK 
blood sample collection coincide with the efficacy or safety assessments, the PK sample 
may be drawn within ± 5 minutes of the scheduled time in first hour and within ± 10 
minutes of the scheduled time after the first hour, at each timepoint, immediately following 
the efficacy assessments. The exact clock time of sample collection will be recorded and 
used in the PK analysis. 
Subjects will be asked to return to the study site 7 days (±3 days) post-surgery for 
evaluation of their safety and well-being. A review of AEs experienced post-surgery, a 
physical examination, 12-lead ECG, and vital signs will be repeated. Hematology, serum 
biochemistry, coagulation and urinalysis parameters will be repeated only if there is a 
clinically significant abnormality or ongoing AE(s). Any changes to the prior and 
concomitant medication that are made after discharge will be reviewed and recorded. 
Efficacy assessments will include numerical pain rating scale (NPRS) for pain intensity, 
pain relief (PR), use of rescue medication, and Patient Rating of Treatment 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 29 of 81 
satisfactoriness. Safety assessments will include monitoring of AEs and SAEs, clinical 
laboratory tests, ECGs, and vital sign measurements. 
3.2. 
Rationale for Study Design and Control Groups 
This study will evaluate the efficacy, tolerability, safety, and pharmacokinetic properties 
of a known drug substance administered via an alternative formulation/dosage form.  
This study will explore the analgesic effects of dosing with DFN-15 (a solution of 
celecoxib) in an accepted model of postoperative pain.  Third molar extraction produces 
generally reliable and persistent pain symptoms for a period typically lasting over 24 
hours, which will allow for analysis of single dose analgesic properties.  
Pharmacokinetic evaluations will allow determination of exposure in patients with acute 
postoperative pain and examination of any exposure-response relationship for DFN-15 
doses.  Efficacy measures will be collected in order to gain a better knowledge of the 
onset of analgesic effects, as well as characterizing the duration and extent of analgesic 
effects following a surgical procedure.  These analgesic effects will be evaluated 
between three potentially effective doses of DFN-15 in comparison with a placebo 
control. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 30 of 81 
4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate in 
the study: 
1. Subjects must be scheduled to undergo elective bilateral lower (mandibular) third molar 
extraction under local anesthesia (as specified in the anesthetic protocol, Section 5.1.1), 
with mandibular third molars involving a full or partial bony impaction confirmed by 
radiographic evidence (panoramic x-ray). Extraction of 1 or 2 impacted or non-impacted 
maxillary third molars as part of the surgical procedure is permitted but not required.  
2. Subjects must voluntarily provide signed, written, and dated informed consent prior to 
any study-specific procedures. 
3. Subjects must be between 18-60 years of age, inclusive, at the time of screening. 
4. Subjects must be generally healthy, ambulatory, able to understand and willing to comply 
with study procedures, study restrictions, assessments, and requirements per the discretion 
of the investigator. 
5. Subjects must be deemed able to comprehend English and fully understand the informed 
consent form (ICF). 
6. Subjects must have a body mass index (BMI) ≥19.0 to ≤35.0 kg/m2 
7. Women are eligible only if all the following apply: 
8. Not pregnant (women of child bearing potential must have negative urine pregnancy tests 
at screening and prior to surgery/ randomization; 
9. Not lactating; 
10. Not planning to become pregnant during the study; 
11. Surgically sterile (irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, bilateral salpingectomy, or tubal occlusion), bilateral tubal ligation, or at 
least two years post-menopausal; or is practicing double-barrier contraception; or using 
an insertable, injectable, transdermal, or combination oral contraceptive approved by the 
FDA for greater than 2 months prior to screening visits. Commits to the use of a double-
barrier, insertable, injectable, transdermal or combination oral contraceptive for the 
duration of the study and for 30 days after the last dose study drug administration. In 
addition, a female subject whose partner has had a vasectomy, or who abstains from sex, 
or who is involved in a same sex relationship is eligible. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in 
the study: 
1. History of allergy or hypersensitivity to celecoxib and similar pharmacological agents 
including any NSAID (including aspirin), or to any pre- and post- operative medications 
used in this study, including lidocaine, oxycodone or acetaminophen, as judged by the 
investigator. Subjects with conditions known to be contraindications to NSAIDS (risk of 
thrombovascular events and renal insufficiency.) 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 31 of 81 
2. Evidence or history of clinically significant haematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, neurologic diseases, malignancies, or any other 
clinically significant disease or disorder which, in the opinion of the investigator, may 
either put the subject at risk because of participation in the study, or influence the results 
or the subject’s ability to participate in the study, including but not limited to: 
a. Any bleeding or blood coagulation disorders 
b. History of an upper GI disorder within 6 months of Screening visit (e.g. gastric 
or duodenal ulcers) 
c. History of gastric bypass within 6 months of Screening visit 
d. Dysphagia 
3. History of migraine or frequent headaches, low back pain, or other acute or chronic pain 
conditions that according to the investigator’s judgment could interfere with efficacy and 
safety evaluations as required by the protocol. 
4. Acute illness or unresolved local infection prior to surgery that can interfere with the 
conduct of the study, as judged by the investigator. 
5. History of previous or ongoing psychiatric disease/condition including psychosis, affective 
disorder, anxiety disorder, borderline state and personality disorder according to the 
criteria in the Diagnostic and Statistical Manual of Mental Disorders. The following 
exceptions may be applied: 
a. Subjects with history of mild unipolar depression may be included if eligible 
otherwise, and not currently receiving SNRIs and medications referenced in 
Exclusion 10. 
b. Subjects with mild ADHD or mild anxiety may be included if eligible otherwise, 
and not currently receiving SNRIs and medications referenced in Exclusion 10.  
6. Known or suspected drug (including analgesic drugs or tranquilizers) or alcohol abuse or 
dependence, as defined by DSM-IV, and not in full remission, as judged by the 
investigator, or history of alcohol abuse or excessive intake of alcohol, defined as regular 
weekly intake of >15 units for men and >10 units for women.  (1 unit = 25 mL spirits, 125 
mL wine, 250 mL beer or lager).  
7. Any clinically significant abnormalities in clinical chemistry, hematology, coagulation 
parameters, urinalysis or serology results at screening that in the investigator’s judgment 
puts the subject at risk due to study participation.  
8. Any clinically significant 12-lead ECG abnormalities at screening according to the 
judgment of the investigator. 
9. Evidence of any clinically significant vital signs abnormality that in the investigator’s 
opinion significantly increases the risks for study participation. 
10. Positive results on urine drug screen or alcohol breath test indicative of illicit drug 
(Cocaine Metabolites, Marijuana (THC), MDMA (Ecstasy) and Phencyclidine) or alcohol 
abuse at screening and/or prior to extraction procedure. Positive results for prescription, 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 32 of 81 
(Amphetamines, Barbiturates, Benzodiazepines, Methadone, Methamphetamine, Opiates, 
Oxycodone, and Tricyclic Antidepressants.) The following exception may apply: 
a. Over-the-counter medications (non-NSAIDs), multi-vitamins and supplements 
are allowable per the opinion of the investigator or sponsor (see Exclusion 13-c).  
11. Frequent use of tobacco (smoking, snuff) or other nicotine-containing products (nicotine 
chewing gum, nicotine plaster, or other smoking cessation therapy).  Frequent use is 
defined as smoking or consumption/intake of nicotine products more than 2 days per week 
during the last 12 weeks prior to enrollment.  Note: occasional smokers/users of nicotine 
products (<5 cigarettes per day, and maximally 2 days per week) may be included in the 
study, provided that they refrain from smoking and/or the use of nicotine containing 
products for at least 10 days before administration of investigational product and for the 
duration of the study (through Day 7, ±3 days). 
12. Excessive intake of caffeine-containing foods or beverages (more than 5 units or equivalent 
per day) within 48 hours prior to surgery.  One caffeine unit is contained in the following 
items: 1 cup of coffee, 2 cans of cola, 1 glass of tea, ½ cup of energy drink (e.g., Red Bull), 
or 3 chocolate bars. 
13. Routinely uses pain medication, including any of the following: 
a. Any opioid medication equivalent to 5 mg oral morphine per day for 3 or more 
days per week within 4 weeks before surgery. 
b. Nonsteroidal anti-inflammatory drugs [NSAIDs] or selective COX-2 inhibitors 
more than 5 times per week within 4 weeks before surgery. 
c. Cannabinoids within 4 weeks before surgery. 
14. Currently taking any corticosteroid chronically (except for an inhaled steroid for 
pulmonary disease, and local topical or ophthalmic steroid) or has taken systemic 
corticosteroids within 4 weeks of the proposed date of surgery. 
15. Currently taking central nervous system (CNS) active drugs such as hypnotics, sedatives, 
monoamine oxidase inhibitors, sympathomimetic amines, benzodiazepines, tricyclic 
antidepressants, or serotonin norepinephrine reuptake inhibitors (SNRIs), and 
anticonvulsants for pain.  
a. Subjects taking a stable dose of selective serotonin reuptake inhibitors (SSRIs) to 
treat mild depression for at least 30 days prior to screening may be included if 
eligible otherwise. 
16. Donated blood products/ blood loss >500 mL 30 days prior to Screening or between 
Screening and surgery. 
17. Member or relative of study staff or the Sponsor directly involved in the study. 
18. Previous participation in this study. 
19. Has received another new chemical entity (defined as a compound which has not been 
approved for marketing) or has participated in any other clinical study that included drug 
treatment within 30 days prior to the Screening visit. Note: subjects consented and 
screened, but not dosed in such a study, are not excluded. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 33 of 81 
20. Previous exposure to DFN-15 in a clinical trial. 
21. Currently receiving or have received within 7 days prior to investigational product 
administration in the study, any drug (s) that is metabolized by hepatic microsomal 
enzyme CYP 2D6. For examples of drugs that are metabolized by CYP2D6, please refer 
to Table 3-1 ‘in the FDA’s development resource ‘Drug Development and Drug 
Interactions: 
Table 
of 
Substrates, 
Inhibitors 
and 
Inducers’ 
available 
at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Drug
InteractionsLabeling/ucm093664.htm. 
 
4.3. 
Post-Operative Inclusion Criteria 
1. Subjects must report “moderate” to “severe” baseline pain within 6 hours post-
surgery, as characterized on a 4-point categorical pain intensity scale (0= none, 
1= mild, 2= moderate, 3= severe)  
2. Subjects must report a score on the 11-point Numerical Pain Rating Scale 
(NPRS) of ≥5 within 6 h post-surgery, where 0 represents ‘No pain’ and 10 
represents ‘worst pain imaginable’ at study baseline.  
3. Subject has had no evidence of any clinically significant abnormality during or 
following surgery that, in the judgment of the investigator, significantly increases 
the risks due to study participation. 
4. In the judgment of the investigator, study participation would not put the subject 
at risk from the specified surgical procedure, anesthetic protocol, or specified 
analgesic regimen.  
4.4. 
Discontinuation of Subjects 
4.4.1. 
Procedures for Withdrawal 
A subject may request to be withdrawn from study participation at any time, without 
disclosing the reason if chosen not to. Subject may be discontinued from the study by 
the Investigator or the Sponsor at any time if either determines that it is not in the 
Subject’s best interest to continue participation or due to non-compliance with the 
protocol.  Investigator is encouraged to contact the study Medical Monitor to discuss 
details surrounding non-compliance. Subjects who withdraw consent to continue 
treatment or who are discontinued from the study before completing the 
protocol-specified duration of treatment should be encouraged to complete the early 
termination assessments and procedures outlined for 8 hours after treatment initiation. 
Subjects will be encouraged to agree to return to the study site 7 days (±3 days) post-
surgery for evaluation of their safety and well-being.  The date the subject is withdrawn 
and the primary reason for discontinuation will be recorded in the subject’s case report 
form (CRF). 
4.4.2. 
Replacement of Subjects 
Subjects who discontinue after randomization will not be replaced in this study. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 34 of 81 
4.5. 
Lifestyle Guidelines 
4.5.1. 
Confinement 
Prior to the surgical procedure (Day 1), subjects will arrive at the study clinic to prepare 
for the procedure and confirm eligibility to participate in the study.  Following the third 
molar extraction procedure, subjects who achieve adequate pain intensity will be 
randomized and initiate dosing with study drug.  Subjects may be discharged from the 
study clinic about 8 hours after receiving the study drug treatment. For safety and 
welfare of the subject, the site may choose to have subjects stay overnight.  Subjects will 
be allowed to ambulate normally as per standard of care instructions after surgery. 
4.5.2. 
Diet 
Subjects will remain NPO (nothing by mouth), including water, from check-in (i.e., at 
least 2 hours before the administration of the dose of study medication to randomized 
subjects) until 2 hours post-dose, on Day 1 (study day).  After 2 hours post-dose, 
subjects will be permitted to consume water, or gelatin snacks.  Subjects are prohibited 
from ingesting solid foods or carbonated beverages for at least 6 hours post-dose.  
 
 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 35 of 81 
5. 
TREATMENTS 
5.1. 
Surgical Procedure  
Study staff will verify admission and surgery schedule the day of the scheduled procedure. 
Subjects who continue to meet all eligibility requirements for study enrollment are eligible 
to receive study drug as long as the Post-Operative Inclusion Criteria are met. 
5.1.1. 
Anesthetic Care 
The subject may be administered local anesthesia with Lidocaine 2% with epinephrine 
with (maximum volume of 20 mL). Nitrous oxide and benzocaine gel are allowed. 
Sedation will not be allowed.  Long acting local anesthetics (e.g. bupivacaine and 
ropivacaine) and steroids are also prohibited.  
5.1.2. 
Surgery 
Surgical removal of the impacted third molars will be carried out per the surgeon’s 
standard of care practice. Two (2) mandibular third molar teeth will be extracted.  The 
mandibular third molars must involve a full or partial bony impaction confirmed by 
radiographic evidence.  Extraction of 1 or 2 impacted or non-impacted maxillary third 
molars as part of the surgical procedure is permitted but not required.  
5.1.3. 
Post-operative Care 
It is anticipated that subjects will receive study medication once subject meets the post-
operative inclusion criteria.  Post-surgical follow-ups will be scheduled 7 days (±3 days) 
post-surgery for evaluation of their safety and well-being. 
5.2. 
Disallowed medications 
• 
Except as indicated in the rescue analgesic regimen, any additional analgesic 
(morphine, ketorolac, ibuprofen, acetaminophen etc.).  
• 
General anesthesia, long acting local anesthetics (e.g. bupivacaine, ropivacaine) or 
other sedative medications. 
5.3. 
Administration of Study Medication 
Study drug will be administered as follows: 
1. Subject must be in an upright position before administering study drug.   
2. Study drug will be administered to the subject by qualified medical staff.  
3. Subjects will receive a single dose of the assigned study treatment (DFN-15 [62.5 
mg, 125 mg, or 250 mg] or placebo) administered, as a total volume of 10 mL, 
according to the randomization number.  
5.4. 
Identity of Study Medication 
DFN-15 is an oral solution containing 25 mg/mL of celecoxib.  Each mL of DFN-15 will 
contain 25 mg celecoxib.  DFN-15 will also contain the inactive ingredients, lauroyl 
polyoxylglycerides, glyceryl caprylate, caprylic/capric triglyceride, polyoxyl 35 castor oil, 
polyoxyl 40 hydrogenated castor oil, propyl gallate, menthol, magnasweet, sucralose, 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 36 of 81 
acesulfame potassium, peppermint flavor, banana flavor, bubble gum flavor, glycerol, 
ethanol, and water.   
DFN-15 and matching placebo are packaged in amber-colored glass bottles containing 4.8 
mL solution per bottle (120 mg) and equipped with child-resistant and tamper-evident 
caps.   
A 6-month accelerated and 12-month real time stability data from the clinical batch meets 
stability specifications. The drug product for the clinical study will be continued to be 
supported with appropriate stability testing for the duration of any clinical study. 
The DFN-15 formulation and the matching placebo are manufactured for the Reddy’s 
Laboratories Limited by:  Contract Pharmaceuticals Limited Canada, 7600 Danbro 
Crescent, Mississauga, ON L5N 6L6, Canada 
The active pharmaceutical ingredient for DFN-15 is manufactured for Dr. Reddy’s by:  
Hetero Drugs, Ltd., Narasapuram Village, Nakkapally Mandal, Vishakhapatnam, Andhra 
Pradesh, India.  Manufacturing of the study drug was performed according to Good 
Manufacturing Practice for Medicinal Products and all relevant regulatory requirements. 
5.5. 
Method of Assigning Subjects to Treatment Groups 
A computer-generated randomization scheme will be prepared prior to study initiation.  
Subjects will be randomly assigned to treatment with DFN-15 62.5 mg, DFN-15 125 
mg, DFN-15 250 mg, or placebo in a 1:1:1:1 assignment ratio according to the 
randomization scheme.  All study doses administered will be according to the treatment 
assignment. Male and female subjects (approximate ratio of 1:1) who meet all of the 
inclusion criteria (including postoperative inclusion criteria) and none of the exclusion 
criteria will be stratified.  
5.6. 
Selection of Doses 
The selection of doses of DFN-15 to be evaluated in this exploratory study is based upon 
pharmacokinetic modelling using data from PK studies of DFN-15 in healthy subjects, 
and from the exposure-pain intensity response relationship that is reported for 
Celebrex® in acute pain.  
5.7. 
Selection of Timing of Dose 
Subjects will receive a single dose of study medication.  Study drug will be administered 
if the subject achieves adequate pain symptoms (i.e. NPRS ≥5 out of 10 and pain of 
‘moderate’ or ‘severe’ intensity on a 4-point categorical pain intensity scale) to be 
randomized in the study.  The exact time of study drug administration start will be 
recorded in the subject’s CRF.   
5.8. 
Blinding and Unblinding of Study Medications 
All doses administered in this study will be under double-blind conditions; both the 
subject and the investigator/site staff directly involved with the surgery, or 
efficacy/safety/PK assessments and the Sponsor personnel, will be blinded to the 
treatment assignment.   


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 37 of 81 
Each dose of study medication will be prepared by a designated unblinded pharmacist at 
the site, as per the randomization schedule. Each dose will consist of a total volume of 
10 mL of solution administered orally. The unblinded pharmacist, who is not otherwise 
involved in the study, will prepare dose per the randomization schedule by pulling four 
bottles of either active or placebo oral solution. Pharmacist will pull solution from each 
of the four bottles into each of the four 2.5 mL dosing syringes, and provide the blinded 
dosing syringes containing the oral solution dose to the blinded staff member/s, who will 
administer the study medication as per Section 5.3. 
The study site will be provided with individually sealed envelopes identifying the study 
medication each subject receives in the study.  The treatment for an individual subject may 
be unblinded in the event of an emergency, or if the safety of a subject is at risk and the 
treatment plan for that subject depends on which study medication he or she received. In 
the event of emergent medically necessary unblinding, the blind may be broken by removing 
the code break envelopes provided for the assigned randomization number without 
breaking the code for any other subject.   
Unless the subject is at immediate risk, the investigator must make diligent attempts to 
contact the designated Medical Monitor before unblinding the subject’s data. If a subject’s 
data are unblinded without the prior knowledge of the Medical Monitor, the investigator 
must notify the Medical Monitor as soon as possible and no later than the next business 
morning. All circumstances surrounding a premature unblinding must be clearly 
documented. 
The sealed randomization envelopes should be stored in a locked area with controlled access 
until required to break the blind in the event of an emergent condition in a treated subject.   
5.9. 
Treatment Compliance and Safety 
Designated study personnel will directly administer study medication with designated 
study personnel verifying medication administration. Time of medication administration 
(T0 = time of dosing) will be recorded into the CRF. 
Study investigators will review the investigational brochure prepared for DFN-15 in 
order to be aware of the safety related events which may be anticipated with its use.  A 
fully stocked emergency crash cart, defibrillator, oxygen, and personnel trained in 
emergency resuscitation will be available at the study center at all times during the 
confinement period. 
5.10. 
Drug Accountability 
The investigator (or designee) will sign for the study medication when received and will 
conduct an inventory of the supplies and verify that study drug supplies are received 
intact and in the correct amounts before completing a supplies receipt.  The inventory of 
supplies at the study site may be checked at any time during the study by the unblinded 
monitor.  The study medication must be handled and stored as described and dispensed 
only to those subjects formally enrolled in the study. 
It is the responsibility of the Investigator (or designee) to ensure that the study drug has 
been correctly documented for the amount received and dispensed.  A full drug 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 38 of 81 
accountability log will be maintained at the study site at all times.  All discrepancies 
must be accounted for and documented.   
At the completion of the study, and after reconciliation of all delivery and usage records, 
any unused study medication supplied by the sponsor will be returned to the sponsor (or 
designee) or destroyed per written instructions from the sponsor.   
5.11. 
Packaging, Labeling, and Storage 
DFN-15 (celecoxib oral solution) and matching placebo will be contained in an amber-
colored color glass bottle fitted with a child-resistant (CR) cap. The study packaging will 
be performed by a designated central supply management vendor.  All packaging and 
labeling operations will be performed according to Good Manufacturing Practice for 
Medicinal Products and all relevant regulatory requirements.   
Study medication should be stored in a pharmacy or locked and secured in a storage 
facility at the study site at temperatures between 20ºC to 25ºC (68ºF to 77ºF); excursions 
permitted between 15°C and 30°C (59°F and 86°F) [See USP controlled room 
temperature].  Do not refrigerate or freeze.  The room should be accessible only to 
authorized individuals.  The study medication should also be protected against direct 
heat, light, and humidity. A temperature log or chart should be maintained to monitor the 
environment at the study site. 
Deviations from the storage requirements or any observed potential problems with the 
investigational product (i.e. breakage, cracks, leakage, mislabeling), including any 
actions taken, must be documented on the sponsor provided “Investigational Product 
Complaint Form” and reported to the sponsor.  
5.12. 
Prior and Concomitant Medications 
All medications and other treatments taken by subjects within 28 days before dosing and 
during the study will be recorded in the CRF. Any changes in the concomitant 
medications after discharge from the study, that is either prescribed or self-administered, 
will be documented and reviewed at the end of study visit. 
5.13. 
Prohibited Medications 
Prior to surgery, subjects should refrain from taking analgesics or anti-inflammatory 
agents whose duration of action will affect scheduled study evaluations.  After study drug 
treatment, subjects must be willing to refrain from use of pharmacologic or non-
pharmacologic treatments, and other forms of pain relief other than the pain relief regimen 
prescribed during the study. 
The following medications are prohibited throughout the study:  
• anticonvulsants,  
• Monoamine Oxidase Inhibitors (MAOIs), 
• Tricyclic Antidepressants (TCA),  
• Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) (Serotonin selective 
Reuptake Inhibitors (SSRI) treatments are allowed if taken for at least 30 days 
before the screening period of the study at an unchanged, stable dose), 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 39 of 81 
• Narcotics (other than pre-specified rescue analgesic regimen of 1-2 tablets of 5 mg 
oxycodone), including: hydrocodone, codeine, fentanyl, meperidine, tramadol, 
opioid combinations, 
• Acetaminophen (other than pre-specified rescue analgesic regimen of 325 mg 
acetaminophen Q4H prn), and nonsteroidal anti-inflammatory agents (NSAIDS). 
Aspirin (acetylsalicylic acid) is prohibited unless taken for cardiac or 
cardiovascular prophylaxis at a dose no higher than 100 mg daily,   
• Sedatives (including benzodiazepines) used as minor tranquilizers or hypnotics are 
not allowed unless approved by the investigator and medical monitor, 
• Gabapentin or pregabalin,  
• Medication or therapies that may act synergistically with the study drug e.g. 
barbiturates, drugs with enzyme inducing properties (CYP 2B6 inhibitors, CYP2C9 
inhibitors and inducers, CYP3A4 inhibitors) e.g. rifampicin, St. John’s Wort, etc., 
• Medications that are metabolized by the hepatic microsomal enzyme CYP2D6. 
(please refer to Table 3-1 in the FDA’s  development resource ‘Drug Development 
and Drug Interactions: Table of Substrates, Inhibitors and Inducers’ available at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResourc
es/DrugInteractionsLabeling/ucm093664.htm, for drugs that are substrates for 
CYP2D6. 
• General anesthetics, long-active local anesthetics (e.g. bupivacaine, ropivacaine), 
•  Anti-psychotic medications (e.g. neuroleptics such as haloperidol). 
5.14. 
Concomitant Interventions and Procedures 
All interventions or procedures, whether diagnostic or therapeutic, will be recorded in 
the CRF, along with time, date, and reason for the intervention or procedure.  If an 
intervention or procedure is implemented to treat an AE, the event must be recorded as 
an AE, along with all relevant information. 
Use of antibiotics may be allowed per the surgeon’s standard of care practice. 
Medication or therapy may be given when deemed necessary by the Investigator to treat 
adverse events.  Such administration, however, may require discontinuation of the subject 
from further study participation.  The administration of any additional medication must 
be documented in the Subject’s Source Note as appropriate. 
The use of concomitant medications during the study, or changes in the dose or dosing 
frequency of medications used prior to the study start will be documented. 
Use of physical therapy for management of pain is not permitted from baseline assessment 
until 8 hours post-dose. 
5.15. 
Rescue Medication 
Allowed Postoperative Analgesic Regimen 
1. From end of surgery until prior to T0 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 40 of 81 
No analgesic concomitant medications are allowed. If subjects are 
inappropriate to randomize, they must be screen failed. 
2. Post T0 rescue analgesic regimen (T0-T8) 
        
The following will comprise the post T0 supplemental analgesic medication 
regimen: 1-2 tablets (5 mg) oxycodone/ (325 mg) acetaminophen Q4H prn.  
For subjects who require additional analgesia, additional analgesic medication may be 
administered per the surgeon’s standard of care.   
Efforts should be made to encourage the Subject to wait at least 120 minutes after 
initiation of study therapy (T0) before receiving post T0 supplemental analgesic 
medications, if possible.  If subjects rescue, they will record their NPRS, PR and Patient 
Rating of Treatment satisfactoriness prior to receiving rescue medication.   


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 41 of 81 
6. 
STUDY PROCEDURES 
Schedules of study procedures for overall study assessments and day-of-dosing 
assessments are provided in APPENDIX A: . 
6.1. 
Order of Study Procedures 
The order of the procedures to be performed at any scheduled time, where applicable, 
will be as follows: 
1. Demographics, eligibility, medical history 
2. 12-lead ECG 
3. Vital Signs 
4. 4-point PI (pre-dose timepoint only) 
5. 11-point NPRS 
6. PR 
7. Patient Rating of Treatment satisfactoriness (8-hours post-dose timepoint only) 
8. Collection of pharmacokinetic blood samples 
9. Collection of clinical laboratory blood samples 
Efficacy assessment windows are referenced in Sections 6.3.5 and 6.3.6. PK collection 
windows are referenced in Section 6.2.2. Efficacy assessments and PK samples are to be 
targeted for specified timepoints, with ECG completed within a window of ± 45 
minutes, and vital signs should be completed within a window of ± 30 minutes prior, as 
illustrated in Sections 6.4.2 and 6.4.3. The actual time the study procedure is completed 
will be recorded. 
6.2. 
Pharmacokinetic Assessments 
6.2.1. 
Pharmacokinetic Groups 
Pharmacokinetic samples will be collected from all randomized participants prior to and 
following administration of study medication.  A maximum of twelve 4 mL blood 
samples will be taken from each participant up to 8 hours after study drug 
administration.  
6.2.2. 
Sample Collection 
About 4 mL whole blood will be collected in K2-EDTA/K3EDTA collection tubes. 
Plasma samples will be collected within ±5 minutes of the scheduled post-dose time 
through 1 hour after dosing; samples collected after the first hour after dosing may be 
collected within ±10 minutes, immediately following the efficacy assessments.  Actual 
times will be recorded for all events, and any deviation outside the specified ranges must 
be clearly documented in the subject’s study records. 
6.2.3. 
Processing, Storage, and Shipping of Pharmacokinetic Samples 
Immediately after the collection of each sample, the collection tube will be gently 
inverted and then placed in wet ice.  Within 30 minutes of withdrawal, the tubes will be 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 42 of 81 
centrifuged at about 3,000 rpm for 10 minutes to separate the plasma.  Two aliquots of 
equal volumes of plasma (the primary containing about 1 ml and the secondary 
containing the remaining amount) will be transferred from each sample with clean 
pipettes and placed in 2 polypropylene storage tubes.  The storage tubes will be labeled, 
at minimum, with protocol number, subject number, and relative time of sample (e.g., 
0.5H post dose), and biologic matrix to be analyzed (e.g., plasma).  Within 60 minutes of 
the collection time, the storage tubes will be placed into a freezer at –20ºC or below; 
they will remain in the freezer until shipped. 
At a time designated by the sponsor, the samples will be packed with sufficient dry ice 
to keep them frozen for at least 48 hours and shipped to the following address: 
Investigator: Malleswar Kollu, Director Bioanalytical 
Site: Sannova Analytical, Inc. 
155 Pierce Street 
Somerset, NJ 08873 
Tel: 732-560-0066 
Fax: 732-560-0266 
 
On the day prior to shipment, clinical staff will notify (via telephone or email) the 
analytical laboratory of the pending shipment. 
6.2.4. 
Bioanalytical Methodology 
Plasma samples will be assayed for concentrations of using a validated method of liquid 
chromatography coupled with tandem mass spectrometry, at Sannova Analytical, Inc. 
6.3. 
Demographic and Efficacy Assessment 
6.3.1. 
Demographics  
Demographics information will be collected during screening visit including age, sex, 
ethnicity, race, weight, height, and BMI and recorded into source and CRF as Kg/m2. 
6.3.2. 
Medical/Medicinal History 
The Investigator or designee will document each subject’s medical and medicinal history 
during the screening visit.  Medical and medicinal history will be updated on Day 1 
when the subject is admitted to the study unit, and the subject inclusion/exclusion 
criteria will be reviewed to confirm that they continue to meet the required study 
inclusion and exclusion criteria. 
6.3.3. 
Physical Examination 
The Investigator or designee will perform a physical examination (HEENT, 
cardiovascular, respiratory, gastrointestinal, neurological, dermatologic, and 
musculoskeletal systems) during the screening visit, after completion of the 8-hour post-
dose efficacy and safety assessments (prior to discharge,) and at the end of study visit on 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 43 of 81 
Day 7.  Body weight and height will be measured, and BMI will be calculated during the 
screening visit only.    
The study Investigator may perform a physical examination (the extent of which is 
determined by the study investigator) at any time during the study if indicated by change 
in a subject’s medical history or condition. 
6.3.4. 
Dental Examination 
At the screening visit, the Investigator or designee will perform a panoramic x-ray 
documenting the impacted mandibular third molar teeth. An oral examination will also be 
performed as part of end of study assessment to ensure incision wound healing is 
progressing as expected. 
6.3.5. 
Pain Intensity: 4-Point Categorical Pain Intensity (PI) and Numerical 
Pain Rating Scale (NPRS)  
PI will be assessed using Numerical pain rating scale (NPRS) by the study subject, 
following training on how to perform the assessment, for their current tooth extraction 
pain according to an 11-point numeric pain rating scale (0 - 10) where 0 equates to ‘no 
pain’, and 10 equates to ‘worst pain imaginable’.  See Appendix B.1: 
Pain Intensity 
Assessment. 
After surgery, when the subject is sufficiently awake to be able to follow directions, 
subjects will be assessed for postoperative inclusion criteria.   Subjects will be eligible 
for randomization if pain intensity is reported as ‘moderate’ or ‘severe’ level on a 4-
point categorical pain intensity (PI) rating scale (with categories of ‘none’, ‘mild’, 
‘moderate’, or ‘severe’), plus an NPRS score ≥5 (scale of 0 to 10 where 0 is ‘no pain’ 
and 10 is the ‘worst pain imaginable’).  The 4-point categorical rating scale for pain 
intensity will be completed only at baseline.   
Subjects will be randomized and administered the study medication within 15 minutes of 
meeting the post-operative inclusion criteria (baseline score).   The NPRS score 
completed prior to randomization will be utilized as the baseline pain intensity score.  
T0 is the time of first study drug administration. 
NPRS will be performed at: baseline, then 15, 30, and 45 minutes, then at 1, 1.5, 2, 3, 4, 
5, 6, 7, and 8 hours after treatment initiation (T0).  Pain intensity assessments will also 
be completed before taking first rescue medication dose (within 5 minutes prior to 
rescue dose) and/or at time of early discontinuation. All assessments should continue per 
protocol even after rescue is taken. 
There will be a ± five (5) minute window allowed for the timing of each pain intensity 
assessment in the first 2 hours post T0 then a ±10-minute window for subsequent PI 
assessments.   
As much as possible, rescue analgesic medication should be administered only if PI 
prior to rescue is ≥4 on the numerical pain rating scale (NPRS). 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 44 of 81 
6.3.6. 
Pain Relief (PR) 
Pain Relief (PR) will be assessed by the study subject according to a 5-point 
categorical scale, where (where 0= no relief, 1= little relief, 2= some relief, 3= a lot of 
relief, 4= complete relief).  See Appendix B.2: 
5-Point 
Categorical 
Pain 
Relief 
Assessment. 
PR will be assessed at: 15, 30, and 45 minutes, then at 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours 
after treatment initiation (T0).  PR assessments will also be completed before taking first 
rescue medication dose, (within 5 minutes prior to rescue dose) and/or at time of early 
discontinuation.  
There will be a ± five (5) minute window allowed for the timing of each PR assessment 
in the first 2 hours post T0 then a ±10 minute window for subsequent PR assessments.   
6.3.7. 
Time to Perceptible Pain Relief and Time to Meaningful Pain Relief 
Time to perceptible pain relief and time to meaningful pain relief will be measured using 
the ‘two stopwatch’ method.  For each randomized subject, two stopwatches will be 
started immediately after administration of the first study dose (T0).  The first stopwatch 
will be given to each subject with the instructions to stop the watch when they first 
perceive pain relief to occur (‘time to perceptible relief’).  Once the first watch is 
stopped, the second stopwatch will be given to the subject with the instructions to stop 
the watch when they are first experiencing meaningful pain relief (‘time to meaningful 
relief’).  The stopwatch times to perceptible and meaningful pain relief will be recorded 
in the subject’s CRF. 
6.3.8. 
Patient Rating of Treatment satisfactoriness 
Subjects will be asked to evaluate the performance of their study medication as a pain 
treatment in response to the following inquiry; “Please rate how well your pain has been 
controlled since you received study medication? 0-poor, 1-fair, 2-good, 3-very good, or 
4-excellent.”  See Appendix B.3: 
5-Point Patient Rating of Treatment 
Satisfactoriness. 
The assessment will be completed at 8 hours after treatment initiation, prior to discharge 
from the research center (before 8-hour post-dose PK and safety lab collection), or at 
least 5 minutes prior to first rescue analgesic dose, and/or early discontinuation. 
6.4. 
Safety Assessments Description  
6.4.1. 
Clinical Laboratory Tests 
During the screening visit, at the 8-hour discharge or early discontinuation, subjects will 
have blood samples collected for routine clinical laboratory testing.  Clinical laboratory 
testing should only be performed at the end of study visit on Day 7 if there is a clinically 
significant abnormality or ongoing AE(s). The hematology, coagulation profile, serum 
chemistry, and serology parameters, as well as urinalysis parameters that will be 
evaluated at each of these times is listed in APPENDIX C: PANEL OF CLINICAL 
LABORATORY TESTS   
In addition, a urine drug screen and alcohol breath test will be conducted at the 
screening visit, and during admission/Check-in to the study unit on Day 1.  Urine drug 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 45 of 81 
screen will include urine screen for cocaine, marijuana, opiates, amphetamines, 
methamphetamines, phencyclidine (PCP), benzodiazepines, barbiturates, methadone, 
oxycodone, ecstasy (MDMA), and propoxyphene. 
Urine pregnancy testing will be completed at the screening visit, at prior to surgery on 
Day 1 and at the end of study visit at Day 7.  
Clinical safety laboratory test will also be collected at time of termination from the study 
for subjects who prematurely discontinue study participation. 
6.4.2. 
Vital Sign Measurements 
Resting vital signs (VS) will include resting blood pressure, resting pulse rate, and 
respiratory rate. Resting tests must be obtained after resting (seated or supine with ECG 
leads connected, consistently applied) for ≥ 5 minutes.  Resting vital signs will be 
collected at screening, Day 1 prior to surgery, at pre-dose baseline, and then at 1, 2, 4, 
and 8 hours after the administration of study medication, or at time of early 
discontinuation, and at the end of study visit on Day 7 (± 3 days). Screening resting vital 
signs will be done in 3 determinations about 2 minutes apart to ascertain subject’s true 
baseline heart rate and blood pressure values.   
Vital signs may be checked at additional times on an ad hoc basis per the judgment of 
the Investigator or study staff.  VS will have a ±30-minute window. 
Actual times will be recorded for all events, and any deviation outside the specified 
healthy subject ranges must be clearly documented in the subject’s study records.  The 
Investigator or the Sponsor’s Medical Monitor may exercise his/her judgment to 
terminate a subject’s participation in the study due to clinically significant changes in 
any clinical parameter. 
6.4.3. 
Electrocardiograms 
A 12-lead ECG will be completed for all subjects at screening, Day 1 prior to surgery, at 
pre-dose baseline, and at 1, 2, 4, and 8 hours after treatment initiation or at time of early 
discontinuation, as well as at the end of study visit on Day 7 (± 3 days).  At the 
Screening Visit, the12-lead ECG will be used to exclude subjects with a clinically 
significant abnormal ECG. ECGs will have a ± 45 minute window. 
The findings (i.e., classification as “normal”, “abnormal not clinically significant” or 
“abnormal clinically significant will be recorded in the subject’s CRF.   
6.5. 
Assessments by Visit 
6.5.1. 
Screening Visit 
Subjects meeting the eligibility criteria listed in Section 4 may be enrolled in the study 
after the nature and purpose of the protocol have been explained to them, and they have 
voluntarily granted written informed consent to participate.  All subjects will have a 
screening evaluation within 28 days before study drug administration.  After informed 
consent is obtained, the following procedures will be performed at the screening visit for 
all subjects: 
• Review of inclusion/exclusion criteria eligibility 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 46 of 81 
• Demographics and medical/medicinal history (Section 6.3.2) 
• Dental examination and panoramic x-ray (Section 6.3.4) 
• Physical examination (Section 6.3.3) 
• Measurement of body weight and height and calculation of BMI (Section 6.3.3) 
• 12-lead ECG (Section 6.4.3) 
• Measurement of resting vital signs (Section 6.4.2) 
• Clinical laboratory tests (Section 6.4.1) 
• Drug and alcohol screen (Section 6.4.1) 
• Urine pregnancy test for women of childbearing potential (Section 6.4.1) 
• Assessment and monitoring of AEs (Section 7) 
6.5.2. 
Day 1 (Prior to surgery) 
The subjects will be admitted to the study unit on the morning of the surgical procedure 
and the following assessments will be conducted on the day of Check-in (Day 1 prior to 
surgery) for all subjects: 
• Medical/Medicinal history update (Section 6.3.2) 
• 12-lead ECG (Section 6.4.3) 
• Measurement of resting vital signs (Section 6.4.2) 
• Drug and alcohol screen (Section 6.4.1) 
• Urine pregnancy test (Section 6.4.1) 
• Eligibility assessment.  Subjects who continue to meet pre-operative eligibility 
criteria will undergo two mandibular third molar extractions per Section 5.1. 
• Patient training program for pain assessments (Section 6.3.5) 
• Assessment and monitoring of AEs (Section 7) 
 
6.5.3. 
Day 1 (After surgery/Pre-dose Baseline) 
The following assessments will be conducted on Day 1 after surgery prior to 
administration of Dose 1 (T0) for all subjects while confined at the study clinic: 
• Assessment of baseline pain intensity (4-point categorical pain intensity (PI) 
scale and 11-point numerical pain rating scale (NPRS) (Section 6.3.5) 
• 12-lead ECG (Section 6.4.3) 
• Measurement of resting vital signs pre-dose (Section 6.4.2)  
• Pre-dose PK sample collection (Section 6.2) 
• Randomization, if subject meets I/E criteria 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 47 of 81 
• Monitoring of AEs and concomitant medication (Section 7) 
Dosing: Subject who meet post-operative inclusion criteria and are randomized into the 
study will receive the study drug per randomization assignment within 15 minutes of 
meeting qualifying baseline pain scores.  The time of the study drug administration will 
be designated as T0. 
6.5.4. 
Day 1 (Post Dose) 
The following assessments will be conducted after surgery following administration of 
the study drug for all subjects while confined at the study clinic: 
• 11-point Pain Intensity Numerical Rating Scale (NPRS) and 5-point Categorical 
Pain Relief Scale (PR) assessments at baseline, 15, 30, 45 minutes, and at 1, 1.5, 
2, 3, 4, 5, 6, 7, and 8 hours after study drug administration (T0).   (Sections 6.3.5 
and 6.3.6) 
• Measurement of time to pain relief via the ‘two stopwatch’ method (Section 
6.3.7) 
• Administer Patient Rating of Treatment satisfactoriness at 8 hours after study 
drug administration, prior to first rescue medication administration, and/or prior 
to early discontinuation. (Section 6.3.8) 
• 12-Lead ECG at 1, 2, 4, and 8 hours after treatment initiation (Section 6.4.3) 
• Measurement of resting vital signs at the following time points: at 1, 2, 4, and 8 
hours after treatment initiation.  (Section 6.4.2)  
• A maximum of twelve 4_mL blood samples will be taken from each participant 
at pre-dose and at 15, 30, and 45 minutes, and at 1, 1.5, 2, 2.5, 3, 4, 6, and 8 
hours following dosing (Section 6.2). 
• Clinical laboratory tests at 8 hours (Section 6.4.1) 
• Physical examination at 8 hours (Section 6.3.3) 
• Monitoring of AEs and concomitant medication (Section 7) 
Pain assessments (NPRS, PR and Patient Assessment of Treatment satisfactoriness), 
clinical safety lab tests, and 12-lead ECG and other procedures that are scheduled at the 
8-hour post dose time point should be collected at the time of early study termination (if 
it should occur). 
6.5.5. 
End of Study Visit (Day 7 ± 3 days) 
The following end of study safety assessments will be conducted for all subjects during 
the end of study visit on Day 7. 
• Physical examination (Section 6.3.3) 
• 12-lead ECG (Section 6.4.3) 
• Resting Vital signs (Section 6.4.2) 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 48 of 81 
• Clinical laboratory tests, only if there is a clinically significant abnormality or 
ongoing AE(s) (Section 6.4.1) 
• Urine pregnancy test for women of childbearing potential (Section 6.4.1) 
• Monitoring of AEs and concomitant medications (Section 7) 
Change in concomitant medications after discharge will be documented and reviewed. 
Clinically significant adverse events, examination or test results will be followed until 
appropriate resolution can be documented. 
In the event of early termination (ET), every attempt should be made to have the subject 
return to the site to complete procedures listed within this section and in APPENDIX A: 
.  
The efficacy measures utilized in this study are commonly used in clinical studies 
performed in acute postoperative pain populations.  The timing of assessments is 
intended to evaluate the time to onset of analgesia, duration of effect and magnitude of 
benefit. 
The selected pharmacokinetic sampling times and parameters are appropriate to support 
the objectives of this study.  Sample times will allow evaluation of the rate and extent of 
absorption of the study dose, and help in establishing exposure-response analysis, if any.  
Safety measures used in this study are standard for clinical trials of investigational 
medications.  
6.6. 
Clinical Stopping Rules 
This study will be discontinued if it is determined that there is a significant safety risk 
posed towards study subjects.  Potential safety risks will be evaluated continuously 
throughout the course of enrollment in the study.   
 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 49 of 81 
7. 
ADVERSE EVENTS 
The investigator is responsible for the detection and documentation of events meeting 
the criteria and definition of an Adverse Event (AE), Serious AE (SAE), or Serious 
Suspected Adverse Reaction (SSAR) as provided in this protocol.  During the study, 
when there is a safety evaluation, the investigator or site staff will be responsible for 
detecting AEs and SAEs, as detailed in this section of the protocol. 
7.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related. 
An AE may be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a study medication, 
whether or not considered causally associated with the use of the study medication.  Any 
abnormal laboratory value deemed clinically significant by the investigator, regardless 
of causal relationship, must be reported as an AE. 
Examples of an AE include the following: 
• significant or unexpected worsening or exacerbation of the condition or 
indication under study 
• exacerbation of a chronic or intermittent preexisting condition, including either 
an increase in frequency or intensity of the condition (e.g., abnormal physical 
examination finding) 
• signs, symptoms, or clinical sequelae of a suspected interaction 
• signs, symptoms, or clinical sequelae of a suspected overdose of the study 
medication or a concurrent medication (overdose per se should not be reported as 
an AE or SAE, unless non-serious or serious sequelae occur) 
• symptoms or behavior suggesting cognitive or psychiatric disturbance 
The following examples are not considered AE’s: 
• medical or surgical procedure (e.g., endoscopy, appendectomy), although the 
condition that leads to the procedure is an AE 
• anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
(including laboratory values) present or detected at the start of the study that do 
not worsen 
• the disease or disorder being studied, or expected progression, signs, or 
symptoms of the disease or disorder being studied, unless they become more 
severe or occur with a greater frequency than expected for the subject’s condition 
All AE’s, whether volunteered, elicited, or noted on physical examination, and 
regardless of causality or seriousness, will be assessed and recorded in the CRF 
beginning after administration of study medication through the final follow-up 
assessment (approximately 7 ± 3 days after the last study drug administration).  AE’s 
will be assessed and recorded after administration of study medication through the Day 7 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 50 of 81 
visit (see Sections 7.2 and 7.3). In addition, if the investigator becomes aware of the 
occurrence of a SAE within 30 days of the last visit, the SAE should be reported as 
outlined in Section 7.7. 
7.2. 
Definition of a Serious Adverse Event (SAE) 
An SAE is defined as any event that meets the following criteria: 
• It results in death or is life-threatening (i.e., presents an immediate risk of death 
from the event as it occurred).  (This criterion is not intended to include an AE 
that, had it occurred in a more severe form, might have caused death.) 
• It results in persistent or substantial disability or incapacitation.  (This criterion is 
not intended to include experiences of relatively minor medical significance, 
such as uncomplicated headache, diarrhea, or sprained ankle.) 
• It results in hospitalization. 
• It results in prolongation of an existing hospitalization. 
• It is a congenital anomaly or birth defect. 
• It requires medical or surgical intervention to prevent any of the above outcomes. 
Medical and scientific judgment should be exercised in determining whether an AE is 
serious when considering important medical events that may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent any of the other outcomes listed.  Examples of such 
medical events that may also be considered serious include, but are not limited to, 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalization. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline does not meet the definition of an SAE. 
Social or convenience admission to a hospital or prolongation of a hospitalization for 
social or convenience reasons not associated with the occurrence of an AE does not meet 
the definition of an SAE. 
7.2.1. 
SAEs That Occur Before Administration of Study Medication 
Before administration of study medication, only SAEs assessed by the investigator as 
related to study participation (e.g., related to study procedures or a change in existing 
therapy) will be transcribed onto the SAE reporting form and reported to the sponsor. 
7.2.2. 
SAEs That Occur After Study Completion 
If an Investigator becomes aware of an SAE or death that occurs in a subject more than 
30 days after the subject receives study medication and that investigator considers the 
event to be related to the study medication, the investigator is obligated to report the 
SAE to the sponsor. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 51 of 81 
7.3. 
Definition of a Suspected Adverse Reaction (SAR) 
A SAR is defined as any adverse event for which there is a reasonable possibility that 
the adverse event was caused by the study drug.  For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
7.4. 
Definition of a Serious Suspected Adverse Reaction (SSAR) 
A SSAR is any Suspected Adverse Reaction that is determined to be serious, based on 
the outcomes of a SAE described in Section 7.2; i.e. death, life-threatening, causes or 
prolongs inpatient hospitalization, causes a persistent of significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital 
abnormality/birth defect. 
7.5. 
Recording and Evaluating Adverse Events and Serious Adverse Events 
It is the responsibility of the Investigator to collect all adverse events (AEs), serious and 
non-serious, derived by spontaneous, unsolicited reports of subjects, by observation and 
by routine open questionings e.g., "How have you felt since I last saw you?" 
For randomized and enrolled patients, AEs will be captured from the time of signing of 
Informed Consent Form until End of Study or Early Termination. Adverse events/ 
Serious Adverse Events (SAEs) should be followed to resolution, stabilization, or until 
30 days after the last dose of the study drug upon which patients will be referred to their 
primary medical provider for follow-up. 
All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate eCRF.  
Subjects should be instructed to report any adverse event that they experience to the 
Investigator, after signing the Informed Consent.  Investigators should make an 
assessment for adverse events at each visit and record the event on the appropriate 
adverse event eCRF.  
Pre-existing conditions will be recorded in the subject’s source record and eCRF on the 
Medical History or appropriate page.  
A treatment-emergent AE (TEAE) will be defined as an AE that begins or that worsens 
in severity after at least one dose of study drug has been administered. 
Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that 
are detected during the study or are present at baseline and significantly worsen during 
the study should be reported as adverse events.  
The Investigator will exercise his or her medical and scientific judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. Significant abnormal laboratory values occurring during the clinical study 
will be followed until repeat tests return to normal, stabilize, or are no longer clinically 
significant. The Investigator will attempt to establish a diagnosis of the event on the 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 52 of 81 
basis of signs, symptoms, or other clinical information.  In such cases, the diagnosis, not 
the individual signs or symptoms, should be documented as the AE or SAE. 
Adverse event reporting will extend from signing of informed consent until End of Study 
visit /Early Termination visit. All AEs, regardless of the relationship to study drug, will be 
recorded in the subject source record and eCRF.  Standard medical terminology should be 
used when describing AEs. The anatomical location of the AEs must be specified where 
applicable. 
 
7.5.1. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study, using his or her clinical judgment.  The intensity of each AE and SAE 
recorded in the CRF should be assigned to one of the following categories: 
• mild:  an event that is easily tolerated by the subject, causes minimal discomfort, 
and does not interfere with everyday activities 
• moderate:  an event that is sufficiently discomforting to interfere with normal 
everyday activities 
• severe:  an event that prevents normal everyday activities 
An AE that is assessed as severe should not be confused with an SAE.  Severity is a term 
used to describe the intensity of a specific event, and both AEs and SAEs can be 
assessed as severe.  The event itself, however, may be of relatively minor medical 
significance (such as a severe headache).  This is not the same as serious, which is based 
on the subject’s or event’s outcome or on action criteria usually associated with events 
that pose a threat to a subject’s life or functioning (see Section 7.2). 
7.5.2. 
Assessment of Causality 
The investigator is obligated to use his or her clinical judgment to assess the relationship 
between the study medication and the occurrence of each AE or SAE.  The investigator 
will assess the relationship to the study medication by using the following criteria: 
• Definitely Related:  An AE has a strong temporal relationship to the study drug.  
The AE is most likely explained by study drug.  Dechallenge and rechallenge (if 
possible) are positive.  The AE is consistent with a known response to the study 
drug.  Another etiology is unlikely or significantly less likely. 
• Probably Related:  An AE has a strong temporal relationship to the study drug.  
The AE is more likely explained by study drug than by another cause.  
Dechallenge (if performed) is positive. 
• Possibly Related:  An AE has a reasonable temporal relationship to study drug.  
The AE could have been due to another equally likely cause.  Dechallenge is 
positive. 
• Not Related:  The subject did not receive the study drug OR the AE has no 
temporal relationship to study drug OR the AE has a much more likely alternate 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 53 of 81 
etiology OR the AE is due to an underlying or concurrent illness or effect of 
another drug. 
Even in situations in which minimal information is available for the initial SAE report, it 
is important that the investigator always make an assessment of causality for every event 
before transmitting the SAE reporting form and completing the AE CRF page(s).  The 
causality assessment is one of the criteria used when determining regulatory reporting 
requirements.  The investigator may change his or her opinion of causality in light of 
follow-up information and amend the SAE reporting form and AE CRF page(s) 
accordingly. 
7.5.3. 
Assessment of Outcome 
All SAEs must be followed until they are resolved, the condition stabilizes, the events 
are otherwise explained, or the subject is lost to follow-up.  The investigator will assess 
the outcome of the event by using the following terms: 
• Recovered/Resolved:  The event resolved or the subject recovered without 
sequelae.  An event (either serious or non-serious) occurred and had an endpoint, 
and the subject experienced no restrictions.  Examples include stent placement 
for coronary artery disease (a device implanted is not a sequela), an 
appendectomy (a scar is not a sequela), a postoperative wound infection, or an 
upper respiratory tract infection. 
• Recovered/Resolved with sequelae:  The event has at least one secondary 
outcome that may result in permanent disability, functional limitation, or both.  
Such sequelae are usually limited to SAEs.  Examples include hip replacement 
resulting in foot drop (foot drop is not the intended outcome but is a risk of 
surgery), stroke resulting in paralysis, or emboli formation after a bacterial 
infection resulting in a renal infarct and loss of renal function. 
• Not Recovered/Not resolved:  At the end of the study, a non-serious event 
either has not changed in intensity or may not have recovered to baseline values, 
and the outcome is unknown.  Examples include headache, low-grade fever, or 
nausea. 
• Unknown: The subject has withdrawn from the study prematurely or is lost to 
follow-up, and the status of the event is unknown. 
• Fatal 
7.5.4. 
Assessment of Expectedness 
For the purposes of IND safety reporting, adverse events and suspected adverse events 
should be assessed as being expected or unexpected.  An AE or SAR is considered 
unexpected if it is not listed in the investigator brochure or is not listed at the specificity 
or severity that has been observed; or, if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 54 of 81 
7.6. 
Follow-up of Adverse Events and Serious Adverse Events 
Non-serious AEs will be followed after the last scheduled study visit, until an 
appropriate resolution can be documented. 
After the occurrence of an AE or SAE, the investigator is required to follow each subject 
proactively and provide further information on the subject’s condition.  All AEs and 
SAEs documented at a previous visit or contact are designated as ongoing and will be 
reviewed at subsequent visits or contacts. 
SAEs will be followed until the event resolves, the condition stabilizes, the event is 
otherwise explained, or the subject is lost to follow-up.  The investigator will ensure that 
follow-up information provided to the sponsor includes results of any additional 
laboratory tests or investigations, histopathologic examinations, or consultations with 
other healthcare professionals that serve to clarify the nature of the event, the cause of 
the event, or both. 
New or updated information will be recorded on the originally completed SAE reporting 
form and entered into the CRF pages, with all changes signed and dated by the 
investigator.  The updated SAE reporting form should be resubmitted to the sponsor 
within the time frames outlined in Section 7.7. 
7.7. 
Prompt Reporting of Serious Adverse Events to the Sponsor 
Once the investigator determines that an event meets the protocol definition of an SAE, 
he or she must notify the sponsor (both Medical Monitor and Pharmacovigilance 
Contact) within 24 hours. 
Any SAE or any outcome of death due to any cause, which occurs, during the 
course of this study, regardless of relationship to study medication, must be 
reported to the sponsor immediately (within 24 hours of site knowledge). 
Complete the SAE details reporting form and forward by email or fax, in parallel, 
to the following sponsor and Medical Monitor contacts: 
 
Dr. Srinivas Shenoy B., MD 
Dr. Shahida Hassan, MD 
Principal Scientist Clinical Development 
Associate Director- Pharmacovigilance 
Dr. Reddy’s Laboratories, Inc. 
Fax : 908-450-1510 
Email: srinivasshenoyb@drreddys.com 
Email: SAE@drreddys.com 
 
Dr. John Ruckle 
Medical Monitor 
Lotus Clinical Research 
Email: MedicalMonitorDFN-15-CD-010@lotuscr.com 
 
Questions surrounding SAEs or other emergent medical questions should be directed to 
the medical hotline at 877-508-8727. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 55 of 81 
Sponsor Pharmacovigilance Contact information: 
SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS 
Dr. Reddy’s Laboratories, Inc. 
North American Pharmacovigilance Center  
Email ID: SAE@drreddys.com 
 
US Toll-Free Fax Number: +1 877 445 3741 
Local US Fax Number: +1 908 450 1510 
 
SAE Reporting Instructions: 
1. All SAEs must be reported immediately (within 24 hours of becoming aware of the event). 
Please email the signed, scanned copy of the completed SAE form to SAE@drreddys.com 
and MedicalMonitorDFN-15-CD-010@lotuscr.com or fax the completed SAE form to 
fax number: +1 908 450 1510. 
 
2. An email acknowledgement of receipt of SAE will be sent to the reporting site within one 
business day.  
 
 
In the initial e-mail, the investigator must provide to the sponsor the following CRF 
pages, completed to the greatest extent possible: 
• AE record 
• medical history 
• prior and concomitant medications 
Also, the following documents are to be forwarded: any laboratory results, diagnostic 
test results, or medical reports relevant to the SAE.  Subject’s full names should be 
redacted from any documents that are not CRFs to protect the subject’s identity.  The 
subject initials and subject numbers should be added to these documents as identifiers.  
E-mail/ E-Fax transmission is the preferred method to transmit SAE information.  In rare 
circumstances and in the absence of e-mail capacity, notification by fax is acceptable.  
If the investigator does not have all information regarding an SAE, he or she must not 
wait to receive additional information before notifying the sponsor of the event.  The 
form must be updated when additional information is received.  Follow-up information 
received on all SAEs must be forwarded to the sponsor by using the same procedure and 
timelines as for an initial report. 
7.8. 
Regulatory Reporting Requirements  
The investigator must promptly report all SAEs to the sponsor in accordance with the 
procedures detailed in Section 7.7, “Prompt Reporting of Serious Adverse Events to the 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 56 of 81 
Sponsor.”  Reporting of SAEs to the Regulatory Authorities will be the responsibility of 
the Sponsor. Serious Unexpected Suspected Adverse Reactions (SUSARs) will be 
reported to the Regulatory Authorities.  The sponsor has a legal responsibility to notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about 
the safety of a product under clinical investigation.  Prompt notification of SAEs by the 
investigator to the appropriate project contact for SAE receipt is essential so that SSARs 
that are either unexpected or observed with increasing occurrence be reported and legal 
obligations and ethical responsibilities regarding the safety of other subjects are met. 
Investigator letters are prepared according to sponsor policy and are forwarded to the 
investigators as necessary.  An investigator letter is prepared for any SAR that is 
attributable to study medication, serious, and unexpected.  The purpose of the 
investigator letter is to fulfill specific regulatory and Good Clinical Practice (GCP) 
requirements regarding the product under investigation. 
The investigator, or responsible person according to local requirements, must comply 
with requirements related to the reporting of SAEs to the IRB or IEC. It will be 
Investigator/CRO responsibility to report the SAE to all the participating Investigators 
during the study. 
7.9. 
Precautions 
If a female subject becomes pregnant during the study, study product must be 
discontinued immediately, the subject should immediately be withdrawn from the study 
and early termination study procedures must be performed. The subject must be 
followed through the pregnancy and delivery and up to 4 weeks after delivery for infant 
status. 
Pregnancy occurring during a clinical investigation, although not considered a SAE, 
must be reported by the Investigator to Sponsor within the same timelines as a SAE 
(within 24 hours). The Investigator should report the event to the Sponsor immediately 
and complete the Pregnancy Report Form (see Section 7.7 for contact information). 
The expected date of delivery or expected date of the end of the pregnancy should be 
included in this information. The Investigator is instructed to contact the subject every 3 
months until the end of her pregnancy and report the outcome to the sponsor. The 
Investigator is instructed to contact the subject for 4 weeks after delivery for follow up 
on infant status. 
Details of the pregnancy, delivery and health of the infant should be recorded on the 
Pregnancy Report Form. 
The following outcomes of pregnancy fall under the criteria for serious adverse events 
and should be reported as such: delivery complications, spontaneous abortion, stillbirth, 
death of newborn baby, congenital anomaly, and anomaly in a miscarried/stillborn fetus.  


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 57 of 81 
8. 
STATISTICAL METHODOLOGY 
8.1. 
Determination of Sample Size 
The sample size of 120 subjects for this study was selected empirically without a formal 
statistical assumption. However, group sizes of 30-40 per group are typically sensitive in 
the dental pain model to detect acute drug effects. 
8.2. 
Study Endpoints 
8.2.1. 
Efficacy Endpoints 
The primary efficacy endpoint will be the summed pain intensity difference over the first 
6 hours (SPID6) between DFN-15 doses and placebo. The comparison of primary 
interest is DFN-15 doses vs. placebo. 
Key secondary efficacy variables will include the following: 
• 
Total Pain Relief (TOTPAR) over 2, 4, 6 and 8 hours using a 5-point categorical scale 
(TOTPAR2, TOTPAR4, TOTPAR6 and TOTPAR8) 
• 
Summed Pain Intensity Differences (SPID) at 2, 4 and 8 hours post-dose (SPID2, SPID4 
and SPID8) 
• Time to perceptible and meaningful pain relief as measured by two stopwatch 
technique 
• 
Proportion of subjects reporting treatment satisfaction outcome as either 2 = good, 3 = 
very good or 4 = excellent, on the 5-point categorical scale  
• 
Time to use of rescue medication and percentage of patients using rescue medication 
• 
Pain intensity difference at each NPRS time point (15, 30, and 45 min and 1, 1.5, 2, 3, 4, 
5, 6, 7, and 8 h) 
• 
Pain relief at each time point (15, 30, and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 h) 
• 
Characterization of plasma pharmacokinetic profiles of DFN-15 doses in fasting 
conditions (using Cmax AUC0-t, Tmax; Other pharmacokinetic parameters like AUC0-0.25, 
AUC0-0.5, AUC0-0.75, AUC0-1, AUC0-2, AUC0-3, AUC0-4, AUC0-6 will also be calculated) 
Additional exploratory analysis will be performed and pre-specified in the Statistical 
Analysis Plan (SAP). 
The comparison of primary interest in the study is DFN-15 250 mg dose versus placebo. 
The other comparisons include DFN-15 125 mg versus placebo, DFN-15 62.5 mg versus 
placebo and between two DFN-15 dose levels. 
8.2.2. 
Pharmacokinetic Endpoints 
Key pharmacokinetic endpoints will be Cmax, AUC0-t and Tmax. Other pharmacokinetic 
parameters like AUC0-0.25, AUC0-0.5, AUC0-0.75, AUC0-1, AUC0-2, AUC0-3, AUC0-4, 
AUC0-6 will also be calculated. Any other additional parameters requiring estimation 
will be included in the PK Analysis Plan. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 58 of 81 
8.2.3. 
Safety Endpoints 
The safety endpoints will include the following: 
1) 
incidence of AE’s and SAEs 
2) 
incidence of abnormal clinical laboratory tests, including routine blood 
chemistry and hematology, coagulation parameters and urinalysis 
3) 
incidence of clinically significant changes in vital signs parameters 
4) 
incidence of clinically significant abnormal ECG findings 
8.3. 
General Considerations for Statistical Analysis 
8.3.1. 
Analysis Datasets  
Modified Intent-to-Treat (mITT) Analysis Set: The mITT set will include all subjects 
who receive study drug, and have recorded at least one post dosing efficacy score.   
Safety Set:  The safety set will include all treated subjects and will be used for safety and 
tolerability assessments.   
Pharmacokinetic Set:  The pharmacokinetic set will include all subjects who have 
received a dose of DFN-15 and have at least one quantifiable concentration of celecoxib 
in plasma.   
Non-compartmental analysis as specified in a PK Analysis Plan will be used to estimate 
pharmacokinetic parameters and to present descriptive statistics using the 
Pharmacokinetic Set. Additional exposure-response analysis may be built in the full 
statistical analysis plan (SAP). Comparisons will be performed at the 0.05 two-sided 
significance level unless otherwise specified. No adjustments for multiplicity will be 
performed. Additional details of the analysis will be provided in the SAP and/or the 
clinical study report. The SAP will supersede the protocol in case of a discrepancy. 
8.3.2. 
Procedures for Handling Missing Data  
Unless indicated otherwise no imputation will be done for missing data.  However, AEs 
with missing severity assessments will be tabulated as “severe,” and AEs with missing 
relationship assessments will be tabulated as “related” for the purpose of analysis; and 
the missing data will be presented in data listing as is. 
8.3.2.1. 
PI and PR Scores Before and After Analgesic Rescue Medication 
All subjects are expected to assess their postoperative pain intensity and pain relief 
according to the pain intensity and pain relief schedule following the administration of 
study medication; those PI and PR assessments are referenced as the scheduled PIs and 
PRs.  Subjects who require rescue analgesia are expected to report their pain intensity 
and pain relief within 5 minutes before taking the rescue medication; these PI and PR are 
referenced as the pre-rescue PI and PR.  When the assessment of a scheduled PI and PR 
are done after the rescue medication the scheduled PI and PR scores will be replaced by 
the pre-rescue PI and PR scores for the purpose of efficacy analysis. This method is 
referenced as the Last Observation Carried Forward (LOCF).  The original scheduled PI 
and PR scores will be displayed on data listing along with the ‘imputed’ PI and PR 
scores.  


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 59 of 81 
8.3.3. 
Definitions for Assessment Windows 
For the purpose of data analysis, baseline measures for a given period will be the last 
measurements taken before the subject receives the study medication. 
8.3.4. 
Derived Variables 
Pain intensity scores (range from 0 to 10) should be recorded at pre-dose (Time 0; 
baseline) and at the defined post-dose intervals.  PI data with missing baseline PI score 
will be excluded from the analysis.   
8.3.5.1. 
PID and SPID     
Pain intensity Difference at time t (PIDt) = PI0 – PIt, where t =15, 30, and 45 minutes, 
then 1, 1.5, 2, 3, 4, 5, 6, 7 and 8 hours; PI0 is baseline PI score. 
Percent improvement in pain intensity at time t (% PIDt) = 100*(PI0 – PIt)/PI0 
Time weighted SPID calculations will be computed by multiplying a weight factor to 
each pain score prior to summation.  The weight factor at each time point is the time 
elapsed since the previous observation.  
8.3.4.1. 
 TOTPAR 
Time weighted TOTPAR calculations will be computed by multiplying a weight factor 
to each PR prior to summation.  The weight factor at each time point is the time elapsed 
since the previous observation.  
8.4. 
Study Population Summaries 
Population summaries will be provided for the safety analysis set included in this study. 
8.4.1. 
Disposition 
The summary tables will provide frequency counts for subject disposition (all treated 
subjects, subjects who completed the study, subjects who discontinued from the study, 
and reason for discontinuation) by treatment group and study overall.   
Disposition in terms of number of subjects excluded from each analysis sets (mITT, 
safety and pharmacokinetic) will also be provided by treatment groups and study overall. 
8.4.2. 
Demographics 
The demographic summary will include descriptive statistics for age, sex, race, weight, 
height, and BMI for the overall and by treatment group.  
8.4.3. 
Protocol Violations 
All protocol violations and deviations will be identified.  Tabulation may provide if data 
warrant. 
8.4.4. 
Treatment Compliance 
Doses of study medication will be administered by the study subjects under observation 
of study personnel while confined to the study site.  The exact time of administration of 
study medication will be documented within each subject’s CRF.  No formal summary 
of treatment compliance will be produced. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 60 of 81 
8.4.5. 
Prior and Concomitant Medications 
All prior and concomitant medications will be tabulated for the overall study population.  
Prior and concomitant medications will be coded to the therapeutic drug classes and 
generic drug names using the World Health Organization (WHO) Drug classifications 
version 1Q2013 or higher. 
8.5. 
Efficacy Analysis 
8.5.1. 
SPID and PID Analyses 
Time weighted SPID6 is the primary efficacy endpoint.  The difference among the 
treatment groups for the primary endpoint, as well as the secondary endpoints of SPID2, 
SPID4 and SPID8 will be evaluated using analysis of variance. Model will be an 
ANCOVA with treatment as main effect, and baseline PI as a covariate.  If multiple 
centers are enrolled, then center may be added as an exploratory factor and the 
interaction with treatment will be explored.  
A sensitivity analysis will be performed to examine the interaction between the 
treatment and analysis center.  If the interaction is considered significant at 0.10 
significant level a subgroup analysis by analysis center will be performed to examine the 
treatment effect at each site in order to understand the nature of the interaction between 
the treatment and analysis center.   
Analgesic effect of DFN-15 at each dose level compared to placebo will be evaluated 
using Dunnett’s test.  
PID at each time point will be summarized with descriptive statistics (sample size, mean, 
standard deviation, median, minimum, and maximum) for each treatment group; change 
from baseline within a group will be tested with 1-sample t-test.  Group mean by time 
profile will be graphically presented for pain intensity measurements.   
8.5.2. 
TOTPAR and Pain Relief Analyses 
The difference among the treatment groups for the secondary endpoints of TOTPAR2, 
TOTPAR4, TOTPAR6 and TOTPAR8 will be evaluated using analysis of variance with 
an analysis model and sensitivity analysis similar to that specified for the primary 
endpoint.  
Analgesic effect of DFN-15 at each dose level compared to placebo will be evaluated 
using Dunnett’s test. 
PR at each time point will be summarized with descriptive statistics (sample size, mean, 
standard deviation, median, minimum, and maximum) for each treatment group.  Group 
mean by time profile will be graphically presented for pain relief measurements.   
8.5.3. 
Time to Event End Points 
There are 2 types of time to event endpoints in this study: 
1) Time to perceptible pain relief and time to meaningful pain relief as measured by 
two stopwatch technique post first dose of study drug 
2) Time to first dose of rescue medication post study drug dose 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 61 of 81 
Time to event endpoints will be derived for each subject.  Subjects without the event 
will be censored at time of last evaluation.  Time to analgesic onset and time to rescue 
will be summarized graphically with Kaplan-Meier curves and compared across 
treatments using the log-rank test. Estimated percentiles for time to relief will be 
tabulated by treatment group along with number and percent subjects censored for this 
analysis. If center effect is significant based on the time weighted SPID6, the log-rank 
test for time to pain relief will be stratified by analysis center.  
8.5.4. 
Patient Rating of Treatment satisfactoriness  
Number and percent of subjects in each satisfaction category (0-poor, 1-fair, 2-good, 3-
very good, or 4-excellent) will be tabulated by treatment group.  The difference between 
the groups in global pain control will be evaluated based on proportion of subjects rated 
their pain control as good, very good, or excellent using Fisher’s exact test.   
8.5.5. 
Proportion of Subjects Requiring Rescue Medication  
The analysis will evaluate the relative risk (DFN-15 vs. Placebo) of requiring rescue 
medication during the study.  Proportions of subjects who used rescue medication at 
least once will be tabulated by treatment group; differences between each DFN-15 dose 
group and placebo will be assessed using the relative risk approach.  Observed 
incidence, estimated relative risk ratio and corresponding 95% CI for the relative risk 
will be provided.   
The number of times rescue medication used during the in-patient 8 hour evaluation 
phase will also be tabulated by treatment group. Incidence of rescue medication use will 
be summarized and analyzed with a generalized linear model using a logit link. 
8.5.6. 
Subgroup Analyses for Efficacy 
No subgroup analysis for efficacy endpoints is planned. Subgroup analyses may be 
performed as exploratory analyses if warranted. 
8.6. 
Safety and Tolerability Evaluations 
8.6.1. 
Extent of Exposure 
All subjects will be expected to receive a single dose of study medication. No formal 
evaluation of the extent of exposure will be performed. 
8.6.2. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (Version 16 or higher) will be used to 
classify all AEs with respect to system organ class and preferred term. 
Four types of summaries will be produced for the AE summary: 
1. an overall summary of AEs: number and percentage of subjects with at least 
one event and number of events for each severity for all AEs, and SAEs 
2. a summary table of AEs and SAEs by system organ class and preferred term and 
severity  
3. a summary table of AEs and SAEs by system organ class and preferred term and 
causal relationship to the Investigational Drug  


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 62 of 81 
4. a summary table of AEs and SAEs by preferred terms in descending order of 
total incidence 
AEs will be tabulated by treatment group and overall. AEs that lead to premature 
discontinuation from the study or to death will be listed separately via data listings.    
8.6.3. 
Clinical Laboratory Tests 
Laboratory values collected at each time point will be summarized by treatment group 
without formal statistical testing. 
8.6.4. 
Vital Sign Measurements 
Resting vital sign values at each time point collected will be summarized by treatment 
without formal statistical testing. 
8.6.5. 
Electrocardiograms 
The number and proportion of subjects with abnormal ECG findings at each time point 
collected will be tabulated by treatment group.  A data listing will be provided for 
subjects with changes from normal at baseline to abnormal and clinically significant 
after baseline by treatment. 
8.6.6. 
Subgroup Analyses for Safety Endpoints 
No subgroup analysis is planned for safety endpoints. 
8.7. 
Summaries of Pharmacokinetic Endpoints 
Pharmacokinetic and pharmacokinetic-pharmacodynamic analyses will be conducted 
under a separate PK analysis plan. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 63 of 81 
9. 
STUDY ADMINISTRATION 
9.1. 
Regulatory and Ethical Considerations 
9.1.1. 
Regulatory Authority Approval 
The sponsor will obtain approval to conduct the study from the appropriate regulatory 
agency in accordance with any applicable country specific regulatory requirements 
before any site may initiate the study in that country. 
9.1.2. 
Ethical Conduct of the Study and Ethics Approval 
This study will be conducted according to GCP; US 21 Code of Federal Regulations 
(CFR) Part 50 (Protection of Human Subjects); US 21 CFR Part 56 (IRBs); US 21 CFR 
Part 54 (Financial Disclosure); International Conference on Harmonization (ICH) 
Guidance for Industry, E6 GCP: Consolidated Guidance; the Nuremberg Code; and, 
where applicable the principles of the Declaration of Helsinki (Recommendations 
guiding Medical Doctors in Biomedical Research Involving Human Subjects), and with 
the NH&MRC National Statement on Ethical Conduct in Human Research (2007).   
9.1.2.1. 
Ethics Committees 
The investigator (or sponsor, where applicable) is responsible for ensuring that this 
protocol, the site’s informed consent form, and any other information that will be 
presented to potential subjects (e.g., advertisements or information that supports or 
supplements the informed consent form) are reviewed and approved by the appropriate 
IRB or IEC.  The investigator agrees to allow the IRB or IEC direct access to all relevant 
documents.  The IRB or IEC must be constituted in accordance with all applicable 
regulatory requirements.  The sponsor will provide the investigator with relevant 
documents or data needed for IRB or IEC review and approval of the study.  Before 
investigational products can be shipped to the site, the sponsor must receive copies of 
the IRB or IEC approval, the approved informed consent form, and any other 
information that the IRB or IEC has approved for presentation to potential subjects. 
If the protocol, the informed consent form, or any other information that the IRB or IEC 
has approved for presentation to potential subjects is amended during the study, the 
investigator is responsible for ensuring that the IRB or IEC reviews and approves, where 
applicable, these amended documents.  The investigator must follow all applicable 
regulatory requirements pertaining to the use of an amended informed consent form, 
including obtaining IRB or IEC approval of the amended form, before new subjects 
consent to take part in the study using the new version of the form.  The investigator 
must promptly forward to the sponsor copies of the IRB or IEC approval of the amended 
informed consent form or other information and the approved amended informed 
consent form or other information.  IRB or IEC approval of the consent forms must be 
obtained in addition to the approval given for the clinical study.  Regulatory review and 
approval may be required in some countries before IRB or IEC approval can be sought. 
9.1.2.2. 
General Considerations 
The ethical standards defined within GCP are intended to ensure the following: 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 64 of 81 
• Human subjects are provided with an adequate understanding of the possible 
risks of their participation in the study, and they have a free choice to participate 
or not. 
• The study is conducted with diligence and in conformance with the protocol in 
such a way as to ensure the integrity of the findings. 
• The potential benefits of the research justify the risks. 
Dr. Reddy’s Laboratories Limited is the sponsor of study DFN-15-CD-010.  The 
sponsor is responsible for all of the following: 
• selecting qualified investigators 
• providing investigators with the information they need to conduct the 
investigation properly 
• ensuring proper monitoring of the investigation 
• ensuring that appropriate regulatory agencies and all participating investigators 
are properly informed of significant new information regarding AEs or risks 
associated with DFN-15. 
9.1.3. 
Informed Consent 
The investigator will be provided with a sample informed consent form for this study.  
Investigators are encouraged to use the sample form; however, they may adapt the 
information to suit the needs of their institution, if necessary (although it must reflect the 
required elements of informed consent specified in 21 CFR Part 50.25).  The final 
informed consent form must be accepted by the sponsor and approved by the IRB or 
IEC.  Investigators must provide the sponsor with an unsigned copy of the final 
informed consent form before and after it is approved by the IRB or IEC.  If any new 
information becomes available that might affect subjects’ willingness to participate in 
the study, or if any amendments to the protocol require changes to the informed consent 
form, the investigator will be provided with a revised informed consent form.  The IRB 
or IEC must provide written approval of any revisions to the informed consent form in 
advance of its use. 
Investigators must provide subjects with all the information necessary to make an 
informed decision about their participation in the study, including the nature and 
intended purpose of the study, possible benefits, and possible risks. 
All information in the informed consent form should be provided in a language (whether 
written or spoken) that is as nontechnical as practical and that is understandable to the 
subjects. 
Before written informed consent is obtained, the subject should be given ample time and 
opportunity to inquire about the details of the study.  All questions must be answered to 
the satisfaction of the subject (or his or her legally authorized representative). 
Before a subject undergoes procedures specific to the protocol, the informed consent 
form must be signed and dated by the subject (or his or her legally authorized 
representative) and any other signatories as required by the IRB or IEC. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 65 of 81 
After all required signatures have been obtained, a copy of the informed consent form 
should be provided to the subject, and the original must be kept on file at the site and 
made available for review by the sponsor.  Documentation of the informed consent 
discussion must be noted in the subject’s case history. 
9.1.4. 
Investigator Reporting Requirements 
The investigator is responsible for completing and maintaining adequate and accurate 
CRFs and source documentation.  Source documentation constitutes original records 
(first point of entry, either hard copy or electronic), which may include progress notes, 
medication administration records, operation reports, laboratory reports, discharge 
summaries, and so on.   
A complete description of the investigator’s responsibilities is presented in APPENDIX 
D: . 
9.2. 
Study Monitoring 
The sponsor is responsible for ensuring the proper conduct of the study with regard to 
subject protection, ethics, protocol adherence, site procedures, and integrity of the data.  
At regular intervals during the study, the investigator will be provided with study 
monitors and will contact the study site via visits to the site, telephone calls, and letters 
in order to review study progress and CRF completion and to address any concerns or 
questions regarding the study conduct.  During monitoring visits, the following aspects 
of study conduct will be carefully reviewed: subjects’ informed consent documents, 
subject recruitment procedures, subjects’ compliance with the study procedures, source-
data verification, drug accountability, use of concomitant therapy by subjects, AE and 
SAE documentation and reporting, and quality of data. 
9.3. 
Quality Assurance 
The sponsor, a regulatory authority, or an IRB representative may visit the study site at 
any time during the study or after completion of the study to perform audits or 
inspections.  The purpose of a sponsor audit or regulatory inspection is to examine 
systematically and independently all study-related activities and documents to determine 
whether these activities were conducted according to the protocol, GCP, ICH guidelines, 
and any other applicable regulatory requirements.  Investigators should contact the 
sponsor immediately if contacted by a regulatory agency about an inspection at their 
site. 
9.4. 
Study and Site Closure 
If the sponsor, investigator, or officials from regulatory agencies discover conditions 
arising during the study that indicate that the study should be halted or that the study site 
should be closed, this action may be taken after appropriate consultation between the 
sponsor and investigator.  Conditions that may warrant termination of the study include, 
but are not limited to, the following: 
• discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 66 of 81 
• submission of knowingly false information from the research facility to the 
sponsor, study monitor, or regulatory agencies 
• failure of the investigator to comply with GCP (e.g., ICH guidelines, regulatory 
agency guidelines) 
• insufficient adherence to protocol requirements or an unacceptably high rate of 
missing, erroneous, or improperly collected data 
• evidence from the blinded data of sufficient technical problems with the study 
that one could believe with a high degree of certainty that subjects are being 
exposed to the investigational drug without a realistic expectation of evaluable 
data 
• a decision on the part of the sponsor to suspend or discontinue testing evaluation 
or development of the product 
• failure of the investigator to enroll subjects into the study at an acceptable rate. 
9.5. 
Records Retention 
9.5.1. 
Health Insurance Portability and Accountability Act of 1996 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subjects’ health information, including, but not 
limited to, the Standards for Individually Identifiable Health Information, 45 CFR 
Parts 160 and 164 (the Health Insurance Portability and Accountability Act of 1996 
privacy regulation).  The Investigator shall ensure that study subjects authorize the use 
and disclosure of protected health information in accordance with the privacy 
regulations of the Health Insurance Portability and Accountability Act and in a form 
satisfactory to the sponsor. 
9.5.2. 
Financial Disclosure 
Financial disclosure is required for this study. 
9.5.3. 
Access to Original Records 
Regulatory authorities expect that monitors, auditors, and representatives of national and 
international government regulatory agency bodies have access to original source 
documentation (see examples in Section 9.1.4) to ensure data integrity.  “Original” in 
this context is defined as the first documentation of an observation and does not 
differentiate between hard-copy and electronic records. 
9.5.4. 
Archiving of Study-Related Documents 
Records related to this clinical study must be retained either for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product.  The sponsor will notify the investigator as to when these documents no longer 
need to be retained for this use. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 67 of 81 
9.6. 
Provision of Study Results and Information to Investigators 
When a clinical study report is completed, the sponsor will provide the major findings of 
the study to the investigators. 
In addition, details of the study treatment assignment will be provided to the 
investigators to enable them to review the data to determine the outcome of the study for 
their subjects. 
The sponsor may list and summarize the results from coded samples by subject number 
in the clinical study report.  In this event, the investigator and study staff would have 
access to the research results and would be able to link the results to a particular subject.  
The investigator and study staff would be directed to hold this information 
confidentially. 
9.7. 
Information Disclosure and Inventions 
9.7.1. 
Ownership 
All information provided by the sponsor and all data and information generated by the 
site as part of the study (other than a subject’s medical records) are the sole property of 
Dr. Reddy’s. 
All rights, title, and interests in any inventions, know-how, or other intellectual or 
industrial property rights that are conceived or reduced to practice by site staff during 
the course of or as a result of the study are the sole property of Dr. Reddy’s and are 
hereby assigned to Dr. Reddy’s. 
If a written contract is executed between Dr. Reddy’s and the study site for the conduct 
of the study and that contract includes ownership provisions inconsistent with this 
statement that contract’s ownership provisions shall apply rather than this statement. 
9.7.2. 
Confidentiality 
All information provided by Dr. Reddy’s and all data and information generated by the 
site as part of the study (other than a subject’s medical records) will be kept confidential 
by the investigator and other site staff.  This information and data will not be used by the 
investigator or other site personnel for any purpose other than conducting the study.  
These restrictions do not apply to the following:  1) information that becomes publicly 
available through no fault of the investigator or site staff, 2) information that must be 
disclosed in confidence to an IEC or IRB solely for the evaluation of the study results, 3) 
information that must be disclosed in order to provide appropriate medical care to a 
study subject, or 4) study results that may be published as described in Section 9.7.3.  If 
a written contract for the conduct of the study is executed and that contract includes 
confidentiality provisions inconsistent with this statement, that contract’s confidentiality 
provisions shall apply rather than this statement. 
9.7.3. 
Publication 
For multicenter studies, the first publication or disclosure of study results shall be a 
complete, joint, multicenter publication or disclosure coordinated by Dr. Reddy’s.  
Thereafter, any secondary publications will reference the original publication(s).  If no 
multicenter publication is submitted for publication within 18 months of study database 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 68 of 81 
hard lock, then the site shall be free to disclose its own results, subject to sponsor rights 
under Section 9.7.1. 
Before submitting material for publication, presentation, or use for instructional 
purposes, or before otherwise disclosing the study results generated by the site 
(collectively, a “publication”), the investigator shall provide Dr. Reddy’s with a copy of 
the proposed publication and allow Dr. Reddy’s a period of at least 90 days to review the 
proposed publication.  Proposed publications shall not include either Dr. Reddy’s 
confidential information (other than the study results) or the personal data (such as name 
or initials) of any subject. 
At Dr. Reddy’s request, the submission or other disclosure of a proposed publication 
will be delayed a further 90 days to allow Dr. Reddy’s to seek patent or similar 
protection of any inventions, know-how, or other intellectual or industrial property rights 
disclosed in the proposed publication. 
If a written contract is executed for the conduct of the study and that contract includes 
publication provisions inconsistent with this statement, that contract’s publication 
provisions shall apply rather than this statement. 
9.7.4. 
Data Management 
The investigator (or designee) will enter subject data by using the FDA Code 21 Part 11 
compliant electronic CRF defined by clinical data management and will be performed in 
accordance with applicable standards and data-cleaning procedures.  Database freeze 
will occur when data management quality-control procedures are completed.   
In addition, validated laboratory data will be transmitted electronically from the clinical 
laboratory to Dr. Reddy’s or its designee. 
The investigator or designee must record all required data using the previously specified 
data collection method defined per CRF guidelines; an explanation must be documented 
for any critical data points.  The investigator must sign and date a declaration in the CRF 
attesting that he or she is responsible for the quality of all data recorded and that the data 
represent a complete and accurate record of each subject’s participation in the study. 
Medical coding will use MedDRA version 21.0 or higher for concomitant diseases and 
AEs, and WHO-DD version March 2018 or later for medications. 
9.7.5. 
Data Security 
Access to the data will be strictly controlled. 
9.8. 
Subject Tracking 
Drug accountability logs, a subject identification log (to be retained by the Investigator 
only), and a subject enrollment log will be used to track subject participation in the 
study. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 69 of 81 
10. 
REFERENCES 
 
1. Marret E, Kurdi O, Zufferey P, Bonnet F. Effects of nonsteroidal anti-inflammatory drugs 
on patient-controlled analgesia morphine side effects: meta-analysis of randomized 
controlled trials. Anesthesiology. 2005;102(6):1249-1260. 
2. Adams EH, Breiner S, Cicero TJ, et al. A comparison of the abuse liability of tramadol, 
NSAIDs, and hydrocodone in patients with chronic pain. J Pain Symptom Manage. 
2006;31(5):465-476. 
3. Borer JS, Simon LS. Cardiovascular and gastrointestinal effects of COX-2 inhibitors and 
NSAIDs: achieving a balance. Arthritis Res Ther. 2005;7 Suppl 4:S14-22. 
4. White PF, Tang J, Wender RH, et al. The effects of oral ibuprofen and celecoxib in 
preventing pain, improving recovery outcomes and patient satisfaction after ambulatory 
surgery. Anesth Analg. 2011;112(2):323-329. 
5. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with Celecoxib vs 
nonsteroidal anti-inflammatory drugs for osteoarthritis and reumatoid arthritis: the 
CLASS study: a randomized controlled trial. Journal of the American Medical 
Association. 2000;284(10):1247–1255. 
6. Lefkowith JB, Geis GS, Silverstein F. Safety of celecoxib vs other nonsteroidal anti-
inflammatory drugs. JAMA. 2000;284(24):3123-3124. 
7. Goldstein JL, Silverstein FE, Agrawal NM, et al. Reduced risk of upper gastrointestinal 
ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol. 
8. Moore RA, Derry S, Makinson GT, McQuay HJ. Tolerability and adverse events in 
clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and 
meta-analysis of information from company clinical trial reports. Arthritis Res Ther. 
2005;7(3):R644-665. 
9. Reuben SS, Connelly NR: Postoperative analgesic effects of celecoxib or rofecoxib after 
spinal fusion surgery. Anesth Analg 2000; 91:1221–5. 
10. Leese P, Hubbard R, Karim A et al. Effects of celecoxib, a novel cyclooxygenase-2 
inhibitor, on platelet function in healthy adults: a randomized, controlled randomized, 
controlled trial. J Clin Pharmacol 2000; 40:124–32. 
11. Warner TD, Giuliano F, Vojnovic I et al. Nonsteroid drug selectivities for cyclo-
oxygenase-1 rather than cyclooxygenase- 2 are associated with human gastrointestinal 
toxicity: A full in vitro analysis. Proc Natl Acad Sci USA 1999;96:7563–8. 
12. Reuben SS, Connelly NR: Postoperative analgesic effects of celecoxib or rofecoxib after 
spinal fusion surgery. Anesth Analg 2000; 91:1221–5. 
13. Celebrex [package insert].  New York, NY: G. D. Searle, LLC; 5/2016. Accessed 16 JAN 
2018 from http://labeling.pfizer.com/ShowLabeling.aspx?id=793. 
 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 70 of 81 
11. 
APPENDIX A: OVERVIEW OF STUDY SCHEDULE 
Assessments 
Screening 
Day 1 
Day 1 Treatment Period (0H = time of dosing) 
Dis-
charge 
EOS 
Day -28 to 
Day -1 
Check-
in / 
Prior to 
Surgery 
Surgery 
Pre-Dose 
Baseline 
0H 
15 
min 
30 
min 
45 
min 
1H 
1.5H 
2H 
2.5H 
3H 
4H 
5H 
6H 
7H 
8H 
Day 4 
to Day 
10 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess I/E 
eligibility 
X 
X a 
 
X b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/ 
medicinal 
history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/ 
Weight, height, 
BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs c 
X 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Clinical 
laboratory 
evaluation 
(Hematology, 
Coagulation, 
Serology, 
Serum, 
Urinalysis) d  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X e 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 71 of 81 
Assessments 
Screening 
Day 1 
Day 1 Treatment Period (0H = time of dosing) 
Dis-
charge 
EOS 
Day -28 to 
Day -1 
Check-
in / 
Prior to 
Surgery 
Surgery 
Pre-Dose 
Baseline 
0H 
15 
min 
30 
min 
45 
min 
1H 
1.5H 
2H 
2.5H 
3H 
4H 
5H 
6H 
7H 
8H 
Day 4 
to Day 
10 
Dental 
examination, 
including 
radiologic 
studies (if 
applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
pregnancy test 
(Women of 
child bearing 
potential) f 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine drug 
screen g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol screen g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, hepatitis 
B&C screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-L ECG h  
X 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Third molar 
extraction 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient training 
program (pain 
assessments) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4-Point 
Categorical 
 
 
 
X i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 72 of 81 
Assessments 
Screening 
Day 1 
Day 1 Treatment Period (0H = time of dosing) 
Dis-
charge 
EOS 
Day -28 to 
Day -1 
Check-
in / 
Prior to 
Surgery 
Surgery 
Pre-Dose 
Baseline 
0H 
15 
min 
30 
min 
45 
min 
1H 
1.5H 
2H 
2.5H 
3H 
4H 
5H 
6H 
7H 
8H 
Day 4 
to Day 
10 
Pain Intensity 
Scale (PI) 
11-point Pain 
Intensity 
Numerical 
Rating Scale 
(NPRS) j 
 
 
 
X i 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
5-point 
Categorical 
Pain Relief 
Scale (PR) k 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
5-point Patient 
Rating of 
Treatment 
satisfactoriness 
assessment l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Randomization
/ Study drug 
administration 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood 
sampling m 
 
 
 
X n 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Two stopwatch 
technique for 
perceptible and 
meaningful 
pain relief o 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 73 of 81 
Assessments 
Screening 
Day 1 
Day 1 Treatment Period (0H = time of dosing) 
Dis-
charge 
EOS 
Day -28 to 
Day -1 
Check-
in / 
Prior to 
Surgery 
Surgery 
Pre-Dose 
Baseline 
0H 
15 
min 
30 
min 
45 
min 
1H 
1.5H 
2H 
2.5H 
3H 
4H 
5H 
6H 
7H 
8H 
Day 4 
to Day 
10 
AE assessment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record rescue 
medication use 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE monitoring 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Record 
concomitant 
medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a) 
Assess updates since screening and evaluate for continued eligibility. 
b) 
Subject will be randomized if all I/E criteria are met, including post-operative inclusion criteria. 
c) 
Vitals include systolic and diastolic (seated) blood pressure, pulse rate and respiratory rate, seated or supine. To be completed prior to early withdrawal, prior to pain assessments, when applicable. 
d) 
Clinical laboratory evaluations will be performed according to the schedule in Appendix C. Any of the above laboratory parameters (or any additional laboratory parameter not part of the clinical lab 
evaluation) may be assessed unscheduled based on the discretion of the investigator during the study, and may be assessed during the study after consultation with the study Medical Monitor, unless 
needed in emergency to ensure the safety of the subject; in such a case, Medical Monitor should be notified as soon as possible. 
e) 
Day 7, End of study follow-up safety lab draws are to be performed only if there is a clinically significant abnormality or ongoing AE(s). 
f) 
Urine pregnancy test will be performed for all female subjects of child-bearing potential at Screening, Prior to Surgery and Randomization and at End of Study. 
g) 
Urine screen for common drugs of abuse and alcohol breathalyzer test will be performed for all subjects at screening, and prior to admission for surgery (Check-in).   
h) 
For timepoints where ECG coincides with vital signs collection, ECG must be conducted first or concurrently with vital signs. Should pain assessments and PK/ safety lab samples also coincide, 
ECG and vitals must precede applicable pain assessments, then PK and safety lab draws are to follow pain assessments; see item (l). To be completed prior to early withdrawal, when applicable. 
i) 
Pre-dose assessments only; determines randomization if “moderate” to “severe” baseline pain outcome (PI) and NPRS score ≥5.  
j) 
In addition to the stated assessment schedule, pain intensity will be assessed by the patient using the 11-point NPRS immediately within ±5 minutes of provision of rescue medication. Assessment will 
also be completed prior to early withdrawal. 
k) 
In addition to the stated pain relief assessment schedule, pain relief will be assessed by the patient using a 5-point categorical pain relief (PR) scale immediately before provision of rescue medication. 
Assessment will also be completed prior to early withdrawal. 
l) 
Patient Rating of Treatment satisfactoriness’ assessment will be completed at 8 hours after treatment initiation, or at time of first provision of rescue medication, whichever is earlier. Assessment will 
also be completed prior to early withdrawal. 
m) 
Whenever the time of a PK blood sample collection coincides with efficacy assessments, the PK sample will be drawn after the efficacy assessments are taken. Any PK sample within the first hour 
post-dose (including the sample taken at 1-hour post-dose) may be drawn ±5 minutes within the scheduled time. Any PK sample after the 1st hour post-dose may be drawn ±10 minutes within the 
scheduled time. The exact clock time of sample collection will be recorded and used in the PK analysis. To be completed prior to early withdrawal, after pain assessments, when applicable. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 74 of 81 
n) 
Pharmacokinetic (PK) blood samples drawn during treatment period, Hour 0, will be drawn immediately prior to dosing. 
o) 
All randomized subjects will be provided with two stopwatches at time of study medication administration. Subjects will be instructed to stop the first stopwatch when they first perceive pain relief to 
occur (time to perceptible relief). Subjects will be instructed to stop the second stopwatch when they first experience meaningful pain relief (time to meaningful relief).


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 75 of 81 
12. 
APPENDIX B: STUDY-SPECIFIC INFORMATION 
12.1. 
Appendix B.1: Pain Intensity Assessment 
 
4-Point Categorical Pain Intensity Scale Assessment (PI) 
Finish the statement by checking the appropriate box. “My pain at this time is:”  
 None        
 Mild       
 Moderate        
 Severe 
 
 
 
 
Assessment of Pain Intensity- 11-Point Numerical Pain Rating Scale (NPRS) 
 
On a scale of 0-10, please rate your pain by marking an ‘X” in the appropriate box 
that best describes your pain NOW. 
  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Pain 
 
 
 
 
 
 
 
 
 
worst  
pain 
imaginable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 76 of 81 
12.2. 
Appendix B.2: 5-Point Categorical Pain Relief Assessment 
(PR) 
 
Finish the statement by checking the appropriate box. “My pain relief at this time is:”  
 None - No Pain Relief        
 A Little Pain Relief    
 Some Pain Relief        
 A Lot of Pain Relief 
 Complete Pain Relief 
 
 
 
 
12.3. 
Appendix B.3: 5-Point Patient Rating of Treatment 
Satisfactoriness 
The following question will be answered by the subject 8 hours after study treatment 
initiation, or prior to first rescue analgesic dose, or prior to early discontinuation: 
“Overall, please rate how well your pain has been controlled since you received 
study medication?” 
  Poor (0) 
  Fair (1) 
  Good (2) 
  Very Good (3) 
  Excellent (4) 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 77 of 81 
13. 
APPENDIX C: PANEL OF CLINICAL LABORATORY TESTS   
Name of Clinical Laboratory Test 
Screening 
Discharge  
End of Study 
Hematology 
Total RBC count 
√ 
√ 
√ * 
Hematocrit 
Hemoglobin 
Total Leukocyte count 
Differential Leucocyte count (absolute counts and 
percentages of Neutrophils, Eosinophils, 
Basophils, Lymphocytes, Monocytes and Band 
forms) 
Total Platelet Count 
Coagulation Parameters 
Prothrombin Time (PT) 
√ 
√ 
√ * 
Activated Plasma Thromboplastin Time (Aptt) 
INR 
Serum Bio-chemistry 
Total Protein 
√ 
√ 
√ * 
Albumin 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 78 of 81 
Globulin 
A/G ratio 
Serum Electrolytes (Na+, K+, Cl-, HCO3-) 
Blood Urea Nitrogen 
Serum Creatinine 
Total Bilirubin 
Direct Bilirubin 
ALT 
AST 
Alkaline Phosphatase 
Random/Fasting Blood Glucose 
Total Cholesterol 
Triglycerides 
Serology 
Anti-HIV 1 and 2 Ab titre 
√ 
 
 
HBsAg titre 
Anti-HCV antibody titre 
Urinalysis 
Color and Appearance 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 79 of 81 
pH 
√ 
√ 
√ * 
Specific Gravity 
Blood 
Proteins 
Glucose 
Nitrites 
Leukocyte Esterase 
Bilirubin 
Urobilinogen 
Microscopy 
 
* Day 7, End of study follow-up safety lab draws are to be performed only if there is a clinically significant abnormality or ongoing AE(s). 
Urine pregnancy tests are to be performed at Day 7, end of study follow-up visit for all female subjects. 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 80 of 81 
14. 
APPENDIX D: INVESTIGATOR OBLIGATIONS 
As an investigator, you are responsible for ensuring that the study is conducted 
according to the protocol, the signed Statement of Investigator, and all applicable 
regulations. 
Debarment 
Individuals ineligible to conduct or be involved with clinical studies, including those 
ineligible as a result of debarment under the Generic Drug Enforcement Act of 1992, 
will not be allowed to conduct or work on studies sponsored by Dr. Reddy’s.  You are 
required to disclose immediately to the sponsor, in writing, if any person involved in the 
conduct of the study is debarred pursuant to a hearing by FDA under this antifraud law 
or if any proceeding for debarment is pending or is (to the best of your knowledge) 
threatened. 
Institutional Review Board 
You are required to obtain initial and continuing review and approval by an IRB or IEC 
that complies with the requirements specified in 21 CFR Part 56.  Before initiating the 
trial, you must have written approval from the IRB or IEC for the protocol, informed 
consent form, subject recruitment procedures (e.g., advertisements), and any other 
written information to be provided to the subjects.  You must submit the Investigator’s 
Brochure and any updates to the IRB or IEC for review.  The IRB or IEC must also 
provide written approval of any amendments to the protocol that affect the conduct of 
the study and any changes to the informed consent form in advance of use.  If the 
duration of the study is longer than 1 year, re-approval by the IRB or IEC must be 
obtained on a yearly basis (or at more frequent intervals if required by the IRB or IEC).  
All IRB or IEC approvals must be forwarded to the sponsor. 
You must provide reports of all SAEs from your site to the IRB or IEC.  You are also 
responsible for providing the IRB or IEC with Safety Reports of any SAEs from any 
other study conducted with the study medication.  The latter will be provided to you by 
the sponsor. 
Confidentiality and Safety of Subjects 
You are responsible for protecting the rights, safety, and welfare of subjects under your 
care and for the control of the drug(s) under investigation. 
You are responsible for keeping a record of all screened subjects, including full names 
and last known addresses.  All subjects will be identified on the CRFs by initials and 
subject numbers.  Demographic information including date of birth, sex, race and 
ethnicity will also be recorded on the CRFs.  Confidentiality of subject data will be 
maintained in accordance with local laws. 
In addition to your responsibilities for reporting AEs identified during the course of a 
subject’s participation in the study, you must also report any SAEs that occur within 
30 days after the last dose of study medication (regardless of relationship to study 
medication) and any serious adverse drug reactions (SAEs for which you consider that 


PROTOCOL DFN-15-CD-010 
Dr. Reddy’s Laboratories 
 
 
 
 
 
  
 
Protocol: DFN-15-CD-010 
Version 2.0 – 02 May 2018 
  
 
 
Page 81 of 81 
there is a reasonable possibility that the study medication caused the response) that you 
become aware of at any time (even if the event occurs more than 30 days after the 
subject’s last exposure to study medication).  This obligation is in addition to any 
protocol-specified requirement for reporting AEs occurring after the last dose of study 
medication.  Please refer to Sections 7.7 and 7.8 of this protocol for contact information 
and SAE reporting requirements. 
Study-Related Records 
You are required to maintain complete and accurate study documentation in compliance 
with current GCP standards and all applicable federal, state, and local laws, rules, and 
regulations related to the conduct of a clinical study. 
You are required to make all study documentation promptly available for inspection, 
review, or audit at your study site upon request by the sponsor, its representatives, or any 
appropriate regulatory agencies. 
Accountability of the Investigational Product 
You or your designee (i.e., the pharmacist) is responsible for accountability of the 
investigational product at the site.  You or your designee must maintain records of the 
product’s delivery to the site, inventory at the site, use by each subject, and the return to 
the sponsor or alternative disposition of any unused product.  These records must 
include dates; quantities; batch, serial, or lot numbers; and expiration dates (if 
applicable). 
You should ensure that the investigational product is used only in accordance with the 
protocol. 
 

SAP_001.pdf: 
_____________________________________________________________________________________ 
 
SD-SA-100 Version 1.0 
- Confidential –   
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Randomized, Double-Blind, Placebo-Controlled, Efficacy, Tolerability, Safety 
and Pharmacokinetic Study of Single Doses of DFN-15 in Post-Surgical Dental 
Pain 
 
 
 
 
Protocol Number: 
DFN-15-CD-010 
 
Protocol Version: 
2.0/02MAY2018  
 
Prepared For: 
Dr. Reddy’s Laboratories Limited 
 
8-2-337, Road No. 3 
  
Banjara Hills 
 
Hyderabad – 500034, Telangana 
 
India 
 
Prepared By: 
Lotus Clinical Research®, LLC 
 
 
100 W California Blvd, Unit 25 
                                         Pasadena, CA 91105 
 
626-397-2390 office  
                                         info@LotusCR.com 
                                         www.LotusCR.com 
 
  
SAP Version: 
2.0  
 
Version Effective Date: 08OCT2018  
 
 


Lotus Clinical Research 
Study- DRL DFN-15-CD-0 I 0 
Statistical Analysis Plan Version: 2.0 
Effective Date: 080CTI018 
Reviewers and Approvals 
This Statistical Analysis Plan has been reviewed and the following signatures document 
approval. 
t t f 
-
'') 
) 
Sean Kanter 
Associate Director of Biostatistics 
Lotus Clinical Research®. LLC 
 
D1 c tor of Biom 
cs 
Lotus Clinical Research®, LLC 
Dr. Srinivas Shenoy B., MD 
Principal Scientist-Clinical Development 
Dr. Reddy's Laboratories Limited 
SO.SA-100 v.I.O 
Confidential 
nc C(T £::_)1? 
Date 
Date 
Date 
PageZ of28 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 3 of 28 
 
TABLE OF CONTENTS 
 
TABLE OF CONTENTS .............................................................................................................. 3 
LIST OF IN-TEXT TABLES ......................................................................................................... 5 
LIST OF ABBREVIATIONS (COMMONLY USED) ...................................................................... 6 
1.0 
Purpose of the Analyses ............................................................................................... 7 
2.0 
Protocol Summary ........................................................................................................ 7 
2.1 
Study Objectives ........................................................................................................... 7 
2.1.1 
Safety .................................................................................................................... 7 
2.1.2 
Efficacy .................................................................................................................. 7 
2.1.3 
Pharmacokinetics .................................................................................................. 8 
2.2 
Overall Study Design and Plan ..................................................................................... 8 
2.3 
Study Population ......................................................................................................... 11 
2.4 
Study Material and Treatment Regimens .................................................................... 11 
2.5 
Randomization ............................................................................................................ 11 
2.6 
Sample Size Determination ......................................................................................... 11 
3.0 
General Analysis and Reporting Conventions ............................................................. 11 
4.0 
Analysis Populations .................................................................................................. 13 
4.1 
Modified ITT Population .............................................................................................. 13 
4.2 
Safety Population ........................................................................................................ 13 
4.3 
Per-Protocol Population .............................................................................................. 13 
4.4 
Pharmacokinetic Population (PK) ................................................................................ 13 
5.0 
Patient Summaries ..................................................................................................... 13 
5.1 
Disposition of Subjects ................................................................................................ 13 
5.2 
Major Protocol Deviations ........................................................................................... 14 
6.0 
Demographic and Other Baseline Characteristics ....................................................... 14 
6.1 
Demographics and Baseline Characteristics ............................................................... 14 
6.2 
Medical History ........................................................................................................... 14 
6.3 
Prior and Concomitant Medication .............................................................................. 14 
6.4 
Non-Medication Therapies and Surgery Details .......................................................... 15 
7.0 
Measurements of Treatment Exposure and Compliance ............................................ 15 
8.0 
Efficacy Evaluation ..................................................................................................... 15 
8.1 
Overview of Analysis Issues ....................................................................................... 15 
8.1.1 
Handling of Dropouts or Missing/Invalid Data....................................................... 15 
8.2 
Efficacy Endpoints ...................................................................................................... 15 
8.2.1 
Pain Intensity Difference ...................................................................................... 15 
8.2.2 
Summed Pain Intensity Difference ....................................................................... 16 
8.2.3 
Proportion of Responders .................................................................................... 17 
8.2.4 
Pain Relief ........................................................................................................... 17 
8.2.5 
Total Pain Relief (TOTPAR) ................................................................................. 17 
8.2.6 
Peak Pain Relief .................................................................................................. 18 
8.2.7 
Time to Peak Pain Relief ..................................................................................... 18 
8.2.8 
Proportion of Subjects Satisfied with Treatment ................................................... 18 
8.2.9 
Time to Perceptible and Meaningful Pain Relief ................................................... 18 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 4 of 28 
8.2.10 Time to Administration of First Dose of Rescue Medication ................................. 18 
8.2.11 Proportion of Subjects Receiving Rescue Medication .......................................... 19 
8.3 
General Analysis Methods .......................................................................................... 19 
8.4 
Exploratory Analysis ................................................................................................... 19 
8.5 
Examination of Subgroups .......................................................................................... 19 
9.0 
Safety Evaluation ........................................................................................................ 19 
9.1 
Overview of Safety Analysis Methods ......................................................................... 19 
9.2 
Adverse Events ........................................................................................................... 20 
9.3 
Deaths, Serious Adverse events, and Other Significant Adverse Events .................... 21 
9.4 
Clinical Laboratory Evaluation ..................................................................................... 22 
9.5 
Vital Signs, Physical Measurements, and Physical Examinations ............................... 22 
9.5.1 
Vital Signs and Physical Measurements .............................................................. 22 
9.5.2 
Physical Examinations ......................................................................................... 22 
9.6 
12-Lead Electrocardiogram (ECG) .............................................................................. 22 
9.7 
Surgical Wound Healing Evaluation ............................................................................ 23 
10.0 
Pharmacokinetic Evaluation........................................................................................ 23 
10.1 Plasma Concentration ................................................................................................. 23 
10.2 PK Parameters Derivation ........................................................................................... 23 
11.0 
Other Analyses ........................................................................................................... 23 
12.0 
Interim Analyses and Data Monitoring ........................................................................ 23 
13.0 
Changes to the Analyses Planned in the Protocol ...................................................... 24 
14.0 
References ................................................................................................................. 24 
15.0 
Appendices ................................................................................................................. 24 
15.1 Tables for Final Study Report ..................................................................................... 24 
15.2 Figures for Final Study Report .................................................................................... 26 
15.3 Listing for Final Study Report ...................................................................................... 26 
16.0 
Document History ....................................................................................................... 27 
 
 
 
 
 
 
 
 
 
 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 5 of 28 
 
LIST OF IN-TEXT TABLES  
Table 1 
Protocol-Specified Visits and Visit Windows .............................................................10 
Table 2 
Table of Adverse Event Start/End Date/Time Imputation Rules ................................21 
 
 
 
 
 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 6 of 28 
LIST OF ABBREVIATIONS (COMMONLY USED) 
Abbreviation 
Definition 
Adam 
Analysis Data Model 
AE 
Adverse event 
ANOVA  
Analysis of variance 
BMI 
Body mass index 
BOCF 
Baseline observation carried forward 
bpm 
Beats per minute 
CI 
Confidence interval 
cm 
Centimeters 
CRF 
Case report form 
CSR 
Clinical study report 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
EOS  
End of study 
HR 
Heart rate 
ICH 
International Conference on Harmonisation 
I/E 
Inclusion and Exclusion (criteria for study participation) 
ITT 
Intent-to-treat 
kg 
Kilograms 
LOCF 
Last observation carried forward 
M 
Meters 
MedDRA 
Medical Dictionary for Regulatory Affairs 
mITT 
Modified intent-to-treat 
mmHg 
Millimeters of mercury 
NPO 
Nil per Oral 
NPRS 
Numerical Pain Rating Scale 
PI  
Pain Intensity 
PR 
Pain Relief 
PT 
MedDRA Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SBP 
Systolic Blood Pressure 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SOC 
MedDRA System Organ Class 
SPI 
Summed Pain Intensity 
SPID 
Summed Pain Intensity Difference 
TEAE 
Treatment-emergent adverse event 
TOTPAR 
Total Pain Relief 
WHODrug  
World Health Organization Drug Dictionary  
WLOCF 
Windowed last observation carried forward 
 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 7 of 28 
1.0 
Purpose of the Analyses 
This Statistical Analysis Plan (SAP) is being developed after review of the Dr. Reddy’s 
Laboratories Limited, protocol number DFN-15-CD-010 Final Version 2.0 (02MAY2018), but 
before any analyses of the data. The SAP contains detailed information to guide the 
performance of the statistical analysis and reporting of the study data for use in the final clinical 
study report (CSR). This SAP is being written with due consideration of the recommendations 
outlined in the most recent International Conference on Harmonization (ICH) E9 Guideline 
entitled ‘Guidance for Industry: Statistical Principles for Clinical Trials’ and the most recent ICH 
E3 Guideline, entitled ‘Guidance for Industry: Structure and Content of Clinical Study Reports’ 
and the most recent FDA draft ‘Guidance for Industry - Analgesic Indications: Developing Drug 
and Biological Products’, dated February 2014. 
This SAP describes the data sets that will be analyzed and the subject characteristics, efficacy, 
and safety assessments that will be evaluated. This SAP provides details of the specific 
statistical methods that will be used. If additional analyses are required to supplement the 
planned analyses described in this SAP, they may be completed and will be identified as post 
hoc in the CSR. 
 
2.0 
Protocol Summary 
2.1 
Study Objectives 
2.1.1 
Safety 
To evaluate the safety of DFN-15 relative to placebo control in subjects with moderate to severe 
acute pain following elective bilateral lower third molar extraction, as assessed by: 
• 
Treatment emergent adverse event (TEAE) reports, 
• 
Laboratory test results,  
• 
Vital signs,  
• 
Physical examinations,  
• 
ECG findings,  
• 
Evaluation of wound healing. 
 
2.1.2 
Efficacy 
Primary Objective 
To evaluate the efficacy of DFN-15 doses relative to placebo control in subjects with predose 
moderate to severe acute pain following elective bilateral lower third molar extraction using the 
summed pain intensity difference (SPID) scores over the first 6 hours (SPID6) postdose.  
Secondary Objective 
To evaluate the efficacy of DFN-15 relative to placebo control postdose in subjects with predose 
moderate to severe acute pain following elective bilateral lower third molar extraction using:  
• 
Total Pain Relief (TOTPAR) over 2, 4, 6 and 8 hours. 
• 
The SPID scores over various intervals, including SPID2, SPID4 and SPID8. 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 8 of 28 
• 
Times to perceptible and meaningful pain relief. 
• 
Proportion of subjects reporting treatment satisfaction outcome scores of 2 (good), 3 
(very good), or 4 (excellent) on a 5-point categorical scale. 
• 
Time to administration of first dose of rescue medication. 
• 
Percent of subjects receiving rescue medication. 
• 
Pain intensity difference at each NPRS timepoint (15, 30, and 45 minutes and 1, 1.5, 2, 
3, 4, 5, 6, 7 and 8 hours). 
• 
Pain relief at each NPRS timepoint (15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7 
and 8 hours).  
• 
NPRS responder analyses defined as the proportion of subjects who achieve ≥ 30% and 
≥ 50% improvement in NPRS (responders).  
• 
Peak pain relief over 8 hours and the time until peak pain relief. 
2.1.3 
Pharmacokinetics 
Pharmacokinetic parameters will be calculated by a separate vendor for all subjects for the 
single oral dose taken based on the concentrations of DFN-15 (celecoxib) in plasma at predose 
and between 15 minutes to 8 hours postdose. Details of the PK modeling, including any criteria 
for inclusion/exclusion from the PK population will be described in a separate PK Analysis Plan. 
The calculated parameters that will be summarized in CSR appendices if available will include:  
1) peak (maximum) observed plasma drug concentration (Cmax) 
2) time to Cmax (Tmax) 
3) AUC from 0 to x hours after dose will also be calculated for AUC0-0.25, AUC0-0.5, AUC0-0.75, 
AUC0-1, AUC0-2, AUC0-3, AUC0-4, AUC0-6 and AUC0-8.  
 
2.2 
Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled parallel design study, to be conducted at 
1-3 centers in the United States. An adequate number of subjects will be screened to randomize 
approximately 120 male and female subjects, 18 to 60 years old (inclusive), who are scheduled 
to undergo elective bilateral lower third molar extraction. Subjects who meet all of the inclusion 
and none of the exclusion criteria in the protocol will be randomized in a 1:1:1:1 ratio in a 
double-blind fashion to receive a single oral dose of either DFN-15 62.5 mg, DFN-15 125 mg, 
DFN-15 250 mg or matching placebo.   
The study periods include a screening period (within 28 days of the scheduled extraction of the 
impacted third molars), a pre-surgery period (up to 2 hours prior to procedure), surgery, 
baseline period (up to 6 hours post-surgery), treatment period (up to 8 hours after dosing) and a 
post –surgery/ treatment period between 4 and 10 days after surgery. The screening period will 
involve the collection of demographic information, height, weight and body mass index (BMI), 
urine pregnancy test (in case of women of child-bearing potential), medical and medicinal 
history, physical examination, dental examination, vital signs measurement (blood pressure, 
pulse rate, respiratory rate), clinical laboratory investigation (hematology, serology, coagulation 
parameters, serum chemistry and urinalysis), 12-lead ECG and a panoramic x-ray to document 
the impacted mandibular third molar teeth.   


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 9 of 28 
At screening and upon admission/Check-in (Day 1) to the clinic, prior to dental surgery, subjects 
will be screened for alcohol consumption and illicit drug use by alcohol breathalyzer test and 
urine drug screen, respectively. Subjects continuing to meet I/E criteria will proceed to undergo 
their planned surgery for extraction of the impacted mandibular molars on both sides.  As a pre-
requisite for randomization, subjects will be required to report within 6 h post-surgery (Baseline 
period) :  a) “moderate” to “severe” baseline pain as characterized on a 4-point categorical pain 
intensity (PI) scale (0= none, 1= mild, 2=moderate, 3= severe), and b) a score of ≥5, on the 11-
point Numerical Pain Rating Scale (NPRS) where 0 represents ‘no pain’ and 10 represents 
‘worst pain imaginable’, on the provided paper diary. Eligible subjects will be randomized and 
will receive a single dose of the assigned study treatment (a total volume of 10 mL). The start 
time of dosing will be recorded as T0. Subjects will be randomized and administered the study 
medication within 15 minutes of meeting the post-operative inclusion criteria (baseline score). 
Subjects with inadequately controlled pain symptoms may request rescue analgesic medication. 
The rescue medication for this study will be 1-2 oxycodone 5 mg/acetaminophen 325 mg q 4 h 
PRN. Subjects will be encouraged to delay using the rescue medication if their pain is tolerable 
until 120 minutes post-dose of study medication. A subject who is administered rescue pain 
medication will continue completing pain assessments until 8 hours after treatment initiation. 
The use of ice packs will not be allowed in the 8-hour observation period.  All randomized 
subjects will be provided with a paper diary to record pain assessments. A subject training 
program will be implemented to ensure that all subjects understand the relevant scales and 
assessments prior to study participation. At study medication administration, two stopwatches 
will be started, to measure times to ‘perceptible’ and ‘meaningful’ pain-relief. Subjects will be 
instructed to stop the first stopwatch when they first perceive pain relief to occur (time to 
perceptible relief). Subjects will be instructed to stop the second stopwatch when they first 
experience meaningful pain relief (time to meaningful relief). Stopwatch times of perceptible 
relief and meaningful relief will be recorded using exact stopwatch time displayed.  
The following efficacy assessments will be completed by the subjects at 15, 30, and 45 min and 
at 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours after study medication administration, as well as within 5 
minutes prior to first use of rescue medication and at early termination from the study, if it 
occurs. Subjects will be asked to record responses for the following assessments, in order: 
• 
Pain intensity (PI) using the 11-point Numerical Pain Rating Scale (NPRS). 
• 
Pain relief (PR) using a 5-point categorical scale (where 0= no pain relief, 1= little pain 
relief, 2= some pain relief, 3= a lot of pain relief, 4= complete pain relief). 
In addition, at 8 hours post-dose or within 5 minutes prior to first use of rescue medication 
(whichever is earlier), subjects will be asked to record within the provided patient diary: 
• 
‘Patient Rating of Treatment Satisfactoriness’ using a 5-point verbal rating scale 
(0=poor,1=fair, 2 =good, 3=very good, 4=excellent). 
Randomized subjects will remain NPO (nil per oral or nothing by mouth), including water, from 
Check-in (i.e., at least 2 hours before the administration of the dose of study medication to 
randomized subjects) until 2 hours post-dose, on Day 1 (study day). After 2 hours post-dose, 
subjects may be permitted to consume water, or gelatin snacks. Subjects are prohibited from 
ingesting solid foods or carbonated beverages for at least 6 hours post-dose. 
Safety assessments will include 12-lead ECGs, vital sign parameters, physical exam and clinical 
labs.  12-lead ECGs will be performed before surgery, at baseline (before administration of the 
study treatment) and repeated at 1, 2, 4 and 8 hours post-dose, with a window period of ± 45 
minutes for each timepoint. Vital sign parameters (sitting pulse rate, sitting or supine blood 
pressure and respiratory rate) will be measured and recorded before surgery, at baseline, 1, 2, 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 10 of 28 
4, and 8 hours (before discharge), with a window period of ± 30 minutes for each timepoint. Vital 
signs may be performed concurrently with ECG if supine position is performed. Safety vital 
signs and ECG may be performed prior to initiation of efficacy assessments should they 
coincide, with priority designated toward efficacy assessment timepoints. At discharge (8 hours 
post-surgery) from the clinical facility, all AEs reported for the subjects will be reviewed. A 
physical examination, including evaluation of the incision site for hematomas, and clinical 
laboratory evaluation (coagulation parameters and specific hematology, serum biochemistry and 
urinalysis parameters) will be conducted. 
All subjects will have blood drawn at specified timepoints for pharmacokinetic evaluation.  
Pharmacokinetic blood samples will be drawn immediately prior to dosing and at 15 min, 30 
min, 45 min, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0 and 8.0 hours post-dose, to estimate the 
concentrations of celecoxib, using a validated LC-MS/MS method.  Whenever the times of PK 
blood sample collection coincide with the efficacy or safety assessments, the PK sample may 
be drawn within ± 5 minutes of the scheduled time in first hour and within ± 10 minutes of the 
scheduled time after the first hour, at each timepoint, immediately following the efficacy 
assessments. The exact clock time of sample collection will be recorded and used in the PK 
analysis. 
Subjects will return to the research center 7 days (± 3 days) post-surgery for evaluation of their 
safety and well-being. Any AEs experienced post-surgery will be reviewed. A physical 
examination of the subject will be performed, 12-lead ECG, and vital signs parameters will be 
repeated. Hematology, coagulation parameters, serum biochemistry and urinalysis parameters 
will be repeated only if there is a clinically significant abnormality or ongoing AE(s). Any 
changes to the prior and concomitant medication made after discharge will be reviewed and 
recorded. 
A subject may request to be withdrawn from study participation at any time, without disclosing 
the reason if chosen not to. Subject may be discontinued from the study by the Investigator or 
the Sponsor at any time if either determines that it is not in the subject’s best interest to continue 
participation or due to non-compliance with the protocol. Investigator is encouraged to contact 
the study Medical Monitor to discuss details surrounding non-compliance. Subjects who 
withdraw consent to continue treatment or who are discontinued from the study before 
completing the protocol-specified duration of treatment should be encouraged to complete the 
early termination assessments and procedures outlined for 8 hours after treatment initiation. 
Subjects will be encouraged to agree to return to the study site 7 days (±3 days) post-surgery 
for evaluation of their safety and well-being. The date the subject is withdrawn and the primary 
reason for discontinuation will be recorded in the subject’s case report form (CRF).  
The protocol-defined visits are presented in the following (example) table:  
Table 1 
Protocol-Specified Visits and Visit Windows 
Study Phase 
Visit Time 
Screening 
From days -28 to -1 
Day 1 Prior to Dose 
Day 1 up to 6 hours post-surgery 
Day 1 Post-Dose 
Day 1.  Assessments at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 
3, 4, 5, 6, 7, and 8 hours after administration of study 
medication 
Follow-up 
Day 7 
 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 11 of 28 
2.3 
Study Population 
The study will consist of approximately120 male and female subjects, 18 to 60 years old 
(inclusive), who are scheduled to undergo elective bilateral lower third molar extraction.  The full 
list of inclusion and exclusion criteria are mentioned in sections 4.1 and 4.2 of the protocol 
respectively. 
2.4 
Study Material and Treatment Regimens 
DFN-15 is an oral solution containing 25 mg/mL of celecoxib.  Each mL of DFN-15 will contain 
25 mg celecoxib.  DFN-15 will also contain the inactive ingredients, lauroyl polyoxylglycerides, 
glyceryl caprylate, caprylic/capric triglyceride, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated 
castor oil, propyl gallate, menthol, magnasweet, sucralose, acesulfame potassium, peppermint 
flavor, banana flavor, bubble gum flavor, glycerol, ethanol, and water.   
DFN-15 and matching placebo are packaged in amber-colored glass bottles containing 4.8 mL 
solution per bottle (120 mg) and equipped with child-resistant and tamper-evident caps.   
Treatment consists of a single dose of either DFN-15 62.5 mg, DFN-15 125 mg, DFN-15 250 
mg or matching placebo of total volume of 10 mL of oral solution.   
The 10 mL dose will be prepared by a designated unblinded pharmacist at site, as per the 
randomization schedule. Designated blinded study staff will dose subjects and administer study 
assessments. Blinded study staff will remain blinded to the dose administered to each subject 
throughout the study. 
2.5 
Randomization 
A computer-generated randomization scheme will be prepared prior to study initiation. 
Subjects will be randomly assigned to treatment with DFN-15 62.5 mg, DFN-15 125 
mg, DFN-15 250 mg, or placebo in a 1:1:1:1 assignment ratio according to the randomization 
scheme. Randomization will occur after the subject has qualifying baseline pain, other post-
operative inclusion criteria are met, and all Pre-Dose Baseline assessments have been 
performed on Day 1.  All study doses administered will be according to the treatment 
assignment.  No stratification will be performed as part of the randomization; however, male and 
female subjects will be enrolled in an approximate ratio of 1:1.  Subjects who discontinue after 
randomization will not be replaced in this study. 
2.6 
Sample Size Determination 
The sample size of 120 subjects for this study was selected without a formal statistical 
calculation. However, group sizes of 30-40 per group are typically sufficient to detect a 
treatment effect over placebo in the dental pain model. 
 
3.0 
General Analysis and Reporting Conventions 
This section discusses general policies to be employed in the analysis and reporting of the data 
from the study. Departures from these general policies are provided in the specific detailed 
sections of this SAP. When this situation occurs, the rules set forth in the specific section take 
precedence over the general policies. 
All continuous study assessments will be summarized by treatment and timepoint (as 
applicable) using descriptive statistics (n, mean, median, SD, minimum, and maximum). All the 
categorical study assessments, including responder variables, will be summarized by treatment 
and timepoint (as applicable) using frequency counts and percentages. Changes from baseline 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 12 of 28 
for continuous outcomes will be presented as their corresponding continuous measures for 
post-baseline visits. Shifts from baseline for the ECG outcomes will be presented in shift tables 
by timepoint and treatment group. All study data will be listed by subject, treatment group, and 
timepoint (as applicable).  
No preliminary rounding will be performed; rounding will only occur after the analysis. To round, 
consider the digit to the right of the last significant digit: if <5, then round down; if ≥5, then round 
up. Means and medians will be presented with one more decimal place than the precision of the 
data. Standard deviations will be presented with two more decimal places than the precision of 
the data. Percentages will be presented with one decimal place. Minimums and maximums will 
be presented with the same precision as the original data. 
All analyses will be performed using the SAS System® version 9.3 or higher. The domain (Study 
data tabulation Model [SDTM]) and analysis (Analysis Data Model [ADaM]) data sets will be 
taken as input to the SAS programs that generate the report-ready tables, figures and listings. 
The SDTM and ADaM data sets will be provided to the sponsor along with display deliveries. 
The specifications for the domain data sets and analysis data sets will be provided in a separate 
document. 
For all efficacy analyses, subjects will be analyzed according to their randomized treatment 
group, regardless of the actual treatment received, unless otherwise indicated. For all safety 
analyses, subjects will be analyzed by treatment group according to the actual product received 
during treatment, i.e., “as treated.” 
The following conventions will be used throughout the study analysis: 
• 
Assessment visit times are defined by time after administration of study drug. 
• 
Time T0 is the time of first treatment with study drug. 
• 
Baseline value is defined as the last valid measurement prior to first treatment 
administration (prior to T0). 
• 
Pain Intensity Difference (PID) and changes from baseline are defined as post-baseline 
value minus baseline value. 
• 
The date of first treatment with study drug is Day 1.  
• 
Percentage PID and percent change from baseline is computed as: 
(post-baseline value - baseline value) × 100 / (baseline value). 
• 
Treatment difference is computed as DFN-15 mean minus control mean. (Note: for the 
SPID statistics, for which the treatment goal is to reduce the score over time, 
improvement will be represented as a negative number.)  
• 
SPID statistics will be computed using the trapezoid rule for computing area under the 
curve. 
• 
All statistical tests will be two-tailed and at the α = 0.05 significance level 
• 
Duration of an AE will be computed in days or hours as the stop date/time of the event 
minus the start date/time plus 1. If reported as ongoing at the time of database lock, the 
stop date is defined as the date of the last visit or the last date of any AE for the subject 
in the database, whichever is later. Missing dates will be imputed as described in 
Section 9.2 Table 2. 
• 
The number of days/hours in the study is computed as: 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 13 of 28 
Date/time of study completion /withdrawal - the date/time of first treatment 
administration (Day 1) + 1.  
• 
If duplicate values are obtained at a given timepoint (e.g., repeated vital sign 
measurements), the last value will be used unless it is noted that the measurement was 
in error for that value. Values that compromise interpretation will not be used in 
summaries (e.g., values that were obtained post-dose will not be summarized as pre-
dose values). 
 
4.0 
Analysis Populations 
4.1 
Modified ITT Population 
The mITT population includes all subjects who are randomized, receive study medication and 
have recorded at least one post dosing pain intensity (PI) score. This population will be used to 
summarize and analyze efficacy outcomes and treatment grouping will be based on randomized 
treatment. 
4.2 
Safety Population 
The safety population includes all subjects who receive a dose of study medication (DFN-15 or 
placebo). This population will be used to summarize safety and demographic data, and for these 
summaries, treatment grouping will be based on treatment actually received.  
4.3 
Per-Protocol Population 
The per-protocol population includes all mITT subjects who complete all pain assessments for 
at least 8 hours post-dose and have no major protocol deviations that impact subject safety or 
the interpretation of the primary analysis.  Major protocol deviations excluding subjects from the 
Per Protocol population will be defined prior to unblinding (Section 5.2).  This population will be 
analyzed by randomized treatment, unless otherwise indicated in the Blinded Data Review 
Meeting (BDRM).  In the BDRM, a decision may be made to analyze the PP population as per 
treatment actually received in study by subjects. 
4.4 
Pharmacokinetic Population (PK)  
The pharmacokinetic (PK) population will be determined by the PK Vendor and documented in a 
separate PK Analysis Plan.   
 
5.0 
Patient Summaries 
5.1 
Disposition of Subjects 
A subject is considered randomized once the subject is assigned a treatment randomization 
number. If a subject is randomized but does not receive treatment, they will be included in the 
All Randomized population summaries, but no others.  
Investigators are instructed to encourage subjects to attend all visits. If subjects are unable or 
unwilling to return, the reason for the subject withdrawal will be recorded. Subjects who 
successfully complete the 8-hour post treatment assessment period will be counted as 
treatment period completers regardless if they complete the study, by returning for the 7 day 
end of study visit, or not.   
All treated/randomized subjects and the populations for which they qualify will be listed. The 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 14 of 28 
number of subjects who are screened, and who fail screening or withdraw consent prior to 
randomization will be listed and summarized in total. Subjects who are randomized, subjects 
who are treated, subjects who complete the treatment period of 8 hours on study medication, 
subjects who complete follow-up, as well as subjects who withdraw early from the study and the 
reason for withdrawal will be summarized by treatment group and overall in the subject 
disposition summary tables, both overall and by center (if applicable).  Days/Hours in study will 
be calculated as date/time of subject’s last visit minus date/time of study drug administration 
plus 1. Subjects that complete any portion of a day will be counted as on study during that day.  
5.2 
Major Protocol Deviations 
Protocol deviation information will be captured in the CRF and in site logs by site and CRO 
personnel. All protocol deviations will be designated by the medical monitor(s) as major or minor 
prior to unblinding. A major deviation is one that may affect the outcome, analysis or 
interpretation of the study results. If present, major protocol deviations will be summarized and 
all protocol deviations will be presented in a by-subject listing. 
 
6.0 
Demographic and Other Baseline Characteristics 
6.1 
Demographics and Baseline Characteristics 
Demographic variables include age, sex, race, and ethnicity. Baseline characteristics will 
include weight (kg) and BMI (kg/m2) as well as the qualifying (baseline) NPRS and 4-point 
categorical pain intensity scores.  Demographics and baseline characteristics will be presented 
in a by-subject listing and summarized overall and by treatment group for the Safety population 
and the mITT population, if they differ.  
6.2 
Medical History 
Medical history, as collected at screening, will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 21.0 and summarized by system organ class (SOC) 
and preferred term (PT) in a frequency table based on the safety population. The SOC and PT 
will each be sorted in descending order by overall frequency. Medical histories will also be 
presented in a by-subject listing using the coded and verbatim history terms.  
AEs that occur prior to treatment or that are related to a medical history event will be captured 
as medical history prior to database lock.  
6.3 
Prior and Concomitant Medication 
Prior medications/therapies are those that stop prior to the start of the study medication 
administration. Any medication/therapy that stops at or after the date and time of start of 
treatment or those with missing stop dates are considered concomitant medication/therapy. 
Surgical medications/Anesthesia used during and immediately after surgery will be listed but will 
not be summarized. 
Prior and concomitant medications are collected at screening. and updated throughout the study 
as needed. Prior and concomitant medications will be coded using the March 1, 2018 version of 
the WHODrug. Subjects who take concomitant medications will be presented in a by-subject 
listing of verbatim and coded terms and summarized by drug class and preferred name, overall 
and by treatment group, for the safety population.  
A by subject listing of all prior and concomitant medications will be presented with Surgical 
medications/Anesthesia used during surgery identified.  Additionally, a summary and by-subject 
listing of concomitant medications that were prescribed or modified at or after the time of 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 15 of 28 
discharge on study day will also be presented. 
6.4 
Non-Medication Therapies and Surgery Details 
Prior and concomitant non-medication therapies will be presented in a by-subject listing for each 
treatment group. All surgical information will appear in data listings. 
 
7.0 
Measurements of Treatment Exposure and Compliance 
Because the single dose of study medication is administered at the study center by trained 
study personnel, compliance with study medication is not expected to be an issue. A listing of all 
study medication exposure (including information on any partial administrations) will be 
provided.  
 
8.0 
Efficacy Evaluation 
8.1 
Overview of Analysis Issues 
8.1.1 
Handling of Dropouts or Missing/Invalid Data 
Subjects with missing or invalid PI NPRS data will be imputed using the following rules.  
Subjects who require rescue medication will record their pain intensity (PI) NPRS, Pain Relief 
(PR) and Patient Rating of Treatment Satisfactoriness scores within 5 minutes prior to first use 
of rescue medication. These are referred to as ‘pre-rescue’ PI, PR, and Patient Rating of 
Treatment Satisfactoriness scores, respectively. Any scheduled PI or PR assessments 
scheduled within 4 hours after administration of rescue medication will be replaced by the pre-
rescue score in the efficacy analysis. This method of replacement is referred to as the 
windowed Last Observation Carried Forward (wLOCF).  
After any scheduled PI/PR scores within 4 hours after rescue are appropriately replaced by the 
pre-rescue PI/PR scores, any other scheduled PI/PR scores that are still missing intermittently 
and are not within 4 hours after rescue medication will be imputed using linear interpolation 
between adjacent observed values.  
After all intermittent missing scores are imputed, any scheduled PI/PR scores missing because 
the subject dropped out of the study will be imputed as follows: If the subject drops out due to 
adverse event (AE), the PI score will be imputed using a baseline observation carried forward 
(BOCF) method; if the subject drops out for other reasons, the PI/PR score will be imputed 
using the last observation carried forward (LOCF) method.  PI data with missing baseline PI 
score will be excluded from the analysis. 
For responder endpoints, subjects that drop out will be considered as non-responders for all 
assessment time points after their date/time of drop out.  Similarly, if a subject receives rescue 
medication, then the subject will be treated as a non-responder for all subsequent timepoints.  
No imputation for other efficacy or safety will be performed. 
8.2 
Efficacy Endpoints 
8.2.1 
Pain Intensity Difference 
Pain Intensity Difference (PID) will be calculated based on Pain Intensity (PI) scores.  PI will be 
assessed pre-dose, immediately prior to any use of rescue, and at each post-dose timepoint 
(15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours after T0) during the study using 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 16 of 28 
an 11-point NPRS where 0 equates to no pain and 10 equates to the worst pain imaginable 
pain.  
PID will be calculated at each time point i as PIDi = PIi – PIBL (Pain intensity score at time i and 
Pain intensity score at Baseline). All imputation, as described in Section 8.1.1, will be performed 
prior to the PID calculations.  
PIDi will be summarized descriptively with sample size, mean, standard deviation, median, 
minimum, and maximum for each treatment group.  The unadjusted p-value from a 1-sample t-
test will be presented for each post-baseline nominal timepoint.  Additionally, unadjusted p-
values will be shown at each post-baseline nominal timepoint comparing the mean change from 
baseline values for each treatment, and of all DFN-15 treatments combined, to placebo. This 
will be done using an ANCOVA model with treatment as the main effect and both baseline pain 
intensity and BMI as covariates.  To supplement this analysis, group mean of pain intensity over 
time will be displayed graphically at the nominal timepoints. These scores will also be presented 
in listings. 
8.2.2 
Summed Pain Intensity Difference 
The primary efficacy endpoint is the summed pain intensity difference over the first 6 hours 
(SPID6) between each of the DFN-15 dose levels and placebo.  SPID6 is created by summing 
the time weighted pain intensity differences (PID) scores using the area under the PID curve 
methodology.  
All SPID calculations will be done using the standard trapezoidal rule:  
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆  = 
෍൬𝑃𝑃𝑃𝑃𝑃𝑃𝑖𝑖+ 𝑃𝑃𝑃𝑃𝑃𝑃𝑖𝑖+1
2
൰
𝑥𝑥
𝑖𝑖=0
∗ (𝑇𝑇𝑖𝑖+1 − 𝑇𝑇𝑖𝑖) 
Where: PIDi = Pi – PIBL (Pain Intensity score at time i and Pain Intensity score at Baseline), (Ti+1 
– Ti) is the Time difference in minutes between time i and time i+1, and (Ti+1 – Ti) is the Time 
difference in minutes between time i and time i+1.   
Baseline PI will be defined as the last PI recorded prior to first dose. Time points will be selected 
for inclusion into specific SPID periods based on nominal time points (e.g., all scheduled 
assessments from Baseline to the Hour 6 assessment will be included in SPID6).    
Except for baseline, the actual date/times of assessments will be used in the SPID calculation 
whenever collected.  For baseline, rather than the actual time recorded, baseline pain will be 
considered to be recorded at time 0(i.e., time of first dose). 
All imputation, as described in Section 8.1.1, will be performed prior to the SPID calculations. 
The individual SPID variables will also be presented in subject listings. 
The secondary efficacy SPID outcomes (SPID2, SPID4, and SPID8) are calculated similarly to 
SPID6 adjusting for the respective time periods. 
All SPID endpoints will be analyzed using an ANCOVA with treatment as the main effect and 
both baseline pain intensity and BMI as covariates.  Mean SPID values over time will be 
displayed graphically. 
The results of the ANCOVA will be presented in summary tables with standard summary 
statistics as well as least square (LS) means, active dose level vs. placebo LS mean differences 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 17 of 28 
(treated group – placebo), standard errors, confidence intervals (CI) and paired-comparison p-
values with Dunnett’s test. 
8.2.3 
Proportion of Responders 
NPRS responders are defined as subjects who achieve ≥ 30% (called 30% Responders) or 
≥ 50% (called 50% Responders) improvement in PI NPRS over the baseline value recorded at 
T0 at any time prior to first use rescue and up to 8 hours.  All imputation as described in 
Section 8.1.1 will be performed prior to percent improvement and responder calculations. If any 
scheduled post-baseline NPRS score prior to rescue medication (if rescue was taken) meets or 
exceeds the threshold, regardless of if the subject subsequently loses their response, then the 
subject will be counted as an overall responder.  Otherwise, the subject will be considered a 
non-responder.  In addition, the proportion of subjects who achieve a 30%/50% improvement 
from baseline will also be calculated at each time point and displayed graphically.    
Percent improvement = (baseline value - post-baseline value) × 100 / (baseline value) 
The proportion of subjects experiencing ≥ 30% and ≥ 50% improvement in NPRS (responders) 
will be analyzed using chi square (CMH) test or, alternatively, a Fishers exact test if there are 
less than 5 subjects in any category. The testing of each dose level of DFN-15 vs. placebo will 
be performed separately.  
Summary tables will present the by-treatment group descriptive statistics of proportions with 
active vs. placebo odds ratios, 95% confidence intervals and CMH chi-square or Fisher exact p-
values.  A cumulative proportion of responders figure will also be presented.  
8.2.4 
Pain Relief 
Pain relief scores are captured on the 5-point pain relief scale (0= no pain relief, 1= little pain 
relief, 2= some pain relief, 3= a lot of pain relief, and 4= complete pain relief) at 15, 30, and 45 
minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours as well as immediately prior to any rescue use.  
Pain relief at each postdose timepoint will be summarized descriptively for each treatment 
group.  All imputation, as described in Section 8.1.1, will be performed prior to presentation. 
PR will be summarized descriptively with sample size, mean, standard deviation, median, 
minimum, and maximum for each treatment group.  The unadjusted p-value from a 1-sample t-
test will be presented for each post-baseline nominal timepoint.  To supplement this analysis, 
group mean of pain relief over time will be displayed graphically at the nominal timepoints.  Pain 
relief scores will also be presented in listings. 
8.2.5 
Total Pain Relief (TOTPAR) 
Total Pain Relief (TOTPAR) over 2, 4, 6, and 8 hours.  Total pain relief is calculated similarly to 
SPID replacing the PID values with the pain relief (PR) scores on the 5-point scale where 0= no 
pain relief, 1= little pain relief, 2= some pain relief, 3= a lot of pain relief, and 4= complete pain 
relief.  All imputation, as described in Section 8.1.1, will be performed prior to the TOTPAR 
calculations. 
All TOTPAR endpoints will be analyzed using an ANCOVA with treatment as the main effect 
and baseline pain intensity and BMI as covariates.  The results of the ANCOVA will be 
presented in summary tables with standard summary statistics as well as least square (LS) 
means, active dose level vs. placebo LS mean differences (treated group – placebo), standard 
errors, confidence intervals and paired-comparison p-values with Dunnett’s test. Mean TOTPAR 
values over time will also be displayed graphically. 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 18 of 28 
8.2.6 
Peak Pain Relief 
Peak pain relief is defined as the maximum post-dose score (after imputation) that a subject 
reaches on the 5-point pain relief scale prior to any use of rescue medication (if rescue was 
taken).  This will be summarized with standard summary statistics (count, mean, standard 
deviation, median, minimum, and maximum by treatment group. 
8.2.7 
Time to Peak Pain Relief 
Time to peak pain relief is defined as the earliest post-dose time that a subject reaches their 
maximum positive score on the 5-point pain relief scale prior to rescue medication (if rescue 
was taken). Subjects who do not record at least one positive pain relief score prior to use of 
rescue will be censored at 8 hours. Time to peak pain relief will be analyzed using Kaplan-Meier 
curves for each dose level of DFN-15 to placebo with the log-rank test.  Estimated percentiles 
for time to peak pain relief will be tabulated by treatment group along with the number and 
percent of subjects censored.  Additionally, a Kaplan-Meier curve will present cumulative 
percentages over time graphically.  
8.2.8 
Proportion of Subjects Satisfied with Treatment 
The proportion satisfied with treatment is defined as ratio of subjects reporting treatment 
satisfaction scores of at least 2 on the 5-point scale (0= poor, 1= fair, 2= good, 3= very good, 
and 4= excellent) out of all mITT subjects.  Summary tables will present the by-treatment group 
descriptive statistics of proportions for each active dose level vs. placebo, odds ratios, 95% 
confidence intervals and chi-square or Fisher exact p-values if chi-square test assumptions are 
not met. Treatment satisfaction scores will also be presented in listings. A summary of subject 
satisfaction scores as a continuous variable and ANCOVA analysis with treatment as the main 
effect and both baseline pain intensity and BMI as covariates will also be presented.  
8.2.9 
Time to Perceptible and Meaningful Pain Relief 
Times to perceptible and meaningful pain relief will be measured using the double stopwatch 
method. For each randomized participant, two stopwatches will be started immediately after 
administration of study drug (T0). The first stopwatch will be given to the participant with the 
instructions to stop the watch at first perceptible pain relief (if they notice any decrease in the 
pain they have now). If the first watch is stopped, the second stopwatch will be given to the 
participant with the instructions to stop the watch if they have meaningful pain relief (pain relief 
that is meaningful to them).  Perceptible pain relief will be summarized only for subjects that 
achieve meaningful pain relief (Confirmed Perceptible pain relief). 
Subjects receiving rescue medication prior to stopping the stopwatch or who do not reach 
perceptible pain relief within 8 hours will be censored at 8 hours.  Subjects will be similarly 
censored in calculations of meaningful pain relief.   
Both time to perceptible and meaningful pain relief will be analyzed using Kaplan-Meier curves 
for each dose level of DFN-15 to placebo with the log-rank test.  Estimated percentiles for time 
to perceptible/meaningful pain relief will be tabulated by treatment group along with the number 
and percent of subjects censored. 
8.2.10 
Time to Administration of First Dose of Rescue Medication 
Time to first administration of rescue medication is the date/time of the earliest rescue 
medication use minus the date/time of T0.  If the subject receives no rescue medication, then the 
value will be censored at 8 hours.  
This will be analyzed using Kaplan-Meier curves for each dose level of DFN-15 to placebo with 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 19 of 28 
the log-rank test.  Estimated percentiles for time to first use of rescue will be tabulated by 
treatment group along with the number and percent of subjects censored.      
8.2.11 
Proportion of Subjects Receiving Rescue Medication 
The proportion of subjects receiving rescue medication uses the number of subjects receiving 
rescue medication at any time as the numerator and the number of subjects in the mITT 
population as the denominator.   
Summary tables will present the by-treatment group descriptive statistics of proportions with 
active vs. placebo odds ratios, 95% confidence intervals and CMH chi-square and Fisher exact 
p-values. The proportion of subjects receiving their first dose of rescue at each timepoint will be 
presented graphically. 
8.3 
General Analysis Methods 
SPID and TOPAR endpoints will use Dunnett’s test to account for multiplicity within each of 
those endpoints.  All other p-values are presented without adjustment for multiplicity.  The mITT 
population will be primary population used for all efficacy analyses.  The PP population will be 
used as a supplemental analysis for SPID, TOTPAR, PID by timepoint, PR by timepoint, and 
peak pain relief.    
In all cases, the null hypothesis being tested is that the means of the two treatment groups are 
equal, and the alternative is that the means are not equal: 
• 
H0: there is no treatment difference  
• 
HA: there is a treatment difference 
If more than 1 center is used, then center effect will be added to the SPID6 ANCOVA model to 
investigate the impact.  If the center effect is significant at the 0.05 level, then center will be 
added to the log-rank test for time to meaningful and perceptible pain relief analyses.  
Additionally, treatment-center interactions will be tested in the ANCOVA analysis of the SPID6 
endpoint.  If this interaction is significant at the 0.10 level, then the interaction term will be 
included in a sensitivity analysis. 
8.4 
Exploratory Analysis 
Exploratory analyses may be performed to describe other results of interest from the study.  Any 
such analyses will either be documented in a subsequent version of this SAP or in a post hoc 
SAP.   
8.5 
Examination of Subgroups 
The primary endpoint (SPID6) will be analyzed by subgroup for gender (male or female), 
qualifying pain intensity category (2=moderate or 3=severe on 4-point scale), and BMI (<30 or 
≥30). 
 
9.0 
Safety Evaluation 
9.1 
Overview of Safety Analysis Methods 
All safety outcomes will be summarized using the safety population. Safety outcomes include: 
• 
Incidence of treatment-emergent AEs (TEAEs) 
• 
Changes from baseline in clinical laboratory test results 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 20 of 28 
• 
Changes from baseline in vital sign measurements 
• 
Changes from baseline in physical examinations.  
• 
Changes from baseline in ECG findings,  
• 
Evaluation of surgical wound healing. 
9.2 
Adverse Events 
Treatment-emergent AEs are defined as AEs that start or worsen in severity after the first 
exposure to study medication through the Day 7 visit. Verbatim terms used by investigators to 
identify AEs in the CRFs will be mapped to the appropriate preferred (PT) and system organ 
class (SOC) using a standardized coding dictionary (MedDRA Version 21.0 or higher). All 
coding will be reviewed prior to database lock. All recorded AEs will be listed, but only TEAEs 
will be summarized.  
In addition to a listing of all TEAEs, separate listings of subjects with SAEs and listings of 
subjects with severe, treatment related, and AEs leading to premature discontinuation will be 
provided.  
An overall summary will be prepared giving for each treatment group, all DFN-15 groups 
combined and overall of both the number of events and the number of subjects with TEAEs, 
SAEs, TEAEs by severity, TEAEs by relationship to treatment, and TEAEs leading to premature 
discontinuation.  
The incidence of TEAEs will be summarized for each treatment group by SOC and PT within 
SOC (sorted in descending order by overall frequency). These summaries will be given in 
separate tables for the following categories of TEAEs: 
• 
All TEAEs 
• 
TEAEs leading to premature discontinuation 
• 
SAEs 
Also summarized will be TEAEs by maximum severity and by maximum relatedness to 
treatment. Adverse events will be deemed treatment related if they were recorded as probably, 
possibly, or definitely related.  
If a given subject experiences a TEAE that maps to the same PT more than once, the subject 
will be counted once for the PT at its greatest severity (i.e., mild, moderate, or severe) and 
causality (i.e., attribution to study medication).  
Duration of an AE will be computed in days (or in hours when duration of the AE is less than 1 
day) as the stop date/time of the event minus the start date/time plus 1. If reported as ongoing 
at the time of database lock, the stop date/time is defined as the date/time of the last visit or the 
last date/time of any AE for the subject in the database, whichever is later. If an AE is 
considered resolved, but the stop date is missing, the last day of the month will be imputed if the 
month and year are available. If only the year is available, and the year is the same as the year 
of the last visit, the stop date will be the latest of the last visit date or latest AE for the subject in 
the database. If the year of the AE is prior to the year of the last treatment, the end day and 
month will be set to 31 December. 
For missing or partial start dates, it is most conservative to impute them as temporally related to 
the first dose of study medication. The following chart will be used to impute start date: 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 21 of 28 
Table 2 
Table of Adverse Event Start/End Date/Time Imputation Rules 
Missing Portion 
Prior to 
Treatment 
Same as 
Treatment Start 
Date 
After Treatment Start 
Date 
Day 
Month and Year < 
Month and Year of first 
treatment: 
 
Start Day = first day of 
the month 
Stop Day = last day of 
the month 
Month and Year = 
Month and Year of 
first treatment: 
 
Start Day = Day of 
first treatment 
Stop Day= last 
day of the month 
Month and Year > 
Month and Year of 
First Treatment: 
 
Start Day = first day of 
the month 
Stop Day= last day of 
the month 
Day and Month 
Define Day as 
above, then: 
Year < Year of first 
treatment: 
 
Start Month = July 
Stop Month = Dec 
Year = Year of 
first treatment: 
 
Start Month = 
Month of first 
treatment 
Stop Month = Dec 
Year > Year of first 
treatment: 
 
Month = January 
Stop Month = Dec 
Day, Month, and 
Year 
 
To be conservative, completely missing start dates will be set to the date 
of first treatment, completely missing end dates will be set to the date of 
last contact. 
Time 
Missing start times will be imputed as 00:01 (or the start time of the first 
dose administration if AE occurred on the date of first dose 
administration) 
Missing stop times will be imputed as 23:59  
 
After following these imputation rules, if the start date is imputed as a date after the end date, 
the start date will be set to the end date to provide a positive duration for the AE.  
Missing assessments for AE study medication relationship, or severity will be analyzed as 
related, severe, and associated, respectively. No other imputation is planned for safety data 
unless otherwise specified below. 
9.3 
Deaths, Serious Adverse events, and Other Significant Adverse Events 
A serious adverse event (SAE) is defined as an event that may constitute a significant medical 
hazard or side effect, regardless of the investigator or sponsor’s opinion about its relationship to 
study material. Serious events include, but may not be limited to, any event that: 
• 
Is fatal 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 22 of 28 
• 
Is life-threatening (places the subject at immediate risk of death while the event is 
occurring) 
• 
Requires inpatient hospitalization or prolongs hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
Significant untoward medical events that may not be life-threatening or result in death or 
hospitalization, or events that require intervention to prevent one of the outcomes listed above 
or that result in urgent investigation, may be considered serious. Elective hospitalizations for 
conditions that existed before administration of study material are not to be considered SAEs. 
Serious adverse events and deaths will be listed and summarized separately for the safety 
population. 
9.4 
Clinical Laboratory Evaluation 
Clinical laboratory samples will be collected at screening, Day 1 at the time of discharge, and 
EOS (as applicable). For continuous laboratory parameters, the observed values and changes 
from baseline will be summarized at each scheduled visit, overall and for each treatment group. 
For categorical laboratory parameters, frequency counts and percentages of subjects in each 
category will be provided.  
Laboratory test results will be displayed in by-subject listings, and values outside of the normal 
reference range will be flagged.  
9.5 
Vital Signs, Physical Measurements, and Physical Examinations 
9.5.1 
Vital Signs and Physical Measurements 
Vital signs will be collected at screening, Day 1 prior to surgery, at pre-dose baseline, and then 
at 1, 2, 4 and 8 hours after the administration of study medication, or at the time of early 
discontinuation, and at the end of study visit on Day 7 (± 3 days).   
Observed values and changes from baseline will be summarized using mean and change-from-
baseline descriptive statistics, overall and for each treatment group, for the following 
measurements: systolic blood pressure (mmHg), diastolic blood pressure (mmHg), heart rate 
(beats/minute), and respiratory rate (breaths/minute).  
Body weight and height will be measured, and BMI will be calculated during the screening visit 
only.  These values will be summarized along with other baseline characteristics. Vital signs will 
be displayed in a by-subject listing. 
9.5.2 
Physical Examinations 
Physical examinations are performed at screening, after completion of the 8-hour post-dose 
efficacy and safety assessments (prior to discharge), and at the end of study visit on Day 7 (± 3 
days). 
Findings are recorded as normal or abnormal. Physical exam results will be displayed in a by-
subject listing. 
9.6 
12-Lead Electrocardiogram (ECG) 
A 12-lead ECG will be performed at screening, Day 1 prior to surgery, at pre-dose baseline, and 
at 1, 2, 4, and 8 hours after treatment initiation or at time of early discontinuation, as well as at 
the end of study visit on Day 7 (± 3 days).   


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 23 of 28 
The findings (i.e., classification as “normal,” “abnormal not clinically significant,” or “abnormal 
clinically significant”) will be recorded in the subject’s eCRF. Shifts of results from pre-dose 
baseline to later visits will be summarized in shift tables. ECG results will be displayed in a by-
subject listing. 
9.7 
Surgical Wound Healing Evaluation 
An oral examination will be performed as part of the end of study assessment to ensure incision 
wound healing is progressing as expected.  If an adverse event is identified through this 
examination, it reported in the adverse event summaries. Individual data will be displayed in a 
by-subject listing. 
 
10.0 Pharmacokinetic Evaluation 
All subjects will be enrolled to the pharmacokinetic cohort. Following the single dose of study 
medication, up to 10 blood samples will be collected from each subject. These will be collected 
pre-dose and at the following timepoints: 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 hours post 
dose.  
Subjects who receive placebo will not be included in the PK analysis.  
Additional PK analyses not described in this SAP (e.g. population PK) may be performed and 
will be described in a separate PK Analysis Plan.  
10.1 
Plasma Concentration 
Mean plasma concentrations of DFN-15 at each sampling timepoint will be summarized in a 
separate PK Report according to the analysis as defined in the PK SAP and presented as an 
appendix to the CSR.  Concentrations will be summarized by dose and nominal sampling time 
with descriptive statistics.  Individual plasma concentrations will be presented in by-subject 
listings. 
Mean concentrations (+SD) versus time plots will be presented.  
10.2 
PK Parameters Derivation 
PK Parameters will be derived by a separate pharmacokineticist under a separate analysis plan.  
The PK Analysis plan will detail the analysis methodology and intended parameters/summaries.  
Following completion of the PK analysis, the celecoxib concentrations and PK parameters (for 
individual subject and descriptive statistics for the treatment groups) will be summarized in a 
separate PK Report according to the PK analysis set as defined in the PK SAP and presented 
as an appendix to the CSR.   
 
11.0 Other Analyses 
Any additional analyses conducted will be considered exploratory and identified as post hoc in 
the CSR. 
 
12.0 Interim Analyses and Data Monitoring 
No interim analyses are planned for this study. 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 24 of 28 
13.0 Changes to the Analyses Planned in the Protocol 
Any deviations from the statistical plan will be described and a justification given in the CSR. 
 
14.0 References 
None 
 
15.0 Appendices 
 
15.1 
Tables for Final Study Report 
Number 
Title 
Analysis 
Population 
 Study 
Population 
 
 
14.1.1 
Summary of Subject Disposition 
All 
Subjects 
14.1.2.1 
Summary of Demographic and Baseline Characteristics  
mITT 
Population 
14.1.2.2 
Summary of Demographic and Baseline Characteristics (if 
applicable) 
Safety 
Population 
14.1.3 
Summary of Medical History 
Safety 
Population 
14.1.4 
Summary of Concomitant Medications by Drug Class and 
Medication 
Safety 
Population 
14.1.5 
Summary of Concomitant Medications by Drug Class and 
Medication after Discharge 
Safety 
Population 
 Efficacy 
  
 
14.2.1.1 
Primary Endpoint: Analysis of Summed Pain Intensity Difference 
from T0 to T6 (SPID6)  
mITT 
Population 
14.2.1.2 
Analysis of Summed Pain Intensity Difference from T0 to T6 
(SPID6)  
PP 
Population 
14.2.1.3 
Analysis of Summed Pain Intensity Difference from T0 to T6 
(SPID6) by Gender 
mITT 
Population 
14.2.1.4 
Analysis of Summed Pain Intensity Difference from T0 to T6 
(SPID6) by Qualifying Pain Intensity 
mITT 
Population 
14.2.1.5 
Analysis of Summed Pain Intensity Difference from T0 to T6 
(SPID6) by BMI Category 
mITT 
Population 
14.2.1.6 
Analysis of Summed Pain Intensity Difference from T0 to Other 
Timepoints (SPID2, SPID4, SPID8) 
mITT 
Population 
14.2.1.7 
Analysis of Summed Pain Intensity Difference from T0 to Other 
Timepoints (SPID2, SPID4, SPID8) 
PP 
Population 
14.2.2 
Summary of Pain Intensity and Pain Intensity Difference by 
Timepoint 
mITT 
Population 
14.2.3 
Summary of Pain Intensity and Pain Intensity Difference by 
Timepoint 
PP 
Population 
14.2.4 
Analysis of Proportion of 30% and 50% Responders (NPRS) 
mITT 
Population 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 25 of 28 
Number 
Title 
Analysis 
Population 
14.2.5.1 
Summary of Pain Relief by Timepoint  
mITT 
Population 
14.2.5.2 
Summary of Pain Relief by Timepoint  
PP 
Population 
14.2.5.3 
Analysis of Total Pain Relief (TOTPARx) 
mITT 
Population 
14.2.5.4 
Analysis of Total Pain Relief (TOTPARx) 
PP 
Population 
14.2.6.1 
Summary of Peak Pain Relief 
mITT 
Population 
14.2.6.2 
Summary of Peak Pain Relief  
PP 
Population 
14.2.7.1 
Analysis of Time to Peak Pain Relief 
mITT 
Population 
14.2.7.2 
Analysis of Time to Peak Pain Relief 
PP 
Population 
14.2.8.1 
Proportion of Subjects Satisfied with Treatment 
mITT 
Population 
14.2.8.2 
Analysis of Subject Treatment Satisfaction 
mITT 
Population 
14.2.9 
Analysis of Time to Perceptible Pain Relief 
mITT 
Population  
14.2.10 
Analysis of Time to Meaningful Pain Relief 
mITT 
Population 
14.2.11 
Analysis of Time to First Use of Rescue Medication 
mITT 
Population 
14.2.12 
Proportion of Subjects Receiving Rescue Medication 
mITT 
Population 
Safety 
 
 
14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
(TEAEs) 
Safety 
Population 
14.3.1.2 
Summary of TEAEs by System Organ Class (SOC), and 
Preferred Term (PT) 
Safety 
Population 
14.3.1.3 
Summary of TEAEs Leading to Study Discontinuation by SOC 
and PT 
Safety 
Population 
14.3.1.4 
Summary of Serious TEAEs by SOC and PT 
Safety 
Population 
14.3.1.5 
Summary of TEAEs by SOC, PT, and Maximum Severity 
Safety 
Population 
14.3.1.6 
Summary of TEAEs by SOC, PT, and Maximum Relationship to 
Treatment 
Safety 
Population 
14.3.2.1 
Summary of Chemistry Results and Change from Baseline by 
Time Point 
Safety 
Population 
14.3.2.2 
Summary of Hematology Results and Change from Baseline by 
Time Point 
Safety 
Population 
14.3.2.3 
Summary of Coagulation Results and Change from Baseline by 
Time Point 
Safety 
Population 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 26 of 28 
Number 
Title 
Analysis 
Population 
14.3.2.4 
Summary of Continuous Urinalysis Results and Change from 
Baseline by Time Point 
Safety 
Population 
14.3.2.5 
Summary of Categorical Urinalysis Results by Time Point 
Safety 
Population 
14.3.3 
Summary of Vital Signs and Change from Baseline by Time 
Point 
Safety 
Population 
14.3.4 
12-Lead ECG Shift Table 
Safety 
Population 
15.2 
Figures for Final Study Report 
Number 
Title 
Analysis 
Population 
14.2.1.1 
Mean Pain Intensity by Timepoint Using NPRS (Imputed 
Data) 
mITT Population 
14.2.1.2 
Mean SPID by Timepoint (Imputed Data) 
mITT Population 
14.2.2.1 
Mean Pain Relief by Timepoint (Imputed Data) 
mITT Population 
14.2.2.2 
Mean TOTPAR by Timepoint (Imputed Data) 
mITT Population 
14.2.3.1 
Proportion of Responders (>30%/>50%) at each Timepoint 
mITT Population 
14.2.3.2 
Cumulative Proportion of Responders Analysis at each 
Timepoint 
mITT Population 
14.2.4 
Kaplan-Meier Curve for Time to Peak Pain Relief 
mITT Population 
14.2.5 
Mean Subject Rating of Satisfactoriness by Timepoint 
mITT Population 
14.2.6 
Kaplan-Meier Curve for Time to Confirmed Perceptible Pain 
Relief 
mITT Population 
14.2.7 
Kaplan-Meier Curve for Time to Meaningful Pain Relief 
mITT Population 
14.2.8 
Kaplan-Meier Curve for Time to First Dose of Rescue 
Medication 
mITT Population 
 
 
15.3 
Listing for Final Study Report 
Number 
Title 
Analysis Population 
16.1.1.1 
Randomization and Population Inclusion 
All Screened Subjects 
16.2.1.2 
Screen Failures and Subjects Not Receiving 
Treatment  
All Screened Subjects 
16.2.1.3 
Subject Completion/Early Termination 
All Randomized Subjects 
16.2.1.4 
Protocol Deviations 
All Randomized Subjects 
16.2.2 
Demographics and Baseline Characteristics  
All Randomized Subjects 
16.2.3 
Medical History 
All Randomized Subjects 
16.2.4 
Dental History 
All Randomized Subjects 
16.2.5 
Prior and Concomitant Medications 
All Randomized Subjects 
16.2.6 
Non-Medication Therapy 
All Randomized Subjects 
16.2.7 
Surgery Procedure and Anesthesia 
All Randomized Subjects 
16.2.8 
Post-Operative Pre-Randomization Pain Intensity 
Assessments 
All Randomized Subjects 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 27 of 28 
Number 
Title 
Analysis Population 
16.2.9 
Study Drug Administration 
All Randomized Subjects 
16.2.10.1 
NPRS Pain Intensity Assessments and Summed 
Pain Intensity Differences (SPIDs) 
mITT Population 
16.2.10.2 
Pain Relief Assessments and Total Pain Relief 
(TOTPAR) 
mITT Population 
16.2.10.3 
Time to Perceptible and Meaningful Pain Relief 
mITT Population 
16.2.10.4 
Patient Ratings of Treatment Satisfactoriness 
mITT Population 
16.2.10.5 
Rescue Medication Administration 
mITT Population 
16.2.11.1 
All Adverse Events 
Safety Population 
16.2.11.2 
Serious Adverse Events 
Safety Population 
16.2.11.3 
Adverse Events Leading to Study Discontinuation 
Safety Population 
16.2.12.1 
Chemistry Laboratory Results 
Safety Population 
16.2.12.2 
Hematology Laboratory Results 
Safety Population 
16.2.12.3 
Urinalysis Laboratory Results 
Safety Population 
16.2.12.4 
Coagulation Laboratory Results 
Safety Population 
16.2.13.1 
Vital Signs 
Safety Population 
16.2.13.2 
Physical Examinations 
Safety Population 
16.2.13.3 
ECG Exam Assessments 
Safety Population 
16.2.13.4 
Serology and Pregnancy Laboratory Results 
Safety Population 
16.2.13.5 
Alcohol and Urine Drug Screens 
All Randomized Subjects 
 
 
 
16.0 Document History 
 
Version 
#  
Summary of Changes  
Section 
Changed 
Date 
1.0 
• 
Initial document released 
NA 
13-Aug-2018 
2.0 
• 
Version 2.0 released 
• 
8.2.1 Added analysis of treatment effect  
at each post-baseline timepoint for Pain 
Intensity Difference (Tables 14.2.2, 
14.2.3)  
• 
8.2.2 Added Mean SPID by Timepoint 
(Figure 14.2.1.2) 
• 
8.2.5 Added Mean TOTPAR by 
Timepoint (Figure 14.2.2.2) 
8.2.1, 8.2.2, 
8.2.5, 8.2.8, 
14.0, 15.1, 15.2, 
15.3 
08-Oct-2018 


Lotus Clinical Research 
Statistical Analysis Plan Version: 2.0 
Study – DRL DFN-15-CD-010 
Effective Date: 08OCT2018 
_________________________________________________________________________________________________________ 
SD-SA-100 v.1.0 
Confidential 
Page 28 of 28 
 
Version 
#  
Summary of Changes  
Section 
Changed 
Date 
• 
8.2.8 Added descriptive analysis of 
Subject Treatment  Satisfaction as a 
continuous variable and ANCOVA 
Analysis of the same (Table 14.2.8.2) 
• 
10.2 Clarified location and presentation 
of PK data in study report 
• 
Added Table 14.3.2.5 Summary of 
Categorical  Urinalysis Results by 
Timepoint 
• 
References were removed. 
• 
Minor formatting updates made 
throughout the document.