Clinical trial NCT03006276
Conditions: Migraine Headache
Sponsor: BioDelivery Sciences International
Start date: 2016-12-01; Completion date: 2019-05-01
Enrollment: 622 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Efficacy, Tolerability, and Safety of DFN-15 in episodic migraine with or without aura, being conducted at multiple centers in the United States.

Detailed description:

Arms: arm 1: DFN-15 Active arm 2: DFN-15 Placebo
Interventions: intervention 1: DFN-15 Active intervention 2: DFN-15 Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
NCT #: 
NCT03006276 
Study ID #: 
DFN-15-CD-007 
Study Title: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Efficacy, 
Tolerability, and Safety Study of DFN-15 in Episodic Migraine with or 
without Aura 
Protocol: 
Version 2.0, 09 May 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Efficacy, Tolerability, and Safety Study of DFN-15 in Episodic Migraine 
With or Without Aura 
Protocol Number: 
DFN-15-CD-007 
Study Drug/ 
Investigational Product: 
DFN-15, Celecoxib Oral Solution, 120 mg (25 mg/mL) 
IND Number: 
125,585 
Phase: 
3 
Indication: 
Episodic Migraine With or Without Aura in Adults 
Sponsor: 
Dr. Reddy’s Laboratories Ltd. 
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 
United States 
Protocol Date: 
09 May 2017 
Protocol Version: 
Version 1.0, dated 12 September 2016 
Protocol Amendment 1: 
Version 2.0, dated 09 May 2017 
STATEMENT OF CONFIDENTIALITY 
The information contained in this document is the property or under the control of Dr. Reddy’s 
Laboratories, Ltd. (Dr. Reddy’s) and is provided to you in confidence as an Investigator, potential 
Investigator, or consultant for review by you, your staff, and applicable Institutional Review Board. You 
shall not disclose this information to others without prior written authorization from Dr. Reddy’s, except to 
the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered, and except as may be required by federal, state, or local laws or regulations. 


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Protocol Amendment 1 
Summary of Changes (v_1.0 to v_2.0) 
The following changes were made in Amendment 1 (v_2.0) of the DFN-15-CD-007 Protocol. 
Bold, italicized indicates added text; strikethrough indicates removed text: 
Section 
Revision 
Protocol Approval 
Signatures 
Minor administrative changes to signatories to Protocol Amendment 
1  
1 Synopsis  
Co-Primary Objectives: 
Co-Primary Endpoints 
(for first treated DB1 
attack): 
Secondary Endpoints: 
To assess the proportion of subjects who are free from their 
Screening most bothersome symptom (MBS) among nausea, 
photophobia, and phonophobia at 2 hours postdose (first treated 
DB1 attack) 
The proportion of subjects who are free from their Screening most 
bothersome symptom (MBS) among nausea, photophobia, and 
phonophobia at 2 hours postdose compared between DFN-15 and 
placebo in the DB1 period. 
•
Revised: The proportion of subjects who are free from nausea,
photophobia, and phonophobia at 15, 30, and 45 minutes and
1, 1.5, 2, 4, and 24 hours postdose compared between DFN-15
and placebo in each DB period
•
Revised: The proportion of subjects who have pain relief
(defined as a reduction in migraine pain from predose severe
[Grade 3] or moderate [Grade 2] to mild [Grade 1], or none
[Grade 0] pain, respectively) at 15, 30, and 45 minutes and 1,
1.5, 2, 4, and 24 hours postdose compared between DFN-15
and placebo in each DB period; added definition of headache
pain relief as follows: Headache pain relief is defined for DB1
as a reduction from moderate or severe pain prior to dosing
reduced to mild or none postdose, and for DB2 as moderate
or severe pain predose reduced to mild or none postdose,
or mild pain predose reduced to none postdose
•
Revised: The proportion of subjects with their predose
Screening MBS (and have this symptom predose) absent at
15, 30, and 45 minutes, and 1, 1.5, 2 (DB2 period), 4, and 24
hours postdose compared between DFN-15 and placebo in each
DB period
•
Revised: The proportion of subjects who have sustained pain
relief at 2 to 24 hours, postdose (i.e., pain-free relief at 2 hours


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postdose, with no use of rescue medication and no recurrence of 
headache pain within 2 to 24 hours postdose compared between 
DFN-15 and placebo in each DB period 
•
Revised: Treatment satisfaction at 2 hours and 4 hours postdose
as determined on a 7-point scale compared between DFN-15
and placebo in each DB period. DFN-15 will also be compared
to the same question in the baseline PPMQ-R
4.1 Co-Primary 
Objectives 
•
To assess the proportion of subjects who are free from their
Screening most bothersome symptom (MBS) among nausea,
photophobia, and phonophobia at 2 hours postdose (first treated
DB1 attack).
4.2 Secondary 
Objectives 
•
Revised: To assess the proportion of subjects who are free from
nausea, photophobia, and phonophobia at 15, 30, and 45
minutes and 1, 1.5, 2, 4, and 24 hours postdose
•
Revised: To assess the proportion of subjects with their predose
Screening MBS absent at 15, 30, and 45 minutes and 1, 1.5, 2
(second attack), 4, and 24 hours postdose
•
Revised: To assess the proportion of subjects who have
sustained pain relief at 2 to 24 hours, postdose (i.e., pain-free
relief at 2 hours postdose, with no use of rescue medication and
no recurrence of headache pain within 2 to 24 hours postdose)
6.2 Inclusion Criteria 
Modified Inclusion Criteria 2b to include bilateral tubal ligation to 
list of acceptable forms of contraception 
6.3 Exclusion Criteria 
Revised Exclusion Criteria #32: Subjects with any medical condition 
or procedure that in the judgment of the Investigator and/or Medical 
Monitor would confound the objectives of the study (e.g., clinically 
significant abnormal thyroid-stimulating hormone [TSH] levels, 
systemic lupus erythematosus, a history of gastric bypass 
surgery or other bariatric procedures) 
6.3.1 Additional 
Exclusion Criteria 
Clarification for 
SBP/DBP and QTcF 
Revised for consistency for subjects presenting with a history of 
uncontrolled hypertension. Revised SBP/DBP from ≥ (greater than 
or equal to) to ˃ (greater than) eg, SBP/DBP ˃ 140/90 mmHg  
6.3.1 Additional 
Exclusion Criteria 
Clarification for 
SBP/DBP and QTcF 
Added detailed procedures for subjects presenting at screening with 
ECG QTcF >450 msec. Added detailed procedures for ECG QTcF 
findings at Visits 2 and 3. 
7.3 Storage, Packaging, 
and Labeling 
Revised: The study drug will be shipped to a designee at each study 
site and must be stored in a pharmacy or locked and secured in a 
storage facility (between 20°C and 25°C [68°F and 77°F], USP 
controlled room temperature; excursions permitted between 15°C 


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and 30°C [59°F and 86°F]) environment, and protected against 
direct heat, light, and humidity. 
9.2 Study Assessments 
Revised Table 9-1 Schedule of Assessments as follows: 
Migraine history (including MBS for the co-primary analysis) and 
current treatment status 
9.2.1.1 Screening (Visit 
1) (Day -21 to Day -1)
Clarification that subjects were to collect at least 1 migraine episode 
during the screening period as follows:  
An eDiary will be dispensed at V1 to collect at least 1 migraine 
episode during the screening period and, if eligible, the subject 
will be is randomized (V2) and will continue to collect migraine data 
through end of treatment (V4/ET).  
Clarification of the following Screening Visit assessment: 

Demographics, medical history, prior medications, and migraine
history (including associated symptoms and MBS for the co-
primary analysis, medications taken for migraine management,
satisfaction and headache pain relief with current medication)
9.2.1.4.1 Efficacy 
Assessments Using 
eDiary 
Clarification that subjects were to collect at least 1 migraine episode 
during the screening period. Added clarification to eDiary 
assessment process.   
Subjects will be provided with an eDiary at screening (V1) to collect 
at least 1 migraine attack during the screening period. 
The migraine episode may be treated with medication the 
subject currently uses for a migraine during this period, unless 
otherwise instructed by the Investigator. After at least 1 
migraine attack has been recorded in the eDiary, as instructed, 
the subject will contact the study site to schedule Visit 2 (V2). 
At V2 (randomization), it will be determined if subjects meet all 
study requirements and are eligible to continue in the study. If 
a subject does not meet all requirements, they must return all 
study equipment that was provided at the Screening Visit. If 
randomized, subjects will continue to collect migraine data (for a 
migraine attack treated with study drug), study drug, last food intake 
and fat content, and any rescue medication used to treat a migraine. 
Subjects will record migraine predose assessments, study drug date 
and time taken, and postdose efficacy data in real time in the 2 DB 
periods through V4/ET: 
Addition of the following statement: 
MBS will also be collected during Screening via Migraine 
History evaluation and this Screening MBS will be used for the 


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evaluation of the second co-primary endpoint. 
9.2.2.5 Twelve-Lead 
Electrocardiogram 
Clarified the following: With the exception of QTcF evaluation as 
specified in Section 6.3.1, the overall interpretation and 
determination of the clinical relevance of ECG findings will be the 
responsibility of the Investigator, taking into account the central 
reader’s evaluation, and will be recorded in the subject’s eCRF. 
9.2.2.7 Serious Adverse 
Events (subsection 
Breaking the Blind) 
Updated explanation of management of breaking the blind to 
conform with prior Section 8.4 Blinding. 
10.2 Analysis Datasets 
or Populations 
Added Screened Set and Randomized Set to populations to be 
analyzed. 
Screened Set 
The Screened Set will include all screened subjects. The set of 
analyses, including subject listings and summary tables of 
subject disposition, will be analyzed based on all eligible 
screened subjects who are databased for the study. 
Randomized Set 
Each DB treatment period will have a Randomized Set. The 
randomized set for DB1 will include all subjects who give 
informed consent and are eligible for and randomized into the 
DB1 treatment period. The randomized set for DB2 will include 
all subjects in the randomized set for DB1 who are eligible for 
and are re-randomized into the DB2 treatment period. 
Revised Full Analysis Set to include assessment for pain or 
symptom (among nausea, photophobia, phonophobia) in both 
DB1 and DB2 treatment periods. 
Revised Safety Population to include eDiary recording: The safety 
population will include all subjects who receive at least one dose of 
DB study drug during one or both treatment periods and have it 
recorded in their eDiary. 
Revised Per Protocol Population to include endpoint assessments of 
observed and last observation carried forward (LOCF) for DB1 
treatment period. 
10.4.1 Co-Primary 
Endpoints 
•
The proportion of subjects who are free from their Screening
MBS among nausea, photophobia, and phonophobia at 2 hours
postdose compared between DFN-15 and placebo in the DB1
period.
10.4.2 Secondary 
•
Revised: The proportion of subjects who are free from nausea,
photophobia, and phonophobia at 15, 30, and 45 minutes and


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Endpoints 
1, 1.5, 2, 4, and 24 hours postdose compared between DFN-15 
and placebo in each DB period 
•
Revised: The proportion of subjects who have pain relief
(defined as a reduction in migraine pain from predose severe
[Grade 3] or moderate [Grade 2] to mild [Grade 1], or none
[Grade 0] pain, respectively) at 15, 30, and 45 minutes and 1,
1.5, 2, 4, and 24 hours postdose compared between DFN-15
and placebo in each DB period; added definition of headache
pain relief as follows: Headache pain relief is defined for DB1
as a reduction from moderate or severe pain prior to dosing
reduced to mild or none postdose, and for DB2 as moderate
or severe pain predose reduced to mild or none postdose,
or mild pain predose reduced to none postdose
•
Revised: The proportion of subjects with their predose
Screening MBS (and have this symptom predose) absent at
15, 30, and 45 minutes, and 1, 1.5, 2 (DB2 period), 4, and 24
hours postdose compared between DFN-15 and placebo in each
DB period
•
Revised: To assess the proportion of subjects who have
sustained pain relief at 2 to 24 hours, postdose (i.e., pain-free
relief at 2 hours postdose, with no use of rescue medication and
no recurrence of headache pain within 2 to 24 hours postdose
compared between DFN-15 and placebo in each DB period
•
Revised: Treatment satisfaction at 2 hours and 4 hours postdose
as determined on a 7-point scale compared between DFN-15
and placebo in each DB period. DFN-15 will also be compared
to the same question in the baseline PPMQ-R
10.5.1 Primary Efficacy 
Analysis 
Modified: The first co-primary efficacy endpoint of the proportion of 
subjects who are free from headache pain at 2 hours after the first 
dose of study drug taken for a migraine attack with moderate to 
severe headache pain during the DB1 period, will be analyzed using 
Fisher’s exact test. The second co-primary efficacy endpoint of the 
proportion of subjects who are free from their Screening MBS 
among nausea, photophobia, and phonophobia at 2 hours postdose 
during the DB1 period will be similarly analyzed using Fisher’s exact 
test. A subject’s MBS will be obtained at Screening via Migraine 
History assessment and, for the analysis of the co-primary 
endpoint, that symptom must be present predose but does not 
have to be designated as the MBS at predose.  
10.5.3 Exploratory 
Analysis 
Revised: No exploratory analysis is planned. Exploratory analyses 
based on predose pain level and predose MBS are planned and 
details will be provided in the SAP.  
10.7 Determination of 
Revised the following paragraph to add term ‘Screening’ MBS: 


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Sample Size 
The second co-primary endpoint is the comparison of the proportion 
of subjects who are free from their Screening MBS among nausea, 
photophobia, and phonophobia at 2 hours after the first dose of 
study drug. It is assumed that 28.2% of placebo and 44.7% of 
DFN-15 (treated) subjects will be free from their Screening MBS at 
2 hours. A sample size of 480 subjects will provide 94% power to 
detect this assumed difference between placebo and DFN-15 at a 
5% (2-sided) level of significance and with a 15% dropout rate. 




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1 Protocol Synopsis 
Protocol Number: 
DFN-15-CD-007 
Title: 
A 
Multicenter, 
Randomized, 
Double-Blind, 
Placebo-
Controlled, Efficacy, Tolerability, and Safety Study of DFN-15 
in Episodic Migraine With or Without Aura 
Study Drug/ 
Investigational Product: 
DFN-15, Celecoxib Oral Solution, 120 mg (25 mg/mL) 
Country: 
United States of America 
Phase: 
3 
Co-Primary Objectives: 
To assess the proportion of subjects who are pain-free at 
2 hours postdose (first treated DB1 attack) 
To assess the proportion of subjects who are free from their 
Screening most bothersome symptom (MBS) among nausea, 
photophobia, and phonophobia at 2 hours postdose (first 
treated DB1 attack)  
Number of Subjects: 
Approximately 600 subjects will be randomized. Subjects who 
discontinue study participation prior to completing the study 
will not be replaced. 
Study Design: 
This is a randomized, 2 double-blind (DB) treatment period 
study, to be conducted at approximately 45 centers in the 
United States. Male and female subjects, 18 to 75 years old 
(inclusive), previously diagnosed with at least 12 months’ 
medical history prior to screening of episodic migraine (per 
International Classification of Headache Disorders, 3rd edition 
[beta version]1 [ICHD-3]), who do not have medication 
overuse, who experience 2 to 8 migraine attacks (with or 
without aura) per month, with 14 or fewer headache days per 
month, who can demonstrate 48 hours of headache-free time 
between migraine attacks, and who meet all inclusion and 
none of the exclusion criteria and successfully complete all 
screening procedures, will be randomized in a 1:1 ratio in a 
DB fashion to receive orally either DFN-15 or matching 
placebo, to be used in one migraine attack.  
During the first double-blind (DB1) period, 1 migraine attack 
will be treated with study drug as soon as (and no more than 
1 hour after) experiencing moderate to severe pain level. 
Subjects will then return to the study site within 2 to 7 days of 
the first treatment and, if continuing to be eligible, will be re-
randomized into a second double-blind (DB2) period to treat 
another attack at any pain level. They will then return to the 
study site within 2 to 7 days of the second treatment at the 


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final visit (Visit 4/early termination [V4/ET]). 
Study drug should only be used to treat a new migraine 
attack, not a recurrence, and there should be at least 48 
hours of pain and symptom freedom from a previous attack. 
Once randomized, the total duration of each subject’s 
participation in the study would be up to 10 weeks from 
baseline. 
During the treatment periods, data regarding the study drug 
effect and the associated impact on migraine pain, symptoms, 
functional disability, and subjects’ satisfaction with treatment 
will be collected in real-time in an electronic diary (eDiary) 
(Section 9.2.1.4.1). After study completion or discontinuation, 
subjects should be referred to their usual healthcare 
professional to resume pre-study standard of care, as per the 
Investigator’s discretion. 
During the 2 treatment periods of the study, subjects will have 
an option, if required, to take rescue medication after the 
2 hours postdose time point efficacy data have been recorded 
in the eDiary. Rescue medication will be decided between the 
Investigator and the subject, exclusive of study prohibited 
medications. Rescue medication will not be provided by the 
Sponsor, and its use should be managed by the subject and 
their Investigator. 
Treatment: 
For the DB1 period, all subjects will be randomly assigned in 
a 1:1 ratio to receive either DFN-15 or a matching placebo to 
be used to treat 1 migraine attack as soon as (and no more 
than within 1 hour after) experiencing moderate to severe 
pain. Eligible subjects will then be re-randomized in a 1:1 ratio 
into the DB2 period to receive either DFN-15 or a matching 
placebo to treat another migraine attack at any pain level. The 
migraine attacks and associated treatment and assessments 
are to be recorded in an eDiary. 
Study Duration: 
The duration of study participation will be up to approximately 
13 weeks, including a screening period of approximately 
3 weeks (wherein subjects may be randomized earlier if they 
meet inclusion/exclusion criteria and headache assessment 
criteria; the screening period may also be extended based on 
Investigator judgment and in consultation with the Medical 
Monitor), 2 DB treatment periods with up to 4 weeks allowed 
to experience and treat a migraine attack in each, and 2 to 7 
days to return to the site after treatment. Once randomized, 
the total duration of each subject’s participation in the study 
would be up to 10 weeks from baseline.  
Study Population: 
Male and female subjects, 18 to 75 years old (inclusive), 
previously diagnosed with at least 12 months’ medical history 


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prior to screening of episodic migraine (per ICHD-3), who do 
not have medication overuse, who experience 2 to 8 migraine 
attacks (with or without aura) per month, with 14 or fewer 
headache days per month, who can demonstrate 48 hours of 
headache-free time between migraine attacks, and who meet 
all inclusion and none of the exclusion criteria and 
successfully complete all screening procedures, will be 
included. 
Migraines can be with or without aura. 
Subjects with medication overuse, subjects who use 
mini-prophylaxis for menstrual migraine, subjects who have 
been on unstable doses of migraine prophylactic medications 
within 30 days prior to and through screening, and subjects 
with a history of migralepsy will be excluded. See inclusion 
and exclusion criteria for additional study entry requirements. 
Co-Primary Endpoints (for 
first treated DB1 attack): 
Secondary Endpoints: 
•
The proportion of subjects who are pain-free 2 hours
postdose compared between DFN-15 and placebo in the
DB1 period (defined as a reduction from predose
moderate [Grade 2] or severe [Grade 3] pain to none
[Grade 0]).
•
The proportion of subjects who are free from their
Screening most bothersome symptom (MBS) among
nausea, photophobia, and phonophobia at 2 hours
postdose compared between DFN-15 and placebo in the
DB1 period.
•
The proportion of subjects with treatment-emergent
adverse events (TEAEs) after study drug compared
between DFN-15 and placebo.
•
The proportion of subjects who are free from nausea,
photophobia, and phonophobia at 15, 30, and 45 minutes
and 1, 1.5, 2, 4, and 24 hours postdose compared
between DFN-15 and placebo in each DB period.
•
Time to meaningful pain relief (defined as based on
subject’s perception) within 2 hours postdose compared
between DFN-15 and placebo in each treated attack in
each DB period.
•
Time to pain freedom within 2 hours postdose compared
between DFN-15 and placebo in each DB period.
•
The proportion of subjects who have pain relief at 15, 30,
and 45 minutes and 1, 1.5, 2, 4, and 24 hours postdose
compared between DFN-15 and placebo in each DB
period. Headache pain relief is defined for DB1 as a
reduction from moderate or severe pain prior to dosing
reduced to mild or none postdose, and for DB2 as


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moderate or severe pain predose reduced to mild or none 
postdose, or mild pain predose reduced to none postdose. 
•
The proportion of subjects who are pain-free at 15, 30,
and 45 minutes and 1, 1.5, 2 (DB2 period), 4, and 24
hours postdose compared between DFN-15 and placebo
in each DB period.
•
The proportion of subjects with their Screening MBS (and
have this symptom predose) absent at 15, 30, and
45 minutes, and 1, 1.5, 2 (DB2 period), 4, and 24 hours
postdose compared between DFN-15 and placebo in
each DB period.
•
Change in functional disability score at 2, 4, and 24 hours
postdose compared between DFN-15 and placebo in
each DB period.
•
Among those reporting cutaneous allodynia predose, the
proportion of subjects who are pain-free at 2 and 4 hours
postdose compared between DFN-15 and placebo in
each DB period.
•
The proportion of subjects who are pain-free at 2 and
4 hours postdose whose body mass index (BMI) is < 30
vs. subjects whose BMI is ≥ 30, and whose BMI is < 25
vs. subjects whose BMI is ≥ 25 in each DB period.
•
The proportion of subjects who have pain recurrence
between 2 to 24 hours (i.e., pain-free at 2 hours postdose,
with pain [mild, moderate, or severe] reported at 24 hours
postdose) compared between DFN-15 and placebo in
each DB period.
•
The proportion of subjects who have sustained pain relief
at 2 to 24 hours postdose (i.e., pain-relief at 2 hours
postdose, with no use of rescue medication and no
recurrence of headache pain within 2 to 24 hours
postdose) compared between DFN-15 and placebo in
each DB period.
•
The proportion of subjects who have sustained pain
freedom at 2 to 24 hours postdose (i.e., pain-free at
2 hours postdose, with no use of rescue medication, and
no recurrence of headache pain within 2 to 24 hours
postdose) compared between DFN-15 and placebo in
each DB period.
•
The proportion of subjects who use rescue medication
after 2 hours (2 to 24 hours) postdose compared between
DFN-15 and placebo in each DB period.
•
Treatment satisfaction at 2 hours and 4 hours postdose as
determined on a 7-point scale compared between DFN-15
and placebo in each DB period. DFN-15 will also be
compared to the same question in the baseline PPMQ-R.
•
Treatment satisfaction as measured by Patient Perception
of Migraine Questionnaire-Revised (PPMQ-R) at 24 hours
postdose compared between DFN-15 and placebo in
each DB period.


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Table of Contents 
1 
Protocol Synopsis ...................................................................................................... 9 
Table of Contents ....................................................................................................................13 
1.1 
List of In-Text Figures ...............................................................................................16 
1.2 
List of In-Text Tables.................................................................................................16 
2 
List of Abbreviations .................................................................................................17 
3 
Introduction ...............................................................................................................19 
4 
Study Objectives .......................................................................................................20 
4.1 
Co-Primary Objectives ..............................................................................................20 
4.2 
Secondary Objectives ...............................................................................................20 
5 
Investigational Plan ...................................................................................................21 
5.1 
Overall Study Design and Plan .................................................................................21 
5.2 
Discussion of Study Design .....................................................................................22 
6 
Selection of Subjects and Criteria for Withdrawal ..................................................22 
6.1 
Number of Planned Subjects ....................................................................................22 
6.2 
Inclusion Criteria .......................................................................................................23 
6.3 
Exclusion Criteria ......................................................................................................23 
6.3.1 
Additional Exclusion Criteria Clarification for SBP/DBP and QTcF ..............25 
6.4 
Removal of Subjects from Therapy or Assessments .............................................26 
7 
Investigational Products ...........................................................................................27 
7.1 
Investigational Products Administered ...................................................................27 
7.2 
Identity of Investigational Products .........................................................................28 
7.3 
Storage, Packaging, and Labeling ...........................................................................28 
8 
Administration of Study Treatments ........................................................................28 
8.1 
Method of Assigning Subjects to Treatment Groups .............................................28 
8.1.1 
Screening (Visit 1) .......................................................................................29 
8.1.2 
Randomization (Visit 2) ...............................................................................29 
8.2 
Dose Selection...........................................................................................................29 
8.3 
Selection and Timing of Dose for Each Subject ......................................................30 
8.4 
Blinding ......................................................................................................................30 


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8.5 
Prior and Concomitant Therapy ...............................................................................30 
8.5.1 
Medication History ......................................................................................30 
8.5.2 
Rescue Medication .....................................................................................31 
8.5.3 
Prohibited and Allowed Medications ............................................................31 
8.6 
Treatment Compliance ..............................................................................................32 
9 
Study Procedures ......................................................................................................32 
9.1 
Duration of Treatment ...............................................................................................32 
9.1.1 
Data Recording Using eDiary ......................................................................32 
9.2 
Study Assessments ..................................................................................................33 
9.2.1 
Visit Procedures ..........................................................................................38 
9.2.2 
Safety Assessments....................................................................................40 
9.2.3 
Appropriateness of Measurements ..............................................................49 
10 
Statistical Methods ....................................................................................................50 
10.1 Statistical Analysis Plan ...........................................................................................50 
10.2 Analysis Datasets or Populations ............................................................................50 
10.3 Demographic and Other Baseline Characteristics ..................................................51 
10.4 Efficacy Endpoints ....................................................................................................51 
10.4.1 
Co-Primary Endpoints (for first treated DB1 attack only) .............................51 
10.4.2 
Secondary Endpoints: .................................................................................51 
10.5 Methods of Analysis..................................................................................................52 
10.5.1 
Primary Efficacy Analysis ............................................................................52 
10.5.2 
Secondary Endpoint Analysis ......................................................................53 
10.5.3 
Exploratory Analysis....................................................................................53 
10.5.4 
Subgroup Analysis ......................................................................................53 
10.5.5 
Additional Efficacy Analyses .......................................................................53 
10.5.6 
Safety Analysis ...........................................................................................53 
10.6 Interim Analyses ........................................................................................................54 
10.7 Determination of Sample Size ..................................................................................54 
11 
Quality Assurance and Quality Control ...................................................................55 
11.1.1 
Audit and Inspection ...................................................................................55 
11.1.2 
Monitoring ...................................................................................................55 
11.1.3 
Data Management and Coding ...................................................................55 
12 
Records and Supplies ...............................................................................................56 


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12.1 Drug Accountability ..................................................................................................56 
12.2 Financing and Insurance ..........................................................................................56 
13 
Ethics .........................................................................................................................56 
13.1 Institutional Review Board .......................................................................................56 
13.2 Ethical Conduct of the Study ....................................................................................57 
13.3 Subject Information and Consent ............................................................................57 
13.4 Subject Confidentiality ..............................................................................................57 
14 
Reporting and Publication, Including Archiving .....................................................58 
15 
References .................................................................................................................59 
16 
Investigator Signature Page .....................................................................................61 


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1.1 
List of In-Text Figures 
Figure 5-1 
Trial Design .................................................................................................22 
1.2 
List of In-Text Tables 
Table 7-1 
Investigational Product Details for Study Treatments ..................................27 
Table 9-1 
Schedule of Assessments ...........................................................................34 
Table 9-2 
eDiary Assessments ...................................................................................37 


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2 List of Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the curve 
cGCP 
current Good Clinical Practice 
COX-1, COX-2 
cyclooxygenase-1, cyclooxygenase-2 
DB 
double-blind 
DB1 
first double-blind [treatment period] 
DB2 
second double-blind [treatment period] 
DBP 
diastolic blood pressure 
DDM 
1-O-n-dodecyl-β-D-maltopyranoside
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
ET 
early termination 
FAS 
full analysis set 
FDA 
United States Food and Drug Administration 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HbA1c 
glycosylated hemoglobin 
HBsAg 
hepatitis B surface antigen 
HEENT 
head, eyes, ears, nose and throat 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICHD-3 
International Classification of Headache Disorders, 3rd edition 
(beta version) 
ID 
Identification 


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IRB 
Institutional Review Board 
IWRS 
interactive web response system 
MBS 
most bothersome symptom 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAID 
nonsteroidal anti-inflammatory drug 
PK 
Pharmacokinetic 
PP 
per-protocol 
PPMQ-R 
Patient Perception of Migraine Questionnaire-Revised 
PT 
preferred term 
QTcF 
length of time for the electrical system of the heart to adjust to 
heart rate using Fridericia correction formula 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SNRI 
serotonin norepinephrine reuptake inhibitors 
SOC 
system organ class 
SOP 
standard operating procedure 
SSRI 
selective serotonin reuptake inhibitors 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
V 
Visit 
WHO-DD 
World Health Organization Drug Dictionary 


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3 Introduction 
Acute migraine is a disabling neurological disorder with clinical findings of headache, often 
associated with nausea and vomiting. In the United States (US), about 17% of all women and 
6% of all men suffer from migraine. 
Although the exact mechanism of migraine is not known, the pathophysiology involves a 
combination of vascular and neurologic events in the brain and cranial meninges brain leading 
to trigeminal-vascular activation and release of vasoactive peptides.2 Radiologic findings in 
migraine patients are characterized by hyper-excitation of neuronal networks in multiple cortical 
regions, the brainstem, and the trigeminal nerve ganglion.2-4  
Typical clinical characteristics of migraine headache are unilateral location, pulsating quality, 
moderate or severe pain, aggravation by routine physical activity, and association with nausea 
and/or photophobia and phonophobia. It is important to initiate pharmacotherapy as early as 
possible to abort the migraine before it becomes more resistant to treatment.  
Triptans are the mainstay of acute migraine treatment.5 A current challenge with oral and nasal 
triptans is a relatively slow rate of absorption with corresponding lag in onset of action resulting 
in slower pain relief for some migraine patients.6 Sumatriptan subcutaneous injections have a 
faster onset of action, but tolerability and patient acceptance are lower than for oral triptans.7,8 
Opioids are another treatment option, but they have a high rate of adverse events (AEs) and 
abuse potential.9-11 Guidelines published in 2012 by the American Society of Anesthesiology 
Task Force on Acute Pain Management recommend minimizing opioids and maximizing non-
opioid agents in the control of acute pain.12 
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of drugs with analgesic, antipyretic, 
and anti-inflammatory effects that act by inhibition of prostaglandin biosynthesis through 
isoenzymes, cyclooxygenase (COX)-1 and COX-2.13 NSAIDs that selectively inhibit the COX-2 
enzyme target those prostaglandins that are responsible for inflammation and pain (synthesized 
involving COX-2) while sparing the prostaglandins that are responsible for the maintenance and 
protection of the gastrointestinal (GI) tract (synthesized involving COX-1). Thus, the analgesic 
efficacy of NSAIDs is associated with inhibition of COX-2, whereas a majority of GI adverse 
effects, including bleeding and ulcers of the stomach and intestine appear to be related to the 
inhibition of COX-1. The use of COX-2–selective NSAIDs may provide a therapeutic advantage 
over non-selective NSAIDs for the acute management of migraine due to reduced incidence of 
upper GI ulcers and bleeds and less GI upset. Celecoxib, a selective COX-2 inhibitor, is 
available as an oral capsule in several dosage strengths marketed in the US by Pfizer, Inc. 
under the brand name Celebrex® for the treatment of osteoarthritis, rheumatoid arthritis, 
ankylosing spondylitis, acute pain, and primary dysmenorrhea. 
NSAIDs can produce analgesia that is comparable with that observed with opioid administration, 
while sparing patients many of the opioid-associated side effects such as sedation, nausea and 
vomiting. The analgesic effect of celecoxib is similar to other NSAIDs. 
There is no US Food and Drug Administration (FDA)-approved oral liquid formulation of 
celecoxib. DFN-15 is a new oral liquid formulation containing the COX-2–selective NSAID, 
celecoxib. It is proposed that DFN-15 will be administered to migraine patients as an oral liquid 
in a single dose of 120 mg. Celecoxib is the only active ingredient in the formulation. 


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DFN-15 or DFN-15 prototypes were investigated in 5 clinical trials that included 3 bioavailability 
studies (DFN-15-CD-001, DFN-15-CD-003, and DFN-15-CD-004) conducted in healthy 
volunteers, 1 food-effect study (DFN-15-CD-005) in healthy volunteers, and 1 proof-of-concept 
Phase 2, placebo-controlled, double-blind (DB), crossover study (DFN-15-CD-002) to 
demonstrate the tolerability, safety, and efficacy of DFN-15 for the treatment of acute migraine 
headaches (with or without aura). Details are provided in the DFN-15 Investigator’s Brochure.14 
The rationale for performing clinical studies with DFN-15 is to demonstrate its tolerability, safety, 
and efficacy for the acute relief of migraine with or without aura. The ultimate aim is to provide 
an alternative oral liquid NSAID for migraine patients. Dr. Reddy’s Laboratories will seek an 
indication for DFN-15 for the acute treatment of episodic migraine with or without aura. 
4 Study Objectives 
4.1 
Co-Primary Objectives 
•
To assess the proportion of subjects who are pain-free at 2 hours postdose (first treated
DB1 attack).
•
To assess the proportion of subjects who are free from their Screening most bothersome
symptom (MBS) among nausea, photophobia, and phonophobia at 2 hours postdose
(first treated DB1 attack).
4.2 
Secondary Objectives 
•
Safety and tolerability
•
To assess the proportion of subjects who are free from nausea, photophobia, and
phonophobia at 15, 30, and 45 minutes and 1, 1.5, 2, 4 , and 24 hours postdose
•
To assess time to meaningful pain relief
•
To assess time to pain freedom
•
To assess the proportion of subjects who have pain relief at 15, 30, and 45 minutes
and 1, 1.5, 2, 4, and 24 hours postdose
•
To assess the proportion of subjects who are pain-free at 15, 30, and 45 minutes and
1, 1.5, 2 (second attack), 4, and 24 hours postdose
•
To assess the proportion of subjects with their Screening MBS absent at 15, 30, and
45 minutes and 1, 1.5, 2 (second attack), 4, and 24 hours postdose
•
To assess change in functional disability score at 2, 4, and 24 hours postdose
•
Among those reporting cutaneous allodynia predose, the proportion who are pain-
free at 2 and 4 hours postdose
•
To assess the proportion of subjects who are pain-free at 2 and 4 hours postdose
whose body mass index (BMI) is < 30 vs. subjects whose BMI is ≥ 30, and whose
BMI is < 25 vs. subjects whose BMI is ≥ 25
•
The proportion of subjects who have pain recurrence between 2 to 24 hours (i.e.,
pain-free at 2 hours postdose, with pain [mild, moderate, or severe] reported at
24 hours postdose)
•
To assess the proportion of subjects who have sustained pain relief at 2 to 24 hours,
postdose (i.e., pain-relief at 2 hours postdose, with no use of rescue medication and
no recurrence of headache pain within 2 to 24 hours postdose)


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•
To assess the proportion of subjects who have sustained pain freedom at 2 to 24
hours postdose (i.e., pain-free at 2 hours postdose, with no use of rescue medication
and no recurrence of headache pain within 2 to 24 hours postdose)
•
To assess the proportion of subjects who use rescue medication after 2 hours (2 to
24 hours) postdose
•
To assess treatment satisfaction at 2 hours and 4 hours postdose (7-point scale)
•
To assess treatment satisfaction as measured by Patient Perception of Migraine
Questionnaire-Revised (PPMQ-R) at 24 hours postdose
5 Investigational Plan 
5.1 
Overall Study Design and Plan 
This is a randomized, 2 DB treatment period study, to be conducted at multiple centers in the 
US. Male and female subjects, 18 to 75 years old (inclusive), previously diagnosed with at least 
12 months’ medical history prior to screening of episodic migraine (as defined by International 
Classification of Headache Disorders, 3rd edition [beta version]1 [ICHD-3]), who do not have 
medication overuse, who experience 2 to 8 migraine attacks (with or without aura) per month, 
with 14 or fewer headache days per month, who can demonstrate 48 hours of headache-free 
time between migraine attacks, and who meet all inclusion and none of the exclusion criteria 
and successfully complete all screening procedures, will be randomized in a 1:1 ratio in a DB 
fashion to receive orally either DFN-15 or matching placebo, to be used in one migraine attack.  
During the first double-blind (DB1) period, 1 migraine attack will be treated with study drug as 
soon as (and no more than 1 hour after) experiencing moderate to severe pain level. Subjects 
will then return to the study site within 2 to 7 days of the first treatment and, if continuing to be 
eligible, will be re-randomized into a second double-blind (DB2) period to treat another attack at 
any pain level. They will then return to the study site within 2 to 7 days of the second treatment 
for the final visit (Visit 4/early termination [V4/ET]). See Figure 5-1. 
Study drug should only be used to treat a new migraine attack, not a recurrence, and there 
should be at least 48 hours of pain and symptom freedom from a previous attack. Once 
randomized, the total duration of each subject’s participation in the study would be up to 
10 weeks from baseline. 
During the treatment periods, data regarding the study drug effect and the associated impact on 
migraine pain, symptoms, functional disability, and subjects’ satisfaction with treatment will be 
collected in real-time in an electronic diary (eDiary) (Section 9.2.1.4.1). After study completion or 
discontinuation, subjects should be referred to their usual healthcare professional to resume 
pre-study standard of care, as per the Investigator’s discretion. 
During the 2 treatment periods of the study, subjects will have an option, if required, to take 
rescue medication after the 2 hours postdose time point efficacy data have been recorded in the 
eDiary. Rescue medication will be decided between the Investigator and the subject, exclusive 
of study prohibited medications. Rescue medication will not be provided by the Sponsor, and its 
use should be managed by the subject and their Investigator. 


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Figure 5-1 Trial Design 
5.2 
Discussion of Study Design 
The current study design was chosen to determine the efficacy of DFN-15 for the acute 
treatment of episodic migraine with or without aura. A screening period will allow sufficient time 
for screening laboratory test results availability and verification that subjects meet the inclusion 
and exclusion criteria. 
Subjects will be randomized in a blinded fashion to receive DFN-15 or matching placebo and 
self-administer when experiencing a migraine attack to determine whether DFN-15 can relieve 
migraine pain and symptoms and disability compared with placebo. For the first treated acute 
migraine attack (DB1 period), subjects will treat moderate or severe pain to meet regulatory 
requirements for efficacy determination; for the second attack (DB2 period), subjects will treat 
migraine at any pain level to determine if efficacy is achieved throughout the pain level range.  
During the treatment periods, subjects will have an option, if required, to take rescue medication 
after the 2 hours postdose time point efficacy data has been recorded in the eDiary. Rescue 
medication will be decided between the Investigator and the subject to provide subject comfort 
while supporting clinically relevant data collection (see Section 8.5.2). Rescue medication will 
not be provided by the Sponsor, and its use should be managed by the subject and their 
Investigator. 
6 Selection of Subjects and Criteria for Withdrawal 
6.1 
Number of Planned Subjects 
Approximately 600 subjects will be randomized. Subjects who do not qualify for enrollment after 
the screening period will be terminated as screen failures and will be replaced. Randomized 
subjects who discontinue study participation before study completion will not be replaced. 


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6.2 
Inclusion Criteria 
Subjects may be included in the study if they meet all of the following criteria: 
1.
Able and willing to provide written informed consent
2.
Male or female, 18 to 75 years of age, inclusive, at screening
a. If female and of childbearing potential, the subject must have a negative
serum pregnancy test at screening, does not plan to become pregnant
during the study, and is not lactating.
b. If female and of childbearing potential, the subject must also have a negative
urine pregnancy test at all subsequent study visits after the screening visit
and, unless surgically or otherwise sterile or postmenopausal for > 1 year,
agrees to practice a reliable form of contraception or abstinence during the
study. Acceptable forms of contraception include: bilateral tubal ligation,
implants, injectables, combined oral contraceptives, an intrauterine device, a
vasectomized partner, an exclusively female partner, and double-barrier
methods.
c.
If male (with female partner), the subject must agree to practice a reliable
form of contraception or abstinence during the study.
3.
A history of episodic migraine (per ICHD-3), who experience 2 to 8 migraine attacks
per month for at least the past 12 months, with no more than 14 headache days per
month, and with 48 hours of headache-free time between migraine attacks.
4.
Have migraine with or without aura with onset before age 50 years
5.
Report usual migraine pain of 2 (moderate) or 3 (severe) on headache pain severity
scale without treatment.
6.
Subjects who, in the opinion of the Investigator, are willing and able to:
a. Evaluate and record pain, migraine symptoms, and study drug effectiveness
information in real-time using a subject eDiary for the duration of the study;
b. Record each instance of the use of study drug and rescue medication in real-
time using a subject eDiary for the duration of the study;
c.
Comply with all other study procedures and scheduling requirements.
7.
Ability to read, speak, and understand English proficiently.
6.3 
Exclusion Criteria 
Subjects will be excluded from participating in the study if they meet any of the following criteria: 
1.
Minors, even if they are in the specified study age range
2.
Exposure to DFN-15 prior to the study
3.
Medication overuse:
o
Opioids ≥ 10 days during the 90 days prior to screening
o
Combination medications (e.g., Fiorinal®) ≥ 10 days during the 90 days prior to
screening (applies only if includes opioid and/or barbiturate)
o
NSAIDs or other simple medications > 14 days a month during the 90 days prior
to screening
o
Triptans or ergots ≥ 10 days a month during the 90 days prior to screening
4.
Treated with onabotulinumtoxin A (Botox®) for migraine within 4 months prior to screening.
(If treated for cosmetic reasons, subjects may be included).
5.
On unstable dosages of migraine prophylactic medications within 30 days prior to and
through screening


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6.
Taking mini-prophylaxis for menstrual migraine
7.
On chronic warfarin sodium or equivalent
8.
Cerebrovascular events including but not limited to a history of stroke or transient
ischemic attack
9.
A history of migralepsy (seizure following a migraine) or a concurrent diagnosis of seizure
disorder
10.
Subjects who cannot differentiate between a migraine headache and tension-type or
cluster headache or other types of headache
11.
A history of cluster headaches
12.
Subjects with the diagnosis of “probable migraine” (per ICHD-3)
13.
Subjects who have intolerance to any formulation of celecoxib or sulfonamides, or who
have experienced a significant AE related to any other NSAID, including aspirin, which
caused the condition of asthma, rhinitis, nasal polyps, or Samter’s triad
14.
Subjects for whom NSAIDs are contraindicated (e.g., GI bleed, ulcer, history of acute
renal failure)
15.
Ischemic coronary artery disease including but not limited to angina pectoris, history of
myocardial infarction or documented silent ischemia or coronary artery vasospasm,
including Prinzmetal’s angina; symptomatic peripheral vascular disease
16.
A history of congenital heart disease
17.
Uncontrolled hypertension or screening systolic/diastolic blood pressure (SBP/DBP)
˃ 140/90 mmHg (the values should be confirmed to rule out a transient elevation); see
Section 6.3.1 for details
18.
Any abnormal physiology and/or pathology that, in the opinion of the Investigator or
Sponsor, would be contraindicated for study participation and would not allow the
objectives of the study to be met
19.
Subjects who show any clinical laboratory or electrocardiogram (ECG) abnormality that in
the opinion of the Investigator or Sponsor would endanger the subject or interfere with the
study conduct. If the results of the clinical laboratory or ECG are outside of normal
reference range the subject may still be enrolled, but only if these findings are determined
to be not clinically significant by the Investigator. This determination must be recorded in
the subject’s source document before enrollment.
20.
Fridericia’s corrected QT (QTcF) interval ˃ 450 msec; see Section 6.3.1 for details
21.
Serum creatinine > 1.5 × the upper limit of normal (ULN)
22.
Serum total bilirubin > 1.5 × ULN
23.
Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline
phosphatase > 2.5 × ULN
24.
Subjects with uncontrolled diabetes mellitus, or a glycosylated hemoglobin (HbA1c)
> 7.9%, or with diabetes mellitus requiring insulin
25.
A history of alcohol or substance use disorder (including marijuana) according to the
Diagnostic and Statistical Manual of Mental Disorders, Edition 5 (DSM-5) within 1 year
prior to screening
26.
Current treatment with antipsychotics or use of antipsychotics within 30 days prior to
randomization (if used for non-psychiatric conditions, should be evaluated on a case-by-
case basis with the Medical Monitor)
27.
A positive urine drug screen for recreational drugs, alcohol, marijuana (whether legal or
not) or for prescription drugs not explained by stated concomitant medications
•
Subjects consuming opioids for the treatment of migraine or using opioids or
barbiturates temporarily for a legitimate medical cause may participate as long as
they do not meet the medication overuse criteria in Exclusion Criteria #3, above.


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•
Chronic use of benzodiazepines is allowed if used for legitimate medical use, as
long as the regimen has been stable for at least 3 months prior to screening and is
expected to remain stable throughout the study
•
Chronic use of amphetamines to treat attention deficit disorder (ADD) or attention
deficit hyperactivity disorder (ADHD) and related disorders is allowed as long as
the regimen has been stable for at least 3 months prior to screening and is
expected to remain stable throughout the study
Note: For the above-mentioned conditions, the site must have appropriate 
documentation to justify the mentioned drug use (e.g., documented medical history 
and a valid prescription-based dispensation) 
28.
A history of or current neurological or psychiatric impairment including but not limited to
psychosis, current major depression, bipolar disorder, or cognitive dysfunction that, in the
opinion of the Investigator, would compromise data collection, or any subject who, in the
opinion of the Investigator, is at significant risk for suicide
29.
Subjects who have received treatment with an investigational drug or device within 30
days of randomization, or participated in a central nervous system clinical trial within
2 months prior to randomization
30.
Subjects who have received treatment with CYP2C9 inducers or with CYP2D6 substrates
with a narrow therapeutic window (i.e., thioridazine) within 7 days prior to randomization
31.
Use of prohibited medications pursuant to Section 8.5.3; non-compliance with wash-out
period criteria (Section 8.5.1)
32.
Subjects with any medical condition or procedure that in the judgment of the Investigator
and/or Medical Monitor would confound the objectives of the study (e.g., clinically
significant abnormal thyroid-stimulating hormone [TSH] levels, systemic lupus
erythematosus, a history of gastric bypass surgery or other bariatric procedures)
33.
Subjects with positive screening test for human immunodeficiency virus [HIV], positive
hepatitis B surface antigen (HBsAg), or positive hepatitis C virus [HCV] antibody
34.
History of cancer within the past 5 years (except adequately treated basal cell or
squamous cell skin carcinoma or in situ cervical cancer)
35.
Subjects who should not be enrolled per the precautions, warnings, and contraindications
section of the celecoxib product label or package insert14
36.
Subjects who plan to donate blood, sperm, or oocytes during the study and for 30 days
post last dose of study drug
37.
Subjects who are employees or immediate relatives of the employees of the Sponsor, any
of its affiliates or partners, or of the clinical research study site.
6.3.1 Additional Exclusion Criteria Clarification for SBP/DBP and QTcF 
Subjects presenting with a history of hypertension that is uncontrolled during screening (i.e., 
SBP/DBP ˃ 140/90 mmHg), whether on treatment or not, will be excluded. Subjects who had 
high or uncontrolled blood pressures in the past and are currently controlled with given 
therapies would be eligible for this study. 
Independent of past history, if a subject has a sustained resting SBP/DBP ˃ 140/90 mmHg at 
V1 or V2 they should be excluded. If a subject has a sustained SBP/DBP ˃ 140/90 mmHg at a 
visit after V2, they should be discontinued from the study. Any subject without a known history 
of hypertension that presents at screening with SBP/DBP ˃ 140/90 mmHg should be excluded 
(if at V1 or V2) or discontinued (if at a visit after V2) if the blood pressure reading is due to 
suspected hypertension or another pathological condition, not if due to a transient fluctuation, 
based on the Investigator’s evaluation. If the Investigator believes the blood pressure is falsely 


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elevated, they should repeat the assessment 2 to 3 times with the subject in a semi-reclined 
position in a quiet room. Subjects with persistent elevations, despite repeat assessments, 
should be excluded and referred to an appropriate healthcare provider for further assessment. 
For subjects presenting at screening with an ECG QTcF >450 msec (based on central ECG 
interpretation), the following procedures should be conducted: 
1. Wait until all other inclusion and exclusion criteria have been satisfied.
2. If the subject otherwise appears eligible for the study, with prior Medical Monitor approval,
have the subject return and conduct 2 ECGs with a minimum of 5 minutes between tracings.
3. Transmit these additional ECGs to 
 for central interpretation.
4. Based on the central reader interpretation, if both repeat ECGs show a QTcF ≤450 msec,
the subject may continue in the study at the Investigator's discretion. If one or both repeat
ECGs show QTcF >450 msec, the subject must be screen failed based on Exclusion Criteria
#20.
At Visit 2 or Visit 3, additional clarification for QTcF >450 msec (based on 
interpretation) is 
as follows:  
1. For QTcF between 451 msec and 460 msec (inclusive), the subject may continue in the
study if the Investigator assesses the ECG as not clinically significant (NCS).
2. For QTcF >460 msec:
a) Instruct the subject not to take the study drug until further notice.
b) If the Investigator has assessed the ECG as NCS, have the subject return, after
Medical Monitor approval, to conduct 2 ECGs with a minimum of 5 minutes between
tracings.
c) Transmit these additional ECGs to 
 for central interpretation.
d) If one or both ECGs again shows QTcF >460 msec, based on the central reader,
then the subject must be discontinued from the study.
6.4 
Removal of Subjects from Therapy or Assessments 
Subjects are free to withdraw from the study at any time without providing any reason(s) for 
withdrawal and without prejudice to further treatment. If a subject is to be withdrawn from the 
study by the Investigator, the Investigator should first alert the Medical Monitor, if safety allows, 
or as soon as possible thereafter.  
Subjects may be withdrawn from the study for any of the following reasons, and the date and 
reason(s) for withdrawal will be documented in the electronic case report form (eCRF): 
1.
A subject develops any significant illness, or needs to undergo any acute major surgery,
during the course of the study.
2.
A subject was enrolled and observed to violate any protocol requirement that may affect
the outcome of the study.
3.
A subject withdraws consent.
4.
The Investigator deems it may not be safe or proper for the subject to continue in the
study.






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8.1.1 Screening (Visit 1) 
After written informed consent is obtained and the subject has been confirmed as qualifying to 
enter the screening period, the Investigator or designee will contact the designated interactive 
web response system (IWRS) to obtain a unique subject identification (ID) number to be used 
throughout the study. This subject ID number will not be reused for any other participant in the 
study. This unique identifier comprises the numerical order of the subjects screened and will be 
used to identify the subject on the eCRF. 
8.1.2 Randomization (Visit 2) 
Once a subject’s eligibility for enrollment has been confirmed at the end of the screening period, 
the Investigator (or designee) should contact the IWRS centralized randomization center to 
receive the subject study drug kit assignment. Subjects who do not meet eligibility criteria will be 
registered as screen failures. It is important that the study staff reconfirm the subject’s 
willingness to continue in the study before randomizing the subject to a treatment. 
The planned treatment given to individual subjects will be determined by a randomization 
scheme prepared by the biostatistics group of 
. For both DB periods, all subjects 
will receive orally DFN-15 or a matching placebo in a randomized 1:1 treatment sequencing. As 
detailed in Section 5.1, subjects will treat 1 migraine attack in the DB1 period and, if eligible, be 
re-randomized to enter into the DB2 period. The IWRS will assign the appropriate study drug kit 
to each subject for each treatment period. If a subject discontinues from the study after 
randomization, the subject ID number will not be reused, and the subject will not be allowed to 
re-enter the study. Subjects will be required to return unused study drug and the eDiary 
provided by the site. 
8.2 
Dose Selection 
Test doses of DFN-15, Celecoxib Oral Solution, 120 mg to 240 mg (50 mg/mL) exhibited dose 
proportional bioavailability. The median time to peak concentration of celecoxib oral solution 
was faster (0.67 h) compared to Celebrex (2 h). The mean maximum concentration values and 
mean of partial areas under the curve (AUCs) (from AUC0-0.25 to AUC0-2.00) of DFN-15, Celecoxib 
Oral Solution 50 mg/mL were higher than Celebrex. 
DFN-15, Celecoxib Oral Solution 50 mg/mL showed 60% lower maximum concentration 
following administration of celecoxib under fed conditions than those following administration 
under fasting conditions. Overall bioavailability in terms of AUC was comparable under fasting 
and fed conditions.  
A proof-of-concept, randomized, placebo-controlled, DB, crossover study in patients with 
migraine headaches (with or without aura) showed an increased response with use of DFN-15, 
with the greatest response in the 120 mg DFN-15 treatment group, although the differences 
from 240 mg were not statistically significant, suggesting a ceiling effect at 120 mg.  
DFN-15, Celecoxib Oral Solution 50 mg/mL was shown to be safe and well tolerated in all 
studies. Subsequently, DFN-15 is now being developed as a 25 mg/mL oral solution and, 
considering the outcome from the proof of concept study, a dose of 120 mg for the active arm 
was selected for the Phase 3 studies. See the DFN-15 Investigator’s Brochure for additional 
information on the completed studies.14 


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8.3 
Selection and Timing of Dose for Each Subject 
At the end of the screening period, eligible subjects will be randomized to receive study drug 
(DFN-15 or a matching placebo) as described in Section 5.1. Information about use of study 
drug, predose and postdose assessments, and any rescue medication taken during the study 
will be recorded in the eDiary. For dosing information, see Section 7.1.  
8.4 
Blinding 
In order to blind the study treatment, study drug kits with identical labeling appearance will be 
assigned unique kit numbers by IWRS and the kits will be distributed by 
 to 
the site before the start of dosing. 
This is a DB study. All randomization data will be kept strictly confidential and accessible only to 
authorized personnel until the time of unblinding after database lock at the end of study. 
Blinding is critical to the integrity of this clinical study; however, in the event of a medical 
emergency for an individual subject, in which knowledge of the treatment assignment is critical 
to the subject’s management, the blind for the subject may be broken by the Investigator (or 
designee) by contacting IWRS. Before unblinding, the Investigator (or designee) should have 
determined that the treatment information is necessary to decide the subject’s immediate 
management, and must make every effort to contact the Medical Monitor before unblinding. In 
many cases, especially if the emergency is clearly not related to study treatment, the problem 
may be properly managed without unblinding by assuming that the subject is receiving active 
treatment. In cases of accidental unblinding or when the Medical Monitor cannot be contacted 
before unblinding, the Medical Monitor should be contacted as soon as possible after the 
breaking of the blind and every attempt to preserve the blind for all other study staff should be 
made.  
8.5 
Prior and Concomitant Therapy 
Investigators should document in the eCRF all prior medications for neurological illnesses and 
conditions that the subject has experienced anytime in the past, and other prior medications that 
were taken within 12 weeks before screening. In addition, all concomitant and ongoing 
medications are to be documented in the eCRF. (See also Section 6.3 Exclusion Criteria and 
Section 8.5.3 Prohibited and Allowed Medications.) 
8.5.1 Medication History 
No change in any prophylactic migraine medications will be allowed during the study. 
Subjects will be able to continue their prescribed medications for mild, chronic medical 
conditions as long as the doses of these medications have been stabilized for at least 30 days 
before screening and the medications are not otherwise prohibited or restricted in the protocol. 
See Section 8.5.3 for Prohibited and Allowed Medications. 
Washout periods: Subjects should not have taken the following medications in the time period 
described: 
•
Antipsychotics: at least 30 days prior to randomization (if used for non-psychiatric
conditions, should be evaluated on a case-by-case basis with the Medical Monitor)


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•
Investigational drug(s) or device(s): at least 30 days prior to randomization, or 2 months if
associated with central nervous system
•
Participated in a central nervous system clinical trial: at least 2 months prior to
randomization
•
CYP2C9 inducers (i.e., carbamazepine, enzalutamide, nevirapine, phenobarbital, rifampin,
secobarbital, St. John’s wort): within 7 days prior to randomization; if less than 7 days, the
randomization visit may be rescheduled if the subject agrees to and is willing and able to
follow prohibitions and restrictions per protocol
•
CYP2D6 substrates with a narrow therapeutic window (i.e., thioridazine): within 7 days prior
to randomization; if less than 7 days, the randomization visit may be rescheduled if the
subject agrees to and is willing and able to follow prohibitions and restrictions per protocol
8.5.2 Rescue Medication 
When a subject gets a migraine attack, the study drug should not be taken if the subject has 
treated an episodic migraine attack acutely with any other medication within the past 48 hours, 
or if the subject has used an analgesic for non-migraine pain acutely within the past 48 hours. 
If a subject does not experience sufficient or any pain relief from the study drug, he/she may 
take rescue medication, if needed, after 2 hours or more after taking the study drug, and only 
after completing the 2 hours postdose assessments in the eDiary. The specific rescue 
medication will initially be decided between the Investigator and the subject before or at V2, but 
may be adjusted as needed during the treatment period, with the Investigator ensuring that 
prohibited medications (Section 8.5.3) are not assigned and consulting with the Medical Monitor, 
if needed. Rescue medication will not be provided by the Sponsor, and its use should be 
managed by the subject and their Investigator. Rescue medication related decisions should be 
detailed in the source documents. 
Rescue medication, including NSAIDs or other migraine medications, prescription or 
non-prescription drugs, vitamins, herbal, and dietary supplements (including St John’s Wort), 
should be taken as described above. Subjects should not take prohibited medications listed in 
Section 8.5.3 as a rescue medication. 
8.5.3 Prohibited and Allowed Medications 
The following medications should not be taken during the study: 
•
Antipsychotics (within 30 days prior to randomization; if used for non-psychiatric conditions,
should be evaluated on a case-by-case basis with the Medical Monitor)
•
Opioids are prohibited if used for ≥ 4 days per month
•
CYP2C9 inducers (i.e., carbamazepine, enzalutamide, nevirapine, phenobarbital, rifampin,
secobarbital, St. John’s wort); drugs in this category must not be taken within 7 days prior to
randomization and throughout the study.
•
CYP2D6 substrates with a narrow therapeutic window (i.e., thioridazine); drugs in this
category must not be taken within 7 days prior to randomization and throughout the study
•
Celecoxib should not be taken concomitantly with study drug or used as rescue medication
for study migraines
•
For any questions regarding prohibited and allowed medications, consult the Medical
Monitor


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Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors 
(SNRIs), tricyclic antidepressants, and steroids for chronic conditions are allowed during the 
study if the dose is stable for at least 3 months prior to randomization and is not expected to 
change during the study. These medications cannot be started during the study. If a subject 
develops a need for long-term use of one of these medications during the course of the study, 
the subject must be withdrawn from the trial. Short-term use of these medications during the 
study is prohibited. 
No newly prescribed drugs should be taken by subjects during the study without agreement 
from the site Investigator. These drugs should not have any drug-drug interactions with the 
study drug or be contraindicated in the celecoxib product label or package insert.14 
Subjects will be instructed to refrain from using illicit substances (including marijuana, even if by 
prescription or legal in the particular state) during the study. See also Section 6.3, Exclusion 
Criteria.  
8.6 
Treatment Compliance 
Subjects will be instructed by the study site staff on the proper administration of study drug to 
ensure compliance. Written instructions for use of study drug will be distributed to the 
Investigator sites, and subjects should be confirmed to have, or be provided with, the 
instructions every time study drug is dispensed. 
See Section 5.1 and Section 8.5.2 for details on timing of dosing with study drug and use of 
rescue medication.  
At the end of the DB1 period (V3), subjects will be required to return all used and unused study 
drug from DB1 period before any study drug for the DB2 period will be dispensed. 
At V4/ET, subjects will be required to return all used and unused study drug, study drug 
containers, and completed eDiary. 
9 Study Procedures 
9.1 
Duration of Treatment 
The duration of study participation will be up to approximately 13 weeks, including a screening 
period of approximately 3 weeks (wherein subjects may be randomized earlier than 3 weeks 
provided they meet inclusion/exclusion criteria and headache assessment criteria; the screening 
period may also be extended beyond 3 weeks based on Investigator judgment and in 
consultation with the Medical Monitor), 2 DB treatment periods with up to 4 weeks (each period) 
for subjects to experience and treat migraine attacks, and 2 to 7 days for subjects to return to 
the site after each treatment. Once randomized, the total duration of each subject’s participation 
in the study would be up to 10 weeks from baseline. Migraine attacks and associated treatment 
and assessments will be recorded in an eDiary (see Section 9.2.1.4.1). 
9.1.1 Data Recording Using eDiary 
The eDiary will be used to record migraine attack assessment data in real-time by subjects as 
described in Section 5.1 and Section 9.2.1.4.1, and as shown in Table 9-2. Due to the episodic 
nature of the condition, it is important and compulsory for all subjects to check-in the eDiary 


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every day during the entire study period to ensure presence and eDiary functionality. If a subject 
does not check-in consistently or if he/she does not report a migraine attack in the eDiary for 2 
to 3 weeks, it is recommended that they should be contacted by study staff to check if the 
subject has technical difficulties or confirm they have not experienced a migraine. 
Investigators should train subjects on the proper use of the eDiary and document their 
understanding of the importance of complying with all data entry requirements and, particularly, 
the primary endpoints data entry (i.e., 2-hour postdose assessment). 
9.2 
Study Assessments 
Table 9-1 summarizes the planned study assessments.






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1 V4 will occur up to 10 weeks after Baseline (V2). 
2 Subjects who do not complete both DB periods will complete an ET visit. 
3 Subjects may be randomized earlier during this period if they meet inclusion/exclusion criteria and headache assessment criteria. The screening period may also 
be extended based on Investigator judgment and in consultation with the Medical Monitor. 
4 Before eDiary dispensing, initial screening should determine to the extent poss ble that the subject may be eligible for the study and is able, willing, and 
understands after being instructed how to use the eDiary; eDiary will be dispensed once if the subject is randomized and used throughout the DB periods. At V2, 
randomized subjects will be instructed and re-trained on the eDiary usage to ensure real-time entry of predose and postdose assessments and the level of 
migraine pain to treat (moderate or severe for first treatment and of any pain level for the second). Thereafter, randomized subjects will be reinstructed on eDiary 
usage, and re-trained on instructions as needed.  
5 Physical examination data will be recorded in the source at screening (V1). A complete physical examination will be performed, including examination of head, 
eyes, ears, nose, and throat [HEENT], heart, lungs, abdomen, skin, cervical and axillary lymph nodes, neurological, and musculoskeletal systems. At other visits, 
symptom-driven limited physical examination will be performed. Any subsequent untoward change during the study will be recorded as an AE. Suicidality risk will 
be determined and recorded at screening (V1) and checked at all subsequent visits. Significant suicide risk, in the opinion of the Investigator, is exclusionary at 
V1 and V2. A randomized subject will be discontinued if a significant suicide risk is determined at subsequent visits. At any visit, subjects who are a suicide risk 
should be referred to a mental health specialist. The Medical Monitor should also be notified.  
6 Weight only. 
7 Serum pregnancy test will be performed at screening (V1) for all female subjects of childbearing potential. 
8 Urine pregnancy tests will be performed at all study visits after screening for all female subjects of childbearing potential. 
9 Subjects will be instructed by the study site staff on the proper administration of study drug to ensure compliance. Written instructions for use of the study drug 
will be distr buted to Investigator sites and subjects should be confirmed to have, or be provided with, the instructions every time study drug is dispensed. 
10 Unused study drug returned by subjects should not be redispensed. 
11 When the subject experiences a migraine episode they should contact the site within 1 day of treating with study drug to schedule their next visit. The eDiary will 
be used to record all migraine attacks treated with study drug during the study period. 
12 Screening eDiary information will be kept in the source. It is compulsory for all subjects to check-in the eDiary every day during the entire study period. If a 
subject does not consistently check-in or does not report a migraine attack in the eDiary for 2-3 weeks, it is recommended they should be contacted by study 
staff to check if the subject has technical difficulties or confirm they have not experienced a migraine. 
13 Arrangements should be made by the site for a timely return of the eDiary device for subjects who screen fail. 




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9.2.1 Visit Procedures 
9.2.1.1 Screening (Visit 1) (Day -21 to Day -1) 
Written informed consent will be obtained before any study assessments are performed. 
Screening may take approximately 21 days before enrollment. Subjects may be randomized 
earlier during this period if they meet inclusion/exclusion criteria and headache assessment 
criteria. The screening period may also be extended based on Investigator judgment and in 
consultation with the Medical Monitor.  
An eDiary will be dispensed at V1 to collect at least 1 migraine episode during the screening 
period and, if eligible, the subject will be randomized (V2) and will continue to collect migraine 
data through end of treatment (V4/ET). See eDiary assessments in Section 9.2.1.4.1. The 
following assessments will be performed at screening (V1): 

Written informed consent

Eligibility confirmation per inclusion and exclusion criteria

Dispense eDiary, instruct subject on use of the diary, and allow subject to demonstrate
his/her ability to use the diary correctly

Review/collection of AEs

Demographics, medical history, prior medications, and migraine history (including
associated symptoms and MBS for the co-primary analysis, medications taken for migraine
management, satisfaction and headache pain relief with current medication)

Physical examination, including weight and height measurements, and suicidality check

Vital signs measurement (sitting SBP/DBP, pulse rate, and body temperature)

Serum pregnancy test (human chorionic gonadotropin [hCG]) for female subjects of
childbearing potential

Blood draw for hematology and clinical chemistry, including HbA1c and TSH

Urine collection for urinalysis

Serology for HIV, HBsAg, and HCV

Urine drug test and ethanol screen

12-lead ECG
9.2.1.2 Randomization (Visit 2) (Day 0) 
At V2, randomized subjects will be instructed and re-trained on eDiary usage to ensure real-time 
entry of predose and postdose assessments and the level of migraine pain to treat moderate or 
severe attacks for DB1 period, and pain of any level for the DB2 period. Predose migraine 
assessments will be allowed to be recorded retrospectively in the event a subject did not follow 
the instructions. 

Continued eligibility confirmation per inclusion and exclusion criteria

Review recordings of subject eDiary entries and confirm proper recording and compliance

Review/collection of AEs

Medical history and prior medications, including from eDiary entries

Physical examination (if warranted); suicidality check

Vital signs measurement (sitting SBP/DBP, pulse rate, and body temperature)

Urine pregnancy test for female subjects of childbearing potential

Blood draw for hematology and clinical chemistry

Urine collection for urinalysis

Urine drug test and ethanol screen


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
12-lead ECG

Randomization (DB1 period)

Dispense study drug and instructions for use

Confirm subject completes eDiary

Baseline PPMQ-R questionnaire
9.2.1.3 End of DB1 Period; Re-Randomization to DB2 Period (Visit 3) 
At V3, randomized subjects will be reinstructed on eDiary usage to ensure real-time entry of 
predose and postdose assessments and the level of migraine pain to treat with study drug (at 
any level for the DB2 period). 

Confirm the following:
o
V3 is to be within 2 to 7 days after treatment of a migraine attack with study drug
dispensed at V2 (not applicable to ET)
o
There should be at least 48 hours of pain and symptom freedom from the previously
treated migraine attack

Review recording of subject eDiary entries and confirm proper recording and compliance;
retrain on instructed usage, if necessary

Review/collection of AEs

Physical examination (if warranted); suicidality check

Vital signs measurement (sitting SBP/DBP, pulse rate, and body temperature)

Urine pregnancy test for female subjects of childbearing potential

Blood draw for hematology and clinical chemistry

Urine collection for urinalysis

Urine drug test and ethanol screen

12-lead ECG

Concomitant medication review, including from eDiary entries

Continued eligibility confirmation

Confirm previously dispensed study drug is returned, subject compliance, and study drug
accountability

Re-randomization (DB2 period)

Dispense study drug and instructions for use
9.2.1.4 End of DB2 Period (Visit 4); End of Treatment (or Early Termination) 

Confirm the following:
o
V4 is to be within 2 to 7 days after treatment of a migraine attack with study drug
dispensed at V3 (not applicable to ET)
o
From randomization, the total duration of subject’s participation in the study would be
up to 10 weeks from baseline

Review/collection of AEs

Physical examination (if warranted); suicidality check

Weight of subject

Vital signs measurement (sitting SBP/DBP, pulse rate, and body temperature)

Urine pregnancy test for female subjects of childbearing potential

Blood draw for hematology and clinical chemistry, including HbA1c

Urine collection for urinalysis

Urine drug test and ethanol screen

12-lead ECG


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
Concomitant medication review, including from eDiary entries

Confirm subject compliance and study drug accountability

Review, confirm, and ensure proper recording of eDiary entries by subject

Collection of eDiary; empty study drug containers, and all unused study drug
9.2.1.4.1 Efficacy Assessments 
Subjects will be provided with an eDiary at screening (V1) to collect at least 1 migraine attack 
during the screening period. The migraine episode may be treated with medication the subject 
currently uses for a migraine during this period, unless otherwise instructed by the Investigator. 
After at least 1 migraine attack has been recorded in the eDiary, as instructed, the subject will 
contact the study site to schedule Visit 2 (V2). At V2 (randomization), it will be determined if 
subjects meet all study requirements and are eligible to continue in the study. If a subject does 
not meet all requirements, they must return all study equipment that was provided at the 
Screening Visit. If randomized, subjects will continue to collect migraine data (for a migraine 
attack treated with study drug), study drug, last food intake and fat content, and any rescue 
medication used to treat a migraine. Subjects will record migraine predose assessments, study 
drug date and time taken, and postdose efficacy data in real time in the 2 DB periods through 
V4/ET:  
•
Level of headache pain at predose and at various time points postdose (Levels: 0 =
none; 1 = mild; 2 = moderate; 3 = severe)
•
Time to meaningful pain relief (based on subject’s perception) and time to
pain-freedom after study drug
•
Migraine symptoms and MBS other than pain: nausea, photophobia, and
phonophobia at predose and at various time points postdose; allodynia
•
Functional disability at predose and at various time points postdose; scale: 0 = no
disability, able to function normally; 1 = performance of daily activities mildly
impaired, can still do everything but with difficulty; 2 = performance of daily activities
moderately impaired, unable to do some things; 3 = performance of daily activities
severely impaired, cannot do all or most things, bed rest may be necessary
•
Treatment satisfaction (7-point scale)
•
PPMQ-R
MBS will also be collected during Screening via Migraine History evaluation and this Screening 
MBS will be used for the evaluation of the second co-primary endpoint.  
9.2.2 Safety Assessments 
Safety assessments to be performed (Table 9-1) include the following: 
•
AEs will be collected from signing of the informed consent form (ICF) at screening
(V1) until subject’s completion or discontinuation from the study
•
Concomitant medication review
•
Physical examinations and suicidality check
•
Pregnancy tests in female subjects of childbearing potential
•
Measurement of vital signs (sitting SBP/DBP, pulse rate, and body temperature)
•
Clinical laboratory examination (hematology, chemistry, and urinalysis)
•
12-lead ECG


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Visits may be scheduled as needed for AE management. Adverse event and concomitant 
medication review should be performed at each unscheduled visit. Any protocol-specified safety 
assessment may be repeated or conducted unscheduled as necessary to ensure subject safety. 
9.2.2.1 Physical Examination and Suicidality Check 
A complete physical examination will be performed at screening (V1) by the Investigator, or 
medically qualified designee, and will include examination of the head, eyes, ears, nose, and 
throat [HEENT], heart, lungs, abdomen, skin, cervical and axillary lymph nodes, neurological, 
and musculoskeletal systems. All findings will be kept in the source document. At all subsequent 
visits, symptom-driven limited physical examination will be performed and recorded. Any 
subsequent untoward change during the study will be recorded as an AE. In addition, medical 
history will be recorded at screening, including smoking history, if applicable. 
A suicidality check will be performed at screening (V1), baseline (V2), and at all other visits. In 
the event a subject is evaluated to be at risk at V1 or V2, in the opinion of the Investigator, the 
subject will be excluded from the study. A randomized subject will be discontinued if a 
significant suicide risk is determined at subsequent visits. At any visit, subjects who are found to 
be a suicide risk will be referred to a mental health specialist. The Medical Monitor should also 
be notified. 
9.2.2.2 Pregnancy 
All female subjects of childbearing potential will be required to undergo a serum pregnancy test 
(hCG) at screening (V1), and a urine pregnancy test (beta hCG) at all subsequent study visits. 
All subjects confirmed to be pregnant at any time during the study should be immediately 
discontinued. Female subjects of childbearing potential will be required to use an acceptable 
form of birth control from screening through the end of participation in the study. Although 
pregnancy is not an SAE, the procedures to report pregnancies will be the same as the 
procedures detailed for reporting SAEs (Section 9.2.2.7). Any pregnancy that occurs in a female 
subject (or female partner of a male subject) during the study, or within 30 days after taking the 
last dose of study drug, should be reported to Dr. Reddy’s Laboratories as described in Section 
9.2.2.7. Pregnancies will be followed to the end, whether successful live birth or premature 
termination, type and date of delivery, any congenital malformations or birth defects, or any 
other adverse fetal or neonatal outcomes, and reported on a follow-up Pregnancy Report. 
Sponsor will be notified of all the above pregnancy outcomes. Pregnancy will not be considered 
an AE. 
Male subjects (with female partner) must agree to practice a reliable form of contraception or 
abstinence during the study. 
9.2.2.3 Clinical Laboratory Evaluation 
The following clinical laboratory evaluations will be performed in accordance with assessment 
time points outlined in Table 9-1. 


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Hematology 
Serum chemistry 
Urine analysis (dipstick) 
Hematocrit (Hct) 
Hemoglobin (Hb) 
Glycosylated hemoglobin (HbA1c) 
Mean corpuscular hemoglobin 
(MCH) 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Mean platelet volume  
Red blood cell (RBC) count  
Red cell distribution width  
White blood cell (WBC) count 
with differential (absolute/percent 
basophil count, absolute/percent 
eosinophil count, 
absolute/percent lymphocyte 
count, absolute/percent 
monocyte count, 
absolute/percent neutrophil 
count) 
Albumin 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Creatinine 
Creatine kinase  
Electrolytes (bicarbonate, calcium, 
chloride, magnesium, phosphorus, 
potassium, sodium) 
Thyroid-stimulating hormone (TSH) 
Total bilirubin 
Direct bilirubin 
Total protein 
Urea nitrogen 
Uric acid 
Color  
Appearance 
Specific gravity 
pH 
Protein 
Glucose 
Ketones 
Bilirubin 
Indicators of blood 
Urobilinogen 
Nitrite  
Leukocyte esterase 
Automated microscopic examination 
upon abnormal flagging 
Serology tests: Human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), and hepatitis C virus 
(HCV) ant body analyses 
Urine drug and ethanol screen tests: ethanol, amphetamines, barbiturates, benzodiazepines, cocaine, opiates 
(including methadone), and tetrahydrocannabinoids (THC), and phencyclidine 
Pregnancy test: Serum pregnancy test will be performed on all female subjects of childbearing potential at screening 
visit (or at any other time during the study if needed to confirm a suspected pregnancy after a positive urine 
pregnancy test). A urine pregnancy test will be performed onsite at other time points for all female subjects of 
childbearing potential.  
Hematology (including HbA1c), clinical chemistry, and urinalysis may be repeated during the study as needed to 
evaluate a patient’s condition. Tests not specified in the protocol may be allowed after discussion with the Sponsor’s 
Medical Monitor or designee. 
Hematology (including HbA1c), TSH, clinical chemistry, urinalysis, urine drug test/ethanol 
screen, serum pregnancy tests, HIV, HBsAg, and HCV antibody analyses will be performed at 
the central laboratory (ACM Global Central Laboratory, 160 Elmgrove Park, Rochester, NY 
14624). Reference ranges will be supplied by the central lab and will be used by the Investigator 
to assess the laboratory data for clinical significance and pathological changes. 
9.2.2.4 Vital Signs 
Vital signs, including pulse rate, sitting SBP/DBP, and body temperature, will be collected at 
screening (V1) and at each study visit. Vital signs will be recorded after the subject has rested in 
the sitting position for 5 minutes. (See additional exclusion criteria for SBP/DBP screenings in 
Section 6.3.1). 
Blood pressure measurements are to be taken in the same arm for the duration of the study. 
Body weight (without shoes) will be recorded at screening and V4/ET, and height (without 
shoes) will be recorded at screening only. 
Start and stop dates of last menstrual cycle for all female subjects of childbearing potential will 
be recorded at screening and at each study visit.  


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Vital sign measurements will be repeated if clinically significant per the Investigator’s judgment 
or if machine/equipment errors occur. Out-of-range blood pressure, pulse rate, and body 
temperature measurements will be repeated at the Investigator’s discretion. Any confirmed 
clinically significant vital sign measurement in the Investigator’s opinion must be recorded as 
medical history or an AE, as applicable.  
9.2.2.5 Twelve-Lead Electrocardiogram 
A 12-lead resting ECG will be performed at screening (V1), and at every scheduled study visit, 
and will be reviewed initially by the Investigator for any immediate concerns, and then by a 
central reader, 
 
. At screening, the Investigator will examine the ECG tracings for signs of cardiac 
disease that could exclude the subject from the study. ECGs will be repeated if clinically 
significant abnormalities are observed or artifacts are present. 
 will provide ECG reports to 
the sites and 
 via a portal. With the exception of QTcF evaluation as specified in 
Section 6.3.1, the overall interpretation and determination of the clinical relevance of ECG 
findings will be the responsibility of the Investigator, taking into account the central reader’s 
evaluation, and will be recorded in the subject’s eCRF. 
9.2.2.6 Adverse Events 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical study subject administered a 
study drug and which does not necessarily have a causal relationship with this treatment. A 
TEAE is an AE with a start date on or after the initial dose of study drug and up to 5 days after 
the last dose of study drug. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of the study drug, whether or not related to the study drug. This includes an exacerbation of 
pre-existing conditions or events, intercurrent illnesses, drug interaction, or the significant 
worsening of the indication under investigation that is not recorded elsewhere in the eCRF. 
Anticipated fluctuations of pre-existing conditions, including the disease under study, that do not 
represent a clinically significant exacerbation or worsening need not be considered AEs. 
Migraine headaches will not be captured as AEs. Migraine headaches will be captured by 
the subject in the eDiary provided to them.  
For the purpose of the site’s data collection responsibilities, any untoward event that started or 
worsened after the ICF was signed until the final end-of-study visit (inclusive) is to be 
considered an AE. 
It is the responsibility of the Investigator to document all AEs that occur during the study. 
Adverse events will be elicited by asking the subject a non-leading question, for example, “Have 
you experienced any new or changed symptoms since we last asked/since your last visit?” 
Adverse events should be reported on the appropriate page of the eCRF. 


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Assessment of Severity 
Each AE will be assigned a category by the Investigator as follows: 
Mild 
An AE that is easily tolerated by the subject, causes minimal 
discomfort, and does not interfere with everyday activities. 
Moderate 
An AE that is sufficiently discomforting to interfere with normal 
everyday activities; intervention may be needed. 
Severe 
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed. 
If there is a change in severity of an AE, it must be recorded as a separate event. 
Assessment of Causality 
Every effort will be made by the Investigator to assess the relationship of the AE, if any, to the 
study drug. Causality should be assessed using the categories presented in the following table: 
Not Related 
The event is clearly due to extraneous causes (e.g., diseases, 
environment), which should be specified if known; or the event is 
most likely produced by other factors such as the subject’s clinical 
state, therapeutic interventions, or concomitant therapy and does 
not follow a known response pattern to the study drug. 
Possibly Related 
The event is temporally related to study drug use but can be 
explained by another etiology. Information on the effect of study 
product withdrawal may be lacking. 
Probably Related The event is temporally related to study drug use and is consistent 
with known effects of the study drug and/or improves upon 
withdrawal of the study drug. 
Definitely Related The event follows a reasonable temporal sequence from the time of 
study drug administration and/or follows a known response pattern 
to the study drug and could not have been produced by other 
factors such as the subject’s clinical state, therapeutic intervention, 
or concomitant therapy and either occurs immediately following 
study drug administration or improves on stopping the medication 
or there is a positive reaction at the application site. 
Action Taken 
The Investigator will report the action taken in the appropriate section of the eCRF, as follows: 
•
Dose not changed
•
Drug interrupted
•
Drug withdrawn
•
Not applicable
•
Unknown


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Follow-up of Adverse Events 
The Investigator should follow up on subjects with AEs until the events are resolved or until, in 
the opinion of the Investigator, the events have stabilized or are determined to be chronic. 
Details of AE resolution must be documented in the eCRF. Subjects who have ongoing AEs at 
the time of study completion or ET should be followed up for 30 days after receiving the last 
dose of study drug or until the events resolve, are stabilized, or determined to be chronic, 
whichever occurs first. 
Documentation and Reporting of Adverse Events 
Adverse events will be reported and documented in accordance with the procedures outlined in 
this section. Adverse events will be reported from the time of informed consent through V4/ET 
and documented on the relevant eCRF pages. The following data should be documented for 
each AE: 
•
Description of the symptom event
•
Classification of “serious” or “not serious”
•
Severity
•
Date of first occurrence and date of resolution (if applicable)
•
Action taken
•
Causal relationship
•
Outcome of event (unknown, recovered, not yet recovered, recovered with sequelae,
death [with date and cause reported])
•
Name and contact details of reporter
9.2.2.7 Serious Adverse Events 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence or effect that, at any dose: 
•
Results in death.
•
Is life-threatening. An AE is life-threatening if the subject is at immediate risk of death from
the event as it occurs (i.e., it does not include a reaction that might have caused death if it
had occurred in a more serious form).
•
Requires or prolongs inpatient hospitalization. Complications occurring during
hospitalization are AEs and are SAEs if they cause prolongation of the current
hospitalization. Hospitalization for elective treatment of a pre-existing non-worsening
condition is not, however, considered an AE. The details of such hospitalizations must be
recorded on the medical history or physical examination page of the eCRF.
•
Results in persistent or significant disability/incapacity. An AE is incapacitating or disabling
if it results in a substantial or permanent disruption of the subject’s ability to carry out
normal life functions.
•
Is a congenital anomaly/birth defect.
In addition, medical and scientific judgment is required to decide if prompt notification is required 
in situations other than those defined for SAEs above (i.e., any event that the Investigator 
regards as serious that did not strictly meet the criteria above but that may have jeopardized the 
subject or required intervention to prevent one of the outcomes listed above, or that would 




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Follow-up of Adverse Events 
All follow-up reports will be subject to the same reporting timelines as the Initial Reports. Within 
24 hours of receipt of new information, the updated follow-up SAE form, along with any 
supporting documentation (e.g., subject discharge summary or autopsy reports), should be 
faxed or emailed to the Sponsor. 
The Sponsor must be notified within 5 days if any subject is withdrawn or discontinued study 
drug use due to an AE.  
All AEs experienced by a subject, irrespective of the suspected causality, will be monitored until 
the AEs have resolved, any abnormal laboratory values have returned to baseline or stabilized 
at a level acceptable to the Investigator and Medical Monitor, until there is a satisfactory 
explanation for the changes observed, until the subject is lost to follow-up, until the subject has 
died, or until 30 days after the last dose of the study drug upon which subjects will be referred to 
their primary medical provider for follow-up. 
Unblinding Instructions 
Breaking the Blind 
The blind should be broken for all SAE IND safety reports that are judged to be expedited 
reports for submission to FDA. 
The unblinding procedures and follow-up will be performed in accordance with the protocol and 
the Sponsor’s standard operating procedures (SOPs). 
Blinding is critical to the integrity of this clinical study; however, in the event of a medical 
emergency for an individual subject, in which knowledge of the treatment assignment is critical 
to the subject’s management, the blind for the subject may be broken by the Investigator (or 
designee) by contacting IWRS. Before unblinding, the Investigator (or designee) should have 
determined that the treatment information is necessary to decide the subject’s immediate 
management, and must make every effort to contact the Medical Monitor before unblinding. In 
many cases, especially if the emergency is clearly not related to study treatment, the problem 
may be properly managed without unblinding by assuming that the subject is receiving active 
treatment. In cases of accidental unblinding or when the Medical Monitor cannot be contacted 
before unblinding, the Medical Monitor should be contacted as soon as possible after the 
breaking of the blind and every attempt to preserve the blind for all other study staff should be 
made.  
If the blind is broken, the date, time, and reason must be recorded in the subject’s source 
record, eCRF, and any associated AE report.  
If an Investigator, site personnel performing assessments, or subject is unblinded, the 
unblinding incident and unblinded subject must be listed as a major protocol deviation. 
A subject for whom the blind is broken will discontinue study drug and be scheduled for a safety 
follow-up visit and then discontinued from the study. The subject will be encouraged to stay in 
the study until the AE is resolved or stabilized. 


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For all SAEs observed in the study considered to be drug related, a suspected unexpected 
serious adverse reaction (SUSAR) will be reported by the Sponsor to the FDA as an unblinded 
IND Safety Report. All Investigators and the IRB will receive blinded reports. However, on the 
request of the IRB, the Sponsor will send unblinded reports directly to the IRB.  
Laboratory and Vital Signs Variables 
Vital signs and laboratory abnormalities should be reported as AEs if they are considered to be 
clinically significant, as per the Investigator’s judgment. If an abnormal laboratory value is 
associated with clinical signs and symptoms, the sign/symptom should be reported as an AE, 
and the associated abnormal laboratory result should be considered additional information. 
Pregnancy 
Although pregnancy is not an SAE, the procedures to report pregnancies will be the same as 
the procedures detailed above for reporting SAEs. 
Female subjects should not be pregnant when entering the study and must not become 
pregnant during the study; see Section 9.2.2.2 for additional details. Following administration of 
study drug, any known cases of pregnancy in female subjects or male subjects who impregnate 
their female partners will be reported to the Sponsor within 24 hours of occurrence. All female 
subjects will be withdrawn from the study and administration of study drug will be stopped. The 
pregnancy will be reported immediately by phone and by faxing/emailing a completed 
Pregnancy Report to the Sponsor (or designee) within 24 hours of knowledge of the event. The 
pregnancy will not be processed as an SAE; however, the Investigator will follow the subject 
until completion of the pregnancy and must assess the outcome in the shortest possible time 
but not more than 30 days after completion of the pregnancy. The Investigator should notify the 
Sponsor (or designee) of the pregnancy outcome by submitting a follow-up Pregnancy Report. If 
the outcome of the pregnancy meets the criteria for immediate classification of an SAE (e.g., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus is to 
be documented], stillbirth, neonatal death, or congenital anomaly), the Investigator will report 
the event by phone and by faxing a completed SAE form to the Sponsor (or designee) within 24 
hours of knowledge of the event. 
Overdose 
Overdose is not anticipated in this study as sites will provide randomized subjects with only 1 
dose of study drug per visit.  
The Investigator must notify the Sponsor of any occurrence of overdose with study drug within 
24 hours of becoming aware of the overdose. In the event an overdose leads to an SAE, it will 
be reported to the regulatory board, and medical management will be done by the Investigator 
on a case-by-case basis. 
Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, 
vomiting, and epigastric pain, which are generally reversible with supportive care. 
Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, 
and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic 
ingestion of NSAIDs, and may occur following an overdose. 


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No overdoses of celecoxib were reported during clinical trials. Doses up to 2400 mg/day for up 
to 10 days in 12 patients did not result in serious toxicity. No information is available regarding 
the removal of celecoxib by hemodialysis, but based on its high degree of plasma protein 
binding (> 97%), dialysis is unlikely to be useful in overdose.  
Subjects should be managed with symptomatic and supportive care following an NSAID 
overdosage; there are no specific antidotes. Consider emesis and/or activated charcoal (60 to 
100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic 
cathartic in symptomatic patients seen within 4 hours of ingestion or in subjects with a large 
overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, 
hemodialysis, or hemoperfusion may not be useful due to high protein binding.  
For further details, refer to the full celecoxib package insert.14 
9.2.2.8 Unexpected Adverse Reactions 
Unexpected Adverse Reaction Definition 
An unexpected adverse reaction is any untoward and unintended response that is related to the 
administration of a study drug at any dose that is not consistent with the applicable product 
information (e.g., Investigator’s Brochure for an unauthorized study drug or approved 
prescribing information/summary of product characteristics for an authorized product). 
All SUSARs will be subject to expedited reporting. The Sponsor and/or 
 shall 
ensure that all relevant information about a SUSAR that is fatal or life-threatening is reported to 
the relevant competent authorities and the IRB within 7 days after knowledge by the Sponsor of 
such a case and that relevant follow-up information is communicated within an additional 
8 days. All other SUSARs will be reported to the FDA and the IRB within 15 days after 
knowledge by the Sponsor of such cases. The Investigator should follow up on each SUSAR 
until the event is resolved or until, in the opinion of the Investigator, the event is stabilized or 
determined to be chronic. Post-study SUSARs that occur within 30 days after the subject has 
completed the clinical study must be reported by the Investigator to the Sponsor. 
Warnings and Precautions 
The following warnings and precautions have been issued for celecoxib: 
Do not use this product if you had an allergic reaction (including asthma), urticaria, or other 
allergic-type reactions after taking celecoxib, aspirin, or other NSAID, or right before or after 
coronary artery bypass graft (CABG) surgery. Use caution if you have a history of ulcers or 
other stomach problems, kidney or liver disease, anemia, aspirin-sensitive asthma, high blood 
pressure, congestive heart failure or other heart or circulation problems. This medicine may 
cause the following problems: serious liver problem; bleeding in your stomach or intestines; and 
increased risk for a heart attack or stroke. For further details, refer to the full celecoxib package 
insert.14 
9.2.3 Appropriateness of Measurements 
All efficacy and safety assessments used in this study are widely used and generally considered 
reliable and accurate.  


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10 Statistical Methods 
The statistical analysis methods planned for this study are described below. Additional details 
will be provided in the Statistical Analysis Plan (SAP), which will be finalized before database 
lock and unblinding of the data. 
In general, descriptive statistical methods will be used to summarize the data from this study, 
with hypothesis testing performed for the co-primary and all secondary efficacy endpoints. 
Unless stated otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, 
median, standard deviation, minimum, and maximum for continuous data and frequencies and 
percentages for categorical data. The term “treatment group” refers to treatment assignment: 
DFN-15 or placebo. All data collected during the study will be included in subject data listings. 
Unless otherwise noted, the data will be sorted first by treatment assignment, subject number, 
and then by date within each subject number. 
All statistical analyses are described in Section 10.6. Unless specified otherwise, all statistical 
testing and confidence intervals will be 2-sided and will be performed using a significance 
(alpha) level of 0.05.  
All statistical analyses will be conducted with the SAS® software package version 9.3 or higher. 
10.1 Statistical Analysis Plan 
A SAP will be created and approved before database lock. This document will provide further 
details regarding the definition of analysis variables and analysis methodology to address all 
study objectives. The SAP will serve as a compliment to the protocol and supersedes it in case 
of differences. 
A blinded data review will be conducted before unblinding of subject’s treatment assignment at 
database lock. This review will assess the accuracy and completeness of the study database, 
subject evaluability, and appropriateness of the planned statistical methods. 
10.2 Analysis Datasets or Populations 
Screened Set 
The Screened Set will include all screened subjects. The set of analyses, including subject 
listings and summary tables of subject disposition, will be analyzed based on all eligible 
screened subjects who are databased for the study. 
Randomized Set 
Each DB treatment period will have a Randomized Set. The randomized set for DB1 will include 
all subjects who give informed consent and are eligible for and randomized into the DB1 
treatment period. The randomized set for DB2 will include all subjects in the randomized set for 
DB1 who are eligible for and are re-randomized into the DB2 treatment period. 
Full Analysis Set 
Each DB treatment period will have a full analysis set (FAS), which will include all randomized 
subjects who during the treatment period took at least one dose of study drug and have at least 


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1 post-baseline efficacy assessment for either pain or symptom (among nausea, photophobia, 
phonophobia). Subjects in DB1 will be analyzed according to their randomized treatment. 
Subjects in DB2 will be analyzed according to their re-randomized treatment. The FAS will be 
used for all analyses of efficacy endpoints. 
Safety Population 
The safety population will include all subjects who receive at least one dose of DB study drug 
during one or both treatment periods and have it recorded in their eDiary. Each DB treatment 
period will have a safety population which will include all subjects who were randomized in the 
DB treatment period and who received at least one dose of DB study drug during the treatment 
period. 
Additional information is included in the SAP. The SAP will serve as a compliment to the 
protocol and supersedes it in case of differences. 
Per-Protocol Population 
The per-protocol (PP) population will include all DB1 FAS subjects who have at least 1 post-
baseline endpoint assessment for both co-primary endpoints (observed and last observation 
carried forward [LOCF]), and who have no significant protocol deviations that will impact the 
collection or interpretation of the co-primary endpoints data during the DB1 period. Identification 
of all subjects in the PP population will be determined before the database lock and unblinding. 
10.3 Demographic and Other Baseline Characteristics 
Subject disposition and demographics will be presented and described in the SAP. 
Demographics and baseline characteristics will be summarized descriptively, and all collected 
demographics and baseline characteristics data will be listed. 
10.4 Efficacy Endpoints 
10.4.1 Co-Primary Endpoints (for first treated DB1 attack only) 
•
The proportion of subjects who are pain-free 2 hours postdose compared between DFN-15
and placebo in the DB1 period (defined as a reduction from predose moderate [Grade 2] or
severe [Grade 3] pain to none [Grade 0]).
•
The proportion of subjects who are free from their Screening MBS among nausea,
photophobia, and phonophobia at 2 hours postdose compared between DFN-15 and
placebo in the DB1 period.
10.4.2 Secondary Endpoints: 
•
The proportion of subjects with TEAEs after study drug compared between DFN-15 and
placebo.
•
The proportion of subjects who are free from nausea, photophobia, and phonophobia at 15,
30, and 45 minutes and 1,1.5, 2, 4, and 24 hours postdose compared between DFN-15 and
placebo in each DB period.
•
Time to meaningful pain relief (defined as based on subject’s perception) within 2 hours
postdose compared between DFN-15 and placebo in each treated attack in each DB period.


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•
Time to pain freedom within 2 hours postdose compared between DFN-15 and placebo in
each DB period.
•
The proportion of subjects who have pain relief  at 15, 30, and 45 minutes and 1, 1.5, 2, 4,
and 24 hours postdose compared between DFN-15 and placebo in each DB period.
Headache pain relief is defined for DB1 as a reduction from moderate or severe pain prior to
dosing reduced to mild or none postdose, and for DB2 as moderate or severe pain predose
reduced to mild or none postdose, or mild pain predose reduced to none postdose
•
The proportion of subjects who are pain-free at 15, 30, and 45 minutes and 1, 1.5,
2 (DB2 period), 4, and 24 hours postdose compared between DFN-15 and placebo in each
DB period.
•
The proportion of subjects with their Screening MBS (and have this symptom predose)
absent at 15, 30, and 45 minutes, and 1, 1.5, 2 (DB2 period), 4, and 24 hours postdose
compared between DFN-15 and placebo in each DB period.
•
Change in functional disability score at 2, 4, and 24 hours postdose compared between
DFN-15 and placebo in each DB period.
•
Among those reporting cutaneous allodynia predose, the proportion of subjects who are
pain-free at 2 and 4 hours postdose compared between DFN-15 and placebo in each DB
period.
•
The proportion of subjects who are pain-free at 2 and 4 hours postdose whose BMI is < 30
vs. subjects whose BMI is ≥ 30, and whose BMI is < 25 vs. subjects whose BMI is ≥ 25 in
each DB period.
•
The proportion of subjects who have pain recurrence between 2 to 24 hours (i.e., pain-free
at 2 hours postdose, with pain [mild, moderate, or severe] reported at 24 hours postdose)
compared between DFN-15 and placebo in each DB period.
•
The proportion of subjects who have sustained pain relief at 2 to 24 hours postdose (i.e.,
pain-relief at 2 hours postdose, with no use of rescue medication and no recurrence of
headache pain within 2 to 24 hours postdose) compared between DFN-15 and placebo in
each DB period.
•
The proportion of subjects who have sustained pain freedom at 2 to 24 hours postdose (i.e.,
pain-free at 2 hours postdose, with no use of rescue medication, and no recurrence of
headache pain within 2 to 24 hours postdose) compared between DFN-15 and placebo in
each DB period.
•
The proportion of subjects who use rescue medication after 2 hours (2 to 24 hours)
postdose compared between DFN-15 and placebo in each DB period.
•
Treatment satisfaction at 2 hours and 4 hours postdose as determined on a 7-point scale
compared between DFN-15 and placebo in each DB period. DFN-15 will also be compared
to the same question in the baseline PPMQ-R.
•
Treatment satisfaction as measured by PPMQ-R at 24 hours postdose compared between
DFN-15 and placebo in each DB period.
10.5 Methods of Analysis 
10.5.1 Primary Efficacy Analysis 
Efficacy analyses for the co-primary and secondary endpoints will be based on the FAS 
population. 
The first co-primary efficacy endpoint of the proportion of subjects who are free from headache 
pain at 2 hours after the first dose of study drug taken for a migraine attack with moderate to 
severe headache pain during the DB1 period, will be analyzed using Fisher’s exact test. The 


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second co-primary efficacy endpoint of the proportion of subjects who are free from their 
Screening MBS among nausea, photophobia, and phonophobia at 2 hours postdose during the 
DB1 period will be similarly analyzed using Fisher’s exact test. A subject’s MBS will be obtained 
at Screening via Migraine History assessment and, for the analysis of the co-primary endpoint, 
that symptom must be present predose but does not have to be designated as the MBS at 
predose. 
Analyses will be performed using the last observation carried forward (LOCF) and observed 
data in the FAS population and PP population. 
10.5.2 Secondary Endpoint Analysis 
The analysis and presentation of the secondary efficacy endpoints will be described in the SAP. 
10.5.3 Exploratory Analysis 
Exploratory analyses based on predose pain level and predose MBS are planned and details 
will be provided in the SAP.  
10.5.4 Subgroup Analysis 
Subgroup analyses will be performed as needed, and details will be documented in the SAP. 
10.5.5 Additional Efficacy Analyses 
Other possible analyses and further statistical details, if applicable, will be provided in the SAP. 
10.5.6 Safety Analysis 
All AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA) version 19.0 or higher. A TEAE is an AE with a start date on or after the initial dose 
of study drug and up to 5 days after the last dose of study drug. Only TEAEs will be included in 
summary tables. Migraine headaches will not be captured as AEs. Migraine headaches will be 
captured by the subject in the eDiary provided to them at screening. The information will then be 
entered into the appropriate eCRF page. 
The incidence of all TEAEs will be tabulated by treatment received. These TEAEs will be 
classified by system organ class (SOC) and preferred term (PT). For incidence reporting, if a 
subject reported more than one AE that was coded to the same SOC or PT, the subject will be 
counted only once for that specific SOC or PT.  
An overview of AEs, which includes subject incidence of TEAEs, headache or migraine-related 
TEAEs, study drug-related TEAEs, and SAEs, will be presented. The subject incidence of 
TEAEs, headache- or migraine-related TEAEs, study drug-related TEAEs, and SAEs will be 
summarized by SOC and PT. 
Treatment-emergent adverse events will also be summarized in a table by severity. For TEAEs 
presented by severity, the worst severity during the study will be presented for each subject, 
SOC, and PT. 


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Treatment-emergent adverse events will also be summarized in a table by relationship to study 
drug. For TEAEs presented by relationship to study drug, the strongest relationship to study 
drug during the study will be presented for each subject, SOC, and PT. 
All AEs will also be presented in a by-subject data listing. 
All prior and concomitant medications will be classified using the Anatomical Therapeutic 
Chemical (ATC) classification and preferred drug names from the World Health Organization 
Drug Dictionary (WHO-DD), version March 2016 or later. Medications will be considered 
concomitant if they were taken at any time between the date of first dose and the date of last 
dose of study drug, inclusive. Medications will be considered as prior if stopped before the date 
of first dose of study drug during the DB1 period. 
Prior and concomitant medications will be summarized in separate tables by ATC level 2 and 
preferred drug name for the safety population. 
One combined listing will be provided for prior and concomitant medications. An identifier will be 
provided to show if a medication is prior or concomitant. 
Electrocardiograms, clinical laboratory data, and vital signs measurements will be summarized 
by treatment group and time point along with the change from baseline (V2). During the DB 
period, V2 will be considered as baseline, (i.e., the visit occurring just before treatment). If a 
subject misses a V2 assessment but has a V1 assessment, V1 will be considered as baseline. 
All ECG data, clinical laboratory data, vital signs, physical examinations, study drug use, and 
concomitant medication use will also be presented in by-subject data listings. 
10.6 Interim Analyses 
No interim analysis is planned. 
10.7 Determination of Sample Size 
Approximately 600 subjects will be randomized for the DB1 period. Subjects who discontinue 
participation without completing the study protocol will not be replaced. 
The first co-primary endpoint is the comparison of the proportion of subjects who are pain-free 
at 2 hours after the first dose of study drug. It is assumed that 17.6% of placebo and 29.2% of 
DFN-15 (treated) subjects will be pain-free at 2 hours. A sample size of 600 subjects will provide 
88% power to detect this assumed difference between placebo and DFN-15 at a 5% (2-sided) 
level of significance and with a 15% dropout rate. 
The second co-primary endpoint is the comparison of the proportion of subjects who are free 
from their Screening MBS among nausea, photophobia, and phonophobia at 2 hours after the 
first dose of study drug. It is assumed that 28.2% of placebo and 44.7% of DFN-15 (treated) 
subjects will be free from their Screening MBS at 2 hours. A sample size of 480 subjects will 
provide 94% power to detect this assumed difference between placebo and DFN-15 at a 5% (2-
sided) level of significance and with a 15% dropout rate. 
Since the sample size for the first co-primary endpoint is larger than that of the second co-
primary endpoint, the larger sample size will be used for the study. 


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11 Quality Assurance and Quality Control 
11.1.1 Audit and Inspection 
The study site and study documentation may be subject to quality assurance audit during the 
course of the study by the Sponsor, 
, or its nominated representative. In addition, 
inspections may be conducted by regulatory authorities at their discretion. 
11.1.2 Monitoring 
Source documents for this study include the eDiary and study files stored at the site. Electronic 
CRF data collection must be completed for each subject who signs an ICF. 
In accordance with cGCP and International Council for Harmonisation (ICH) guidelines, the 
study monitor will carry out source document verification at regular intervals to ensure that the 
data collected in the eCRF are accurate and reliable. The frequency of monitoring visits will be 
determined by the rate of subject recruitment.  
The following will be reviewed, at a minimum, at these visits: 
•
Compliance with the protocol
•
Consent procedure
•
Source documents
•
AE procedures
•
Storage and accountability of study drug materials
The monitoring visits also provide the Sponsor with the opportunity to ensure the Investigator’s 
obligations and all applicable ICH or health authority regulation requirements are being fulfilled. 
The Investigator must permit the Medical Monitor, the IRB, the Sponsor’s internal auditors, and 
representatives from regulatory authorities direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the eCRFs. All 
efforts to protect subject confidentiality will be upheld. 
An electronic medical record may be the source document; however, the study site must 
provide a SOP that demonstrates the electronic medical record system is compliant with 
applicable regulations and details the review and approval of data entries by the principal 
Investigator. 
Protocol deviations identified by the site or the study monitor should be reported to the IRB 
according to the IRB’s reporting guidelines. All deviations will be recorded in the 
 
clinical trial management system and will be categorized as major or minor before data analysis. 
11.1.3 Data Management and Coding 
 will be responsible for activities associated with the data management of this 
study. This will include setting up a relevant database 
) and data transfer 
mechanisms, along with appropriate validation of data and resolution of queries. Data generated 
within this clinical study will be handled according to the relevant SOPs of the data management 
and biostatistics departments of 
. 


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Study site staff will enter data directly into the electronic data capture (EDC) system by 
completing the eCRF via a secure internet connection. Data entered into the eCRF must be 
verifiable against source documents at the study site. Any changes to the data entered into the 
EDC system will be recorded in the EDC audit trail, which is compliant with FDA Code of 
Federal Regulations 21 Part 11. 
Data entered into the eCRF will be validated as defined in the data validation plan. External data 
checks will be programmed where appropriate (e.g., for laboratory data, ECGs) as well as for 
cross table checking between eCRFs (e.g., AE and concomitant medication forms). 
Medical coding will use MedDRA version 19.0 or higher for concomitant diseases and AEs, and 
WHO-DD version March 2016 or later for medications. 
Missing or inconsistent data will be queried electronically in the EDC system to the Investigator 
for clarification. Subsequent modifications to the database will be documented. 
12 Records and Supplies 
12.1 Drug Accountability 
Upon receipt of the study drug, the Investigator (or designee) 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 Investigator will retain a copy of this receipt at the 
study site and provide the original receipt to the study monitor, to be stored in the trial master 
file. The inventory of supplies at the study site may be checked at any time during the study by 
the monitor. 
It is the responsibility of the Investigator (or designee) to ensure that the study drug has been 
correctly documented for the amount received, dispensed, and returned on the dispensing log 
that will be provided. A full drug accountability log, provided by 
 will be 
maintained at the study site at all times. The study monitor will arrange regular collection of 
used and unused study drug returned by the subject. The study monitor will also perform an 
inventory of study drug at the close-out visit to the study site. All discrepancies must be 
accounted for and documented. 
12.2 Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement. 
13 Ethics 
13.1 Institutional Review Board 
Before initiation of the study at the study site, the protocol, all protocol amendments, the ICF, 
screenshots of eDiary assessments, and any other relevant study documentation will be 
submitted to the IRB. Written approval of the study and all relevant study information must be 
obtained before the study site can be initiated or the study drug released to the Investigator. Any 
necessary extensions or renewals of IRB approval must be obtained, in particular, for changes 
to the study such as modification of the protocol, the ICF, the written information provided to 
subjects and/or other procedures
 will submit relevant study documentation to the 
central IRB on behalf of the study sites. 


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Page 57 of 61 
CONFIDENTIAL 
In the event that a study site uses a local IRB, it is the responsibility of the site Investigator to 
obtain written approval of the study and all relevant study information before the initiation of 
study activities. Extensions or renewals of local IRB approval or approvals of changes to the ICF 
or other written information provided to subjects will be the responsibility of the site Investigator. 
The Investigator will report promptly to the IRB any new information that may adversely affect 
the safety of the subjects or the conduct of the study. 
 will submit written 
summaries of the study status to the IRB annually or more frequently if requested by the IRB. 
On completion of the study, the Sponsor (or designee) will notify the IRB that the study has 
ended. 
13.2 Ethical Conduct of the Study 
This study will be conducted according to the Guidelines of the World Medical Association 
Declaration of Helsinki in its revised edition (Brazil, 2013) and the ICH guidelines for cGCP as 
well as the demands of national drug and data protection laws and other applicable regulatory 
requirements.15-17 
13.3 Subject Information and Consent 
The Investigator is responsible for ensuring that no subject undergoes any study-related 
examination or activity before that subject has given written informed consent to participate in 
the study. The written consent must be given by the subject after detailed information about the 
study has been given and in accordance with any national provisions on the protection of clinical 
study subjects. The verbal explanation will cover all the elements specified in the written 
information provided for the subject. 
The Investigator or sub-Investigator will inform the subject of the objectives, methods, 
anticipated benefits, and potential risks and inconveniences of the study. The subject should be 
given every opportunity to ask for clarification of any points he or she does not understand and, 
if necessary, ask for more information. At the end of the interview, the subject will be given time 
to consider the study, if this is required, or if the subject requests more time. Subjects will be 
required to sign and date the ICF. Subjects should be able to read and write; the use of a legally 
authorized representative is prohibited in this study. After signatures are obtained, the ICF will 
be kept and archived by the Investigator in the Investigator’s study file for possible inspection by 
regulatory authorities, the IRB, Dr. Reddy’s Laboratories, 
 personnel, or third 
parties authorized by Dr. Reddy’s Laboratories. Subjects will be given a signed copy of the ICF 
for their records. 
It should be emphasized to the subject that he/she is at liberty to withdraw from the study at any 
time, without penalty or loss of benefits to which the subject is otherwise entitled. Subjects who 
refuse to give or who withdraw written informed consent should not be included or continue in 
the study. 
13.4 Subject Confidentiality 
All personal data collected and processed for the purposes of this study should be managed by 
the Investigator and his/her staff with adequate precautions to ensure confidentiality of those 
data, and in accordance with the American Health Insurance Portability and Accountability Act 
of 1996 (HIPAA)18 and applicable local laws and/or regulations on personal data protection.  
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Dr. Reddy’s Laboratories Ltd. 
DFN-15-CD-007 
Protocol Amendment 1 
Page 58 of 61 
CONFIDENTIAL 
Monitors, auditors, and other authorized agents of the Sponsor or 
, the IRB 
approving this research as well as that of any applicable regulatory agency, will be granted 
direct access to the study subjects’ original medical records for verification of clinical study 
procedures and/or data, without violating the confidentiality of the subjects to the extent 
permitted by the law and regulations. In any presentations of the results of this study, or in 
publications, the subjects’ identity will remain confidential. 
14 Reporting and Publication, Including Archiving 
Essential documents are those documents that individually and collectively permit evaluation of 
the study and quality of the data produced. After completion of the study, all documents and 
data relating to the study will be kept in an orderly manner by the Investigator in a secure study 
file. This file will be available for inspection by the Sponsor or its representatives. Essential 
documents should be retained for 2 years after the final marketing approval in an ICH region or 
for at least 2 years since the discontinuation of clinical development of the study drug. It is the 
responsibility of the Sponsor to inform the study site of when these documents no longer need 
to be retained. The Investigator must contact the Sponsor before destroying any study-related 
documentation. In addition, all subject medical records and other source documentation will be 
kept for the maximum time permitted by the hospital, institution, medical practice, or federal law. 
The Investigator shall not publish any articles or make any presentations relating to the study 
drug or referring to data or materials generated as part of the services provided under this 
agreement, without the prior written consent from the Sponsor; such consent shall not be 
unreasonably withheld. 
Publication review process: The Investigator shall submit to the Sponsor for its review a copy of 
any proposed publication resulting from the study at least 30 days before the date of submission 
for publication. If the Sponsor determines that the proposed publication contains patentable 
subject matter which requires protection, the Sponsor may require the delay of publication for a 
further period of time not to exceed 180 days for the purpose of filing patent applications. 
If the Sponsor publishes the results of the study, the Investigators invited to be co-authors of the 
manuscript or abstract will be those who randomized the largest number of valid subjects and/or 
who provided significant input on study design and/or interpretation on study results. 
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CONFIDENTIAL 
15 References 
1. Headache Classification Committee of the International Headache Society (IHS). The
International Classification of Headache Disorders, 3rd edition (beta version).
Cephalalgia. 2013;33(9):629-808.
2. Gasparini CF, Sutherland HG, Griffiths LR. Studies on the pathophysiology and genetic
basis of migraine. Curr Genomics. 2013;14(5):300-15.
3. Schwedt TJ, Dodick DW. Advanced neuroimaging of migraine. Lancet Neurol.
2009;8(6):560-568.
4. Sprenger T, Borsook D. Migraine changes the brain: neuroimaging makes its mark. Curr
Opin Neurol. 2012;25(3):252-262.
5. Bigal ME, Ferrari M, Silberstein SD, Lipton RB, Goadsby PJ. Migraine in the triptan era:
lessons from epidemiology, pathophysiology, and clinical science. Headache. 2009;49
Suppl 1:S21-33.
6. Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine. A comparative review of
pharmacology, pharmacokinetics, and efficacy. Drugs. 2000;60(6):1259-1287.
7. Tfelt-Hansen P. Efficacy and adverse events of subcutaneous, oral, and intranasal
sumatriptan used for migraine treatment: a systematic review based on number needed
to treat. Cephalalgia. 1998;18(8):532-538.
8. Moore JC, Miner JR. Subcutaneous delivery of sumatriptan in the treatment of migraine
and primary headache. Patient Prefer Adherence. 2012;6:27-37.
9. Paulozzi LJ, Zhang K, Jones CM, Mack KA. Risk of adverse health outcomes with
increasing duration and regularity of opioid therapy. J Am Board Fam Med.
2014;27(3):329-338.
10. Levin M. Opioids in headache. Headache. 2014;54(1):12-21.
11. Buse DC, Pearlman SH, Reed ML, Serrano D, Ng-Mak DS, Lipton RB. Opioid use and
dependence among persons with migraine: results of the AMPP study. Headache.
2012;52(1):18-36.
12. American Society of Anesthesiologists Task Force. Practice guidelines for acute pain
management in the perioperative setting: an updated report by the American Society of
Anesthesiologists Task Force on Acute Pain Management. Anesthesiology.
2012;116(2):248-273.
13. Gong L, Thorn CF, Bertagnolli MM, Grosser T, Altman RB, Klein TE. Celecoxib
pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics.
2012;22(4):310-318.
14. DFN-15 Investigator’s Brochure, Version 002: Dr. Reddy’s Laboratories Ltd; June 2016.
(includes celecoxib package insert).
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Protocol Amendment 1 
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CONFIDENTIAL 
15. World Medical Association, Declaration of Helsinki. Ethical Principles for Medical
Research Involving Human Subjects. Last amended by the 59th WMA General
Assembly, Seoul, October 2008.
16. International Council for Harmonisation. ICH Harmonised Tripartite Guideline. Good
Clinical Practice. CPMP/ICH/135/35. 09 May 1997.
17. Title 21 of the Code of Federal Regulations. Food and Drug Administration.
18. US Department of Health and Human Services. The Health Insurance Portability and
Accountability Act (HIPAA) of 1996 (P.L.104-191) [HIPAA].
http://aspe.hhs.gov/admnsimp/pl104191.htm. Effective 21 August 1996.
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16 Investigator Signature Page 
Protocol Title: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Efficacy, Tolerability, and Safety Study of DFN-15 in Episodic 
Migraine With or Without Aura 
Protocol Number: 
DFN-15-CD-007 
Confidentiality and cGCP Compliance Statement 
I, the undersigned, have reviewed this protocol, including appendices, and I will conduct the 
study as described in compliance with this protocol, cGCP, and relevant ICH guidelines. 
Once the protocol has been approved by the IRB, I will not modify this protocol without obtaining 
prior approval of Dr. Reddy’s Laboratories and of the IRB. I will submit the protocol 
modifications or any ICF modifications to Dr. Reddy’s Laboratories and the IRB, and approval 
will be obtained before any modifications are implemented. 
I understand that all information obtained during the conduct of the study with regard to the 
subjects’ state of health will be regarded as confidential. All attempts will be made to ensure that 
no subjects’ names will be disclosed. All subjects will be identified by assigned numbers on all 
eCRFs, laboratory samples, and source documents forwarded to the Sponsor. Clinical 
information may be reviewed by the Sponsor or its agents or regulatory agencies. Agreement 
must be obtained from the subject before disclosure of subject information to a third party. 
Information developed in this clinical study may be disclosed by Dr. Reddy’s Laboratories to 
other clinical investigators, regulatory agencies, or other health authority or government 
agencies as required. 
Investigator Signature 
Date 
Printed Name 
Institution 
_________________________________________________________
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SAP_001.pdf: 
NCT #: 
NCT03006276 
Study ID #: 
DFN-15-CD-007 
Study Title: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Efficacy, 
Tolerability, and Safety Study of DFN-15 in Episodic Migraine with or 
without Aura 
SAP: 
Version 3.0, 08 Nov 2017 
 




Statistical Analysis Plan 
Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
Page 2 of 60 
Summary of Changes (Amendment V2.0 to Amendment V3.0) 
Section 
Revision 
8.1.1 Primary Analyses of the Co-Primary 
Endpoints 
Exclusion rule is revised to apply to both 
co-primary endpoints. 
This analysis will exclude subjects who 
took rescue medication prior to the data 
collection of the 2 hours postdose time 
point (inclusive; LOCF), For the first co
primary efficacy endpoint, subjects who 
have predose pain level = mild (Grade 1) 
will also be excluded as well as subjects 
who have predose pain level = mild (Grade 
1) or none (Grade 0).
8.2 Secondary Endpoints and Analyses 
Exclusion rule is revised: 
Secondary endpoint analyses will be 
conducted as indicated for the FAS1 and 
FAS2 and will exclude subjects who took 
rescue medication prior to the data 
collection of the 2 hours postdose time 
point (inclusive; LOCF). For all secondary 
endpoint analyses in DB1 for the FAS1, 
subjects who have predose pain level = 
mild (Grade 1) or none (Grade 0) will 
also be excluded. For all secondary 
endpoint analyses in DB2 for the FAS2, 
subjects who have predose pain level = 
none (Grade 0) will also be excluded. 
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Statistical Analysis Plan 
Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
Page 4 of 60 
TABLE OF CONTENTS 
1.
GLOSSARY OF ABBREVIATIONS ................................................................. 8 
2.
PURPOSE ...................................................................................................... 10
2.1. 
Responsibilities ................................................................................................................. 10 
2.2. 
Timings of Analyses .......................................................................................................... 10 
3.
STUDY OBJECTIVES ................................................................................... 11 
3.1. 
Co-Primary Objectives ...................................................................................................... 11 
3.2. 
Secondary Objectives ....................................................................................................... 11 
3.3. 
Brief Description ................................................................................................................ 12 
3.4. 
Subject Selection ............................................................................................................... 13 
3.4.1. 
Inclusion Criteria ......................................................................................................... 13 
3.4.2. 
Exclusion Criteria ........................................................................................................ 14 
3.4.3. 
Additional Exclusion Criteria Clarification for SBP/DBP and QTcF ............................ 16 
3.5. 
Determination of Sample Size .......................................................................................... 17 
3.6. 
Treatment Assignment & Blinding ................................................................................... 18 
3.7. 
Administration of Study Drug ........................................................................................... 18 
3.8. 
Study Procedures and Flowchart ..................................................................................... 19 
4.
ENDPOINTS .................................................................................................. 24 
4.1. 
Co-Primary Endpoints ....................................................................................................... 24 
4.2. 
Secondary Endpoints ........................................................................................................ 24 
5.
ANALYSIS SETS ........................................................................................... 26 
5.1. 
Screened Set ...................................................................................................................... 26 
5.2. 
Randomized Set ................................................................................................................. 26 
5.3. 
Safety Set ............................................................................................................................ 26 
      
 
 
 
       
  
 


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Protocol #DFN-15-CD-007 
Amendment V3.0 
 
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5.4. 
Full Analysis Set ................................................................................................................ 26 
5.5. 
Per Protocol Set ................................................................................................................. 26 
5.6. 
Protocol Deviations ........................................................................................................... 27 
6.
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 28 
6.1. 
General Methods ................................................................................................................ 28 
6.1.1. 
Summary Statistics ..................................................................................................... 28 
6.1.2. 
Reporting Precision ..................................................................................................... 29 
6.2. 
KEY DEFINITIONS .............................................................................................................. 29 
6.2.1. 
Baseline ....................................................................................................................... 29 
6.2.2. 
First Dose Date ........................................................................................................... 29 
6.2.3. 
Study Day .................................................................................................................... 30 
6.2.4. 
Treatment Day............................................................................................................. 30 
6.2.5. 
Treatment Emergent Adverse Events ......................................................................... 30 
6.3. 
Missing Data ....................................................................................................................... 30 
6.4. 
Visit Windows ..................................................................................................................... 31 
6.5. 
Pooling of Centers ............................................................................................................. 31 
6.6. 
Subgroups .......................................................................................................................... 31 
7.
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND
MEDICATION................................................................................................. 32 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 32 
7.2. 
Demographic and Other Baseline Characteristics ......................................................... 33 
7.3. 
Migraine History ................................................................................................................. 33 
7.4. 
Medical History and Concomitant Diseases ................................................................... 33 
7.5. 
Medication .......................................................................................................................... 33 
7.5.1. 
Study Drug Accountability ........................................................................................... 33 
7.5.2. 
Prior and Concomitant Medications ............................................................................ 34 
8.
EFFICACY ..................................................................................................... 35 
8.1. 
Co-Primary Efficacy Endpoints and Analyses ................................................................ 35 
8.1.1. 
Primary Analyses of the Co-Primary Endpoints .......................................................... 35 
8.1.2. 
Sensitivity Analyses of the Co-Primary Endpoints ...................................................... 36 
8.1.3. 
Supplemental Analyses of the Absence of Screening MBS ....................................... 36 
      
 
 
 
       
  
 


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Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
Page 6 of 60 
8.2. 
Secondary Endpoints and Analyses ................................................................................ 36 
8.2.1. 
TEAEs ......................................................................................................................... 37 
8.2.2. 
Freedom from Nausea, Photophobia, and Phonophobia Postdose ........................... 37 
8.2.3. 
Time to Pain Relief and Pain Freedom Postdose ....................................................... 37 
8.2.4. 
Headache Pain Relief Postdose ................................................................................. 38 
8.2.5. 
Headache Pain Freedom Postdose ............................................................................ 38 
8.2.6. 
Absence of MBS Postdose ......................................................................................... 38 
8.2.7. 
Change in Functional Disability Score Postdose ........................................................ 38 
8.2.8. 
Headache Pain Freedom Among Subjects with Cutaneous Allodynia ....................... 39 
8.2.9. 
Headache Pain Freedom Among BMI Categories ...................................................... 39 
8.2.10. 
Headache Pain Recurrence Postdose ........................................................................ 39 
8.2.11. 
Sustained Headache Pain Relief Postdose ................................................................ 39 
8.2.12. 
Sustained Headache Pain Freedom Postdose ........................................................... 40 
8.2.13. 
Use of Rescue Medication Postdose .......................................................................... 40 
8.2.14. 
Subject-Rated Treatment Satisfaction Postdose ........................................................ 40 
8.2.15. 
Subject-Rated Treatment Satisfaction at 24 Hours Postdose – PPMQ-R .................. 41 
8.3. 
Exploratory Analyses ........................................................................................................ 42 
8.4. 
Subgroup Analyses ........................................................................................................... 42 
9.
SAFETY ......................................................................................................... 43
9.1. 
Extent of Exposure and Compliance with Study Drug .................................................. 43 
9.2. 
Rescue Medications .......................................................................................................... 43 
9.3. 
Adverse Events .................................................................................................................. 44 
9.4. 
Laboratory Evaluations ..................................................................................................... 45 
9.5. 
Vital Signs ........................................................................................................................... 45 
9.6. 
Twelve-Lead ECG ............................................................................................................... 46 
9.7. 
Physical Examination ........................................................................................................ 46 
9.8. 
Suicidality Check ............................................................................................................... 46 
10. INTERIM ANALYSES .................................................................................... 47 
11. CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ............................. 48 
12. REFERENCE LIST ........................................................................................ 50 
13. PROGRAMMING CONSIDERATIONS .......................................................... 51 
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Protocol #DFN-15-CD-007 
Amendment V3.0 
 
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13.1. 
General Considerations .................................................................................................... 51 
13.2. 
Table, Listing, and Figure Format .................................................................................... 51 
13.2.1. 
General ........................................................................................................................ 51 
13.2.2. 
Headers ....................................................................................................................... 52 
13.2.3. 
Display Titles ............................................................................................................... 52 
13.2.4. 
Column Headers ......................................................................................................... 52 
13.2.5. 
Body of the Data Display ............................................................................................. 53 
13.2.6. 
Footnotes .................................................................................................................... 55 
14. QUALITY CONTROL ..................................................................................... 57 
15. INDEX OF TABLES ....................................................................................... 58 
16. INDEX OF FIGURES ..................................................................................... 59 
17. INDEX OF LISTINGS ..................................................................................... 60 
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Statistical Analysis Plan 
Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
Page 8 of 60 
1.
GLOSSARY OF ABBREVIATIONS
Abbreviation 
Description 
ADD 
Attention Deficit Disorder 
ADHD 
Attention Deficit Hyperactivity Disorder 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRF 
Case Report Form 
DB 
Double-Blind 
DBP 
Diastolic Blood Pressure 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
eDiary 
Electronic Diary 
FAS 
Full Analysis Set 
GI 
Gastrointestinal 
HbA1c 
Glycosylated Hemoglobin 
HBsAg 
Hepatitis B Surface Antigen 
HCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
ICHD-3 
International Classification of Headache Disorders, 3rd Edition 
(Beta Version) 
ID 
Identification 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
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Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
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Abbreviation 
Description 
MBS 
Most Bothersome Symptom 
MedDRA 
Medical Dictionary for Regulatory Activities 
N/A 
Not Applicable 
PPMQ-R 
Patient Perception of Migraine Questionnaire-Revised 
PPS 
Per Protocol Set 
PT 
Preferred Term 
QC 
Quality Control 
QTcF 
Fridericia’s corrected QT 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SBP 
Systolic Blood Pressure 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Table, Listing and Figure 
TSH 
Thyroid-Stimulating Hormone 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
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Statistical Analysis Plan 
Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
Page 10 of 60 
2.
PURPOSE
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives. Exploratory analyses not identified or defined in this SAP may also be 
performed to support the clinical development program.     
2.1. 
RESPONSIBILITIES 
 will perform the statistical analyses and are responsible for the production 
and quality control (QC) of all tables, listings, and figures (TLFs). 
2.2. 
TIMINGS OF ANALYSES 
The primary analysis of safety and efficacy is planned after all subjects complete the 
final study visit or terminate early from the study and all relevant study data have been 
processed and integrated into the final locked data base. 
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Statistical Analysis Plan 
Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
Page 11 of 60 
3.
STUDY OBJECTIVES
3.1. 
CO-PRIMARY OBJECTIVES 
The co-primary objectives of this study are: 
•
To assess the proportion of subjects who are pain-free at 2 hours postdose (first
treated double-blind [DB] treatment period [DB1] attack).
•
To assess the proportion of subjects who are free from their Screening most
bothersome symptom (MBS) among nausea, photophobia, and phonophobia at
2 hours postdose (first treated DB1 attack).
3.2. 
SECONDARY OBJECTIVES 
Secondary objectives for each DB period are: 
•
Safety and tolerability
•
To assess the proportion of subjects who are free from nausea, photophobia, and
phonophobia at 15, 30, and 45 minutes and 1, 1.5, 2, 4, and 24 hours postdose
•
To assess time to meaningful pain relief
•
To assess time to pain freedom
•
To assess the proportion of subjects who have pain relief at 15, 30, and 45 minutes
and 1, 1.5, 2, 4, and 24 hours postdose
•
To assess the proportion of subjects who are pain-free at 15, 30, and 45 minutes and
1, 1.5, 2 (second attack), 4, and 24 hours postdose
•
To assess the proportion of subjects with their Screening MBS absent at 15, 30, and
45 minutes and 1, 1.5, 2 (second attack), 4, and 24 hours postdose
•
To assess change in functional disability score at 2,4, and 24 hours postdose
•
Among those reporting cutaneous allodynia predose, the proportion of subjects who
are pain-free at 2 and 4 hours postdose
•
To assess the proportion of subjects who are pain-free at 2 and 4 hours postdose
whose body mass index (BMI) is < 30 vs. subjects whose BMI is ≥ 30, and whose BMI is
< 25 vs. subjects whose BMI is ≥ 25
•
The proportion of subjects who have pain recurrence between 2 to 24 hours (i.e.,
pain-free at 2 hours postdose, with pain [mild, moderate, or severe] reported at
24 hours postdose)
•
To assess the proportion of subjects who have sustained pain relief at 2 to 24 hours
postdose (i.e., pain relief at 2 hours postdose, with no use of rescue medication and
no worsening of headache pain within 2 to 24 hours postdose)
•
To assess the proportion of subjects who have sustained pain freedom at 2 to 24
hours postdose (i.e., pain-free at 2 hours postdose, with no use of rescue medication
and no recurrence of headache pain within 2 to 24 hours postdose)
•
To assess the proportion of subjects who use rescue medication after 2 hours (2 to
24 hours) postdose
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Statistical Analysis Plan 
Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
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•
To assess treatment satisfaction at 2 hours and 4 hours postdose (7-point scale)
•
To assess treatment satisfaction as measured by Patient Perception of Migraine
Questionnaire-Revised (PPMQ-R) at 24 hours postdose
3.3. 
BRIEF DESCRIPTION 
This is a randomized, 2 DB treatment period dosing study, to be conducted at multiple 
centers in the United States. Male and female subjects, 18 to 75 years old (inclusive), 
previously diagnosed with at least 12 months’ medical history prior to screening of 
episodic migraine (as defined by International Classification of Headache Disorders, 3rd 
edition [beta version]1 [ICHD-3]), who do not have medication overuse, who experience 
2 to 8 migraine attacks (with or without aura) per month, with 14 or fewer headache 
days per month, who can demonstrate 48 hours of headache-free time between 
migraine attacks, and who meet all inclusion and none of the exclusion criteria and 
successfully complete all screening procedures, will be randomized in a 1:1 ratio in a DB 
fashion to receive orally either DFN-15 or matching placebo, to be used in one migraine 
attack.  
During the DB1 treatment period, subjects will treat 1 migraine attack with study drug 
as soon as (and no more than 1 hour after) experiencing moderate to severe pain level. 
If eligible, subjects will be re-randomized into the second DB treatment period (DB2) to 
treat another migraine attack at any pain level.  
The duration of study participation will be up to approximately 13 weeks, including a 
screening period of approximately 3 weeks (wherein subjects may be randomized earlier 
than 3 weeks provided they meet inclusion/exclusion criteria and headache assessment 
criteria; the screening period may also be extended beyond 3 weeks based on 
Investigator judgment and in consultation with the Medical Monitor), 2 DB treatment 
periods with up to 4 weeks (each period) for subjects to experience and treat migraine 
attacks, and 2 to 7 days for subjects to return to the site after treatment. The two DB 
treatment periods combined would total up to 10 weeks.  
Subjects will record criteria in real-time in an electronic diary (eDiary) that will 
include, but is not limited to, the date and time of each migraine attack, the 
occurrence of aura, predose pain level, date and time of study drug use, postdose pain 
level, symptoms and functional disability, treatment satisfaction, last food intake and 
fat content, and date and time of rescue medication. The eDiary will be reviewed for 
compliance and rescue medication. 
The overall study design is presented in Figure 1. 
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Figure 1 Overall Study Design 
3.4. 
SUBJECT SELECTION 
Approximately 600 subjects will be randomized into the study. Subjects who do not 
qualify for enrollment after the screening period will be terminated as screen failures 
and will be replaced. Randomized subjects who discontinue study participation prior to 
study completion will not be replaced. 
3.4.1. 
Inclusion Criteria 
Subjects may be included in the study if they meet all of the following criteria: 
1.
Able and willing to provide written informed consent
2.
Male or female, 18 to 75 years of age, inclusive, at screening
a) If female and of childbearing potential, the subject must  have a negative
serum pregnancy test at screening, does not plan to become pregnant during
the study, and is not lactating.
b) If female and of childbearing potential, the subject must also have a
negative urine pregnancy test at all subsequent study visits after the
screening visit and, unless surgically or otherwise sterile or postmenopausal
for > 1 year, agrees to practice a reliable form of contraception or
abstinence during the study. Acceptable forms of contraception include:
bilateral tubal ligation, implants, injectables, combined oral contraceptives,
an intrauterine device, a vasectomized partner, an exclusively female
partner, and double-barrier methods.
c) If male (with female partner), the subject must agree to practice a reliable
form of contraception or abstinence during the study.
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3.
A history of episodic migraine (per ICHD-3), who experience  2 to 8 migraine
attacks per month for at least the past 12 months, with no more than
14 headache days per month, and with 48 hours of headache-free time
between migraine attacks
4.
Have migraine with or without aura with onset before age 50 years
5.
Report usual migraine pain of 2 (moderate) or 3 (severe) on headache pain
severity scale without treatment
6.
Subjects who, in the opinion of the Investigator, are willing and able to:
a. Evaluate and record pain, migraine symptoms, and study drug
effectiveness information in real-time using a subject eDiary for the
duration of the study;
b. Record each instance of the use of study drug and rescue medication in
real-time using a subject eDiary for the duration of the study;
c. Comply with all other study procedures and scheduling requirements.
7.
Ability to read, speak, and understand English proficiently
3.4.2. 
Exclusion Criteria
Subjects will be excluded from participating in the study if they meet any of the 
following criteria: 
1. Minors, even if they are in the specified study age range
2. Exposure to DFN-15 prior to the study
3. Medication overuse:
o
Opioids ≥ 10 days during the 90 days prior to screening
o
Combination medications (e.g., Fiorinal®) ≥ 10 days during the 90 days prior
to screening (applies only if includes opioid and/or barbiturate)
o
NSAIDs or other simple medications ˃ 14 days a month during the 90 days
prior to screening
o
Triptans or ergots ≥ 10 days a month during the 90 days prior to screening
4. Treated with onabotulinumtoxinA (Botox®) for migraine  within 4 months prior to
screening. (If treated for cosmetic reasons, subjects may be included.)
5. On unstable dosages of migraine prophylactic medications within 30 days prior to
and through screening
6. Taking mini-prophylaxis for menstrual migraine
7. On chronic warfarin sodium or equivalent
8. Cerebrovascular events including but not limited to a history of stroke or
transient ischemic attack
9. A history of migralepsy (seizure following a migraine) or a concurrent diagnosis
of seizure disorder
10. Subjects who cannot differentiate between a migraine headache and tension-
type or cluster headache or other types of headache
11. A history of cluster headaches
12. Subjects with the diagnosis of “probable migraine” (per ICHD-3)
13. Subjects who have intolerance to any formulation of celecoxib or sulfonamides,
or who have experienced a significant AE related to any other NSAID, including
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aspirin, which caused the condition of asthma, rhinitis, nasal polyps, or Samter’s 
triad 
14. Subjects for whom NSAIDs are contraindicated (e.g., gastrointestinal (GI) bleed,
ulcer, history of acute renal failure)
15. Ischemic coronary artery disease including but not limited to angina pectoris,
history of myocardial infarction or documented silent ischemia or coronary
artery vasospasm, including Prinzmetal’s angina; symptomatic peripheral
vascular disease
16. A history of congenital heart disease
17. Uncontrolled hypertension or screening systolic/diastolic blood pressure
(SBP/DBP) > 140/90 mmHg (the values should be confirmed to rule out a
transient elevation); see protocol Section 6.3.1 for details
18. Any abnormal physiology and/or pathology that, in the opinion of the
Investigator or Sponsor, would be contraindicated for study participation and
would not allow the objectives of the study to be met
19. Subjects who show any clinical laboratory or electrocardiogram (ECG)
abnormality that in the opinion of the Investigator or Sponsor would endanger
the subject or interfere with the study conduct. If the results of the clinical
laboratory or ECG are outside of normal reference range the subject may still be
enrolled, but only if these findings are determined to be not clinically significant
by the Investigator. This determination must be recorded in the subject’s source
document before enrollment.
20. Fridericia’s corrected QT (QTcF) interval ˃ 450 msec; see Section 3.4.3 for
details.
21. Serum creatinine > 1.5 × the upper limit of normal (ULN)
22. Serum total bilirubin > 1.5 × ULN
23. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), or
alkaline phosphatase > 2.5 × ULN
24. Subjects with uncontrolled diabetes mellitus, or a glycosylated hemoglobin
(HbA1c) > 7.9%, or with diabetes mellitus requiring insulin
25. A history of alcohol or substance use disorder (including marijuana) according to
the Diagnostic and Statistical Manual of Mental Disorders, Edition 5 (DSM-5)
within 1 year prior to screening
26. Current treatment with antipsychotics or use of antipsychotics within 30 days
prior to randomization (if used for non-psychiatric conditions, should be
evaluated on a case-by-case basis with the Medical Monitor)
27. A positive urine drug screen for recreational drugs, alcohol, marijuana (whether
legal or not) or for prescription drugs not explained by stated concomitant
medications
•
Subjects consuming opioids for the treatment of migraine or using opioids
or barbiturates temporarily for a legitimate medical cause may participate
as long as they do not meet the medication overuse criteria in Exclusion
Criteria #3, above.
•
Chronic use of benzodiazepines is allowed if used for legitimate medical
use, as long as the regimen has been stable for at least 3 months prior to
screening and is expected to remain stable throughout the study
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•
Chronic use of amphetamines to treat attention deficit disorder (ADD) or
attention deficit hyperactivity disorder (ADHD) and related disorders is
allowed as long as the regimen has been stable for at least 3 months prior
to screening and is expected to remain stable throughout the study
Note: For the above-mentioned conditions, the site must have appropriate
documentation to justify the mentioned drug use (e.g., documented
medical history and a valid prescription-based dispensation)
28. A history of or current neurological or psychiatric impairment including but not
limited to psychosis, current major depression, bipolar disorder, or cognitive
dysfunction that, in the opinion of the Investigator, would compromise data
collection, or any subject who, in the opinion of the Investigator, is at significant
risk for suicide
29. Subjects who have received treatment with an investigational drug or device
within 30 days of randomization, or participated in a central nervous system
clinical trial within 2 months prior to randomization
30. Subjects who have received treatment with CYP2C9 inducers or with CYP2D6
substrates with a narrow therapeutic window (i.e., thioridazine) within 7 days
prior to randomization
31. Use of prohibited medications pursuant to Protocol Section 8.5.3; non-
compliance with wash-out period criteria (Protocol Section 8.5.1)
32. Subjects with any medical condition or procedure that in the judgment of the
Investigator and/or Medical Monitor would confound the objectives of the study
(e.g., clinically significant abnormal thyroid-stimulating hormone [TSH] levels,
systemic lupus erythematosus, a history of gastric bypass surgery or other
bariatric procedures)
33. Subjects with positive screening test for human immunodeficiency virus [HIV],
positive hepatitis B surface antigen (HBsAg), or positive hepatitis C virus [HCV]
antibody
34. History of cancer within the past 5 years (except adequately treated basal cell or
squamous cell skin carcinoma or in situ cervical cancer)
35. Subjects who should not be enrolled per the precautions, warnings, and
contraindications section of the celecoxib product label or package insert
36. Subjects who plan to donate blood, sperm, or oocytes during the study and for
30 days post last dose of study drug
37. Subjects who are employees or immediate relatives of the employees of the
Sponsor, any of its affiliates or partners, or of the clinical research study site
3.4.3. 
Additional Exclusion Criteria Clarification for SBP/DBP and QTcF 
Subjects presenting with a history of hypertension that is uncontrolled during screening 
(i.e., SBP > 140 mmHg and/or DBP > 90 mmHg), whether on treatment or not, will be 
excluded. Subjects who had high or uncontrolled BPs in the past and are currently 
controlled with given therapies would be eligible for this study. 
Independent of past history, if a subject has a sustained resting SBP/DBP > 140/90 
mmHg at Visit 1 (V1) or V2, those subjects should be excluded. If a subject has a 
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sustained SBP/DBP > 140/90 mmHg at a visit after V2, those subjects should be 
discontinued from the study. Any subject without a known history of hypertension that 
presents at screening with SBP/DBP >140/90 mmHg should be excluded (if at V1 or V2) 
or discontinued (if at a visit after V2) if the BP reading is due to suspected hypertension 
or another pathological condition, not if due to a transient fluctuation, based on the 
Investigator’s evaluation. If the Investigator believes the BP is falsely elevated, they 
should repeat the assessment 2 to 3 times with the subject in a semi-reclined position in 
a quiet room. Subjects with persistent elevations, despite repeat assessments, should 
be excluded and referred to an appropriate healthcare provider for further assessment. 
For subjects presenting at screening with an ECG QTcF > 450 msec (based on central 
ECG interpretation), the following procedures should be conducted: 
1. Wait until all other inclusion and exclusion criteria have been satisfied.
2. If the subject otherwise appears eligible for the study, with prior Medical Monitor
approval, have the subject return and conduct 2 ECGs with a minimum of 5 minutes
between tracings.
3. Transmit these additional ECGs to ERT for central interpretation.
4. Based on the central reader interpretation, if both repeat ECGs show a QTcF ≤450
msec, the subject may continue in the study at the Investigator's discretion. If one
or both repeat ECGs show QTcF > 450 msec, the subject must be screen failed based
on exclusion criteria #20.
At Visit 2 or Visit 3, additional clarification for QTcF > 450 msec (based on ERT 
interpretation) is as follows:  
1. For QTcF between 451 msec and 460 msec (inclusive), the subject may continue in
the study if the Investigator assesses the ECG as not clinically significant (NCS).
2. For QTcF > 460 msec:
a) Instruct the subject not to take the study drug until further notice.
b) If the Investigator has assessed the ECG as NCS, have the subject return, after
Medical Monitor approval, to conduct 2 ECGs with a minimum of 5 minutes
between tracings.
c) Transmit these additional ECGs to ERT for central interpretation.
d) If one or both ECGs again shows QTcF > 460 msec, based on the central
reader, then the subject must be discontinued from the study.
3.5. 
DETERMINATION OF SAMPLE SIZE 
Approximately 600 subjects will be randomized for the DB1 treatment period. Subjects 
who discontinue participation without completing the study protocol will not be 
replaced. 
The first co-primary endpoint is the comparison of the proportion of subjects who are 
pain-free at 2 hours after the first dose of study drug. It is assumed that 17.6% of 
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placebo and 29.2% of DFN-15 (treated) subjects will be pain-free at 2 hours. A sample 
size of 600 subjects will provide 88% power to detect this assumed difference between 
placebo and DFN-15 at a 5% (2-sided) level of significance and with a 15% dropout rate. 
The second co-primary endpoint is the comparison of the proportion of subjects who are 
free from their Screening MBS among nausea, photophobia, and phonophobia at 2 hours 
after the first dose of study drug. It is assumed that 28.2% of placebo and 44.7% of 
DFN-15 (treated) subjects will be free from their Screening MBS at 2 hours. A sample 
size of 480 subjects will provide 94% power to detect this assumed difference between 
placebo and DFN-15 at a 5% (2-sided) level of significance and with a 15% dropout rate. 
Since the sample size for the first co-primary endpoint is larger than that of the second 
co-primary endpoint, the larger sample size will be used for the study.  
3.6. 
TREATMENT ASSIGNMENT & BLINDING 
The DFN-15-CD-007 study is a randomized, 2 DB treatment period, placebo-controlled 
study. Eligible subjects will be randomized in a 1:1 ratio in both DB periods to receive 
orally either DFN-15 or matching placebo, to be used in one migraine attack. The 
randomization schemes for both DB periods will be generated by the biostatistics group 
of 
. The interactive web response system (IWRS) will assign the appropriate 
study kit to each subject for each DB treatment period. If a subject discontinues from 
the study after randomization, the subject identification (ID) number and randomization 
number will not be reused, and the subject will not be allowed to re-enter the study.  
All randomization data will be kept strictly confidential and accessible only to 
authorized personnel until the time of unblinding after database lock at the end of the 
study. Blinding is critical to the integrity of this clinical study; however, in the event of 
a medical emergency for an individual subject, in which knowledge of the treatment 
assignment is critical to the subject’s management, the blind for the subject may be 
broken by the Investigator (or designee) by contacting IWRS. Before unblinding, the 
Investigator (or designee) should have determined that the treatment information is 
necessary to decide the subject’s immediate management, and must make every effort 
to contact the Medical Monitor prior to unblinding. In many cases, especially if the 
emergency is clearly not related to study treatment, the problem may be properly 
managed without unblinding by assuming that the subject is receiving active treatment. 
In cases of accidental unblinding or when the Medical Monitor cannot be contacted prior 
to unblinding, the Medical Monitor should be contacted as soon as possible after the 
breaking of the blind and every attempt to preserve the blind for all other study staff 
should be made. 
3.7. 
ADMINISTRATION OF STUDY DRUG 
During the DB1 treatment period, randomized subjects will be instructed to use the 
study drug [either DFN-15 120 mg (25 mg/mL) or a matching placebo] in 1 migraine 
attack as soon as (and no more than within 1 hour after) experiencing moderate to 
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severe pain (defined as headache pain rating of Grade 2 [moderate] or Grade 3 [severe] 
on pain severity scale of 0 to 3). In the DB2 treatment period, eligible re-randomized 
subjects will receive study drug to treat 1 migraine attack at any pain level.  
Study drug should only be used to treat a new migraine attack, not a recurrence, and 
there should be at least 48 hours of pain and symptom freedom from a previous attack. 
At the end of DB1 treatment period and prior to the start of the DB2 treatment period, 
all used and unused study drug will need to be returned. At the end of the study, 
subjects will be required to return all used and unused study drug, study drug 
containers, and a completed eDiary.  
3.8. 
STUDY PROCEDURES AND FLOWCHART 
The duration of study participation will be up to approximately 13 weeks, including a 
screening period of approximately 3 weeks, 2 DB treatment periods with up to 4 weeks 
allowed to experience and treat a migraine attack in each, and 2 to 7 days for subjects 
to return to the site after treatment.  
Table 1 summarizes the planned study assessments. 
Table 2 summarizes the eDiary assessments. 
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Table 1 
Schedule of Assessments 
V1 
V2 
V3 
V41/ET2 
Screening 
Randomization 
End of DB1 period – 
Re-randomization 
End of DB2 period (end of 
study) or ET 
Assessment 
Approximately 
21 days3 
Baseline-Day 0 
Study drug dispensed 
should be used to treat a 
migraine attack as soon as 
(and no more than within 1 
hour after) experiencing 
moderate or severe pain. 
Treatment should be 
completed within 4 weeks 
from Baseline. 
Visit is expected within 
2-7 days of treating a
migraine attack with study 
drug dispensed at V2. 
Study drug dispensed at 
this visit should be used 
within 4 weeks to treat a 
migraine attack at any pain 
level. 
Visit is expected within 
2-7 days of treating a
migraine attack with the 
study drug dispensed at V3. 
Once randomized, the total 
duration of each subject’s 
participation in the study 
would be up to 10 weeks 
from Baseline. 
Informed consent 
X 
Inclusion/Exclusion criteria 
X 
X 
X 
Subject eDiary instructions and 
dispensation4 
X 
X 
X 
Adverse events (AEs)  review 
X 
X 
X 
X 
Demographics 
X 
Medical history and prior medications 
X 
X 
Migraine history (including MBS for 
the co-primary analysis) and current 
treatment status  
X 
Physical examination and suicidality 
check5 
X 
X 
X 
X 
Height and weight 
X 
X6 
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1 V4 will occur up to 10 weeks after baseline (V2). 
2 Subjects who do not complete both DB periods will complete an ET visit. 
3 Subjects may be randomized earlier during this period if they meet inclusion/exclusion criteria and headache assessment criteria. The screening period may also be extended 
based on Investigator judgment and in consultation with the Medical Monitor. 
4 Before eDiary dispensing, initial screening should determine to the extent possible that the subject may be eligible for the study and is able, willing, and understands after 
being instructed how to use the eDiary; eDiary will be dispensed once if the subject is randomized and used throughout the DB periods. At V2, randomized subjects will be 
re-instructed and re-trained on the eDiary usage to ensure real-time entry of predose and postdose assessments and the level of migraine pain to treat (moderate or severe for 
first treatment and of any pain level for the second). Thereafter, randomized subjects will be reinstructed on eDiary usage, and re-trained on instructions as needed. 
5 Physical examination data will be recorded in the source at screening (V1). A complete physical examination will be performed, including examination of head, eyes, ears, 
nose, and throat [HEENT], heart, lungs, abdomen, skin, cervical and axillary lymph nodes, neurological, and musculoskeletal systems. At other visits, symptom-driven 
limited physical examination will be performed. Any subsequent untoward change during the study will be recorded as an AE. Suicidality risk will be determined and 
recorded at screening (V1) and checked at all subsequent visits. Significant suicide risk, in the opinion of the Investigator, is exclusionary at V1 and V2. A randomized 
subject will be discontinued if a significant suicide risk is determined at subsequent visits. At any visit, subjects who are a suicide risk should be referred to a mental health 
specialist. The Medical Monitor should also be notified. 
6 Weight only. 
7 Serum pregnancy test will be performed at screening (V1) for all female subjects of childbearing potential. 
8 Urine pregnancy tests will be performed at all study visits after screening for all female subjects of childbearing potential. 
9 Subjects will be instructed by the study site staff on the proper administration of study drug to ensure compliance. Written instructions for use of the study drug will be 
distributed to Investigator sites, and subjects should be confirmed to have, or be provided with, the instructions every time study drug is dispensed. 
10 Unused study drug returned by subjects should not be redispensed. 
11 When the subject experiences a migraine episode, they should contact the site within 1 day of treating with study drug to schedule their next visit. The eDiary will be used to 
record all migraine attacks treated with study drug during the study period.
12 Screening eDiary information will be kept in the source. It is compulsory for all the subjects to check-in the eDiary every day during the entire study period. If a subject 
does not consistently check-in or does not report a migraine attack in the eDiary for 2-3 weeks, it is recommended they should be contacted by study staff to check if the 
subject has technical difficulties or confirm they have not experienced a migraine.
13 Arrangements should be made by the site for a timely return of the eDiary device for subjects who screen fail. 
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Table 2 
eDiary Assessments 
Assessment/Time 
Baseline 
DB1 and DB2 Treatment Period 
Predose 
Postdose 
15, 30, 45 min 
1 h and 1.5 h 
2 h and 4 h 
24 h 
Migraine date/time and aura information, study drug, last food 
intake and fat content, and rescue medication taken for 
migraine attacks  
As applicable1 
Time to meaningful pain relief (based on subject’s perception) 
As applicable up to 2 h postdose 
Time to pain freedom 
As applicable up to 2 h postdose 
Pain level 
X 
X 
X 
X 
X 
Functional disability 
X 
X 
X 
Presence of nausea/photophobia/phonophobia and cutaneous 
allodynia 
X 
X 
X 
X 
X 
Most bothersome symptom (selected between nausea, 
photophobia and phonophobia)2 
X 
PPMQ-R 
X 
X 
Subject treatment satisfaction 
X3
Abbreviations: h = hour(s); min = minutes; PPMQ-R = Patient Perception of Migraine Questionnaire-Revised 
1 End of migraine pain may occur more than 24 hours postdose. 
2 The most bothersome symptom will be collected only if more than 1 symptom is present predose; if only 1 symptom is present, it will be considered the most bothersome. 
3 Treatment satisfaction baseline for the migraine medication to be collected prior to randomization in the PPMQ-R. 
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4.
ENDPOINTS
4.1. 
CO-PRIMARY ENDPOINTS 
The co-primary endpoints of this study are: 
•
The proportion of subjects who are pain-free 2 hours postdose compared
between DFN-15 and placebo in the DB1 treatment period (defined as a
reduction from predose moderate [Grade 2] or severe [Grade 3] pain to none
[Grade 0]).
•
The proportion of subjects who are free from their Screening MBS among nausea,
photophobia, and phonophobia (and have this symptom predose) at 2 hours
postdose compared between DFN-15 and placebo in the DB1 period.
4.2. 
SECONDARY ENDPOINTS 
Secondary endpoints for each DB period are: 
•
The proportion of subjects with treatment-emergent adverse events (TEAEs) after
study drug compared between DFN-15 and placebo.
•
The proportion of subjects who are free from nausea, photophobia, and
phonophobia at 15, 30, and 45 minutes and 1, 1.5, 2, 4, and 24 hours postdose
compared between DFN-15 and placebo.
•
Time to meaningful pain relief (defined as based on subject’s perception) within 2
hours postdose compared between DFN-15 and placebo in each treated attack.
•
Time to pain freedom within 2 hours postdose compared between DFN-15 and
placebo.
•
The proportion of subjects who have pain relief at 15, 30, and 45 minutes and 1,
1.5, 2, 4, and 24 hours postdose compared between DFN-15 and placebo. Headache
pain relief is defined for DB1 as a reduction from moderate or severe pain prior to
dosing to mild or none postdose, and for DB2 as moderate or severe pain predose
reduced to mild or none postdose, or mild pain predose reduced to none postdose.
•
The proportion of subjects who are pain-free at 15, 30, and 45 minutes and 1, 1.5, 2
(DB2 period), 4, and 24 hours postdose compared between DFN-15 and placebo.
•
The proportion of subjects with their Screening MBS (and have this symptom
predose) absent at 15, 30, and 45 minutes, and 1, 1.5, 2 (DB2 period), 4, and 24
hours postdose compared between DFN-15 and placebo.
•
Change in functional disability score at 2, 4, and 24 hours postdose compared
between DFN-15 and placebo.
•
Among those reporting cutaneous allodynia predose, the proportion of subjects who
are pain-free at 2 and 4 hours postdose compared between DFN-15 and placebo.
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•
The proportion of subjects who are pain-free at 2 and 4 hours postdose whose BMI is
< 30 vs. subjects whose BMI is ≥ 30, and whose BMI is < 25 vs. subjects whose BMI is
≥ 25.
•
The proportion of subjects who have pain recurrence between 2 to 24 hours (i.e.,
pain-free at 2 hours postdose, with pain [mild, moderate, or severe] reported at 24
hours postdose) compared between DFN-15 and placebo.
•
The proportion of subjects who have sustained pain relief at 2 to 24 hours postdose
(i.e., pain relief at 2 hours postdose, with no use of rescue medication and no
worsening of headache pain within 2 to 24 hours postdose) compared between DFN-
15 and placebo.
•
The proportion of subjects who have sustained pain freedom at 2 to 24 hours
postdose (i.e., pain-free at 2 hours postdose, with no use of rescue medication, and
no recurrence of headache pain within 2 to 24 hours postdose) compared between
DFN-15 and placebo.
•
The proportion of subjects who use rescue medication after 2 hours (2 to 24 hours)
postdose compared between DFN-15 and placebo.
•
Treatment satisfaction at 2 hours and 4 hours postdose as determined on a 7-point
scale compared between DFN-15 and placebo. DFN-15 will also be compared to same
question in the Baseline PPMQ-R.
•
Treatment satisfaction as measured by PPMQ-R at 24 hours postdose compared
between DFN-15 and placebo.
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5.
ANALYSIS SETS
5.1. 
SCREENED SET 
The Screened Set will include all screened subjects. The set of analyses including 
subject listings and summary tables of subject disposition will be analyzed based on all 
eligible screened subjects who are databased for the study. 
5.2. 
RANDOMIZED SET 
Each DB treatment period will have a Randomized Set. The randomized set for DB1 will 
include all subjects who give informed consent and are eligible for and randomized into 
the DB1 treatment period. The randomized set for DB2 will include all subjects in the 
randomized set for DB1 who are eligible for and are re-randomized into the DB2 
treatment period. 
5.3. 
SAFETY SET 
The Safety Set (SS) will include all subjects who took at least one dose of DB study drug 
during one or both treatment periods, and have it recorded in their eDiary. Subjects will 
be analyzed according to the treatment they receive. The Safety Set 1 (SS1) will include 
randomized subjects who took at least one dose of DB study drug during the DB1 
treatment period. The Safety Set 2 (SS2) will include subjects who were re-randomized 
and took at least one dose of DB study drug during the DB2 treatment period. The SS, 
SS1, and SS2 will be used for all analyses of safety endpoints including summaries of 
TEAEs, ECGs, and clinical laboratory results. 
5.4. 
FULL ANALYSIS SET 
Each DB treatment period will have a Full Analysis Set (FAS). The Full Analysis Set 1 
(FAS1) will include all randomized subjects who took at least one dose of study drug 
during the DB1 treatment period and have at least one post-baseline efficacy time point 
assessment for either pain or symptom (among nausea, photophobia, phonophobia) in 
DB1. The Full Analysis Set 2 (FAS2) will include all re-randomized subjects who took at 
least one dose of study drug during the DB2 treatment period and have at least one 
post-baseline efficacy time point assessment for either pain or symptom (among nausea, 
photophobia, phonophobia). Subjects in the DB1 will be analyzed according to their 
randomized treatment. Subjects in the DB2 will be analyzed according to their re-
randomized treatment. The FAS1 and FAS2 will be used for all analyses of efficacy 
endpoints.  
5.5. 
PER PROTOCOL SET 
The Per Protocol Set (PPS) will include all FAS1 subjects who have at least 1 post-
baseline primary endpoint assessment for both co-primary endpoints (observed and 
LOCF), and who have no significant protocol deviations that will impact the collection 
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or interpretation of the co-primary endpoint data during the DB1 treatment period. 
Identification of subjects in the PPS will be determined before the database lock and 
unblinding. Subjects in the PPS will be analyzed according to their DB1 randomized 
treatment.  
5.6. 
PROTOCOL DEVIATIONS 
Protocol deviations will be captured during monitoring visits or via remote monitoring. 
All deviations will be recorded in the 
 clinical trial management system and 
will be categorized as major or minor. Major protocol deviations will be summarized by 
deviation type using frequency counts. All deviations will be listed by subject. 
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6.
GENERAL ASPECTS FOR STATISTICAL ANALYSIS
6.1. 
GENERAL METHODS 
6.1.1. Summary Statistics 
In general, descriptive statistical methods will be used to summarize the data from this 
study. With appropriate sample sizes, hypothesis testing can be performed for the co-
primary and secondary efficacy endpoints.  
The term “treatment group” refers to the applied treatment regimen during DB1 or DB2 
(DFN-15 120 mg or placebo). All data collected during the study will be included in 
subject data listings. All subjects entered into the database will be included in subject 
data listings. Unless otherwise noted, the data will be sorted first by treatment group, 
subject number, and then by date within each subject number. 
Unless stated otherwise, the term “descriptive statistics” refers to number of subjects 
(n), mean, median, standard deviation, minimum, and maximum for continuous data 
and frequencies and percentages for categorical data.  
All categorical/qualitative data will be presented using absolute frequency counts and 
percentages. The total number of subjects in the treatment group overall (N) in the 
specified population will be used as the denominator for percentage calculations, unless 
stated otherwise in the table shell. All percentages will be presented in parentheses 
with 1 decimal point, unless otherwise specified. Percentages equal to 100 will be 
presented as 100% and percentages will not be presented for zero frequencies.  
Unless specified otherwise, all statistical testing and confidence intervals (CIs) will be 2-
sided and will be performed using a significance (alpha) level of 0.05.  
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6.1.2. Reporting Precision 
Summary statistics will be presented to the following degree of precision: 
Table 3 Reporting Precision 
Statistics 
Degree of Precision 
Mean (of all kinds), Median, 
Quartiles, Confidence limit 
boundaries 
One more decimal place than the raw data 
Standard deviation, Standard error 
Two more decimal places than the raw data 
Minimum, Maximum 
The same number of decimal places as the 
raw data 
P-value
Rounded to 3 decimal places and formatted 
as 0.xxx; P-values smaller than 0.001 as 
‘<0.001’; P-values smaller than 0.0001 as 
‘<0.0001’ 
Percent 
One decimal place 
All fractional numeric values will be presented with a zero to the left of the decimal 
point (for example, 0.12 - 0.30, not .12 - .30). 
All analyses and summaries will be produced using Statistical Analysis System (SAS®) for 
Windows, Release 9.3 (SAS® Institute Inc., Cary, NC, USA) or higher. Summaries will be 
presented by treatment unless otherwise specified. 
6.2. 
KEY DEFINITIONS 
6.2.1. 
Baseline 
Unless specified otherwise, the baseline assessment will be the latest available valid 
measurement taken prior to the administration of the initial dose of study drug during 
each DB period. In the event that a migraine attack happens immediately following 
randomization, the assessments taken on the same day as the administration of the 
initial dose of study drug, but prior to the time study drug is taken, can be considered 
as baseline. 
6.2.2. 
First Dose Date 
The first dose date for DB1 is defined as the first dose of study drug taken after 
randomization in DB1. The first dose date for DB2 is defined as the first dose of DB2 
study drug taken after re-randomization into DB2. 
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6.2.3. 
Study Day 
If the assessment date is after the date of the first dose during each treatment period, 
the study day is calculated as date of assessment - date of the first dose administration 
+ 1. If the assessment date is prior to the date of the first dose during each treatment
period, the study day is calculated as date of assessment - date of the first dose
administration. Study day 1 for each DB treatment period is the day during which the
first dose of study drug during the first treatment period is administered.
6.2.4. 
Treatment Day 
If the assessment date is after the date of the first dose during the current DB 
treatment period, the treatment day is calculated as date of assessment - date of the 
first dose administration during the current DB treatment period + 1. If the assessment 
date is prior to the date of the first dose during the current DB treatment period, the 
treatment day is calculated as date of assessment - date of the first dose administration 
during the current DB treatment period. Treatment day 1 is the day during which the 
first dose of study drug during the current DB treatment period is administered. 
6.2.5. 
Treatment Emergent Adverse Events 
 A TEAE for DB1 is defined as an AE that started on or after the first dose of study drug 
(DFN-15 or placebo) in DB1 or any existing AE that worsens in severity on or after the 
date of the first dose of study drug in DB1 up to 5 days after the date of the last dose of 
study drug in DB1 or up to taking DB2 study drug, whichever occurs first.  
A TEAE for DB2 is defined as an AE that started on or after the first dose of study drug 
(DFN-15 or placebo) in DB2 or any existing AE that worsens in severity on or after the 
date of the first dose of study drug in DB2, up to 5 days after the date of the last dose 
of study drug in DB2. 
6.3. 
MISSING DATA 
Subjects are allowed to withdraw from the study at any time. Subjects who withdraw 
from the study will have all data listed and, wherever relevant, included in any subject 
summaries. Analyses on quantitative and categorical variables will include data from 
subjects with non-missing values. Partial dates will be listed as recorded on the case 
report form (CRF). Imputation of missing or incomplete dates will only be performed for 
summaries of AEs and concomitant medications unless otherwise specified.  
Partial Missing Start or Stop 
Date 
Imputed Start Date 
Imputed Stop Date 
Missing month and day, and 
the year  is present 
January 1 of that year or 
DB period dose date if the 
year is the same as the year 
December 31 of that year 
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Partial Missing Start or Stop 
Date 
Imputed Start Date 
Imputed Stop Date 
of the DB period dose date 
Missing day, but year and 
month are present 
First day of that month or 
DB period dose date if the 
year and month are the 
same as the year and 
month of the DB period 
dose date 
Last day of that month 
Missing month, but year and 
day are present 
Missing month imputed as 
January 
Missing month imputed as 
December 
6.4. VISIT WINDOWS 
There will be no derivation for visit windows in terms of summary of assessments. 
Nominal visits as indicated in Table 1 will be used for TLFs.  
6.5. 
POOLING OF CENTERS 
There will be no pooling of centers. 
6.6. 
SUBGROUPS 
Subgroup analyses will be conducted on the co-primary efficacy endpoints and will be 
exploratory in nature. The following categories will be evaluated in the subgroup 
analyses:  
•
Age (18-34 years, 35-49 years, 50-64, and >=65 years)
•
Gender (male and female)
•
Ethnicity (Hispanic and non-Hispanic)
Subgroup analyses of efficacy are described in Section 8.3. Additional subgroup analyses 
based on baseline information may be performed. These analyses will be data driven, 
exploratory, and described in the Clinical Study Report if conducted. 
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7.
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND
MEDICATION
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition will be presented for the Screened Set, and will include the 
following: 
•
The number of subjects screened
•
The number (%) of subjects who failed screening
•
The number (%) of subjects randomized into DB1
•
The number of subjects re-randomized into DB2
•
The number (%) of subjects in the FAS1
•
The number (%) of subjects in the FAS2
•
The number (%) of subjects in the SS
•
The number (%) of subjects in the SS1
•
The number (%) of subjects in the SS2
•
The number (%) of subjects in the PPS
•
The number (%) of subjects who completed DB1
•
The number (%) of subjects who completed DB2
•
The number (%) of subjects who completed the study
•
The number (%) of subjects who discontinued from DB1 and the primary reason
for discontinuation
•
The number (%) of subjects who discontinued from DB2 and the primary reason
for discontinuation
•
The total number (%) of subjects who discontinued from the study and the
primary reason for discontinuation
The summary will be performed for the Screened Set, as well as for the DB1 and DB2 
treatment periods. The denominators for the percentage calculation will be listed in the 
footnote of subject disposition table.. No statistical testing will be performed on these 
data.  
Subjects’ completion/discontinuation status will be listed, including subject identifier, 
date of completion/early discontinuation and, for those who discontinued early, the 
specific reason(s) for discontinuation. 
The inclusion/exclusion criteria for the subjects who fail screening will be listed. 
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7.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographics and other baseline characteristics will be summarized for the SS, SS1, and 
SS2 by treatment group and overall, with descriptive statistics including n, mean, 
standard deviation, median, minimum, and maximum for numeric variables and 
frequency and percentage for categorical variables. Demographics include age, gender, 
childbearing potential for females, ethnicity, race, height, weight, smoking history, and 
BMI. 
BMI will be calculated as follows: 
BMI (kg/m2) = Weight (kg)/[Height(m)2]. 
All collected demographics and baseline characteristics will be listed.  
7.3. 
MIGRAINE HISTORY 
All migraine history data will be summarized descriptively by treatment group and 
overall for the SS, SS1, and SS2. 
All collected migraine history data will be listed. 
7.4. MEDICAL HISTORY AND CONCOMITANT DISEASES 
A summary table of the number and percentage of subjects by medical history system 
organ class (SOC) and preferred term (PT) will be produced for subjects in the SS. 
Previous and concurrent diseases/conditions will be sorted alphabetically by SOC and PT 
using the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary, 
version 19.0 or higher. For the summary tables, a subject may appear more than once if 
he/she has more than one medical history coded under different SOC categories. 
However, the subject will be counted only once in the overall category.  
A separate by-subject listing for medical history data will also be provided. Surgical 
history including procedure, date of surgery, and reason for surgery will be listed. 
7.5. MEDICATION 
7.5.1. 
Study Drug Accountability 
All data in the study drug accountability log will be listed, which will include the dates 
and kit number(s) of the drug dispensed and returned. 
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7.5.2. 
Prior and Concomitant Medications 
All prior and concomitant medications will be classified using the Anatomical 
Therapeutic Chemical (ATC) classification and preferred drug names from the World 
Health Organization Drug Dictionary (WHO-DD), version March 2016.  
Summaries of medications will be presented in tabular form using the highest level ATC 
term as an upper classification and the preferred drug name as a lower classification 
level. All medications will be summarized by treatment group and overall and sorted by 
descending counts in the upper classification term and the lower classification term 
within the upper. The summary will consist of the frequency and percentage of subjects 
who used the medication at least once. For each subject, the medication will be 
counted only once within the upper classification level and only once within the lower 
classification level. 
Medications will be considered prior if stopped before the DB1 dose date. Medications 
with a start or stop date on or after the DB treatment period dosing date will be 
considered concomitant medications. If a concomitant medication starts on or after the 
start time of DB1 dose administration, it is considered a concomitant medication to the 
study treatment in DB1, but not in DB2. If a concomitant medication starts on or after 
the start time of DB2 dose administration, it is considered a concomitant medication to 
the study treatment in DB2. All medications marked as ongoing are concomitant 
medications. A medication with an incomplete start/stop date will have its date 
imputed as described in SAP Section 6.3 solely to determine if the medication is prior or 
concomitant. 
Summaries of prior and of concomitant medications will be presented separately in 
tables and will be based on the SS. Prior and concomitant medications will be listed by 
subject. An identifier will be included to show if a medication is prior or if it is 
concomitant with respect to the applicable DB treatment period. 
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8.
EFFICACY
8.1. 
CO-PRIMARY EFFICACY ENDPOINTS AND ANALYSES 
8.1.1. 
Primary Analyses of the Co-Primary Endpoints 
The first co-primary efficacy endpoint is the proportion of subjects who are pain-free 
2 hours postdose compared between DFN-15 and placebo in the DB1 treatment period 
(defined as a reduction from predose moderate [Grade 2] or severe [Grade 3] pain to 
none [Grade 0]).  
The second co-primary efficacy endpoint is the proportion of subjects who are free from 
their Screening MBS among nausea, photophobia, and phonophobia at 2 hours postdose 
compared between DFN-15 and placebo in the DB1 treatment period. A subject’s 
Screening MBS is obtained at Screening via Migraine History assessment, and for the 
analysis of the co-primary endpoint that Screening MBS symptom must be present at 
predose but it does not have to be designated as the MBS at predose.  
To test for statistical significance of the co-primary efficacy endpoints, the closed 
sequential testing procedure will be utilized. If the first co-primary endpoint is 
statistically significant at a two-sided 0.05 level of significance, the second co-primary 
endpoint will be tested at a two-sided 0.05 level of significance. The study must show a 
significant statistical beneficial experimental treatment effect for both co-primary 
endpoints to be considered statistically successful, controlling the significance level at 
0.05. Since statistical significance with both co-primary endpoints is required to declare 
trial success, multiplicity due to multiple primary endpoints is a non-issue.    
The first co-primary efficacy endpoint will be analyzed using Fisher’s exact test. 
Following the closed sequential procedure, the second co-primary efficacy endpoint will 
be analyzed using Fisher’s exact test if the first co-primary endpoint is statistically 
significant.  
The proportion of subjects who are pain-free at 2 hours postdose will be calculated as 
the number of subjects who are pain-free at 2 hours postdose divided by the number of 
subjects with non-missing assessment at 2 hours postdose. Missing primary efficacy 
endpoint data will be imputed using the last observation carried forward (LOCF). Results 
based on the LOCF data and the observed data will be displayed separately.  
The number of subjects with response, the number of subjects with non-missing 
assessment, proportions for the DFN-15 and placebo groups, 95% exact CIs for those 
proportions, the odds ratio for response, and the corresponding p-value will be 
presented for the comparison between two treatment groups for the FAS1. This analysis 
will exclude subjects who took rescue medication prior to the data collection of the 2 
hours postdose time point (inclusive; LOCF), as well as subjects who have predose pain 
level = mild (Grade 1) or none (Grade 0). The analysis will also be performed using the 
PPS. 
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If the first co-primary efficacy endpoint is statistically significant, results will be found 
similarly for the second co-primary efficacy endpoint. 
If statistical significance (p < 0.05) is not achieved for either study 006 or study 007 (or 
both studies) co-primary endpoints, additional analyses will be conducted. Detailed 
information will be included in a separated Statistical Analysis Plan.  
8.1.2. 
Sensitivity Analyses of the Co-Primary Endpoints 
Besides the scenario with the observed missing data for the co-primary efficacy 
endpoints, two additional scenarios will be considered for each of the co-primary 
endpoints.  
For the first co-primary endpoint, in one scenario, subjects with missing headache pain 
assessments at 2 hours postdose will be assigned as having a pain level of 3 (severe) at 2 
hours postdose; that is, they will be assigned as having severe headache pain at 2 hours 
postdose. In another scenario, subjects with missing headache pain assessments at 2 
hours postdose will be assigned as having a pain level of 0 (None) at 2 hours postdose; 
that is, they will be assigned as having headache pain freedom at 2 hours postdose.  
For the second co-primary endpoint, in one scenario, subjects with a missing response 
for MBS status will be assigned as being free from their MBS. In another scenario, 
subjects with a missing response for MBS status will be assigned as not being free from 
their MBS. 
For the first co-primary endpoint, proportions of subjects pain-free at 2 hours postdose 
for the DFN-15 and placebo groups, 95% exact CIs for those proportions, and the 
corresponding p-value from Fisher’s exact test for the three scenarios will be 
presented. A similar analysis will be conducted for the proportion of subjects who are 
free from their MBS at 2 hours postdose. 
8.1.3. 
Supplemental Analyses of the Absence of Screening MBS 
Supplemental analysis will be conducted for the proportion of subjects who are free 
from their Screening MBS at 2 hours postdose with break down by individual symptoms 
(nausea, photophobia, and phonophobia) compared between DFN-15 and placebo in the 
DB1 treatment period. 
8.2. 
SECONDARY ENDPOINTS AND ANALYSES 
The secondary endpoints that involve proportions of subjects who have a response will 
be summarized by treatment group and will be analyzed using the LOCF for missing 
secondary efficacy endpoint data.  
Secondary endpoint analyses will be conducted as indicated for the FAS1 and FAS2 and 
will exclude subjects who took rescue medication prior to the data collection of the 2 
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hours postdose time point (inclusive; LOCF). For all secondary endpoint analyses in DB1 
for the FAS1, subjects who have predose pain level = mild (Grade 1) or none (Grade 0) 
will also be excluded. For all secondary endpoint analyses in DB2 for the FAS2, subjects 
who have predose pain level = none (Grade 0) will also be excluded. 
8.2.1. 
TEAEs 
The proportion of subjects who have a TEAE during each DB treatment period will be 
summarized by treatment group for the FAS1 and FAS2.  
8.2.2. 
Freedom from Nausea, Photophobia, and Phonophobia Postdose 
The proportion of subjects who are free from nausea, photophobia, and phonophobia at 
15, 30, and 45 minutes and 1, 1.5, 2, 4, and 24 hours postdose during each DB 
treatment period will be summarized by symptom, treatment group, and time point for 
the FAS1 and FAS2. The corresponding p-values from Fisher’s exact test will be 
computed for the comparison between treatment groups. Subjects who report a 
symptom predose and report the status of the symptom at the particular postdose time 
point will be analyzed. 
8.2.3. 
Time to Pain Relief and Pain Freedom Postdose 
The following two secondary efficacy endpoints are captured in the subject eDiary 
separately from the scheduled time points, and are self-initiated based on the actual 
time of a subject’s perception of pain relief and pain freedom (if they occur) within the 
first 2 hours postdose. Descriptive statistics for the two endpoints will be provided by 
treatment group for the FAS1 and FAS2. Additionally, the two endpoints will be 
summarized and graphically presented by treatment group for the FAS1 and FAS2 using 
Kaplan-Meier survival estimation. Comparisons between treatment groups will be 
performed using the log-rank test. 
8.2.3.1. 
Time to Meaningful Headache Pain Relief Postdose 
Time to meaningful headache pain relief is defined as the time in minutes from the 
time a subject takes study drug until the time a subject indicates meaningful pain relief 
in the eDiary within 2 hours postdose. The time to meaningful headache pain relief 
postdose will be summarized and analyzed using Kaplan-Meier survival estimation for 
the FAS1 and FAS2. The corresponding p-values from a log-rank test will be computed 
for the comparison between treatment groups. 
8.2.3.2. 
Time to Headache Pain Freedom Postdose 
Time to headache pain freedom is defined as the time in minutes from the time a 
subject takes study drug until the time a subject indicates pain freedom in the eDiary 
within 2 hours postdose. The time to headache pain freedom postdose will be 
summarized and analyzed using Kaplan-Meier survival estimation for the FAS1 and FAS2. 
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The corresponding p-values from a log-rank test will be computed for the comparison 
between treatment groups. 
8.2.4. 
Headache Pain Relief Postdose 
The proportion of subjects who have pain relief at 15, 30, and 45 minutes and 1, 1.5, 2, 
4, and 24 hours postdose will be summarized by treatment group and time point for the 
FAS1 and FAS2. For DB1, headache pain relief is defined as a reduction in migraine pain 
from predose severe or moderate to mild or none postdose. For DB2, headache pain 
relief is defined as moderate or severe pain predose  reduced to mild or none postdose, 
or mild pain predose  reduced to none postdose. The corresponding p-values from 
Fisher’s exact test will be computed for the comparison between treatment groups. 
Subjects who report a headache predose and rate the headache pain level at the 
particular postdose time point will be analyzed. 
8.2.5. 
Headache Pain Freedom Postdose 
The proportion of subjects who are pain-free at 15, 30, and 45 minutes and 1, 1.5, 2 
(DB2 period), 4, and 24 hours postdose during each DB treatment period will be 
summarized by treatment group for the FAS1 and FAS2. The corresponding p-values 
from Fisher’s exact test will be computed for the comparison between treatment 
groups.  
8.2.6. 
Absence of MBS Postdose 
The proportion of subjects with their Screening MBS among nausea, photophobia and 
phonophobia absent at 15, 30, and 45 minutes and 1, 1.5, 2 (DB2 period), 4, and 24 
hours postdose during each DB treatment period will be summarized by treatment group 
and time point for the FAS1 and FAS2. The corresponding p-values from Fisher’s exact 
test will be computed for the comparison between treatment groups. Subjects who 
report an MBS at Screening among nausea, photophobia and phonophobia (those with 
only one of the three symptoms reported will have that symptom designated as MBS by 
default), and have this symptom present at predose and report the status of their 
symptoms at the particular postdose time point will be analyzed. 
Absence of Screening MBS will be analyzed similarly at all postdose timepoints for both 
treatment periods. 
8.2.7. 
Change in Functional Disability Score Postdose 
The values of the functional disability scale are: 0 = no disability, able to function 
normally; 1 = performance of daily activities mildly impaired, can still do everything but 
with difficulty; 2 = performance of daily activities moderately impaired, unable to do 
some things; 3 = performance of daily activities severely impaired, cannot do all or 
most things, bed rest may be necessary. 
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The change in functional disability score from baseline to 2, 4, and 24 hours postdose 
during each DB treatment period will be summarized by treatment group for the FAS1 
and FAS2. The corresponding p-values from the Wilcoxon rank-sum test will be 
computed for the comparison between treatment groups. P-values from the Wilcoxon 
signed-rank test will be computed for the change from baseline within each treatment 
group. 
The following levels of change from baseline in functional disability score will be 
compared between DFN-15 and placebo in each DB period: 3 point change, 2 point 
change, 1 point change, 0 point change, -1 point change, -2 point change, and -3 point 
change. The proportion of subjects with those levels of change from baseline during 
each DB treatment period will be summarized by treatment group and time point for 
the FAS1 and FAS2. The corresponding p-values from Fisher’s exact test will be 
computed for the comparison between treatment groups for each category. 
8.2.8. 
Headache Pain Freedom Among Subjects with Cutaneous Allodynia 
The proportion of subjects who are pain-free at 2 and 4 hours postdose during each DB 
treatment period among those subjects reporting cutaneous allodynia prior to dosing 
will be summarized by treatment group and time point for the FAS1 and FAS2. The 
corresponding p-values from Fisher’s exact test will be computed for the comparison 
between treatment groups.  
8.2.9. 
Headache Pain Freedom Among BMI Categories 
The proportion of subjects who are pain-free at 2 and 4 hours postdose whose BMI is < 
30 vs. subjects whose BMI is ≥ 30 during each DB treatment period will be summarized 
by treatment group and time point for the FAS1 and FAS2. The corresponding p-values 
from Fisher’s exact test will be computed for the comparison between treatment 
groups. The same summary will be conducted for subjects whose BMI is < 25 vs. subjects 
whose BMI is ≥ 25. 
8.2.10. 
Headache Pain Recurrence Postdose 
The proportion of subjects who have pain recurrence between 2 to 24 hours postdose 
during each DB treatment period will be summarized by treatment group for the FAS1 
and FAS2. Pain recurrence between 2 to 24 hours is defined as pain-free at 2 hours 
postdose, with pain (mild, moderate, or severe) reported at 24 hours postdose. The 
corresponding p-values from Fisher’s exact test will be computed for the comparison 
between treatment groups. 
8.2.11. 
Sustained Headache Pain Relief Postdose 
The proportion of subjects who have sustained pain relief at 2 to 24 hours postdose 
during each DB treatment period will be summarized by treatment group for the FAS1 
and FAS2. Sustained pain relief at 2 to 24 hours is defined as pain relief at 2 hours 
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postdose, with no use of rescue medication and no worsening of headache pain within 2 
to 24 hours postdose. The corresponding p-values from Fisher’s exact test will be 
computed for the comparison between treatment groups. 
8.2.12. 
Sustained Headache Pain Freedom Postdose 
The proportion of subjects who have sustained pain freedom at 2 to 24 hours postdose 
during each DB treatment period will be summarized by treatment group for the FAS1 
and FAS2. Sustained pain freedom at 2 to 24 hours is defined as pain-free at 2 hours 
postdose, with no use of rescue medication and no recurrence of headache pain within 
2 to 24 hours postdose. The corresponding p-values from Fisher’s exact test will be 
computed for the comparison between treatment groups. 
8.2.13. 
Use of Rescue Medication Postdose 
The proportion of subjects who use rescue medication at 2 to 24 hours postdose during 
each DB treatment period will be summarized by treatment group for the FAS1 and 
FAS2. The corresponding p-values from Fisher’s exact test will be computed for the 
comparison between treatment groups. 
8.2.14. Subject-Rated Treatment Satisfaction Postdose 
The possible values of the subject treatment satisfaction scale are: 1 = very satisfied; 2 
= satisfied; 3 = somewhat satisfied; 4 = neither satisfied nor dissatisfied; 5 = somewhat 
dissatisfied; 6 = dissatisfied; 7 = very dissatisfied.  
Subject-rated treatment satisfaction based on a 7-point scale at 2 and 4 hours postdose 
during each DB treatment period will be summarized by treatment group for the FAS1 
and FAS2. The corresponding p-values from the Wilcoxon rank-sum test will be 
computed for the comparison between treatment groups. 
The subject-rated treatment satisfaction score at 2 and 4 hours postdose and the 
baseline PPMQ-R response for the same question will be compared for the DFN-15 group 
only. The corresponding p-value from the Wilcoxon rank-sum test will be computed for 
this comparison. 
The difference between the subject-rated treatment satisfaction score at 2 and 4 hours 
postdose and the baseline PPMQ-R response for the same question will be summarized by 
treatment group for the FAS1 and FAS2. P-values from the Wilcoxon rank-sum test will be 
computed for the comparison between overall treatment satisfaction score at 2 and 4 
hours postdose and baseline PPMQ-R response for the DFN-15 group only. P-values from 
the Wilcoxon signed-rank test will be computed for the difference between baseline 
PPMQ-R and post baseline for DFN-15 group only. 
Additionally, the subject-rated treatment satisfaction scores at 2 and 4 hours postdose 
will be categorized to report “satisfied” versus “neither/dissatisfied”; 
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“satisfied/neither” versus “dissatisfied”; and “satisfied” versus “neither”, and 
“dissatisfied”. The “satisfied” category consists of scores 1-3, and the 
“neither/dissatisfied” category consists of scores 4-7. The “satisfied/neither” group 
consists of scores 1-4, and the “dissatisfied” group consists of scores 5-7. The “neither” 
group consists of the score 4. Proportions of subjects in the “satisfied” versus 
“neither/dissatisfied”, the “satisfied/neither” versus “dissatisfied”, and the “satisfied” 
versus the “neither” and “dissatisfied” categories will be summarized by treatment 
group for the FAS1 and FAS2. The corresponding p-values from Fisher’s exact test will 
be computed for the comparison between treatment groups. 
8.2.15. Subject-Rated Treatment Satisfaction at 24 Hours Postdose – PPMQ-R 
The PPMQ-R consists of 29 questions that assess a subject’s satisfaction with migraine 
medication in terms of the following subscales: efficacy (11 questions), function (4 
questions), ease of use (2 questions) and cost (2 questions), as well as the degree to 
which side effects were tolerated (tolerability; 10 questions).  
In addition, three global items measuring subject satisfaction in terms of medication 
effectiveness, side effects and overall satisfaction are included. Items that evaluate 
treatment satisfaction are scored on a seven-point Likert-type scale from 1 (very 
satisfied) to 7 (very dissatisfied); whereas items that evaluate tolerability of side 
effects (i.e. bothersomeness of side effects) are scored on a five-point Likert-type scale 
from 1 (not at all) to 5 (extremely). For this study, the two items that comprise the cost 
subscale will not be used since subjects will not pay for the study drug; therefore, 27 
questions and three global items will be used. 
Each subscale score and the total score will be transformed to range from 0 to 100 with 
higher scores indicating better satisfaction or tolerability. Subscale scores and Total 
scores (except the Total Raw core) are transformed to a 0 to 100 range by subtracting 
the lowest possible scale score, dividing by the range of the scale and multiplying by 
100.2 The individual three Global items will not be transformed. The total score consists 
of the average of the efficacy, function, and ease of use subscale scores.3 If a response 
is missing, the particular subscale or global item will be considered non-evaluable.  If a 
subscale or global item is deemed non-evaluable, or missing, the corresponding total 
score will also be considered non-evaluable and assigned as missing.  
The scores at 24 hours postdose for each subscale score, each global item score, the 
total score, and the total raw score will be summarized by treatment group for the FAS1 
and FAS2. The corresponding p-values from the Wilcoxon rank-sum test will be 
computed for the comparison between treatment groups.  
The change from baseline to 24 hours for each subscale score, each global item score, 
the total score, and the total raw score will also be analyzed using the Wilcoxon signed-
rank test. Baseline scores for each subscale score, each global item score, the total 
score, and the total raw score will be summarized by treatment group, and will be 
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compared to 24 hours postdose scores for the DFN-15 group only.  The corresponding p-
value from the Wilcoxon rank-sum test will be computed for these comparisons. 
8.3. 
EXPLORATORY ANALYSES 
Exploratory analysis will be conducted for the proportion of subjects who are pain-free 
2 hours postdose compared between DFN-15 and placebo in the DB1 treatment period 
with different predose pain grades (Moderate [Grade 2] or Severe [Grade 3]), 
respectively. The proportion of subjects who are pain-free at 15, 30, and 45 minutes 
and 1, 1.5, 2 (DB2 period), 4, and 24 hours postdose will also be compared between 
DFN-15 and placebo: during DB1 treatment period, predose severity = Moderate or 
Severe; during DB2 treatment period, predose severity = Mild, Moderate or Severe.  The 
corresponding p-values from Fisher’s exact test will be computed for the comparison 
between treatment groups.  
Exploratory analysis will also be conducted for the proportion of subjects with their 
predose MBS among nausea, photophobia and phonophobia absent at 15, 30, and 45 
minutes and 1, 1.5, 2, 4, and 24 hours postdose during each DB treatment period. The 
corresponding p-values from Fisher’s exact test will be computed for the comparison 
between treatment groups for the FAS1 and FAS2. A subject’s predose MBS is obtained 
from eDiary. 
8.4. 
SUBGROUP ANALYSES 
Exploratory subgroup analyses on the co-primary endpoints will be conducted using the 
following baseline categories for the FAS1: 
•
Age (18-34 years, 35-49 years, 50-64 and >=65 years)
•
Gender (male and female)
•
Ethnicity (Hispanic and non-Hispanic)
For each subgroup, the odds ratio for response and the 95% CI for the odds ratio for 
each of the co-primary endpoints will be calculated using the treatment group, the 
subgroup variable, and the treatment-by-subgroup interaction term as covariates in the 
logistic regression model. Since the results of these subgroup analyses are exploratory, 
future studies can examine the treatment effect among the subgroup covariates that 
have a significant treatment-by-subgroup interaction term. 
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9.
SAFETY
The SS, SS1, SS2, FAS1, and FAS2 will be used for safety analyses.  Safety will be 
assessed on the basis of AE reports, clinical laboratory data, ECG parameters, physical 
examinations, extent of exposure and compliance with study drug use, rescue 
medication use, concomitant medication use, and vital signs. 
9.1. 
EXTENT OF EXPOSURE AND COMPLIANCE WITH STUDY DRUG 
In this trial, subjects are considered compliant if they treat a migraine attack with 
study drug. Study drug exposure will be summarized by treatment group and overall for 
the SS, SS1, and SS2. By definition of the SS1 and SS2, each subject in those cohorts is 
considered compliant.   
During the DB1 treatment period, subjects are expected to administer one dose of study 
drug within 1 hour of experiencing moderate or severe migraine pain. During the DB2 
treatment period, subjects are expected to take a single dose of study drug to treat 
another attack at any pain level.  
The following will be presented for the SS, SS1, and SS2: 
•
The total number of study drug doses
•
The number of days since randomization in DB1
•
Number (%) of subjects who took at least one dose of study drug
The following will be presented for the SS and SS2: 
•
The number of days between the first dosing dates of DB1 and DB2
All study drug dosing information will be listed. For subjects who enter the DB2 period, 
the number of days between the first dosing dates of the DB1 and DB2 periods will also 
be listed. 
9.2. 
RESCUE MEDICATIONS 
Rescue medications are defined as medications taken to treat a migraine attack (in 
addition to the study drug) 2-24 hours after taking the study drug. Rescue medications 
taken during the study will either be reported in the eCRF based on entries in the 
subject eDiary, or will be reported outside of the eDiary.  All rescue medications will be 
classified using the Anatomical Therapeutic Chemical (ATC) classification and preferred 
drug names from the World Health Organization Drug Dictionary (WHO-DD), version 
March 2016.  
Summaries of rescue medications will be presented for the SS, SS1, and SS2 in tabular 
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form using the highest level ATC term as an upper classification and the preferred drug 
name as a lower classification level. All medications will be summarized by treatment 
group and overall and sorted by descending counts in the upper classification term and 
the lower classification term within the upper. For each subject, the medication will be 
counted only once within the upper classification level and only once within the lower 
classification level. 
The number of rescue medication doses taken will be summarized by treatment group 
and overall for the SS, SS1, and SS2. 
Separate listings will be provided for rescue medications taken during each DB 
treatment period. 
9.3. 
ADVERSE EVENTS 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA; 
version 19.0 or higher). Migraine headaches will not be captured as AEs. Migraine 
headaches will be captured by the subject in the eDiary provided to them, and the 
information will be entered into the appropriate eCRF page. 
All AEs will be listed by subject.  The following listings of AEs will be provided: 
•
All AEs
•
Study-drug related AEs
•
Serious adverse events (SAEs)
•
AEs leading to death
•
Adverse events leading to study-drug termination
Only TEAEs will be included in summary tables. Summaries for AEs will be presented for 
the SS, SS1, and SS2. An overall summary table of TEAEs will be produced for the 
following categories: 
•
Any TEAE
•
Study-drug related TEAEs
•
Serious TEAEs
•
TEAEs leading to study-drug termination
•
TEAEs leading to death
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All TEAEs will be classified by system organ class (SOC) and preferred term (PT). 
Frequency count and the number of unique subjects of a TEAE will be tabulated by 
treatment(s) received. For the number of unique subjects reporting, if a subject 
reported more than one AE that was coded to the same SOC or PT, the subject will be 
counted only once for that specific SOC or PT. 
The following summaries of TEAEs will also be provided: 
•
TEAEs by SOC and PT
•
Study-drug related TEAEs by SOC and PT
•
Serious TEAEs by SOC and PT
•
TEAEs by maximum severity (mild, moderate, severe or missing) by SOC and PT
•
TEAEs by strongest causality relationship (not related, possibly related, probably
related, definitely related or missing) by SOC and PT
For TEAEs presented by relationship to study treatment(s), the strongest relationship to 
study treatment(s) during the study will be presented for each subject if coded to the 
same SOC or PT. For TEAEs presented by severity, the worst severity during the study 
will be presented for each subject if coded to the same SOC or PT. TEAEs with missing 
causality will be counted as related. TEAEs with missing severity will be counted as 
severe. The same will be true in the individual summaries. 
9.4. 
LABORATORY EVALUATIONS 
Abnormal-clinically significant lab results for clinical laboratory categories including 
hematology, clinical chemistry, serology, TSH, urinalysis, as well as results for urine 
drug screens and serum and urine pregnancy tests will be recorded on the eCRF. 
Parameters will be standardized according to the International System of Units (SI) prior 
to summarization. Baseline and post-baseline assessments, as well as the change from 
baseline, will be summarized for hematology, clinical chemistry, and urinalysis using 
descriptive statistics. The overall clinical significance and shift from baseline to end of 
study assessments will be provided in a summary table for hematology, clinical 
chemistry, and urinalysis. Summaries for laboratory evaluations will be presented for 
the SS, SS1, and SS2. Separate listings will be produced for each laboratory test group 
(hematology, clinical chemistry, serology/TSH, urinalysis, urine drug screens, and serum 
and urine pregnancy tests).   
9.5. 
VITAL SIGNS 
Vital signs measurements will include sitting blood pressure (mmHg), pulse rate (bpm), 
oral temperature (Celsius), and menses details. Baseline and post-baseline assessments, 
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as well as the change from baseline, will be summarized for the SS, SS1, and SS2 for 
SBP, DBP, pulse rate, and oral temperature using descriptive statistics.  
All vital signs data will be listed. 
9.6. 
TWELVE-LEAD ECG 
Twelve-lead ECGs will be performed at screening and at every study visit. The overall 
ECG interpretation and shift from baseline to end of study assessments, as well as the 
change from baseline, will be summarized for the SS, SS1, and SS2. 
All ECG findings collected in the CRF will be listed. 
9.7. 
PHYSICAL EXAMINATION 
Abnormal physical examination findings will be listed. 
9.8. 
SUICIDALITY CHECK 
Suicidality check findings collected in the CRF will be listed. 
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10.
INTERIM ANALYSES
No interim analyses are planned for this study. 
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11.
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL
The following are analyses that are not present in the current version of the protocol (V 
2.0, 09MAY2017). 
•
Section 3.2: The modification of this below secondary objective:
o
To assess the proportion of subjects who have sustained pain relief at 2 to 24
hours postdose (i.e., pain relief at 2 hours postdose, with no use of rescue
medication and no worsening of headache pain within 2 to 24 hours postdose).
•
Section 4.2: The modification of this below secondary endpoint:
o
The proportion of subjects who have sustained pain relief at 2 to 24 hours
postdose (i.e., pain relief at 2 hours postdose, with no use of rescue
medication and no worsening of headache pain within 2 to 24 hours postdose)
compared between DFN-15 and placebo.
•
Section 5.3: The modification of Safety Analysis Set definition:
o
The Safety Set (SS) will include all subjects who took at least one dose of DB
study drug during one or both treatment periods, and have it recorded in their
eDiary. Subjects will be analyzed according to the treatment they receive. The
Safety Set 1 (SS1) will include randomized subjects who took at least one dose
of DB study drug during the DB1 treatment period. The Safety Set 2 (SS2) will
include subjects who were re-randomized and took at least one dose of DB
study drug during the DB2 treatment period. The SS, SS1, and SS2 will be used
for all analyses of safety endpoints including summaries of TEAEs, ECGs, and
clinical laboratory results.
• Section 5.4: The modification of Full Analysis Set definition:
o
Each DB treatment period will have a Full Analysis Set (FAS). The Full Analysis
Set 1 (FAS1) will include all randomized subjects who took at least one dose of
study drug during the DB1 treatment period and have at least one post-
baseline efficacy time point assessment for either pain or symptom (among
nausea, photophobia, phonophobia) in DB1. The Full Analysis Set 2 (FAS2) will
include all re-randomized subjects who took at least one dose of study drug
during the DB2 treatment period and have at least one post-baseline efficacy
time point assessment for either pain or symptom (among nausea,
photophobia, phonophobia). Subjects in the DB1 will be analyzed according to
their randomized treatment. Subjects in the DB2 will be analyzed according to
their re-randomized treatment. The FAS1 and FAS2 will be used for all
analyses of efficacy endpoints
• Section 8.1.1: The modification of the co-primary efficacy endpoint analyses:
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o
To test for statistical significance of the co-primary efficacy endpoints, the
closed sequential testing procedure will be utilized. If the first co-primary
endpoint is statistically significant at a two-sided 0.05 level of significance,
the second co-primary endpoint will be tested at a two-sided 0.05 level of
significance. The study must show a significant statistical beneficial
experimental treatment effect for both co-primary endpoints to be
considered statistically successful, controlling the significance level at 0.05.
Since statistical significance with both co-primary endpoints is required to
declare trial success, multiplicity due to multiple primary endpoints is a non-
issue.
o
The first co-primary efficacy endpoint will be analyzed using Fisher’s exact
test. Following the closed sequential procedure, the second co-primary
efficacy endpoint will be analyzed using Fisher’s exact test if the first co-
primary endpoint is statistically significant.
o
The number of subjects with response, the number of subjects with non-
missing assessment, proportions for the DFN-15 and placebo groups, 95%
exact CIs for those proportions, the odds ratio for response, and the
corresponding p-value will be presented for the comparison between two
treatment groups for the FAS1. This analysis will exclude subjects who took
rescue medication prior to the data collection of the 2 hours postdose time
point (inclusive), as well as subjects who have predose pain level = mild
(Grade 1) or none (Grade 0).
o
If the first co-primary efficacy endpoint is statistically significant, results will
be found similarly for the second co-primary efficacy endpoint.
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12.
REFERENCE LIST
1. Headache Classification Committee of the International Headache Society (IHS).
The International Classification of Headache Disorders, 3rd edition (beta
version). Cephalalgia. 2013;33(9):629-808.
2. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of
the Kansas City cardiomyopathy questionnaire: a new health status measure for
heart failure. Journal of the American College of Cardiology. 2000:35(5): 1245-
55.
3. Kimel M, Hsieh R, McCormack J, Burch SP, Revicki DA. Validation of the revised
patient perception of migraine questionnaire (PPMQ-R): measuring satisfaction
with acute migraine treatment in clinical trials. Cephalalgia. 2008:28:510-23.
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13.
PROGRAMMING CONSIDERATIONS
The following conventions are recommended approaches for programming and for TLFs.  
All TLFs and statistical analyses will be generated using SAS® for Windows, Release 9.3 
(SAS® Institute Inc., Cary, NC, USA) or higher. Computer-generated TLFs will adhere to 
the following specifications.   
The layout of the tables should be as consistent as possible, taking into account 
indentation and spacing, and consistency should be maintained within capitalization of 
words in the main title and row and column headers.  Common row titles should be 
checked and the titles should be of a standard layout specifying the table number, title 
and analysis set. Table development should also take into account programming 
efficiency.  
13.1. GENERAL CONSIDERATIONS 
•
A separate SAS program will be created for each output.
•
Each output will be stored in a separate file.
•
Output files will be delivered in Word format.
•
Numbering of TLFs will follow International Conference of Harmonization (ICH) E3
guidance.
13.2. TABLE, LISTING, AND FIGURE FORMAT 
13.2.1. 
General 
•
All TLFs will be produced in landscape format, unless otherwise specified.
•
All TLFs will be produced using the Courier New font, size 8.
•
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides.
•
Headers and footers for figures will be in Courier New font, size 8.
•
Legends will be used for all figures with more than 1 variable, group, or item
displayed.
•
TLFs will be in black and white (no color), unless otherwise specified.
•
Specialized text styles, such as bolding, italics, borders, shading, and superscripted
and subscripted text, will not be used in the TLFs, unless otherwise specified. On
some occasions, superscripts 1, 2, or 3 may be used (see below).
•
Only standard keyboard characters will be used in the TLFs. Special characters, such
as non-printable control characters, printer-specific, or font-specific characters, will
not be used. Hexadecimal-derived characters will be used, where possible, if they
are appropriate to help display math symbols (e.g., μ). Certain subscripts and
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis.
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•
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate.
13.2.2. 
Headers 
•
All output should have the following header at the top left of each page:
Sponsor Name: Dr. Reddy’s Laboratories, Ltd.
Protocol: DFN-15-CD-007 (1007754)
•
All output should have Page n of N at the top right corner of each page. TLFs should
be internally paginated in relation to the total length (i.e., the page number should
appear sequentially as page n of N, where N is the total number of pages in the
table). The following header should appear at the top right of each page:
Page n of N
Status: Draft/Final (Data Extraction Date: DDMMMYYYY)
•
The date output was generated should appear along with the program name as a
footer on each page, as follows:
Program: M:\...\xxx.sas
Date/Time of Generation: DDMMYYYY; Data Source: Listing xxx
13.2.3. 
Display Titles 
•
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1).
ICH E3 numbering is strongly recommended but sponsor preferences should be
obtained prior to final determination (see also template 03.007C “Table of Contents
for Tables Listings and Figures in Statistical Analysis Plan”). A decimal system (x.y
and x.y.z) should be used to identify TLFs with related contents. The title is
centered. The analysis set should be identified on the line immediately following
the title. The title and table designation are single spaced. A solid line spanning the
margins will separate the display titles from the column headers. There will be 1
blank line between the last title and the solid line.
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
FAS Analysis Set 
13.2.4. 
Column Headers 
•
Column headings should be displayed immediately below the solid line described
above in initial upper-case characters.
•
In the case of efficacy tables, the variable (or characteristic) column will be on the
far left followed by the treatment group columns and total column (if applicable).
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P-values may be presented under the total column or in separate p-value column (if
applicable). Within-treatment comparisons may have p-values presented in a row
beneath the summary statistics for that treatment.
•
For numeric variables, include “unit” in column or row heading when appropriate.
•
Analysis set sizes will be presented for each treatment group in the column heading
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for
the descriptive statistics representing the number of subjects in the analysis set.
•
The order of treatments in the tables and listings will be Placebo first in the case of
placebo controlled studies and Active comparators first in the case of active
comparator trials, followed by a total column (if applicable).
13.2.5. 
Body of the Data Display 
13.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
•
alphanumeric values are left-justified;
•
whole numbers (e.g., counts) are right-justified; and
•
numbers containing fractional portions are decimal aligned.
13.2.5.2. Table Conventions 
•
Units will be included where available.
•
If the categories of a parameter are ordered, then all categories between the
maximum and minimum category should be presented in the table, even if n=0 for
all treatment groups in a given category that is between the minimum and maximum
level for that parameter. For example, the frequency distribution for symptom
severity would appear as:
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
•
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation
from the Study, etc.), then only those categories for which there is at least 1
subject represented in 1 or more groups should be included.
•
An Unknown or Missing category should be added to any parameter for which
information is not available for 1 or more subjects.
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•
Unless otherwise specified, the estimated mean and median for a set of values
should be printed out to 1 more significant digit than the original values, and
standard deviations should be printed out to 2 more significant digits than the
original values. The minimum and maximum should report the same significant digits
as the original values. For example, for systolic blood pressure:
N 
 XX 
Mean 
XXX.X
Std Dev 
X.XX
Median 
XXX.X
Minimum 
XXX 
Maximum 
XXX 
•
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to
3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
value should be less than 0.0001 then present as <0.0001. If the p-value is returned
as >0.999 then present as >0.999
•
Percentage values should be printed to one decimal place, in parentheses with no
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to
display values that round down to 0.0.  A common convention is to display as '<0.1',
or as appropriate with additional decimal places. Unless otherwise noted, for all
percentages, the number of subjects in the analysis set for the treatment group who
have an observation will be the denominator. Percentages after zero counts should
not be displayed and percentages equating to 100% should be presented as 100%,
without any decimal places.
•
Tabular display of data for medical history, prior / concomitant medications, and all
tabular displays of adverse event data should be presented by the body system,
treatment class, or SOC with the highest occurrence in the active treatment group
in decreasing order, assuming all terms are coded. Within the body system, drug
class and SOC, medical history (by preferred term), drugs (by ATC1 code), and
adverse events (by preferred term) should be displayed in decreasing order. If
incidence for more than 1 term is identical, they should then be sorted
alphabetically. Missing descriptive statistics or p-values which cannot be estimated
should be reported as “-”.
•
The percentage of subjects is normally calculated as a proportion of the number of
subjects assessed in the relevant treatment group (or overall) for the analysis set
presented. However, careful consideration is required in many instances due to the
complicated nature of selecting the denominator, usually the appropriate number of
subjects exposed. Describe details of this in footnotes or programming notes.
•
For categorical summaries (number and percentage of subjects) where a subject can
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be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
•
Where a category with a subheading (such as system organ class) has to be split over
more than one page, output the subheading followed by “(cont)” at the top of each
subsequent page.  The overall summary statistics for the subheading should only be
output on the first relevant page.
13.2.5.3. Listing Conventions 
•
Listings will be sorted for presentation in order of treatment groups as above,
subject number, visit/collection day, and visit/collection time.
•
Missing data should be represented on subject listings as either a hyphen (“-”) with
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the
footnote “N/A = not applicable”, whichever is appropriate.
•
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing
portions of dates should be represented on subject listings as dashes (--JUL2000).
Dates that are missing because they are not applicable for the subject are output as
“N/A”, unless otherwise specified.
•
All observed time values must be presented using a 24-hour clock HH:MM or
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was
measured as part of the study.
•
Units will be included where available.
13.2.5.4. Figure Conventions 
•
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis
and endpoint (e.g., treatment mean change from Baseline) values will be displayed
on the Y-axis.
13.2.6. 
Footnotes 
•
A solid line spanning the margins will separate the body of the data display from the
footnotes.
•
All footnotes will be left justified with single-line spacing immediately below the
solid line underneath the data display.
•
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3,
etc. if a reference footnote. Each new footnote should start on a new line where
possible.
•
Subject specific footnotes should be avoided, where possible.
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Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
Page 56 of 60 
•
Footnotes will be used sparingly and must add value to the table, figure, or data
listing. If more than six lines of footnotes are planned, then a cover page may be
used to display footnotes, and only those essential to comprehension of the data will
be repeated on each page.
•
The last line of the footnote section will be a standard source line that indicates the
name of the program used to produce the data display, date the program was run,
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’).
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Statistical Analysis Plan 
Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
Page 57 of 60 
14.
QUALITY CONTROL
SAS programs are developed to produce output such as analysis data sets, summary 
tables, data listings, figures or statistical analyses. 
 Standard Operation 
Procedure (SOP) 03.010 and 03.013 provide an overview of the development of such SAS 
programs. 
 SOP 03.009 describes the QC procedures that are performed for all SAS 
programs and output. Quality control is defined here as the operational techniques and 
activities undertaken to verify that the SAS programs produce the output by checking 
for their logic, efficiency and commenting and by review of the produced output.   
For all data sets, tables and listings generated by SAS, 
 will create SAS 
codes independently, and then use SAS PROC COMPARE procedure to perform 100% 
electronic comparison for all numerical and character values. In addition, the Lead 
Biostatistician, Lead Programmer and Senior Statistical Reviewer will review all TLFs for 
consistency and accuracy.  
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Statistical Analysis Plan 
Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
Page 58 of 60 
15.
INDEX OF TABLES
Index of tables can be found in table shells. 
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Statistical Analysis Plan 
Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
Page 59 of 60 
16.
INDEX OF FIGURES
Index of figures can be found in figure shells. 
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Statistical Analysis Plan 
Dr. Reddy’s Laboratories, Ltd. 
Protocol #DFN-15-CD-007 
Amendment V3.0 
 
Page 60 of 60 
17.
INDEX OF LISTINGS
Index of listings can be found in listing shells. 
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