A Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of DFN-02 in Episodic Migraine With or Without Aura
Phase: PHASE2
Conditions: Migraine Headaches
Sponsor: Upsher-Smith Laboratories

Study Protocol 
 
 
 
Official Title of the Study 
 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy and 
 
Safety Study of DFN-02 (Sumatriptan Nasal Spray 10 mg) in Episodic Migraine 
 
With or Without Aura 
 
NCT Number: 
 
 
NCT02856802 
 
Document Date:  
 
 
June 1, 2016 
 
 

16. 
APPENDICES 
 
16.1 
Study Information 
 
16.1.1 
Protocol and Protocol Amendments 
 
Clinical Study Protocol DFN-02-CD-012 version 1.0 dated 01 June 2016 
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CONFIDENTIAL 
 
CLINICAL STUDY PROTOCOL 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Efficacy and Safety Study of DFN-02 (Sumatriptan Nasal Spray 
10 mg) in Episodic Migraine With or Without Aura 
Protocol Number: 
DFN-02-CD-012 
Study Medication/ 
Investigational Product: 
DFN-02  
IND Number: 
108,088 
Phase: 
2 
Indication: 
Episodic Migraine With or Without Aura in Adults 
Sponsor: 
Dr. Reddy’s Laboratories Ltd. 
 
 
Sponsor Agent: 
Dr. Reddy’s Laboratories Inc. 
 
 
Protocol Date: 
01 June 2016 
Protocol Version: 
Version 1.0 
 
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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1 Protocol Synopsis 
Protocol Number: 
DFN-02-CD-012 
 
 
Title: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Efficacy and Safety Study of DFN-02 (Sumatriptan Nasal 
Spray 10 mg) in Episodic Migraine With or Without Aura 
 
 
Study Medication/ 
Investigational Product: 
DFN-02 
 
 
Country: 
United States of America 
 
 
Phase: 
2 
 
 
Objectives: 
 
Primary Objective: 
To assess the proportion of patients who are pain-free at 
2 hours postdose (first double-blind [DB1] treatment period) 
 
 
Secondary Objectives 
 
To assess the proportion of patients who are pain-free at 
2 hours postdose (second double-blind [DB2] treatment 
period) 
 
(Each Double-Blind [DB] Period) 
• 
To assess the proportion of patients who are pain-free at 
10, 15, 20, 30, 60, and 90 minutes postdose 
• 
To assess the proportion of patients who have pain relief 
at 10, 15, 20, 30, 60, 90, and 120 minutes postdose 
• 
To assess the proportion of patients with their most 
bothersome 
symptom 
(MBS) 
among 
nausea, 
photophobia, and phonophobia, absent at 10, 15, 20, 30, 
60, 90, and 120 minutes postdose 
• 
To assess the proportion of patients who are free from 
nausea, photophobia, and phonophobia at each postdose 
time point 
• 
To assess time to meaningful pain relief 
• 
To assess time to pain freedom  
• 
 
 
  
• 
To assess the proportion of patients who have sustained 
pain freedom at 24 hours (2 to 24 hours) postdose 
(i.e., pain-free at 2 hours postdose, with no use of rescue 
medication or additional study medication and no 
recurrence of headache pain within 2 to 24 hours 
postdose) 
• 
To assess change in functional disability score at 2 hours 
and 24 hours postdose  
• 
To assess the proportion of patients who use a second 
dose of the study medication or rescue medication after 
2 hours (2 to 24 hours) postdose  
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• 
To assess treatment satisfaction at 2 hours postdose 
(7-point scale)  
• 
To assess treatment satisfaction as measured by Patient 
Perception of Migraine Questionnaire-Revised (PPMQ-R) 
at 24 hours postdose  
• 
Tolerability as assessed by adverse events (AEs) (also 
overall) 
• 
Safety as assessed by clinical laboratory tests, vital signs 
and electrocardiogram (ECG) (also overall) 
 
 
Exploratory Objectives  
(Each DB Period): 
• 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Patients: 
Approximately 100 patients will be randomized. Patients who 
discontinue study participation prior to completing the study 
will not be replaced. 
 
 
Study Design: 
This is a randomized, 2 DB treatment period dosing study, to 
be conducted at multiple centers in the United States. 
Previously diagnosed patients with a history of episodic 
migraine (as defined by International Classification of 
Headache Disorders, 3rd edition [beta version]1 [ICHD-3]), 
who experience an average of 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 headaches, will be 
randomized in a 1:1 ratio in both DB periods to receive either 
DFN-02 (sumatriptan nasal spray) 10 mg or a matching 
placebo.  
There will be a screening period to evaluate whether the 
patient fits the migraine inclusion criteria and does not have 
medication overuse. Patients with at least a 12-month 
medical history of acute migraine will be eligible for 
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enrollment in the treatment period. Patients will continue to 
take their normal migraine medication during this screening 
period.  
Randomized patients will be instructed to use the study 
medication in 1 migraine attack as soon as (and no more than 
within 1 hour after) experiencing moderate to severe pain 
(defined as headache pain rating of Grade 2 [moderate] or 
Grade 3 [severe] on pain severity scale of 0 to 3). Patients will 
return to the study site within 2 to 7 days in the DB1 treatment 
period and, if continuing to be eligible, will be re-randomized 
into a DB2 treatment period to receive either DFN-02 
(sumatriptan nasal spray) 10 mg or a matching placebo to 
treat 1 migraine attack at any pain level. They will then return 
to the study site within 2 to 7 days of their second treatment 
for study completion assessments. Once randomized, the 
total duration of each patient’s participation in the study would 
be up to 10 weeks. 
After using the first dose of study medication in their migraine 
attack, patients will have the option to take another dose of 
study medication for the same attack if they experience relief 
but feel it is insufficient, or, if required, take rescue medication 
more than 2 hours after the first dose and after completing in 
the electronic diary (eDiary) 
the 2 hours postdose 
assessments. No more than 2 doses of study medication will 
be taken in a 24-hour period. Rescue medication will be 
decided between the Investigator and the patient. 
During both treatment periods, data regarding the study 
medication effect on pain and symptoms and the associated 
impact on function and the patient’s satisfaction with the study 
medication will be collected. Patients will record criteria in 
real-time in an 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 medication 
use, postdose pain level, symptoms and functional disability, 
treatment satisfaction, and date and time of rescue 
medication. The eDiary will be reviewed for compliance and 
rescue medication. Data will be entered into the electronic 
case report form (eCRF). After study completion or early 
termination, patients should be referred to their usual 
healthcare professional to resume pre-study standard of care, 
as per the Investigator discretion. 
 
 
Treatment: 
For the DB1 treatment period, all patients will be randomly 
assigned in a 1:1 ratio to receive either DFN-02 10 mg or a 
matching placebo to be used in 1 migraine attack as soon as 
(and no more than within 1 hour after) experiencing moderate 
to severe pain. Eligible patients will then be re-randomized in 
a 1:1 ratio into the DB2 period to receive either DFN-02 
10 mg or a matching placebo to treat another migraine attack 
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at any pain level. In each treated migraine attack, study 
medication may be repeated once (if needed), more than 2 
hours after the initial dose and after completing in the eDiary 
the 2 hours postdose assessments. 
 
 
Study Duration: 
The duration of study participation will be up to approximately 
13 weeks, including a screening period of approximately 
3 weeks (wherein patients may be randomized earlier than 3 
weeks provided 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 (each period) for patients to 
experience and treat migraine attacks, and 2 to 7 days for 
patients to return to the site after treatment. The 2 DB 
treatment periods combined would total up to 10 weeks. 
 
 
Study Population: 
Male and female patients 18 to 75 years of age, inclusive, 
previously diagnosed with ICHD-3 episodic migraine 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 at least 48 hours of headache-free time 
between migraine headaches, will be included. Migraines can 
be with or without aura, but the aura cannot last longer than 
60 minutes. 
Patients with medication overuse, patients who use 
mini-prophylaxis for menstrual migraine, patients who have 
been on unstable doses of migraine prophylactic medications 
30 days prior to and through screening, and patients with 
migralepsy will be excluded. See inclusion and exclusion 
criteria for additional study entry requirements. 
 
 
Primary Efficacy Endpoint 
(DB1 period): 
Proportion of patients who are pain-free at 2 hours after the 
first dose of study medication compared between DFN-02 
and placebo (defined as a reduction from predose moderate 
[Grade 2] or severe [Grade 3] pain to none [Grade 0])  
 
 
Secondary Endpoints: 
Proportion of patients who are pain-free at 2 hours after the 
first dose of study medication compared between DFN-02 
and placebo (any pain level) (DB2 period) 
 
(Each DB Period): 
• 
Proportion of patients who are pain-free at 10, 15, 20, 30, 
60, and 90 minutes postdose 
• 
Proportion of patients who have pain relief at 10, 15, 20, 
30, 60, 90 and 120 minutes postdose 
• 
Proportion of patients with their MBS among nausea, 
photophobia, and phonophobia, absent at 10, 15, 20, 30, 
60, 90, and 120 minutes postdose  
• 
Proportion of patients who are free from nausea, 
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photophobia, and phonophobia at each postdose time 
point 
• 
Time to meaningful pain relief 
• 
Time to pain freedom  
• 
 
 
 
• 
Proportion of patients who have sustained pain freedom 
at 24 hours (2 to 24 hours) postdose (i.e., pain-free at 
2 hours postdose, with no use of rescue medication or 
additional study medication and no recurrence of 
headache pain within 2 to 24 hours postdose) 
• 
Change in functional disability score at 2 hours and 
24 hours postdose  
• 
Proportion of patients who use a second dose of the study 
medication or rescue medication after 2 hours (2 to 
24 hours) postdose  
• 
Treatment satisfaction at 2 hours postdose (7-point scale)  
• 
Treatment satisfaction as measured by PPMQ-R at 24 
hours postdose  
• 
Tolerability as assessed by AEs (also overall) 
• 
Safety as assessed by clinical laboratory tests, vital signs 
and ECG (also overall) 
 
 
Exploratory Endpoints: 
(Each DB Period): 
• 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety: 
• 
Physical examinations, including weight and height 
measurement 
• 
Serum/urine pregnancy test for female patients of 
childbearing potential 
• 
Clinical laboratory evaluation, including hematology, 
clinical chemistry, and urinalysis 
• 
Vital sign measurements (sitting systolic and diastolic 
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blood pressure, pulse rate, and body temperature) 
• 
Recording of 12-lead ECGs 
• 
AEs 
• 
Concomitant medication review 
 
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2 Table of Contents 
1 
Protocol Synopsis ................................................................................................. 3 
2 
Table of Contents .................................................................................................. 9 
3 
List of Abbreviations ........................................................................................... 13 
4 
Introduction ......................................................................................................... 15 
5 
Study Objectives ................................................................................................. 17 
5.1 
Primary Objective ................................................................................................ 17 
5.2 
Secondary Objectives ......................................................................................... 17 
5.3 
Exploratory Objectives (Each DB Period) .......................................................... 17 
6 
Investigational Plan ............................................................................................. 18 
6.1 
Overall Study Design and Plan ........................................................................... 18 
6.2 
Discussion of Study Design ............................................................................... 19 
7 
Selection of Patients and Criteria for Withdrawal ............................................. 19 
7.1 
Number of Planned Patients ............................................................................... 19 
7.2 
Inclusion Criteria ................................................................................................. 20 
7.3 
Exclusion Criteria ................................................................................................ 20 
7.3.1 
Additional Exclusion Criteria .................................................................. 22 
7.4 
Removal of Patients from Therapy or Assessments ........................................ 23 
8 
Investigational Products ..................................................................................... 23 
8.1 
Investigational Products Administered ............................................................. 23 
8.2 
Identity of Investigational Products ................................................................... 24 
8.3 
Storage, Packaging, and Labeling ..................................................................... 24 
9 
Administration of Study Treatments .................................................................. 25 
9.1 
Method of Assigning Patients to Treatment Groups ........................................ 25 
9.1.1 
Screening (Visit 1) ................................................................................. 25 
9.1.2 
Randomization (Visit 2) ......................................................................... 25 
9.2 
Selection of Doses in the Study ......................................................................... 25 
9.3 
Selection and Timing of Dose for Each Patient ................................................. 26 
9.4 
Blinding ................................................................................................................ 26 
9.5 
Prior and Concomitant Therapy ......................................................................... 26 
9.5.1 
Medication History ................................................................................ 26 
9.5.2 
Rescue Medication ............................................................................... 27 
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9.5.3 
Prohibited and Allowed Medications ...................................................... 27 
9.6 
Treatment Compliance ........................................................................................ 28 
10 
Study Procedures ................................................................................................ 28 
10.1 Duration of Treatment ......................................................................................... 28 
10.1.1 
Data Recording Using eDiary ................................................................ 28 
10.2 Study Assessments ............................................................................................ 29 
10.2.1 
Visit Procedures .................................................................................... 34 
10.2.2 
Efficacy Assessments ........................................................................... 37 
10.2.3 
Safety Assessments.............................................................................. 37 
10.2.4 
Appropriateness of Measurements ........................................................ 45 
11 
Statistical Methods .............................................................................................. 45 
11.1 Statistical Analysis Plan ..................................................................................... 45 
11.2 Analysis Datasets or Populations ...................................................................... 46 
11.3 Demographic and Other Baseline Characteristics ............................................ 46 
11.4 Efficacy Endpoints .............................................................................................. 47 
11.4.1 
Primary Efficacy Endpoint ..................................................................... 47 
11.4.2 
Secondary Efficacy Endpoints ............................................................... 47 
11.4.3 
Exploratory Endpoints ........................................................................... 48 
11.5 Safety Endpoints ................................................................................................. 48 
11.6 Methods of Analysis............................................................................................ 48 
11.6.1 
Primary Efficacy Analysis ...................................................................... 48 
11.6.2 
Secondary Efficacy Analysis ................................................................. 49 
11.6.3 
Exploratory Efficacy Analysis ................................................................ 49 
11.6.4 
Subgroup Analysis ................................................................................ 49 
11.6.5 
Additional Efficacy Analyses ................................................................. 49 
11.6.6 
Safety Analysis ..................................................................................... 49 
11.7 Interim Analyses .................................................................................................. 50 
11.8 Determination of Sample Size ............................................................................ 50 
12 
Quality Assurance and Quality Control ............................................................. 50 
12.1.1 
Audit and Inspection ............................................................................. 50 
12.1.2 
Monitoring ............................................................................................. 51 
12.1.3 
Data Management and Coding ............................................................. 51 
13 
Records and Supplies ......................................................................................... 52 
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13.1 Drug Accountability ............................................................................................ 52 
13.2 Financing and Insurance .................................................................................... 52 
14 
Ethics ................................................................................................................... 52 
14.1 Institutional Review Board ................................................................................. 52 
14.2 Ethical Conduct of the Study .............................................................................. 53 
14.3 Patient Information and Consent ....................................................................... 53 
14.4 Patient Confidentiality ......................................................................................... 53 
15 
Reporting and Publication, Including Archiving ............................................... 54 
16 
References ........................................................................................................... 55 
17 
Investigator Signature Page ............................................................................... 58 
 
 
 
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2.1 
List of In-Text Figures 
Figure 6-1 
Trial Design ........................................................................................... 19 
 
 
2.2 
List of In-Text Tables 
Table 8-1 
Investigational Product Details for Study Treatments ............................ 24 
Table 10-1 
Schedule of Assessments ..................................................................... 30 
Table 10-2 
eDiary Assessments ............................................................................. 33 
 
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3 List of Abbreviations 
5-HT 
5-hydroxy-tryptamine 
ADD 
attention deficit disorder 
ADHD 
attention deficit hyperactivity disorder 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
CAD 
coronary artery disease 
cGCP 
current Good Clinical Practice 
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 
Food and Drug Administration 
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 Conference on Harmonisation 
ICHD-3 
International Classification of Headache Disorders, 3rd edition 
(beta version) 
ID 
identification 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
LOCF 
last observation carried forward 
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MAO-A 
monoamine oxidase-A 
MBS 
most bothersome symptom 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOH 
medication overuse headaches 
NSAID 
nonsteroidal anti-inflammatory drug 
PK 
pharmacokinetic 
PP 
per-protocol 
PPMQ-R 
Patient Perception of Migraine Questionnaire-Revised 
PT 
preferred term 
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 
THC 
tetrahydrocannabinoids 
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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4 Introduction 
Migraine headache is a disabling neurological disorder with clinical findings of headache, 
often associated with nausea, photophobia, and phonophobia. In the United States (US), 
about 17% of all women and 6% of all men suffer from migraine.2  
Although the exact mechanism of migraine headache is not known, the pathophysiology is 
related to alteration in the neurochemical balance of the brain to trigeminal-vascular 
activation and release of vasoactive peptides. Radiological investigations in migraine 
patients are characterized by hyperexcitation of neuronal networks in the occipital lobe of the 
cortex, the brainstem, and the trigeminal nerve ganglion.3,4 
Clinically, migraine with aura occurs in 5 phases: prodrome, aura, headache, resolution, and 
postheadache. The prodrome phase is associated with nonspecific symptoms such as 
fatigue, muscle pain in the neck and head, cognitive impairment, anxiety, and irritability. 
Auras are focal neurological changes typically of a visual or somatosensory nature, lasting 
less than 60 minutes. Auras are considered to occur as the result of electrical disturbances 
in the brain. Auras occur in approximately 15% of migraine attacks. The headache phase 
can be divided into mild, moderate, and severe phases. The mild phase is the period of time 
from headache awareness to the onset of moderate pain.
 
 
In general, the headache phase lasts 4 to 72 hours. The postheadache phase 
lasts up to 48 hours and is characterized with symptoms similar to those of the prodrome.5,6 
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 severe and more resistant to 
treatment.7 
Several therapies such as triptans, ergot alkaloids, nonsteroidal anti-inflammatory drugs 
(NSAIDs), aspirin and caffeine combinations, and/or opioids are used by physicians for the 
treatment of acute migraine. Migraine-specific therapies, such as triptans or ergot alkaloids, 
have become the treatment of choice when patients respond poorly to NSAIDs or 
combination regimens of aspirin and caffeine. For most migraine sufferers, triptans are the 
drug class of choice both from efficacy and tolerability perspectives.8  
Sumatriptan, a 5-hydroxy-tryptamine (5-HT)1B/1D receptor agonist developed by 
GlaxoSmithKline, is marketed under the brand name of Imitrex®. Sumatriptan is one of the 
most commonly used triptans for the treatment of acute migraine headache. Oral, intranasal, 
and subcutaneous injectable formulations of sumatriptan are approved by the US Food and 
Drug Administration (FDA) and are available on the market. The relative bioavailability for 
Imitrex following subcutaneous administration is significantly higher compared to intranasal 
or oral administration.9-11 The therapeutic response rate at 2 hours is dependent upon the 
mode of administration—subcutaneous 70%, oral 59%, and intranasal 61%.12  
The onset of action with subcutaneous sumatriptan (10 minutes) is faster than with 
intranasal (30 to 45 minutes) or oral (45 to 60 minutes) delivery.9,10,13,14 The intranasal route 
of delivery for sumatriptan can be preferable compared to the oral or subcutaneous routes 
due to the slow rate of absorption of the oral form and invasiveness of self-injection. 
However, even with sumatriptan nasal spray, the issue of a relatively slow rate of absorption 
and lower bioavailability remains.9 
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Dr. Reddy’s has developed a nasal formulation of DFN-02 composed of sumatriptan and 
 a permeation enhancer. The safety and 
effectiveness of sumatriptan have been well established.9,10 
 is a permeation-enhancing 
excipient that belongs to a class of nonionic surfactants classified as alkylglycosides, which 
consists of alkyl chains of various lengths linked to a sugar moiety, have been studied for 
their ability to promote increased bioavailability of drugs via the nasal, oral, and ocular 
routes.15 The mechanisms by which alkylglycosides exert their permeation-enhancing effects 
on the nasal epithelium in vivo are unclear. The permeation enhancement properties of 
 
have been characterized for several therapeutic compounds in development and have been 
discussed in a number of journal publications15-21 (
 drug master file, reference data on 
file). 
 
 
 
 
 
 
 
 
One pivotal Phase 1 study (DFP-02-CD-009)26 and four pilot Phase 1 studies 
(DFP-02-CD-008,22 2419/11,23 1931/09,24 and 2010/1025) have been conducted in a total of 
154 healthy adult male and female volunteers at a dose range of 5 mg to 20 mg. DFN-02 
was generally well-tolerated without any clinically meaningful changes in laboratory 
parameters or vital signs. 
Overall, the pharmacokinetic (PK) data suggest that sumatriptan achieved peak plasma 
concentration rapidly at approximately 10 minutes following 10 mg DFP-02 intranasal spray, 
approximately 5 minutes sooner than that of the 4 mg and 6 mg Imitrex injections. This 
profile may lead to improved onset of therapeutic benefit for patients suffering from migraine 
headaches. 
In addition, in one Phase 3 open-label clinical safety study (DFP-02-CD-010),27 167 patients 
used DFN-02 (studied as DFP-02) to treat migraine attacks for up to 6 months. Overall, 
4 patients experienced 5 serious adverse events (SAEs). Three of the SAEs were 
treatment-emergent (one subject each; diverticulitis, pyelonephritis and menometrorrhagia), 
and all 5 SAEs were considered by the Investigator to be not related to study medication. No 
new safety results were noted; the study results are currently being summarized and will be 
reported in the next version of the Investigator’s Brochure. 
In summary, DFN-02 is being developed for the treatment of acute migraine headaches with 
and without aura. Nonclinical and clinical studies to date have demonstrated acceptable 
tolerability, as well as a favorable PK profile, to allow further characterization in terms of 
safety tolerability and efficacy. 
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5 Study Objectives 
5.1 
Primary Objective 
The primary objective of the study is to assess the proportion of patients who are pain-free at 
2 hours postdose (first double-blind [DB1] treatment period). 
5.2 
Secondary Objectives 
The secondary objectives of the study are to assess the proportion of patients who are pain-
free at 2 hours postdose (second double-blind [DB2] treatment period) 
(Each Double-Blind [DB] Period) 
• 
To assess the proportion of patients who are pain-free at 10, 15, 20, 30, 60, and 
90 minutes postdose  
• 
To assess the proportion of patients who have pain relief at 10, 15, 20, 30, 60, 90, and 
120 minutes postdose 
• 
To assess the proportion of patients with their most bothersome symptom (MBS) among 
nausea, photophobia, and phonophobia, absent at 10, 15, 20, 30, 60, 90, and 120 
minutes postdose 
• 
To assess the proportion of patients who are free from nausea, photophobia, and 
phonophobia at each postdose time point  
• 
To assess time to meaningful pain relief 
• 
To assess time to pain freedom 
• 
 
• 
To assess the proportion of patients who have sustained pain freedom at 24 hours (2 to 
24 hours) postdose (i.e., pain-free at 2 hours postdose, with no use of rescue medication 
or additional study medication and no recurrence of headache pain within 2 to 24 hours 
postdose) 
• 
To assess change in functional disability score at 2 hours and 24 hours postdose  
• 
To assess the proportion of patients who use a second dose of the study medication or 
rescue medication after 2 hours (2 to 24 hours) postdose  
• 
To assess treatment satisfaction at 2 hours postdose (7-point scale) 
• 
To assess treatment satisfaction as measured by Patient Perception of Migraine 
Questionnaire-Revised (PPMQ-R) at 24 hours postdose  
• 
Tolerability as assessed by adverse events (AEs) (also overall) 
• 
Safety as assessed by clinical laboratory tests, vital signs, and electrocardiogram (ECG) 
(also overall) 
 
5.3 
Exploratory Objectives (Each DB Period) 
The exploratory objectives for each treatment period include: 
• 
 
 
 
 
  
 
 
 
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• 
 
 
 
 
 
 
 
 
6 Investigational Plan 
6.1 
Overall Study Design and Plan 
This is a randomized, 2 DB treatment period dosing study, to be conducted at multiple 
centers in the US. Previously diagnosed patients with a history of episodic migraine (as 
defined by International Classification of Headache Disorders, 3rd edition [beta version]1 
[ICHD-3]), who experience an average of 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, will be randomized in a 1:1 ratio in both DB periods to 
receive either DFN-02 (sumatriptan nasal spray) 10 mg or a matching placebo. 
There will be a screening period to evaluate whether the patient fits the migraine inclusion 
criteria pursuant to ICHD-3, and does not have medication overuse. Patients with at least a 
12-month medical history of acute migraine will be eligible for enrollment in the treatment 
period. Patients will continue to take their normal migraine medication during this screening 
period. 
During the screening period, the electronic diary (eDiary) will be dispensed in order for the 
patient to enter information for daily check-in, record at least 1 migraine attack, and rescue 
medication use, to determine the patient’s ability to properly use the eDiary. If eligible and 
randomized, patients in the DB1 treatment period will be instructed to use the study 
medication in 1 migraine attack as soon as (and no more than within 1 hour after) 
experiencing moderate to severe migraine pain (defined as headache pain rating of Grade 2 
[moderate] or Grade 3 [severe] on a pain severity scale of 0 to 3). If the patient is not able to 
use study medication for the first migraine after randomization, they should be instructed to 
use the study medication for the next attack. Those patients who do not experience a 
migraine attack, and/or who do not treat any migraine attack with study medication or record 
eDiary data, will not be allowed to continue into the DB2 treatment period, and will be 
discontinued. After treating a migraine attack with study medication, patients should be 
instructed to contact the site within 24 hours of the treated migraine (or the next working day) 
to schedule their next visit. 
Patients will return to the study site within 2 to 7 days in the DB1 treatment period and, if 
continuing to be eligible, will be re-randomized into a DB2 treatment period to treat 
1 migraine attack at any pain level. They will then return to the study site within 2 to 7 days 
of the second treatment. Once randomized, the total duration of each patient’s participation 
in the study would be up to 10 weeks.  
If after taking the first dose of study medication a patient does not experience sufficient relief, 
he/she may take a second dose of study medication for the same attack, or take rescue 
medication more than 2 hours after taking the first dose of study medication, and only after 
completing in the eDiary the 2 hours postdose assessment. If a patient does not experience 
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any relief at all from the first dose of study medication after 2 hours, he/she should not take a 
second dose, but may take rescue medication instead, if needed. Rescue medication will be 
decided between the Investigator and the patient. No more than 2 doses of study medication 
will be taken in a 24-hour period. 
During both DB treatment periods, data regarding the migraine attack, study medication 
effect and the associated impact on migraine pain, symptoms, function, rescue medication, 
and the patient’s satisfaction will be collected by the patient in real-time in an eDiary. See 
Section 10.2.1.4.1 for eDiary assessment criteria. The eDiary will be reviewed for 
compliance and rescue medication, and data will be entered into the electronic case report 
form (eCRF). After study completion or discontinuation, patients should be referred to their 
usual healthcare professional to resume pre-study standard of care, as per the Investigator 
discretion.  
Figure 6-1 Trial Design  
 
6.2 
Discussion of Study Design 
The current study design was chosen to determine the efficacy of DFN-02 for the treatment 
of acute migraine pain. A screening period will allow sufficient time for screening laboratory 
test results availability and verification that patients meet the inclusion and exclusion criteria. 
Patients will be randomized in a blinded fashion to receive DFN-02 or placebo and 
self-administer when experiencing a migraine attack to determine whether DFN-02 can 
relieve migraine pain, and symptoms and disability compared with placebo. For the first 
treated acute migraine attack (DB1 treatment period), patients will treat moderate or severe 
pain to meet regulatory requirements for efficacy determination; for the second attack (DB2 
period), patients will treat migraine at any pain level to determine if efficacy is achieved 
throughout the pain level range. Patients are allowed to use a second dose of study 
medication or take rescue medication more than 2 hours after taking the first dose of study 
medication in the attack, as described in Section 6.1 and Section 9.5.2, to optimize patient 
comfort while supporting clinically relevant data collection. 
7 Selection of Patients and Criteria for Withdrawal 
7.1 
Number of Planned Patients  
Approximately 100 patients will be randomized into the study. Patients who do not qualify for 
enrollment after the screening period will be terminated as screen failures and will be 
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replaced. Randomized patients who discontinue study participation prior to study completion 
will not be replaced. 
7.2 
Inclusion Criteria 
Patients 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  
Note: If female and of childbearing potential (not surgically sterile or ≤ 1 year 
after the onset of amenorrhea due to menopause), the patient must (a) have a 
negative serum pregnancy test at screening and a negative urine test at V2, (b) 
not be lactating, and (c) agree to practice a reliable form of contraception or 
abstinence during the study. Acceptable forms of contraception include implants, 
injectable contraceptives, combined oral contraceptives, an intrauterine device, a 
vasectomized partner, and double-barrier methods. 
Note: If male (with female partner), the patient must agree to practice a reliable 
form of contraception or abstinence during the study. 
3. 
A history of episodic migraine (as defined by ICHD-3), who experience an 
average of 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 headaches 
4. 
Patients who have migraine with or without aura. If migraine with aura, the aura 
cannot last longer than 60 minutes. 
5. 
Patients who, in the opinion of the Investigator, are willing and able to: 
a. Evaluate and record pain, migraine symptoms, and study medication 
effectiveness information in real-time using an eDiary for the duration of the 
study; 
b. Record each instance of the use of study medication and rescue 
medication in a patient eDiary in real-time for the duration of the study; 
c. Comply with all other study procedures and scheduling requirements. 
6.  Patients who can use the nasal spray device correctly after instruction 
 
7.3 
Exclusion Criteria 
Patients 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. 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 (only applies if combination medication contains an 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 
3. Prior exposure to DFN-02 (or DFP-02) 
4. Treated with onabotulinumtoxinA (Botox®) or other botulinum toxin treatment within 
4 months prior to screening for migraine prophylaxis (patients who were treated with 
same for cosmetic purposes may be allowed on a case-by-case basis after approval 
from the Medical Monitor) 
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5. On unstable dosages of migraine prophylactic medications within 30 days prior to 
and through screening 
6. Taking mini-prophylaxis for menstrual migraine 
7. Patients with hemiplegic migraine, or other forms of neurologically complicated 
migraine 
8. Patients who have prolonged aura (i.e., more than 1 hour) 
9. A history of stroke or transient ischemic attack 
10. A history of migralepsy (seizure following a migraine) or a concurrent diagnosis of 
seizure disorder 
11. Patients who cannot differentiate between a migraine headache and tension-type or 
cluster headache 
12. A history of more than occasional tension-type headache (based on Investigator 
judgment) 
13. A history of cluster headaches 
14. Known intolerance to sumatriptan (any formulation), or who have experienced a 
significant AE related to any triptan medication, including sumatriptan 
15. Non-responsiveness to subcutaneous sumatriptan (≤ 6 mg dosage), in the opinion of 
the Investigator 
16. Prior ischemic coronary artery disease (CAD): angina pectoris, history of myocardial 
infarction or documented silent ischemia or coronary artery vasospasm, including 
Prinzmetal’s angina 
17. Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac 
accessory conduction pathway disorders 
18. Uncontrolled hypertension or systolic blood pressure (SBP) > 140 mmHg or diastolic 
blood pressure (DBP) > 90 mmHg (the values should be reconfirmed to rule out a 
transient fluctuation; see Section 7.3.1 for details  
19. Peripheral vascular disease or ischemic bowel disease 
20. Patients using monoamine oxidase-A (MAO-A) inhibitor that cannot be completely 
washed out (at least 15 days) 
21. Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake 
inhibitors (SNRIs), tricyclic antidepressants, and steroids for chronic conditions, 
unless the dose is stable for at least 3 months prior to randomization and is not 
expected to change during the study 
22. Known intolerance to nasal sprays 
23. Patients taking any medications or with illnesses likely to affect the physiology of the 
nasal mucosa (i.e., patients with colds [upper respiratory infections], influenza, nasal 
septum surgery, or chronic nasal rhinitis) 
24. Any abnormal nasal physiology or pathology, or any other abnormal physiology 
and/or pathology that, in the opinion of the Investigator, would not allow the 
objectives of the study to be accomplished 
25. Acute sinusitis. Patients may be rescreened 7 days after resolution of acute sinusitis 
infection/symptoms with no complaints of headache pain and if, in the opinion of the 
Investigator, it will not interfere with accomplishing the objectives of the study 
26. Chronic sinusitis 
27. Severe renal impairment (defined as creatinine > 1.5 × the upper limit of normal 
[ULN]) 
28. Serum total bilirubin > 1.5 × ULN  
29. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), or 
alkaline phosphatase > 2.5 × ULN 
30. Patients with uncontrolled diabetes mellitus, or a glycosylated hemoglobin (HbA1c) 
> 7.9%, or with diabetes mellitus requiring insulin 
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31. A history of alcohol or substance abuse (including marijuana) within 1 year that would 
compromise data collection 
32. A positive urine drug screen for recreational drugs, alcohol, marijuana (whether legal 
or not), or for prescription drugs not explained by stated concomitant medications: 
a. Patients 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 headaches (MOH) criteria.  
b. Benzodiazepines are allowed if used for legitimate medical reasons. 
c. 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) 
33. A history of or current neurological or psychiatric impairment, or cognitive dysfunction 
that, in the opinion of the Investigator, would compromise data collection 
34. Use of antipsychotics at least 15 days prior to randomization (if used for non-
psychiatric conditions, should be evaluated on a case-by-case basis with the Medical 
Monitor) 
35. Patients who received treatment with an investigational drug or device within 30 days 
prior to randomization, or within 3 months if associated with central nervous system 
36. Patients who participated in a central nervous system clinical trial within 3 months 
prior to randomization 
37. Patients who test positive for human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg), or hepatitis C virus (HCV) antibody serology testing 
38. Patients with any other medical condition that, in the judgment of the Investigator or 
Medical Monitor, would confound the objectives of the study (e.g., clinically significant 
abnormal thyroid-stimulating hormone [TSH] levels, cancer history** [except basal 
cell carcinoma], systemic lupus erythematosis). **Exceptions to be made if the 
Investigator believes, with Sponsor approval, that the current status will not interfere 
with primary objectives 
39. Patients who are employees or immediate relatives of the employees of the Sponsor, 
any of its affiliates or partners, or of the clinical study research site 
 
7.3.1 Additional Exclusion Criteria 
Patients 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. 
Patients 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 patient has a sustained resting SBP > 140 mmHg and/or 
DBP > 90 mmHg at Visit 1 (V1) or Visit 2 (V2), those patients should be excluded. Any 
patient without a known history of hypertension that presents at screening with SBP > 140 
mmHg and/or DBP > 90 mmHg should be excluded 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 patient in a semi-reclined position in a 
quiet room. Patients with persistent elevations, despite repeat assessments, should be 
excluded and referred to an appropriate healthcare provider for further assessment.  
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7.4 
Removal of Patients from Therapy or Assessments 
Patients 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 patient 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.  
Patients 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 eCRF: 
1. 
A patient develops any significant illness, or needs to undergo any acute major 
surgery, during the course of the study. 
2. 
A patient was enrolled and observed to violate any protocol requirement that 
may affect the outcome of the study. 
3. 
A patient withdraws consent. 
4. 
The Investigator deems it may not be safe or proper for the patient to continue in 
the study. 
 
A patient who becomes pregnant at any time during the study must be discontinued. 
Patients prematurely withdrawing from the study after entering the treatment period will be 
encouraged to complete the early termination (V4/ET) evaluations according to this protocol. 
In the event that a patient discontinues prematurely from the study due to a treatment-
emergent adverse event (TEAE) or serious TEAE, the TEAE or serious TEAE will be 
followed until it resolves (returns to normal or baseline values) or stabilizes, or until it is 
judged by the Investigator to be no longer clinically significant. 
Once a patient is withdrawn, they may not re-enter the study. 
Reasonable efforts will be made to contact patients who are lost to follow-up. At a minimum, 
2 attempts by telephone contact and a certified letter should be sent. These attempts to 
contact must be documented in the patient’s file.  
The Sponsor has the right to terminate the study at any time in the event of SAEs, or if 
special circumstances occur relating to the study medication that the Sponsor deems 
unfeasible to continue the study. In this event, the Investigators will be informed of the 
reason for study termination. 
8 Investigational Products 
8.1 
Investigational Products Administered 
DFN-02 and placebo (undistinguishable from DFN-02) will be provided in a single-use nasal 
spray device calibrated to deliver 100 μL spray. Refer to the Instructions for Use document 
for handling instructions and proper usage of the delivery device to administer the dose of 
DFN-02. Details of study treatment information are provided in Table 8-1. 
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Table 8-1 
Investigational Product Details for Study Treatments 
 
Preparations to be Administered 
Product Code 
DFN-02 
Placebo 
 
Manufacturer 
 
 
 
Dose 
10 mg 
-- 
 
Route 
Nasal 
Nasal 
 
Formulation 
Nasal spray 
Nasal spray 
 
Strength 
Each device contains 10 mg of 
sumatriptan 
-- 
 
All study drug supplies (DFN-02 and placebo) will be provided by the Sponsor or Sponsor 
affiliates. Patients will be instructed by the site staff on the proper administration of study 
medication to ensure compliance (see Section 9.6 for additional details on treatment 
accountability and compliance). Written instructions for use of the study medication will be 
distributed to Investigator sites, and patients should be confirmed to have, or be provided 
with, them every time study medication is dispensed. Rescue medication will not be provided 
by the Sponsor, and its use should be managed by the patient and their Investigator. 
8.2 
Identity of Investigational Products 
DFN-02 (sumatriptan nasal spray) is a novel formulation designed to improve relief of 
migraine symptoms by decreasing time to onset. DFN-02 is composed of sumatriptan and a 
permeation-enhancing agent, 
, delivered as an aqueous, intranasal 
solution in a metered spray. 
The DFN-02 and the matching placebo intranasal spray are manufactured for Dr. Reddy’s 
Laboratories Ltd, by: 
 USA. 
Manufacturing of the study medication was performed according to Good Manufacturing 
Practice (GMP) for Medicinal Products and all relevant regulatory requirements. Additional 
details regarding study medication may be found in the DFN-02 Investigator’s Brochure.28  
8.3 
Storage, Packaging, and Labeling 
The Sponsor will supply sufficient quantities of DFN-02 10 mg nasal and placebo spray to 
allow for completion of this study.  
The study medication 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 at a controlled, room temperature 
(20°C to 25°C, 68°F to 77°F) environment; excursions are permitted to 15°C to 30°C (59°F 
to 86°F). The room should be accessible only to authorized individuals. Records will be 
made of the receipt and dispensation of all study medication. 
Nasal devices, individually blistered and labeled, will be joined by a perforated seal that may 
be subsequently separated if necessary. Nasal spray device pairs in a blister pack will then 
be packaged in a carton that will be labelled as well. Each pair of labels will contain a kit 
number, the name and address of the Sponsor Agent, and any other information required by 
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local regulations. The patient will be instructed to return all used and unused study 
medication and all the packaging at their next visit.  
The study packaging will be performed by: 
 
. 
All packaging and labelling operations will be performed according to GMP for Medicinal 
Products and all relevant regulatory requirements. 
9 Administration of Study Treatments 
9.1 
Method of Assigning Patients to Treatment Groups 
The DFN-02-CD-012 study is a randomized, 2 DB treatment periods, placebo-controlled 
study. Treatment sequences will be assigned randomly in each DB period with a 1:1 ratio to 
receive either DFN-02 or matching placebo (Figure 6-1). 
9.1.1 Screening (Visit 1) 
After written informed consent is obtained and the patient 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 patient identification (ID) number 
to be used throughout the study. This patient ID number will not be reused for any other 
participant in the study. This unique identifier comprises the numerical order of the patients 
screened and will be used to identify the patient on the eCRF. 
9.1.2 Randomization (Visit 2) 
Once a patient’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 patient study medication kit assignment. Patients who do not meet 
eligibility criteria will be registered as screen failures. It is important that the study staff 
reconfirm the patient’s willingness to continue in the study prior to randomizing the patient to 
a treatment. 
The planned treatment given to individual patients will be determined by a randomization 
scheme prepared by the biostatistics group of INC Research. For both DB periods, all 
patients will receive intranasal DFN-02 10 mg or a matching placebo in a randomized 1:1 
treatment sequencing. As detailed in Section 6.1, patients will treat 1 migraine attack in the 
DB1 treatment period and, if eligible, be re-randomized to enter into the DB2 treatment 
period. The IWRS will assign the appropriate study medication kit to each patient for each 
treatment period. If a patient discontinues from the study after randomization, the patient ID 
number will not be reused, and the patient will not be allowed to re-enter the study. Patients 
will be required to return unused study medication and the eDiary provided by the site. 
9.2 
Selection of Doses in the Study 
The human dose range of DFP-02 evaluated in the pivotal study (DFP-02-CD-009)26 and the 
4 pilot studies (DFP-02-CD-008, 2419/11, 1931/09, 2010/10), was based upon doses of the 
marketed intranasal formulations of Imitrex nasal spray.22-25 The concentration of 0
 
 was chosen based on early development work (data on file) to optimize the PK profile 
of sumatriptan. These studies indicated no safety, tolerability, or clinically meaningful 
changes in vital signs and laboratory parameters. The highest single-dose of sumatriptan in 
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DFN-02 for current and future clinical studies is 10 mg. The safety and tolerability of this 
dose was evaluated in a long-term safety study (DFP-02-CD-010)27 that showed no new 
safety findings. 
9.3 
Selection and Timing of Dose for Each Patient 
At the end of the screening period, eligible patients will be randomized to receive study 
medication (DFN-02 or a matching placebo) as described in Section 6.1. Information about 
use of study medication, predose and postdose assessments, and any rescue medication 
taken during the study will be recorded in the eDiary. For dosing information, see 
Section 8.1.  
9.4 
Blinding 
In order to blind the study treatment, study medication kits with identical labeling appearance 
will be assigned unique kit numbers by IWRS and the kits will distributed by 
 
 to the site prior to 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 patient, in which knowledge of the treatment 
assignment is critical to the patient’s management, the blind for the patient 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 
patient’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 
patient 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.  
9.5 
Prior and Concomitant Therapy 
Investigators should document in the eCRF all prior medications for neurological illnesses 
and conditions that the patient has experienced anytime in the past, and other prior 
medications that were taken within 1 year prior to screening. In addition, all concomitant and 
ongoing medications are to be documented in the eCRF. (See also Section 7.3 exclusion 
criteria and Section 9.5.3 prohibited and allowed medications.) 
9.5.1 Medication History 
No change in any prophylactic migraine medications will be allowed during the study. 
Patients 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 prior to screening and the medications are not otherwise prohibited or restricted in 
the protocol. See Section 9.5.3 for prohibited and allowed medications. 
Washout periods: Patients should not have taken the following medications in the time 
period described: 
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• 
Monoamine oxidase (MAO) inhibitors: at least 15 days prior to randomization 
• 
Antipsychotics: at least 15 days prior to randomization (if used for non-psychiatric 
conditions, should be evaluated on a case-by-case basis with the Medical Monitor) 
• 
Investigational drug(s) or device(s): at least 30 days prior to randomization, or 3 months 
if associated with central nervous system 
• 
Participated in a central nervous system clinical trial: at least 3 months prior to 
randomization 
 
9.5.2 Rescue Medication 
If a patient does not experience sufficient relief with the first dose of the study medication, 
he/she may take a second dose of study medication or take rescue medication after 2 hours 
or more after taking the first dose of study medication and only after completing in the eDiary 
the 2 hours postdose assessments. If a patient does not experience any relief at all from the 
first dose of study medication after 2 hours, he/she should not take a second dose, but may 
take rescue medication instead, if needed.  
If a patient gets a migraine attack, the first dose of the study medication should not be taken 
if the patient has treated an episodic migraine attack acutely with any other medication within 
the past 48 hours, or if the patient has used an analgesic for non-migraine pain acutely 
within the past 48 hours. 
The specific rescue medication will initially be decided mutually between the Investigator and 
the patient prior to or at V2, but may be adjusted as needed during the treatment period, with 
the Investigator ensuring that prohibited medications (as listed below) 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 patient 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. Patients should not take prohibited medications listed 
in Section 9.5.3 as a rescue medication. 
9.5.3 Prohibited and Allowed Medications 
The following medications should not be taken during the study: 
• 
MAO inhibitors  
• 
Triptans (except study medication) and other 5-HT1 receptor agonists  
• 
Ergotamine or ergot-type medications 
• 
Antipsychotics (for any reason) 
• 
Opioids are prohibited if used for ≥ 4 days per month. Additional caution should be 
exercised with use of tramadol. To ensure patient safety in the study, patients should not 
take tramadol and triptan drugs concomitantly due to the risk of serotonin syndrome. If a 
patient has taken study medication, they should not take tramadol for at least 24 hours; if 
a patient has taken tramadol, they should not take study medication for at least 48 hours, 
or for at least 5 half-lives of tramadol, whichever is longer. 
 
SSRIs, 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 
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expected to change during the study. These medications cannot be started during the study. 
If a patient develops a need for long-term use of one of these medications during the course 
of the study, the patient must be withdrawn from the trial. Short term use of these 
medications during the study is prohibited. 
No newly prescribed drugs should be administered during the study without agreement from 
the site Investigator. These drugs should not have any drug-drug interactions with the study 
medication or be contraindicated in the Imitrex product label or package insert. 
Patients will be instructed to refrain from using illicit substances (including marijuana) during 
the study. Please refer to Section 7.3 for exclusion criteria.  
9.6 
Treatment Compliance 
Patients will be instructed by the study site staff on the proper administration of study 
medication to ensure compliance. Written instructions for use of study medication will be 
distributed to the Investigator sites, and patients should be confirmed to have, or be provided 
with, the instructions every time study medication is dispensed. 
See Section 6.1 and Section 9.5.2 for details on timing of dosing with study medication and 
use of rescue medication.  
At the end of the DB1 treatment period (V2), patients will be required to return all used and 
unused study medication from DB1 before any study medication for the DB2 treatment 
period will be dispensed. 
At V4/ET, patients will be required to return all used and unused study medication, study 
medication containers, and completed eDiary. 
10 Study Procedures 
10.1 Duration of Treatment 
The duration of study participation will be up to approximately 13 weeks, including a 
screening period of approximately 3 weeks (wherein patients 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 patients to experience and treat migraine attacks, and 2 to 7 days 
for patients to return to the site after treatment. The combined 2 DB treatment periods would 
total up to 10 weeks. Migraine attacks and associated treatment and assessments will be 
recorded in an eDiary (see Section 10.2.1.4.1). 
10.1.1 Data Recording Using eDiary 
The daily eDiary will be used to record migraine attack assessment data in real-time by 
patients as described in Section 6.1 and Section 10.2.1.4.1, and as shown in Table 10-2. It is 
compulsory for all patients to check-in the eDiary every day during the entire study period to 
ensure presence and functionality. If a patient 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 patient has technical difficulties or confirm 
they have not experienced a migraine. 
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Investigators should train patients 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 endpoint data entry (i.e., 2-hour postdose assessment). 
10.2 Study Assessments 
Table 10-1 summarizes the planned study assessments.
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Table 10-1 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 medication 
dispensed at this visit 
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 
medication dispensed at 
V2. 
Study medication 
dispensed at this visit 
should be used to treat a 
migraine attack at any pain 
level. 
Visit is expected within 
2-7 days of treating a 
migraine attack with the 
study medication 
dispensed at V3. 
Treatment should be 
completed within 10 weeks 
from Baseline. 
Informed consent 
X 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
Patient eDiary instructions and 
dispensation4 
X 
X 
X 
 
Adverse events review 
X 
X 
X 
X 
Demographics 
X 
 
 
 
Medical history and prior medications 
X 
X 
 
 
Migraine history and current treatment 
status  
X 
 
 
 
Physical examination5 
X 
X 
X 
X 
Height and weight 
X 
 
 
X6 
Vital signs (pulse rate, SBP/DBP,7 
body temperature); record menses 
(start/stop dates) 
X7 
X7 
X 
X 
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Serum pregnancy test (hCG)8, 9 
X 
 
 
 
Urine pregnancy test8, 9 
 
X 
X 
X 
Clinical laboratory tests (hematology, 
chemistry, urinalysis) 
X 
X 
X 
X 
Glycosylated hemoglobin (HbA1c), 
TSH* *[screening only] 
X 
 
 
X 
Serology (HIV, HBsAg, HCV) 
X 
 
 
 
Urine drug test and ethanol screen 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
Concomitant medication review 
 
 
X 
X 
Randomization (V2)/Re-randomization 
(V3) 
 
X 
X 
 
Dispense DB study medication10 
 
X 
X 
 
Patient compliance and study 
medication accountability11 
 
 
X 
X 
Patients record data in the eDiary12  
 
 
 
 
Review, confirm, and ensure proper 
recording of the patient eDiary entries13 
 
X 
X 
X 
Collect eDiary14 
 
 
 
X 
Abbreviations: AE = adverse event; BP = blood pressure; DB = double-blind; DBP = diastolic blood pressure; ECG = electrocardiogram; eDiary = electronic diary; 
ET = early termination; HbA1c = glycosylated hemoglobin; HBsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; IWRS = Interactive Web Response System; SBP = systolic blood pressure; TSH = thyroid-stimulating hormone; V = Visit 
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1 V4 will occur up to 10 weeks after baseline (V2). 
2 Patients who do not complete both DB periods will complete an ET visit. 
3 Patients may be randomized earlier than 21 days 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 Prior to eDiary dispensing, initial screening should determine to the extent possible that the patient may be eligible for the study and is able, willing, and understands after 
being instructed how to use the eDiary. The eDiary will be dispensed once, and information for at least 1 migraine attack should be entered if the patient is randomized; 
the eDiary should continue to be used throughout the DB periods. At V2 and V3, randomized patients will be re-instructed on the eDiary to ensure real-time entry of 
predose and postdose assessments and the level of migraine pain to treat Grade 2 [moderate] or Grade 3 [severe] for DB1 treatment period, and any pain level for the 
DB2 treatment period. 
5 At screening (V1), complete physical examination will be performed and recorded in the source document that includes examination of head, eyes, ears, nose, and throat 
[HEENT], heart, lungs, abdomen, skin, cervical and axillary lymph nodes, neurological, and musculoskeletal systems. 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. 
6 Weight only. 
7 At screening, patients with a history of hypertension that is uncontrolled (i.e., SBP > 140 mmHg and/or DBP > 90 mmHg), whether on treatment or not, will be excluded. 
Patients 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 
patient has a sustained resting SBP > 140 mmHg and/or DBP > 90 mmHg at V1 or V2, they should be excluded. Any patient without a known history of hypertension that 
presents at screening with SBP > 140 mmHg and/or DBP > 90 mmHg should be excluded 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 patient in a semi-reclined position in a quiet room. Patients with persistent elevations, despite repeat assessments, should be excluded 
and referred to an appropriate healthcare provider for further assessment.  
8 Serum pregnancy test will be performed at screening (V1) for all female patients of childbearing potential (or at any other time during the study if needed to confirm a 
suspected pregnancy from a positive urine pregnancy test). 
9 Urine pregnancy tests will be performed at all study visits after screening for all female patients of childbearing potential. 
10 Patients will be instructed by the study site staff on the proper administration of study medication to ensure compliance. Written instructions for use of the study 
medication will be distributed to Investigator sites, and patients should be confirmed to have, or be provided with, the instructions every time study medication is 
dispensed. 
11 Unused study medication, including empty study medication containers, should be returned by patients. Unused study medication should not be redispensed. 
12 When the patient experiences a migraine episode, they should contact the site within 24 hours of treating with study medication to schedule their next visit. The eDiary 
will be used to record all migraine attacks treated with study medication during the study period. 
13 Screening eDiary information will be kept in the source document. It is compulsory for all the patients to check-in the eDiary every day during the entire study period. If a 
patient does not check-in consistently or does not report a migraine attack in the eDiary for 2 to 3 weeks, it is recommended they should be contacted by study staff to 
check if the patient has technical difficulties or confirm they have not experienced a migraine. 
14 Arrangements should be made by the site for a timely return of the eDiary device for patients who screen fail. 
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Table 10-2 eDiary Assessments 
 
Randomization
Predose 
Baseline 
Postdose 
10, 15, 20, 
30 min 
1 h 
1.5 h 
2 h 
24 h  
Migraine start and aura information, study medication, 
and non-study medication taken for migraine attacks 
dosing 
As applicable1 
Time to meaningful pain relief 
 
 
As applicable up to 2 hours postdose 
 
Time to pain freedom 
 
 
As applicable up to 2 hours postdose 
 
Pain level2 
 
X 
X 
X 
X 
X 
X 
Functional disability3 
 
X 
 
 
X 
X 
Presence of nausea/photophobia/phonophobia and 
 
 
X 
X 
X 
X 
X 
X 
Most bothersome symptom (selected between 
nausea, photophobia and phonophobia)4 
 
X 
 
 
 
 
 
PPMQ-R 
X 
 
 
 
 
 
X 
Patient treatment satisfaction (7-point scale)5 
 
 
 
 
 
X 
 
Abbreviations: h = hour(s); min = minutes; PPMQ-R = Patient Perception of Migraine Questionnaire-Revised 
1 End of migraine pain, and non-study medication use may occur more than 24 hours postdose. 
2 Pain levels: 0 = none; 1 = mild; 2 = moderate; 3 = severe 
3 Functional disability 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 
4 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. 
5 Treatment satisfaction baseline for the migraine medication to be collected prior to randomization in the PPMQ-R. 
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10.2.1 Visit Procedures 
10.2.1.1 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. An eDiary 
will be dispensed at V1 to collect at least 1 migraine episode and, if the patient is 
randomized (V2), to continue to collect migraine data through end of treatment (V4). 
See eDiary assessments in Section 10.2.1.4.1. The following assessments will be 
performed at the screening visit: 
• 
Written informed consent 
• 
Eligibility confirmation per inclusion and exclusion criteria 
• 
Dispense eDiary, instruct patient on use of the diary, and allow patient 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, medications taken for migraine management, satisfaction 
and headache pain relief with current medication) 
• 
Physical examination, including weight and height measurements 
• 
Vital signs measurement (sitting SBP/DBP, pulse rate, and body temperature); 
record menses 
• 
Serum pregnancy test (human chorionic gonadotropin [hCG]) for women 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 
 
10.2.1.2 Randomization (Visit 2) (Day 0) 
At V2 (and V3), randomized patients will be reinstructed on eDiary usage to ensure 
real-time entry of pre- and postdose assessments and the level of migraine pain to 
treat moderate or severe attacks for DB1 treatment period, and pain of any level for the 
DB2 treatment period. Predose migraine assessments will be allowed to be recorded 
retrospectively in the event a patient did not follow the instructions. 
• 
Continued eligibility confirmation per inclusion and exclusion criteria 
• 
Review recordings of patient eDiary entries and confirm proper recording and 
compliance; retrain if necessary 
• 
Review/collection of AEs 
• 
Medical history and prior medications, including from eDiary entries 
• 
Physical examination (if warranted) 
• 
Vital signs measurement (sitting SBP/DBP, pulse rate, and body temperature); 
record menses 
• 
Urine pregnancy test for women of childbearing potential 
• 
Blood draw for hematology and clinical chemistry 
• 
Urine collection for urinalysis 
• 
Urine drug test and ethanol screen 
• 
12-lead ECG 
• 
Randomization (DB1 period) 
• 
Dispense study medication and instructions for use 
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• 
Confirm patient completes PPMQ-R questionnaire 
 
10.2.1.3 End of DB1 Period; Re-Randomization to DB2 Period (Visit 3) 
• 
Confirm the following: 
o Visit is within 2 to 7 days of treatment of a migraine attack with study 
medication dispensed at V2 
o There should be at least 48 hours of pain and symptom freedom from the 
previously treated migraine attack 
o Treatment should be completed within 4 weeks from V2 
• 
Review recording of patient eDiary entries and confirm proper recording and 
compliance; retrain if necessary 
• 
Review/collection of AEs 
• 
Physical examination (if warranted) 
• 
Vital signs measurement (sitting SBP/DBP, pulse rate, and body temperature); 
record menses 
• 
Urine pregnancy test for women 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 medication is returned, patient compliance, 
and study medication accountability 
• 
Re-randomization (DB2 period) 
• 
Dispense study medication and instructions for use 
 
10.2.1.4 End of DB2 Period (Visit 4); End of Treatment (or Early Termination)  
• 
Confirm the following:  
o Visit is within 2 to 7 days of treatment of a migraine attack with study 
medication dispensed at V3 (or ET, if applicable) 
o Treatment should be completed within 10 weeks from V2 
• 
Review/collection of AEs 
• 
Physical examination (if warranted) 
• 
Weight of patient 
• 
Vital signs measurement (sitting SBP/DBP, pulse rate, and body temperature); 
record menses 
• 
Urine pregnancy test for women 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 
• 
Concomitant medication review, including from eDiary entries 
• 
Confirm patient compliance and study medication accountability 
• 
Review, confirm, and ensure proper recording of eDiary entries by patient 
• 
Collection of eDiary; empty study medication containers, and all unused study 
medication  
 
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10.2.1.4.1 eDiary Assessments 
Patients will be provided with an eDiary at screening (V1) to collect at least 1 migraine 
episode data and, if randomized (V2), to continue to collect migraine date and time (for 
migraine attacks treated with study medication) and any non-study medication used to 
treat migraine in the study. At V2 and V3, patients will be re-instructed on the eDiary 
usage to ensure real-time entry of predose and postdose recordings. (Predose 
migraine assessments will be allowed to be recorded retrospectively in the event a 
patient did not follow the instructions.) All patients should be instructed to return the 
eDiary to the study site.  
At baseline (V2), patients will complete the PPMQ-R questionnaire in the eDiary; 
record the migraine pain start and end (date and time) when they get the migraine; 
record the baseline pain level; record the functional disability scale; and record 
presence of symptoms and MBS (among nausea, photophobia, and phonophobia) just 
before taking the study medication. 
At postdose, patients will record time to meaningful pain relief (based on their 
perception), and time to pain-free after study medication within 2 hours postdose. 
Patients will also record their functional disability at 2 hours and 24 hours postdose, 
and their pain level and presence of MBS at 10, 15, 20, 30 minutes, and at 1, 1.5, 2, 
and 24 hours postdose. Patients will record their treatment satisfaction at 2 hours 
postdose, and complete the PPMQ-R questionnaire again at 24 hours postdose. 
Patients will also record study medication dosing and use of rescue medication in the 
eDiary at applicable timings.  
The following eDiary assessments will be recorded by the patient in accordance with 
Table 10.2.  
• Migraine pain and symptoms: 
o Migraine pain start and end (date and time) 
o Level of headache pain predose and at various time points after (0 = none; 
1 = mild; 2 = moderate; 3 = severe) 
o Time to meaningful pain relief (based on patient’s perception) and time to 
pain-free after study medication 
o Migraine symptoms and MBS other than pain (nausea, photophobia, 
phonophobia, at predose, and at various time points, postdose) 
o 
 
• PPMQ-R: The PPMQ-R is a self-administered satisfaction measurement for 
acute migraine treatment.  
• Functional disability 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).  
• Overall treatment satisfaction, measured by asking questions to the patients, and 
the answers will be assessed on a 7-point scale (1 = very satisfied, 2 = satisfied, 
3 = somewhat satisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat 
dissatisfied, 6 = dissatisfied, and 7 = very dissatisfied). 
• Study medication and rescue use. 
Visits may be scheduled as needed for AE management. Adverse event and 
concomitant medication review should be performed at each unscheduled visit.  
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10.2.2 Efficacy Assessments 
All efficacy data will be collected in the eDiary. The efficacy assessments are shown in 
Section 10.2.1.4.1 and Section 11.4. 
The primary efficacy endpoint is the proportion of patients who are pain-free (defined 
as a reduction from predose moderate [Grade 2] or severe [Grade 3] pain to none 
[Grade 0]) at 2 hours after the first dose of study medication compared between 
DFN-02 and placebo. 
Secondary and exploratory efficacy endpoints are listed in Section 11.4.2 and Section 
11.4.3, respectively. 
10.2.3 Safety Assessments 
Safety assessments, performed according to the schedule of assessments, include the 
following: 
• 
Physical examination 
• 
Serum/urine pregnancy test in female patients of childbearing potential 
• 
Clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis) 
• 
Vital signs measurement (sitting SBP/DBP, pulse rate, and body temperature) 
• 
Recording of 12-lead ECGs 
• 
AEs  
• 
Concomitant medication review (including confirmation and recording of 
medications entered into the eDiary in the eCRF) 
 
Any protocol-specified safety assessment may be repeated or conducted unscheduled 
as necessary to ensure patient safety. 
10.2.3.1 Physical Examination 
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. 
10.2.3.2 Pregnancy 
All female patients 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 patients confirmed to be pregnant at any time during the 
study should be immediately discontinued. Patients 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 
10.2.3.7). Any pregnancy that occurs in a female patient (or female partner of a male 
patient) during the study, or within 30 days after taking the last dose of study 
medication, should be reported to Dr. Reddy’s Laboratories as described in Section 
10.2.3.7. Pregnancies will be followed to the end of the pregnancy, whether successful 
live birth or premature termination, type and date of delivery, any congenital 
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malformations or birth defects or any other adverse fetal or neo-natal 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 patients (with female partner) must agree to practice a reliable form of 
contraception or abstinence during the study. 
10.2.3.3 Clinical Laboratory Evaluation 
The following clinical laboratory evaluations will be performed in accordance with 
assessment time points outlined in Table 10-1. 
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) antibody 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 patients 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 patients 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, laboratory, urine 
drug test/ethanol screen, serum pregnancy tests, HIV, HBsAg, and HCV antibody 
analyses will be performed at a central laboratory. Reference ranges will be supplied 
by Eurofins Central Laboratory and used by the Investigator to assess the laboratory 
data for clinical significance and pathological changes. 
10.2.3.4 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 
patient has rested in the sitting position for 5 minutes. (See additional exclusion criteria 
for SBP/DBP screenings in Section 7.3.1 and assessments in Table 10-1). 
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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 females of childbearing potential will 
be recorded at screening and at each study visit.  
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.  
10.2.3.5 Twelve-Lead Electrocardiogram 
A 12-lead resting ECG will be performed at screening (V1), and at every study visit. 
Each ECG will be reviewed by the Investigator. Tracings will be printed, signed, and 
dated by the Investigator and kept in the patient’s file. The overall interpretation and 
determination of the clinical relevance of ECG findings will be the responsibility of the 
Investigator and will be recorded in the patient’s eCRF. 
10.2.3.6 Adverse Events 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical study patient 
administered a study medication 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 medication and up to 5 days after the last dose of study medication. 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 medication, whether or not related to the study medication. 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 patient 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 informed consent form (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 patient 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 patient, 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 medication. 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 patient’s clinical 
state, therapeutic interventions, or concomitant therapy and does 
not follow a known response pattern to the study medication. 
Possibly Related 
The event is temporally related to study medication 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 medication use and is 
consistent with known effects of the study medication and/or 
improves upon withdrawal of the study medication. 
Definitely Related The event follows a reasonable temporal sequence from the time of 
study medication administration and/or follows a known response 
pattern to the study medication and could not have been produced 
by other factors such as the patient’s clinical state, therapeutic 
intervention, or concomitant therapy and either occurs immediately 
following study medication 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 
Follow-up of Adverse Events 
The Investigator should follow up on patients 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. Patients who 
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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 medication 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]). 
10.2.3.7 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 patient 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 patient’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 patient or required intervention to prevent one of the outcomes 
listed above, or that would suggest any significant hazard, contraindication, side effect, 
or precaution that may be associated with the use of the study medication). 
Reporting of Serious Adverse Events 
Patients should report all SAEs that occur during the clinical study, or within 30 days of 
receiving the last dose of study medication, to the Investigator. It is the responsibility of 
the Investigator to follow the procedures described below, whether or not the SAE is 
considered to be related to the study medication.  
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At the first occurrence of an SAE, the Investigator should complete an SAE report and 
notify the Sponsor within 24 hours of occurrence of the SAE. An SAE report consists of 
the SAE form, the concomitant medication form, and any available supporting 
documentation (e.g., hospital discharge summary). A copy of the SAE form must be 
emailed within 24 hours to the attention of Dr. 
 at: 
Dr. Reddy’s Laboratories Inc. 
 
 
 
 
The Investigator should not wait to receive additional information to fully document the 
event before notification of an SAE, though additional information may be requested. 
Where applicable, information from relevant laboratory results, hospital case records, 
and autopsy reports should be obtained. 
Instances of death, congenital abnormality, or an event that is of sufficient clinical 
concern to influence the overall assessment of safety, if brought to the attention of the 
Investigator at any time after cessation of study medication administration and linked 
by the Investigator to this study, should be reported to the study Medical Monitor.  
The Sponsor and/or INC Research will promptly notify all relevant parties of findings 
that could adversely affect the safety of patients, influence patients’ desire to continue 
in the study, impact the conduct of the study, or alter the Institutional Review Board 
(IRB) approval of the study. In addition, INC Research, on behalf of the Sponsor, will 
expedite the reporting to all concerned Investigators and to the IRB (where required) of 
all adverse reactions that are both serious and unexpected. The Sponsor will expedite 
the reporting of all adverse reactions that are both serious and unexpected and for 
which there is a reasonable possibility of their being caused by the study medication, to 
the regulatory authorities as soon as possible but in no case later than 15 calendar 
days after becoming aware of their occurrence through an IND Safety Report 21 CFR 
320.31(d)(3). 
If the AE is fatal or life-threatening, and with reasonable possibility of its being related 
to the study medication, the Sponsor must also notify the FDA as soon as possible, but 
in no case later than 7 calendar days after becoming aware of its occurrence, by 
telephone or fax pursuant to 21 CFR 320.31(d)(3). 
If the patient took one or more suspect medicinal product(s) other than the study 
medication, the relevant manufacturer(s) of this medicinal product(s) will be informed 
about the SAE by the Sponsor if the Investigator assesses there is a reasonable 
possibility the concomitant drug caused the SAE. The Investigator must provide their 
causality assessment for any concomitant medication taken by the patient. 
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., patient discharge summary or 
autopsy reports), should be faxed or emailed to the Sponsor. 
The Sponsor must be notified within 5 days if any patient is withdrawn or discontinued 
study medication use due to an AE.  
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All AEs experienced by a patient, 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 patient is 
lost to follow-up, until the patient has died, or until 30 days after the last dose of the 
study medication upon which patients 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). 
The blind should not be broken at the study site level except in a medical emergency 
(where knowledge of the study medication received would affect the treatment of the 
emergency). For a medical emergency, the blind must only be broken following 
discussion on a case-by-case basis, at the discretion of the Investigator/treating 
physician/Sponsor. 
If the blind is broken, the date, time, and reason must be recorded in the patient’s 
source record, eCRF, and any associated AE report.  
If an Investigator, site personnel performing assessments, or patient is unblinded, the 
unblinding incident and unblinded patient must be listed as a major protocol deviation. 
A patient for whom the blind is broken will discontinue study medication and be 
scheduled for a safety follow-up visit and then discontinued from the study. The patient 
will be encouraged to stay in the study until the AE is resolved or stabilized. 
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 patients should not be pregnant when entering the study and must not become 
pregnant during the study; please see Section 10.2.3.2 for additional details. Following 
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administration of study medication, any known cases of pregnancy in female patients 
or male patients who impregnate their female partners will be reported to the Sponsor 
within 24 hours of occurrence. All female patients will be withdrawn from the study and 
administration of study medication 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 patient 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 
The Investigator must notify the Sponsor of any occurrence of overdose with study 
medication within 24 hours of becoming aware of the overdose. More than 4 doses 
within 2 hours will be considered as an overdose for this study. 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. 
No gross overdoses in clinical practice have been reported. Coronary vasospasm was 
observed after intravenous administration of Imitrex Injection. Overdoses would be 
expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly cause 
convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, 
cyanosis, ataxia, mydriasis, and paralysis. The elimination half-life of sumatriptan is 
about 2 hours, therefore, monitoring of patients after overdose should continue for at 
least 10 hours or while symptoms or signs persist. It is unknown what effect 
hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.11 
10.2.3.8 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 medication at any dose that is not consistent 
with the applicable product information (e.g., Investigator’s Brochure for an 
unauthorized study medication or summary of product characteristics for an authorized 
product). 
All SUSARs will be subject to expedited reporting. The Sponsor and/or INC Research 
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 patient has completed the 
clinical study must be reported by the Investigator to the Sponsor. 
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Warnings and Precautions  
The following warnings and precautions have been issued for sumatriptan: 
Sumatriptan should not be given to patients with documented ischemic or vasospastic 
CAD. It is strongly recommended that sumatriptan not be given to patients in whom 
unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, 
hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female 
with surgical or physiological menopause, male over 40 years of age) unless a 
cardiovascular evaluation provides satisfactory clinical evidence that the patient is 
reasonably free of CAD and ischemic myocardial disease or other significant 
underlying cardiovascular disease. If, during the cardiovascular evaluation, the 
patient’s medical history or ECG investigations reveal findings indicative of, or 
consistent with, coronary artery vasospasm or myocardial ischemia, sumatriptan 
should not be administered. For further details, please refer to the full Imitrex product 
insert. 
10.2.4 Appropriateness of Measurements 
All efficacy and safety assessments used in this study are widely used and generally 
considered reliable and accurate.  
11 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 primary and all secondary efficacy 
endpoints. Unless stated otherwise, the term “descriptive statistics” refers to number of 
patients (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-02 10 mg or placebo. All data collected during the 
study will be included in patient data listings. Unless otherwise noted, the data will be 
sorted first by treatment assignment, patient number, and then by date within each 
patient number. 
All statistical analyses are described in Section 11.6. 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. 
11.1 Statistical Analysis Plan 
A SAP will be created and approved prior to 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 prior to unblinding of patient’s treatment 
assignment at database lock. This review will assess the accuracy and completeness 
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of the study database, patient evaluability, and appropriateness of the planned 
statistical methods. 
11.2 Analysis Datasets or Populations  
Full Analysis Set 
Each DB treatment period will have a full analysis set (FAS), which will include all 
randomized patients who during the treatment period took at least one dose of study 
medication, have at least one post-baseline efficacy time point assessment during the 
2 hours postdose, and did not use a second dose of study medication or rescue 
medication prior to the data collection of the 2 hours postdose time point (inclusive). 
Safety Population 
The safety population will include all patients who receive at least one dose of DB 
study medication during both treatment periods.  
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 patients who have at least 1 
post-baseline primary endpoint assessment, who have no significant protocol 
deviations that will impact the collection or interpretation of the primary endpoint data 
during the DB1 treatment period. Identification of all patients in the PP population will 
be determined before the database lock and unblinding. 
11.3 Demographic and Other Baseline Characteristics 
Patient disposition will be presented for each treatment group, as applicable, and 
overall. They may include, but are not limited to, the following: 
• 
The number of patients screened 
• 
The number of patients who failed screening 
• 
The number of patients randomized at baseline and the number of patients 
re-randomized at V3 
• 
The number (%) of patients in the FAS population 
• 
The number (%) of patients in the Safety population 
• 
The number (%) of patients in the PP population 
• 
The number (%) of patients who completed the study 
• 
The number (%) of patients who discontinued from the study and the primary 
reason for discontinuation 
 
Demographics and baseline characteristics will be summarized descriptively for the 
FAS population by treatment group and overall. They may include, but are not limited 
to, the following variables: 
• 
Demographics (age, age group, gender, ethnicity, race, height, weight, body mass 
index)  
• 
Baseline disease characteristics (i.e., migraine subtype and current treatment 
status, glycosylated hemoglobin (HbA1c), serology [HIV/HBsAg/HCV antibody]) 
• 
Medical history and medication history 
• 
Physical examination at screening 
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All collected demographics and baseline characteristics data will be listed. 
11.4 Efficacy Endpoints 
11.4.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is: 
Proportion of patients who are free from headache pain at 2 hours after the first 
dose of study medication taken for a migraine attack with moderate to severe 
headache pain during the DB1 treatment period  
Note: Freedom from headache pain is defined as a reduction from predose 
moderate (Grade 2) or severe (Grade 3) pain to none (Grade 0). 
 
11.4.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
Proportion of patients who are free from headache pain at 2 hours after the first 
dose of study medication taken for a migraine attack with headache pain of any 
level during the DB2 treatment period  
Note: Freedom from headache pain is defined as a reduction from predose mild 
(Grade 1), or moderate (Grade 2), or severe (Grade 3) pain to none (Grade 0). 
 
(Each DB Period) 
• 
Proportion of patients who are pain-free at 10, 15, 20, 30, 60, and 90 minutes after 
the first dose of study medication  
• 
Proportion of patients who have pain relief at 10, 15, 20, 30, 60, 90, and 120 
minutes postdose defined for DB1 as a reduction from predose moderate or severe 
pain to mild or none postdose, and for DB2 as pre-dose mild, moderate, or severe 
pain reduced to mild or none postdose) 
• 
Proportion of patients with their MBS among nausea, photophobia, and 
phonophobia, absent at 10, 15, 20, 30, 60, 90, and 120 minutes postdose after the 
first dose of study medication taken for a migraine attack  
• 
Proportion of patients who are free from nausea, photophobia, and phonophobia at 
each postdose time point after the first dose of study medication taken for a 
migraine attack 
• 
Time to meaningful pain relief  
• 
Time to pain freedom  
• 
 
  
• 
Proportion of patients who have sustained pain freedom at 24 hours (2 to 24 hours) 
after the first dose of study medication taken for a migraine attack  
Note: Sustained pain freedom at 24 hours is defined as pain free at 2 hours 
postdose, with no use of rescue medication or additional study medication and no 
recurrence of headache pain within 2 to 24 hours postdose 
• 
Change in functional disability score at 2 hours and 24 hours after the first dose of 
study medication taken for a migraine attack  
• 
Proportion of patients who use a second dose of the study medication or rescue 
medication after 2 hours (2 to 24 hours) postdose  
• 
Treatment satisfaction at 2 hours postdose  
• 
Treatment satisfaction as measured by PPMQ-R at 24 hours postdose  
 
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11.4.3 Exploratory Endpoints 
The exploratory endpoints for each DB treatment period include:  
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
11.5 Safety Endpoints 
The safety endpoints include:  
• 
Tolerability as assessed by AEs for each treatment period and overall 
• 
Safety as assessed by clinical laboratory tests, vital signs, and ECG for each 
treatment period and overall. 
 
11.6 Methods of Analysis 
11.6.1 Primary Efficacy Analysis 
Efficacy analysis for primary, secondary, and exploratory endpoints will be based on 
the FAS population. 
The primary efficacy endpoint, the proportion of patients who are free from headache 
pain at 2 hours after the first dose of study medication taken for a migraine attack with 
moderate to severe headache pain during the DB1 treatment period, will be analyzed 
using Fisher’s exact test. The response rate will be calculated as the number of 
patients who are pain-free at 2 hours postdose divided by the number of patients with 
non-missing assessment at 2 hours postdose. The number of patients with non-missing 
assessment, the number of patients with response, the response rate, and the p-value 
for comparing DFN-02 10 mg versus placebo will be presented. 
Analysis will be performed using the last observation carried forward (LOCF) and 
observed data in the FAS population and PP population. 
Additional sensitivity analyses and data handling rules for missing data of the primary 
endpoint will be documented in detail in the SAP. 
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11.6.2 Secondary Efficacy Analysis 
The secondary endpoints for proportion of patients who are free from headache pain, 
for proportion of patients with their MBS absent, for proportion of patients who are free 
from nausea, photophobia, and phonophobia, for proportion of patients who have pain 
relief, for proportion of patients who have sustained pain freedom, and for proportion of 
patients who use a second dose of the study medication or rescue medication, will be 
analyzed using Fisher’s exact test similarly to the described analysis for the primary 
endpoint. 
The secondary endpoints for time to meaningful pain relief and time to pain freedom 
will be analyzed using Kaplan-Meier product-limit method.  
The secondary endpoints for the change in functional disability score at 2 hours and 
24 hours after the first dose of study medication will be analyzed using Wilcoxon 
signed-rank test. The secondary endpoints for treatment satisfaction at 2 hours 
postdose as measured on the 7-point scale, and at 24 hours postdose as measured by 
the PPMQ-R, will be analyzed using the Wilcoxon rank-sum test. 
11.6.3 Exploratory Efficacy Analysis 
 
11.6.4 Subgroup Analysis 
Subgroup analyses of the efficacy data will be performed as needed and details to be 
documented in the SAP. All subgroup analyses will be exploratory. 
11.6.5 Additional Efficacy Analyses 
Additional efficacy analyses will be performed on the PP population. Further statistical 
details and possible other analyses will be provided in the SAP. 
11.6.6 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 medication and up to 5 days after the last dose of study 
medication. Only TEAEs will be included in summary tables. Migraine headaches will 
not be captured as AEs. Migraine headaches will be captured by the patient 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 patient reported more than one AE that was coded to the same SOC or 
PT, the patient will be counted only once for that specific SOC or PT.  
An overview of AEs, which includes patient incidence of TEAEs, headache or 
migraine-related TEAEs, study medication-related TEAEs, and SAEs, will be 
presented. The patient incidence of TEAEs, headache- or migraine-related TEAEs, 
study medication-related TEAEs, and SAEs will be summarized by SOC and PT. 
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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 patient, SOC, and PT. 
Treatment-emergent adverse events will also be summarized in a table by relationship 
to study medication. For TEAEs presented by relationship to study medication, the 
strongest relationship to study medication during the study will be presented for each 
patient, SOC, and PT. 
All AEs will also be presented in a by-patient 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 medication, inclusive. Medications 
will be considered as prior if stopped before the date of first dose of study medication 
during the DB1 treatment 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). All ECG data, clinical laboratory data, vital signs, physical examinations, study 
medication use, and concomitant medication use will also be presented in by-patient 
data listings. 
11.7 Interim Analyses 
No interim analysis is planned. 
11.8 Determination of Sample Size 
One hundred patients will be randomized for the DB1 treatment period. Patients who 
discontinue participation without completing the study protocol will not be replaced. 
The primary endpoint is the comparison of the proportion of patients who are pain-free 
at 2 hours after the first dose of study medication. It is assumed that 15% of placebo 
and 42% of DFN-02 (treated) patients will be pain-free at 2 hours. A sample size of 
50 patients in each DB1 dosing arm will provide 81% power to detect this assumed 
difference between placebo and DFN-02 at a 5% (2-sided) level of significance.  
12 Quality Assurance and Quality Control 
12.1.1 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, INC Research, or its nominated 
representative. In addition, inspections may be conducted by regulatory authorities at 
their discretion. 
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12.1.2 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 patient who signs an ICF. 
In accordance with cGCP and International Conference on 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 patient 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 medication 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 patient 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 
INC Research clinical trial management system and will be categorized as major or 
minor prior to data analysis. 
12.1.3 Data Management and Coding 
INC Research will be responsible for activities associated with the data management of 
this study. This will include setting up a relevant database (Medidata RAVE) 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 INC 
Research. 
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, 
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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. 
13 Records and Supplies 
13.1 Drug Accountability 
Upon receipt of the study medication, the Investigator (or designee) will conduct an 
inventory of the supplies and verify that study medication 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 
medication 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 INC Research, will be maintained at the study site at all times. The study 
monitor will arrange regular collection of used and unused study medication returned 
by the patient. The study monitor will also perform an inventory of study medication at 
the close-out visit to the study site. All discrepancies must be accounted for and 
documented. 
13.2 Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement. 
14 Ethics 
14.1 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 medication 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 patients and/or 
other procedures. INC Research will submit relevant study documentation to the 
central IRB on behalf of the study sites. 
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 
prior to 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 patients will be 
the responsibility of the site Investigator. 
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The Investigator will report promptly to the IRB any new information that may adversely 
affect the safety of the patients or the conduct of the study. INC Research 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. 
14.2 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.29-31 
14.3 Patient Information and Consent 
The Investigator is responsible for ensuring that no patient undergoes any 
study-related examination or activity before that patient has given written informed 
consent to participate in the study. The written consent must be given by the patient 
after detailed information about the study has been given and in accordance with any 
national provisions on the protection of clinical study patients. The verbal explanation 
will cover all the elements specified in the written information provided for the patient. 
The Investigator or sub-Investigator will inform the patient of the objectives, methods, 
anticipated benefits, and potential risks and inconveniences of the study. The patient 
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 patient will be given time to consider the study, if this is required, or if the patient 
requests more time. Patients will be required to sign and date the ICF. Patients 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, INC Research personnel, or third parties 
authorized by Dr. Reddy’s Laboratories. Patients will be given a signed copy of the ICF 
for their records. 
It should be emphasized to the patient that he or she is at liberty to withdraw from the 
study at any time, without penalty or loss of benefits to which the patient is otherwise 
entitled. Patients who refuse to give or who withdraw written informed consent should 
not be included or continue in the study. 
14.4 Patient 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)32 and applicable local laws and/or 
regulations on personal data protection.  
Monitors, auditors, and other authorized agents of the Sponsor or INC Research, the 
IRB approving this research as well as that of any applicable regulatory agency, will be 
granted direct access to the study patients’ original medical records for verification of 
clinical study procedures and/or data, without violating the confidentiality of the patients 
to the extent permitted by the law and regulations. In any presentations of the results of 
this study, or in publications, the patients’ identity will remain confidential. 
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15 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 medication. 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 patient 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 medication 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 prior to the 
date of submission for publication. If the Sponsor determines that the proposed 
publication contains patentable patient 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 patients and/or who provided significant input on study design and/or 
interpretation on study results. 
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16 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. Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, et al. 
Sex differences in the prevalence, symptoms, and associated features of 
migraine, probable migraine and other severe headache: results of the 
American Migraine Prevalence and Prevention (AMPP) Study. Headache. 
2013;53(8):1278-99. 
 
3. Bigal ME, Lipton RB. The epidemiology, burden and co-morbidities of migraine. 
Neurol Clin. 2009;27(2):321-34. 
 
4. Matharu MS, Bartsch T, Ward N, Frackowiak RS, Weiner R, Goadsby PJ. 
Central neuromodulation in chronic migraine patients with suboccipital 
stimulators: a PET study. Brain. 2004;127(Pt.1):220-30. 
 
5. Goadsby PJ. Patho-physiology of migraine. Neurol Clin. 2009;27(2):335-60. 
 
6. Headache Classification Subcommittee of the International Headache Society 
(IHS). The International Classification of Headache Disorders, 2nd Edition, 1st 
revision May 2005. 
 
7. Mullins CD, Weis KA, Perfetto EM Subedi PR, Healey PJ. Triptans for migraine 
therapy: a comparison based on number needed to treat and doses needed to 
treat. J Manag Care Pharm. 2005;11(5):394-402. 
 
8. Tfelt-Hansen P, Saxena PR, Dahlöf C, Pascual J, Láinez M, Henry P, et al. 
Ergotamine in the acute treatment of migraine: a review and European 
consensus. Brain. 2000;123(Pt.1):9-18. 
 
9. Imitrex® (sumatriptan) Nasal Spray US Package Insert, GlaxoSmithKline. 
Research Triangle Park, NC 27709. February 2010. 
 
10. Imitrex® (sumatriptan) Oral Tablet US Package Insert, GlaxoSmithKline. 
Research Triangle Park, NC 27709. February 2010. 
 
11. Imitrex® (sumatriptan) Subcutaneous Injection US Package Insert, 
GlaxoSmithKline. Research Triangle Park, NC 27709. February 2010. 
  
12. Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine: a comparative 
review of pharmacology, pharmacokinetics and efficacy. Drugs. 
2000;60(6):1259-87. 
 
13. Pilgrim AJ. The clinical profile of sumatriptan: efficacy in migraine. Eur Neurol. 
1994;34(Suppl 2):26-34. 
 
14. 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):532-8. 
 
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15. Pillion DJ, Hosmer S, Meezan E. Dodecylmaltoside-mediated nasal and ocular 
absorption of lyspro-insulin: independence of surfactant action from multimer 
dissociation. Pharm Res. 1998;15(10):1637-9. 
 
16. Pillion DJ, Ahsan F, Arnold JJ, Balusubramanian BM, Piraner O, Meezan E. 
Synthetic long-chain alkyl maltosides and alkyl sucrose esters as enhancers of 
nasal insulin absorption. J Pharm Sci. 2002;91(6):1456-62. 
 
17. Pillion DJ, Atchison JA, Gargiulo C, Wang RX, Wang P, Meezan E. Insulin 
delivery in nosedrops: new formulations containing alkylglycosides. 
Endocrinology. 1994;135(6):2386-91. 
 
18. Mustafa F, Yang T, Khan MA, Ahsan F. Chain length-dependent effects of 
alkylmaltosides on nasal absorption of enoxaparin. J Pharm Sci. 
2004;93(3):675-83. 
 
19. Maggio ET. Intravail™: highly effective intranasal delivery of peptide and protein 
drugs. Expert Opin Drug Deliv. 2006;3(4):529-39. 
 
20. Eley JG, Tirumalasetty PP. In vitro assessment of alkylglycosides as 
permeability enhancers. AAPS PharmSciTech. 2001;2(3):E19. 
 
21. Tirumalasetty PP, Eley JG. Evaluation of dodecylmaltoside as a permeability 
enhancer for insulin using human carcinoma cells. J Pharm Sci. 
2005;94(2):246-55. 
 
22. A randomized, four-way crossover study to compare DFP-02 and subcutaneous 
sumatriptan pharmacokinetics, safety, and tolerability in healthy adult male and 
female subjects under fasted condition (Study No. DFP-02-CD-008). Celerion. 
30 July 2013. 
 
23. An open-labeled, randomized, three-treatment, three-period, three-sequence, 
single dose, crossover study, to compare the pharmacokinetics, safety and 
tolerability of three dose levels (5 mg, 10 mg, 15 mg) of sumatriptan nasal spray 
container of Dr. Reddy’s Laboratories Ltd., India in healthy, adult male subjects 
under fasting conditions (Study No. 2419/11). Lotus Centre of Excellence for 
Clinical Research. 01 June 2012. 
 
24. A blinded, randomized, balanced, three treatment, three period, three 
sequence, single dose, crossover pilot study, to compare the pharmacokinetics, 
safety and tolerability of two nasal spray containers (Test 1, Test 2) of 
sumatriptan 20 mg of Dr. Reddy’s Laboratories Ltd., India and sumatriptan 20 
mg nasal spray (reference) of Dr. Reddy’s Laboratories Ltd., India in healthy, 
adult male subjects under fasting conditions (Study No. 1931/09). Lotus Centre 
of Excellence for Clinical Research. 12 March 2010. 
 
25. A blinded, randomized, balanced, four treatment, four period, four sequence, 
single dose, crossover pilot study, to compare the pharmacokinetics, safety and 
tolerability of three nasal spray containers (Test 1, Test 2, Test 3) of 
sumatriptan 20 mg of Dr. Reddy’s Laboratories Ltd., India and Imitrex® 
(sumatriptan 20 mg) Nasal spray of GlaxoSmithKline, USA in healthy, adult 
male subjects under fasting conditions (Study No. 2010/10). Lotus Centre of 
Excellence for Clinical Research. 09 February 2011. 
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26. A randomized, three-way crossover study to compare the pharmacokinetics, 
safety, and tolerability of intranasal DFP-02 10 mg and subcutaneous 6 mg and 
4 mg sumatriptan in healthy adult subjects (Study No. DFP-02-CD-009). 
Celerion. 05 May 2015. 
 
27. A multicenter, open-label safety study of DFP-02 (10 mg) for the treatment of 
acute migraine in patients with 2 to 6 migraine headaches a month (Study No. 
DFP-02-CD-010). Celerion. Report writing is ongoing. 
 
28. DFN-02 Investigator’s Brochure. Bridgewater, NJ: Dr. Reddy’s Laboratories Ltd; 
2016. 
 
29. 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. 
 
30. International Conference on Harmonisation. ICH Harmonised Tripartite 
Guideline. Good Clinical Practice. CPMP/ICH/135/35. 17 January 1997. 
 
31. Title 21 of the Code of Federal Regulations. Food and Drug Administration. 
 
32. 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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17 Investigator Signature Page 
 
Protocol Title: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Efficacy and Safety Study of DFN-02 (Sumatriptan Nasal Spray 
10 mg) in Episodic Migraine With or Without Aura 
Protocol Number: 
DFN-02-CD-012 
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 Ltd./Dr. Reddy’s Laboratories Inc. 
and of the IRB. I will submit the protocol modifications or any ICF modifications to 
Dr. Reddy’s Laboratories Inc. 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 patients’ state of health will be regarded as confidential. All attempts will be made 
to ensure that no patients’ names will be disclosed. All patients 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 patient before disclosure of 
patient information to a third party. 
Information developed in this clinical study may be disclosed by Dr. Reddy’s 
Laboratories Inc. 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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