Conditions: Migraine
Keywords: migraine migraine headache acute migraine acute migraine headache
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 342
Healthy volunteers: no

Brief summary:
This is an open-label, twelve-month safety study. There is a screening period followed by a run-in period to record migraine activity. Qualified subjects will receive study medication for up to twelve months for the treatment of multiple migraine attacks. Using the electronic diary (eDiary) to confirm they are experiencing a qualified migraine, subjects will self-administer the patches and respond to questions in the eDiary post treatment administration.

Detailed description:
This is an open-label, twelve-month safety study. There is a screening period followed by a run-in period (14 to 21 days) to determine eligibility for treatment with study medication based on daily eDiary data collection. Qualified subjects will receive study medication on Day 1 for up to twelve months for the treatment of migraine headaches. Migraines will be treated with a single dose, consisting of two patches, but subjects can treat multiple migraine attacks throughout the 12 months. Using the eDiary to confirm they are experiencing a qualified migraine, subjects will self-administer the patches and continue to respond to questions in the eDiary for 48 hours post treatment administration.

Arms:
arm 1: M207 Microneedle System 3.8 mg (1.9 mg/patch x 2 patches)

Interventions: intervention 1: M207 Microneedle System
Intervention descriptions: intervention 1: M207 Microneedle System 3.8 mg

Protocol document:
Prot_001.pdf: 
 
C O N F I D E N T I A L 
Zosano Pharma Corporation  34790 Ardentech Court  Fremont, CA 94555 
 
 
 
CLINICAL PROTOCOL  
 
 
STUDY TITLE: 
A Long-Term, Open-Label Study to Evaluate the Safety of M207 
(Zolmitriptan Intracutaneous Microneedle System) in the Acute 
Treatment of Migraine 
 
PROTOCOL NUMBER: 
CP-2017-001 
 
PROTOCOL VERSION: 
Version 3  
 
PROTOCOL DATE:  
Original: 22 June 2017 
 
 
 Amendment 1: 30 January 2018 
 
 
 Amendment 2: 06 April 2018 
 
STUDY DRUG: 
M207 (Zolmitriptan Intracutaneous Microneedle System)  
 
SPONSOR: 
Zosano Pharma Corporation 
 
34790 Ardentech Court 
 
Fremont, CA 94555 
 
Tel: 510-745-1200 
 
MEDICAL MONITOR:  
Pete Schmidt, MD 
 
 
 
 
 
 
 
 
Zosano Pharma Corporation 
 
 
 
 
 
 
 
 
Tel: 510-745-1251  
 
CRO: 
Syneos Health 
 
3201 Beechleaf Court, Suite 600 
 
Raleigh, NC  27604 
 
USA 
 
 
This document is a confidential communication of Zosano Pharma Corporation.  The recipient agrees that no 
information contained herein will be published or disclosed without prior written approval of Zosano 
Pharma, except that this document may be disclosed to appropriate institutional review boards or duly 
authorized representatives of the US Food and Drug Administration (FDA) or other regulatory agencies 
under the condition that they are asked to maintain confidentiality. 


 
Zosano Pharma Corporation 
 
Protocol No. CP-2017-001v3 
 
Version 3 - 06 April 2018 
Confidential 
Page 2 of 92 
 
 
 
PROTOCOL SIGNATURE PAGE - PRINCIPAL INVESTIGATOR 
 
 
Protocol Number: 
CP-2017-001 
 
Study Title: 
A Long-Term, Open-Label Study to Evaluate the Safety of M207 
(Zolmitriptan Intracutaneous Microneedle System) in the Acute Treatment 
of Migraine 
 
Protocol Version:  
3: Amendment 2  
 
Protocol Date:  
06 April 2018 
 
I have received and read the protocol version 3 dated 06 April 2018.  I agree to undertake the 
protocol as defined therein, and I will work according to the principles of GCP as described in 21 
CFR parts 50, 54, 56, and 312, and according to applicable local requirements.  I am aware that 
my adherence to the above protocol is mandatory and that any changes in the protocol or 
informed consent form must first be approved by Zosano Pharma Corporation and the 
Institutional Review Board/Ethics Committee, except those changes necessary to eliminate 
apparent immediate hazards to subjects.  Failure to adhere to these stipulations may constitute a 
breach of United States (U.S.) Federal Regulations and may result in termination of the study. 
 
 
Principal 
Investigator 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Printed Name 
 
 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
5-HT receptors 
5-hydroxytryptamine receptors 
AE 
Adverse event 
ALT 
Alanine transferase (same as SGPT) 
ANOVA 
Analysis of variance 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase (same as SGOT) 
AUC 
Area Under the Curve 
AUClast 
Area under the curve calculated from minute 0 to the last measurable 
plasma concentration 
AUC0-2 hr 
Area under the curve calculated from 0 hour to the 2 hour plasma 
concentration  
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CAD 
Coronary artery disease 
CDMS 
Clinical data management system 
CFR 
Code of Federal Regulations 
cm2 
Centimeter squared 
Cmax 
Maximum observed plasma concentration 
CPK 
Creatinine phosphokinase 
CRF 
Case report form 
CRO 
Contract research organization 
CTA 
Clinical Trials Authorization 
CTM 
Clinical trial material 
CVA 
Cerebral vascular accident 
dL 
Deciliter 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
F 
Fahrenheit 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
HDL 
HIPAA 
High-density lipoprotein 
Health Insurance Portability and Accountability Act 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHS 
International Headache Society 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 


 
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IXRS 
Interactive Voice/Web Recognition System 
J 
Joules 
Kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last Observation Carried Forward 
M207 
Intracutaneous Microneedle System (M207) 
Mg 
Milligrams 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter  
MM 
Medical Monitor 
NDA 
New drug application 
NSAID 
Nonsteroidal anti-inflammatory drug 
PCP 
Phencyclidine 
PE 
Physical examination 
PRSPB 
Patch-related superficial punctate bruising 
PV 
Pharmacovigilance 
RDC 
Remote Data Capture 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous  
SD 
Standard deviation 
SEM 
Standard error of the mean 
SNRI 
Serotonin-norepinephrine reuptake inhibitors 
SOP 
Standard operating procedures 
SSRI 
Selective serotonin reuptake inhibitors 
TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attacks 
Tmax 
Time to maximum concentration 
TMF 
Trial master file 
U/L 
Units per liter 
U.S. 
United States 
WOCBP 
Women of child-bearing potential 
ZP 
Zosano Pharma  


 
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PROTOCOL SYNOPSIS 
TITLE 
A Long-Term, Open-Label Safety Study to Evaluate the Safety of M207 
(Intracutaneous Microneedle System) in the Acute Treatment of Migraine 
SPONSOR 
Zosano Pharma Corporation 
CLINICAL PHASE 
Phase 3, Open-Label Safety 
INDICATION 
Acute migraine (with or without aura) in adults  
OBJECTIVES 
• 
The primary objective of the study is to assess the long-term safety 
of 3.8 mg (administered as two 1.9 mg patches) of M207 for the 
acute treatment of migraine  
• 
The secondary objective of the study is to evaluate the efficacy of 
3.8 mg (administered as two 1.9 mg patches) of M207 for the acute 
treatment of migraine 
 
TRIAL DESIGN 
Open-Label, Multicenter, Safety Study  
INVESTIGATIONAL 
TREATMENT 
M207 Intracutaneous Microneedle patch system, 3.8 mg administered as two 
1.9 mg patches (to be worn for 30 minutes) 
BLINDING 
N/A 
RANDOMIZATION 
N/A  
STUDY 
POPULATION 
Adults who suffer from 2-8 migraine attacks per month on average 
NUMBERS OF 
SUBJECTS 
Approximately 400 subjects will be screened to ensure up to 300 subjects are 
eligible to enter the two-week run-in period and approximately 250 subjects 
eligible for the treatment phase: 
• 
At least 150 subjects must complete the safety follow-up for 
six months 
• 
At least 50 subjects must complete the safety follow-up for one year 
 
ELIGIBILITY 
Inclusion Criteria: 
Subjects presenting with all of the following may be included in the study: 
1. Able to provide written informed consent 
2. Women or men 18 to 75 years of age 
3. Greater than 1 year history of episodic, migraine (with or without aura) 
with onset prior to 50 years of age.  Diagnosis must comply with 
International Headache Society (IHS ICHD-3beta) diagnostic criteria.  


 
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Diagnostic criteria must include a history of at least five attacks not 
attributed to any other disorder that include all of the following criteria: 
a) Headache attacks lasting 4-72 hours (untreated or unsuccessfully 
treated) 
b) Headache has at least two of the following characteristics: 
(i) unilateral location 
(ii) pulsating quality 
(iii) moderate or severe pain intensity 
(iv) aggravation by or causing avoidance of routine physical activity 
(e.g., walking or climbing stairs) 
c) During headache at least one of the following: 
(i) nausea and/or vomiting 
(ii) both photophobia and phonophobia  
4. Migraine history during the 6-month period prior to initial screening 
must include: 
a) at least 2 migraines per month 
b) no more than 8 migraines per month 
c) no more than 15 headache days per month 
5. Women of child-bearing potential must not be pregnant, must agree to 
avoid pregnancy during the trial, and must use an acceptable double-
barrier method of birth control (examples of methods include partner 
using condom, female using IUD, hormonal or non-hormonal 
contraceptive, diaphragm with spermicide, or contraceptive sponge) for 
the duration of the trial.  
6. No significant ECG findings, defined by: 
a) ischemic changes defined as > 1mm of down-sloping ST segment 
depression in at least two contiguous leads, 
b) Q-waves present in at least two contiguous leads, 
c) clinically significant intra-ventricular conduction abnormalities (left 
bundle branch block or Wolf-Parkinson-White syndrome), or 
d) clinically significant arrhythmias (e.g., current atrial fibrillation) 
7. Able to understand and operate the electronic diary 
8. Able to apply the demo study drug patches 
9. In the opinion of the investigator, subject is willing to treat a minimum 
of 2 migraines per month with study medication and is willing to 
consistently perform eDiary completion for up to 12 months. 
 


 
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Exclusion Criteria: 
Subjects presenting with any of the following will not be included in the 
study: 
1. Contraindication to triptans 
2. Use of any prohibited concomitant medications within 10 days of the 
Run-in Period (See Section 6.2.11 for list of prohibited concomitant 
medications prohibited for the duration of the study) 
3. Use of any prescription anti-coagulant including Pradaxa (dabigatran), 
Coumadin (warfarin sodium), Eliquis (apixaban), and/or Xarelto 
(rivaroxaban) within 30 days prior to screening and throughout the 
duration of the study. 
4. History of hemiplegic migraine or migraine with brain stem aura 
(formerly called basilar migraine) 
5. Participation in another investigational trial during the 30 days prior to 
the Run-in Period or during this study 
6. Diagnosis of cancer (other than non-invasive skin cancer) within the 
5 years prior to the Run-in Period 
7. History of unstable psychiatric illness requiring medication changes or 
hospitalization in the 12 months prior to the Run-in Period 
8. Known allergy or sensitivity to zolmitriptan or its derivatives or 
formulations 
9. Known allergy or sensitivity to adhesives and/or titanium 
10. Planned participation in activities which cause inflammation, irritation, 
sunburn, lesions, and/or tattoos at the intended application site from 
two weeks prior to screening through the last day of study participation 
11. Use of greater than 5 doses of opioid or barbiturate containing 
medications in the 30 days prior to screening and/or who anticipate 
using more than 5 doses per month of these medications at any time 
during the study 
12. Women who are pregnant, breast-feeding or plan a pregnancy during 
this study 
13. Clinically significant liver disease (SGPT > 150 U/L; SGOT > 130 U/L 
or LDH > 750 U/L)  
14. History of coronary artery disease (CAD), coronary vasospasm 
(including Prinzmetal's angina), aortic aneurysm, peripheral vascular 
disease or other ischemic diseases (e.g., ischemic bowel syndrome or 
Raynaud’s syndrome) 
15. Three or more of the following CAD risk factors identified during 
screening: 


 
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a) Current tobacco use 
b) Hypertension (systolic BP > 140 or diastolic BP > 90) or receiving 
anti-hypertensive medication for treatment of hypertension 
c) Hyperlipidemia – LDL > 159 mg/dL and/or HDL < 40 mg/dL (or on 
prescribed anti-cholesterol treatment) 
d) Family history of premature coronary artery disease (CAD) 
(< 55 years of age in male first degree relatives or < 65 years of age 
in female first degree relatives) 
e) Diabetes mellitus 
16. History of cerebral vascular accident (CVA), transient ischemic attacks 
(TIA), or seizures 
17. History of concurrent illness that requires hospitalization within the 
30 days prior to the Run-in Period 
18. Any other household member currently participating in a M207 study or 
relatives of site staff 
19. Any reason to believe that compliance with the study requirements and 
completion of evaluations required for this study will not be possible 
20. Any language barrier that, in the opinion of the Investigator, would 
preclude communication or compliance with the study requirements 
21. History or current abuse or dependence on alcohol or drugs that in the 
opinion of the investigator would interfere with adherence to study 
requirements  
22. Any positive urine drug screen for phencyclidine (PCP), MDMA 
(ecstasy), cocaine, and/or methamphetamine(s) 
23. Any clinically relevant abnormal findings in the subject’s medical 
history, physical exam, vital signs or laboratory tests that, in the opinion 
of the Investigator, may put the subject at risk 
 
Eligibility Criteria for Study Treatment  
To be eligible for Treatment, subjects must continue to meet all eligibility 
criteria for the study and the following criteria observed during the Run-in 
Period: 
1. At least one qualifying migraine attack in the last 14 calendar days prior 
to Visit 3 (Day 1).  The following constitutes a migraine that qualifies 
during the Run-in Period: 
a. Headache has at least two of the following characteristics: 
• 
unilateral location 
• 
pulsating quality 


 
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• 
moderate or severe pain intensity 
• 
aggravation by or causing avoidance of routine physical 
activity (e.g., walking or climbing stairs) 
b. During headache at least one of the following: 
• 
nausea and/or vomiting 
• 
both photophobia and phonophobia  
2. No more than seven headache days (headache days include both 
qualifying migraines and/or other headache types) in the last 14 calendar 
days prior to Visit 3 (Day 1) 
3. During the run-in period, good eDiary compliance will be confirmed by 
subject eDiary completion of at least 10 out of the last 14 calendar days 
prior to Visit 3 (Day 1) 
4. Demonstrated ability to properly operate the eDiary  
5. Demonstrated ability to properly apply the demo study drug patches 
6. In the opinion of the investigator, subject is willing and able to treat all 
eDiary-confirmed migraines for up to 12 months with good eDiary 
completion compliance 
7. Confirmation of continuing good general health, or stable non-serious 
disease that in the opinion of the Investigator will not place the subject 
at risk 
 
CENTERS 
Multicenter in the United States 
STUDY DURATION 
1 week screening period, two-week (+ up to 1 week) run-in period, 6 to 
12 month treatment period, and a two-week safety follow-up visit 
EFFICACY 
ASSESSMENTS 
Headache symptoms at time of treatment, 30 min, 2 hour, 12 hour, 24 hour and 
48 hours post patch application:   
• 
Pain severity (0 = none, 1 = mild, 2 = moderate, 3 = severe)  
• 
Most bothersome other symptom (present/absent) 
• 
Nausea (Absent/Present) 
• 
Photophobia (Absent/Present) 
• 
Phonophobia (Absent/Present) 
• 
Rescue medication use 
• 
Pain relief (present/absent) 
• 
Migraine recurrence 
• 
Migraine-ACT Questions (Assessment of Current Therapy) 
 


 
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SAFETY 
ASSESSMENTS 
• 
Subject-reported skin assessments 30 min, 2 hours, 12 hours, 24 hours and 
48 hours 
• 
Investigator skin assessment at all post-treatment visits  
• 
Adverse Events 
• 
Physical exam including height and weight 
• 
Vital signs including blood pressure  
• 
Clinical Laboratory determinations including serum chemistries and 
hematological parameters 
• 
12-lead ECGs  
• 
Assessment of concomitant medications 
 
STUDY 
PROCEDURES 
• 
Screening procedures may be performed in 1 to 7 days 
• 
Run-in period for 2 (+ up to 1) weeks prior to Day 1  
• 
Clinic visits include Screening, drug dispensation visit Day 1, Month 1, 2, 3, 
6, 9, 12 (or early discontinuation) 
• 
A minimum of 2 migraine attacks treated per month with subject skin 
assessment recordings at 30 minutes, 2 hours, 12 hours, 24 hours and 48 
hours post patch application 
 
STATISTICAL 
ANALYSES 
The safety population will include all subjects who received any amount of 
study drug (i.e., applied at least 1 patch).  Adverse events will be summarized 
overall and by preferred term and system organ class.  Adverse events will 
also be summarized by severity and relationship to study drug. Serious AEs 
and AEs leading to discontinuation of study drug will also be summarized.  
Actual values and changes from baseline for clinical laboratory test results 
and vital sign measurements will be summarized using descriptive statistics 
(n, mean, SD, median, minimum, and maximum).  ECG parameters will be 
summarized using shift tables.  The number and percentage of subjects 
experiencing Bruising, Erythema, and Edema and other skin assessments will 
be tabulated. 
All efficacy endpoints will be summarized using descriptive statistics.  
Further details regarding efficacy analyses can be found in the statistical 
analysis plan. 


 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE - PRINCIPAL INVESTIGATOR ..............................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .........................................3 
PROTOCOL SYNOPSIS ........................................................................................................5 
TABLE OF CONTENTS ......................................................................................................11 
LIST OF TABLES .................................................................................................................14 
LIST OF FIGURES ...............................................................................................................14 
1 
INTRODUCTION .......................................................................................................16 
1.1 
Background ....................................................................................................................16 
1.2 
Clinical Pharmacology, Efficacy, and Safety of Zolmitriptan .......................................17 
1.2.1 Human pharmacokinetics ........................................................................................17 
1.2.2 CP-2016-001 Clinical Efficacy and Safety Study ...................................................19 
1.2.2.1 
Primary Efficacy Analysis ..........................................................................20 
1.2.2.2 
Secondary Efficacy .....................................................................................21 
1.2.2.3 
Previous Co-Primary Endpoints in Migraine Trials for Comparison .........22 
1.2.2.4 
Safety Results .............................................................................................24 
1.3 
Study Rationale ..............................................................................................................28 
2 
STUDY OBJECTIVES................................................................................................29 
2.1 
Primary Objective ..........................................................................................................29 
2.2 
Secondary Objectives ....................................................................................................29 
3 
INVESTIGATIONAL PLAN .....................................................................................30 
3.1 
Study Design ..................................................................................................................30 
3.2 
Selection of Study Population........................................................................................31 
3.2.1 Number of Subjects .................................................................................................31 
3.2.2 Inclusion Criteria .....................................................................................................31 
3.2.3 Exclusion Criteria ...................................................................................................33 
3.2.4 Eligibility Criteria for Study Treatment ..................................................................35 
3.2.5 Prior and Concomitant Medications Allowed During the Study ............................36 
3.2.6 Early Termination ...................................................................................................36 
3.2.6.1 
Withdrawal of Subjects...............................................................................36 
3.2.6.2 
Replacement of Subjects.............................................................................37 
3.2.6.3 
Premature Discontinuation of the Trial ......................................................37 
4 
STUDY TREATMENTS .............................................................................................38 
4.1 
Identity of Investigational Products ...............................................................................38 
4.1.1 M207 .......................................................................................................................38 
4.1.2 Product Description and Patch Application ............................................................38 
4.2 
Dispensing Clinical Trial Material (CTM) Kits ............................................................41 


 
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4.3 
Packaging, Labeling, and Receipt of Supplies ..............................................................42 
4.4 
Study Drug Stability, Storage, and Retention ................................................................42 
4.5 
Study Drug Kit Administration, Dispensation, Accountability, and Return .................42 
4.6 
System Performance ......................................................................................................43 
4.7 
Medication Compliance .................................................................................................43 
5 
SAFETY AND EFFICACY ASSESSMENTS ...........................................................44 
5.1 
Safety .............................................................................................................................44 
5.2 
Efficacy ..........................................................................................................................44 
6 
STUDY PROCEDURES AND SCHEDULE .............................................................45 
6.1 
Study Schedule ..............................................................................................................45 
6.1.1 Screening (Visit 1): Up to 1 Week Prior to Start of the Run-in Period ..................47 
6.1.2 Run-in Period: 2 Weeks [up to +1 week] Prior to Dispensation of Study Medication 
through Day 1 ....................................................................................................48 
6.1.2.1 
First Day of Run-in (Visit 2):  Week -2 (up to week -3) ............................48 
6.1.2.2 
Daily through Run-in Period (2 weeks [+ up to 1 additional week]) .........49 
6.1.3 Day 1 (Visit 3, Dispense Study Medication) ..........................................................49 
6.1.4 Treatment Phase: Up to 12 Months .........................................................................50 
6.1.5 Month 1 (Visit 4), Month 2 (Visit 5), Month 3 (Visit 6), Month 6 (Visit 7) ..........52 
6.1.6 Month 9 (Visit 8) and Month 12 End of Study Final Visit (Visit 9/or Early 
Termination) ......................................................................................................53 
6.1.7 Monthly Phone Contacts at Months 4, 5, 7, 8, 10, and 11 (± 7 days) .....................54 
6.1.8 Two Week Post Study Safety Visit (Visit 10) ........................................................54 
6.2 
Study Procedures ...........................................................................................................54 
6.2.1 Informed Consent ....................................................................................................54 
6.2.2 Inclusion/Exclusion Criteria ...................................................................................55 
6.2.3 Medical History and Demographics........................................................................55 
6.2.4 Randomization ........................................................................................................55 
6.2.5 Migraine Assessment of Current Therapy (Migraine-ACT) ...................................55 
6.2.6 Physical Examination ..............................................................................................55 
6.2.7 Height and Weight ..................................................................................................55 
6.2.8 Vital Signs ...............................................................................................................55 
6.2.9 Clinical Laboratory Tests ........................................................................................56 
6.2.10 Twelve-Lead Electrocardiogram .............................................................................57 
6.2.11 Concomitant and Prohibited Medications ...............................................................57 
6.2.12 Assessment of Adverse Events ...............................................................................59 
6.2.13 Subject Reported and Investigator Reported Skin Assessments .............................59 
6.2.13.1 
Investigator Skin Assessments ...................................................................59 
6.2.13.2 
Bruising.......................................................................................................60 
6.2.13.3 
Other Skin Assessments – Erythema and Edema .......................................60 
7 
STATISTICS ................................................................................................................62 
7.1 
Analysis Variables .........................................................................................................62 
7.1.1 Safety Endpoints .....................................................................................................62 


 
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7.1.2 Efficacy Endpoints ..................................................................................................62 
7.2 
Populations for Analysis ................................................................................................63 
7.3 
Statistical Methods .........................................................................................................63 
7.3.1 Baseline Characteristics ..........................................................................................63 
7.3.2 Safety Analyses .......................................................................................................63 
7.3.3 Efficacy Analyses ...................................................................................................64 
8 
ADVERSE EVENTS ...................................................................................................65 
8.1 
Reporting Period ............................................................................................................65 
8.2 
Adverse Event Definitions .............................................................................................65 
8.2.1 Adverse Events (Adverse Experiences) ..................................................................65 
8.2.1.1 
Serious Adverse Event Definitions .............................................................66 
8.2.1.2 
Unexpected Adverse Event.........................................................................68 
8.2.1.3 
Severity Ratings ..........................................................................................68 
8.2.1.4 
Relationship to Study Drug ........................................................................68 
8.3 
Documentation and Reporting of Adverse Events by Investigator ...............................69 
8.3.1 Reporting Requirements for Serious Adverse Events .............................................70 
8.3.1.1 
Investigator Reporting Responsibilities to the Independent Ethics 
Committee and Other Agencies ..................................................................70 
8.3.2 Reporting Requirements for Non-Serious Adverse Event ......................................71 
8.4 
Follow up of Adverse Events.........................................................................................71 
8.5 
Contacts for Serious Adverse Events and Medical Monitoring ....................................71 
9 
EMERGENCY PROCEDURES ................................................................................72 
9.1 
Emergency Contact ........................................................................................................72 
9.2 
Unblinding Procedures ..................................................................................................72 
9.3 
Emergency Treatment ....................................................................................................72 
10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .......................................73 
10.1 Study Monitoring ...........................................................................................................73 
10.2 Audits and Inspections ...................................................................................................73 
10.3 Institutional Review Board (IRB)/Independent Committee ..........................................73 
10.4 Participant Recruitment .................................................................................................74 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................74 
12 
ETHICS ........................................................................................................................75 
12.1 Ethics Review ................................................................................................................75 
12.1.1 Ethical Conduct of the Study ..................................................................................75 
12.2 Written Informed Consent .............................................................................................75 
12.3 Disclosure of Data .........................................................................................................76 
13 
DATA HANDLING AND RECORDKEEPING .......................................................77 
13.1 Inspection of Records ....................................................................................................77 
13.2 Case Report Forms.........................................................................................................77 
13.3 Retention of Records .....................................................................................................78 


 
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14 
REFERENCES.............................................................................................................79 
APPENDIX 1 – FITZPATRICK SKIN TYPE CHART (SUBJECT COMPLETED) ....80 
APPENDIX 2 – THE MIGRAINE ASSESSMENT OF CURRENT THERAPY 
(MIGRAINE-ACT) ................................................................................................................82 
APPENDIX 3 – EDIARY QUESTIONS ..............................................................................83 
APPENDIX 4 – SUBJECT SKIN GRADING CARD ........................................................87 
APPENDIX 5 – INVESTIGATOR ASSESSMENTS - SKIN SIGNS OR SYMPTOMS AND 
PHOTOGRAPHS ..................................................................................................................89 
APPENDIX 6 – INVESTIGATOR ASSESSMENTS – RATING FOR BRUISING, 
ERYTHEMA, EDEMA AND PHOTOGRAPHS ...............................................................91 
 
LIST OF TABLES 
Table 1: 
Key Pharmacokinetic Parameters ..........................................................................17 
Table 2: 
Comparison of exposure – M207 vs Oral and Intranasal Zolmitriptan 
(Phase 1 Study and Literature Comparisons).........................................................18 
Table 3: 
Most Common Adverse Events .............................................................................19 
Table 4: 
Co-Primary Endpoints: Primary Analysis – mITT population ..............................21 
Table 5: 
Nausea Freedom.....................................................................................................23 
Table 6: 
Phonophobia Freedom ...........................................................................................23 
Table 7: 
Photophobia Freedom ............................................................................................24 
Table 8: 
Treatment Emergent Adverse Events Occurring in Two or More Subjects ..........25 
Table 9: 
Investigator Visual Dermal Adverse Events ..........................................................26 
Table 10: Schedule of Study Procedures ...............................................................................45 
Table 11: Clinical Laboratory Tests .......................................................................................56 
Table 12: Prohibited Concomitant Medications ....................................................................58 
 
LIST OF FIGURES 
Figure 1: Proportion of Subjects with Pain-freedom at 15, 30, 45, 60, 120, 180, and 
240 min after treatment with M207 3.8 mg and placebo .......................................20 
Figure 2: Percentage of Subjects with Pain-Freedom at 0.5, 0.75, 1, 2, 24, and 
48 hours after treatment with M207 and placebo ..................................................21 
Figure 3: Percentage of Subjects with Pain Relief at 0.5, 0.75, 1, 2, 24, and 48 hours 
after treatment with M207 and placebo .................................................................22 
Figure 4: Subject-reported Patch Application Site Reactions (Redness, Bruising, 
and Swelling) .........................................................................................................27 
Figure 5: Subject Reported Patch Application Bruising .......................................................27 
Figure 6: Subject Reported Patch Application Swelling .......................................................28 
Figure 7: Study Design ..........................................................................................................30 
Figure 8: 5 cm2 Patch with Zolmitriptan Coated Titanium Microneedle Array ...................39 


 
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Figure 9: Handheld Gen 6 Patch Ring Assembly and Applicator .........................................39 
Figure 10: *M207 Patch Application ......................................................................................40 
 


 
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1 
INTRODUCTION 
1.1 
Background 
According to International Headache Society (IHS) diagnostic criteria, the prevalence of 
migraine has been reported to be 18% of females and 6% of males within the adult population 
(Lipton 2002).  An estimated 37 million Americans have acute migraine attacks.  Less than half 
receive optimal medical care.  
There is still an important unmet need in treating migraine despite the availability in the last 
20 years of numerous triptans that bind selectively to the 5-HT1B and 5-HT1D receptors.  Triptans 
offer good efficacy and tolerability and, with several alternative formulations (intranasal and SC 
injection), they can overcome the gastric stasis, nausea, and vomiting that commonly accompany 
migraine.  However, currently available triptans have several shortcomings including lack of 
universal efficacy, inconsistency of response, numerous adverse events, slow onset of action 
when administered orally, high recurrence rate and potential for Medication Overuse Headache.  
Zolmitriptan is a 5HT1B/D agonist widely used for the treatment of migraine.  Like other 
compounds in the triptan class, it has been shown to be effective and well tolerated in placebo-
controlled clinical trials.  Zolmitriptan is available as a conventional release tablet (2.5 mg and 
5.0 mg), a “fast melt” orally disintegrating tablet (2.5 mg and 5.0 mg), and a nasal spray (2.5 mg 
and 5.0 mg).  The last two formulations were developed to potentially provide a more convenient 
way to take the drug versus that of the conventional release tablet. 
The bioavailability of zolmitriptan conventional release tablets has been found to be between 
41 and 48%, and administration with food reduced Cmax and AUC by 13-16% (Seaber 1998).  
Zolmitriptan is metabolized to N-desmethyl zolmitriptan (potent active metabolite), N-oxide 
zolmitriptan, and indole-acetic acid metabolites.  Some of the metabolites appear to be formed 
from first-pass metabolism.  This first pass metabolism can be impacted by drugs that affect the 
cytochrome p-450 system.  Also, absorption is reported to be lower during an actual migraine 
attack.  
A product that avoids first-pass metabolism, the potential for food interaction and lesser 
absorption during a migraine could have advantages over existing zolmitriptan formulations.  
Additionally, an important consideration for a non-oral formulation of zolmitriptan is the high 
incidence of nausea that occurs during a migraine attack.  In 60-70% of migraine attacks, nausea 
is a significant symptom that patients experience.  Therefore, a product that can be administered 
without using the gastrointestinal system (and is therefore not susceptible to be vomited up) 
could be advantageous for the patient experiencing a migraine. 


 
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1.2 
Clinical Pharmacology, Efficacy, and Safety of Zolmitriptan 
1.2.1 
Human pharmacokinetics 
A Phase 1 study (CP2015-007) compared the pharmacokinetics of the parent compound and the 
metabolites, and tolerability of various doses of intracutaneous zolmitriptan (M207) doses to a 
standard oral dose (2.5 mg) of zolmitriptan.  Additionally, since onset of effect may be an 
important attribute of the intracutaneous system, the study included a comparison of Tmax values 
with SC sumatriptan 6.0 mg.  The study provided preliminary information on the potential 
advantages of the M207 system use for the treatment of migraine. 
The study compared single administrations of 5 regimens of M207, as well as 2.5 mg of oral 
zolmitriptan and 6.0 mg of subcutaneous sumatriptan in a 7-way crossover design in 20 healthy 
volunteers.   
The calculated key pharmacokinetic parameters for the zolmitriptan regimens and subcutaneous 
sumatriptan are shown in Table 1. 
Table 1: Key Pharmacokinetic Parameters 
 
Dose (mg) 
Cmax (SD) 
ng/mL 
Tmax  Med 
(Range) 
AUC0-2hr 
(SD) ng/mL 
hour 
AUC0-last 
(SD) ng/mL 
hour 
AUC0-last 
Dose 
BA v 
Oral 
A  
(M207) 
0.48 
1.8 (0.53) 
20 (2-30) 
2.1 (0.73) 
2.8 (1.36) 
5.8 
67% 
B  
(M207) 
0.48 x 2 
3.7 (1.05) 
20 (2-30) 
4.2 (0.95) 
6.5 (1.97) 
7.5 
87% 
C  
(M207) 
1.9 
6.8 (2.75) 
20 (2-30) 
7.4 (2.53) 
12.3 (4.31) 
6.5 
76% 
F  
(M207) 
1.9 x 2 
14.6 (4.46) 
17.5 (2-30) 
16.4 (5.34) 
27.8 (9.93) 
7.3 
85% 
G  
(M207) 
3.8 
22.6 (14.00) 
15 (2-30) 
19.3 (5.37) 
31.7 (8.35) 
8.3 
97% 
D  
(Oral Zolmi) 
2.5 
3.8 (1.51) 
60 (30-240) 
4.7 (2.24) 
22.2 (10.79) 
8.6 
100% 
E  
(SC Suma) 
6.0 
88.8 (27.56) 
10 (5-20) 
70.9 (14.15) 100.9 (23.29) 
16.8 
 
 
Perhaps most relevant to the potential utility of this product for the treatment of migraine is the 
Tmax for the M207 regimens, showing much more rapid absorption of the zolmitriptan from 
intracutaneous administration compared to oral administration. 
Rapoport et al 1997 compared oral doses ranging from 1 mg to 10 mg to placebo in 
1258 patients, and found that efficacy increased as a function of dose, and that all doses of 


 
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Zolmitriptan were well-tolerated, although the incidence of adverse events did increase as a 
function of dose. 
Doses of 25 mg of oral zolmitriptan for the treatment of migraine were evaluated in two 
additional studies (Schoenen et al 1994 and Visser et al 1996) and in both studies this dose was 
well-tolerated. 
Comparative Systemic Exposure:  M207 vs Oral and Intranasal Zolmitriptan 
Maximal plasma concentrations of zolmitriptan seen with M207 in the Phase 1 study 
(CP-2015-007) at the dose Zosano plans to study appear to be in the range of those seen with 
2.5 mg to 10 mg oral, or 5 mg intranasal (see Table 2).  Comparisons based on AUC values show 
that the exposure with M207 appears to be lower than with oral or intranasal zolmitriptan 
administration.  How the different pharmacokinetic profile of M207 influences efficacy and 
tolerability when used for the acute treatment of migraine was evaluated in the CP-2016-001 
trial. 
Table 2: Comparison of exposure – M207 vs Oral and Intranasal Zolmitriptan (Phase 1 
Study and Literature Comparisons) 
Treatment (Study) 
Cmax (ng/ml) 
AUC0-last (ng/ml*hr) 
M207 0.96 mg (Study 2015-007) 
3.73 
6.5 
M207 1.9 mg (Study 2015-007) 
6.40 
12.3 
M207 2 x 1.9 mg (Study 2015-007) 
14.6 
27.8 
Zolmitriptan 2.5 mg oral (Study 2015-007) 
3.8 
22.2 
Zolmitriptan 5.0 mg Intranasal (Yates 2003) 
6.51 
42.1 
Zolmitriptan 10 mg oral (Seaber 1998) 
16.6(M) -20.9(F) 
84.4(M)-108.6(F) 
 
Adverse Events Reported in Phase 1 Trial 
In the Phase 1 study of M207, 19 of 20 subjects reported an adverse event either related to M207 
administration or SQ sumatriptan administration.  Nearly all the adverse events were mild in 
intensity and short in duration.  The most common adverse events reported are shown in Table 3.  
The adverse events appear to be similar to those previously reported for zolmitriptan and 
sumatriptan.  Most of the adverse events judged to be related to study drug were also rated as 
mild in severity.  There was a higher incidence of adverse events following the higher doses of 
M207 and SQ sumatriptan.  The following table displays adverse events reported by 4 or more 
subjects (Most Common Adverse Events Table 3). 


 
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Table 3: Most Common Adverse Events 
Adverse Events 
Part 1 
Part 2 
Part 3 
Total 
M207 
0.48 mg 
M207 
0.48 mg * 2 
M207 
1.9 mg 
Zolmi 
2.5 mg 
(oral) 
Suma 
6.0 mg 
SC 
M207 
1.9 mg * 2 
M207 
3.8 mg 
Headache 
3 
2 
4 
0 
0 
4 
4 
17 
Hot flushes 
0 
0 
0 
0 
0 
2 
2 
4 
Paresthesia 
0 
2 
3 
0 
6 
10 
8 
29 
Throat and jaw 
tightness, 
heaviness, ache 
0 
0 
1 
0 
0 
2 
2 
5 
 
Vital Signs/ECGs/Labs 
There were no clinically meaningful changes in ECG or laboratory parameters in any of the 
subjects, and mean values for ECG parameters had minimal changes in the post-dosing period.  
There were small mean increases in systolic and diastolic blood pressure following M207 3.8 mg 
and sumatriptan 6.0 mg. 
The changes were in the 3-12 mm Hg range, and all M207 groups were near Baseline at 1 hour. 
1.2.2 
CP-2016-001 Clinical Efficacy and Safety Study 
The CP-2016-001 efficacy and safety study evaluated the patient population, endpoints, placebo 
comparator, and study design typically used in trials of therapies for acute treatment of migraine, 
consistent with the FDA 2014 Guidance Document.  This study compared three doses of M207 
(1.0 mg, 1.9 mg, and 3.8 mg administered as two 1.9 mg patches) to placebo for the treatment of 
a single migraine attack.   
Five-hundred and eighty-nine subjects were enrolled in this multi-center, double-blind, 
randomized, placebo-controlled study, of whom 365 were randomized.  Of those randomized, 
333 treated subjects were included in the safety analysis, and 321 subjects qualified for the 
modified intent-to-treat (mITT) population.  The comparison with placebo for the 3.8 mg group 
was highly significant for both co-primary endpoints (pain freedom at 2 hours p = .0001 and 
most bothersome symptom freedom at 2 hours p = 0.0009). 
The percentage of subjects with pain-freedom after treatment with M207 3.8 mg and placebo 
over time is shown in Figure 1. 


 
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Figure 1: Proportion of Subjects with Pain-freedom at 15, 30, 45, 60, 120, 180, and 240 min 
after treatment with M207 3.8 mg and placebo 
 
 
1.2.2.1 Primary Efficacy Analysis 
The primary efficacy analysis compared each active treatment with placebo to the co-primary 
endpoints of proportion of subjects who were pain free at 2 hours and the proportion of subjects 
who were most bothersome symptom free at 2 hours.  The order of testing was pre-specified in 
the analysis plan with the first two tests being the highest dose (3.8 mg) vs placebo for the two 
co-primaries, followed by pain freedom and most bothersome symptom freedom at 2 hours (in 
that order) for the 1.9 mg dose vs placebo.   
As shown in Table 4, the comparison with placebo for the 3.8 mg group was highly significant 
for both co-primary endpoints (pain freedom at 2 hours p = 0.0001 and most bothersome 
symptom freedom at 2 hours p = 0.0009). 
For the 1.9 mg group, the comparison for pain freedom at 2 hours showed superiority as 
compared to placebo, but the comparison for most bothersome other symptom at 2 hours was not 
statistically significant.  Because of the pre-defined order of testing, statistical significance for 
pain freedom at 2 hours cannot be claimed for the 1.0 mg group, even though the p-value was 
less than 0.05. 


 
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Table 4: Co-Primary Endpoints: Primary Analysis – mITT population 
Treatment Group 
 
Placebo  
(n=77) 
1.0 mg  
(n=79) 
1.9 mg 
(n=83) 
3.8 mg  
(n=82) 
Pain Freedom at 2 hours 
N (%)  
11 (14.3%)  
24 (30.4%) 
23 (27.7%) 
34 (41.5%) 
Difference from 
Placebo 
 
16.1 % 
13.4 % 
27.2 % 
P-Value 
 
0.0149 
0.0351 
0.0001 
Freedom from Most Bothersome Symptom at 2 hours 
N (%)  
33 (42.9%) 
45 (57.0%) 
44 (53.0%) 
56 (68.3%) 
Difference from 
Placebo 
 
14.1 % 
10.2 % 
25.4 % 
P-Value 
 
0.0706 
0.1694 
0.0009 
 
1.2.2.2 Secondary Efficacy 
The percentage of subjects with pain-freedom after treatment with M207 and placebo over time 
is shown in Figure 2.  The percentage of subjects who were pain free was higher for the 3.8 mg 
M207 group as compared to placebo beginning at 45 minutes post-dose and continuing through 
48 hours post-dose. 
Figure 2: Percentage of Subjects with Pain-Freedom at 0.5, 0.75, 1, 2, 24, and 48 hours 
after treatment with M207 and placebo 
 


 
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1.2.2.3 Previous Co-Primary Endpoints in Migraine Trials for Comparison 
Prior to issuance of the Guidance Document in October of 2014, the four co-primary endpoints 
utilized in acute treatment of migraine trials were pain relief, nausea freedom, photophobia 
freedom and phonophobia freedom at 2 hours.  Although this trial was not powered to “win” on 
these endpoints, many current products are approved and labeled based on these endpoints.  
Therefore, we present the data for these four “old” endpoints here. 
Pain relief (improvement to mild or none) from moderate or severe at the various timepoints 
post-dose is shown in Figure 3.  The percentages are high for all treatment groups, and 80.5% at 
2 hours for the M207 3.8 mg group compares very favorably with many approved products.  The 
placebo rates are also quite high, and the therapeutic gain (active – placebo) seems in line with 
approved products. 
Figure 3: Percentage of Subjects with Pain Relief at 0.5, 0.75, 1, 2, 24, and 48 hours after 
treatment with M207 and placebo 
 
 
The following tables display nausea freedom, photophobia freedom, and phonophobia freedom 
at the various post-dose timepoints.  Once again, the 3.8 mg M207 group has high percentages at 
2 hours for nausea freedom and photophobia freedom and the separation from placebo is 
apparent.  For phonophobia freedom, the separation between placebo and active was less 
apparent at earlier timepoints, and only at later timepoints were the differences notable. 
 


 
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Table 5: Nausea Freedom 
Nausea Freedom 
(mITT) 
Treatment Group 
Timepoint 
Placebo 
(n=77) 
1.0 mg 
(n=79) 
1.9 mg 
(n=83) 
3.8 mg 
(n=82) 
15 Minutes 
36.4% 
39.2% 
41.0% 
32.9% 
30 Minutes 
59.7% 
55.7% 
49.4% 
53.7% 
45 Minutes 
63.6% 
58.2% 
66.3% 
62.2% 
1 hour 
63.6% 
68.4% 
71.1% 
76.8% 
2 hours 
63.6% 
75.9% 
74.7% 
81.7% 
3 hours 
58.4% 
78.5% 
74.7% 
79.3% 
4 hours 
54.5% 
78.5% 
73.5% 
79.3% 
12 hours 
45.5% 
75.9% 
71.1% 
80.5% 
24 hours 
44.2% 
72.2% 
74.7% 
79.3% 
48 hours 
41.6% 
72.2% 
72.3% 
70.7% 
 
Table 6: Phonophobia Freedom 
Phonophobia 
Freedom (mITT) 
Treatment Group 
Timepoint 
Placebo 
(n=77) 
1.0 mg 
(n=79) 
1.9 mg 
(n=83) 
3.8 mg 
(n=82) 
15 Minutes 
14.3% 
20.3% 
15.7% 
25.6% 
30 Minutes 
35.1% 
34.2% 
28.9% 
45.1% 
45 Minutes 
37.7% 
44.3% 
43.4% 
57.3% 
1 hour 
46.8% 
48.1% 
57.8% 
61.0% 
2 hours 
55.8% 
58.2% 
61.4% 
69.5% 
3 hours 
54.4% 
63.3% 
71.1% 
73.2% 
4 hours 
57.1% 
69.6% 
69.9% 
74.4% 
12 hours 
44.2% 
73.4% 
68.7% 
78.0% 
24 hours 
42.9% 
69.6% 
68.7% 
76.8% 
48 hours 
42.9% 
72.2% 
68.7% 
70.7% 
 


 
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Table 7: Photophobia Freedom 
Photophobia 
Freedom (mITT) 
Treatment Group 
Timepoint 
Placebo 
(n=77) 
1.0 mg 
(n=79) 
1.9 mg 
(n=83) 
3.8 mg 
(n=82) 
15 Minutes 
9.1% 
11.4% 
9.6% 
11.0% 
30 Minutes 
22.1% 
27.8% 
24.1% 
26.8% 
45 Minutes 
24.7% 
43.0% 
33.7% 
41.5% 
1 hour 
33.8% 
48.1% 
44.6% 
53.7% 
2 hours 
41.6% 
60.8% 
56.6% 
69.5% 
3 hours 
44.2% 
65.8% 
61.4% 
72.0% 
4 hours 
45.5% 
65.8% 
63.9% 
74.4% 
12 hours 
42.9% 
74.7% 
66.3% 
75.6% 
24 hours 
42.9% 
72.2% 
68.7% 
73.2% 
48 hours 
40.3% 
70.9% 
67.5% 
68.3% 
 
1.2.2.4 Safety Results 
No serious adverse events occurred in this study.  Adverse events including investigator and 
subject-reported dermal events at the patch site were generally mild and transient.  Treatment-
emergent adverse events that occurred in two or more subjects summarized by System Organ 
Class/Preferred Term are shown in Table 8, and Investigator Dermal Adverse Events are shown 
in Table 9.  Subject Reported Patch Application Site Reactions (redness, bruising and swelling) 
are shown in Figure 4, Figure 5 and Figure 6, respectively. 


 
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Table 8: Treatment Emergent Adverse Events Occurring in Two or More Subjects 
System Organ 
Class/Preferred Term 
Treatment Group 
Placebo 
(N=83) 
M207 
1 mg 
(N=80) 
M207 
1.9 mg 
(N=87) 
M207 
3.8 mg 
(N=83) 
Total 
(N=333) 
No. (%) 
Subjects 
No. (%) 
Subjects 
No. (%) 
Subjects 
No. (%) 
Subjects 
No. (%) 
Subjects 
General disorders and 
administration site 
conditions 
12 (14.5%) 
23 (28.8%) 
31 (35.6%) 
38 (45.8%) 
104 (31.2%) 
  Application site erythema 
9 (10.8%) 
13 (16.3%) 
17 (19.5%) 
22 (26.5%) 
61 (18.3%) 
  Application site bruise 
3 (3.6%) 
5 (6.3%) 
12 (13.8%) 
12 (14.5%) 
32 (9.6%) 
  Application site pain 
1 (1.2%) 
2 (2.5%) 
2 (2.3%) 
8 (9.6%) 
13 (3.9%) 
  Application site 
  haemorrhage 
0 (0.0%) 
3 (3.8%) 
5 (5.7%) 
4 (4.8%) 
12 (3.6%) 
  Application site swelling 
3 (3.6%) 
1 (1.3%) 
3 (3.4%) 
2 (2.4%) 
9 (2.7%) 
  Application site oedema 
0 (0.0%) 
1 (1.3%) 
3 (3.4%) 
2 (2.4%) 
6 (1.8%) 
  Application site 
  discolouration 
1 (1.2%) 
1 (1.3%) 
1 (1.1%) 
1 (1.2%) 
4 (1.2%) 
 
 
 
 
 
 
Musculoskeletal and 
connective tissue disorders 
0 (0.0%) 
1 (1.3%) 
2 (2.3%) 
4 (4.8%) 
7 (2.1%) 
  Muscle tightness 
0 (0.0%) 
0 (0.0%) 
1 (1.1%) 
2 (2.4%) 
3 (0.9%) 
  Musculoskeletal stiffness 
0 (0.0%) 
0 (0.0%) 
1 (1.1%) 
1 (1.2%) 
2 (0.6%) 
  Myalgia 
0 (0.0%) 
1 (1.3%) 
0 (0.0%) 
1 (1.2%) 
2 (0.6%) 
 
 
 
 
 
 
Gastrointestinal disorders 
1 (1.2%) 
2 (2.5%) 
2 (2.3%) 
1 (1.2%) 
6 (1.8%) 
  Nausea 
0 (0.0%) 
2 (2.5%) 
1 (1.1%) 
1 (1.2%) 
4 (1.2%) 
  Vomiting 
1 (1.2%) 
1 (1.3%) 
0 (0.0%) 
0 (0.0%) 
2 (0.6%) 
 
 
 
 
 
 
Investigations 
1 (1.2%) 
1 (1.3%) 
1 (1.1%) 
0 (0.0%) 
3 (0.9%) 
  Blood creatine 
  phosphokinase increased 
1 (1.2%) 
0 (0.0%) 
1 (1.1%) 
0 (0.0%) 
2 (0.6%) 
 
 
 
 
 
 
Infections and infestations 
0 (0.0%) 
1 (1.3%) 
1 (1.1%) 
0 (0.0%) 
2 (0.6%) 
 


 
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Table 9: Investigator Visual Dermal Adverse Events 
Patch-Related 
Superficial 
Punctate Bruising 
(PRSPB) 
N 
Treatment Group 
Placebo 
(N=83) 
M207 
1 mg 
(N=80) 
M207 
1.9 mg 
(N=87) 
M207 
3.8 mg 
(N=83) 
83 
78 
84 
83 
 
None 
82 (98.8%) 
73 (93.6%) 
72 (85.7%) 
74 (89.2%) 
 
≤ 25% ZP patch application 
site has punctate bruising 
spots 
1 (1.2%) 
5 (6.4%) 
9 (10.7%) 
4 (4.8%) 
 
≥ 26% to < 50% ZP patch 
application site has punctate 
bruising spots 
0 (0.0%) 
0 (0.0%) 
2 (2.4%) 
2 (2.4%) 
 
> 50% ZP patch application 
site has punctate bruising 
spots 
0 (0.0%) 
0 (0.0%) 
1 (1.2%) 
3 (3.6%) 
 
 
 
 
 
 
Edema 
N 
83 
78 
84 
83 
 
None 
83 (100.0%) 77 (98.7%) 
81 (96.4%) 
82 (98.8%) 
 
Slight Edema 
0 (0.0%) 
1 (1.3%) 
3 (3.6%) 
1 (1.2%) 
 
Moderate Edema 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
 
Severe Edema 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
 
 
 
 
 
 
Erythema 
N 
83 
78 
84 
83 
 
None 
78 (94.0%) 
71 (91.0%) 
71 (84.5%) 
64 (77.1%) 
 
Mild Redness 
5 (6.0%) 
7 (9.0%) 
10 (11.9%) 
16 (19.3%) 
 
Well-defined Redness 
0 (0.0%) 
0 (0.0%) 
3 (3.6%) 
3 (3.6%) 
 
Beet Redness 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
 
Subjects’ ratings of the application sites for erythema, edema, and bruising are shown in the 
following figures (note that the number of subjects who entered values for 4, 12, and 48 hours 
was smaller than at 30 minutes and 24 hours, as amendment #3 which required the addition of 4, 
12, and 48 hour assessments was implemented mid-study. 


 
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Figure 4: Subject-reported Patch Application Site Reactions (Redness, Bruising, and 
Swelling) 
 
 
Figure 5: Subject Reported Patch Application Bruising 
 


 
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Figure 6: Subject Reported Patch Application Swelling 
 
 
1.3 
Study Rationale 
This study is designed to evaluate the safety of repeated use of M207 2 x 1.9 mg, over the course 
of 6-12 months of use.  The recently-completed study (CP-2016-001) showed that tolerability 
was acceptable when M207 was used for a single migraine treatment.  It also demonstrated that 
subjects were able to evaluate their application site reactions in their e-diaries and most subjects 
reported redness at the site of application at some time points post treatment.  This study will 
assess the effects of repeated treatment for multiple migraine attacks.  Both subjects and 
investigators will evaluate the effects of treatment by outpatient and in-clinic assessments. 


 
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2 
STUDY OBJECTIVES 
This open-label study is designed to evaluate the long-term safety of repeat administration of 
M207 in subjects with migraine.  
2.1 
Primary Objective 
• To assess the long-term safety of 3.8 mg (administered as two 1.9 mg patches) of 
M207 for the acute treatment of migraine 
 
2.2 
Secondary Objectives 
• To assess the efficacy of 3.8 mg (administered as two 1.9 mg patches) of M207 for 
the acute treatment of migraine 


 
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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
The study is outlined in Figure 7. 
Figure 7: Study Design 
SCREENING PERIOD 
 
(up to 7 days) 
 
Up to one week prior to start of 
Run-in period 
VISIT 2 (START OF RUN-IN 
PERIOD) 
(may be combined with Visit 1) 
 
Run-in period is two weeks (plus up 
to 1 week) prior to Day 1 (Visit 3) 
TREATMENT PERIOD 
 
Day 1 up to 12 months 
 
Informed consent 
discussion and form 
signed; Perform screening 
lab work and other 
screening tests. 
↓ 
If preliminary entry criteria 
indicate that the subject is 
not eligible, report the 
subject as a screen failure. 
 
 
 
→ 
 
 
If preliminary entry criteria 
indicate that the subject is 
probably eligible, complete the 
eDiary training, issue an 
eDiary, and schedule the 
Day 1 visit for 2 weeks later 
(plus up to 1 week if needed) 
↓ 
Subject records migraine 
activity on the eDiary for a 
minimum of 14 days and up to 
21 days.   
↓ 
If the subject does not meet all 
the inclusion criteria and the 
eligibility criteria for study 
treatment, and/or meets one or 
more of the exclusion criteria, 
report the subject as a run-in 
failure. 
 
 
 
 
 
 
 
 
 
 
 
→ 
 
 
 
 
 
 
 
 
 
 
If the subject meets all the 
inclusion and none of 
exclusion criteria, dispense 
study medication to the 
subject at Visit 3: 
↓ 
Subject will treat migraine 
attacks for up to 12 months. 
Subject will complete eDiary 
upon confirmation of each 
qualifying migraine and will 
self-administer the patches.  
Subject will continue to 
complete the eDiary at 
specified time points.  
 
 
This is an open-label, twelve-month safety study.  There will be a screening period followed by a 
14-day run-in period to record migraine activity.  Screening activities may be completed in a 
period as short as one day or may be spread out over up to one week.  On the day of screening 
procedures, if preliminary entry criteria indicate that the subject is probably eligible, the eDiary 
training can be completed, the eDiary can be issued, and the subject may begin the run-in period.  


 
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If during the run-in period, additional information becomes available to exclude the subject 
(e.g., return of 12-lead ECG or lab results), the subject should be notified of screen failure and 
instructed to return any provisional eDiary device (if applicable) to the center.   
The run-in period is to determine eligibility for treatment with study medication based on daily 
eDiary data collection, and is planned to be 2 weeks in duration but may be extended up to an 
additional 1 week to accommodate scheduling, and/or to confirm diary compliance and 
eligibility.  The run-in period will be a minimum of 14 days and no more than 21 days in 
duration.  Qualified subjects will receive study medication at Day 1 (Visit 3) for up to twelve 
months for the treatment of migraine headaches.  Migraines will be treated with a single dose, 
consisting of two patches, but subjects can treat multiple migraine attacks throughout the 
12 months.  Using the eDiary to confirm they are experiencing a qualified migraine, subjects will 
self-administer the patches and continue to respond to questions in the eDiary for 48 hours post 
treatment administration.  
3.2 
Selection of Study Population 
3.2.1 
Number of Subjects 
Approximately 400 subjects will be screened to ensure that at least 300 subjects enter the run-in 
period and that at least 250 subjects are enrolled into the treatment phase.  Fifty subjects must 
complete the entire one-year treatment period and 150 subjects must complete a minimum of 
six months of treatment. 
3.2.2 
Inclusion Criteria 
Subjects presenting with all of the following may be included in the study: 
1. 
Able to provide written informed consent 
2. 
Women or men 18 to 75 years of age 
3. 
Greater than 1 year history of episodic, migraine (with or without aura) with onset 
prior to 50 years of age.  Diagnosis must comply with International Headache 
Society (IHS ICHD-3beta) diagnostic criteria.  Diagnostic criteria must include a 
history of at least five attacks not attributed to any other disorder that include all 
of the following criteria: 
a) 
Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) 
b) 
Headache has at least two of the following characteristics: 
i. 
unilateral location 
ii. 
pulsating quality 


 
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iii. 
moderate or severe pain intensity 
iv. 
aggravation by or causing avoidance of routine physical activity 
(e.g., walking or climbing stairs) 
c) 
During headache at least one of the following: 
i. 
nausea and/or vomiting 
ii. 
both photophobia and phonophobia 
4. 
Migraine history during the 6-month period prior to the screening period must 
include: 
a) 
at least 2 migraines per month 
b) 
no more than 8 migraines per month 
c) 
no more than 15 headache days per month 
5. 
Women of child-bearing potential must not be pregnant, must agree to avoid 
pregnancy during the trial, and must use an acceptable double-barrier method of 
birth control (examples of methods include partner using condom, female using 
IUD, hormonal or non-hormonal contraceptive, diaphragm with spermicide, or 
contraceptive sponge) for the duration of the trial.  
6. 
No significant ECG findings, defined by: 
a) 
ischemic changes defined as > 1mm of down-sloping ST segment depression 
in at least two contiguous leads, 
b) 
Q-waves present in at least two contiguous leads, 
c) 
clinically significant intra-ventricular conduction abnormalities (left bundle 
branch block or Wolf-Parkinson-White syndrome), or 
d) 
clinically significant arrhythmias (e.g., current atrial fibrillation) 
7. 
Able to understand and operate the electronic diary 
8. 
Able to apply the demo study drug patches 
9. 
In the opinion of the investigator, subject is willing to treat a minimum of 
2 migraines per month with use of study medication and is willing to consistently 
perform eDiary completion for up to 12 months. 
 


 
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3.2.3 
Exclusion Criteria 
Subjects presenting with any of the following will not be included in the study: 
1. 
Contraindication to triptans 
2. 
Use of any prohibited concomitant medications within 10 days of the Run-in 
Period (See Section 6.2.11 for list of prohibited concomitant medications 
prohibited for the duration of the study) 
3. 
Use of any prescription anti-coagulant including Pradaxa (dabigatran), Coumadin 
(warfarin sodium), Eliquis (apixaban), and/or Xarelto (rivaroxaban) within 
30 days prior to screening and throughout the duration of the study. 
4. 
History of hemiplegic migraine or migraine with brain stem aura (formerly called 
basilar migraine) 
5. 
Participation in another investigational trial during the 30 days prior to the Run-in 
Period or during this study 
6. 
Diagnosis of cancer (other than non-invasive skin cancer) within the 5 years prior 
to the Run-in Period 
7. 
History of unstable psychiatric illness requiring medication changes or 
hospitalization in the 12 months prior to the Run-in Period 
8. 
Known allergy or sensitivity to zolmitriptan or its derivatives or formulations 
9. 
Known allergy or sensitivity to adhesives and/or titanium  
10. 
Planned participation in activities which cause inflammation, irritation, sunburn, 
lesions, and/or tattoos at the intended application site from two weeks prior to 
screening through the last day of study participation 
11. 
Use of greater than 5 doses of opioid or barbiturate containing medications in the 
preceding 30 days prior to screening and/or who anticipate using more than 
5 doses per month of these medications at any time during the study 
12. 
Women who are pregnant, breast-feeding or plan a pregnancy during this study 
13. 
Clinically significant liver disease (SGPT > 150 U/L; SGOT > 130 U/L or LDH 
> 750 U/L)  
14. 
History of coronary artery disease (CAD), coronary vasospasm (including 
Prinzmetal's angina), aortic aneurysm, peripheral vascular disease or other 
ischemic diseases (e.g., ischemic bowel syndrome or Raynaud’s syndrome) 
15. 
Three or more of the following CAD risk factors identified during screening: 


 
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• Current tobacco use 
• Hypertension (systolic BP > 140 or diastolic BP > 90) or receiving anti-
hypertensive medication for treatment of hypertension 
• Hyperlipidemia – LDL > 159 mg/dL and/or HDL < 40 mg/dL (or on 
prescribed anti-cholesterol treatment) 
• Family history of premature coronary artery disease (CAD) (< 55 years of age 
in male first degree relatives or < 65 years of age in female first degree 
relatives) 
• Diabetes mellitus 
16. 
History of cerebral vascular accident (CVA), transient ischemic attacks (TIA), or 
seizures 
17. 
History of concurrent illness that requires hospitalization within the 30 days prior 
to the Run-in Period 
18. 
Any other household member currently participating in a M207 study or relatives 
of site staff 
19. 
Any reason to believe that compliance with the study requirements and 
completion of evaluations required for this study will not be possible 
20. 
Any language barrier that, in the opinion of the Investigator, would preclude 
communication or compliance with the study requirements 
21. 
History or current abuse or dependence on alcohol or drugs that in the opinion of 
the investigator would interfere with adherence to study requirements 
22. 
Any positive urine drug screen for phencyclidine (PCP), MDMA (ecstasy), 
cocaine, and/or methamphetamine(s) 
23. 
Any clinically relevant abnormal findings in the subject’s medical history, 
physical exam, vital signs or laboratory tests that, in the opinion of the 
Investigator, may put the subject at risk 


 
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3.2.4 
Eligibility Criteria for Study Treatment  
To be eligible for Treatment, subjects must continue to meet all eligibility criteria for the study 
and the following criteria observed during the Run-in Period: 
1. 
At least one qualifying migraine attack in the last 14 calendar days prior to Visit 3 
(Day1).  The following constitutes a migraine that qualifies during the Run-in 
Period: 
a) 
Headache has at least two of the following characteristics: 
• unilateral location 
• pulsating quality 
• moderate or severe pain intensity 
• aggravation by or causing avoidance of routine physical activity 
(e.g., walking or climbing stairs) 
b) 
During headache at least one of the following: 
• nausea and/or vomiting 
• both photophobia and phonophobia  
2. 
No more than seven headache days (headache days include both qualifying 
migraines and/or other headache types) in the last 14 calendar days prior to Visit 3 
(Day 1) 
3. 
During the run-in period, good eDiary compliance will be confirmed by subject 
completion of at least 10 out of the 14 calendar days prior to Visit 3 (Day 1)  
4. 
Demonstrated ability to properly operate the eDiary 
5. 
Demonstrated ability to properly apply the demo study drug patches  
6. 
In the opinion of the investigator, subject is willing and able to treat all eDiary-
confirmed migraines for up to 12 months with good eDiary completion 
compliance 
7. 
Confirmation of continuing good general health, or stable non-serious disease that 
in the opinion of the Investigator will not place the subject at risk 


 
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3.2.5 
Prior and Concomitant Medications Allowed During the Study 
Medications that are considered necessary for the subject’s welfare and are not specifically 
prohibited (Section 6.2.11), may be given at the discretion of the investigator.  All medication(s) 
taken within 30 days prior to the screening visit and throughout the study must be recorded in the 
appropriate source document and in the case report form (CRF).  Over the counter medications, 
topical skin ointments and/or creams, prescription medications, herbal supplements and/or 
vitamins will be recorded as concomitant medications. 
Migraine prophylaxis medications are allowed if subjects have been on a stable dose for at least 
30 days prior to screening and with no changes during the study. 
Medications with ergot or another triptan or vasoconstrictor drugs are prohibited on the day of a 
confirmed migraine prior to M207 application and for 24-hours post-administration of M207. 
Aspirin, acetaminophen, NSAIDS and other PRN or daily medications indicated specifically for 
migraine symptoms are prohibited on the day of a confirmed migraine prior to M207 application 
and during the two hours following M207 application. 
Following M207 application, subjects will enter into the eDiary whether they took any 
medications (other than M207) for migraine symptoms prior to M207 application (on the day of 
application) or during the 48 hours post M207 application. 
3.2.6 
Early Termination  
3.2.6.1 Withdrawal of Subjects 
Subjects may be withdrawn from treatment or from the study for the following reasons: 
• Subject did not experience at least 6 qualifying migraines within 12 weeks after patch and 
applicator dispensation (Visit 3);  
• At their own request or at the request of their legally authorized representative; 
• If, in the investigator’s opinion, continuation of treatment would be detrimental to the 
subject’s well-being; 
• If the subject experiences any AE believed to be possibly or probably related to study 
drug and severe enough to warrant withdrawal of treatment; 
• If the subject starts and continues to use a prohibited drug, as listed in Section 6.2.11;  
• If the subject is non-compliant with the study drug, eDiary completion, or any other 
requirement of this protocol; or 
• If a subject becomes pregnant anytime during the study. 


 
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Subjects who early terminate from the study after applying study medication, will return for an 
early termination visit and a two-week safety follow-up visit if they applied any patches.  For all 
subjects who are withdrawn from study drug or from the study, the reason must be recorded on 
the appropriate source document and on the appropriate CRF.  The subject must be followed up 
to establish whether the reason was an AE, and, if so, this must be reported in accordance with 
the procedures in Section 8.3.  Subjects with ongoing systemic and skin AEs at study termination 
will be followed until all significant changes have resolved or become medically stable.  
To the extent possible, all examinations scheduled and all data normally collected at completion 
of the study (the final study visit) must be performed on all subjects who receive study drug but 
do not complete the study according to protocol.  These assessments must be done at the time of 
the subject’s early termination visit. 
The investigator must make at least three documented attempts (phone, email, etc.) to contact 
subjects lost to follow-up up until the time of database lock.  This includes one certified letter 
sent to the subject’s primary place of residence.  A copy must be maintained in the source 
documentation. 
3.2.6.2 Replacement of Subjects 
Subjects who discontinue after starting treatment but before six months will be replaced to 
ensure adequate enrollment, i.e., 150 subjects in the study who complete six months and 
50 subjects who complete a year.  
3.2.6.3 Premature Discontinuation of the Trial  
The Sponsor has the right to terminate this study at any time.  Reasons for termination of the 
study may include, but are not limited to, the following: 
• The Health Authority or IRB/EC terminates the study; 
• The incidence or severity of AEs in this or other studies indicates a potential hazard to 
subjects; 
• Subject enrollment is unsatisfactory; 
• The trial is not conducted in accordance with the procedures defined in the approved 
protocol (i.e., protocol deviations, failure to ensure the quality of the data collected); 
• New information on the study drug warrants study termination;  
• The discretion of the Sponsor 
The IRB/Ethics Committee(s) and Health Authorities should be informed about a premature 
discontinuation of the trial. 


 
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4 
STUDY TREATMENTS 
4.1 
Identity of Investigational Products 
4.1.1 
M207 
The M207 patches will be manufactured by Zosano Pharma in Fremont, CA (see Investigator’s 
Brochure for more information).   
4.1.2 
Product Description and Patch Application 
The Zosano M207 Intracutaneous Microneedle System is a novel drug delivery technology 
which consists of a disposable titanium patch centered on an adhesive backing with microneedles 
that are dry-coated with the drug product formulation, and a reusable handheld applicator that 
ensures that the patch is applied with a defined application speed and energy to the site of 
administration. 
The M207 Intracutaneous Microneedle System is a proprietary disposable patch and a reusable 
applicator.  The zolmitriptan-coated titanium microneedle array (3 cm2 array) is attached to a 
5 cm2 adhesive patch (Figure 8).  A magnified image of the zolmitriptan-coated microneedles is 
shown in Figure 8.  The patch system is composed of several parts.  The patch is mounted inside 
a polycarbonate plastic ring with a co-molded desiccant (Figure 9).  
The M207 drug product used in CP-2017-001 is packaged in a nitrogen purged foil pouch or cup 
(see Figure 10).  The reusable applicator is shown in Figure 9 and Figure 10 with a lock-out 
function to avoid accidental firing.  The applicator provides a spring-driven piston to apply the 
patch with consistent impact energy of 0.26 Joules.  The user presses the handheld reusable 
applicator onto the patch ring assembly for attachment, then the applicator is un-locked by 
twisting the cap.  The user applies the patch by pressing the applicator/patch ring assembly onto 
the skin site and holding it to the arm for 3 seconds (Figure 10).   


 
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Figure 8: 5 cm2 Patch with Zolmitriptan Coated Titanium Microneedle Array 
 
M207 Intracutaneous Patch 
with Titanium Array 
 
Magnified section – M207 
Intracutaneous Patch with 
Titanium Array 
 
 
Figure 9: Handheld Gen 6 Patch Ring Assembly and Applicator 
 
 
Outer ring 
with 
desiccant  
 
Patch 
adhesive 
and backing 
Zolmitriptan 
coated 
titanium 
microneedle 
array 
Patch Ring Assembly 
Gen 6 Applicator 


 
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Figure 10: *M207 Patch Application 
     
 
Open the foil pouches or cups (depending on 
the kit dispensed). 
     
 
Snap one patch-ring assembly  
onto the applicator. 
 
Twist applicator cap clockwise from 
Position 1 to Position 2 to unlock for patch 
application. 
 
Press applicator downward to apply patch to 
upper arm.  Press down firmly against the 
skin until you hear a click then hold for 
3 seconds.  Patches are left on for 30 minutes.  


 
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Remove the outer ring in order to load and 
apply the second patch. 
 
Repeat all of the above steps to apply second 
patch next to the first patch. 
*See subject training video and instructions for use for exact instructions on how to apply the patches 
 
4.2 
Dispensing Clinical Trial Material (CTM) Kits 
All subjects in the study will receive open label M207, 3.8 mg to administer as two 1.9 mg 
patches to treat each qualified migraine during the study. 
There are two types of M207 kits for each subject, starter kits and refill kits, clearly labeled and 
visually distinguishable.  Each M207 CTM kit includes either 4 (starter kit) or 8 (refill kit) 
individual foil pouches or cups.  Each pouch or cup contains one patch.  The starter kit dispensed 
on day 1 contains the applicator.  Refill kits will be dispensed as needed throughout the study.  A 
replacement applicator will be issued at approximately six months, and or/as needed if a 
previously dispensed applicator is defective or lost.   
Zosano may employ an electronic system for supply management of clinical trial material 
(CTM) kits.  The CTM system, if employed, is for drug supply management purposes only.  
There is no drug randomization as drug assignment is open-label. 
At each medication dispensation visit, after it has been established that a subject continues to 
qualify for the study, study staff will document the total number of patches dispensed to each 
subject and unopened (unused) patches returned at each visit in the eCRF and drug 
accountability records. 


 
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4.3 
Packaging, Labeling, and Receipt of Supplies 
In this study, M207 drug product patches will be open-label. 
The M207 patches are individually packaged in foil pouches or cups.  There are two types of 
M207 kits for each subject, starter kits and refill kits, which are clearly labeled and visually 
distinguishable.  Each starter kit contains an applicator and 4 individual foil pouches or cups, and 
each refill kit contains 8 individual foil pouches or cups. Each pouch or cup contains one patch. 
The kit labels contain at minimum the manufacturer’s name, CTM kit number, storage 
conditions, and a statement indicating that the study drug is for investigational use only.  
The pharmacist or designee will inventory and acknowledge receipt of all shipments of study 
drug. 
Optional Instructions for Use (IFU) Survey 
Each starter kit of cup-packaged products include a card inviting subjects to participate in an 
optional online survey inclusive of questions about their experience with the IFU for the 
cup-packaged product.  The invitation card provides the link to the survey website and states that 
the survey is voluntary and optional.  The card also states that if the online survey is completed, 
the subject will receive a small stipend.  The survey consists of approximately 5 questions to 
collect information about the clarity of the IFU instructions for application of 2 cup-packaged 
patches to achieve a full dose.   
4.4 
Study Drug Stability, Storage, and Retention 
M207 patches are stable at 15-30°C.  The M207 patches and handheld applicators, packaged in 
individual subject kits, should be stored at a controlled room temperature (15-30°C).  All CTM 
must be kept in a locked and temperature controlled area with access restricted to designated 
study personnel.  
4.5 
Study Drug Kit Administration, Dispensation, Accountability, and Return 
The study drug will be dispensed only to qualified subjects included in this study in accordance 
with the eligibility criteria specified in the study protocol. 
Throughout the study, upon eDiary confirmation of each migraine qualifying for treatment, 
subjects will self-administer the study drug.  Study personnel will train subjects on how to apply 
the patches with the M207 applicator. 
The study physician or designee will record the CTM kit numbers dispensed to each subject on 
the drug accountability record.  The designated site monitor will periodically check the supplies 
of CTM to ensure accountability of used applicators and unused kits.  If necessary, subjects may 
return for unscheduled visits for dispensation of additional drug kits.  Subjects should be 


 
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instructed to bring all unused patches to every clinic visit.  Returned patches may be re-dispensed 
for use to the same subject; however, all patches must be accounted for on the drug 
accountability log as returned and re-dispensed.  The number of patches dispensed at each visit, 
date dispensed, the number of patches used, and the number of returned unused patches at each 
visit will be documented.  Any discrepancies between the ‘actual’ number of patches returned 
versus the ‘expected’ number to be returned will be explained.  If a subject did not apply both 
patches to treat a migraine, the site must document the reason in the subject’s source record. 
Final study drug accountability will be completed after the last subject visit.  All drug 
accountability records will be filed in the site file and TMF as appropriate.   
At the end of the study, all unused study drug kits and used and unused applicators will be 
inventoried and returned as per the sponsor’s instructions. 
4.6 
System Performance  
An applicator associated with field observations of atypical appearance or system performance 
should be returned directly to Zosano Pharma.  Return instructions for defective applicators with 
malfunctions are provided in the M207 Site User Manual.  A description of the field observation 
should accompany the shipment. Only problem applicators will be returned to Zosano Pharma.   
4.7 
Medication Compliance 
The investigator will emphasize the importance of correctly self-administering the study 
medication each time a qualifying migraine is confirmed through the eDiary.  Subjects will be 
instructed to bring the following items to the clinic visit: 
• eDiary 
• M207 applicator 
• Any unused M207 patches 
 
Subjects may discard used patches.  The subject will record information regarding each study 
drug administration in the eDiary. 


 
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5 
SAFETY AND EFFICACY ASSESSMENTS 
5.1 
Safety 
Safety assessments will be initiated after the informed consent form (ICF) has been signed and 
will conclude when the post-study procedures are completed (or early discontinuation).   
Safety will be assessed through the following: 
• Physical exam including height (at screening and final visit only) and weight 
• Vital signs including blood pressure 
• Clinical laboratory determinations including serum chemistries and hematological 
parameters 
• 12-lead ECGs  
• Assessment of concomitant medications 
• All treatment-emergent systemic and skin AEs (TEAEs) 
• Subject reported Skin Assessment  
• Investigator Skin assessment 
 
5.2 
Efficacy 
• Pain freedom  
• Most bothersome other symptom freedom 
• Pain relief  
• Nausea freedom  
• Photophobia freedom  
• Phonophobia freedom  
• Rescue medication use  
• Migraine recurrence 
• Subject satisfaction with treatment as assessed by the Migraine-ACT 


 
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6 
STUDY PROCEDURES AND SCHEDULE 
6.1 
Study Schedule  
A schedule of study procedures is presented in Table 10. 
Table 10: Schedule of Study Procedures 
Procedure 
VISIT 11 
Screening 
VISIT 21 
Start of 
Run-In 
VISIT 3 
 
VISIT 4, 5, 6 
 
VISIT 7 
 
VISIT 8 
 
VISIT 9 Final 
visit or ET 
VISIT 10 Two 
Week Post 
Study Visit 
Up to 1 week 
prior to 
Run-in 
Week -2  
(up to -3)  
Day 1 
(dispense 
patches) 
Month 1, 2, 3 
Month 6 
Month 9 
Month 12 
Two Week 
Safety visit 
Day/Visit Windows 
 
 
 
Day 28, 56, 
84 + 7 days 
Day 168 
+ 7 days 
Day 252 + 7 
days 
Day 336 
+ 7 days 
14 (+ up to 14) 
days following 
final visit or ET 
Week 
 
 
 
Week 4, 8, 12 
Week 24 
Week 36 
Week 48 
Week 50 - 52 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion/ 
Eligibility Criteria 
X 
X 
X 
 
 
 
 
 
Med History/ Migraine History 
X 
 
 
 
 
 
 
 
Fitzpatrick Skin Scale (subject 
completed) 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Physical Exam3 
X 
 
X 
 
X 
 
X 
 
Weight/Height (Height only at 
screen and final visit or ET) 4 
X 
 
X 
X 
 
X 
X 
 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
Lab Chem/Hematology 
(fasting) 
X6 
 
 
 
 
 
X 
 
Serum or Urine Pregnancy 
(only for WOCBP) 
X - Serum 
 
X - Urine 
X - Urine 
X - Urine 
X - Urine 
X - Urine 
 
Drug Abuse Testing 
X 
 
 
 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
X 
 
X 
 
Train Subject on How to Apply 
Patches (using demo patches) 
 
X 
X 
 
 
 
 
 


 
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Procedure 
VISIT 11 
Screening 
VISIT 21 
Start of 
Run-In 
VISIT 3 
 
VISIT 4, 5, 6 
 
VISIT 7 
 
VISIT 8 
 
VISIT 9 Final 
visit or ET 
VISIT 10 Two 
Week Post 
Study Visit 
Up to 1 week 
prior to 
Run-in 
Week -2  
(up to -3)  
Day 1 
(dispense 
patches) 
Month 1, 2, 3 
Month 6 
Month 9 
Month 12 
Two Week 
Safety visit 
Train/dispense eDiary 
 
X 
X 
 
 
 
 
 
Dispense Study Medication 
 
 
X 
X 
X 
X 
 
 
Study Drug Self-
Administration 
 
 
 
 
 
 
 
 
Subject eDiary Reported Skin 
Assessments  
 
 
 
 
 
 
 
 
Migraine-ACT (subject 
completed) 
 
 
 
X 
X 
X 
X 
 
Investigator Skin Assessments 
 
 
 
X 
X 
X 
X 
X 
Monthly phone contacts to 
subject7 
 
 
 
 
 
 
 
 
Collect Unused 
Patch(es)/Perform Drug 
Accountability8 
 
 
 
X 
X 
X 
X 
 
Collect and Review eDiary 
data 
 
 
X 
X 
X 
X 
X 
 
Record Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Record Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
1 Visit 1 and Visit 2 may be combined into one visit.  On the day of screening procedures, if preliminary entry criteria indicate that the subject is probably eligible, the eDiary can be issued and the 
subject may begin the run-in period.  If during the run-in period, additional information becomes available to exclude the subject (e.g., return of 12-lead ECG or lab results), the subject should be 
notified of screen failure and instructed to return any provisional eDiary device (if applicable) to the center. 
3 Physical exam to include (but not limited to) HEENT, Dermatologic, Neurological, General Appearance, Lymph Nodes, Cardiovascular, Respiratory, Gastrointestinal, and Musculoskeletal 
4 Weight at each visit; both height and weight to be collected at screening and final visit only (or early termination visit)  
5 Vital signs include temperature, respiratory rate (RR), blood pressure (BP), and heart rate (HR) 
6 Clinically significant abnormal values may be repeated to confirm eligibility 
7 Phone contacts monthly at months 4, 5, 7, 8, 10, and 11 to remind subjects to treat at least two migraine attacks per month and to assess for adverse events and concomitant medication use 
8 Subjects may return for an unscheduled visit to pick up additional study medication as needed. 


 
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All study visits and procedures will be performed according to the Schedule of Study Procedures 
as listed in Table 10.  Subject visits should be scheduled as soon as possible within the specified 
windows. 
Subjects must be fasting (i.e., nothing by mouth for at least 4 hours; drinking water during the 
4-hour fast before clinical laboratory assessments is permitted) for all laboratory collections.   
6.1.1 
Screening (Visit 1): Up to 1 Week Prior to Start of the Run-in Period  
In order to determine if a subject meets entry criteria, the following activities and evaluations 
will be performed during screening. Screening activities may be completed over a period as short 
as one day or spread out over up to one week. On the day of screening procedures, if preliminary 
entry criteria indicate that the subject is probably eligible, the eDiary training can be completed, 
the eDiary can be issued, and the subject may begin the run-in period; i.e., Visits 1 and 2 may be 
combined.  If during the run-in period, additional information becomes available to exclude the 
subject (e.g., return of 12-lead ECG or lab results), the subject should be notified of screen 
failure and instructed to return any provisional eDiary device (if applicable) to the center.   
The following procedures are to be performed during screening: 
• Provide informed consent discussion; collect signed ICF (must be done prior to 
commencing screening assessments) 
• Assess subject eligibility based on inclusion/exclusion criteria 
• Record demographics 
• Subject will be instructed to complete the Fitzpatrick Skin Scale questionnaire 
(See Appendix 1) 
• Record medical history including migraine history, allergies, and current drug and 
alcohol use 
• Perform PE, including height and weight 
• Record vital signs: temperature, respiratory rate (RR), blood pressure (BP), and heart rate 
(HR)  
• Collect blood (4-hr fasting) for clinical laboratory measurements including clinical 
chemistries and hematology 
• Collect blood for serum pregnancy for all women of child-bearing potential (WOCBP) 
• Urine drug screen 


 
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• Perform 12-lead electrocardiogram (ECG) 
• Record concomitant medications taken within 30 days prior to Screening 
• Register in the case report form any subject who becomes a screen failure 
 
6.1.2 
Run-in Period: 2 Weeks [up to +1 week] Prior to Dispensation of Study Medication 
through Day 1 
The Run-in period can begin on the day screening activities are completed, and should be 
14 days in duration prior to Visit 3.  However, the run-in period may be extended up to an 
additional 1 week, to a maximum total of 21 days, to accommodate scheduling and/or to confirm 
compliance and presence of migraine.  The Day 1 visit (Visit 3) should be scheduled as soon as 
possible after 2 weeks of run-in within the specified window, to determine if a subject still meets 
entry criteria, including the occurrence of at least one qualifying migraine attack per a 14-day 
period.  The following activities and evaluations will be performed during the Run-in period: 
6.1.2.1 First Day of Run-in (Visit 2):  Week -2 (up to week -3) 
• Record vital signs: temperature, respiratory rate (RR), blood pressure (BP), and heart rate 
(HR)  
• Record concomitant medications 
• Record adverse events 
• Train the subject on how to apply the patches (using demo patches) and the use of the 
eDiary 
• Record that the subject understands how to apply the patch and can administer a demo 
patch 
• Dispense eDiary  
o Subject declares most bothersome symptom other than pain (nausea [with or 
without vomiting], photophobia, or phonophobia—that is most bothersome most of 
the time with their migraines) and it is entered in the eDiary 
 


 
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6.1.2.2 Daily through Run-in Period (2 weeks [+ up to 1 additional week]) 
• Subject records daily headache activity in eDiary.  If the subject did not experience a 
headache in the past 24 hours, the eDiary will require the subject to answer whether 
he/she experienced excessive yawning, mood changes, or excessive fatigue (tiredness). 
• Subjects must have at least one qualifying migraine in the last 14 calendar days prior to 
visit 3 (day 1) in the run-in period to meet eligibility for treatment (see Section 3.2.4 for 
Eligibility Criteria for Study Treatment) 
 
6.1.3 
Day 1 (Visit 3, Dispense Study Medication) 
• Perform brief physical exam, including weight 
• Record vital signs: temperature, respiratory rate (RR), blood pressure (BP), and heart rate 
(HR)  
• Review run-in eDiary data for subject compliance and eligibility for treatment 
• Confirm subject is willing to treat all eDiary-confirmed migraine attacks with study 
medication, and is willing to consistently perform eDiary completion for up to 12 months 
• Record concomitant medications, including medication(s) taken to treat migraine attacks 
• Urine pregnancy test for all WOCBP 
• Record Adverse events 
• Train the subject on how to apply the patch to the upper arm with the applicator and have 
the subject practice applying the demo patches to his/her arm 2-3 times (more is 
allowable, if necessary) 
• Record that the subject can apply patch(es) with the applicator unaided 
• Instruct the subject to apply the patches on the same upper arm for each application 
• Reconfirm subject’s eligibility based on inclusion/exclusion criteria 
• Dispense CTM kit and the applicator  
• Provide instructions for scheduling the next visit in one month 


 
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• Remind the subject that ergot, another triptan and/or vasoconstrictor drugs are prohibited 
on the day of patch application prior to applying and within 24-hours post-administration 
of the patch 
• Provide any follow-up eDiary training necessary and re-dispense the eDiary  
• Dispense the Subject Skin Grading Card (Appendix 4) and instruct the subject to refer to 
this card when grading their skin reaction(s)/symptom(s) in the eDiary. 
 
6.1.4 
Treatment Phase: Up to 12 Months  
Visit 3 will be considered the “Day 1” visit for data capture purposes.  Subjects will be instructed 
to complete the eDiary at the time of each suspected migraine attack.  Once the eDiary confirms 
that the migraine qualifies for treatment, the subject will follow the steps provided to 
self-administer the study drug.  If necessary, subjects may return for unscheduled visits for 
dispensation of additional drug kits. 
The following constitutes a migraine that qualifies for treatment with study drug: 
• No medication has already been taken to treat the migraine symptoms on the day of the 
suspected attack before applying M207. 
• Presence of at least two of the following characteristics: 
o Unilateral location 
o Pulsating quality 
o Moderate or severe pain intensity 
o Aggravation by or causing avoidance of routine physical activity (e.g., walking or 
climbing stairs) 
• During headache, at least one of the following: 
o Nausea and/or vomiting 
o BOTH photophobia AND phonophobia 
 


 
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The following procedures are to be started at Day 1 after receiving study medication: 
• Using the eDiary, the subject will record the following to confirm the headache meets the 
qualifications for a migraine: 
o Migraine symptoms and pain assessment 
• Once the qualifying migraine has been confirmed, subject self-administers the study drug 
patches.  Patches cannot be applied to a previous application site unless the site is free of 
redness, swelling, and/or bruising.  In addition, patches must not be applied to any area 
where the skin appears tattooed, sunburned, broken and/or irritated. 
• Each set of two patches must be applied next to one another (or one above the other), on 
the same arm.  If any skin appears broken or irritated, subsequent doses will be applied a 
few inches away from the previously applied patches on the same arm (or both patches 
on the other arm) to avoid applying in an irritated area. 
• Qualifying migraine attacks cannot be treated any earlier than 48 hours after the time of 
patches application for a previously treated migraine attack. 
• Subject will continue to record the following in the eDiary at specified time points as 
follows: 
o Migraine symptoms and pain assessment at the time of treatment, 30 minutes, 
2 hour, 12 hours, 24 hours, and 48 hours post patch application 
o Subject reported skin assessment for bleeding at 30 minutes only 
o Subject reported skin assessment for bruising, swelling, and/or redness (at 
30 minutes, 2 hours, 12 hours, 24 hours and 48 hours post patch administration 
time points only) 
o Subject reported skin pain and skin itching at 48 hours post patch administration 
• Dispense the Subject Skin Grading Card (Appendix 4) with the eDiary and instruct the 
subject to refer to this card when grading their skin reaction(s)/symptom(s) in the eDiary.  
The Grading Card will include a subject reminder to contact the study physician if he/she 
experiences any serious or severe skin reaction(s) at any time point or for worsening or 
non-resolving reactions at approximately 3 days post patches application (at 72 hours).  
In addition, the eDiary will remind the subject to call the study physician if he/she 
experiences any skin reaction(s) and/or symptom(s) at the patch application site which 
worsens rather than improves over approximately a five-day period.  If the subject 


 
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contacts the study physician at any time point for worsening or non-resolving reactions, 
the subject must be seen for an unscheduled visit.  The skin reaction(s)/symptom(s) will 
be assessed, recorded as an adverse event in the eCRF and followed to resolution.   
6.1.5 
Month 1 (Visit 4), Month 2 (Visit 5), Month 3 (Visit 6), Month 6 (Visit 7) 
Visits must be scheduled to occur on (or within +7 days) of the protocol specified study day, ie, 
on study days 28 (Month 1), 56 (Month 2), 84 (Month 3), and 168 (Month 6).  The following 
procedures will be performed at each visit: 
• Administer the Migraine Assessment of Current Therapy (Migraine-ACT) which is 
completed by the subject 
• Collect any unused patches, perform accountability, and dispense patches with applicator  
• Perform physical exam, (Month 6 only) (height does not need to be recorded) 
• Record vital signs: temperature, respiratory rate (RR), blood pressure (BP), and heart rate 
(HR)  
• Collect urine for urine pregnancy test for all WOCBP 
• Collect urine for drug abuse testing (Month 6 only) 
• Perform 12-lead electrocardiogram (ECG) (Month 6 only) 
• Ensure subject is dispensed the Subject Skin Grading Card (to be used with eDiary 
entries).   
• Collect and review subject’s eDiary data with the subject for the following: 
o Subject compliance with study drug treatment and subject responses in eDiary 
• Perform Investigator Skin Assessment (presence of blisters, scaly or flakey skin, erosions 
or open sores, scarring, hyperpigmentation, bruising, redness, and/or swelling) of upper 
arm where patches have been applied 
• Any cutaneous signs or symptoms found on the investigator skin assessment will be 
recorded as an adverse event on the eCRF and followed to resolution.  
• Record concomitant medications 
• Record adverse events.  In addition, any skin reaction(s) entered into the eDiary by the 
subject must also be recorded as an adverse event in the eCRF and followed to resolution. 


 
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6.1.6 Month 9 (Visit 8) and Month 12 End of Study Final Visit (Visit 9/or Early Termination)   
The Month 9 and 12 visits are to be scheduled on (or within ± 7 days) of the protocol specified 
study day, i.e., on study days 252 (Month 9) and 336 (Month 12).  The following procedures will 
be performed.  If a subject terminates early from the study at any time after applying M207, an 
Early Termination visit must be scheduled to occur within 7-14 days after the subject’s last patch 
application. 
• Administer the Migraine Assessment of Current Therapy (Migraine-ACT) to be 
completed by the subject 
• Collect the applicator, any unused patches, and perform accountability 
• Dispense M207 patches (Month 9 only) 
• Perform physical exam, including weight and height (Month 12 final visit/or early 
termination only) 
• Record vital signs: temperature, respiratory rate (RR), blood pressure (BP), and heart rate 
(HR)  
• Collect blood (4-hr fasting) for clinical laboratory measurements including clinical 
chemistries and hematology (Month 12 final visit/or early termination only) 
• Collect urine for urine pregnancy test for all WOCBP 
• Perform 12-lead electrocardiogram (ECG) (Month 12 final visit/or early termination 
only) 
• Ensure subject is dispensed a Subject Skin Grading Card (at Month 9 only) 
• Collect and review subject’s eDiary data with the subject for the following: 
o Subject compliance with study drug treatment and subject responses in eDiary 
• Perform Investigator Skin Assessment (presence of blisters, scaly or flakey skin, erosions 
or open sores, scarring, hyperpigmentation, bruising, redness, and/or swelling) of upper 
arm where patches have been applied 
• Any cutaneous signs or symptoms found on the investigator skin assessment will be 
recorded as an adverse event on the eCRF and followed to resolution.  
• Record concomitant medications 


 
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• Record adverse events. In addition, any skin reaction(s) entered into the eDiary by the 
subject must also be recorded as an adverse event in the eCRF and followed to resolution. 
 
6.1.7 
Monthly Phone Contacts at Months 4, 5, 7, 8, 10, and 11 (± 7 days)  
Contact subject each month to assess for adverse events, collect and record concomitant 
medications and remind subject to continue to treat a minimum of 2 qualifying migraine attacks 
per month. 
6.1.8 
Two Week Post Study Safety Visit (Visit 10) 
This visit will occur 14-28 days after the End of Study Final Visit (or Early Termination visit).  
The following procedures will be performed: 
• Record vital signs: temperature, respiratory rate (RR), blood pressure (BP), and heart rate 
(HR) 
• Perform Investigator Skin Assessment (presence of blisters, scaly or flakey skin, erosions 
or open sores, scarring, hyperpigmentation, bruising, redness, and/or swelling) of upper 
arm(s) where patches have been applied 
• Any cutaneous signs or symptoms found on the investigator skin assessment will be 
recorded as an adverse event on the eCRF and followed to resolution.  
• Record concomitant medications 
Record adverse events   
6.2 
Study Procedures 
6.2.1 
Informed Consent 
Each study participant (or legally authorized representative) will be required to read, sign, and 
date the current institutional review board/independent ethics committee (IRB/IEC) approved 
version of the ICF.  The consent process should also be documented in the study site’s source 
documents.  Informed consent must be obtained prior to performing any study-specific 
procedures.  Both the participant and the study staff member who participated in the consent 
discussion with the participant must sign and date the ICF.  Each study participant will be given 
a copy of the ICF.  All participants will have an opportunity to ask questions before signing the 
ICF, and the study staff member who obtains consent will probe the subject to ascertain 
understanding of the elements of consent. 


 
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6.2.2 
Inclusion/Exclusion Criteria 
All inclusion criteria and eligibility criteria for subject treatment, and none of the exclusion 
criteria must be satisfied prior to assignment of a CTM kit to the subject and the start of study 
drug dosing.   
6.2.3 
Medical History and Demographics 
Demographic information and a medical history, including history of menopausal status, will be 
obtained during screening.  The medical history should include all current conditions, allergies, 
including recent illnesses and relevant past medical history.  Subjects will be asked about current 
use of illicit drugs or alcohol.  Information will also be obtained on the subject’s history of 
migraine therapy.  The Fitzpatrick Skin Type Questionnaire scale (Appendix 1) will also be 
administered at screening to document the subject’s skin type. 
6.2.4 
Randomization 
Not applicable. 
6.2.5 
Migraine Assessment of Current Therapy (Migraine-ACT) 
See Appendix 2 for the Migraine Assessment of Current Therapy (Migraine-ACT).  This subject 
completed questionnaire will be administered at each clinic visit starting at Month 1. 
6.2.6 
Physical Examination 
A physical exam will include, but is not limited to, HEENT, dermatologic, brief neurological, 
general appearance, lymph nodes, cardiovascular, respiratory, gastrointestinal, and 
musculoskeletal examinations. 
6.2.7 
Height and Weight 
Subjects will have height measured only at the screening and the final visit (or early termination 
visit).  Weight will be collected at screening, Day 1, Month 1, 2, 3, 6, Month 9 and Month 12, the 
final visit (or early termination visit).  The subject must not wear shoes during the height 
measurement.   
The subject should wear light clothing and no shoes during weight measurements.  Subjects 
should be weighed on the same clinic scale during this study.  
6.2.8 
Vital Signs 
All subjects will have vital signs (temperature, RR, BP, and HR) measured at screening and all 
subsequent visits. 


 
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Whenever possible, vital sign measurements will be taken before any blood samples are taken. 
6.2.9 
Clinical Laboratory Tests 
Subjects must be fasting (i.e., nothing by mouth for at least 4 hours before the visit; drinking 
water during the 4-hour fast before clinical laboratory assessments is permitted).  All samples 
(except urine pregnancy tests) will be processed by a central laboratory.  The following 
parameters will be assessed:   
Table 11: Clinical Laboratory Tests 
Serum Chemistry 
Hematology 
Additional Tests 
 
Glucose 
 
Aspartate aminotransferase (AST) 
 
Alanine aminotransferase (ALT) 
 
Alkaline phosphatase (AP) 
 
Lactate dehydrogenase (LDH) 
 
Sodium 
 
Phosphorus 
 
Potassium 
 
Chloride 
 
Creatine phosphokinase (CPK) 
 
Globulin 
 
Cholesterol (HDL and LDL) 
 
Creatinine 
 
Blood urea nitrogen (BUN) 
 
Prothrombin (PT) and INR 
(International Normalized Ratio) 
 
Serum calcium 
 
Total bilirubin 
 
Triglyceride 
 
Gamma glutamyl transpeptidase 
 
Hematocrit  
 
Hemoglobin 
 
Red Blood Cell Count 
 
White Blood Cell Count 
with Differential 
 
Platelet Count 
 
Mean corpuscular volume 
 
Mean corpuscular 
hemoglobin 
 
Mean corpuscular 
hemoglobin 
concentration 
 
Serum (at screen visit only) 
and Urine Pregnancy 
(WOCBP only)1 
 
2 Urine drug screens will 
test for: 
amphetamines, 
barbiturates, cocaine, 
cannabinoids, opioids, 
phencyclidine (PCP), 
and methamphetamines 


 
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Serum Chemistry 
Hematology 
Additional Tests 
(GGT) 
 
Serum glutamic pyruvic 
transaminase (SGPT) 
 
Serum glutamic oxaloacetic 
transaminase (SGOT) 
 
Uric acid 
1 If positive at any visit during the study, confirm by serum pregnancy test. 
2 Positive drug screen for phencyclidine (PCP), MDMA (ecstasy), cocaine, and/or 
methamphetamine(s) is exclusionary.  Eligibility of subjects who test positive for cannabinoids is up 
to the discretion of the investigator. 
 
Clinically significant abnormal values at screening may be repeated to confirm eligibility. 
The central laboratory will provide a laboratory manual and appropriate supplies (containers and 
labels).  Laboratory values that are out of range will be identified and may be repeated at the 
investigator’s discretion with sponsor approval.  The investigator will determine if any out-of-
range laboratory values that emerge during treatment are clinically significant and if so, record 
these on the appropriate source document and on the AE CRF page if applicable.  All clinically 
significant out-of-range laboratory values will be followed until they return to normal, or become 
medically stable.  
6.2.10 Twelve-Lead Electrocardiogram 
The ECGs will be sent to a central ECG laboratory for interpretation.  ECG equipment and an 
ECG manual will be provided by the central ECG lab. 
Any clinically significant abnormality noted by the central reader on the screening ECG will be 
recorded on the appropriate source document and will result in exclusion of the subject from this 
study.  The investigator may refer the subject for further evaluation and will continue to follow 
the subject’s condition until the changes have resolved or the subject is medically stable.  
6.2.11 Concomitant and Prohibited Medications 
Concomitant medications, taken within 30 days of screening and throughout the study, include 
over the counter medications, topical skin ointments and/or creams, prescription medications, 
herbal supplements, and/or vitamins.  These medications will be recorded on the appropriate 
source document and on the appropriate CRF at all visits including screening, run-in, and end of 
study (or early discontinuation) through the duration of the study.   


 
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Migraine prophylaxis medications are allowed if subjects have been on a stable dose for at least 
30 days prior to screening and with no changes during the study. 
Medications with ergot or another Triptan or vasoconstrictor drugs are prohibited on the day of 
the confirmed migraine prior to M207 application and for 24-hours post-administration of M207. 
Aspirin, acetaminophen, NSAIDS, and other PRN or daily medications taken specifically for 
migraine symptoms are prohibited on the day of a confirmed migraine prior to M207 application 
and during the two hours following patch application. 
On the day of M207 application, subjects will enter into the eDiary whether they took any 
medications (other than M207) for migraine symptoms prior to M207 application and/or during 
the 48 hours post M207 application. 
Table 12 lists all prohibited concomitant medications taken within 10 days prior to the Run-in 
Period and for the duration of this study. 
Table 12: Prohibited Concomitant Medications 
Drug Type 
Medication 
Monoamine oxidase inhibitors 
Selegiline 
Tranylcypromine 
Isocarboxazid 
phenelzine 
Selective serotonin reuptake 
inhibitors (SSRIs) 
Paroxetine 
Fluoxetine 
Sertraline 
Citalopram 
Escitalopram 
Fluvoxamine 
Serotonin-norepinephrine reuptake 
inhibitors (SNRIs) 
Duloxetine 
Venlafaxine 
Desvenlafaxine 
Milnacipran 
Levomilnacipran 
All Prescription Anticoagulants 
Pradaxa 
Coumadin 
Eliquis 
Xarelto 
 


 
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6.2.12 Assessment of Adverse Events 
AEs are collected from the time of signing the informed consent form and throughout the study 
duration.  New systemic and skin AEs will be recorded on the appropriate source document and 
CRF. 
6.2.13 Subject Reported and Investigator Reported Skin Assessments 
Subject reported  bruising, bleeding (at 30 minutes only), erythema, edema, skin itching and skin 
pain are collected through the eDiary and will also be recorded as adverse events in the eCRF. 
The subject is also provided a Subject Skin Grading Card to help him/her assess whether they 
have any skin reaction(s) and how to grade any reaction(s) (see Appendix 4).  If the subject 
contacts the investigator at any time point for worsening or non-resolving reactions, the subject 
must be seen for an unscheduled visit.  The skin reaction(s)/symptom(s) will be assessed, 
recorded as adverse events in the eCRF and followed to resolution.   
In addition, investigator skin assessments in Section 6.2.13.1 will be completed at each in-clinic 
visit during the treatment period.  Any findings related to the upper arm(s) where the patches 
were applied will be recorded as an adverse event in the eCRF and followed until the signs/ 
symptoms resolve.   
6.2.13.1 Investigator Skin Assessments 
The following skin assessment will be made by the investigator at each in clinic visit starting at 
month 1.  The entire surface area of the outer upper arm from the upper shoulder to the elbow 
will be assessed for the following skin signs or symptoms.   For further instructions, photographs 
and descriptors are in Appendix 5 (Investigator Assessments - Skin Signs or Symptoms and 
Photographs) and Appendix 6 (Investigator Assessments – Rating for Bruising, Erythema, 
Swelling and Photographs). 
Skin signs or symptoms  
Indicate arm assessed: Subject’s Left and/or Right 
(circle)  
Blisters or pustules? 
Present:  Yes or No 
If Yes, describe: 
 
Scaly or flakey skin? 
Present:  Yes or No 
If Yes, describe: 
 
Erosions or open sores? 
Present:  Yes or No 
If Yes, describe: 
 


 
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Skin signs or symptoms  
Indicate arm assessed: Subject’s Left and/or Right 
(circle)  
Scarring? 
Present:  Yes or No 
If Yes, describe: 
 
Hyperpigmentation or Hypopigmentation? 
Present:  Yes or No 
If Yes, describe: 
 
 
6.2.13.2 Bruising  
The Bruising assessment will be performed by the investigator at each in clinic visit starting at 
Month 1.  
Bruising assessments (visual rating) will be performed using the following ratings: 
Symptom 
Rating (circle) 
M207 application 
sites have bruising 
spots? 
0 (clear) = None  
1 (mild) = ≤ 25% Present in the upper arm region of all M207 applications  
2 (moderate) = ≥ 26 to  50% Present in the upper arm region of all M207 
applications 
3 (severe) = > 50% Present in the upper arm region of all M207 applications  
 
6.2.13.3 Other Skin Assessments – Erythema and Edema 
Erythema and Edema will be assessed by the investigator at each in clinic visit starting at 
Month 1.  
The following ratings will be used to describe the amount of erythema and edema indicative of 
irritation: 
Symptom 
Rating (circle) 
Skin Erythema 
0 (clear) = None 
1 (mild) = ≤ 25% Present in the upper arm region of all M207 applications 
2 (moderate) = ≥ 26 to  50% Present in the upper arm region of all M207 
applications 
3 (severe) = > 50% Present in the upper arm region of all M207 applications  
 


 
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Symptom 
Rating (circle) 
Skin Edema 
0 (clear) = None 
1 (mild) = ≤ 25% Present in the upper arm region of all M207 applications 
2 (moderate) = ≥ 26 to  50% Present in the upper arm region of all M207 applications 
3 (severe) = > 50% Present in the upper arm region of all M207 applications  
 
Adverse Events of Special Interest:  Any site reactions requiring further evaluation or care 
(e.g., by a dermatologist), as well as those resulting in scarring are considered adverse events of 
special interest.  If these reactions are detected, the de-identified photograph of the patch 
application site and contralateral arm (containing the date of photograph, visit number and 
subject number) must be transmitted to the sponsor within 24 hours of the clinic visit for further 
dermatological evaluation.   


 
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7 
STATISTICS 
A complete description of the statistical analyses to be performed will be provided in a statistical 
analysis plan (SAP), which will be finalized prior to database lock.   
7.1 
Analysis Variables 
7.1.1 
Safety Endpoints 
• Changes from baseline in physical examination findings at Months 6 and 12 
• Changes from baseline in vital signs at Months 1, 2, 3, 6, 9, 12, and at the 2-week 
post-study visit 
• Changes from baseline in clinical laboratory parameters at Month 12 
• Changes from baseline and/or shifts in 12-lead ECG parameters at Months 6 and 12  
• Frequency of concomitant medications 
• Incidence of treatment-emergent systemic and skin AEs (TEAEs) 
• Frequencies of type of redness, severity of swelling, amount of bruising, and amount of 
bleeding (30 minutes only) at the application site as reported by the subject at 30 minutes, 
2 hour, 12 hour, 24 hour, and 48 hours post-dose  
• Frequencies of amount of skin itching and severity of pain at the application site as 
reported by the subject at 48 hours post-dose  
• Frequencies of amount of bruising, erythema, and edema at the application site as 
assessed by the Investigator at Months 1, 2, 3, 6, 9, 12, and at the 2-week post-study visit 
• Proportion of subjects with presence of skin signs and symptoms as assessed by the 
Investigator at Months 1, 2, 3, 6, 9, 12, and at the 2-week post-study visit 
 
7.1.2 
Efficacy Endpoints 
• Proportion of subjects with pain freedom at 30 minutes, 2 hours, 12 hours, 24 hours, and 
48 hour post-dose 
• Proportion of subjects with most bothersome other symptom freedom at 30 minutes, 
2 hours, 12 hours, 24 hours, and 48 hours post-dose 


 
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• Proportion of subjects with pain relief at 30 minutes, 2 hours, 12 hours, 24 hours and 
48 hours post-dose 
• Proportion of subjects with nausea freedom at 30 minutes, 2 hours, 12 hours, 24 hours 
and 48 hours post-dose 
• Proportion of subjects with photophobia freedom at 30 minutes, 2 hours, 12 hours, 
24 hours and 48 hours post-dose 
• Proportion of subjects with phonophobia freedom at 30 minutes, 2 hours, 12 hours, 
24 hours and 48 hours post-dose 
• Proportions of subjects using rescue medication within 2 hours post-dose 
• Proportion of subjects with migraine recurrence at 24 and 48 hours post-dose  
• Proportion of subjects with sustained pain freedom from 2 to 24 hours post-dose and 
from 2 to 48 hours post-dose 
• Frequency of responses on the migraine ACT 
 
7.2 
Populations for Analysis 
The Safety Population will include all subjects who receive any amount of study drug (applied at 
least one patch).  The mITT (modified intent-to-treat) population will include all subjects who 
receive any amount of study drug to treat a qualifying migraine, and who have efficacy data.  
7.3 
Statistical Methods 
7.3.1 
Baseline Characteristics 
Demographic and baseline characteristic variables such as age, gender, race/ethnicity, height, 
and weight will be summarized using descriptive statistics.  For categorical variables, 
frequencies and percentages will be presented.  Continuous variables will be summarized using 
descriptive statistics (n, mean, median, standard deviation [SD], minimum, and maximum). 
7.3.2 
Safety Analyses  
Safety will be assessed by the monitoring and recording of AEs, clinical laboratory tests, vital 
signs, physical examination findings, ECG parameters, and Investigator and subject reported skin 
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All safety analyses will be based on the Safety Population.  Adverse events will be coded using 
the current Medical Dictionary for Regulatory Activities (MedDRA) dictionary (using the latest 
version) and will be summarized overall and by preferred term and system organ class.  Adverse 
events will also be summarized by severity and relationship to study drug.  Serious AEs and AEs 
leading to discontinuation of study drug will also be summarized. 
Actual values and changes from baseline for assessments of clinical laboratory test results, ECG 
parameters, and vital sign measurements will be summarized at each visit using descriptive 
statistics (n, mean, SD, median, minimum, and maximum) or shift tables as appropriate.  The 
number and percentage of subjects experiencing Bruising, Erythema, Edema and other skin 
assessments will also be summarized. 
All data gathered will be listed by patient and parameter, separate listings of all abnormal 
laboratory findings will be provided, and clinically significant abnormalities will be recorded as 
AEs.  
7.3.3 
Efficacy Analyses 
All efficacy analyses will be based on the mITT Population.  The proportion of subjects 
experiencing pain freedom, most bothersome other symptom freedom, pain relief, nausea 
freedom, photophobia freedom, phonophobia freedom, those using rescue medication, those with 
sustained pain freedom, and those with migraine recurrence will be summarized using 
descriptive statistics.  Frequencies and percentages will be provided for all subject responses on 
the ACT.  Further details regarding efficacy analyses can be found in the statistical analysis plan. 


 
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8 
ADVERSE EVENTS 
All systemic and cutaneous AEs, regardless of suspected causal relationship to the 
investigational products, will be reported as described in the following sections.  Subject 
reported bruising, bleeding, erythema, edema, skin itching and skin pain are collected through 
the eDiary and will also be recorded as adverse events in the eCRF and followed to resolution.   
For all systemic and cutaneous AEs, the investigator must obtain adequate information both to 
determine the outcome of the AE and to assess whether it meets the criteria for classification as a 
SAE (see Section 8.2.1.1) requiring immediate notification (within 24 hours) to the Medical 
Monitor (MM) and Pharmacovigilance Group (PV) by completing a SAE Report Form.  
Sufficient information should also be obtained by the investigator to determine the causality of 
the AE, since he/she is required to assess causality.  For systemic and cutaneous AEs with a 
causal relationship to the investigational product, including all application site reactions, 
investigator is required to follow-up until the event or its sequelae resolve or stabilize at a level 
acceptable to the investigator. 
Pregnancy:  In the event that a pregnancy occurs, it will not be considered an AE but requires 
notification within 24 hours of investigator awareness to the Medical Monitor and 
Pharmacovigilance Group by completing a Pregnancy Report Form.  The investigator will follow 
the pregnancy and report the outcome.  The subject will be discontinued from the study if she 
becomes pregnant anytime during the study. 
8.1 
Reporting Period 
Collection of systemic and cutaneous AEs will be initiated after the ICF has been signed and will 
conclude when the post-study procedures are completed (or Early Discontinuation).  The 
investigator will also report to the Medical Monitor and Pharmacovigilance any SAEs that come 
to his/her attention that occur within 30 days after study drug administration.   
8.2 
Adverse Event Definitions 
8.2.1 
Adverse Events (Adverse Experiences) 
Collection of systemic and cutaneous AEs will be initiated after the ICF has been signed and 
conclude when the post-study procedures are completed (or Early Discontinuation).  This 
includes the time between screening and the first patch application. 
An AE is any untoward medical event that occurs in a clinical investigation, where a subject is 
administered a medicinal (investigational) product or medical device, and which does not 
necessarily have a causal relationship between the event and the treatment.  An AE can be any 


 
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unfavorable and unintended sign or symptom, including clinically significant abnormal 
laboratory result, concomitant illness, or worsening of an existing medical condition. 
A Treatment Emergent Adverse Event (TEAE) is an event that emerges during treatment having 
been absent pre-treatment, or worsens relative to the pre-treatment state. 
Abnormal laboratory tests that are clinically significant, as determined by the investigator, 
should be reported as AEs if: 
• the test result is associated with accompanying symptoms;  
• the test result requires additional diagnostic testing or medical/surgical intervention;  
• the test result leads to discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; 
• the test result is considered to be an AE by the investigator or sponsor. 
 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
8.2.1.1 Serious Adverse Event Definitions 
A serious adverse event (SAE) or reaction is any untoward medical occurrence that at any dose:  
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization (Emergency 
department outpatient visits for an event not fulfilling any of the other definitions of SAE 
given do not qualify as hospitalization.  If an emergency department visit leads to 
inpatient hospitalization, it would qualify as an SAE.); 
• Results in persistent or significant disability/incapacity; or 
• Is a congenital anomaly/birth defect. 
• Other important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 


 
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medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
Definition of disability:  A substantial disruption of a person’s ability to conduct normal life 
functions. 
Life-threatening SAE:  Any AE that places the subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred (i.e., it does not include a reaction that 
had it occurred in a more severe form, might have caused death). 
Hospitalization:  AEs reported from clinical studies resulting in hospitalization or prolongation 
of hospitalization are considered serious.  Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 
• Respite care (e.g., caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• Routine emergency department admissions; or 
• Same day surgeries (as outpatient/same day/ambulatory procedures). 
 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is 
not in itself an SAE.  Examples include: 
• Admission for treatment of a preexisting condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (e.g., for work-up of 
persistent pre-treatment lab abnormality); 
• Social admission (e.g., subject has no place to sleep); 
• Administrative admission (e.g., for yearly PE); or 
• Pre-planned treatments or surgical procedures that have been noted in the baseline 
documentation for the entire protocol and/or for the individual subject. 


 
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8.2.1.2 Unexpected Adverse Event 
An unexpected AE is any AE the nature or severity of which is not consistent with the applicable 
product information (e.g., current investigator’s brochure); or if an investigator’s brochure is not 
required or available, the specificity or severity of which is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current application, 
as amended. 
8.2.1.3 Severity Ratings 
The investigator will evaluate the severity of each AE using the following definitions: 
Mild - event may be noticeable to subject; does not influence daily activities; usually does not 
require intervention. 
Moderate - event may be of sufficient severity to make a subject uncomfortable; performance of 
daily activities may be influenced; intervention may be needed. 
Severe - event may cause severe discomfort; usually interferes with daily activities; subject may 
not be able to continue in the study; treatment or other intervention usually needed. 
Life-Threatening – Event that, in the view of the investigator, places the subject at immediate 
risk of death from the reaction as it occurred (i.e., it does not include a reaction that, had it 
occurred in a more severe form, might have caused death). 
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
subject's usual function) but would not be classified as serious unless it met one of the criteria for 
SAEs, listed above.  Additionally, an SAE of abdominal pain in an elderly patient that results in 
hospitalization to rule out diverticulitis may be mild, whereas severe abdominal pain (that 
interferes with most daily activities) in a younger, stoic patient may not result in hospitalization, 
and thus be a severe non-serious AE.  
8.2.1.4 Relationship to Study Drug 
The investigator’s assessment of causality must be provided for all systemic and topical AEs 
(serious and non-serious).  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility or likelihood that the investigational product caused 
or contributed to an AE.  If the investigator’s final determination of causality is unknown and the 
investigator does not know whether or not the investigational product caused the event, then the 
event will be handled as “related to investigational product” for reporting purposes.  Thus, it is 


 
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imperative that all initial SAE reports include an assessment of causality.  If the investigator's 
causality assessment is "unknown but not related to investigational product", this should be 
clearly documented on study records. 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting requirements, 
if applicable. 
After careful medical consideration, the investigator will evaluate the relationship of each AE to 
study drug applying the following definitions:  
Probably Related 
An AE that is likely due to the use of the study drug.  The relationship in time is suggestive.  An 
alternative explanation is unlikely, e.g., concomitant drug(s), concurrent illness(es). 
Possibly Related 
An AE that might be caused by the use of the study drug.  The relationship in time is reasonable; 
therefore, a causal relationship cannot be excluded.  An alternative explanation is inconclusive, 
e.g., concomitant drug(s), concurrent illness(es), but unlikely. 
Not Related 
An AE that is judged to be clearly due only to extraneous causes (disease or illness, environment, 
etc.).   
The cause must be noted on the appropriate source document and on the AE CRF page. 
8.3 
Documentation and Reporting of Adverse Events by Investigator 
Each AE is to be assessed to determine if it meets the criteria for an SAE.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate. 
All AEs, both expected and unexpected, occurring during this clinical trial must be recorded on 
the AE page of the eCRF.  AEs will be described in precise medical terms, along with the date 
and time of onset and the date and time of resolution, action taken and outcome.  In order to 
avoid vague, ambiguous or colloquial expressions, the AE should be recorded in standard 
medical terminology rather than the subject’s own words.  Whenever possible, the Investigator 
should group together into a single term signs and symptoms which constitute a single diagnosis.  
Each AE is to be evaluated for duration, severity, seriousness and causal relationship to the 
investigational drug.  The severity of the AE and its relationship to the test product will be 


 
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assessed by the Investigator.  When reporting SAEs, the AE form of the eCRF and the SAE form 
must be completed in a consistent manner.  For example, the same AE term should be used on 
both forms.  
8.3.1 
Reporting Requirements for Serious Adverse Events 
ALL SERIOUS ADVERSE EVENTS, REGARDLESS OF CAUSE(S) OR RELATIONSHIP 
TO STUDY DRUG, MUST BE REPORTED IMMEDIATELY TO PHARMACOVIGILANCE 
GROUP (PV) AND MEDICAL MONITOR (MM) BY TELEPHONE (24/7 Safety Line), FAX, 
OR EMAIL (Contact info are provided in Section 8.5). 
All SAE reporting will adhere to 21 CFR 312.32 for IND safety reporting, applicable FDA and 
ICH-GCP regulations. 
If an SAE occurs, PV and MM are to be notified within 24 hours of awareness of the event by 
the investigator.  In particular, if the SAE is fatal or life-threatening, notification to PV and MM 
must be made immediately, irrespective of the extent of available AE information.  This 
timeframe also applies to additional new information (follow-up) on previously forwarded SAE 
reports.  An initial assessment of causality must be included in all SAE reports. 
To report an SAE, the investigator must complete the SAE Report Form, and to report a 
pregnancy, the investigator must complete the Pregnancy Report Form.  Occurrence of any 
SAE/pregnancy must be reported immediately (within 1 working day) once the investigative site 
has knowledge of the event.  The investigator must also provide any relevant information 
regarding the SAE and respond to requests for follow-up in a timely manner.  All SAEs will also 
be reported on the AE CRF page and concomitant medications administered in association with 
the SAE will be documented on the appropriate CRF. 
If an SAE occurs and comes to the attention of the investigator after study termination within 
30 days of the last dose of study drug(s), it must be reported immediately to the sponsor in the 
same way as the SAEs occurring during the study. 
8.3.1.1 Investigator Reporting Responsibilities to the Independent Ethics Committee and Other 
Agencies 
The investigator must promptly report to the IRB/IEC or independent ethics committees (IEC) 
all changes in the research activity and all unanticipated problems involving risk to human 
subjects or others.  This includes all SAEs that have occurred at the study site and all 
study-related SAEs that have resulted in an expedited safety report to the FDA (serious, 
unexpected SAEs possibly or probably related to study drug).  The investigator must send all 
IRB/IEC documentation (including notifications and acknowledgements) to the sponsor or its 


 
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designee.  The investigator must not make any changes in the research without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to human subjects. 
8.3.2 
Reporting Requirements for Non-Serious Adverse Event  
Non-serious systemic and skin AEs experienced after the randomization phase of the study will 
be reported on the AE CRF pages, which will be submitted to the sponsor or its designee.   
8.4 
Follow up of Adverse Events 
All SAEs must be followed up until resolution or, in the investigator’s opinion, a stable condition 
is reached, or until the subject is lost to follow up.  All follow up reports should be made by 
completing the SAE Report Form and by utilizing the same reporting procedures as the initial 
report. 
Based on the medical judgment of the investigator, all non-serious systemic and skin AEs will be 
followed until 14 days after the final two week safety follow-up visit.  All non-resolved, 
non-serious systemic and skin AEs beyond such date will be recorded as “ongoing” without 
further follow up. 
8.5 
Contacts for Serious Adverse Events and Medical Monitoring 
In case of an SAE or any medical-related issues, the investigator will contact the medical 
monitor at any time.   
Medical Monitor: 
Pete Schmidt, MD 
Tel:  510-745-1251  
 
For SAE Reporting, the investigator will send the SAE Report Form to the PV Group (24/7 
Safety Line) by one of the following: 
• Fax:  1-877-464-7787 (US toll-free) 
• Scanned and emailed:  INCDrugSafety@INCResearch.com 
 


 
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9 
EMERGENCY PROCEDURES 
9.1 
Emergency Contact 
In emergency situations, the investigator should contact the medical monitor by telephone at the 
numbers listed on the title page of the protocol.  If an SAE occurs, the PV Group is to be notified 
within 24 hours of awareness of the event by the investigator.  In particular, if the SAE is fatal or 
life-threatening, notification to the PV Group and the sponsor must be made immediately, 
irrespective of the extent of available AE information. 
9.2 
Unblinding Procedures 
Not applicable.  There is no blinding of treatment assignment in this study. 
9.3 
Emergency Treatment 
During and following a subject’s participation in the study, the investigator/institution should 
ensure that adequate medical care is provided to a subject for any systemic or topical AEs, 
including clinically significant laboratory values, related to the study.  The 
investigator/institution should inform a subject when medical care is needed for intercurrent 
illness(es) of which the investigator becomes aware. 


 
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10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
10.1 Study Monitoring 
The study will be monitored by the Sponsor and/or Sponsor's representatives at all stages of 
study conduct from inception to completion in accordance with current GCPs.  This monitoring 
will be in the form of site visits and other communication and will include review of original 
source documents and eCRFs.  The Sponsor's monitor or representative will notify the Principal 
Investigator prior to conducting any investigational site visit.  The frequency of these visits will 
depend upon the progress of the study, and will include monitoring to assess facilities and 
equipment, recruiting, record-keeping, protocol adherence, data collection, AE reporting and 
other factors. 
10.2 Audits and Inspections 
The clinical site will be subject to audit and inspection by the Sponsor or designee during or at 
the end of the study as appropriate. 
The Investigator will permit representatives of Zosano’s monitoring team or FDA/local health 
authority auditors to inspect facilities and records relevant to this study. 
10.3 Institutional Review Board (IRB)/Independent Committee 
This protocol will be submitted to an appropriate central or local IRB/IEC and its written 
unconditional approval obtained and submitted to Zosano or its designee before arrival of the 
first subject. 
Zosano will supply relevant data for Investigators to submit to the IRB/IEC for the protocol’s 
review and approval.  Written verification of IRB/IEC unconditional approval of the protocol 
and the subject Informed Consent Form (ICF) will be transmitted to Zosano or its designee prior 
to granting access to the eCRF to study sites.  This approval must refer to the study by exact 
protocol title and number, identify documents reviewed and state the date of approval. 
The Investigator must promptly report to the IRB/IEC all changes in the research activity and all 
unanticipated problems involving risk to human subjects or others.  This includes all SAEs that 
have resulted in an expedited safety report to the FDA (serious, unexpected AEs possibly related 
to study drug).  Concurrently, the Investigator must send the study Sponsor documentation of 
such IRB/IEC notification and acknowledgement(s).  The Investigator must not make any 
changes in the research without IRB/IEC approval, except where necessary to eliminate apparent 
immediate hazards to human subjects. 


 
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10.4 Participant Recruitment 
If an Investigator chooses to advertise for subjects, whether in professional or consumer 
publications, radio, or television, all advertising must be approved by Zosano and the IRB/IEC 
prior to initiation. 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
The clinical site will be monitored routinely to ensure GCP compliance.  The eCRF will be 
verified against the source document and any queries concerning the eCRF will be generated and 
resolved/reconciled to assure data integrity, and to assure clean data before study close out.  The 
clinical site may be audited by the Sponsor or Sponsor designee for quality control and quality 
assurance purposes.  The clinical site may also be audited by the regulatory agency. 


 
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12 
ETHICS 
12.1 Ethics Review 
The IRB/IEC will review and approve the study protocol, the ICF and other relevant substantive 
data before the study is initiated.  A copy of the IRB/IEC approval letter for the protocol and the 
consent form/subject information sheet which specifically identifies the protocol name and the 
Zosano protocol number, must be sent to Zosano (or designee) prior to initiating the study.  
Subsequently, the Investigator is responsible for keeping the IRB/IEC advised of the progress of 
the study as deemed appropriate but, in any case, at least once a year during the course of the 
study and for keeping the IRB/IEC informed of any significant adverse reactions. 
12.1.1 Ethical Conduct of the Study 
This study will be conducted in strict compliance with GCP, IRB/IEC and other relevant 
regulatory requirements.  The Investigator must ensure that each subject’s anonymity is 
maintained as described within this protocol.  On the eCRFs or other documents submitted to 
Zosano or its designee, subjects must be identified only by their initials and a subject number.  
Documents that are not for submission to Zosano and/or its designee (i.e., signed ICFs) should be 
kept in strict confidence by the Investigator, in compliance with Federal regulations and ICH 
GCP Guidelines.  The Investigator and institution must permit authorized representatives of 
Zosano or its designee, or the regulatory agencies and the IRB/IEC direct access to review the 
subject’s original medical records for verification of study-related procedures and data.  Direct 
access includes examining, analyzing, verifying, and reproducing any records and reports that 
are needed for the evaluation of the study.  The Investigator is obligated to inform the subject in 
the ICF that his/her study-related records will be reviewed by the above named representatives. 
12.2 Written Informed Consent 
Prior to study inception, each study participant (or legally authorized representative) will be 
required to read, sign and date an IRB/IEC-approved ICF that explains the nature, purpose, 
possible risks and benefits, and the duration of the study.  The study staff member who 
participated in the consent discussion with the participant must also sign and date the ICF.  Each 
participant will be given a copy of the ICF. 
The Investigator or designee shall give either the subject or the subject’s legally authorized 
representative adequate opportunity to read the ICF before it is signed and dated. 
The ICF must contain the subject’s dated signature or the signed and dated signature of the 
subject’s legally authorized representative (if applicable).  In addition, the dated signature of the 
person who conducted the informed consent discussion will also be documented on the consent 


 
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form.  Each subject’s signed ICF must be kept on file by the Investigator and be available for 
possible inspection by regulatory authorities, and/or the study Sponsor or the regulatory 
compliance monitor, or the IRB/IEC.  All subjects will be informed of the nature of the program, 
its possible hazards, and their rights to withdraw at any time from the study without prejudice 
and without jeopardy to the subject’s future medical care at the center.  Documentation of the 
informed consent and subject information discussion must appear in the subject’s medical 
record.  HIPAA authorization must also be provided (if applicable). 
A copy of the IRB/IEC-approved ICF must be sent to Zosano or designee. 
Each subject must agree to cooperate in all aspects of the study and must give informed written 
acknowledgment (ICF) to the Investigator for participation. 
Signed acknowledgments (ICF) must remain in the subject’s file and be available for verification 
by monitors at any time. 
12.3 Disclosure of Data 
Individual subject medical information obtained as a result of this study is considered 
confidential, and disclosure to third parties other than those noted below is prohibited.  Subject 
confidentiality will be further assured by utilizing subject identification code numbers to 
correspond to treatment data in the computer files. 
However, such medical information may be given to the subject’s personal physician, or to other 
appropriate medical personnel responsible for the subject’s welfare. 
In addition, data generated as a result of this study are to be available for inspection upon request 
by FDA or local health authority auditors, the Sponsor’s monitors, or by the IRB/IEC.  
Therefore, absolute confidentiality cannot be guaranteed. 


 
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13 
DATA HANDLING AND RECORDKEEPING 
13.1 Inspection of Records 
All study-related documents and records are subject to inspection and audit by the Sponsor 
(or designee), and by the FDA, IRB/IEC or other relevant regulatory bodies.  The Statement of 
Investigator Form FDA 1572 and/or appropriate local health authority documents authorize the 
FDA or local health authority to inspect the data where the clinical trial was conducted. 
The Investigator/institution guarantees access to source documents by the study Sponsor or its 
designee, the FDA, other regulatory bodies and the IRB/IEC.  It is important that the Investigator 
and other study personnel are available during the monitoring visits, and that sufficient time is 
devoted to the process.  If the FDA or local health authority should schedule an inspection, 
Zosano’s Clinical Operations and Regulatory Affairs departments should be advised prior to the 
time this inspection is to occur. 
13.2 Case Report Forms 
All clinical study data will be collected by the Investigator and staff, recorded on source 
documents and captured electronically in the proprietary subject e-source application, if 
appropriate.  Clinical data includes the following: demographics, history, physical examination, 
vital signs, clinical laboratory test results, safety ECGs, adverse event queries, adverse events, 
and concomitant medication queries. 
The data will be directly recorded on or transcribed to the study-specific eCRF.  The clinical 
investigator(s) will assume responsibility (by electronically signing the eCRF) for ensuring the 
completeness and accuracy of all clinical documents. 
Staff at each investigator site will perform data entry into the eCRF.  Study subjects will perform 
data entry in response to questions on the eDiary.  The Remote Data Capture (RDC) database 
that has been validated for this protocol will automatically generate data discrepancy notices 
within the system that will be identified to the clinic for resolution.  A list of all data quality 
checks utilized in the validation of the data will be provided in the Data Management Plan 
(DMP).  Query resolution will take place within the system and an audit trail will be attached to 
any data changes that will identify the user who is making the change and time that this change 
has occurred.  The eCRF will be monitored against source documents by the Sponsor’s 
representative and any subsequent data discrepancies identified will be captured within the 
CDMS. 
The eCRF development and database validation programs will be documented in the Data 
Management Plan (DMP) and will be tested before the database is released for data entry.  The 


 
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validation of the data once entered into the eCRF/database will occur dynamically or nightly 
dependent upon the type of edit check required.  Any data discrepancies identified as a result of 
this validation routine will be documented. 
13.3 Retention of Records 
The Investigator must maintain adequate records for the study including completed eCRFs, 
medical records, laboratory reports, signed ICFs, drug disposition records, adverse event reports, 
information regarding subjects who discontinued, all correspondence with the IRB/IEC and the 
Sponsor (or designee) and other pertinent data. 
All records are to be retained by the Investigator as required by applicable law or regulation. 
To avoid any possible errors, the Investigator must contact Zosano (or designee) prior to the 
destruction of any study records.  The Investigator will also notify Zosano (or designee) in the 
event of accidental loss or destruction of any study records. 


 
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14 
REFERENCES 
Dahlöf, C, Solomon G. The burden of migraine to the individual suffer: a review. Eur J Neurol. 
1998;5: 525–33. 
Guidance for Industry: Migraine: Developing Drugs for Acute Treatment. 2014 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75:800-2. 
Lipton R, Scher A, Kolodner K, et al. Migraine in the United States: epidemiology and patterns 
of health care use. Neurol. 2002;58(6):885-94. 
Rapoport A, Ramadan N, Adelman J, et al. Optimizing the dose of zolmitriptan (Zomig, 
311C90) for the acute treatment of migraine. A multicenter, double-blind, placebo-controlled, 
dose range-finding study. Neurology. 1997;49(5):1210-18. 
Schoenen J, Caekebeke P, Louis, G, et al. An open study to investigate the absorption and 
tolerability of oral 311C90 and to obtain a preliminary indication of efficacy in migraine 
patients. Proceedings of the 10th Migraine Trust Symposium. New advances in headache 
research. 1994;vol. 4:11-2. 
Seaber E, Peck R, Smith D, et al. The absolute bioavailability and effect of food on the 
pharmacokinetics of zolmitriptan in healthy volunteers. Br J Clin Pharmacol. 1998 
Nov;46(5): 433–9.  
Visser W, Klein K, Cox R, et al. 311C90, a new central and peripherally acting 5-HT1D receptor 
agonist in the acute oral treatment of migraine: a double-blind, placebo-controlled, dose-range 
finding study. Neurology. 1996 Feb;46(2):522-6. 
Yates R, Nairn K, Dixon R et al. Pharmacokinetics Dose Proportionality, and Tolerability of 
Single and Repeat Doses of Nasal Spray Formulation of Zolmitriptan Healthy Volunteers. J Clin 
Pharmaco 2002; 42:1244-50. 
 


 
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APPENDIX 1 – Fitzpatrick Skin Type Chart (Subject Completed)  
 
Add up the score for each of the questions.  At the end, there is a scale providing a range 
for each of the skin-type categories. 
 
 
 
 
 
 
 


 
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APPENDIX 2 – The Migraine Assessment of Current Therapy (Migraine-ACT) 
 
Subject Questions related to their M207 study medication: 
 
When you take your treatment: Does your migraine medication work consistently, in the 
majority of your attacks?  Yes or No. 
 
When you take your treatment: Does the headache pain disappear within 2 hours? Yes or No. 
 
When you take your treatment: Are you able to function normally within 2 hours? Yes or No. 
 
When you take your treatment: Are you comfortable enough with your medication to be able to 
plan your daily activities? Yes or No. 
 


 
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APPENDIX 3 – eDiary Questions 
 
Most Bothersome Symptom (To be completed when site is setting up the eDiary for the 
subject) 
• Ask the subject what his/her most bothersome symptom is.  This is the symptom other 
than pain that is most bothersome most of the time with their migraine. (Sick to their 
stomach, sensitive to light, sensitive to sound/noise) 
 
Run-in Period Diary, Nightly Questions (Start the evening of Visit 2) 
• Did you have a headache in the past 24 hours? (Yes, No) 
• If No is answered for bullet one question 
o Did you experience excessive yawning today? (Yes, No) 
o Did you experience mood changes today? (Yes, No) 
o Did you experience excessive fatigue (tiredness) today? (Yes, No) 
• If yes, please answer the following questions based on your headache symptoms in the 
last 24 hours: 
o How bad was your headache pain at its worst? (Mild, Moderate, Severe) 
o Was the headache pain on only one side of your head? (Yes, No) 
o Was the headache pulsating (throbbing)? (Yes, No) 
o Did activity make your headache get worse? (Yes, No) 
o Were you nauseated (sick to your stomach)? (Yes, No) 
o Did you vomit (throw up)? (Yes, No) 
o Did light bother you? (Yes, No) 
o Did sound or noise bother you? (Yes, No) 
o Did you take any medication to treat your headache? (Yes, No) 
 


 
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Migraine Treatment Diary (Starts at Day 1 when subject feels he/she is experiencing a 
migraine attack) 
Please fill in your diary when you feel you are experiencing a migraine attack 
• Are you currently experiencing a migraine attack? (Yes, No) 
• How bad is your headache pain?  (Mild, Moderate, Severe) 
• Is the headache pain on only one side of your head? (Yes, No) 
• Is the headache pulsating (throbbing)? (Yes, No) 
• Does activity make your headache pain get worse? (Yes, No) 
• Are you nauseated (sick to your stomach)? (Yes, No) 
• Did you vomit (throw up)? (Yes, No) 
• Does light bother you? (Yes, No) 
• Does sound or noise bother you? (Yes, No) 
• Have you taken any medication to treat your headache? (Yes, No)  
• Were you experiencing an aura (e.g., flickering light, flashes, or spots) at the start of 
headache? (Yes, No) 
• What day and time did your headache start? (Today, Yesterday) Choose time 
• Did you wake up with this headache? (Yes, No) 
• eDiary confirms whether this is a qualified migraine and instructs subject to apply the 
patches: 
• If a non-qualifying migraine: 
o The following text shows - DO NOT APPLY THE PATCHES.  YOU HAVE 
NOT REPORTED a qualifying migraine.  Please save your answers and return to 
the diary next time you think you are experiencing a migraine attack. 
• If a qualifying migraine: 
o The following text shows - You have reported a qualifying Migraine.  Please 
apply the patches now.  After applying the patches, press next to answer the 
remaining questions. 
• Where were the study drug patches applied? (Both to left arm, Both to right arm, Other) 
o If Other is checked for above question – the following text shows - You have 
applied the patches incorrectly.  Both patches must be applied.  What was the 


 
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reason for not applying both? (Applied one patch to left arm, Applied one patch to 
right arm, Technical problem with applicator and/or patch, None were applied) 
 
Questions at the 30-minute diary post patch application 
Please remove the patches from your upper arm, fold in half, and discard 
• How bad is your headache pain? (None, Mild, Moderate, Severe) 
• Are you nauseated (sick to your stomach)? (Yes, No) 
• Did you vomit (throw up)? (Yes, No) 
• Does light bother you? (Yes, No) 
• Does sound or noise bother you? (Yes, No) 
• Since applying the patches, did you take any medication to treat your migraine other than 
the patches you applied? 
• After removing the patches, how much redness do you see on the skin? (None, Mild 
redness, Moderate colored redness, Beet colored redness) 
• After removing the patches, how much swelling do you see? (None, Slight swelling, 
Moderate swelling, Severe swelling) 
• After removing the patches, how much bruising of the skin do you see? (None, Less than 
a quarter of the application site has bruising spots, About one-half of the application site 
has bruising spots, More than one-half of the application site has bruising spots) 
• After removing the patches, how much bleeding do you see? (None, pink color on skin, 
visible blood drop, active bleeding) 
 
 
 
 
 
 
 
 


 
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Post patch application:  2, 12, 24, 48 hours post patch application 
• How bad is your headache pain? (None, Mild, Moderate, Severe) 
• Are you nauseated (sick to your stomach)? (Yes, No) 
• Did you vomit (throw up)? (Yes, No) 
• Does light bother you? (Yes, No) 
• Does sound or noise bother you? (Yes, No) 
• Since applying the patches, did you take any medication to treat your migraine other than 
the patches you applied? (Yes, No) 
• At the patch application sites, how much redness on the skin do you see now? (None, 
Mild redness, Moderate colored redness, Beet colored redness) 
• At the patch application sites, how much swelling on the skin do you see now? (None, 
Slight swelling, Moderate swelling, Severe swelling) 
• At the patch application sites, how much bruising of the skin do you see now? (None, 
Less than a quarter of the application site has bruising spots, about one-half of the 
application site has bruising spots, more than one half of the application site has bruising 
spots) 
Post patch application: Additional questions at 48 hour only 
• Do you have any skin itching at the application sites? (None, Mild itching, Moderate 
itching, Sever itching)  
• Do you have any skin pain at the application sites? (None, Mild pain, Moderate pain, 
Severe pain) 
 
Post patch application: 48 hour notification 
• The following text shows – If you are experiencing any skin reaction which worsens 
rather than improves in the next 5 days, please contact your study physician 
 


 
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APPENDIX 4 – Subject Skin Grading Card 
 
• 
Subject Instructions:  
• 
Use the images and text descriptions to best grade any skin effects you may be 
seeing. 
• 
Select the options in your eDiary that best correspond to what you are seeing.  
The eDiary options are listed above the photographs for your reference. 
• 
Please contact your research site if you experience what you consider to be a 
serious or severe skin reaction at any time 
• 
Please contact your research site for worsening or non-resolving skin effects 
present at 72-hours (3 days) after applying the patches  
• 
When you return to the clinic, you will be expected to tell your study physician 
how long the skin effects lasted.  
 
Redness 
 
None 
Mild redness 
Moderate colored 
Beet colored redness 
 
redness 
 
        
         
          
 
 
 
Faintly detectible, 
Dull red, clearly 
Deep, dark red 
 
very light color 
distinguishable 
 


 
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Swelling 
 
None 
Slight swelling 
Moderate swelling 
Severe swelling 
 
        
         
          
 
 
 
Barely perceptible 
Clearly perceptible  
Significant elevation of 
 
elevation of skin 
elevation of skin 
skin, extending beyond 
 
 
limited to the 
the application site 
 
 
application site 
 
Bruising 
 
None 
Less than a quarter of 
About one-half of the 
More than one-half of  
 
the application site 
application site has 
the application site has 
 
has bruising spots 
bruising spots 
bruising spots 
 
        
         
         
 
 
Bleeding 
 
None 
Pink color on skin 
Visible blood drop 
Active bleeding 
 
        
         
         
 


 
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APPENDIX 5 – Investigator Assessments - Skin Signs or Symptoms and Photographs 
As stated in Section 6.2.13.1 Investigator Skin Assessments will be made by the investigator at 
each in clinic visit starting at month 1.  The entire surface area of the upper arm where patches 
have been applied will be assessed for the following signs or symptoms.  Below are photographs 
depicting what these skin signs and symptoms may look like and how to describe them.  Any 
findings will be recorded as an adverse event and followed to resolution. 
Blisters or pustules: If present, describe the number size and location 
 
 
Scaly or flakey skin: If present, describe the color of scale (white, yellow, hemorrhagic), 
thickness of scale (fine or thick), amount (minimal/trace to over more than half of the lesion) 
 
 
 
Erosions or open sores:  If present, describe the size and whether there is any crusting 
 
 
 
Scarring: If present, desribe size, color (erythematous, hypopigmented, hyperpigmented), 
thickness, shape (whether limited to area of application or extends beyond) 
 
 
 


 
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Hyperpigmentation or Hypopigmenation: If present, desribe color (tan, brown, black, blue, 
gray, white), size (for example greater or less than 1 cm), and distribution (limited to application 
sites or beyond application sites) 
 
 
Hyperpigmentation 
 
 
Hypopigmentation 
 


 
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APPENDIX 6 – Investigator Assessments – Rating for Bruising, Erythema, Edema and 
Photographs 
The Bruising, Erythema, and Edema assessment will be performed by the investigator at each in 
clinic visit starting at Month 1 and performed using the following ratings.  When determining the 
percentage of application sites affected for a given sign, the investigator should consider the 
entire outer arm from the top of the shoulder to the elbow as the denominator.  Any findings with 
ratings of 1 (mild), 2 (moderate), or 3 (severe) must be recorded as an adverse event in the eCRF 
and followed to resolution.  The investigator will use the definitions of AE Severity Ratings for 
Mild, Moderate, Severe, Life-Threatening (Section 8.2.1.3) to assess the Severity of the AE. 
Symptom 
Rating (circle) 
M207 application 
sites have bruising 
spots? 
0 (clear) = None 
1 (mild) = ≤ 25% Present in the upper arm region of all M207 applications  
2 (moderate) = ≥ 26 to  50% Present in the upper arm region of all M207 
applications 
3 (severe) = > 50% Present in the upper arm region of all M207 applications  
 
Symptom 
Rating (circle) 
Skin Erythema 
0 (clear) = None 
1 (mild) = ≤ 25% Present in the upper arm region of all M207 applications 
2 (moderate) = ≥ 26 to  50% Present in the upper arm region of all M207 
applications 
3 (severe) = > 50% Present in the upper arm region of all M207 applications  
 
Symptom 
Rating (circle) 
Skin Edema 
0 (clear) = None 
1 (mild) = ≤ 25% Present in the upper arm region of all M207 applications 
2 (moderate) = ≥ 26 to  50% Present in the upper arm region of all M207 
applications 
3 (severe) = > 50% Present in the upper arm region of all M207 applications  
 
The photographs below for bruising, erythema, and edema are examples for the investigator as to 
what these skin reaction(s) in the upper arm region may look like.  The investigator will use the 
definitions of AE Severity Ratings for Mild, Moderate, Severe, Life-Threatening 
(Section 8.2.1.3) to assess the Severity of the AE. 
 


 
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Bruising  
 
 
None (Clear) 
Mild 
Moderate 
Severe 
 
Erythema 
 
 
None (Clear) 
Mild 
Moderate 
Severe 
 
Edema 
 
 
None (Clear) 
Mild 
Moderate 
Severe 
 

SAP_000.pdf: 
Statistical Analysis Plan 
Zosano Pharma Corporation Protocol #CP-2017-001 
Final Version 1.0 
Syneos Health #1009439 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
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Document Type: 
Template 
Document ID: 
03.007A.03 
Issue Date:              02 MAY 2016  
Effective Date:    30 MAY 2016  
 
Sponsor Name: 
Zosano Pharma Corporation  
Protocol Number and Title: 
 
CP-2017-001 
A Long-Term, Open-Label Study to Evaluate the 
Safety of M207 (Zolmitriptan Intracutaneous 
Microneedle System) in the Acute Treatment of 
Migraine 
Protocol Version and Date: 
Original: 22 June 2017 
Protocol Amendment 
Numbers and Dates 
Amendment 1: 30 January 2018 
Amendment 2: 06 April 2018 
 
 
Syneos Health Project Code: 
1009439 
Author(s): 
 Roshan Serasinghe 
 Senior Biostatistician 
 
SAP Version: 
 Final Version 1.0 
SAP Version Date:  
30-NOV-2018 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Zosano. Acceptance of 
this document constitutes agreement by the recipient that no information contained herein will 
be published or disclosed without prior written authorization from an official of Zosano.  
However, this document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the 
condition that they are requested to keep it confidential. In the event of an actual or suspected 
breach of this obligation, Syneos Health should be notified promptly. 


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Revision History 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
Final 
30-Nov-2018 
Roshan Serasinghe 
Final Version 1.0 
 
 




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TABLE OF CONTENTS 
Contents 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................. 8 
2. 
PURPOSE ...................................................................................................... 10 
2.1. 
Responsibilities ................................................................................................................. 10 
2.2. 
Timings of Analyses .......................................................................................................... 10 
3. 
STUDY OBJECTIVES ................................................................................... 11 
3.1. 
Primary Objective .............................................................................................................. 11 
3.2. 
Secondary Objectives ....................................................................................................... 11 
3.3. 
Brief Description ................................................................................................................ 11 
3.4. 
Subject Selection ............................................................................................................... 11 
3.4.1. 
Inclusion Criteria ......................................................................................................... 11 
3.4.2. 
Exclusion Criteria ........................................................................................................ 11 
3.5. 
Determination of Sample Size .......................................................................................... 11 
3.6. 
Treatment Assignment & Blinding ................................................................................... 12 
3.7. 
Administration of Study Medication ................................................................................ 12 
3.8. 
Study Procedures and Flowchart ..................................................................................... 12 
4. 
ENDPOINTS .................................................................................................. 15 
4.1. 
Efficacy EndpointS ............................................................................................................ 15 
4.2. 
Safety Endpoints ................................................................................................................ 15 
5. 
ANALYSIS SETS ........................................................................................... 17 
5.1. 
Safety Set ............................................................................................................................ 17 
5.2. 
Modified Intent-to-Treat ..................................................................................................... 17 


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5.3. 
Protocol Deviations ........................................................................................................... 17 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 18 
6.1. 
General Methods ................................................................................................................ 18 
6.2. 
Key Definitions ................................................................................................................... 19 
6.2.1. 
Baseline ....................................................................................................................... 19 
6.2.2. 
Age .............................................................................................................................. 19 
6.2.3. 
Study Day .................................................................................................................... 19 
6.3. 
Missing Data ....................................................................................................................... 19 
6.4. 
Visit Windows ..................................................................................................................... 20 
6.5. 
Pooling of Centres ............................................................................................................. 20 
6.6. 
Subgroups .......................................................................................................................... 20 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION................................................................................................. 21 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 21 
7.2. 
Demographic and Other Baseline Characteristics ......................................................... 21 
7.3. 
Medical History and Concomitant Diseases ................................................................... 21 
7.4. 
Other Baseline Characteristics ........................................................................................ 22 
7.5. 
Medication .......................................................................................................................... 22 
7.5.1. 
Prior, Concomitant Medications, and Prohibited Medications .................................... 22 
7.5.2. 
Rescue Medications .................................................................................................... 23 
8. 
EFFICACY ..................................................................................................... 24 
8.1. 
Efficacy Endpoints and Analysis ..................................................................................... 24 
8.1.1. 
The Proportion of Migraines and Subjects Experiencing Pain Freedom .................... 24 
8.1.2. 
The Proportion of Migraines and Subjects Experiencing Most Bothersome Other 
Symptom Freedom ....................................................................................................................... 24 
8.1.3. 
The Proportion of Migraines with Nausea Freedom, Photophobia Freedom, and 
Phonophobia Freedom ................................................................................................................. 24 
8.1.4. 
The Proportion of Migraines with Pain-Relief .............................................................. 25 
8.1.5. 
The Proportion of Migraines Requiring Rescue Medication within 2 Hours Post-Dose
 
25 
8.1.6. 
The Proportions of Migraines with Sustained Pain Freedom from 2 to 24 Hours Post-
Dose and from 2 to 48 Hours Post-Dose ..................................................................................... 25 


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8.1.7. 
The Proportion of Migraines with Migraine Recurrence within 24 and 48 Hours Post-
Dose 
25 
8.1.8. 
Migraine-ACT Questions (Assessment of Current Therapy) ...................................... 26 
9. 
ANALYSIS OF PHARMACOKINETICS ........................................................ 27 
10. ANALYSIS OF PHARMACODYNAMICS ...................................................... 28 
11. SAFETY ......................................................................................................... 29 
11.1. 
Extent of Exposure and Compliance ............................................................................... 29 
11.2. 
Adverse Events .................................................................................................................. 30 
11.2.1. 
Subject Assessed Skin Adverse Events ..................................................................... 31 
11.2.2. 
Investigator Skin Assessments ................................................................................... 32 
11.3. 
Laboratory Evaluations ..................................................................................................... 34 
11.4. 
Vital Signs ........................................................................................................................... 35 
11.5. 
12-Lead ECG ....................................................................................................................... 36 
11.6. 
Physical Examination ........................................................................................................ 36 
11.7. 
Other Safety ........................................................................................................................ 36 
12. INTERIM ANALYSES .................................................................................... 37 
13. CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ............................. 38 
14. REFERENCE LIST ........................................................................................ 39 
15. PROGRAMMING CONSIDERATIONS .......................................................... 40 
15.1. 
General Considerations .................................................................................................... 40 
15.2. 
Table, Listing, and Figure Format .................................................................................... 40 
15.2.1. 
General ........................................................................................................................ 40 
15.2.2. 
Headers ....................................................................................................................... 41 
15.2.3. 
Display Titles ............................................................................................................... 41 
15.2.4. 
Column Headers ......................................................................................................... 41 
15.2.5. 
Body of the Data Display ............................................................................................. 42 
15.2.6. 
Footnotes .................................................................................................................... 44 


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16. QUALITY CONTROL ..................................................................................... 45 
17. INDEX OF TABLES ....................................................................................... 46 
18. INDEX OF FIGURES ..................................................................................... 48 
19. INDEX OF LISTINGS ..................................................................................... 49 
20. MOCK-UPS .................................................................................................... 51 
20.1. 
Table Mock-Ups ................................................................................................................. 51 
20.2. 
Figure Mock-Ups ................................................................................................................ 51 
20.3. 
Listing Mock-Ups ............................................................................................................... 51 
 
 
 
 


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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
ACT 
Assessment of Current Therapy 
AE 
Adverse event 
ALT 
Alanine transferase  
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
cm 
Centimeter  
CPK 
Creatinine phosphokinase 
CTM 
Clinical trial material 
CRF 
Case report form 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
HDL 
High-density lipoprotein 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
Kg 
Kilogram 
LDH 
Lactate dehydrogenase 


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Abbreviation 
Description 
LDL 
Low-density lipoprotein 
M207 
Intracutaneous Microneedle System (M207) 
MBS 
Most Bothersome Symptom 
Mg 
Milligrams 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter  
NSAID 
Nonsteroidal anti-inflammatory drug 
PCP 
Phencyclidine 
PE 
Physical examination 
PT 
Preferred Term or Prothrombin 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard deviation 
SGPT 
Serum glutamic pyruvic transaminase 
SGOT 
Serum glutamic oxaloacetic transaminase 
SNRI 
Serotonin-norepinephrine reuptake inhibitors 
SOC 
System Organ Class 
SSRI 
Selective serotonin reuptake inhibitors 
TEAE 
Treatment-emergent adverse event 
TLFs 
Tables, Listings, and Figures 
WOCBP 
Women of child-bearing potential 
 
 


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives.  
2.1. 
RESPONSIBILITIES 
Syneos Health will perform the statistical analyses and are responsible for the 
production and quality control of all tables, figures and listings (TLFs). 
2.2. 
TIMINGS OF ANALYSES 
The final analysis will be conducted by Syneos Health after all subjects complete the 
final study visit or terminate early from the study, and the database has been locked. 
 


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3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
To assess the long-term safety of 3.8 mg (administered as two 1.9 mg patches) of M207 
for the acute treatment of migraine. 
3.2. 
SECONDARY OBJECTIVES 
To assess the efficacy of 3.8 mg (administered as two 1.9 mg patches) of M207 for the 
acute treatment of migraine. 
3.3. 
BRIEF DESCRIPTION 
This is an open-label, twelve-month safety study. There is a screening period followed 
by a run-in period (14 to 21 days) to determine eligibility for treatment with study 
medication based on daily eDiary data collection. Qualified subjects will receive study 
medication on Day 1 for up to twelve months for the treatment of migraine headaches. 
Migraines will be treated with a single dose, consisting of two patches, but subjects can 
treat multiple migraine attacks throughout the 12 months. Using the eDiary to confirm 
they are experiencing a qualified migraine, subjects will self-administer the patches 
and continue to respond to questions in the eDiary for 48 hours post treatment 
administration. 
3.4. 
 SUBJECT SELECTION 
Approximately 400 subjects will be screened to ensure that at least 300 subjects enter 
the run-in period and that at least 250 subjects are enrolled into the treatment phase. 
Fifty subjects must complete the entire one-year treatment period and 150 subjects 
must complete a minimum of six months of treatment. 
3.4.1. Inclusion Criteria 
The inclusion criteria are detailed in Sections 3.2.2 of protocol amendment 2.0  
3.4.2. Exclusion Criteria 
The exclusion criteria are detailed in Sections 3.2.3 of protocol amendment 2.0  
3.5. 
DETERMINATION OF SAMPLE SIZE 
The sample size chosen for this study was selected without statistical considerations. It 
has been determined adequate to meet the study objectives.    


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3.6. 
TREATMENT ASSIGNMENT & BLINDING 
This study is an open label study. There is no blinding of treatment assignment in this 
study. 
3.7. 
ADMINISTRATION OF STUDY MEDICATION 
All subjects in the study will receive open label M207, 3.8 mg to administer as two 1.9 
mg patches to treat each qualified migraine during the study. 
There are two types of M207 kits for each subject, starter kits and refill kits, clearly 
labeled and visually distinguishable. Each M207 Clinical trial material (CTM) kit includes 
either 4 (starter kit) or 8 (refill kit) individual foil pouches or cups. Each pouch or cup 
contains one patch. The starter kit dispensed on day 1 contains the applicator. Refill 
kits will be dispensed as needed throughout the study. A replacement applicator will be 
issued at approximately six months, and or/as needed if a previously dispensed 
applicator is defective or lost. 
At each medication dispensation visit, after it has been established that a subject 
continues to qualify for the study, study staff will document the total number of 
patches dispensed to each subject and unopened (unused) patches returned at each 
visit in the electronic case report form (eCRF) and drug accountability records. 
3.8. 
STUDY PROCEDURES AND FLOWCHART 
All study visits and procedures will be performed according to the Schedule of Study 
Procedures as listed in Table 1. Subject visits should be scheduled as soon as possible 
within the specified windows. 
A screening visit 1 will be conducted up to one week prior to start of the run-in-period.  
The following assessments will be performed at screening to determine subject’s 
eligibility. Demographic data (including name, sex, age, race, ethnicity, height, and 
weight), Fitzpatrick Skin Scale Questionnaire, Medical history, Migraine History, Prior 
and concomitant medications, Physical Examination (PE) including body weight (kg), 
height (cm) and BMI (kg/m2) will be reported. Each subject will have vital sign 
measurements; heart rate (HR), blood pressure (BP), temperature (TEMP), and 
respiratory rate (RR), 12-lead Electrocardiogram (ECG), laboratory tests for 
hematological, chemistry, and additional laboratory tests. 
A screening visit 2 (start of run-in-period) will be conducted within two to three weeks 
prior to dispensation of study medication.  
The following assessments and activities will be performed during visit 2. Vital sign 
measurements (HR, BP, TEMP, and RR), Concomitant medications, training of eDiary, 
and dispense of eDiary.  


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Table 1: Schedule of Study Procedures 
Procedure 
VISIT 11 
Screening 
VISIT 21 
Start of Run-
In 
VISIT 3 
 
VISIT 4, 5, 6 
 
VISIT 7 
 
VISIT 8 
 
VISIT 9 Final 
visit or ET 
VISIT 10 Two 
Week Post 
Study Visit 
Up to 1 week 
prior to 
Run-in 
Week -2  
(up to -3)  
Day 1 
(dispense 
patches) 
Month 1, 2, 3 
Month 6 
Month 9 
Month 12 
Two Week 
Safety visit 
Day/Visit Windows 
 
 
 
Day 28, 56, 
84 + 7 days 
Day 168 
+ 7 days 
Day 252 + 7 
days 
Day 336 
+ 7 days 
14 (+ up to 14) 
days following 
final visit or ET 
Week 
 
 
 
Week 4, 8, 12 
Week 24 
Week 36 
Week 48 
Week 50 - 52 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion/ 
Eligibility Criteria 
X 
X 
X 
 
 
 
 
 
Med History/ Migraine History 
X 
 
 
 
 
 
 
 
Fitzpatrick Skin Scale (subject 
completed) 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Physical Exam3 
X 
 
X 
 
X 
 
X 
 
Weight/Height (Height only at 
screen and final visit or ET) 4 
X 
 
X 
X 
 
X 
X 
 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
Lab Chem/Hematology 
(fasting) 
X6 
 
 
 
 
 
X 
 
Serum or Urine Pregnancy 
(only for WOCBP) 
X - Serum 
 
X - Urine 
X - Urine 
X - Urine 
X - Urine 
X - Urine 
 
Drug Abuse Testing 
X 
 
 
 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
X 
 
X 
 
Train Subject on How to Apply 
Patches (using demo patches) 
 
X 
X 
 
 
 
 
 
Train/dispense eDiary 
 
X 
X 
 
 
 
 
 
Dispense Study Medication 
 
 
X 
X 
X 
X 
 
 
Study Drug Self-
 
 
 
 
 
 
 
 


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Procedure 
VISIT 11 
Screening 
VISIT 21 
Start of Run-
In 
VISIT 3 
 
VISIT 4, 5, 6 
 
VISIT 7 
 
VISIT 8 
 
VISIT 9 Final 
visit or ET 
VISIT 10 Two 
Week Post 
Study Visit 
Up to 1 week 
prior to 
Run-in 
Week -2  
(up to -3)  
Day 1 
(dispense 
patches) 
Month 1, 2, 3 
Month 6 
Month 9 
Month 12 
Two Week 
Safety visit 
Administration 
Subject eDiary Reported Skin 
Assessments  
 
 
 
 
 
 
 
 
Migraine-ACT (subject 
completed) 
 
 
 
X 
X 
X 
X 
 
Investigator Skin Assessments 
 
 
 
X 
X 
X 
X 
X 
Monthly phone contacts to 
subject7 
 
 
 
 
 
 
 
 
Collect Unused 
Patch(es)/Perform Drug 
Accountability8 
 
 
 
X 
X 
X 
X 
 
Collect and Review eDiary 
data 
 
 
X 
X 
X 
X 
X 
 
Record Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Record Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
1 Visit 1 and Visit 2 may be combined into one visit.  On the day of screening procedures, if preliminary entry criteria indicate that the subject is probably eligible, the eDiary 
can be issued and the subject may begin the run-in period.  If during the run-in period, additional information becomes available to exclude the subject (e.g., return of 12-lead 
ECG or lab results), the subject should be notified of screen failure and instructed to return any provisional eDiary device (if applicable) to the center. 
3 Physical exam to include (but not limited to) HEENT, Dermatologic, Neurological, General Appearance, Lymph Nodes, Cardiovascular, Respiratory, Gastrointestinal, and 
Musculoskeletal 
4 Weight at each visit; both height and weight to be collected at screening and final visit only (or early termination visit)  
5 Vital signs include temperature, respiratory rate (RR), blood pressure (BP), and heart rate (HR) 
6 Clinically significant abnormal values may be repeated to confirm eligibility 
7 Phone contacts monthly at months 4, 5, 7, 8, 10, and 11 to remind subjects to treat at least two migraine attacks per month and to assess for adverse events and concomitant 
medication use 
8 Subjects may return for an unscheduled visit to pick up additional study medication as needed. 


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4. 
ENDPOINTS 
4.1. 
EFFICACY ENDPOINTS 
• 
Proportion of Migraines that are pain free at 30 minutes, 2 hours, 12 hours, 24 
hours, and 48 hours post-dose 
• 
Proportion of subjects with pain freedom at 30 minutes, 2 hours, 12 hours, 24   
 
hours, and 48 hours post-dose for the 1st, 5th,15th, and 25th migraine  
 
a subject experiences 
• 
Proportion of migraines with most bothersome other symptom freedom at 30 
minutes, 2 hours, 12 hours, 24 hours, and 48 hours post-dose 
• 
Proportion of subjects with most bothersome other symptom freedom at 30  
 
minutes, 2 hours, 12 hours, 24 hours, and 48 hours post-dose for the  
1st, 5th, 15th, and 25th migraine a subject experiences 
• 
Proportion of migraines with pain relief at 30 minutes, 2 hours, 12 hours, 24 
hours and 48 hours post-dose 
• 
Proportion of migraines with nausea freedom at 30 minutes, 2 hours, 12 hours, 
24 hours and 48 hours post-dose 
• 
Proportion of migraines with photophobia freedom at 30 minutes, 2 hours, 12 
hours, 24 hours and 48 hours post-dose 
• 
Proportion of migraines with phonophobia freedom at 30 minutes, 2 hours, 12 
hours, 24 hours and 48 hours post-dose 
• 
Proportions of migraines that require rescue medication within 2 hours post-dose 
• 
Proportion of migraines that recurred  within 24 and 48 hours post-dose  
• 
Proportion of migraines with sustained pain freedom from 2 to 24 hours post-
dose and from 2 to 48 hours post-dose 
• 
Frequency of responses on the migraine assessment of current therapy (ACT) 
4.2. 
SAFETY ENDPOINTS  
• 
Changes from baseline in physical examination findings at Months 6 and 12 
• 
Changes from baseline in vital signs at Months 1, 2, 3, 6, 9, 12, and at the 2-
week post-study visit 
• 
Changes from baseline in clinical laboratory parameters at Month 12 
• 
Changes from baseline and/or shifts in 12-lead ECG parameters at Months 6 and 
12  
• 
Frequency of concomitant medications 


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• 
Incidence of treatment-emergent systemic and skin AEs (TEAEs) 
• 
Frequencies of type of redness, severity of swelling, amount of bruising, and 
amount of bleeding (30 minutes only) at the application site as reported by the 
subject at 30 minutes, 2 hour, 12 hour, 24 hour, and 48 hours post-dose  
• 
Frequencies of amount of skin itching and severity of pain at the application site 
as reported by the subject at 48 hours post-dose  
• 
Frequencies of amount of bruising, erythema, and edema at the application site 
as assessed by the Investigator at Months 1, 2, 3, 6, 9, 12, and at the 2-week 
post-study visit 
• 
Proportion of subjects with presence of skin signs and symptoms as assessed by 
the Investigator at Months 1, 2, 3, 6, 9, 12, and at the 2-week post-study visit 
 


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5. 
ANALYSIS SETS 
5.1. 
SAFETY SET  
The Safety Population will include all subjects who receive any amount of study drug 
(applied at least one patch). 
All safety analyses will be based on the Safety Population. 
5.2. 
MODIFIED INTENT-TO-TREAT 
The modified intent-to-treat (mITT) population will include all subjects who receive any 
amount of study drug to treat a qualifying migraine, and who have efficacy data. 
All efficacy analyses will be based on the mITT Population. 
 
5.3. 
PROTOCOL DEVIATIONS 
Protocol deviations will be captured during monitoring visits or via remote monitoring. 
All deviations will be recorded in the Syneos Health clinical trial management system 
and will be categorized as major or minor. Major protocol deviations will be summarized 
by deviation type using frequency counts. All deviations will be listed by subject. 
 


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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
The statistical analysis will be conducted following the principles specified in the 
International Council for Harmonisation (ICH) Topic E9 Statistical Principles for Clinical 
Trials (CPMP/ICH/363/96). 
All statistical tabulations and analyses will be done using SAS®, Version 9.4 or higher. 
All results collected in the database will be presented in listings. 
Unless otherwise stated, summary statistics including the number of subjects (n), mean, 
standard deviation (SD), median, minimum and maximum will be presented for 
continuous variables. Generally, the minimum and maximum values will be presented to 
the same decimal precision as the raw values, the mean and median values to one 
more, and the standard deviation, to two more decimal places than the raw values. This 
decimal place convention may be followed for all data elements.  For categorical 
variables, per category, the absolute counts (n) and percentages (%) of subjects with 
data, and if appropriate, the number of subjects with missing data, will be presented. 
Percentages will be presented to one decimal place. 
For adverse events, medical history and concomitant medications reported on a per-
subject basis, the denominator for the percentage calculation will be the number of 
subjects at risk in each treatment group. A subject will be considered at risk if the 
subject is in the analysis set and in the subgroup of interest. 
All p-values will be rounded to 4 decimal places. If a p-value is less than 0.0001 it will 
be displayed as “< 0.0001”. 
Due to technical issues with the eDiary, any duplicate eDiary entries for a given time 
point will utilize the earliest recorded entry for analyses. 
Unless otherwise specified all efficacy analyses will be based upon the modified intent-
to-treat population and all safety as well as demographic and baseline characteristic 
analyses will be based upon the safety population.  
Only data from nominal protocol scheduled visits will be included in the summary 
tables. Data from unscheduled visits will not be included in the summary tables but will 
be included in the listings.  Subjects who withdraw/drop out from the study will have 
their collected ET visit data included in the analysis based on the closest visit window.  
Visit windows will be assigned by splitting the periods between visits at the midpoint 
between the visits.  If more than one record falls within the window, the one closest to 
the target date will be used in the analysis.  


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6.2. 
KEY DEFINITIONS 
6.2.1. Baseline 
Baseline assessment for migraine and headache endpoints will be based upon the data 
recorded in the eDiary at time 0, prior to the first administration of Investigational 
Product. Baseline MBS is recorded at Visit 2. For other variables, the baseline 
assessment will be the latest available valid measurement taken prior to the first 
administration of Investigational Product.  
6.2.2. 
Age 
Age, in completed years, at screening will be calculated for each subject and will be 
defined as: 
Age (years) = integer value ((Date of Screening – Date of Birth + 1) / 365.25). 
6.2.3. 
Study Day 
Study Day 1 is the day when a subject enters the treatment period. Study Day -1 is the 
day before the subject enters the treatment period, all assessments prior to study Day -
1, including the Screening and Admission visits, will have negative study days. 
If the date of interest occurs on or after the first study drug administration date, study 
day will be calculated as (date of interest – first study drug administration date + 1). If 
the date of interest occurs prior to the first study drug administration date, study day 
will be calculated as (date of interest – first study drug administration date). 
6.3. 
MISSING DATA 
There will be no imputation for missing data, unless otherwise specified. 
AEs and CMs with incomplete start dates will be considered as treatment-emergent or 
prior/concomitant, respectively, according to the following algorithm: 
1. 
If the AE occurrence type is specified for the AE on the eCRF, it will be 
used to determine treatment-emergence.  This will be verified using the 
algorithms below (steps 3 through 5). 
2. 
If a medication started and stopped prior to the start of study treatment, the  
 
medication will be considered prior. This will be verified using the algorithms  
 
below (steps 3 through 5). 
3. 
Only the start year is reported: If the year is after or the same as the year of the  
first dose date, the event will be considered treatment-emergent. 
4. 
Only the start month and year are reported: If the month/year is after or the  
same as the month/year of the first dose date, then the event will be considered 
treatment-emergent. 


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5. 
If the event occurred or medication was started on or after the date of the first 
dose date, then the event will be considered treatment-emergent. 
The missing severity of an AE will be imputed to “severe”; the missing relationship to 
study drug of an AE will be imputed to “probably related”. 
6.4. 
VISIT WINDOWS 
Nominal Visits will be used in the analyses as reported on the eCRF. As per section 6.1, 
the subjects who withdraw/drop out from the study will have their ET visit data 
collected included in the analysis based on the closest visit window. 
6.5. 
POOLING OF CENTRES 
There will be no adjustment for multiple centers. 
6.6. 
SUBGROUPS 
No subgroups analysis will be performed. 


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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
The number of subjects who were screened, entered run-in, entered the treatment 
phase, treated, completed 6 months, completed 12 months, and terminated from the 
study early will be summarized. The reasons for early termination of treatment or from 
the study will be summarized. Subjects who sign informed consent but do not enter the 
treatment phase will be listed along with failure type (screening or run-in) and reason 
for failure. Additionally, a summary of subjects present at each visit will be 
summarized. The number of subjects in each analysis population will be reported. 
Inclusion/exclusion criteria definitions and violations will be listed. If no 
inclusion/exclusion criteria violations are reported, this will be noted in place of the 
listing. 
7.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline characteristic variables such as age, gender, race/ethnicity, 
height, and weight will be summarized using descriptive statistics.  For categorical 
variables, frequencies and percentages will be presented. Continuous variables will be 
summarized using descriptive statistics (n, mean, median, SD, minimum, and 
maximum). 
Age at Study day 1 = (Study day 1 visit date - date of birth + 1) / 365.25 and truncated 
to complete years. 
Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs) * 0.4536 
BMI (kg/m2) = Weight (kg)/[Height(m)2]. 
Baseline characteristics, including medical history, Fitzpatrick skin scale results, 
migraine history, headache/migraine medication history and current drug or alcohol 
usage will also be summarized descriptively for the safety population. 
7.3. 
MEDICAL HISTORY AND CONCOMITANT DISEASES 
A summary table of the number and percentage of subjects by medical history system 
organ class (SOC) and preferred term (PT) will be produced using the safety population. 
Previous and concurrent diseases/conditions will be sorted alphabetically by SOC and PT 
using the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary, 
version 20.0 or higher. For the summary tables, a subject will be counted only once 
within preferred term if he/she experienced multiple episodes of the same event.   
A separate by-subject listing for medical history data will also be provided.  


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7.4. 
OTHER BASELINE CHARACTERISTICS 
The Fitzpatrick Skin Scale Questionnaire will be completed by the subjects at baseline 
will also be listed for each subject.  
7.5. 
MEDICATION 
All medications including Concomitant medications, prohibited medications, and Rescue 
Medications will be classified using the Anatomical Therapeutic Chemical (ATC) 
classification and preferred drug names from the World Health Organization Drug 
Dictionary (WHO-DD), version March 2016.  
Summaries of medications will be presented in tabular form using the highest level ATC 
term as an upper classification and the preferred drug name as a lower classification 
level. All medications will be summarized and sorted by descending counts in the upper 
classification term and the lower classification term within the upper. For each subject, 
the medication will be counted only once within the upper classification level and only 
once within the lower classification level. 
Separate listings will be provided for concomitant, prohibited, and rescue medications 
taken during the study separately.  
7.5.1. Prior, Concomitant Medications, and Prohibited Medications 
All medications taken within 30 days of screening and throughout the study, including 
over the counter medications, topical skin ointments and/or creams, prescription 
medications, herbal supplements, and/or vitamins will be reported as concomitant 
medications or prior medications.  
Migraine prophylaxis medications are allowed if subjects have been on a stable dose for 
at least 30 days prior to screening and with no changes during the study. 
Medications with ergot or another Triptan or vasoconstrictor drugs are prohibited on the 
day of the confirmed migraine prior to M207 application and for 24-hours post-
administration of M207. 
Aspirin, acetaminophen, NSAIDS, and other PRN or daily medications taken specifically 
for migraine symptoms are prohibited on the day of a confirmed migraine prior to M207 
application and during the two hours following patch application. 
Below is the list of all prohibited concomitant medications taken within 10 days prior to 
the Run-in Period and for the duration of this study (table 2): 


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Table 2: Prohibited Concomitant Medications 
Drug Type 
Medication 
Monoamine oxidase inhibitors 
Selegiline 
Tranylcypromine 
Isocarboxazid 
phenelzine 
Selective serotonin reuptake inhibitors (SSRIs) 
Paroxetine 
Fluoxetine 
Sertraline 
Citalopram 
Escitalopram 
Fluvoxamine 
Serotonin-norepinephrine reuptake inhibitors (SNRIs) 
Duloxetine 
Venlafaxine 
Desvenlafaxine 
Milnacipran 
Levomilnacipran 
All Prescription Anticoagulants 
Pradaxa 
Coumadin 
Eliquis 
Xarelto 
 
Medications with a stop date before the treatment dosing date will be considered prior 
medications. Medications with a start or stop date on or after the treatment dosing date 
will be considered concomitant medications. All medications marked as ongoing are 
concomitant medications.  
A medication with an incomplete stop date will be considered concomitant if  
• 
Month is missing and year is equal to or after the year of treatment dosing date 
• 
Day is missing and year is equal to the year of the treatment dosing date and  
          month is equal to or after the month of the treatment dosing date. 
All medications will be provided in a listing. 
7.5.2. Rescue Medications 
Rescue medications are defined as medications taken to treat a migraine attack (in 
addition to the study drug) within 2 hours after taking the study drug. Rescue 
medications taken during the study will be reported in the eCRF as concomitant 
medications.   


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8. 
EFFICACY 
All efficacy analyses will be based on the mITT Population.   
8.1. 
EFFICACY ENDPOINTS AND ANALYSIS 
The following efficacy endpoints will be summarized using descriptive statistics: 
8.1.1. 
The Proportion of Migraines and Subjects Experiencing Pain Freedom  
The proportion of subjects who are pain-free without the use of rescue 
medication (i.e., a pain severity score of 0 and no rescue medication reported 
within the given timeframe) at 30 minutes, 2 hours, 12 hours, 24 hours, and 48 
hours after dosing for the 1st, 5th, 15th, and 25th migraine a subject 
experiences will be summarized descriptively;  
The proportion of migraines that are pain-free without the use of rescue 
medication (i.e., a pain severity score of 0 and no rescue medication reported 
within the given timeframe) at 30 minutes, 2 hours, 12 hours, 24 hours, and 48 
hours after dosing will be summarized descriptively.  
8.1.2. The Proportion of Migraines and Subjects Experiencing Most Bothersome 
Other Symptom Freedom  
The proportion of subjects with absence of the most bothersome (MBS) other 
symptom among nausea, photophobia, and phonophobia at 30 minutes, 2 
hours, 12 hours, 24 hours, and 48 hours after dosing for the 1st, 5th, 15th, and 
25th migraine a subject experiences will be summarized descriptively.  In 
order to be MBS free, the subject must not have taken a rescue medication up 
until the specified time point. 
The proportion of migraines that are MBS free without the use of rescue 
medication at 30 minutes, 2 hours, 12 hours, 24 hours, and 48 hours after 
dosing will be summarized descriptively. 
The MBS is the symptom other than pain that is most bothersome most of the   
time with their migraine. (Sick to their stomach, sensitive to light, sensitive to  
sound/noise). Patients are asked to identify their most bothersome migraine-
associated symptom in addition to pain at Visit 2.  
A subject’s MBS is obtained via the eDiary, and must be present pre-dose in 
order to be included in the analysis.  
 
8.1.3. 
The Proportion of Migraines with Nausea Freedom, Photophobia Freedom, 
and Phonophobia Freedom 
Regardless of the associated symptom identified as MBS, all three important 
migraine-associated symptoms (i.e., nausea/vomiting, photophobia, and  


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phonophobia) will be assessed separately. A binary scale (present or absent)  
will be used for associated symptoms. The proportion of migraines that are  
nausea-free, photophobia-free, and phonophobia-free without the use of 
 rescue medication at 30 minutes, 2 hours, 12 hours, 24 hours, and 48 hours  
after dosing will be summarized descriptively. Both nausea and vomiting must  
be absent in order for the migraine to be considered nausea-free. 
 
8.1.4. 
The Proportion of Migraines with Pain-Relief 
In addition to all above, the proportion of migraines with pain relief without 
rescue medication use (improvement of pain severity to mild or none from 
moderate or severe at baseline, or to none from mild at baseline) at 30 
minutes, 2 hours, 12 hours, 24 hours, and 48 hours after dosing will also be 
summarized descriptively. 
8.1.5. The Proportion of Migraines Requiring Rescue Medication within 2 Hours 
Post-Dose  
Rescue medications are defined as medications taken to treat a migraine 
attack (in addition to the study drug) within 2 hours after taking the study 
drug. Rescue medication data will be obtained from the eDiary. The proportion 
of migraines requiring rescue medication within 2 hours of initial treatment 
will be summarized descriptively. 
8.1.6. 
The Proportions of Migraines with Sustained Pain Freedom from 2 to 24 
Hours Post-Dose and from 2 to 48 Hours Post-Dose   
The proportion of migraines that are “sustained pain-free”, defined as having 
no headache pain at 2 hours after dose, with no use of rescue medication, and 
no relapse of headache pain within 24 hours (24-hour sustained pain-free) post-
dose will be summarized descriptively. 
The proportion of migraines that are sustained pain-free from 2 to 48 hours 
will also be summarized descriptively. 
8.1.7. 
The Proportion of Migraines with Migraine Recurrence within 24 and 48 
Hours Post-Dose  
Migraine recurrence between 2 to 24 hours (or 2 to 48 hours) is defined as 
pain-free at 2 hours post-dose, with pain (mild, moderate, or severe) reported 
within 24 hours (or 48 hours) post-dose or with rescue medication taken at any 
time 2 to 24 hours (or 48 hours).  
The proportion of migraines that have recurred between 2 to 24 hours post-
dose (and 2 to 48 hours post-dose) will be summarized. 


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8.1.8. Migraine-ACT Questions (Assessment of Current Therapy)  
The frequencies and percentages will be provided for all subject responses on  
the ACT by visit.  Note that if a subject has not treated any migraine attacks 
since the most recent in clinic study visit, the ACT response will be missing.  
Missing data will not be imputed. 


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9. 
ANALYSIS OF PHARMACOKINETICS 
Not Applicable 
 
 


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10. 
ANALYSIS OF PHARMACODYNAMICS 
Not Applicable 


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11. 
SAFETY 
Safety will be assessed through the following: 
• 
Physical examination findings including height (at screening and final visit only) 
and weight, 
• 
Vital signs including blood pressure, 
• 
Clinical laboratory determinations including serum chemistries and 
hematological parameters, 
• 
12-lead ECGs, 
• 
Assessment of concomitant medications, 
• 
All treatment-emergent systemic and skin AEs (TEAEs), 
• 
Subject reported Skin Assessment, and  
• 
Investigator Skin Assessment. 
All safety analyses will be based on the Safety Population.  Adverse events will be coded 
using the current Medical Dictionary for Regulatory Activities (MedDRA) dictionary 
(version 20.0 or higher) and will be summarized overall and by preferred term and 
system organ class.  Adverse events will also be summarized by severity and relationship 
to study drug. Serious AEs and AEs leading to discontinuation of study drug will also be 
summarized. 
Clinical laboratory test results and ECG parameters will be summarized at each visit 
using shift tables or listings of abnormal results as appropriate.  The number and 
percentage of subjects experiencing Bruising, Erythema, Edema and other skin 
assessments will also be summarized. 
All data gathered will be listed by patient and parameter, separate listings of all 
abnormal laboratory findings will be provided, and clinically significant abnormalities 
will be recorded as AEs.  
11.1. 
EXTENT OF EXPOSURE AND COMPLIANCE 
Treatment duration will be calculated as (number of days=last dose date - first dose 
date+1).  First and last dose dates will be determined from the dates of patch 
application recorded in the eDiary.  Average treatment duration per subject in days will 
be summarized. Frequencies of duration, 0-6 months, 6-12 months, and >12 months will 
be provided.   
Study drug exposure will be captured as the total number of doses. Patch application is 
captured in the eDiary, and a subject is considered as having received one dose 
regardless if one or two patches are applied. The average number of treated migraines 
per month per subject for months 1-12 and overall will also be summarized, as well as 
frequencies provided for ≥12 doses and ≥24 doses.  Also, the frequency of the number of 
subjects with at least 2 doses per month on average for at least 6 months will be 
provided.   


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Compliance will be assessed as the percentage of subjects treating at least 2 migraines 
per month.  Months will be defined starting with the day IP was provided to the subject 
and calculated as each consecutive 30-day period following the day IP was first 
provided. 
All study drug dosing information will be listed.  
11.2. 
ADVERSE EVENTS  
All systemic and skin AEs, regardless of suspected causal relationship to the 
investigational products, will be reported. Subject assessed skin adverse events such as 
skin redness (erythema), skin swelling (edema), skin bruising, skin bleeding, skin itching 
and skin pain are collected through the eDiary and will also be recorded as adverse 
events in the eCRF.  
All Adverse Events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA; version 20.0 or higher). Migraine headaches will not be captured as 
AEs.  
All AEs will be listed by subject.  The following listings of AEs will be provided: 
• 
All AEs, 
• 
Study-drug related AEs, 
• 
Serious adverse events (SAEs), 
• 
AEs leading to death, and 
• 
Adverse events leading to study-drug withdrawal. 
Only TEAEs will be included in summary tables. An Overview summary table of TEAEs 
will be produced showing the following categories: 
• 
Any TEAE, 
• 
Study-drug related TEAEs, 
• 
Serious TEAEs, 
• 
TEAEs leading to study-drug withdrawal, and 
• 
TEAEs leading to death. 
All TEAEs will be classified by system organ class (SOC) and preferred term (PT). 
Frequency count and the number of unique subjects of a TEAE will be tabulated by 
treatment received. For the number of unique subjects reporting, if a subject reported 
more than one AE that was coded to the same SOC or PT, the subject will be counted 
only once for that specific SOC or PT. 
The following summaries of TEAEs will also be provided: 
• 
TEAEs by SOC and PT, 
• 
Study-drug related TEAEs by SOC and PT, 


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• 
Serious TEAEs by SOC and PT, 
• 
TEAEs by maximum severity (mild, moderate, severe or missing) by SOC and PT, 
and  
• 
TEAEs by strongest causality relationship (not related, possibly related, probably  
 
related, definitely related or missing) by SOC and PT. 
For TEAEs presented by relationship to study treatment(s), the strongest relationship to 
study treatment(s) during the study will be presented for each subject if coded to the 
same SOC or PT. For TEAEs presented by severity, the worst severity during the study 
will be presented for each subject if coded to the same SOC or PT. TEAEs with missing 
causality will be counted as related. TEAEs with missing severity will be counted as 
severe. The same will be true in the individual summaries. 
TEAEs by SOC and PT and by severity and causality will be presented 3 ways: subject 
reported AEs from the eDiary, other subject reported AEs, and all AEs combined (eDiary 
and other).  For subject reported AEs from the eDiary, the average time to resolution in 
days will be summarized. 
11.2.1. Subject Assessed Skin Adverse Events  
Subject reported skin bruising, skin bleeding (at 30 minutes only), skin redness 
(erythema), skin swelling (edema), skin itching and skin pain at the application site are 
collected through the eDiary and will also be recorded as adverse events in the eCRF. 
The frequencies of type of redness, severity of swelling, amount of bruising, and 
amount of bleeding (30 minutes only) at the application site as reported by the subject 
at 30 minutes, 2 hour, 12 hour, 24 hour, and 48 hours post-dose will be summarized.   
The frequencies of amount of skin itching and severity of pain at the application site as 
reported by the subject at 48 hours post-dose will also be summarized. 
Frequency tables of eDiary skin assessments will be provided using the greatest severity 
or greatest amount for each parameter as reported by the subject at any time during 
the study.  The denominator will be the number of subjects in the safety population.  
Tables will also be generated using the data from all treated migraines so the 
denominator will be the number of treated migraines that have eDiary data. 
The proportion of attacks and the proportion of subjects with no skin findings will be 
summarized by time point.  Also, the proportion of attacks and subjects with any 
amount of all 3 symptoms (redness, swelling, and bruising) at the same time and all 
combinations of the 3 symptoms will be summarized by time point. 
All subject assessed skin adverse events will also be listed. 
The type of redness, severity of swelling, amount of bruising, amount of bleeding, 
amount of skin itching, and severity of pain will be collected using eDiary cards and 
assessed as follows: 
 


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Skin Symptom/ 
Time Points 
Assessment  
Redness (Erythema)/ 
at 30 minutes, 2 hour, 
12 hour, 24 hour, and 
48 hours post-dose 
None 
Mild redness 
Moderate colored redness 
Beet colored redness 
Swelling (Edema)/  
at 30 minutes, 2 hour, 
12 hour, 24 hour, and 
48 hours post-dose 
None 
Slight swelling 
Moderate swelling 
Severe swelling 
Bruising/ 
at 30 minutes, 2 hour, 
12 hour, 24 hour, and 
48 hours post-dose  
None 
Less than a quarter of the application site has bruising spots 
About one-half of the application site has bruising spots 
More than one-half of the application site has bruising spots 
Bleeding/ 
30 minutes post-dose 
only 
 
None 
Pink color on skin 
Visible blood drop 
Active bleeding 
Itching/ 
at 48 hours post-dose 
only 
None 
Mild itching 
Moderate itching 
Sever itching 
Pain/ 
at 48 hours post-dose 
only 
None 
Mild pain 
Moderate pain 
Severe pain 
 
11.2.2. Investigator Skin Assessments  
The investigator skin assessment will be made at each in clinic visit starting at month 1.  
The entire surface area of the outer upper arm from the upper shoulder to the elbow 
will be assessed for the following skin signs or symptoms.    
Investigator reported skin bruising, skin redness (erythema), and skin swelling (edema) 
at the application site will be collected and will also be recorded in the eCRF. 
The amount of bruising, erythema, and edema and the presence of skin signs and 
symptoms will be categorized and assessed as follows:  


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Skin signs or symptoms  
Indicate arm assessed: Subject’s Left 
and/or Right (circle)  
Blisters or pustules? 
Present:  Yes or No 
If Yes, describe: 
Scaly or flakey skin? 
Present:  Yes or No 
If Yes, describe: 
Erosions or open sores? 
Present:  Yes or No 
If Yes, describe: 
Scarring? 
Present:  Yes or No 
If Yes, describe: 
Hyperpigmentation or Hypopigmentation? 
Present:  Yes or No 
If Yes, describe: 
Bruising assessments (visual rating) will be performed using the following ratings: 
Symptom 
Rating (circle) 
M207 application 
sites have 
bruising spots? 
0 (clear) = None  
1 (mild) = ≤ 25% Present in the upper arm region of all M207 
applications  
2 (moderate) = ≥ 26 to ≤ 50% Present in the upper arm region of all 
M207 applications 
3 (severe) = > 50% Present in the upper arm region of all M207 
applications  
 
Erythema Severity Categories: 
Symptom 
Rating (circle) 
Skin Erythema 
0 (clear) = None 
1 (mild) = ≤ 25% Present in the upper arm region of all M207 
applications 
2 (moderate) = ≥ 26 to ≤ 50% Present in the upper arm region of all 
M207 applications 
3 (severe) = > 50% Present in the upper arm region of all M207 
applications  
 
Edema Severity Categories: 
Symptom 
Rating (circle) 
Skin Edema 
0 (clear) = None 
1 (mild) = ≤ 25% Present in the upper arm region of all M207 


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applications 
2 (moderate) = ≥ 26 to ≤ 50% Present in the upper arm region of all 
M207 applications 
3 (severe) = > 50% Present in the upper arm region of all M207 
applications  
The frequencies of amount of bruising, erythema, and edema at the application site as  
assessed by the Investigator at Months 1, 2, 3, 6, 9, 12, and at the 2-week post-study 
visit will be summarized. The proportion of subjects with any amount of all 3 symptoms 
(erythema, edema, and bruising) and all combinations of the 3 symptoms will be 
summarized by time point. 
The proportions of subjects with presence of skin signs and symptoms as assessed by the  
Investigator at Months 1, 2, 3, 6, 9, 12, and at the 2-week post-study visit will also be 
summarized. 
All investigator skin assessments will also be listed. 
11.3. 
LABORATORY EVALUATIONS 
The lab results for clinical laboratory categories including hematology, serum chemistry 
as well as results for urine drug screens and serum and urine pregnancy tests will be 
recorded on the eCRF at the study visits mentioned in Table 1. The parameters given in 
the Table 3 will be assessed. 
Table 3: Clinical Laboratory Tests 
Serum Chemistry 
Hematology 
Additional Tests 
 
Glucose 
Aspartate aminotransferase 
(AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (AP) 
Lactate dehydrogenase (LDH) 
Sodium 
Phosphorus 
Potassium 
 
Hematocrit  
Hemoglobin 
Red Blood Cell Count 
White Blood Cell Count 
with Differential 
Platelet Count 
Mean corpuscular 
volume 
Mean corpuscular 
hemoglobin 
 
Serum (at screen visit 
only) and Urine Pregnancy 
(WOCBP only)1 
2 Urine drug screens will 
test for: 
amphetamines, 
barbiturates, cocaine, 
cannabinoids, opioids, 
phencyclidine (PCP), and 
methamphetamines 


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Serum Chemistry 
Hematology 
Additional Tests 
Chloride 
Creatine phosphokinase (CPK) 
Globulin 
Cholesterol (HDL and LDL) 
Creatinine 
Blood urea nitrogen (BUN) 
Prothrombin (PT) and INR 
(International Normalized Ratio) 
Serum calcium 
Total bilirubin 
Triglyceride 
Gamma glutamyl transpeptidase 
(GGT) 
Serum glutamic pyruvic 
transaminase (SGPT) 
Serum glutamic oxaloacetic 
transaminase (SGOT) 
Uric acid 
Mean corpuscular 
hemoglobin 
concentration 
 
Low, normal, and high classifications will be applied to determine whether the 
laboratory test value was below (low), within (normal), or above (high) its reference 
range. The number and percentage of subjects with indicated shifts (low, normal, high) 
in their results from baseline to post-baseline will be presented.  
Separate listings will be produced for each laboratory test group (hematology, serum 
chemistry, urine drug screens, and serum and urine pregnancy tests).  A listing of all 
abnormal results will be provided. 
11.4. 
VITAL SIGNS  
All subjects will have vital signs including body temperature (TEMP), respiratory rate 
(RR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) 


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measured at screening and all subsequent visits. Weight will be collected at selected 
visits, and height will be collected at screening and final visit only (or early termination 
visit). 
A listing of abnormal vital signs results will be provided using the ranges below. All vital 
signs measurements will also be listed for each subject. 
Vital Sign 
Low Cutoff 
High Cutoff 
 
Systolic Blood Pressure 
Diastolic Blood Pressure 
Heart Rate 
Respiratory rate 
Body Temperature 
 
90 mmHg 
60 mmHg 
50 beats/minute 
12 breaths/minute 
36.1 degrees Celsius 
 
139 mmHg 
89 mmHg 
100 beats/minute 
20 breaths/minute 
37.5 degrees Celsius 
 
11.5. 
12-LEAD ECG  
Twelve-lead ECG will be performed at screening, months 6 and 12 study visits. 
Abnormal ECG results will be listed. All ECG findings collected in the CRF will also be 
listed.    
11.6. 
PHYSICAL EXAMINATION 
Physical examination (PE) which includes (but not limited to) HEENT, Dermatologic, 
Neurological, General Appearance, Lymph Nodes, Cardiovascular, Respiratory, 
Gastrointestinal, and Musculoskeletal will be performed at screening, day 1, months 6 
and 12 study visits. The overall PE findings (normal, abnormal clinically significant, 
abnormal not clinically significant) will be listed. 
All PE findings collected in the CRF will also be listed.    
11.7. 
OTHER SAFETY 
Fitzpatrick skin scales, drug abuse testing, and pregnancy test results collected in the 
CRF will be listed.  


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12. 
INTERIM ANALYSES 
No planned interim analysis for this study 


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13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
Efficacy endpoints were changed from “the proportion of subjects” to “the proportion 
of migraines” since this is a multiple dose study.  Two efficacy endpoints were added: 
the proportion of subjects with pain freedom and the proportion of subjects with MBS 
freedom for the 1st, 5th, 15th, and 25th migraine a subject experiences. 
 


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14. 
REFERENCE LIST 
1. 
A Long-Term, Open-Label Study to Evaluate the Safety of M207 (Zolmitriptan  
Intracutaneous Microneedle System) in the Acute Treatment of Migraine, Zosano 
Pharma, Protocol No.CP-2017-0016, amendment 2, 06 Apr 2018. 
 


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15. 
PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using 
SAS® for Windows, Release 9.4 (SAS® Institute Inc., Cary, NC, USA). Computer-
generated table, listing and figure output will adhere to the following specifications.   
The format of the table shells will be followed as closely as possible; however, in the 
course of programming and familiarization with the database, some changes may 
become necessary. All changes will be documented. Major changes will be documented 
through a formal amendment to this document. 
SDTM datasets will be created from the clinical database and external data, following 
the Study Data Tabulation Model Implementation Guide Version 3.2. Analysis will be 
based on analysis datasets created from the SDTM datasets. 
The below programming considerations will be followed unless already specified in the 
above text. 
15.1. 
GENERAL CONSIDERATIONS 
• 
One SAS program can create several outputs. / A separate SAS program will be 
created for each output. 
• 
One output file can contain several outputs. / Each output will be stored in a 
separate file. 
• 
Output files will be delivered in Word format / pdf format. 
• 
Numbering of TFLs will follow ICH E3 guidance (or other logical order for studies 
performed according to GPP) 
15.2. 
TABLE, LISTING, AND FIGURE FORMAT 
15.2.1. General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size 8  
• 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
• 
Headers and footers for figures will be in Courier New font, size 8. 
• 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 


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not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
15.2.2. Headers 
• 
All output should have the following header at the top left of each page: 
<Sponsor Name> Protocol XXX (Syneos Health study number xxx)                
Draft/Final Run <date> 
• 
All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (i.e., the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the table). 
• 
The date output was generated should appear along with the program name as a 
footer on each page. 
15.2.3. Display Titles 
• 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination (see also template 03.007C “Table of Contents  
for Tables Listings and Figures in Statistical Analysis Plan”). A decimal system (x.y 
and x.y.z) should be used to identify TLFs with related contents. The title is 
centered. The analysis set should be identified on the line immediately following 
the title. The title and table designation are single spaced. A solid line spanning the 
margins will separate the display titles from the 
• 
 Column headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Set 
15.2.4. Column Headers 
• 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values may be presented under the total column or in separate p-value column (if 
applicable). Within-treatment comparisons may have p-values presented in a row 
beneath the summary statistics for that treatment. 


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• 
For numeric variables, include “unit” in column or row heading when appropriate. 
• 
Analysis set sizes will be presented for each treatment group in the column heading 
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set. 
• 
The order of treatments in the tables and listings will be Placebo first in the case of 
placebo controlled studies and Active comparators first in the case of active 
comparator trials, followed by a total column (if applicable). 
15.2.5. Body of the Data Display 
15.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
15.2.5.2. Table Conventions 
• 
Units will be included where available 
• 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
• 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 
• 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
• 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 


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N 
  XX 
Mean 
XXX.X 
Std Dev 
 X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
• 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
value should be less than 0.0001 then present as <0.0001. If the p-value is returned 
as >0.999 then present as >0.999 
• 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to 
display values that round down to 0.0.  A common convention is to display as '<0.1', 
or as appropriate with additional decimal places. Unless otherwise noted, for all 
percentages, the number of subjects in the analysis set for the treatment group who 
have an observation will be the denominator. Percentages after zero counts should 
not be displayed and percentages equating to 100% should be presented as 100%, 
without any decimal places.  
• 
Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of adverse event data should be presented by the body system, 
treatment class, or SOC with the highest occurrence in the active treatment group 
in decreasing order, assuming all terms are coded. Within the body system, drug 
class and SOC, medical history (by preferred term), drugs (by ATC1 code), and 
adverse events (by preferred term) should be displayed in decreasing order. If 
incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics or p-values which cannot be estimated 
should be reported as “-”. 
• 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
• 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
• 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page.  The overall summary statistics for the subheading should only be 
output on the first relevant page. 


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15.2.5.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 
• 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
• 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
• 
Units will be included where available 
15.2.5.4. Figure Conventions 
• 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis. 
15.2.6. Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
• 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
• 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
• 
Subject specific footnotes should be avoided, where possible. 
• 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page.  
• 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


Statistical Analysis Plan 
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16. 
QUALITY CONTROL 
 “SAS programs are developed to produce output such as analysis data sets, summary 
tables, data listings, figures or statistical analyses. Syneos Health SOP 03.010 and 
03.013 provide an overview of the development of such SAS programs. 
Syneos Health SOP 03.009 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the 
output by checking for their logic, efficiency and commenting and by review of the 
produced output.”   


Statistical Analysis Plan 
Zosano Pharma Corporation Protocol #CP-2017-001 
Final Version 1.0 
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17. 
INDEX OF TABLES 
Table Number 
Table Title 
 
 
14.1.1.1.1 
Reasons for Screen Failures and Run-In Failures All Subjects 
14.1.1.1.2 
Subject Disposition All Subjects 
14.1.1.2 
Protocol Deviations Safety Population 
14.1.1.3 
Demographics and Baseline Characteristics Safety Population 
14.1.1.4 
Migraine History Safety Population 
14.1.1.5 
Medical History by Sysytem Organ Class and Preferred Term Safety Population 
14.1.1.6 
Prior Medications Safety Population 
14.1.1.7 
Concomitant Medications Safety Population 
14.1.1.8 
Study Drug Exposure Safety Population 
 
 
14.2.1.1.1 
Summary of Pain Freedom at 30 Minutes and 2, 12, 24, and 48 Hours Postdose Over All 
Migraine Attacks Modified Intent-to-Treat Population 
14.2.1.1.2 
Summary of Subjects with Pain Freedom at 30 Minutes and 2, 12, 24, and 48 Hours 
Postdose by Migraine Number Modified Intent-to-Treat Set 
14.2.1.2.1 
Summary of Freedom from Most Bothersome Symptom (MBS) at 30 minutes, 2 hours, 12 
hours, 24 hours, and 48 hours Postdose over all Migraine Attacks and MBS  Modified 
Intent-to-Treat Population 
14.2.1.2.2   
Absence of Most Bothersome Symptom (MBS) at 30 Minutes and 2, 12, 24, and 48 Hours 
Postdose by Migraine Number and MBS  Modified Intent-to-Treat Population 
14.2.1.3 
Summary of Freedom from Nausea, Photophobia, and Phonophobia, 30 Minutes and 2, 
12, 24, and 48 Hours Postdose Over All Migraine Attacks Modified Intent-to-Treat 
Population 
14.2.1.4 
Pain Relief at 30 Minutes and 2, 12, 24, and 48 Hours Postdose Over All Migraine Attacks 
Modified Intent-to-Treat Population 
14.2.1.5 
Use of Rescue Medication within 2 Hours Postdose Over All Migraine Attacks Modified 
Intent-to-Treat Population 
14.2.1.6.1 
Sustained Pain Freedom from 2 to 24 Hours Postdose Over All Migraine Attacks Modified 
Intent-to-Treat Population 
14.2.1.6.2 
Sustained Headache Pain Freedom from 2 to 48 Hours Postdose Over All Migraine 
Attacks Modified Intent-to-Treat Population 
 
 
14.3.1.1 
Overview of Treatment Emergent Adverse Events Safety Population 
14.3.1.2a 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term – ALL 
Adverse Events Safety Population 


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Table Number 
Table Title 
14.3.1.2b 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term – E-
Diary Skin Assessment Reported Adverse Events Safety Population 
14.3.1.2c 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term – Other 
Subject Reported Adverse Events Safety Population 
14.3.1.3a 
Study Drug-Related Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term – ALL Adverse Events Safety Set 
14.3.1.3b 
Study Drug-Related Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term – E-Diary Skin Assessment Reported Adverse Events Safety Set 
14.3.1.3c 
Study Drug-Related Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term – Other Subject Reported Adverse Events Safety Set 
14.3.1.4 
Serious Treatment Emergent Adverse Events by System Organ Class and Preferred Term– 
ALL Adverse Events Safety Set 
14.3.1.5 
Treatment Emergent Adverse Events of Special Interest by System Organ Class and 
Preferred Term– ALL Adverse Events Safety Set 
14.3.1.6a 
Treatment Emergent Adverse Events by Maximum Severity by System Organ Class and 
Preferred Term – ALL Adverse Events Safety Population 
14.3.1.6b 
Treatment Emergent Adverse Events by Maximum Severity by System Organ Class and 
Preferred Term – E-Diary Skin Assessment Reported Adverse Events Safety Population 
14.3.1.6c 
Treatment Emergent Adverse Events by Maximum Severity by System Organ Class and 
Preferred Term – Other Subject Reported Adverse Events Safety Population 
14.3.2.1 
Summary of Subject Reported Skin Assessment by Time After Patch Application Safety 
Population 
14.3.2.2 
Summary of Subject Reported Skin Assessment by Time After Patch Application – All 
Migraines Safety Population 
14.3.2.3 
Summary of Investigator Reported Skin Assessment by Visit  Safety Population 
14.3.2.4 
Number of Treated Qualifying Migraines per Subject Safety Population 
14.3.2.5 
Number of Treated Qualifying Migraines per Month by Subject Safety Population 
14.3.2.6 
Number of Symptoms by Time Points – All Migraines  Safety Population 
 
 
14.3.3.1.1 
Shift in Laboratory Tests: Hematology  Safety Population 
14.3.3.2.1 
Shift in Laboratory Tests: Serum Chemistry  Safety Population 


Statistical Analysis Plan 
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18. 
INDEX OF FIGURES 
Figure Number 
Figure Title 
 
 
14.3.2.7.1 
Mean Redness Score by Time Points for All Migraines  Safety Population 
14.3.2.7.2 
Mean Swelling Score by Time Points for All Migraines  Safety Population 
14.3.2.7.3 
Mean Bruising Score by Time Points for All Migraines  Safety Population 
 


Statistical Analysis Plan 
Zosano Pharma Corporation Protocol #CP-2017-001 
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19. 
INDEX OF LISTINGS 
Listing 
Number 
Table Title 
 
 
16.2.1 
Subject Disposition Enrolled Population 
16.2.2 
Protocol Deviations Enrolled Population 
16.2.3 
Subject Enrollment and Screen Failures Screened Population 
16.2.4.1 
Demographics Enrolled Population 
16.2.4.2 
Migraine History Enrolled Population 
16.2.4.3 
Migraine Assessment of Current Therapy (Migraine ACT) Enrolled Population 
16.2.4.4 
Medical History Enrolled Population 
16.2.4.5 
Prior and Concomitant Medications Enrolled Population 
16.2.5.1 
Study Drug Accountability Enrolled Population 
16.2.6.1 
eDiary: Subject Reported Skin Assessment Safety Population 
16.2.6.2.1 
eDiary: Symptoms Safety Population 
16.2.6.2.2 
eDiary: Pain Data Safety Population 
16.2.6.2.3 
eDiary: Other Pre-Dose Symptoms Safety Population 
16.2.6.2.4 
eDiary: All Information Safety Population 
16.2.6.3 
Investigator Skin Assessment: Symptoms Safety Population 
16.2.7.1   
Adverse Events  Safety Population 
16.2.7.2 
Serious Adverse Events Safety Population 
16.2.7.3 
Adverse Events Leading to Death Safety Population 
16.2.7.4 
Adverse Events Leading to Study Drug Termination Safety Population 
16.2.8.1.1 
Laboratory Tests – Hematology Screened Population 
16.2.8.1.2 
Laboratory Tests – Serum Chemistry Screened Population 
16.2.8.1.3 
Laboratory Tests – Other Tests Screened Population 
16.2.8.1.4 
Laboratory Tests – Drug Abuse Testing Screened Population 
16.2.8.1.5 
Laboratory Tests – Pregnancy Test Screened Population 
16.2.8.2 
ECG Interpretation Screened Population 
16.2.8.3.1 
Vital Signs Screened Population 
16.2.8.3.2 
Subjects with Abnormal Values of Vital Sign Parameters Screened Population 
16.2.8.4 
Physical Examinations Screened Population 


Statistical Analysis Plan 
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Listing 
Number 
Table Title 
16.2.8.5 
Fitzpatrick Skin Scale Screened Population 
16.2.8.6 
Current Alcohol Drug Use Screened Population 
16.2.9.1 
Monthly Phone Contact Screened Population 
 
 
 


Statistical Analysis Plan 
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20. 
MOCK-UPS 
20.1. 
TABLE MOCK-UPS 
Table shells will be provided as a separate document.  
20.2. 
FIGURE MOCK-UPS 
Figure shells will be provided as a separate document.   
20.3. 
LISTING MOCK-UPS 
Listing shells will be provided as a separate document.