Clinical trial NCT04066023
Conditions: Cluster Headache
Keywords: Episodic cluster headache Chronic cluster headache
Sponsor: Zosano Pharma Corporation
Start date: 2019-10-03; Completion date: 2021-04-14
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double-blind, placebo-controlled study. Subjects who meet the entry criteria will be randomized o receive one of three blinded treatments \[C213 1.9 mg patch and placebo patch; C213 3.8 mg (1.9 mg x 2 patches), two placebo patches\] on Day 1 and will have up to 48 weeks to confirm and treat a cluster headache. Subjects will self-administer the patches and respond to questions in the electronic diary (eDiary) until 1-hour post treatment administration.

Detailed description:
This is a randomized, double-blinded, placebo-controlled study. Approximately 120 subjects who meet the entry criteria will be randomized 1:1:1 to receive one of three blinded treatments \[C213 1.9 mg patch and placebo patch; C213 3.8 mg (1.9 mg x 2 patches), two placebo patches\].

Qualified subjects will randomize to the double-blind treatment period at Day 1 and will have up to 48 weeks to confirm and treat a cluster headache. Using the eDiary to confirm they are experiencing a cluster headache, subjects will self-administer the patches and continue to respond to questions in the eDiary until 1-hour post treatment administration.

Arms: arm 1: C213, 1.9 mg administered as one 1.9 mg patch and one placebo patch arm 2: C213 3.8 mg administered as two 1.9 mg patches arm 3: Placebo microneedle system administered as two placebo patches
Interventions: intervention 1: C213 Microneedle System intervention 2: Placebo
Intervention descriptions: intervention 1: The C213 System is a proprietary disposable patch and a reusable applicator. The zolmitriptan-coated titanium microneedle array (3 cm\^2 array) is attached to a 5 cm\^2 adhesive patch. intervention 2: The C213 System is a proprietary disposable patch and a reusable applicator. The placebo patch is a single use, 3 cm\^2 Placebo (intracutaneous microneedle) system that contains no active ingredients.

Protocol documents:
Prot_000.pdf: 
 
C O N F I D E N T I A L 
Zosano Pharma  34790 Ardentech Court  Fremont, CA 94555 
 
 
CLINICAL PROTOCOL 
 
 
 
STUDY TITLE: 
Randomized, Double-Blind, Multi-Center, Parallel-Group 
Comparison of the Efficacy and Safety of the C213 (Zolmitriptan 
Intracutaneous Microneedle System) to Placebo for the Acute 
Treatment of Cluster Headaches 
 
PROTOCOL NUMBER: 
CP-2019-001  
 
PROTOCOL VERSION: 
Version 4.0 
 
PROTOCOL DATE:  
Original: 
 
27 June 2019 
 
 
 
 
Amendment 1: 
16 July 2019 
 
 
 
 
Amendment 2: 
01 October 2019 
 
 
 
 
Amendment 3: 
15 April 2020 
 
STUDY DRUG: 
C213 (Zolmitriptan Intracutaneous Microneedle System) 
 
SPONSOR:  
Zosano Pharma, Corporation 
 
34790 Ardentech Court 
 
Fremont, CA 94555 
 
Tel: 510-745-1200 
 
MEDICAL MONITOR:  
Pete Schmidt, MD, MSc 
 
 
 
 
 
 
 
 
Zosano Pharma Corporation 
 
 
 
 
 
 
 
 
 
Tel: 510-745-1251 
 
 
 
This document is a confidential communication of Zosano Pharma.  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. 
 
 


C O N F I D E N T I A L
Zosano Pharma  34790 Ardentech Court  Fremont, CA 94555
Clinical Protocol
SPONSOR APPROVAL PAGE
Protocol CP-2019-001
Study Title: Randomized, Double-Blind, Multi-Center, Parallel-Group Comparison of the 
Efficacy and Safety of the C213 (Zolmitriptan Intracutaneous Microneedle System) to Placebo 
for the Acute Treatment of Cluster Headaches
Protocol Version: Amendment 3, Version 4 dated:  15 April 2020
Protocol approved by:
Donald Kellerman, Pharm.D
Vice President, Clinical Development and Medical Affairs
Date
Hayley Lewis
Senior Vice President, Operations and Regulatory Affairs
Date
Pete Schmidt, MD
Medical Monitor
Date
04/15/2020
04/15/2020
04/15/2020


Zosano Pharma Corporation 
 
Protocol No. CP-2019-001v4 
 
 
 
15 April 2020 
Confidential 
Page 2 of 68 
 
PROTOCOL SIGNATURE PAGE -PRINCIPAL INVESTIGATOR 
 
 
Protocol Number: 
CP-2019-001 
 
Study Title: 
Randomized, Double-Blind, Multi-Center, Parallel-Group Comparison of 
the Efficacy and Safety of the C213 (Zolmitriptan Intracutaneous 
Microneedle System) to Placebo for the Acute Treatment of Cluster 
Headaches 
 
Protocol Version:  
4.0 
 
Protocol Date:  
 15 April 2020 
 
I have received and read the protocol dated 15 April 2020.  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 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) 
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 
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 
eCRF 
CRO 
Electronic Case report form 
Contract Research Organization 
CTA 
Clinical Trials Authorization 
CTM 
Clinical trial material 
CVA 
Cerebral vascular accident 
C213 
Zolmitriptan Intracutaneous Microneedle System 
dL 
Deciliter 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
F 
Fahrenheit 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HDL 
HIPAA 
High-density lipoprotein 
Health Insurance Portability and Accountability Act 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IHS 
International Headache Society 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Randomization System 
J 
Joules 


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Kg 
Kilogram 
LDH 
Lactate dehydrogenase 
M207 
Zolmitriptan Microneedle System 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligrams 
mITT 
mL 
MM 
Modified Intent-to-Treat 
Milliliter  
Medical Monitor 
NDA 
New drug application 
PCP 
Phencyclidine 
PE 
Physical examination 
PRSPB 
PV 
Patch-related superficial punctate bruising 
Pharmacovigilance 
RDC 
Remote Data Capture 
RR 
Respiratory Rate 
RTSM 
Randomization and Trial Supply Management system 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous  
SD 
Standard deviation 
SEM 
Standard error of the mean 
SOP 
Standard operating procedures 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum concentration 
TIA 
Transient ischemic attacks 
TMF 
U/L 
Trial master file 
Units per liter 
U.S. 
United States 
WOCBP 
ZP-Zolmi 
Women of child-bearing potential 
Zosano Pharma Zolmitriptan Microneedle System 
 


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PROTOCOL SYNOPSIS 
TITLE 
Randomized, double-blind, multi-center, parallel-group 
comparison of the efficacy and safety of the C213 (Zolmitriptan 
Intracutaneous Microneedle System) to placebo for the acute 
treatment of cluster headaches 
SPONSOR 
Zosano Pharma Corporation 
CLINICAL PHASE 
Phase 2/3 
INDICATION 
Acute treatment of cluster headaches in adults  
OBJECTIVES 
• To compare the efficacy of C213 at doses of 1.9 mg and 3.8 mg 
(1.9 mg x 2 patches) to placebo in the acute treatment of cluster 
headaches  
• To compare the safety of C213 at doses of 1.9 mg and 3.8 mg 
(1.9 mg x 2 patches) to placebo in the acute treatment of cluster 
headaches 
• To assess the dose-response relationship of C213 on efficacy 
and tolerability 
TRIAL DESIGN 
Multi-center, multiple dose, randomized, double-blind, placebo-
controlled, parallel-group 
INVESTIGATIONAL 
TREATMENT 
Single-dose treatment (to be applied for 30 minutes) of the 
following: 
• C213, 1.9 mg on a 3 cm2 patch and one placebo patch or 
• C213, 3.8 mg on two 3 cm2 patches (1.9 mg x 2) or 
• Placebo microneedle system: two 3 cm2 patches 
BLINDING 
Double-blind  
RANDOMIZATION 
1:1:1 (placebo, 1.9 mg, 3.8 mg)   
STUDY POPULATION 
Adults who suffer from chronic or episodic cluster headache  
NUMBERS OF 
SUBJECTS 
Approximately 120 subjects will be randomized at approximately 
13 US sites. 
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 65 years of age 
3. Greater than 1-year history of episodic or chronic cluster 
headache with onset prior to 50 years of age.  Diagnosis must 
comply with ICHD-3 (International Headache Society (IHS) 


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diagnostic criteria).  Diagnostic criteria must include a history 
of at least 5 attacks not attributed to any other disorder that 
include all of the following criteria: 
a) Severe or very severe unilateral orbital, supraorbital and/or 
temporal pain lasting 45-180 minutes (average, when 
untreated) 
b) Either or both of the following: 
(1) At least one of the following symptoms or signs, 
ipsilateral to the pain:   
(a) Conjunctival injection and/or lacrimation 
(b) Nasal congestion and/or rhinorrhea 
(c) Eyelid edema 
(d) Forehead and facial sweating 
(e) Miosis and or/ptosis 
(2) A sense of restlessness or agitation 
c) Attacks have a frequency between one every other day and 
eight per day for more than half of the time when the 
disorder is active. 
d) Not better accounted for by another ICHD diagnosis 
4. Cluster history during the 12-month period prior to the 
screening visit must include: 
a) At least 1 cluster period 
b) Averaging 2-6 headaches per day 
c) Lasting at least 7 days 
5. Subject can distinguish cluster headaches from other 
headaches (i.e., migraine and tension-type headaches) 
6. Women of child-bearing potential must not be pregnant, must 
agree to avoid pregnancy during the trial, and must use one of 
the following or be surgically sterilized: intrauterine device, or 
a hormonal contraceptive  
7. Able to understand the operation of the electronic diary and 
able to apply the demo study drug patch correctly. 
 
Exclusion Criteria: 
Subjects presenting with any of the following will not be included 
in the study: 
1. Contraindications to triptans 
2. Use of any prohibited concomitant medications within 7 days 
of screening 
3. History of hemiplegic migraine or migraine with brainstem 


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aura 
4. Participation in another investigational trial within 30 days or 
5 half-lives of investigational product (whichever is longer). 
5. Previous M207/C213 exposure in a clinical trial  
6. Subject has other significant pain problems that might 
confound the study assessments in the opinion of the 
investigator 
7. Diagnosis of any malignant disease (other than adequately 
treated or excised non-metastatic basal cell carcinoma or 
squamous cell carcinoma of the skin) within the 5 years prior 
to screening 
8. History of unstable psychiatric illness requiring medication or 
hospitalization in the 12 months prior to study screening 
9. Subjects who have a known allergy or sensitivity to 
zolmitriptan or its derivatives or formulations 
10. Subjects who have a known allergy or sensitivity to adhesives 
11. Subjects who have skin lesions or tattoos covering the entire 
potential area(s) of C213 application  
12. Woman who are pregnant, breast-feeding or plan a pregnancy 
during this study 
13. Clinically significant liver disease (ALT > 150 U/L; 
AST > 130 U/L or bilirubin > 2x ULN) 
14. Clinically significant kidney disease (eGFR < 60 ml/min / 
1.73 m² or to creatinine > 1.5 x ULN) 
15. Subject has clinically 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 in at least two contiguous leads 
c) clinically significant intra-ventricular conduction 
abnormalities (left bundle branch block or Wolf-
Parkinson-White syndrome) 
d) clinically significant arrhythmias (e.g., current atrial 
fibrillation) 
16. 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) 
17. Three or more of the following CAD risk factors: 
a) Current tobacco use 
b) Hypertension (systolic BP > 140 or diastolic BP > 90) 


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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 
18. History of cerebral vascular accident (CVA), transient 
ischemic attacks (TIA), or seizures 
19. History of concurrent illness that requires hospitalization 
within 30 days prior to study screening 
20. Any other household member currently participating in a C213 
study or relative of site staff member 
21. Any reason to believe that compliance with the study 
requirements and completion of evaluations required for this 
study will not be possible 
22. Any language barrier that, in the opinion of the Investigator, 
would preclude communication and compliance with the study 
requirements 
23. History or current abuse of or dependence on alcohol or drugs 
that would interfere with the results or adherence to study 
requirements, and/or current tobacco cigarette smoking 
24. Any positive drug screens for phencyclidine (PCP), MDMA 
(ecstasy), cocaine, and/or meth/amphetamine(s) 
25. Current or planned use of hallucinogens (e.g. psilocybin) 
during the trial 
26. Any clinically relevant abnormal findings in the physical 
exam, vital signs or laboratory tests that, in the opinion of the 
Investigator, may put the subject at risk 
 
 
 
 
 
 
 
 
 
 
 


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CENTERS 
Multicenter in the United States 
STUDY DURATION 
Screening:  1 to 7 days, Double-blind Period: Subject has up to 
48 weeks to administer study medication, End of Study Visit is 
1-8 days following administration of study drug 
STUDY PROCEDURES 
• Screening activities may be performed in 1 to 7 days [+ 3 days] 
• Double-blind period for up to 48 weeks [+ or – 7 days]  
• Phone contacts monthly [every 28 days + or – 3 days] 
• Pregnancy urine testing for WOCBP monthly [every 28 days + 
or – 7 days] 
• Rescue therapy allowed at or after 20 min post dose 
• One single treatment by subject with symptom recording at 
pre-dose, 5 min, 10 min, 15 min, 20 min, 30 min, and 60 min  
• End of study or early discontinuation Visit 3 is 1-8 days 
post-cluster headache treatment 
CRITERIA FOR 
EVALUATION: 
EFFICACY AND 
SAFETY 
Co-Primary Efficacy Endpoints: 
• 
Proportion of subjects who achieve pain relief at 15 minutes. 
Headache pain is assessed using a 4-point scale (0 = none, 
1 = mild, 2 = moderate, 3 = severe). Pain relief is defined by a 
decrease in pain from severe to mild or none without the use of 
acute rescue medication. 
• 
Proportion of subjects who achieve sustained pain relief from 
15 minutes to 60 minutes post patch application. Sustained 
pain relief requires a pain rating of mild or none at each 
timepoint from 15 minutes to 60 minutes without the use of 
acute rescue medication.   
 
Secondary Efficacy Endpoints: 
• 
Proportion of subjects that achieve pain relief at 5, 10, 20, and 
30 minutes post patch application 
• 
Proportion of subjects that achieve sustained pain relief from 5 
to 60 minutes and from 10 to 60 minutes post patch application 
• 
Proportion of subjects that achieve pain freedom at 10- and 
15-minutes post patch application 
• 
Proportion of subjects that achieve sustained pain freedom 
from 10 to 60 minutes and from 15 to 60 minutes post patch 
application 
• 
Proportion of subjects with rescue therapy use within 
20 minutes post patch application 
• 
Proportion of subjects able to perform their usual daily 
activities as assessed by the subject 
 


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SAFETY 
• Incidence of adverse events  
• Physical exam including height and weight 
• Vital signs including blood pressure  
• Serum chemistries and hematological parameters 
• Serum and urine pregnancy for women of child-bearing 
potential 
• 12-lead ECGs  
• Assessment of concomitant medications 
• Investigator visual skin Assessments 
 
STATISTICAL 
METHODS: 
EFFICACY ANALYSIS: 
For the primary efficacy analysis, the proportion of subjects 
achieving pain relief at 15 minutes and sustained pain relief from 
15 minutes to 60 minutes post-dose will be analyzed separately 
using a Cochran Mantel Haenszel test stratified by cluster 
headache subtype (chronic or episodic).  A significance test of the 
treatment difference comparing each C213 dose to placebo will be 
tested at the two-sided 0.05 level, and odds ratios and their 
corresponding 95% confidence intervals will be calculated.  
Secondary endpoints will be analyzed using similar methods.  A 
fixed sequence procedure will be applied to the two C213 arms and 
the primary and secondary efficacy endpoints to adjust for 
multiplicity and to control for overall type I error. 
 
Safety Analyses: 
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.  
All safety data will be listed by subject and parameter, separate 
listings of all abnormal laboratory findings will be provided, and 
clinically significant abnormalities will be recorded as AEs.  
 
Sample Size: 
It is anticipated that 20% of subjects receiving placebo and 55% of 
subjects receiving active treatment will achieve pain relief at 
15 minutes and sustained pain relief from 15 minutes to 60 minutes 
post-dose.  Based on a two-sided chi-square test with continuity 
correction and an alpha level of 0.05, 40 patients/arm will provide 
approximately 80% power to detect this same difference between 
two treatment groups, assuming a 15% dropout rate. 
 


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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 .................................................................................................15 
1.1 
Background C213 for the Acute Treatment of Cluster Headache ...................15 
1.2 
Clinical Pharmacology, Efficacy, and Safety of zolmitriptan and other studies 
of Cluster Headache .........................................................................................16 
1.3 
Study Rationale and Choice of Design ............................................................20 
2 
STUDY OBJECTIVES ..........................................................................................22 
2.1 
Primary Objective ............................................................................................22 
2.2 
Secondary Objectives.......................................................................................22 
3 
INVESTIGATIONAL PLAN ................................................................................23 
3.1 
Study Design ....................................................................................................23 
3.2 
Selection of Study Population ..........................................................................24 
3.2.1 
Number of Subjects..............................................................................24 
3.2.2 
Inclusion Criteria .................................................................................24 
3.2.3 
Exclusion Criteria: ...............................................................................25 
3.2.4 
Eligibility Criteria for Randomization .................................................27 
3.2.5 
Prior and Concomitant Medications Allowed During the Study .........27 
3.2.6 
Early Termination ................................................................................27 
4 
STUDY TREATMENTS .......................................................................................29 
4.1 
Identity of Investigational Products .................................................................29 
4.1.1 
C213 .....................................................................................................29 
4.1.2 
Comparator Product:  ZP-Placebo .......................................................29 
4.1.3 
Product Description and Patch Application .........................................29 
4.2 
Method of Assigning Subjects to Treatment Group ........................................32 
4.3 
Dose, Dose Schedule, and Route of Administration........................................32 
4.4 
Packaging, Labeling, and Receipt of Supplies .................................................32 
4.5 
Study Drug Stability, Storage, and Retention ..................................................33 
4.6 
Study Drug Kit Assignment, Dispensation, and Accountability .....................33 
4.7 
System Performance ........................................................................................33 
4.8 
Medication Compliance ...................................................................................33 


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5 
EFFICACY AND SAFETY ANALYSIS VARIABLES ......................................34 
5.1 
Efficacy ............................................................................................................34 
5.2 
Safety ...............................................................................................................34 
6 
STUDY PROCEDURES AND SCHEDULE ........................................................36 
6.1 
Study Schedule.................................................................................................36 
6.1.1 
Screening Visit 1: Up to 1 Week [ + 3 days] Prior to Randomization 
and Start of the Double-Blind Period ...................................................37 
6.1.2 
Visit 2, Day 1 Randomization ..............................................................38 
6.1.3 
Double-Blind Treatment Phase: Day 1 through up to 48 Weeks 
[336 Days + or – 7 days] ......................................................................39 
6.1.4 
Pregnancy Tests (every 4 weeks ± 7 days) ..........................................40 
6.1.5 
Investigator (or designee) Phone Contact to Subjects (every 4 weeks ± 
3 days) ..................................................................................................40 
6.1.6 
Investigator (or designee) Phone Contact to Subject– Following 
application of C213 (+ 2 days) ............................................................40 
6.1.7 
Visit 3 - Day 1-8 Following Treatment of Cluster Headache / End of 
Study (or Early Discontinuation) Visit (+3 days) ................................41 
6.2 
Study Procedures .............................................................................................42 
6.2.1 
Informed Consent.................................................................................42 
6.2.2 
Inclusion/Exclusion Criteria ................................................................42 
6.2.3 
Medical History, Substance Use, Cluster Headache History and 
Demographics ......................................................................................42 
6.2.4 
Randomization .....................................................................................42 
6.2.5 
Physical Examination...........................................................................42 
6.2.6 
Height and Weight ...............................................................................42 
6.2.7 
Vital Signs ............................................................................................43 
6.2.8 
Clinical Laboratory Tests .....................................................................43 
6.2.9 
Twelve-Lead Electrocardiogram .........................................................44 
6.2.10 
Previous, Concomitant and Prohibited Medications ............................44 
6.2.11 
Assessment of Adverse Events ............................................................45 
6.2.12 
Investigator Skin Assessment ..............................................................45 
6.2.13 
Medication Compliance .......................................................................46 
7 
STATISTICS .........................................................................................................47 
7.1 
Analysis Populations ........................................................................................47 
7.2 
Estimate of Sample Size ..................................................................................47 
7.3 
Demographic and Baseline Characteristics .....................................................47 
7.4 
Efficacy Analysis .............................................................................................47 
7.4.1 
Primary Analysis ..................................................................................47 
7.4.2 
Secondary Analyses .............................................................................48 


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7.5 
Safety Analysis ................................................................................................48 
8 
ADVERSE EVENTS .............................................................................................50 
8.1 
Reporting Period ..............................................................................................50 
8.2 
Adverse Event Definitions ...............................................................................50 
8.2.1 
Adverse Events (Adverse Experiences) ...............................................50 
8.3 
Documentation and Reporting of Adverse Events by Investigator .................54 
8.3.1 
Reporting Requirements for Serious Adverse Events .........................54 
8.3.2 
Reporting Requirements for Non-Serious Adverse Event ...................55 
8.4 
Follow up of Adverse Events ...........................................................................55 
8.5 
Contacts for Serious Adverse Events and Medical Monitoring.......................56 
9 
EMERGENCY PROCEDURES ............................................................................57 
9.1 
Emergency Contact ..........................................................................................57 
9.2 
Unblinding Procedures.....................................................................................57 
9.3 
Emergency Treatment ......................................................................................57 
10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ....................................58 
10.1 
Study Monitoring .............................................................................................58 
10.2 
Audits and Inspections .....................................................................................58 
10.3 
Institutional Review Board (IRB)/Independent Committee ............................58 
10.4 
Participant Recruitment ...................................................................................58 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .....................................59 
12 
ETHICS..................................................................................................................60 
12.1 
Ethics Review ..................................................................................................60 
12.1.1 
Ethical Conduct of the Study ...............................................................60 
12.2 
Written Informed Consent ...............................................................................60 
12.3 
Disclosure of Data............................................................................................61 
13 
DATA HANDLING AND RECORDKEEPING ..................................................62 
13.1 
Inspection of Records ......................................................................................62 
13.2 
Case Report Forms ...........................................................................................62 
13.3 
Publication Policy ............................................................................................63 
13.4 
Retention of Records........................................................................................63 
14 
REFERENCES ......................................................................................................64 
APPENDIX  1 
INVESTIGATOR ASSESSMENTS – RATING FOR BRUISING, 
ERYTHEMA, EDEMA AND PHOTOGRAPHS .................................................65 
APPENDIX 2 
SAMPLE SUBJECT EDIARY QUESTIONS.....................................67 
 


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LIST OF TABLES 
Table 1: 
Key Pharmacokinetic Parameters ..............................................................16 
Table 2: 
Treatment Emergent Adverse Events Occurring in Two or More Subjects19 
Table 3: 
Investigator Visual Dermal Adverse Events ..............................................20 
Table 4: 
Schedule of Study Procedures ...................................................................36 
Table 5: 
Clinical Laboratory Tests ...........................................................................43 
Table 6: 
Prohibited Concomitant Medications ........................................................44 
 
LIST OF FIGURES 
Figure 1: 
Study Design ..............................................................................................23 
Figure 2: 
5 cm2 Patch with Zolmitriptan Coated Titanium Microneedle Array .......30 
Figure 3: 
Handheld Gen 6 Patch Ring Assembly and Applicator .............................30 
Figure 4: 
*C213 Patch Application ...........................................................................31 
 


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1 
INTRODUCTION 
1.1 
Background C213 for the Acute Treatment of Cluster Headache 
Cluster headache is a debilitating and painful disorder that affects approximately 0.1% of the 
U.S. population.  The excruciating headaches, lasting from 15 minutes to 3 hours and averaging 
45-60 minutes, and are often described as the worst pain the sufferer has ever experienced.  A 
number of acute treatments have been utilized, including injectable triptans, inhaled oxygen and 
neurostimulation.  Perhaps the most important attribute for an acute treatment of cluster 
headache is rapid onset of pain relief or freedom (Rozen et al 2012). 
Zosano is evaluating C213 for the acute treatment of cluster headache (both episodic and 
chronic).  Intranasal and oral zolmitriptan products have been evaluated for the treatment of 
cluster headache, in randomized, placebo-controlled trials and found to be effective.  
Unfortunately, these trials only demonstrated significant efficacy at 30 minutes, which is not 
ideal for these intense and short-lived attacks (Cittadini et al 2006, Bahra et al 2000, Hedlund et 
al 2009). 
Subcutaneous (SC) sumatriptan is also effective for the treatment of cluster headache and 
relieves headache pain in a significant percentage of sufferers (Ekbom et al 1993).  This is likely 
due to the rapid absorption of sumatriptan following injection.  Zosano conducted a 
pharmacokinetic study (CP-2015-007) comparing plasma concentrations of sumatriptan 
following subcutaneous administration with several dose levels of C213 and oral zolmitriptan 
2.5 mg.  The mean plasma concentrations following C213 3.8 mg, oral zolmitriptan 2.5 mg, and 
subcutaneous sumatriptan 6.0 mg are shown below.  Note that the plasma concentrations of 
sumatriptan were divided by 10 to account for differences in potency, as the slide is intended to 
illustrate the comparative pharmacokinetic curves. 
 


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By visual inspection, one can see that plasma concentrations of zolmitriptan were detectable very 
quickly after C213 administration, and the time to maximum concentration is similar to 
subcutaneous sumatriptan.  As has been described several times, time to maximum concentration 
of oral zolmitriptan is approximately one hour (Seaber et al 1998), which is far less desirable for 
treating cluster headaches. 
If the rapid absorption of zolmitriptan following C213 administration results in fast relief of the 
severe pain of cluster headache, C213 would be a valuable addition to the therapeutic options 
currently available to cluster headache sufferers.  The goal of this trial is to compare C213 doses 
of 1.9 mg and 3.8 mg (administered as two patches of 1.9 mg) to placebo for the treatment of 
acute cluster headache. 
1.2 
Clinical Pharmacology, Efficacy, and Safety of zolmitriptan and other 
studies of Cluster Headache 
Human Pharmacokinetics 
A Phase 1 study compared the PK of intracutaneous zolmitriptan and its metabolites as well as 
the tolerability of various doses of intracutaneous zolmitriptan to a standard oral dose (2.5 mg) of 
zolmitriptan (CP-2015-007).  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 C213 
system use for the treatment of cluster headaches. 
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  
(ZP Zolmi) 
0.48 
1.8 (0.53) 
20 (2-30) 
2.1 (0.73) 
2.8 (1.36) 
5.8 
67% 
B  
(ZP Zolmi) 
0.48 x 2 
3.7 (1.05) 
20 (2-30) 
4.2 (0.95) 
6.5 (1.97) 
7.5 
87% 
C  
(ZP Zolmi) 
1.9 
6.8 (2.75) 
20 (2-30) 
7.4 (2.53) 
12.3 (4.31) 
6.5 
76% 
F  
(ZP Zolmi) 
1.9 x 2 
14.6 (4.46) 
17.5 (2-30) 
16.4 (5.34) 
27.8 (9.93) 
7.3 
85% 
G  
(ZP Zolmi) 
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 
NA 


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Perhaps most relevant to the potential utility of this product for the treatment of cluster headache 
is the Tmax for the ZP-Zolmitriptan regimens, showing much more rapid absorption of the 
zolmitriptan from intracutaneous administration than from oral administration. 
Efficacy Measurements 
The efficacy of C213 for the acute treatment of cluster headaches has not been established.  The 
efficacy of zolmitriptan given by oral tablet or nasal spray has been demonstrated in large 
placebo-controlled trials (Rapoport et al 1997, Dawson et al 2005, Dahlof et al 1998).  In a 
meta-analysis of zolmitriptan nasal spray for cluster headache, the authors found that headache 
response was observed at 30 minutes (primary endpoint) in a larger proportion of subjects than 
placebo for both 5 mg and 10 mg doses (48.3% vs 29.5%, P = .0004, and 63.1% vs 29.5%, 
P ≤ .001, respectively).  Furthermore, significantly more subjects were pain free at 30 minutes in 
both dose groups as compared to placebo (34.8% vs 19.3%, P = .007 for 5 mg, and 44% vs 
19.3%, P ≤ .001 for 10 mg).  Similarly, oral zolmitriptan was found to be effective in episodic 
cluster headache at both the 10 mg (59.5%) and 5mg (56.6%) doses versus placebo (42.2%, 
P ≤ 0.01 for both doses) Bahra et al 2000.  The oral formulation was not found to be significantly 
different from placebo in chronic cluster.  
Subcutaneous sumatriptan 6 mg was evaluated in two double-blind, placebo-controlled, 
crossover trials of individuals with cluster headache.  Pain relief rates at 15 minutes for SC 
sumatriptan were 74% and 75% compared with placebo pain relief rates of 26% and 35%.  In 
both trials, SC sumatriptan was significantly more effective than placebo.  Thus, pain relief rates 
appeared higher with the more rapidly absorbed product (Imitrex product information). 
Safety Assessments  
As with efficacy, the safety of various formulations of zolmitriptan has been extensively studied, 
predominantly in migraine patients.   
The safety of oral zolmitriptan at significantly higher doses (and presumably higher plasma 
concentrations) than those proposed for the C213 program, has been evaluated in two large 
placebo-controlled studies of migraine.  Dahlof et al 1998 evaluated 1181 subjects who received 
zolmitriptan doses of 5 mg, 10 mg, 15 mg or 20 mg (more than 200 subjects per dose group).  
The incidence of adverse events was 61%, 75%, 79% and 76% respectively.  \The most 
commonly reported adverse events were asthenia, dizziness, paresthesia and feelings of 
heaviness.  Most of the adverse events were mild or moderate in intensity, not serious, transient 
and resolved without intervention.  The incidence of chest-related adverse events i.e., tightness, 
pain, heaviness, and pressure was low.  Administration of zolmitriptan, even at the highest dose, 
was not associated with significant effects on clinical laboratory tests or ECGs.  
Rapoport et al 1997 compared oral doses ranging from 1 mg to 10 mg of zolmitriptan to placebo 
in 1258 migraine patients and found that efficacy increased as a function of dose, and that all 
doses of zolmitriptan were well-tolerated, although the incidence of adverse events was 
dose-related. 


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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. 
Long-Term Safety Studies of Zolmitriptan 
Two large long-term studies have established the long-term safety of oral zolmitriptan and 
intranasal zolmitriptan.  The International Zolmitriptan Study group studied 2058 patients who 
treated 31579 migraines with 5 mg oral zolmitriptan over one year and found the drug to be well-
tolerated.  Dawson et al evaluated 538 patients who treated 20717 attacks over 1 year with 
intranasal zolmitriptan 5 mg, and also found a high degree of tolerability.  Therefore, the 
long-term safety of frequent administration of zolmitriptan administered from two different 
formulations has been well established. 
Zosano Pharma Protocol CP-2016-001 Safety Data 
1.2.1 
Safety Results of Protocol CP-2016-001 
Study CP-2016-001 was a dose ranging study comparing the safety and efficacy of M207/C213 
to placebo in the acute treatment of migraine attacks.  365 subjects were enrolled in this study.  
No serious adverse events occurred in the efficacy and safety study CP-2016-001 in subjects 
with migraine.  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 2, 
and Investigator Dermal Adverse Events are shown in Table 3. 


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Table 2: 
Treatment Emergent Adverse Events Occurring in Two or More Subjects 
System Organ 
Class/Preferred Term 
Treatment Group 
Placebo 
(N=83) 
C213 
1 mg 
(N=80) 
C213 
1.9 mg 
(N=87) 
C213 
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 
  hemorrhage 
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 edema 
0 (0.0%) 
1 (1.3%) 
3 (3.4%) 
2 (2.4%) 
6 (1.8%) 
  Application site 
  discoloration 
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 3: 
Investigator Visual Dermal Adverse Events 
Patch-Related 
Superficial 
Punctate Bruising 
(PRSPB) 
N 
Treatment Group 
Placebo 
(N=83) 
C213 
1 mg 
(N=80) 
C213 
1.9 mg 
(N=87) 
C213 
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%) 
 
1.3 
Study Rationale and Choice of Design 
C213 is a novel formulation of zolmitriptan for intracutaneous delivery, which when 
administered results in rapid systemic absorption of zolmitriptan and time to maximum 
concentration of plasma zolmitriptan of approximately 15 minutes.  This product was evaluated 
in a previous migraine trial (CP-2016-001), and the 3.8 mg dose was superior to placebo for both 
co-primary endpoints.  The 1.9 mg dose was superior to placebo for 1 of 2 co-primary endpoints 
(pain freedom at 2 hours).  Tolerability was good, and the most common adverse reactions were 
application site reactions, that all resolved over a course of hours to days. 
Cluster headaches are severe, debilitating and exquisitely painful, but the attacks are of shorter 
duration than in migraine.  Given the characteristics of the attacks, any drug administered to 
abort the attacks must be rapidly absorbed to be of benefit.  Previous trials of subcutaneous 
sumatriptan have demonstrated that a rapidly absorbed triptan can relieve the pain associated 
with a cluster attack.  Thus, C213 with observed Tmax ranging from 2-30 minutes seen in a 


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previous Phase 1 study, may be absorbed rapidly enough to produce systemic levels of 
zolmitriptan, sufficient to relieve a cluster headache attack. 
The doses of C213 used in this study are 3.8 mg, that was found to be effective in a previous 
migraine efficacy trial and 1.9 mg, that was effective for pain reduction in the same trial.  There 
is anecdotal clinical evidence that lower doses of injected triptans may be effective for cluster 
headache attacks. 
Sample size determination was estimated based on the characteristics of C213 and the results of 
previous trials of pharmacologic agents for the treatment of cluster headache.  The only product 
approved for treating cluster headache is subcutaneous sumatriptan, and the effect size in those 
trials was significant.   However, the trials were crossover designs utilizing paper diaries 
conducted in the 1990s.  The more recent trials with zolmitriptan (particularly nasal spray) had 
smaller effect sizes, perhaps due to slower absorption than seen with SC sumatriptan.  C213 has 
pharmacokinetics more similar to SC sumatriptan than the zolmitriptan formulations.  Therefore, 
we estimated the effect size of C213 to be somewhere between that of SC sumatriptan and that of 
intranasal zolmitriptan. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• To compare the efficacy of C213 at doses of 1.9 mg and 3.8 mg (1.9 mg x 2 patches) to 
placebo in the acute treatment of cluster headache attacks 
 
2.2 
Secondary Objectives 
• To compare the safety of C213 at doses of 1.9 mg and 3.8 mg (1.9 mg x 2 patches) to 
placebo in the acute treatment of cluster headache attacks 
• To assess the dose-response relationship of C213 on efficacy and tolerability 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
The study is outlined in Figure 1. 
Figure 1: 
Study Design 
SCREENING PERIOD 
1-7 days 
DOUBLE BLIND TREATMENT PERIOD –  
DAY 1 – DAY 336 
Up to one week prior to 
Randomization 
 
  
Starts on Day 1 = Randomization 
 
Up to 48 weeks from Day 1 
 
Obtain ICF and all required 
screening procedures.  If subject 
qualifies for randomization, 
schedule visit 2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If preliminary entry criteria 
indicate that the subject is not 
eligible for randomization, 
register the subject as a screen 
failure. 
 
→ 
 
 
 
 
 
If the subject still qualifies for 
randomization at visit 2, the subject 
will be assigned by the Medidata 
RTSM randomization system one of 
the following kits: 
 
1. C213 1.9 mg patch and 
placebo patch administered 
upon confirmed cluster 
headache or 
 
2. C213 3.8 mg (1.9 mg x 2 
patches) administered upon 
confirmed cluster headache 
or 
 
3. Placebo (two patches) 
administered upon 
confirmed cluster headache 
 
 
If the subject does not meet all the 
inclusion and/or meets one or more 
of the exclusion criteria, record the 
subject as a screen failure in the 
Medidata EDC system. 
 
 
 
 
 
 
 
 
→ 
 
 
 
 
→ 
 
 
 
→ 
 
 
 
 
 
 
 
 
Subject will have up to 
48 weeks to confirm and treat 
a cluster headache attack.  
Subject will answer questions 
about his/her headache 
symptoms in the eDiary.  
Upon confirmation of a 
qualifying cluster headache, 
the subject will self-administer 
the patches.  The subject will 
continue to complete the 
eDiary at specified time points 
out to 60 minutes post dose. 
 
 
Subject will be seen for 
their final visit within 
1-8 days post C213 
application. 
 
 
This is a randomized, double-blinded, placebo-controlled study.  Subjects who have consented 
and meet the entry criteria will be randomized to receive one of three blinded treatments.   
Qualified subjects will randomize to the double-blind treatment period at Day 1 and will have up 
to 48 weeks to confirm and treat a cluster headache.  Using the eDiary to confirm the subject is 
experiencing a cluster headache, subjects will self-administer the patches and continue to 
respond to questions in the eDiary for 1-hour post treatment administration.  


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3.2 
Selection of Study Population 
3.2.1 
Number of Subjects 
Approximately 120 subjects will be randomized into the study at approximately 13 study sites.   
 
3.2.2 
Inclusion Criteria 
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 65 years of age 
3. Greater than 1-year history of episodic or chronic cluster headache with onset prior to 
50 years of age.  Diagnosis must comply with ICHD-3 (International Headache Society 
(IHS) diagnostic criteria.  Diagnostic criteria must include a history of at least 5 attacks 
not attributed to any other disorder that include all of the following criteria: 
a) Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 
45-180 minutes (average, when untreated) 
b) Either or both of the following: 
1. At least one of the following symptoms or signs, ipsilateral to the pain:   
(a) Conjunctival injection and/or lacrimation 
(b) Nasal congestion and/or rhinorrhea 
(c) Eyelid edema 
(d) Forehead and facial sweating 
(e) Miosis and or/ptosis 
2. A sense of restlessness or agitation 
c) Attacks have a frequency between one every other day and eight per day for more 
than half of the time when the disorder is active 
d) Not better accounted for by another ICHD diagnosis 
4. Cluster history during the 12-month period prior to the screening visit must include: 
a) at least 1 cluster period 
b) averaging 2-6 headaches per day 
c) lasting at least 7 days 
5. Subject can distinguish cluster headaches from other headaches (i.e., migraine and 
tension-type headaches) 


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6. Women of child-bearing potential must not be pregnant, must agree to avoid pregnancy 
during the trial, and must use one of the following or be surgically sterile: intrauterine 
device or a hormonal contraceptive 
7. Able to understand the operation of the electronic diary and able to apply the demo study 
drug patch correctly. 
 
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 7 days prior to screening (See 
Table 6 Prohibited Concomitant Medications) 
3. History of hemiplegic migraine or migraine with brainstem aura 
4. Participation in another investigational trial within 30 days or 5 half-lives of 
investigational product (whichever is longer) 
5. Previous M207/C213 exposure in a clinical trial  
6. Subject has other significant pain problems that might confound the study assessments in 
the opinion of the Investigator. 
7. Diagnosis of any malignant disease (other than adequately treated or excised 
non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin) within the 
5 years prior to screening 
8. History of unstable psychiatric illness requiring medication or hospitalization in the 
12 months prior to study screening 
9. Subjects who have a known allergy or sensitivity to zolmitriptan or its derivatives or 
formulations 
10. Subjects who have known allergy or sensitivity to adhesives 
11. Subjects who have skin lesions or tattoos covering the entire potential area(s) of C213 
application 
12. Women who are pregnant, breast-feeding or plan a pregnancy during this study 
13. Clinically significant liver disease (ALT > 150 U/L; AST > 130 U/L or bilirubin 
> 2x ULN)  
14. Clinically significant kidney disease (eGFR < 60 ml/min /1.73 m² or to creatinine 
> 1.5 x ULN) 
15. Subject has clinically 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 in at least two contiguous leads 


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c) clinically significant intra-ventricular conduction abnormalities (left bundle branch 
block or Wolf-Parkinson-White syndrome) 
d) clinically significant arrhythmias (e.g., current atrial fibrillation) 
16. 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) 
17. Three or more of the following CAD risk factors: 
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 
18. History of cerebral vascular accident (CVA), transient ischemic attacks (TIA), or seizures 
19. History of concurrent illness that requires hospitalization within 30 days prior to study 
screening 
20. Any other household member currently participating in a C213 study or relative of site 
staff member 
21. Any reason to believe that compliance with the study requirements and completion of 
evaluations required for this study will not be possible 
22. Any language barrier that, in the opinion of the Investigator, would preclude 
communication and compliance with the study requirements 
23. History or current abuse of or dependence on alcohol or drugs that would interfere with 
the results or adherence to study requirements, and/or current tobacco cigarette smoking 
24. Any positive drug screens for phencyclidine (PCP), MDMA (ecstasy), cocaine, and/or 
meth/amphetamine(s) 
25. Current or planned use of hallucinogens (e.g. psilocybin) during the trial 
26. Any clinically relevant abnormal findings in the 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 Randomization 
To be eligible for randomization and the double-blind period, subjects must meet all inclusion 
and exclusion criteria.  In addition, the following must be confirmed on the day of 
randomization: 
1. Demonstrated ability to properly use the eDiary 
2. Willing to enter eDiary data to determine if he/she is experiencing a qualifying cluster 
headache attack and complete the eDiary questions after applying the patches 
3. Demonstrated ability to apply the demonstration study drug patches 
4. 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 
 
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 6.2.10), may be given at the discretion of the investigator.  The 
administration of such medication must be recorded in the appropriate source document and in 
the electronic case report form (eCRF) for the duration of the study.   
For the cluster headache to be qualifying for study medication, no medications specifically taken 
for the subject’s headache symptoms are allowed within 24 hours prior to onset of the current 
cluster headache symptoms. If rescue therapy is required by the subject, rescue therapy other 
than a triptan or ergot is permitted at or after 20 minutes post study drug administration.   
Oxygen will be provided in an “E” cylinder (680L), with a flow-rate adjustable regulator and a 
non-rebreather facemask.  
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: 
• 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 6.2.10; or  
• If the subject is non-compliant with the study drug and dosing schedule, or any other 
requirement of this protocol. 


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For all subjects who are withdrawn from the study, the reason must be recorded on the 
appropriate source document and on the appropriate eCRF.  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 (see Section 6.1.4).  This can be done until study 
closure but preferably as close as possible to the time of the subject’s early termination.   
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 being randomized will not be replaced.  
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 
C213 
The C213 patches will be manufactured by Zosano Pharma in Fremont, CA (see Investigator’s 
Brochure for more information).   
4.1.2 
Comparator Product:  ZP-Placebo 
The Placebo will be manufactured by Zosano Pharma.  The placebo patch is a single use, 3 cm2 
Placebo (intracutaneous microneedle) system that contains no active ingredients. 
The Placebo patch is supplied and packaged in an identical fashion as the C213 1.9 mg coated 
patch thereby maintaining the blinding. 
4.1.3 
Product Description and Patch Application 
The Zosano C213 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 C213 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.  A 
magnified image of the zolmitriptan-coated microneedles is shown in Figure 2.  The patch 
system is composed of several parts.  The patch is mounted inside a polycarbonate plastic ring 
with a co-molded desiccant (Figure 3). 
The completed system is packaged in a nitrogen purged foil cup.  The reusable applicator is 
shown in Figure 3 and Figure 4 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 4).  The system was used in the Zosano Pharma Phase 1 study CP-2015-007, 
conducted in Australia under Clinical Trials Authorization (CTA), two phase 1 PK studies, 
CP-2018-002 and CP-2019-001 conducted in the US, a Phase 2 efficacy study CP-2016-001 and 
a long-term safety study CP-2017-001, conducted in the US.  The intended regimens for this 
clinical study will be 1.9 mg plus one placebo patch, two patches of 1.9 mg (3.8 mg total dose), 
or two placebo patches delivered to the upper arm. 


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Figure 2: 
5 cm2 Patch with Zolmitriptan Coated Titanium Microneedle Array 
 
C213 Intracutaneous Patch with 
Titanium Array 
 
Magnified section – C213 
Intracutaneous Patch with 
Titanium Array 
 
Figure 3: 
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 4: 
*C213 Patch Application 
 
Open the foil cups.  
 
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.  
     
 
Remove the outer ring in order to load and 
apply the second patch. 


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Repeat the above steps to apply second patch 
next to the first patch.  Both patches are to be 
removed at 30 minutes post application, and 
should be discarded and not returned to the 
clinic. 
*See subject training video and instructions for use for exact instructions on how to apply the patches 
 
4.2 
Method of Assigning Subjects to Treatment Group 
Approximately 120 subjects will be randomly assigned to receive one of the three treatments in a 
1:1:1 ratio: C213 1.9 mg administered as one active and one placebo patch, C213 3.8 mg 
administered as two active patches, or placebo administered as two placebo patches.  
Randomization will be stratified by study center and cluster headache subtype (chronic or 
episodic).  Zosano will employ RTSM randomization system for randomization and subsequent 
clinical trial material (CTM) kit assignments.  A contract research organization will be 
responsible for generating the randomization schedule.   
At randomization (Day 1), once it has been established that a subject qualifies for the study, 
study staff will log in to Medidata using appropriate credentials and input subject-specific 
information.  In accordance with the randomization schedule, the RTSM will assign the 
randomization number and the unique CTM kit number to the subject.  Each subject must be 
given only the CTM kit assigned by the RTSM randomization system.  The study staff will 
document the kit number assigned in the eCRF.  Subjects are to be randomized in the order in 
which they qualify from the screening phase for inclusion in the study. 
4.3 
Dose, Dose Schedule, and Route of Administration 
The study drug will be dispensed only to qualified, randomized subjects included in this study in 
accordance with the eligibility criteria specified in the study protocol. 
When a subject experiences a qualifying headache (as confirmed by answering questions in the 
eDiary), the subject will self-administer the study drug.  Subjects will be trained on how to 
administer the patches using the C213 applicator supplied in the kit. 
4.4 
Packaging, Labeling, and Receipt of Supplies 
In this study, C213 active and placebo patches will be double-blinded. 
The C213 patches (active or placebo) are individually packaged in cups.  Two patches per dose 
and one applicator will be packaged in a CTM kit based on the randomization schedule.  The kit 
labels will 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.  


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The on-site pharmacist or designee will inventory and acknowledge receipt of all shipments of 
study drug.  The study site personnel will access the RTSM in Medidata to confirm receipt of 
each study drug shipment. 
4.5 
Study Drug Stability, Storage, and Retention 
C213 patches are stable at 20-25°C.  The patches and handheld applicators, packaged in 
individual subject kits, should be stored at controlled room temperature (20-25◦C/68◦F-77◦F).  All 
CTM kits must be kept in a locked area with access restricted to designated study personnel.  
Sites do not need to report excursions in the range of 15°C to 20°C.  Sites must report all 
excursions under 15°C and over 25°C.  
4.6 
Study Drug Kit Assignment, Dispensation, and Accountability 
A kit will be supplied to each subject based on the kit number assigned by the RTSM in 
Medidata. The pharmacist or designee will record the CTM kit number 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. 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.  The kits dispensed and used for each subject 
must be documented. Any discrepancies must be documented. 
4.7 
System Performance  
A C213 Site User’s Manual will be provided.  An applicator associated with field observations of 
atypical appearance or system performance that cannot be resolved after consulting the C213 
Site User’s Manual should be returned directly to Zosano Pharma following the instructions 
provided in the manual.  A description of the field observation should accompany the shipment. 
Only defective applicators will be returned to Zosano.   At the end of the study, all unused kits 
will be dispositioned per Zosano Pharma instructions. 
4.8 
Medication Compliance 
The investigator will emphasize the importance of correctly self-administering the study 
medication once a qualifying cluster headache is confirmed through the eDiary.  Subjects will be 
instructed to bring the following items to the final clinic visit following administration of their 
dose: 
• eDiary 
• C213 applicator 
• Any unused C213 patches  
 
Subjects may discard used patches.  Date and time of dose and information regarding the 
subject’s study drug administration will be recorded in the eDiary.   


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5 
EFFICACY AND SAFETY ANALYSIS VARIABLES 
5.1 
Efficacy 
The co-primary efficacy endpoints are the proportion of subjects who achieve pain relief at 
15 minutes and the proportion of subjects who achieve sustained pain relief from 15 minutes to 
60 minutes.  Headache pain is assessed using a 4-point scale (0 = none, 1 = mild, 2 = moderate, 
3 = severe).  Pain relief is defined by a decrease in pain from severe to mild or none without the 
use of acute rescue medication.  Sustained pain relief requires a pain rating of mild or none at 
each timepoint from 15 minutes to 60 minutes without the use of acute rescue medication.   
The secondary efficacy endpoints for this study are:  
• Proportion of subjects that achieve pain relief at 5, 10, 20, and 30 minutes post patch 
application 
• Proportion of subjects that achieve sustained pain relief from 5 to 60 minutes and from 
10 to 60 minutes post patch application 
• Proportion of subjects that achieve pain freedom at 10 minutes and 15 minutes post patch 
application 
• Proportion of subjects that achieve sustained pain freedom from 10 to 60 minutes and 
from 15 to 60 minutes post patch application 
• Proportion of subjects using rescue therapy within 20 minutes post patch application 
• Proportion of subjects able to perform their usual daily activities as assessed by the 
subject 
 
5.2 
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: 
• Incidence of adverse events 
• Physical exam including height and weight 
• Vital signs including blood pressure 
• Clinical laboratory determinations including coagulation studies 
• Serum pregnancy and urine pregnancy for women of child-bearing potential 
• 12-lead ECGs  


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• Assessment of concomitant medications 
• Investigator visual skin assessments 
 


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6 
STUDY PROCEDURES AND SCHEDULE 
6.1 
Study Schedule  
A schedule of study procedures is presented in Table 4. 
Table 4: 
Schedule of Study Procedures 
Procedure 
VISIT 11 
Screening 
[+3 days] 
VISIT 2 
Randomization 
Day1 
48 Week 
Double-blind 
Period 
[+ or – 7 days] 
VISIT 3 
End of Study  
(or Early 
Discontinuation) 
[+ 3 days] 
Up to 1 week 
prior to 
Randomization 
Day 1 – start of 
double-blind 
period 
Day 1 – Day 336 
Day 1-8 
Informed Consent 
X 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
Medical History including 
Cluster headache, nicotine, 
alcohol use, and substance 
abuse history  
X 
 
 
 
Demographics 
X 
 
 
 
Randomization 
 
X 
 
 
Physical Exam 
X 
X 
 
X 
Weight2/Height 
X 
X2 
 
X2 
Vital Signs 
X 
X 
 
X 
Adverse Events Collection 
 
X 
 
X 
Concomitant 
meds/therapies Collection 
X 
X 
 
X 
Chemistry, coagulation & 
Hematology (fasting) 3 
X3 
 
 
X 
Serum or Urine Pregnancy 
4 (only for WOCBP) 
X - Serum 
X – Urine 
dipstick 
X – Urine 
dipstick4 
X - Serum 
Drug Abuse Testing 
X 
 
 
 
12-lead ECG 
X 
 
 
X 
Train on patch application 
using demonstration 
patches 
 
X 
 
 
Train/dispense eDiary 
 
X 
 
 
Dispense CTM 
 
X 
 
 
Study Drug Self-
Administration 
 
 
X 
 
Subject eDiary 
Assessments  
 
 
X 
 
Investigator Skin 
Assessment 
 
X 
 
X 
Investigator Phone call to 
subject 5, 6 
 
 
X5, 6 
 
Collect Unused Patch(es) 
and Applicator/Perform 
Drug Accountability 
 
 
 
X 
Collect eDiary 
 
 
 
X 


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1 
Qualifying headache and treatment of a cluster headache must occur within 48 weeks of randomization 
2 
Both height and weight at screening only and weight only at visit 2 and 3  
3 
Clinically significant abnormal lab values may be repeated and if not clinically significant on repeat, subject 
may be eligible for randomization  
4 
Urine pregnancy for WOCBP will be collected monthly [+ or – 7 days] after randomization day 1 to ensure no 
pregnancy prior to study drug administration. 
5 
Following randomization, the investigator (or designee) will contact the subject monthly [+ or – 3 days] to 
assess for adverse events, concomitant medications and to provide study related reminders regarding eDiary use 
and/or C213 application instructions in advance of the qualifying cluster attack. 
6 
The investigator (or designee) will contact the subject within 2 days after C213 application to assess for 
Adverse Events and to schedule the subject for a final visit 1-8 days after C213 application. 
 
All study visits and procedures will be performed according to the Schedule of Study Procedures 
as listed in Table 4.  Screening activities may be completed over a period as short as one day or 
spread out over up to one week.  Subject visits should generally 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 [ + 3 days] Prior to Randomization and Start of 
the Double-Blind 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.  Once lab and ECG reports are available and 
reviewed by the investigator and eligibility is confirmed, the subject may be scheduled for 
Visit 2 and randomization.    
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 
• Record medical history including cluster headache, drug, alcohol, nicotine, and substance 
abuse history 
• Record year of subject’s first cluster attack, approximate number of attacks per day 
during the last cluster period, average duration (in days) of cluster period, 
approximate number of cluster headache periods during the past 12 months, type of 
cluster headache (chronic or episodic), and the subject’s usual signs and symptoms 
• Record whether the subject has a history of illicit drug use in the past year, currently 
uses alcohol, and/or whether the subject is a nicotine user and frequency of use. 


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• 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, hematology, and coagulation 
• Collect blood for serum pregnancy for all women of child-bearing potential (WOCBP).  
WOCBP is defined as women who are neither 1 year post-menopausal or surgically 
sterile. 
• Collect urine for urine drug screen 
• Perform 12-lead electrocardiogram (ECG) 
• Record concomitant medications taken within 60 days prior to Screening 
• Register in IWRS all subjects who become screen failures 
 
6.1.2 
Visit 2, Day 1 Randomization 
• Perform physical exam, including weight 
• Perform investigator skin assessment of the upper arm where patches are intended to be 
applied 
• Record vital signs: temperature, respiratory rate (RR), blood pressure (BP), and heart rate 
(HR)  
• Record concomitant medications, including medication taken to treat cluster headaches 
• Urine pregnancy for all WOCBP 
• Record Adverse events 
• Train the subject on how to apply the patches to the upper arm with the demo applicator 
and have the subject practice applying the demo patches to his/her arm 2-3 times (more is 
allowable, if necessary) 
• Review the definition of a qualifying cluster headache for the study with the subjects 
• Record that the subject can apply patches with the applicator unaided 
• Reconfirm subject’s eligibility based on inclusion/exclusion criteria 
• Randomize subject  
• Dispense CTM kit that includes the applicator and one dose (each dose consists of 
2 patches) as assigned by the RTSM in Medidata 


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• Provide instructions for scheduling the next visit within 1-8 days of experiencing and 
treating a qualifying cluster headache with C213 
• Remind the subject that if rescue therapy is required, rescue therapy other than a triptan 
or ergot is permitted at or after 20 minutes post study drug administration.   
• Provide eDiary training necessary and dispense the eDiary  
6.1.3 
Double-Blind Treatment Phase: Day 1 through up to 48 Weeks [336 Days + or – 
7 days]  
Subjects will have up to 48 weeks to confirm and treat a qualifying cluster headache. Subjects 
will be instructed to complete the eDiary at the time of a suspected cluster headache.  Once the 
eDiary confirms that the subject has a “qualifying” cluster headache, the subject will follow the 
steps provided to self-administer the study drug.   
6.1.3.1 
Day 1 through Week 48: Treatment of a Qualifying Cluster Headache 
The following constitutes a cluster headache that qualifies for treatment with study drug: 
• Severe unilateral orbital, supraorbital and/or temporal pain 
• Either or both of the following:  
1) at least one of the following symptoms or signs, ipsilateral to the pain:  
 conjunctival injection and/or lacrimation  
 nasal congestion and/or rhinorrhea  
 eyelid edema  
 forehead and facial sweating  
 miosis and/or ptosis  
2) a sense of restlessness or agitation 
The following procedures are to be performed by the subject for a cluster headache from Day 1 
through 48 weeks of the double-blind period: 
• Using the eDiary, the subject will record the following to confirm the headache meets the 
qualifications for a cluster headache: 
Cluster headache symptoms and pain assessment 
• Once the qualifying cluster headache has been confirmed, subject self-administers the 
study drug patches.  Subjects will apply two patches to the upper arm.  
• Subject will continue to record the following in the eDiary, post self-administration of the 
patches at 5 min, 10 min, 15 min, 20 min, 30 min and 60 mins. 


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Cluster headache symptoms, pain assessment, and whether rescue therapy was 
needed 
• For the cluster headache to be qualifying for study medication, no triptans or ergots are 
allowed within 24 hours prior to onset of cluster headache. If rescue therapy is required 
by the subject, rescue therapy other than a triptan or ergot is permitted at or after 20 
minutes post study drug administration.   
• Subject will contact the site to schedule a Visit 3 follow-up visit within 1-8 days of study 
drug treatment following administration of study drug. 
 
6.1.4 
Pregnancy Tests (every 4 weeks ± 7 days) 
• A urine pregnancy test will be collected on WOCBP every month from the day of 
randomization during the double-blind period to ensure the subject is not pregnant prior 
to administration of study medication. 
• Due to the COVID-19 pandemic, a urine pregnancy test kit will be sent to WOCBP 
for in-home testing on a monthly basis. The Investigator (or designee) will contact the 
subject to review and document the result.  
 
6.1.5 
Investigator (or designee) Phone Contact to Subjects (every 4 weeks ± 3 days) 
Following randomization, the investigator (or designee) will contact the subject monthly to 
assess for: 
• Adverse events, concomitant medications and to provide study related reminders 
regarding eDiary use and/or C213 application instructions in advance of administering 
study medication for the qualifying cluster attack. 
 
6.1.6 
Investigator (or designee) Phone Contact to Subject– Following application of 
C213 (+ 2 days) 
The investigator (or designee) will contact the subject within 2 days after C213 application to 
assess for: 
• Adverse events and to schedule the subject for a final visit 1-8 days after C213 
application. 
 


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6.1.7 
Visit 3 - Day 1-8 Following Treatment of Cluster Headache / End of Study (or 
Early Discontinuation) Visit (+3 days)  
The following procedures will be performed at the Day 1-8 / end of study (or early 
discontinuation): 
• Collect the applicator and any unused patches and perform drug accountability 
• Perform physical exam, including 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, coagulation, hematology, and serum pregnancy for WOCBP 
• Collect serum pregnancy for all WOCBP 
• Perform 12-lead electrocardiogram (ECG) 
• Collect and review subject’s eDiary data with the subject for the following: 
Subject compliance with study drug treatment and/or rescue therapy use 
• Investigator Skin Assessment 
• Record concomitant medications 
• Review of adverse events 
Due to the COVID-19 pandemic, if any subjects cannot or elect not to be seen in clinic, the Visit 
3/End of Study Visit may take place via a virtual video (such as FaceTime, WhatsApp, Skype, 
Zoom).  Any procedure such as vital signs, blood collection, and ECG, which cannot be 
collected on site or remote will be indicated as ‘not done’ in both the source documents and if 
prompted to specify a reason in the eCRF as due to the pandemic. 
 
During this call, the following procedures will be performed: 
 
• Perform drug accountability and confirm with subject that both patches were applied and 
arrange to have the applicator and eDiary sent back to the clinical site 
• Review subject’s eDiary data with the subject for the following: 
Subject compliance with study drug treatment and rescue therapy use 
• Investigator Skin Assessment 
• Record concomitant medications 
• Review of adverse events 


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• Investigator to verify results of in-home urine pregnancy test (WOCBP only) 
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. 
6.2.2 
Inclusion/Exclusion Criteria 
All inclusion criteria and none of the exclusion criteria must be satisfied prior to randomization 
and assignment of a CTM kit number to the subject and the start of study drug dosing.   
6.2.3 
Medical History, Substance Use, Cluster Headache 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, including 
recent illnesses and relevant past medical history.  Subjects will be asked about current use of 
illicit drugs, nicotine containing products, and alcohol.  Information will also be obtained on the 
subject’s history of cluster headache therapy.   
6.2.4 
Randomization 
Randomization will be conducted at Day 1 after verifying that the participant meets all inclusion 
criteria and has none of the exclusion criteria.  Participants who meet the study eligibility criteria 
and give informed consent will be randomized to one of three doses (1.9 mg, 3.8 mg, or 
placebo). 
6.2.5 
Physical Examination 
A PE will be performed during screening for inclusion, at Day 1 and End of Study (or early 
discontinuation).  The physical exam will include, but is not limited to, HEENT, dermatologic 
(investigator skin assessment), brief neurological, general appearance, lymph nodes, 
cardiovascular, respiratory, gastrointestinal and musculoskeletal examination. 
6.2.6 
Height and Weight 
Subjects will have both height and weight measured at screening, and weight only will be 
collected at Day 1, and the End of Study visit (or early discontinuation).  The subject must not 
wear shoes during the height measurement.   


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The subject should wear light clothing and no shoes during weight measurements.  Subjects 
should be weighed on the same clinic scale during this study.  
6.2.7 
Vital Signs 
All subjects will have vital signs (temperature, RR, BP, and HR) measured at screening and all 
subsequent visits.   
Whenever possible, vital sign measurements will be taken before any blood samples are taken. 
6.2.8 
Clinical Laboratory Tests 
Blood samples will be collected for clinical laboratory tests at screening and at the End of Study 
visit (or early discontinuation).  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 will be processed by a central laboratory.  The following 
parameters will be assessed:   
Table 5: 
Clinical Laboratory Tests 
Serum Chemistry 
Hematology 
Additional Tests 
 Aspartate aminotransferase 
(AST) 
 Alanine aminotransferase 
(ALT) 
 Cholesterol (HDL and LDL) 
 Bilirubin 
 Creatinine 
 Glomerular filtration rate (GFR) 
 Triglyceride 
 Alkaline phosphatase 
 Hematocrit  
 Hemoglobin 
 Red Blood Cell Count 
 White Blood Cell Count  
 Platelet Count 
 Serum and Urine 
Pregnancy (WOCBP 
only)* 
 Urine drug screen 
 Coagulation**  
 PT/INR 
 PTT 
* WOCBP is defined as women who are neither 1 year post-menopausal or surgically sterile. 
**Coagulation sample is to be sent to Eurofins on the day of collection on dry ice. 
 
Laboratory tests will be performed at screening and at the End of Study visit (or early 
discontinuation).  Clinically significant abnormal values at screening may be repeated to confirm 
eligibility.  Pregnancy tests will be performed on all women of child-bearing potential every 
month [+ or – 7 days] after randomization to ensure no pregnancy prior to study drug 
administration.  
The urine drug abuse screen will be performed at screening and will test for amphetamines, 
barbiturates, cocaine, phencyclidine (PCP), and meth/amphetamines. 
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-


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range laboratory values that emerge during treatment are clinically significant and if so, record 
these on the appropriate source document and on the AE eCRF page if applicable.  All clinically 
significant out-of-range laboratory values will be followed until they return to normal or become 
medically stable.  
6.2.9 
Twelve-Lead Electrocardiogram 
The ECG, done at screening and at the End of Study visit (or early discontinuation), and 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 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.  
6.2.10 
Previous, Concomitant and Prohibited Medications 
Concomitant medications will be recorded on the appropriate source document and on the 
appropriate eCRF at all visits including screening, randomization day, and end of study (or early 
discontinuation).  All previous and concomitant medications taken within 90 days prior to the 
screening visit must be recorded in the source document and eCRF.  When new medications are 
started and come to the attention of the investigator between scheduled visits, they will be 
recorded that day on the appropriate source document and on the appropriate eCRF.  
No triptans or ergots are allowed within 24 hours prior to onset of current cluster headache 
symptoms.  If rescue therapy is required by the subject, rescue therapy other than a triptan or 
ergot is permitted at or after 20 minutes post study drug administration.   Ergots and triptans may 
be resumed 24 hours after dosing with study medication. 
No lotions, ointments or powders applied to the skin immediately before (within an hour) or for 
24 hours after applying the patches are allowed. 
Table 6 lists all prohibited medications. Medications listed in Table 6 are prohibited from 7 days 
prior to screening through the final visit.   
Table 6: 
Prohibited Concomitant Medications 
Drug Type 
Medication 
Prescription anticoagulants 
Entire class 
Monoamine oxidase inhibitors 
Entire class 
Potent CYP450 3A4 Inhibitors 
Ketoconazole 
Erythromycin 
Clarithromycin 
Cimetidine 
Grapefruit 
CYP450 1A2 Inhibitors/Inducers 
Ciprofloxacin 


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Drug Type 
Medication 
Enoxacin 
Fluvoxamine 
Alpha-Naphthoflavone 
Furafylline 
Omeprazole (OTC) 
Lansoprazole (OTC) 
Fluvoxamine 
Enoxacin 
Phenytoin 
Rifampin 
Ritonavir 
teriflunomide 
Methoxsalen 
Mexiletine 
Tobacco Cigarettes  
 
6.2.11 
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 
eCRF. 
6.2.12 
Investigator Skin Assessment 
The investigator will perform a visual skin assessment of bruising, erythema, and edema at the 
randomization visit and at the End of Study (or early discontinuation) visit.  Any adverse events 
including application site reactions will be documented on the appropriate eCRF page and must 
be followed until resolution or medically stable.  
At the End of Study (or early discontinuation) visit, the entire surface area of the outer upper arm 
where the two patches were applied will be assessed for the following skin signs or symptoms.   
Any findings with an intensity rating of 1 (Mild intensity), 2 (Moderate intensity), or 3 (Severe 
intensity) 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. 
For further instructions, photographs and descriptors are in Photograph and Appendix 1 
(Investigator Assessments – Rating for Bruising, Erythema, Swelling and Photographs). 
1.1.1.1 Bruising  
The Bruising assessment will be performed by the investigator at Visit 3 End of Study or Early 
discontinuation.  


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Bruising assessments (visual rating) will be performed using the following ratings: 
Symptom 
Intensity Rating (circle) 
Bruising where 
C213 was applied? 
0 = Clear   
1 = Mild intensity  
2 = Moderate intensity 
3 = Severe intensity 
 
1.1.1.2 Erythema and Edema 
Erythema and Edema will be assessed by the investigator at Visit 3 End of Study or early 
termination. 
The following ratings will be used to describe the amount of erythema and edema indicative of 
irritation: 
Symptom 
Rating (circle) 
Skin Erythema 
where C213 was 
applied? 
0 = Clear   
1 = Mild intensity  
2 = Moderate intensity 
3 = Severe intensity  
 
Symptom 
Rating (circle) 
Skin Edema where 
C213 was applied? 
0 = Clear   
1 = Mild intensity  
2 = Moderate intensity 
3 = Severe intensity  
 
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.   
6.2.13 
Medication Compliance 
Subject compliance with study drug administration will be reviewed at the End of Study (or early 
discontinuation) visit.  The applicator and any unused patches will be collected. 


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7 
STATISTICS 
A full description of the statistical analyses to be performed at study completion will be provided 
in a Statistical Analysis Plan (SAP), which will be finalized prior to database lock and 
unblinding of the study. 
Unless otherwise noted, significance tests of treatment differences will be tested at the two-sided 
0.05 level. 
7.1 
Analysis Populations 
Modified Intent-to-Treat (mITT) Population 
All randomized patients who have a qualifying headache and at least one post-application pain 
score recorded within the first 15 minutes post-application will be included in the mITT 
population.  This is the primary population for efficacy analyses and patients will be analyzed 
based on their randomized treatment.   
Safety Population 
The safety population will include all patients who received any amount of study drug. All safety 
analyses will be performed using this population, analyzed as treated.    
7.2 
Estimate of Sample Size 
It is anticipated that 20% of subjects receiving placebo and 55% of subjects receiving active 
treatment will achieve pain relief at 15 minutes and sustained pain relief from 15 minutes to 60 
minutes post-dose.  Based on a two-sided chi-square test with continuity correction and an alpha 
level of 0.05, 40 subjects/arm will provide approximately 80% power to detect this same 
difference between two treatment groups, assuming a 15% dropout rate. 
   
7.3 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics such as age, gender, race/ethnicity, height, and weight, 
will be summarized by treatment group using descriptive statistics.  Medical History will be 
coded using MedDRA and summarized by SOC and Preferred Term using frequency counts.  
Baseline disease characteristics will also be summarized. 
7.4 
Efficacy Analysis 
7.4.1 
Primary Analysis  
The co-primary efficacy endpoints are the proportion of subjects who achieve pain relief at 
15 minutes and the proportion who achieve sustained pain relief from 15 minutes to 60 minutes 
post patch application.  These two endpoints will be analyzed separately using a Cochran Mantel 
Haenszel test stratified by cluster headache subtype (episodic or chronic) and will utilize the 
mITT population.  A significance test of the treatment difference comparing each C213 dose to 


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placebo will be tested at the two-sided 0.05 level, and odds ratios and their corresponding 95% 
confidence intervals will be calculated.  Headache pain will be assessed using a 4-point scale 
(0 = none, 1 = mild, 2 = moderate, 3 = severe), with pain relief defined by a decrease in pain 
from severe to mild or none without the use of acute rescue medication.  Sustained pain relief 
requires a pain rating of mild or none at each timepoint from 15 minutes to 60 minutes without 
the use of acute rescue medication.  Handling of missing data as well as sensitivity analyses will 
be described in the SAP. 
7.4.2 
Secondary Analyses 
Secondary endpoints will be analyzed using similar methods as the primary endpoints and will 
utilize the mITT population. 
To adjust for multiplicity and to control for overall type I error, a fixed sequential testing 
procedure will be applied to the primary analyses for the two C213 arms and the secondary 
efficacy analyses.  If the primary efficacy analyses for the 3.8 mg arm both produce a result that 
is statistically significant at the 0.05 level, a significance level of 0.05 will be used for the 
primary analyses of the 1.9 mg arm and for the secondary efficacy analyses in an ordered 
fashion.  If any subsequent analysis does not produce a statistically significant result at the 0.05 
level, then the remaining analyses will automatically be considered non-significant.  The order of 
testing for each endpoint and each C213 dose group will be provided in the SAP. 
7.5 
Safety Analysis 
Safety analyses will be performed using the Safety population.  Safety will be assessed by: 
• Incidence of adverse events 
• Physical exam including height and weight 
• Vital signs including blood pressure 
• Clinical laboratory determinations including serum chemistries and hematological 
parameters 
• Pregnancy testing for women of child-bearing potential 
• 12-lead ECGs  
• Assessment of concomitant medications 
• Investigator visual skin assessments 
 
Adverse events will be coded using the latest version of MedDRA 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.   


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All safety data will be listed by subject and parameter, separate listings of all abnormal 
laboratory findings and ECG findings will be provided, and clinically significant abnormalities 
will be recorded as AEs.  Additional safety analyses will be described in the SAP.  


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8 
ADVERSE EVENTS 
All systemic and skin AEs, regardless of treatment group or suspected causal relationship to the 
investigational products, will be reported as described in the following sections. 
For all systemic and skin 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 skin 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, and Zosano Pharma concurs with that assessment. 
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 through the time of birth and report the outcome.  Information about the subject’s 
newborn or subject’s pregnant partner will be followed for up to 1 month after the birth. 
8.1 
Reporting Period 
Collection of systemic and skin 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) 
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 
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. 
Collection of systemic and skin 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 dosing.  


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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 
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. 


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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. 
 
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. 


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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 skin 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 the investigational product caused the event, then the event 
will be handled as “related to investigational product” for reporting purposes.  Thus, it is 
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 eCRF, 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:  


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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 using 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 eCRF 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 
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 


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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 eCRF page and concomitant medications administered in association with 
the SAE will be documented on the appropriate eCRF. 
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 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 eCRF 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 last visit.  All non-resolved, non-serious systemic and skin AEs 
beyond such date will be recorded as “ongoing” without further follow up. 


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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.   
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 US Number:  1-866-352-7864 
• Scanned and emailed:  POISafetyDesk@pharm-olam.com 
• Copy Pete Schmidt, MD, MSc, Zosano Pharma Medical Monitor 
(pschmidt@zosanopharma.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 
If a medical emergency occurs and a decision regarding the subject’s clinical treatment requires 
knowledge of the treatment assignment, the study blind may be broken for the specific subject.  
Unless the medical emergency is deemed to be life-threatening, the medical monitor must first be 
consulted before unblinding.  The investigator would then access Medidata for unblinding. 
The date, time, and reason for unblinding must be documented in the source documents and on 
the applicable eCRF.  Investigators should note that the occurrence of a SAE should not 
routinely trigger immediate unblinding.  If the medical monitor was not notified prior to breaking 
the blind, the investigator must notify the medical monitor of any and all blinds broken within 24 
hours of each occurrence. 
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 skin 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. 
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. 


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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 agency(s) 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 
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 


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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 because 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 
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. 


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13.3 
Publication Policy 
All information concerning Zosano Pharma operations, patent applications, formulas, 
manufacturing processes, and basic scientific data provided by Zosano Pharma to the 
investigator and not previously publishes, are considered confidential and remain the sole 
property of Zosano Pharma. 
It is understood by the investigator that Zosano Pharma will use the information obtained in this 
clinical study in connection with C213, and therefore may disclose this information as required 
to other Zosano investigators, appropriate international regulatory agencies, or others.  In 
agreeing to participate in this study, the investigator understands that he/she has an obligation to 
provide complete test results and all data developed during this study to Zosano Pharma.  Zosano 
Pharma requires that permission to publish details of this study must be obtained in writing by 
Zosano as further detailed in the Clinical Study Agreement signed by the investigator and/or 
institution.  
13.4 
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 
Bahra A, Gawel MJ, Hardebo JE, et al. Oral zolmitriptan is effective in the acute treatment of 
cluster headache. Neurology. 2000 May 9;54(9):1832-9. 
Cittadini E, May A. Straube A, et al Effectiveness of Intranasal Zolmitriptan in Acute Cluster 
Headache.  Arch Neurol. 2006:1537-1542  
Dahlof C, Diener HC, Goadsby PJ, et al. Zolmitriptan, a 5-HT1B/1D receptor agonist for the 
acute oral treatment of migraine: a multicentre, dose-range finding study. Eur J Neurol. 1998 
Nov;5(6):535-543. 
Dawson AJ, Charlesworth BR, Green J, et al. INDEX Study Group. Zolmitriptan nasal spray 
exhibits good long-term safety and tolerability in migraine: results of the INDEX trial. 
Headache. 2005 Jan;45(1):17-24. 
Ekbom K, Monstad I, Prusinski A, et. Al. Subcutaneous Sumatriptan in the acute treatment of 
cluster headache; a dose comparison study.  The Sumatriptan Cluster Headache Study Group 
Acta Neurol Scand 1993, July 88(1) 63-69. 
Hedlund C, Rapoport AM, Dodick DW, et al. Zolmitriptan nasal spray in the acute treatment of 
cluster headache: a meta-analysis of two studies. Headache. 2009 Oct;49(9):1315-23. 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75:800-2. 
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. 
Rozen TD, Fishman RS. Cluster headache in the United States of America: demographics, 
clinical characteristics, triggers, suicidality, and personal burden. Headache. 2012 Jan;52(1):99-
113. 
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 , 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. 


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APPENDIX  1 
INVESTIGATOR ASSESSMENTS – RATING FOR BRUISING, 
ERYTHEMA, EDEMA AND PHOTOGRAPHS 
The Bruising, Erythema, and Edema assessment will be performed by the investigator at the final 
visit 3 (or early discontinuation).  Any findings with an intensity rating of 1 (Mild intensity), 
2 (Moderate intensity), or 3 (Severe intensity) 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 
Intensity Rating (circle) 
Bruising spots 
where C213 was 
applied? 
0 = Clear   
1 = Mild intensity  
2 = Moderate intensity 
3 = Severe intensity  
 
Symptom 
Intensity Rating (circle) 
Skin Erythema 
where C213 was 
applied? 
0 = Clear   
1 = Mild intensity  
2 = Moderate intensity 
3 = Severe intensity  
 
Symptom 
Intensity Rating (circle) 
Skin Edema where 
C213 was applied? 
0 = Clear   
1 = Mild intensity  
2 = Moderate intensity 
3 = Severe intensity 
 
The photographs below for bruising, erythema, and edema are intensity 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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Intensity Ratings 
Bruising  
 
 
None (Clear) 
Mild 
Moderate 
Severe 
 
Erythema 
 
 
None (Clear) 
Mild 
Moderate 
Severe 
 
Edema 
 
 
None (Clear) 
Mild 
Moderate 
Severe 
 


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APPENDIX 2 
SAMPLE SUBJECT eDIARY QUESTIONS 
Qualifying Cluster Headache Double-Blind Period (eDiary is Activated at Visit 2) 
• Are you having a cluster headache now? (Yes, No) 
• How bad is your headache pain? (Mild, Moderate, Severe) 
• Are you experiencing any of the following (please scroll down and select all that apply)? 
Feeling Restless/Agitated? (Yes, No) 
Eye redness or tearing on the same side as pain? (Yes, No) 
Runny or stuffy nose on the same side as pain? (Yes, No) 
Swollen eyelid on the same side as pain? (Yes, No) 
Forehead and face sweating on the same side as pain? (Yes, No) 
Drooping of the upper eye lid, or pupil getting smaller on same side as pain? (Yes, 
No) 
None of the above (Yes, No) 
• Did you treat your cluster headache with a triptan or ergot in the past 24 hours? 
• If a non-qualifying headache: 
The following text shows - DO NOT APPLY THE PATCHES.  YOU HAVE NOT 
REPORTED a qualifying cluster headache.  Please save your answers and return 
to the diary next time you think you are experiencing a headache. 
• If a qualifying headache: 
The following text shows - You have reported a qualifying headache.  Please apply 
the first patch now.  After applying the first patch, please respond to the 
question below: 
Have you applied your first patch? (Yes, No) 
 
Please apply the second patch now. 
 
Post Patches Application Questions at: 30 min 
• Where were the study drug patches applied? (Both to left arm, Both to right arm, One 
patch to each arm, One patch to left arm, One patch to right arm) 
• Please remove the patches from your upper arm, fold in half, and discard.  Press the next 
button once you have removed both patches. 


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• *Reminder* Text – You have 1 post treatment questionnaire left to complete.  Please do 
not turn off your device. You may press next to complete this questionnaire. 
 
Post Patches Application Questions/text at:  5, 10, 15, 20, 30, 60 min 
• How bad is your headache pain? (None, Mild, Moderate, Severe) 
• Did you take any medication, since your last diary entry, other than the patches you 
applied to treat your headache? (Yes, No)  
• Do you feel able to perform your usual daily activities? (Yes/No) 
• Your next assessment is due at [time]. Please keep your device with you. (at 5, 10, 15, 20, 
30 minute) 
• Thank you. You have answered all study related questions and your physician will 
contact you about setting up your final visit (at 60 minutes only) 
 

SAP_001.pdf: 
CONFIDENTIAL 
 
14APR2021 
Statistical Analysis Plan 
 
Protocol Title: Randomized, Double-Blind, Multi-Center, Parallel-Group Comparison of 
the Efficacy and Safety of the C213 (Zolmitriptan Intracutaneous 
Microneedle System) to Placebo for the Acute Treatment of Cluster 
Headaches 
Protocol Number: Protocol No. CP-2019-001 (27 June 2019), Amendment 1, Dated 16 July 
2019, Amendment 2, Dated 01 October 2019 and Amendment 3, Dated 15 
April 2020 
Investigational 
Product: 
C213 (Zolmitriptan Intracutaneous Microneedle System) 
Dose Single-dose treatment (to be applied for 30 minutes to the upper arm) of 1.9 
mg or 3.8 mg  
Phase: 2/3 
Sponsor: Zosano Pharma Corporation 
34790 Ardentech Court 
Fremont, CA 94555 
SAP Author: Jean M. Engels 
Zosano Pharma Corporation 
SAP Version: Final Version 1.0 
SAP Date: 14APR2021 
CONFIDENTIAL 


 
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14APR2021 
DOCUMENT HISTORY 
Version 
Date 
Author 
Description 
1.0 
14APR2021 
Jean M. Engels 
 Final Version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
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TABLE OF CONTENTS 
DOCUMENT HISTORY ..................................................................................................2 
TABLE OF CONTENTS ..................................................................................................4 
ABBREVIATIONS ............................................................................................................6 
1. 
OVERVIEW ...........................................................................................................7 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................7 
2.1 
Study Objectives ..........................................................................................7 
2.1.1 Primary Objective ............................................................................7 
2.1.2 Secondary Objectives.......................................................................7 
2.2 
Study Endpoints ...........................................................................................8 
2.2.1 Efficacy Endpoints ...........................................................................8 
2.2.2 Safety Endpoints ..............................................................................8 
3. 
OVERALL STUDY DESIGN AND PLAN .........................................................9 
3.1 
Selection of Study Population ......................................................................9 
3.2 
Method of Treatment Assignment and Randomization ...............................9 
3.3 
Treatment Blinding ....................................................................................10 
3.4 
Minimization of Missing Data / Dropout rate............................................10 
4. 
ANALYSIS AND REPORTING ........................................................................11 
4.1 
Interim Analysis .........................................................................................11 
4.2 
Final Analysis ............................................................................................11 
5. 
SAMPLE SIZE DETERMINATION .................................................................12 
6. 
ANALYSIS POPULATIONS .............................................................................13 
7. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ..................................14 
7.1 
General Statistical Methodology................................................................14 
7.1.1 Adjustments for Multiplicity and Other Alpha Control .................14 
7.1.2 Data Handling for Subjects Who Withdraw from the Study .........14 
7.1.3 Methods for Handling Missing Data..............................................14 
7.2 
Efficacy Assessments.................................................................................15 
7.2.1 Co-primary Efficacy Endpoints .....................................................15 
7.2.2 Pain Relief ......................................................................................15 
7.2.3 Sustained Pain Relief .....................................................................15 
7.2.4 Secondary Efficacy Assessments ...................................................16 
7.3 
Safety Assessments ....................................................................................17 


 
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7.3.1 Adverse Event and Prior/Concomitant Medication handling 
conventions ....................................................................................17 
8. 
STUDY SUBJECTS AND DEMOGRAPHICS.................................................18 
8.1 
Disposition of Subjects and Withdrawals ..................................................18 
8.2 
Protocol Deviations ....................................................................................18 
8.3 
Demographics and Other Baseline Characteristics ....................................18 
9. 
EFFICACY ANALYSES ....................................................................................19 
9.1 
Primary Efficacy Analysis .........................................................................19 
9.1.1 Sensitivity and Supporting Analyses .............................................19 
9.2 
Secondary Efficacy Analyses ....................................................................19 
9.3 
Exploratory Efficacy Analyses ..................................................................20 
10. 
SAFETY AND TOLERABILITY ANALYSIS .................................................20 
10.1 
Adverse Events ..........................................................................................21 
10.1.1 Adverse Events Leading to Discontinuation of Study Drug ..........21 
10.1.2 Serious Adverse Events .................................................................21 
10.1.3 Deaths ............................................................................................21 
10.2 
Clinical Laboratory Evaluations ................................................................21 
10.3 
Vital Signs ..................................................................................................22 
10.4 
Physical Examination.................................................................................22 
10.5 
Electrocardiogram (ECG) ..........................................................................22 
10.6 
Investigator Visual Skin Assessment .........................................................22 
11. 
MEDICATIONS ..................................................................................................24 
11.1 
Concomitant Medications ..........................................................................24 
11.2 
Extent of Exposure .....................................................................................24 
12. 
CHANGES FROM PLANNED ANALYSIS .....................................................24 
13. 
APPENDICES ......................................................................................................25 
13.1 
Appendix 1 .................................................................................................25 
13.1.1 General Reporting Conventions .....................................................25 
13.1.2 Population Summary Conventions ................................................26 
 


 
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ABBREVIATIONS 
ABBREVIATION DEFINITION OR DESCRIPTION 
AE 
Adverse Event 
ADaM 
Analysis Data Model 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CMH 
Cochran Mantel Haenszel 
CRF 
Case Report Form 
CRO 
Contract Research Organization  
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eDiary 
Electronic Diary 
e.g. 
Exempli gratia (for example) 
EMA 
European Medicines Agency 
ET 
Early Termination 
FDA 
Food and Drug Administration 
ICH 
International Council for Harmonization 
i.e. 
id est (that is) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
N, n 
Number (of subjects) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
 


 
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1. OVERVIEW 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for 
protocol CP-2019-001: A randomized, double-blind, multi-center, parallel-group 
comparison of the efficacy and safety of the C213 (Zolmitriptan Microneedle System) to 
placebo for the acute treatment of cluster headaches, dated 27 June 2019, Amendment 1, 
dated 16 July 2019, Amendment 2, dated 01 October 2019 and Amendment 3, dated 15 
April 2020.  
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by FDA, European Medicines Agency (EMA), and International Council for 
Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for 
Human Use: Guidance on Statistical Principles in Clinical Trials.   
The planned analyses identified in this SAP may be included in clinical study reports 
(CSRs), regulatory submissions, or future manuscripts.  Also, post-hoc exploratory 
analyses not necessarily identified in this SAP may be performed to further examine 
study data.  Any post-hoc, or unplanned exploratory analysis performed will be clearly 
identified as such in the final CSR. 
In preparation of this SAP, the following documents were reviewed and considered in 
addition to the literature references cited in this SAP: 
x Clinical Research Protocol CP-2019-001 Final v1.0 issued 27 June 2019, 
Amendment 1, dated 16 July 2019, Amendment 2, dated 01 October 2019 and 
Amendment 3, dated 15 April 2020. 
x Case report forms (CRFs) for Protocol CP-2019-001 
x ICH Guidance on Statistical Principles for Clinical Trials (E9) 
x FDA response to meeting request dated 07 February 2019 
Per FDA request, Amendment 3 incorporated changing time zero from the time of the 
second patch application to be the time of the first patch application, so that the primary 
efficacy endpoint would be measured at 15 minutes from the start of dosing.   
The reader of this SAP is encouraged to also read the clinical protocol, and other 
identified documents, for details on the planned conduct of this study.   
 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective is to compare the efficacy of C213 at doses of 1.9 mg and 3.8 mg 
(1.9 mg x 2 patches) to placebo in the acute treatment of cluster headache attacks. 
2.1.2 Secondary Objectives 
The secondary objective is to compare the safety of C213 at doses of 1.9 mg and 3.8 mg 
(1.9 mg x 2 patches) to placebo and to assess the dose-response relationship of C213 on 


 
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efficacy and tolerability. 
 
2.2 Study Endpoints 
2.2.1 Efficacy Endpoints  
The co-primary efficacy endpoints are:  
x The proportion of subjects who achieve pain relief at 15 minutes and the 
proportion of subjects who achieve sustained pain relief from 15 minutes to 60 
minutes.  Headache pain is assessed using a 4-point scale (0 = none, 1 = mild, 2 = 
moderate, 3 = severe).  Pain relief is defined by a decrease in pain from severe to 
mild or none without the use of acute rescue medication.  Sustained pain relief 
requires a pain rating of mild or none at each timepoint from 15 minutes to 60 
minutes without the use of acute rescue medication.  The co-primary efficacy 
endpoints will compare the 1.9 mg and 3.8 mg treatment arms separately to 
placebo.  
 
Secondary efficacy endpoints: 
x Proportion of subjects that achieve pain relief at 5, 10, 20 and 30 minutes post 
patch application 
x Proportion of subjects that achieve sustained pain relief from 5 to 60 minutes 
and from 10 to 60 minutes post patch application 
x Proportion of subjects that achieve pain freedom at 10 and at 15 minutes post 
patch application 
x Proportion of subjects that achieve sustained pain freedom from 10 to 60 
minutes and from 15 to 60 minutes post patch application 
x Proportion of subjects using rescue therapy within 20 minutes post patch 
application 
x Proportion of subjects able to perform their usual daily activities as assessed by 
the subject at 5, 10, 15, 20, 30 and 60 minutes post patch application 
2.2.2 Safety Endpoints 
Safety will be assessed by: 
x Incidence of adverse events (AEs) 
x Physical examination findings 
x Vital signs including blood pressure 
x Clinical laboratory determinations including coagulation studies 
x Serum pregnancy and urine pregnancy for women of child-bearing potential 
x 12-lead electrocardiogram (ECG) parameters  


 
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x Assessment of concomitant medications 
x Investigator visual skin assessments 
3. OVERALL STUDY DESIGN AND PLAN 
This is a phase 2/3, randomized, multicenter, double-blinded, placebo-controlled study 
that will investigate the efficacy and safety of C213 in the acute treatment of cluster 
headache attacks.  Subjects who have consented and meet the entry criteria will be 
randomized to receive one of three blinded treatments.  Approximately 120 subjects will 
be randomized.  The study is to be conducted at approximately 13 investigational sites in 
the United States. 
Qualified subjects will be randomized to the double-blind treatment period on Day 1 and 
will have up to 48 weeks to confirm and treat one cluster headache.  Using an electronic 
diary (eDiary) to confirm the subject is experiencing a cluster headache, subjects will 
self-administer the patches and respond to questions in the eDiary until 1-hour post 
treatment.  
The total duration of this study could be up to approximately 50 weeks over 3 visits, with 
up to 48 weeks of treatment duration and a variable length of screening (up to 10 days).  
This study will consist of a Screening visit (Visit 1, up to 1 week prior to randomization), 
Randomization visit (Visit 2, Day 1), up to a 48-week treatment period (Day 1 - Day 
336), and End of Study/Early Discontinuation visit (Visit 3, 1-8 days post-treatment). 
Screening activities may be completed over a period as short as one day or spread out 
over up to one week.  At Visit 2, subjects will return to the site for additional baseline 
assessments and randomization (Day 1).  If they meet all study randomization criteria, 
they will be randomly assigned in a 1:1:1 ratio to receive C213 1.9 mg administered as 
one active and one placebo patch, C213 3.8 mg administered as two active patches, or 
placebo administered as two placebo patches.   
 
3.1 Selection of Study Population 
For a complete list of inclusion and exclusion criteria please refer to the initial protocol 
issued 27 June 2019, Amendment 1, dated 16 July 2019, Amendment 2, dated 01 October 
2019 and Amendment 3, dated 15 April 2020. 
 
3.2 Method of Treatment Assignment and Randomization 
To be eligible for randomization and the double-blind period, subjects must meet all 
inclusion and no exclusion criteria.  In addition, the following must be confirmed on the 
day of randomization: 
1. Demonstrated ability to properly use the eDiary 


 
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2. Willing to enter eDiary data to determine if he/she is experiencing a qualifying 
cluster headache attack and complete the eDiary questions after applying the 
patches 
3. Demonstrated ability to apply the demonstration study drug patches 
4. 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 
 
3.3 Treatment Blinding 
This is a double-blind study.  Unless otherwise specified, all study personnel are to 
remain blinded to study drug.  Treatment assignments will not be revealed until all 
subjects have completed the study and the database has been finalized and closed.  
 
If a medical emergency occurs and a decision regarding the subject’s clinical treatment 
requires knowledge of the treatment assignment, the study blind may be broken for the 
specific subject.  Unless the medical emergency is deemed to be life-threatening, the 
medical monitor must first be consulted before unblinding.  
 
3.4 Minimization of Missing Data / Dropout rate 
It is important to avoid missing data from clinical trials.  The following strategies are 
designed to minimize drop-outs and missing data in this study: 
x Minimizing the burden on subjects, with only three visits scheduled over the 
course of the trial (with reasonable visit window flexibility).   
x Providing payment for subjects’ time at clinic visits, as approved by the 
Institutional Review Board.   
x Allowing rescue medication/therapy at or after 20 minutes post patch 
administration. 
x Training of site personnel on emphasizing to subjects the importance of 
completing the eDiary assessments in order to minimize missing data. 
x Employing an eDiary training module for subjects to complete prior to the 
distribution of the eDiary. 
x Using alarms and reminder alerts for eDiary data entry. 
x Instituting an eDiary reminder card for subject use that shows the timepoints 
when subjects need to enter data. 
x Having a web portal available to site personnel where missing eDiary data can 
be easily identified so site personnel can be retrained on the importance of 
emphasizing to subjects the need to complete eDiary assessments, if 
necessary. 
Due to the COVID-19 pandemic, the protocol was amended in April 2020 to allow for a 
visit 3 telemedicine visit.  If any subjects cannot or elect not to be seen in clinic, the Visit 


 
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3/End of Study Visit may take place via a virtual video (such as FaceTime, WhatsApp, 
Skype, Zoom).  During this call, the Principal Investigator will assess for adverse events, 
skin reactions where C213 was applied, concomitant medication/rescue medication use, 
and drug accountability.  For the subjects who are female of child-bearing potential, the 
sites will send a urine pregnancy test kit (monthly per protocol) and after dosing, verify 
that there is no pregnancy. In addition, the Sponsor, on a case by case basis, will consider 
allowing an ‘out of window’ Visit 3/End of Study Visit (in person). Any procedure such 
as vital signs, blood collection, and ECG which cannot be collected on site or remote will 
be indicated as ‘not done’ in both the source documents and eCRF, and if prompted, with 
a reason specified in the eCRF as due to the pandemic. 
 
4. ANALYSIS AND REPORTING 
4.1 Interim Analysis 
There is no interim analysis planned for this study. 
 
4.2 Final Analysis 
All final, planned analyses will be performed after the last subject has completed all 
study assessments, all relevant study data have been processed and integrated into the 
analysis database, and the database has been locked.  
Any post-hoc, exploratory analyses completed to support planned study analyses, which 
were not identified in this SAP, will be documented and reported in appendices to the 
CSR.  Any results from these unplanned analyses (post-hoc) will also be clearly 
identified in the text of the CSR. 
 
 


 
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5. SAMPLE SIZE DETERMINATION 
The study is planned to enroll approximately 120 subjects total in a 1:1:1 randomization, 
that is, 40 subjects in each of the placebo, C213 1.9 mg, and C213 3.8 mg groups.  It is 
anticipated that 20% of subjects receiving placebo and 55% of subjects receiving active 
treatment will achieve pain relief at 15 minutes and sustained pain relief from 15 minutes 
to 60 minutes post-dose.  Based on a two-sided chi-square test with continuity correction 
and an alpha level of 0.05, 40 subjects per arm will provide approximately 80% power to 
detect this same difference between two treatment groups, assuming a 15% dropout rate. 
 
 


 
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6. ANALYSIS POPULATIONS 
The following analysis populations are planned for this study:  
x Safety Population: The safety population will include all subjects who received 
any amount of study drug. All safety analyses will be performed using this 
population, analyzed as treated.  
x Modified Intention-To-Treat Population (mITT): All randomized subjects who 
have a qualifying headache and at least one post-application pain score recorded 
within the first 15 minutes post-application will be included in the mITT 
population.  This is the primary population for efficacy analyses and subjects will 
be analyzed based on their randomized treatment. 
 
 
 


 
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7. GENERAL ISSUES FOR STATISTICAL ANALYSIS 
7.1 General Statistical Methodology 
Descriptive summaries will be provided where appropriate for each of the primary and 
secondary variables.  In general, tables will summarize data by treatment group.  
Baseline characteristic and safety tables will be completed for the Safety Population 
unless otherwise specified.  Efficacy tables will be presented for the mITT Population.  
Continuous, quantitative, variable summaries will include the number of subjects (N) 
with non-missing values, mean, standard deviation (SD), median, minimum, and 
maximum.  
Categorical, qualitative, variable summaries will include the frequency and percentage of 
subjects who are in the particular category.  In general, the denominator for the 
percentage calculation will be based upon the total number of subjects in the study 
population for the treatment group unless otherwise specified.  
Baseline values are defined as the last non-missing measurement prior to patch 
administration.  Change from baseline will be defined as the post-baseline visit value 
minus the baseline value.   
Subjects are not supposed to change study sites; however, should this be necessary to 
allow a subject to continue in the study, subjects will be analyzed under the site where 
they were initially enrolled. 
Study day after patch administration is defined as assessment date – patch administration 
date +1.  Dates prior to patch administration are defined as assessment date – patch 
administration date.   
All analyses will be performed using Statistical Analysis System (SAS®) Software 
version 9.3 or later.  
 
7.1.1 Adjustments for Multiplicity and Other Alpha Control 
There will be no adjustments made for multiplicity to control the overall type I error.   
7.1.2 Data Handling for Subjects Who Withdraw from the Study 
Subjects who withdraw/drop out from the study will have their early termination (ET) 
visit data collected within 1-8 days following the time of the subject’s early termination.  
Safety data will be included in the Visit 3 end of study summaries as appropriate per the 
definition of the safety population.  The subjects’ efficacy data will be included in the 
efficacy analyses according to the definition of mITT.   
7.1.3 Methods for Handling Missing Data 
Missing pain and daily activities data for participants in the mITT population will be 
imputed via last observation carried forward (LOCF).  Prior to imputing missing endpoint 
data for the endpoint sustained pain relief 15-60 minutes, pain relief will be assessed at 
each of the 15, 20, 30, and 60-minute timepoints that have data available. If any of these 


 
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timepoints has a pain severity rating of moderate or severe, or if the subject has used a 
rescue medication/therapy, then the subject will be considered to have not achieved 
sustained pain relief and this endpoint will not be imputed.  Otherwise, missing pain data 
will be imputed using LOCF.  Missing data for all sustained pain relief and sustained pain 
freedom endpoints will be handled this way.    
Missing safety data will not be imputed. Due to COVID-19, it is unavoidable that some 
subjects will be missing certain safety assessments, such as (but not limited to) Visit 3 
clinical labs, vital signs, and ECG. This is because the Visit 3 occurred during the 
pandemic and telemedicine visit was necessary.  Safety summaries will be generated 
using observed data, and missing safety assessments will be captured as protocol 
deviations. 
Missing rescue medication data will be handled as described in section 7.2.4.4. 
 
7.2 Efficacy Assessments 
There are two primary efficacy endpoints. Other secondary and exploratory efficacy 
endpoints are tested to better understand the potential clinical benefit of C213 on cluster 
headache subjects. 
7.2.1 Co-primary Efficacy Endpoints 
7.2.2 Pain Relief 
One of the co-primary efficacy endpoints is the proportion of subjects who achieve pain 
relief at 15 minutes post patch administration.  Headache pain will be assessed using a 4-
point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe), with pain relief defined by a 
decrease in pain from severe to mild or none, without the use of acute rescue medication 
within 15 minutes post patch administration.  Subjects record their answers in the eDiary 
to the question: “How bad is your headache pain?”. Subjects are also asked in the eDiary, 
“Did you take any medication, since your last diary entry, other than the patches you 
applied to treat your headache?” in order to assess rescue medication use (see section 
7.2.4.4). 
7.2.3 Sustained Pain Relief 
The other co-primary efficacy endpoint is the proportion of subjects who achieve 
sustained pain relief from 15 minutes to 60 minutes post patch administration.  Sustained 
pain relief requires a pain rating of mild or none at each timepoint from 15 minutes to 60 
minutes without the use of acute rescue medication at any time during the 60 minutes 
post patch administration.   
 


 
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7.2.4 Secondary Efficacy Assessments 
7.2.4.1 Pain Freedom 
Pain freedom is defined by a rating of none using the 4-point scale (0 = none, 1 = mild, 2 
= moderate, 3 = severe) without the use of acute rescue medication up until the timepoint 
being assessed (10 or 15 minutes). 
 
7.2.4.2 Sustained Pain Freedom 
Sustained pain freedom requires a pain rating of none at each timepoint from 10 (or 15) 
minutes to 60 minutes without the use of acute rescue medication at any time during the 
60 minutes post patch administration. 
 
7.2.4.3 Pain Relief and Sustained Pain Relief 
Secondary endpoints of pain relief (at 5, 10, 20, and 30 minutes post patch 
administration) and sustained pain relief (5 and 10 minutes to 60 minutes post patch 
administration) will be assessed in the same manner as the primary endpoints.  For 
example, pain relief at 5 minutes requires a rating of mild or none without the use of 
acute rescue medication within 5 minutes post patch administration.  Sustained pain relief 
requires a pain rating of none at each timepoint from 5 (or 10) minutes to 60 minutes 
without the use of acute rescue medication at any time during the 60 minutes post patch 
administration. 
7.2.4.4 Rescue Medication/Therapy Use  
 
A subject is considered to have taken a rescue medication by a given timepoint if the 
answer to the eDiary question, ‘Did you take any medication, since your last diary entry, 
other than the patches you applied to treat your headache?’ is answered Yes at that 
timepoint or any preceding timepoint.  The specific medication/therapy is to be recorded 
as a concomitant medication in the CRF. 
 
If rescue medication use data are missing for a given timepoint and there are no “Yes” 
responses at a previous timepoint, missing values will be imputed using the next 
available value (next observation carried backward). If rescue medication data are still 
missing after imputation, then it will be assumed a rescue medication was not taken. 
For the 60-minute timepoint, if rescue medication use data are missing at 60 minutes and 
there are no “Yes” responses at a previous timepoint, then the subject is considered not to 
have taken the rescue medication by the 60-minute timepoint. 
7.2.4.5 Ability to Perform Daily Activities 
Whether or not subjects are able to perform their usual daily activities is assessed by 
subject responses (Yes or No) in the eDiary to the question, “Do you feel able to perform 
your usual daily activities?” If a subject responds “Yes” but has used a rescue 
medication, the subject is considered as not being able to perform the usual daily 
activities. 


 
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7.3 Safety Assessments 
Safety will be assessed by: 
x AEs and serious adverse events (SAEs) 
x Clinical laboratory test results including coagulation 
x Vital signs (heart rate, blood pressure, respiration rate, temperature) 
x Abnormal physical examination findings 
x Abnormal 12-lead ECG parameters (HR, RR, PR, QRS, QT, QTcB, QTcF) 
x Ratings from Investigator visual skin assessments 
7.3.1 Adverse Event and Prior/Concomitant Medication handling conventions 
To handle missing or partial AE and prior/concomitant medication dates, the following 
rules will be applied. 
For partial start dates: 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2. If the month is unknown, then: 
a. If the year matches the year of the first dose date, then impute the month 
and day of the first dose date. 
b. Otherwise, assign “January.” 
3. If the day is unknown, then: 
a. If the month and year match the month and year of the first dose date, then 
impute the day of the first dose date. 
b. Otherwise, assign “01.” 
 
For partial end dates: 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2. If the month is unknown, then assign “December.” 
3. If the day is unknown, then assign the last day of the month. 
 
Adverse events are categorized as either pre-treatment adverse events or treatment-
emergent adverse events based on the response to the CRF question “Did the AE occur 
prior to patch administration?” 
After implementing the rules above, to determine whether medications with missing start 
or stop dates are prior or concomitant medications, the following strategy will be used: 
 


 
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1. If the start date and stop date are both missing, then the medication is considered 
to be both a prior and a concomitant medication. 
2. If the start date is missing but the stop date is not missing and is before the day of 
patch administration, then the medication is considered to be a prior medication, 
otherwise it is considered to be both prior and concomitant. 
3. If the stop date is missing but the start date is not missing and is on or within 5 
days after the date of patch application, then the medication is considered to be 
concomitant. 
4. If the stop date is missing but the start date is not missing and is prior to the date 
of patch application, then the medication is considered to be both prior and 
concomitant. 
The missing severity of an AE will be imputed to “severe”; the missing relationship to 
study drug of an AE will be imputed to “related”.  
 
8. STUDY SUBJECTS AND DEMOGRAPHICS 
8.1 Disposition of Subjects and Withdrawals 
The numbers and percentage of subjects randomized, completing the study, and 
withdrawing from the study, along with reasons for withdrawal, will be tabulated overall 
and by treatment group.  The number and percentage of subjects in each analysis 
population will be reported.   
8.2 Protocol Deviations 
Protocol deviations will be checked on complete data for all subjects, determined during 
a (blinded) data review meeting before database lock, unblinding, and the final analysis.  
Protocol deviations are collected on the CRF. 
Protocol deviations will be summarized by treatment group for the Safety population.  
Protocol “violations” are not differentiated from deviations; instead, each deviation is 
identified either as “major” or “minor” depending upon its potential impact upon the 
integrity of the study data or the subject’s well-being.  Any deviation related to the 
COVID-19 pandemic is required to be entered in the EDC by the investigational site with 
the word COVID entered as prefix to the deviation texts. 
Individual subjects with protocol deviations will be listed. 
8.3 Demographics and Other Baseline Characteristics 
Descriptive summaries of the demographic and other baseline characteristics will be 
completed for all subjects in the safety population by treatment groups. 
Descriptive summaries of demographic and other baseline conditions will include: 
x Demographics (age, gender, race/ethnicity, height, weight, body mass index 
(BMI), alcohol use, smoking history, and illicit drug use).  In addition to the 
safety population, these will also be repeated for all randomized subjects and 
the mITT population. 


 
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x Cluster headache history characteristics such as type (chronic or episodic) 
and each subject’s usual signs and symptoms. The number of years since first 
cluster headache will be calculated using the following formula:  ([year of 
informed consent]-[year of first cluster attack]). 
 
Medical History will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.0 and summarized by System Organ Class (SOC) and Preferred 
Term using frequency counts by treatment group.   
 
9. EFFICACY ANALYSES 
9.1 Primary Efficacy Analysis  
The proportion of subjects who achieve pain relief at 15 minutes and the proportion who 
achieve sustained pain relief from 15 minutes to 60 minutes post patch administration 
will be analyzed separately using Fisher’s Exact test, with missing data imputed using 
LOCF (see section 7.1.3).  The analyses will include all subjects in the mITT population. 
A significance test of the treatment difference comparing each C213 dose (1.9 mg and 2.8 
mg) to placebo will be tested at the two-sided 0.05 level.  
 
9.1.1 Sensitivity and Supporting Analyses 
The primary analysis may be followed by a sensitivity analysis to investigate the impact 
of missing data on the treatment estimates.   
9.1.1.1 C213 patients as failure and placebo as responder 
If performed, this sensitivity analysis will be a repeat of the primary efficacy analysis 
where C213 patients with missing data will be imputed as non-responders/failures, and 
placebo patients with missing data as responders.  Thus, for the co-primary outcome 
measure of pain relief at 15 minutes, C213 patients with a missing pain score at 15 
minutes will be considered a treatment failure, and placebo patients with missing data at 
15 minutes will be considered a responder. For the co-primary outcome measure of 
sustained pain relief, C213 patients with a missing pain score at any time from 15-60 
minutes will be considered a treatment failure, and placebo patients with a missing pain 
score will be considered a responder only if all other pain scores within 15-60 minutes 
are not severe or are missing. 
 
9.2 Secondary Efficacy Analyses 
Binary data, with the exception of rescue therapy use, will be summarized by treatment 
group.  Missing data will be imputed using LOCF.  Summaries of the proportion of 
subjects will be calculated and displayed, and a Fisher’s Exact test will be performed. 
Two-sided p-values for the test of no difference between each C213 treatment group and 
placebo will be provided.  Rescue therapy use as reported on the eDiary will be listed by 
subject and timepoint.   


 
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These endpoints will include: 
x Proportion of subjects that achieve pain relief at 5, 10, 20, and 30 minutes post 
patch application 
x Proportion of subjects that achieve sustained pain relief from 5 to 60 minutes 
and from 10 to 60 minutes post patch application 
x Proportion of subjects that achieve pain freedom at 10 minutes and 15 minutes 
post patch application 
x Proportion of subjects that achieve sustained pain freedom from 10 to 60 
minutes and from 15 to 60 minutes post patch application 
x Proportion of subjects using rescue therapy within 20 minutes post patch 
application 
x Proportion of subjects able to perform their usual daily activities as assessed 
by the subject at 5, 10, 15, 20, 30, and 60 minutes post patch application 
 
9.3 Exploratory Efficacy Analyses 
Depending on sample size, the primary efficacy analyses were to be conducted for the 
subgroup of patients in the mITT population who were in the trial prior to Protocol 
Amendment 3 and for those who were enrolled after Amendment 3, with the purpose of 
assessing the impact of the modification of time zero to be the start of the first patch 
application. 
 
10. SAFETY AND TOLERABILITY ANALYSIS 
The safety analysis will be run on the Safety population.  The analysis of safety 
assessments in this study will include summaries or data listings of the following safety 
and tolerability data collected for each subject: 
x Adverse Events including Serious Adverse Events 
x Clinical Laboratory Investigations including coagulation studies 
x Concomitant Medications 
x Vital Signs  
x Physical exam including height and weight 
x Investigator visual skin assessments 
x Electrocardiogram Parameters  
x Pregnancy Tests 
 


 
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10.1 Adverse Events 
All AEs, treatment-emergent adverse events (TEAEs), and SAEs will be coded using 
MedDRA, version 22.0. 
Adverse events are categorized as either pre-treatment adverse events or treatment-
emergent adverse events based on the response to the CRF question “Did the AE occur 
prior to patch administration?” 
An AE summary table or listing will be presented for the following: 
x TEAEs by severity 
x TEAEs leading to study drug discontinuation  
x TEAEs by relationship 
x SAEs 
Summaries of incidence rates (frequencies and percentages) of individual TEAEs by 
MedDRA SOC and preferred term will be prepared if there are a sufficient number of 
adverse events.   
Each subject will be counted only once within each summation level (SOC; preferred 
term).  
In the AE data listings, all AEs will be displayed.  AEs that are treatment-emergent will 
be flagged. 
10.1.1 Adverse Events Leading to Discontinuation of Study Drug  
A listing of AEs leading to discontinuation of study drug will be provided, displaying 
details of the event(s) captured on the CRF. 
10.1.2 Serious Adverse Events 
A listing of SAEs will be provided, displaying details of the event(s) captured on the 
CRF. 
10.1.3 Deaths 
A listing of deaths will be provided for the Safety Population. 
10.2 Clinical Laboratory Evaluations 
Laboratory tests will be performed at the Screening and End of Study (or early 
discontinuation) visits and include analytes for Serum Chemistry and Hematology.  
Pregnancy tests will be performed on all women of child-bearing potential at screening 
and every month [+ or – 7 days] after randomization to ensure no pregnancy prior to 
study drug administration.  The urine drug abuse screen will be performed at screening 
and will test for amphetamines, barbiturates, cocaine, phencyclidine (PCP), and 
meth/amphetamines. 
Laboratory values will be displayed in the by-subject data listings for the Safety 
Population and those that are outside the normal range (“H” or “L”) will be flagged, 


 
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along with corresponding normal ranges.  Pregnancy data collected throughout the study 
will be listed, as well as results from the urine drug abuse screen.  
 
10.3 Vital Signs 
All subjects will have vital signs (temperature, RR, BP, and HR) measured at the 
Screening, Randomization (Day 1), and End of Study (or early discontinuation) visits.   
A by-subject listing of all vital sign data will be provided. 
 
10.4 Physical Examination 
A physical examination including height and weight will be performed during the 
Screening, Randomization (Day 1), and End of Study (or early discontinuation) visits.  
Height will be collected at screening only.  The physical examination will include, but is 
not limited to, HEENT, dermatologic (investigator skin assessment), brief neurological, 
general appearance, lymph nodes, cardiovascular, respiratory, gastrointestinal, and 
musculoskeletal examination. 
Abnormal PE findings will be listed by subject; clinical significance will be indicated as 
well as the abnormality specified.  In addition, a by-subject listing height and weight data 
will be generated.   
 
10.5 Electrocardiogram (ECG) 
A 12-lead ECG will be performed at the Screening and End of Study (or early 
discontinuation) visits.  The standard ECG parameters including rhythm, heart rate, and 
intervals for PR, QRS, QT, QTcB and QTcF (Fridericia’s) correction for heart rate will 
be recorded.  A listing of abnormal ECGs will be generated along with clinical 
significance as determined by the Investigator, any Investigator comments, and the 
results for all ECG parameters.  A by-subject data listing of all ECG results will also be 
provided for each visit.  
 
10.6 Investigator Visual Skin Assessment 
The Investigator will perform a visual skin assessment of bruising, erythema, and edema 
at the randomization visit (Visit 2) and at the End of Study (or early discontinuation) 
visit.  Any adverse events including application site reactions will be documented on the 
appropriate eCRF page and must be followed until resolution or medically stable.  
At the End of Study (or early discontinuation) visit, the entire surface area of the outer 
upper arm where the two patches were applied will be assessed for the following skin signs 
or symptoms.  Any findings with an intensity rating of 1 (Mild intensity), 2 (Moderate 
intensity), or 3 (Severe intensity) must be recorded as an adverse event in the eCRF and 
followed to resolution.   


 
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Bruising assessments (visual rating) will be performed using the following ratings: 
Symptom 
Intensity Rating (circle) 
Bruising where 
C213 was 
applied? 
0 = Clear   
1 = Mild intensity  
2 = Moderate intensity 
3 = Severe intensity 
 
The following ratings will be used to describe the amount of erythema and edema 
indicative of irritation: 
Symptom 
Rating (circle) 
Skin Erythema 
where C213 was 
applied? 
0 = Clear   
1 = Mild intensity  
2 = Moderate intensity 
3 = Severe intensity  
 
Symptom 
Rating (circle) 
Skin Edema 
where C213 was 
applied? 
0 = Clear   
1 = Mild intensity  
2 = Moderate intensity 
3 = Severe intensity  
 
A by-subject data listing for bruising, erythema, and edema will be provided for each 
subject that has a rating of anything but ‘Clear’ at any visit and for those subjects who did 
not have the investigator skin assessment performed.  
 


 
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11. MEDICATIONS 
11.1 Concomitant Medications 
All medications will be coded using WHODrug-Global-B3 version March 2019.  Prior 
and concomitant medications will be summarized by treatment group and by the number 
and percentage of subjects taking each medication, classified by using WHO-DD 
Anatomical Therapeutic Chemical Level 3 and preferred term.  
Prior medications are defined as medications or therapies initiated prior to the start of 
patch administration.  Concomitant medications are defined as any medications other 
than the study drug that a subject receives concurrently with the study drug.  These 
medications will have start dates on, prior to, or within 5 days after the date of patch 
administration and end dates on or after the date of patch administration.  Any medication 
that was stopped more than 90 days prior to informed consent will not be considered 
prior or concomitant. 
Prior and Concomitant medications will be summarized.  All medications will be 
presented in a listing.  
Please refer to Section 7.3 for the conventions used to impute partial start dates and end 
dates of concomitant medications.  
11.2 Extent of Exposure 
Treatment duration is defined as 30 minutes (time that the patch should remain on the 
subject).         
Extent of exposure to study medication will be tabulated by treatment group by 
summarizing the frequency and percentage of subjects whose patch stayed on for 30 
minutes as collected in the CRF.   
A listing of drug accountability data based on CRF data will be provided. 
 
12. CHANGES FROM PLANNED ANALYSIS 
Due to insufficient enrollment numbers, the CMH test as described in the protocol for the 
primary and secondary analyses will not be performed.  The protocol also describes a 
fixed sequential procedure to control for overall type 1 error. This will not be 
implemented since the actual number of randomized subjects is quite a bit less than 
planned and the pre-specified statistical analyses as described in the protocol cannot be 
performed.   
 


 
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13. APPENDICES 
13.1 Appendix 1 
The following reporting conventions will be adopted for the presentation of study data.  
These conventions will enhance the review process and help to standardize presentation 
with common notations. 
13.1.1 General Reporting Conventions 
x All tables and data listings will be developed in Landscape Orientation, unless 
presented as part of the text in a clinical study report (CSR). 
x Specialized text styles, such as bolding, italics, borders, shading, superscripted 
and subscripted text will not be used in tables, figures, and data listings unless 
they add significant value to the table, figure, or data listing.  
x Only standard keyboard characters should be used in tables and data listings. 
Special characters, such as non-printable control characters, printer specific, 
or font specific characters, will not be used on a table, figure, or data listing. 
Hexadecimal character representations are allowed (e.g., P, D, E). 
x All titles will be centered on a page.  The ICH numbering convention is to be 
used for all tables, listings, and graphs (TLGs). 
x All footnotes will be left justified at the bottom of a page.  Footnotes must be 
present on the page where they are first referenced.  Footnotes should be used 
sparingly and must add value to the TLG.  If more than four footnote lines are 
planned then a cover page may be used to display footnotes. 
x Missing values for both numeric and character variables will be presented as 
blanks in a table or data listing.  A zero (0) may be used if appropriate to 
identify when the frequency of a variable is not observed. 
x All date values will be presented as DDMMMYYYY (e.g., 29AUG2001) 
format.  A four-digit year is preferred for all dates. 
x All observed time values will be presented using a 24-hour clock HH:MM:SS 
format (e.g., 01:35:45 or 11:26).  Seconds should only be reported if they 
were measured as part of the study.  
x Time durations will be reported in mixed HHhr MMm SSs notation (e.g., 5h 
32m, or 27h 52m 31s).  The use of decimal notation to present (display) time 
durations should be avoided (e.g. 0.083h = 5m) unless it is necessary to show 


 
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the computation of time differences in a table, figure, or data listing, in which 
case both notations may be used to display the time duration.  
x All TLGs will have the name of the program, location, and a date stamp on 
the bottom of each output.  
x All analysis programs developed for a TLG display will be self-contained to 
facilitate transfer of programs to multiple computing environments and 
transfer to a regulatory agency (if requested).  
13.1.2 Population Summary Conventions 
x Population(s) represented on the tables or data listings will be clearly 
identified in the last title of the Table as “<name of population>” and will be 
identical in name to that identified in the protocol or SAP. 
x Consistent terminology will be used to define and identify a population.  
Common nomenclature may include (a) All Subjects, (b) ITT, (c) Safety, and 
(d) PP. 
x Sub-population(s) or special population(s) descriptions will provide sufficient 
detail to ensure comprehension of the population (e.g., ITT >60 years of age) 
used for analysis in a table or figure. 
x Population sizes may be presented for each treatment or dosing category as 
totals in the column header as (N=xxxx), where appropriate.  
x Population sizes shown with summary statistics are the samples sizes (n) of 
Subjects with non-missing values.  
x All population summaries for categorical variables will include all categories 
that were planned and for which the subjects may have had a response.  
Percentages corresponding to null categories (cells) will be suppressed. 
x All population summaries for continuous variables will include: n, mean, SD, 
minimum, and maximum.  Other summaries (e.g. number missing, median, 
quartiles, 95% confidence intervals, CV or %CV) may be used as appropriate. 
x All percentages are rounded and reported to a single decimal point (xx.x%).  
A percentage of 100% will be reported as 100%.  A percentage of zero will be 
reported as 0. 
x Population summaries that include P values will report the P value to 
three decimal places with a leading zero (0.001).  All P values reported on 
default output from statistical software (i.e., SAS® Software) may be reported 
at the default level of precision. P values <0.001 should be reported as <0.001 
not 0.000.