Clinical trial NCT03978403
Conditions: Migraine
Keywords: Pharmacokinetics Healthy Volunteer
Sponsor: Zosano Pharma Corporation
Start date: 2019-05-29; Completion date: 2019-06-28
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a single-center, open-label, randomized, four-way crossover study. Subjects will receive the four study treatments once, followed by in-clinic monitoring and extensive pharmacokinetic analysis. Dosing occurs \~48 hours apart from patch application, in randomized order. Subjects will have final assessment and be dismissed from the study.

Detailed description:
This is a single-center, open-label, randomized, four-way crossover study. Each subject will receive each of the four study treatments once, followed by in-clinic monitoring and extensive blood sample collection for pharmacokinetic analysis.

Dosing will occur approximately 48 hours apart from the time of patch application, until completion of dosing in randomized order per the treatment sequence schedule. Plasma samples from the dosing days will be sent to the analytical laboratory for analysis and tolerability for each of the dose levels will be summarized.

After completion of the four dosing days, subjects will be assessed one final time and dismissed from the study.

Arms: arm 1: A: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min made on a "Sled" coater packaged in foil pouches; B: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min made on a "MACAP" coater packaged in foil cups; C: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min made on a "miniMac" coater packaged in foil cups; D: Zolmitriptan nasal 2.5 mg/0.1 mL single dose arm 2: A: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min made on a "Sled" coater packaged in foil pouches; B: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min made on a "MACAP" coater packaged in foil cups; C: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min made on a "miniMac" coater packaged in foil cups; D: Zolmitriptan nasal 2.5 mg/0.1 mL single dose arm 3: A: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min made on a "Sled" coater packaged in foil pouches; B: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min made on a "MACAP" coater packaged in foil cups; C: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min made on a "miniMac" coater packaged in foil cups; D: Zolmitriptan nasal 2.5 mg/0.1 mL single dose arm 4: A: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min made on a "Sled" coater packaged in foil pouches; B: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min made on a "MACAP" coater packaged in foil cups; C: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min made on a "miniMac" coater packaged in foil cups; D: Zolmitriptan nasal 2.5 mg/0.1 mL single dose
Interventions: intervention 1: M207 3.8 mg "Sled" (two 1.9 mg patches made on a "Sled" coater, foil pouches) intervention 2: M207 3.8 mg "MACAP" (two 1.9 mg patches made on a "MACAP" coater, foil cups) intervention 3: M207 3.8 mg "MiniMac" (two 1.9 mg patches made on a "MiniMac" coater, foil cups intervention 4: Zolmitriptan 2.5 mg/0.1 mL nasal spray [ZOMIG] single dose
Intervention descriptions: intervention 1: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min wear time made on a "Sled" coater and packaged in foil pouches intervention 2: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min wear time made on a "MACAP" coater and packaged in foil cups intervention 3: M207 3.8 mg administered as two 1.9 mg upper arm patches 30 min wear time made on a "miniMac" coater and packaged in foil pouches intervention 4: Zolmitriptan 2.5 mg/0.1 mL nasal spray \[ZOMIG\] single dose

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: 
A Randomized Open-label Four-way Crossover Study to Compare 
the Pharmacokinetics, Safety, and Tolerability of Three Different 
Formulations of M207 3.8 mg (Administered as two 1.9 mg 
patches) on the Upper arm for 30 Minutes with Intranasal 
Zolmitriptan 2.5 mg in Healthy Volunteers 
PROTOCOL NUMBER:  
CP-2019-002 
PROTOCOL VERSION: 
1.0  
PROTOCOL DATE:  
15 April 2019 
STUDY DRUG:  
 
M207 (Zolmitriptan Microneedle System) 
SPONSOR:  
Zosano Pharma Corporation 
34790 Ardentech Court 
Fremont, CA 94555  
United States 
SPONSOR CONTACT:  
Peter Schmidt, MD, MSc 
34790 Ardentech Court 
Fremont, CA 94555 
United States 
 
 
 
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. 




 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC30min 
Area under the curve from minute 0 to minute 30 
AUCt 
Area under the curve from 0 hours to the last measureable 
concentration 
AUCinf 
Area under the curve extrapolated to infinity 
BMI 
Body Mass Index 
BP 
Blood pressure 
BSAP 
Bone specific alkaline phosphate 
C 
Celsius 
CBC 
Complete blood count 
Ct 
Concentration at time t 
CFR 
Code of Federal Regulations 
CM 
Concomitant medication 
cm2 
Centimeter squared 
Cmax  
Maximum observed plasma concentrations 
CPK 
Creatinine phosphokinase 
CRF 
Case report form 
dL 
Deciliter 
ECG 
Electrocardiogram 
EDTA 
Ethylenediaminetetraacetic acid 
F 
Fahrenheit 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transpeptidase 
H 
Hour 
HCl 
Hydrochloride 
HRT 
Hormone replacement therapy 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IRB 
Institutional Review Board 
IV 
Intravenous 


 
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Abbreviation 
Definition 
J 
Joules 
k 
Apparent elimination rate constant 
kg 
Kilogram 
KIU 
Kilo international units 
µg 
Microgram 
L 
Liter 
LDH 
Lactate dehydrogenase 
µm 
Micrometer 
M207 
Zolmitriptan Microneedle System (M207) 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mL 
Milliliters 
mmol 
millimole(s) 
NSAID 
Nonsteroidal anti-inflammatory drug 
PD 
Pharmacodynamics 
PE 
Physical examination 
PK 
Pharmacokinetics 
PPI 
Proton pump inhibitors 
PRSPB 
Bruising 
PTH 
Parathyroid hormone  
SAE 
Serious adverse event 
SC 
Subcutaneous 
SD 
Standard deviation 
t½ 
Apparent half life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum concentration 
WHO 
World Health Organization 
ZP 
Zosano Pharma 
 


 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE - PRINCIPAL INVESTIGATOR ................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 3 
TABLE OF CONTENTS ............................................................................................................. 5 
PROTOCOL SYNOPSIS ............................................................................................................. 9 
1 
INTRODUCTION ......................................................................................... 15 
1.1 
Background ..................................................................................................................... 15 
1.2 
Investigational Products .................................................................................................. 15 
1.2.1 
M207 (Zolmitriptan Microneedle System) ............................................................. 15 
1.2.2 
Zolmitriptan Nasal Spray ........................................................................................ 15 
2 
STUDY OBJECTIVES ................................................................................. 16 
3 
ETHICAL CONSIDERATIONS ................................................................. 17 
3.1 
Institutional Review ........................................................................................................ 17 
3.2 
Informed Consent ............................................................................................................ 17 
4 
INVESTIGATIONAL PLAN ....................................................................... 18 
4.1 
Overall Study Design ...................................................................................................... 18 
4.2 
Endpoints ......................................................................................................................... 18 
4.3 
Safety Considerations ...................................................................................................... 19 
4.4 
Study Population ............................................................................................................. 19 
4.4.1 
Inclusion Criteria: .................................................................................................... 19 
4.4.2 
Exclusion Criteria: ................................................................................................... 19 
4.5 
Early Termination ........................................................................................................... 21 
5 
STUDY TREATMENTS ............................................................................... 22 
5.1 
Study Drug Treatments ................................................................................................... 22 
5.2 
Study Treatment Assignment and Schedule.................................................................... 22 
5.3 
Study Treatment Accountability Procedures................................................................... 22 
5.4 
Prior and Concomitant Medications Allowed and Prohibited During the Study ............ 23 


 
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6 
STUDY VISIT SCHEDULE AND GENERAL CONSIDERATIONS ..... 24 
6.1 
Screening ......................................................................................................................... 24 
6.1.1 
Screening Visit (Up to 30 days prior to the Admission/Baseline Visit) ................. 24 
6.2 
Admission/Baseline Visit (Day Before the first Dose) ................................................... 25 
6.3 
Study Dosing Days .......................................................................................................... 26 
6.3.1 
Dosing Visit (all Periods) – All Treatments ............................................................ 26 
6.3.1.1 
Pre-Dose - Before treatment Administration on the Day of Dosing ................ 26 
6.3.1.2 
Treatment Administration (time 0 is application of second patch) .................. 27 
6.3.1.3 
2 Minutes after Treatment Administration ....................................................... 27 
6.3.1.4 
5 Minutes after Treatment Administration ....................................................... 27 
6.3.1.5 
10 Minutes after Treatment Administration ..................................................... 27 
6.3.1.6 
15 Minutes after Treatment Administration ..................................................... 27 
6.3.1.7 
20 Minutes after Treatment Administration ..................................................... 27 
6.3.1.8 
30 Minutes after Treatment Administration ..................................................... 27 
6.3.1.9 
45 Minutes after Treatment Administration ..................................................... 28 
6.3.1.10 
60 Minutes after Treatment Administration ..................................................... 28 
6.3.1.11 
90 Minutes after Treatment Administration ..................................................... 28 
6.3.1.12 
Two Hours after Treatment Administration ..................................................... 28 
6.3.1.13 
Four Hours after Treatment Administration ..................................................... 28 
6.3.1.14 
Eight Hours after Treatment Administration .................................................... 28 
6.3.1.15 
Twelve Hours after Treatment Administration ................................................ 28 
6.3.1.16 
Twenty Four Hours after Treatment Administration ........................................ 29 
6.3.1.17 
Zolmitriptan PK Sample Handling ................................................................... 29 
6.4 
End of Study Visit/or Early Termination ........................................................................ 29 
6.5 
Post Study Phone Call - Follow-up on Adverse Events .................................................. 29 
6.6 
Early Termination ........................................................................................................... 29 
7 
STUDY PROCEDURES ............................................................................... 30 
7.1 
General Confinement Restrictions .................................................................................. 30 
7.2 
Collection, Processing and Assay of Samples ................................................................ 30 
7.3 
Assessment Details .......................................................................................................... 30 
7.3.1 
Clinical Laboratory Tests ........................................................................................ 30 


 
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7.3.2 
Vital Signs ............................................................................................................... 31 
7.3.3 
Electrocardiograms .................................................................................................. 31 
7.3.4 
Investigator Visual Skin Assessments of the Application Sites .............................. 31 
7.3.4.1 
Erythema ........................................................................................................... 31 
7.3.4.2 
Edema ............................................................................................................... 32 
7.3.4.3 
Bruising ............................................................................................................ 32 
7.3.4.4 
Bleeding ............................................................................................................ 32 
7.3.5 
Residual Drug on Used M207 Patches .................................................................... 32 
7.3.6 
Residual Drug on Skin after M207 Patch Removal ................................................ 33 
7.3.7 
Recording Adverse Events ...................................................................................... 33 
8 
ADVERSE EVENTS ..................................................................................... 34 
8.1 
Adverse Event Definitions .............................................................................................. 34 
8.2 
Documentation and Reporting of Adverse Events By the Investigator .......................... 35 
8.2.1 
Duration ................................................................................................................... 35 
8.2.2 
Severity Ratings ...................................................................................................... 36 
8.2.3 
Relationship to Study Drug ..................................................................................... 36 
8.3 
Serious Adverse Event Definitions ................................................................................. 37 
8.4 
Reporting Requirements For Serious Adverse Events .................................................... 38 
8.4.1 
Sponsor SAE Contact Information .......................................................................... 38 
8.4.2 
Follow up of Adverse Events .................................................................................. 39 
9 
DATA MANAGEMENT ............................................................................... 40 
9.1 
Data Collection ................................................................................................................ 40 
9.2 
Database Management and Quality Control ................................................................... 40 
10 
STATISTICAL METHODS AND DATA ANALYSIS .............................. 41 
10.1 Sample Size Considerations ............................................................................................ 41 
10.2 Demographics and Baseline Characteristics ................................................................... 41 
10.3 Analysis Population and Handling of Drop-Outs ........................................................... 41 
10.4 Zolmitriptan Pharmacokinetics ....................................................................................... 41 


 
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10.5 Analyses of Safety Data .................................................................................................. 42 
10.6 Analyses of Residual Drug .............................................................................................. 42 
11 
ADMINISTRATIVE PROCEDURES ......................................................... 43 
11.1 Changes to the Protocol................................................................................................... 43 
11.2 Investigator Reporting Responsibilities to the Independent Ethics Committee and Other 
Agencies 43 
11.3 Withdrawal and Study Termination ................................................................................ 43 
11.4 Monitoring ....................................................................................................................... 43 
11.5 Retention of Documents .................................................................................................. 44 
11.6 Publicaton Policy............................................................................................................. 44 
11.7 Auditing Procedures ........................................................................................................ 44 
12 
REFERENCES .............................................................................................. 45 
13 
SCHEDULE OF ASSESSMENTS ............................................................... 46 
APPENDIX 1: 
M207 PATCH ADMINISTRATION ............................................................ 48 
APPENDIX 2: 
ZOLMITRIPTAN PK SAMPLE HANDLING .......................................... 57 
APPENDIX 3: 
HANDLING AND PROCESSING OF USED PATCHES AND SKIN 
SWABS........................................................................................................... 58 
APPENDIX 4: 
SHIPPING PROCEDURES FOR UNUSED PATCHES AND NEW 
APPLICATORS ............................................................................................ 63 
APPENDIX 5: 
DECLARATION OF HELSINKI ................................................................ 65 
 


 
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PROTOCOL SYNOPSIS 
TITLE 
A Randomized Open-label Four-way Crossover Study to Compare 
the Pharmacokinetics, Safety, and Tolerability of Three Different 
Formulations of M207 3.8 mg (Administered as two 1.9 mg 
patches) on the Upper arm for 30 Minutes with Intranasal 
Zolmitriptan 2.5 mg in Healthy Volunteers 
SPONSOR  
Zosano Pharma 
CLINICAL PHASE  
Phase 1 – Single Center 
INDICATION  
Acute Treatment of Migraine 
OBJECTIVES  
1. To compare the pharmacokinetics, safety and tolerability of 
M207 3.8 mg Treatment A to M207 3.8 mg Treatment B to 
M207 3.8 mg Treatment C, worn for 30 minutes on the 
upper arm 
2. To compare the pharmacokinetics, safety and tolerability of 
three formulations of M207 3.8 mg to intranasal zolmitriptan 
2.5 mg 
TREATMENTS 
• Treatment A: M207 3.8 mg administered as two 1.9 mg 
patches, 30 min wear time (upper arm application) – made 
on a “Sled” coater and packaged in foil pouches 
• Treatment B: M207 3.8 mg administered as two 1.9 mg 
patches, 30 min wear time (upper arm application)  - made 
on a “MACAP” coater and packaged in foil cups 
• Treatment C:  M207 3.8 mg administered as two 1.9 mg 
patches, 30 wear time (upper arm application) – made on a 
“MiniMac” coater and packaged in foil cups 
• Treatment D: Intranasal zolmitriptan 2.5mg 
BLINDING  
Open-label 
RANDOMIZATION  
Randomized to the sequence of treatments 
STUDY POPULATION  
Healthy volunteers (females and males); No more than 10% of the 
24 subjects randomized will be of black or African American race  
 


 
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NUMBER OF  
SUBJECTS  
24 (12 females; 12 males) 


 
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ELIGIBILITY  
Inclusion Criteria 
1. Women or men 18 to 50 years of age (inclusive) 
2. Good general health with no clinically significant 
abnormalities as determined by medical history, physical 
examination, CBC, blood chemistry, urinalysis, and ECG.  
3. Negative urine drug and alcohol screens and negative serum 
pregnancy tests (for female subjects) at screening and 
admission/baseline visit. 
4. Consent of female subjects to use a medically effective 
method of contraception throughout the entire study period 
and for 30 days after the subject completes the study.  
Medically effective methods of contraception that may be 
used by the subject include abstinence, use of diaphragm 
and spermicide, intrauterine device (IUD), rings, condom 
and vaginal spermicide, hormonal contraceptives (subjects 
must be stable on hormonal contraceptives for at least 
3 months prior to screening), surgical sterilization 
(hysterectomy, bilateral tubal ligation, hysteroscopic 
sterilization) and post-menopausal (≥ 2 years of 
amenorrhea).   
5. Ability to read, understand, and provide written informed 
consent that they understand the purpose of the study and 
procedures required for the study before enrolling in the 
study, and willingness to comply with all study procedures 
and restrictions. 
Exclusion Criteria 
1. Evidence of significant history of hepatic, reproductive, 
gastrointestinal, renal, bleeding, or hematological disorders 
including coagulation, pulmonary, neurological, respiratory, 
endocrine, or cardiovascular system abnormalities 
(especially hypertension, peripheral vascular disease, 
coronary artery disease, transient ischemic attacks, or 
cardiac rhythm abnormalities), psychiatric disorders, acute 
infection, or other conditions that would interfere with 
study participation or with the absorption, distribution, 
metabolism, or excretion of drugs. 
2. Presence of three or more of the following CAD risk factors 
for cardiovascular disease:  
A. Current tobacco use (subjects who have 
smoked within 30 days of screening)  


 
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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 
3. Any contraindication to zolmitriptan administration 
including: 
• History of coronary artery disease or coronary 
vasospasm 
• Symptomatic Wolf-Parkinson-White syndrome or 
other cardiac accessory conduction pathway 
disorders 
• History of stroke, transient ischemic attack, or 
hemiplegic or basilar migraine 
• Peripheral Vascular Disease 
• Ischemic bowel disease 
• Hypertension (greater than or equal to 140/90 
mmHg at either the screening or admission/baseline 
visit  
• Any history of hepatic impairment defined as ALT 
> 150 U/L, AST > 130 U/L or bilirubin > 2 times 
the ULN 
4. History of contact dermatitis or known dermatological 
disorders that would interfere with the study procedures or 
assessments  
5. Planned participation in activities which cause 
inflammation, irritation, sunburn, lesions, or tattoos at the 


 
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intended application sites from 2 weeks prior to dosing 
through their last day of study participation 
6. Use of any prescription anticoagulant within 30 days prior 
to the first dose  
7. Use of prescription and over the counter medications within 
one week of dosing other than the following: 
• Hormone Replacement Therapy (HRT) 
• Birth control pills, patches, IUD, rings, injections, or 
implants (all hormonal contraceptives) are allowed 
provided the dose has been stable for at least three 
months prior to screening and may be continued 
throughout the study 
• Proton Pump Inhibitors (PPIs) 
• Antihistamines 
• Intermittently used NSAIDS 
• Acetaminophen if medically necessary (not more 
than 1000 mg/day) 
• Exceptions may be allowed on a case by case basis 
8. Subject has a known allergy or sensitivity to zolmitriptan or 
its derivatives or formulations 
9. Subject has a known allergy or sensitivity to tapes or 
adhesives  
10. Use of any other investigational compound within 30 days 
of planned study drug dosing  
11. Current use or history of drug and/or alcohol abuse within 6 
months of screening and deemed to be clinically significant 
by the investigator  
12. History of nasal pathology (e.g., polyps) or abnormal nasal 
exam deemed to be clinically significant by the investigator 
13. Body Mass Index (BMI) lower than 18 kg/m2  or greater 
than 35 kg/m2 
14. If, in the opinion of the investigator, the subject is not 
suitable for the study 
15. Any positive urine drug screen result or alcohol test 
16. Subject currently smokes or is a nicotine a user 


 
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CENTERS  
Single center 
STUDY DURATION  
Screening (up to 30 days prior to dosing); in-clinic duration of 
study participation for each subject is approximately 2 weeks total 
(includes 4 treatment periods), and the End of Study (or Early 
Termination) visit occurs on the day of discharge  
PROCEDURES & 
ASSESSMENTS  
All procedures are performed relative to Time 0 (M207 
application), the time of second patch application.  
• Physical examination (Screening, 8 hr post drug 
administration and End of Study/or Early Termination visit) 
• Clinical laboratory tests (Screening, and End of Study/or 
Early Termination visit) 
• Collection of blood samples (pre-dose, 2, 5, 10, 15, 20, 30, 
45, 60, 90 min, 2 hr, 4 hr, 8 hr, 12 hr and 24 hr post-dose) 
for pharmacokinetics determination 
• Vital signs (Screening, pre-dose and 10 min, 60 min, 2 hr, 
4 hr, 12 hr post-dose and End of study/or Early Termination 
visit) 
• 12-lead ECGs (Screening, pre-dose, 15 min, 12 hr post-dose, 
and End of Study/or Early Termination visit) 
• Investigator visual skin assessment of the M207 application 
site at pre-dose, 30 min, 60 min, 8 hr, 24 hr post-dose, and 
End of Study/or Early termination visit  
• Residual zolmitripan swabbing on the skin at 30 min post-
dose 


 
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1 
INTRODUCTION 
1.1 
Background 
Zosano Pharma has developed a zolmitriptan microneedle system (M207) as a potential therapy 
for the acute treatment of migraine.  To date, three trials have been completed, two 
pharmacokinetic studies in healthy volunteers, and a single treatment efficacy and safety study in 
subjects with migraine. A long-term safety study is ongoing.  In all studies, the M207 system 
(“patch”) was applied to the upper arm for 30 minutes. 
Throughout the development process, the equipment used to manufacture M207 changed in 
preparation for commercialization.  In-vitro testing shows that the content and characteristics of 
the zomitriptan microneedle system have not changed over the course of development.  This 
study is designed to compare pharmacokinetics seen after administration of patches (treatments 
A, B, and C) made from the three different types of equipment. 
1.2 
Investigational Products 
1.2.1 M207 (Zolmitriptan Microneedle System) 
The Zosano M207 (Zolmitriptan Microneedle System) is a novel drug delivery technology which 
consists of a disposable titanium microneedle patch centered on an adhesive backing 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.  
M207 systems consist of zolmitriptan coated titanium array with an adhesive backing that is 
applied using proprietary patch applicators.  Descriptions of the 1.9 mg patches used in the study 
are described below. 
1.2.2 Zolmitriptan Nasal Spray 
Zolmitriptan nasal spray is a commercially available product (Zomig® Nasal Spray) and will be 
purchased for use in this study.  The dose used in this study will be 2.5 mg/0.1 ml.   After the 
subject blows his/her nose, this dose should be administered to either the right or left nostril with 
the subject’s head tilted slightly backward. 
M207 1.9 mg Patch  
The M207 1.9 mg consists of a 3 cm2  titanium array of microneedles that are nominally 340 µm 
in length coated with 1.9 mg of zolmitripan.  The array is applied to the center of a 5 cm2 tan 
adhesive patch.  The patch is attached to the interior of a white to off-white polycarbonate ring 
co-molded with a desiccant, packaged in a foil pouch (treatment A) or cup (treatment B and C). 


 
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2 
STUDY OBJECTIVES 
The study objectives are as follows: 
To compare the pharmacokinetics, safety and tolerability of M207 3.8 mg Treatment A to M207 
3.8 mg Treatment B to M207 3.8 mg Treatment C, each worn for 30 minutes on the upper arm. 
To compare the pharmacokinetics, safety and tolerability of these three formulations of M207 
3.8 mg to Treatment D intranasal zolmitriptan 2.5 mg. 


 
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3 
ETHICAL CONSIDERATIONS 
This study must be conducted in compliance with the protocol; the U.S. Code of Federal 
Regulations (CFR); the International Conference on Harmonisation (ICH-R) Good Clinical 
Practice (GCP) Guidelines; the Declaration of Helsinki (see Appendix 5); and all applicable 
federal, state and local laws, rules and regulations relating to the conduct of the study. 
All members of the Investigator’s staff have signed confidentiality agreements. By signing this 
protocol, the Investigator and investigational staff will regard all information provided by the 
Sponsor and all information obtained during the course of the study as confidential.  
The Investigator must guarantee the privacy of the subjects taking part in the study. Subjects will 
be identified throughout documentation and evaluation by a unique subject study number. 
Throughout the study, a subject’s source data will only be linked to the Sponsor’s clinical study 
database or documentation via a unique identification number. If subject name appears on any 
study document, it must be redacted before the copy of the documents is supplied to the Sponsor. 
Any information concerning the subjects (clinical notes, identification numbers, etc.) must be 
kept on file by the Investigator who will ensure that it is revealed only to the Sponsor, IRB, or 
regulatory authorities for the purposes of trial monitoring, auditing or official inspections. As 
required, in the case of an event where medical expenses are the responsibility of the Sponsor, 
personal information, i.e., full name, social security details, etc., may be released to the Sponsor. 
Appropriate precautions will be taken to maintain confidentiality of medical records and personal 
information in strictest confidence and in accordance with local data protection laws. 
3.1 
Institutional Review 
Prior to the initiation of clinical studies, the protocol, the Informed Consent Form (ICF), 
amendments to the protocol and ICF, advertisements and any other information for subjects will 
be reviewed and approved by Zosano Pharma and by the Independent Ethics Committee (IEC) of 
the participating study center in accordance with the CFR, the ICH-R and institutional EC 
policies.  All protocol amendments (See Section 11.1) and changes to the consent form occurring 
during the study must also be IRB/IEC approved. 
3.2 
Informed Consent 
Prior to study inception, each study participant or the legally authorized representative will be 
required to read, sign, and date an IRB/IEC approved ICF explaining the nature, purpose, 
possible risks and benefits of the study, and the duration of an individual’s participation in the 
study.  The clinical site personnel who conducted the informed consent discussion must also sign 
and date the consent form.  Each subject or legally authorized representative will be given a copy 
of the ICF. 


 
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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a single-center, open-label, randomized, four-way crossover study.  Each subject will 
receive each of the four study treatments once, followed by in-clinic monitoring and extensive 
blood sample collection for pharmacokinetic analysis. 
Dosing will occur approximately 48 hours apart from the time of patch application, until 
completion of dosing in randomized order per the treatment sequence schedule.  Plasma samples 
from the dosing days will be sent to the analytical laboratory for analysis and tolerability for each 
of the dose levels will be summarized. 
After completion of the four dosing days, subjects will be assessed one final time and dismissed 
from the study. 
4.2 
Endpoints 
The endpoints of the study are: 
Safety and Tolerability 
• Incidence of adverse events  
• Change in physical exam findings from pre-dose to 8 hr post-dose  
• Changes in vital signs from pre-dose to 10 minutes, 60 minutes, and 2, 4 and 12 hr 
post-dose  
• Changes in ECG parameters from pre-dose to 15 minutes and 12 hr post-dose  
• Scores from the investigator visual skin assessment for erythema, edema, bruising and 
bleeding at the patch application sites from pre-dose to 30 minutes, 60 minutes, 8 hr and 
24 hr post-dose 
Pharmacokinetics 
• Cmax - maximum observed plasma concentrations 
• Tmax - time to maximum concentration 
• AUC0-last - the area under the plasma concentration time profile from hour 0 to the last 
detectable concentration at time t. 
• AUC0-30min - the area under the plasma concentration time profile from minute 0 to 
minute 30. 
• AUC0-60min - the area under the plasma concentration time profile from minute 0 to 
minute 60. 
• AUC0-120min - the area under the plasma concentration time profile from minute 0 to 
minute 120. 


 
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• k - apparent elimination rate constant will be estimated by linear regression of the 
log-transformed plasma concentrations during the terminal log-linear decline phase. 
• t1/2 - apparent half-life (t1/2) values will be calculated as 0.693/k. 
• AUC0-inf - the AUC value extrapolated to infinity will be calculated as the sum of AUCt, 
and the area extrapolated to infinity, calculated by the concentration at time t (Ct) divided 
by k. 
• Frel - bioavailability relative to each treatment assignment 
4.3 
Safety Considerations 
M207 consisting of two patches each 1.9 mg (3.8 mg), 30 minute upper arm application, has 
been studied in healthy volunteers (in clinic) and subjects with migraine (outpatient).  This 
regimen has been generally well-tolerated, with adverse events observed (dizziness and chest 
tightness) of those typically reported for triptans.  Adverse events reported were almost always 
within the first few minutes after patch application.   
4.4 
Study Population 
The study population will consist of 24 healthy volunteers (12 women and 12 men) 18 to 
50 years of age in general good health. 
4.4.1 Inclusion Criteria: 
1. Women or men 18 to 50 years of age (inclusive) 
2. Good general health with no clinically significant abnormalities as determined by medical 
history, physical examination, CBC, blood chemistry, urinalysis, and ECG. 
3. Negative urine drug and alcohol screens and negative serum pregnancy tests (for female 
subjects) at screening and admission/baseline visit. 
4. Consent of female subjects to use a medically effective method of contraception throughout 
the entire study period and for 30 days after the subject completes the study.  Medically 
effective methods of contraception that may be used by the subject include abstinence, use of 
diaphragm and spermicide, intrauterine device (IUD), rings, condom and vaginal spermicide, 
hormonal contraceptives (subjects must be stable on hormonal contraceptives for at least 3 
months prior to screening), surgical sterilization (hysterectomy, bilateral tubal ligation, 
hysteroscopic sterilization) and post-menopausal (≥ 2 years of amenorrhea).   
5. Ability to read, understand, and provide written informed consent that they understand the 
purpose of the study and procedures required for the study before enrolling in the study, and 
willingness to comply with all study procedures and restrictions. 
4.4.2 Exclusion Criteria: 
1. Evidence of significant history of hepatic, reproductive, gastrointestinal, renal, bleeding, or 
hematological disorders including coagulation, pulmonary, neurological, respiratory, 
endocrine, or cardiovascular system abnormalities (especially hypertension, peripheral 


 
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vascular disease, coronary artery disease, transient ischemic attacks, or cardiac rhythm 
abnormalities), psychiatric disorders, acute infection, or other conditions that would interfere 
with study participation or with the absorption, distribution, metabolism, or excretion of 
drugs. 
2. Presence of three or more of the following CAD risk factors for cardiovascular disease:  
A. Current tobacco use (subjects who have smoked within 30 days of screening) 
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 
3. Any contraindication to zolmitriptan administration including: 
• History of coronary artery disease or coronary vasospasm 
• Symptomatic Wolf-Parkinson-White syndrome or other cardiac accessory conduction 
pathway disorders 
• History of stroke, transient ischemic attack, or hemiplegic or basilar migraine 
• Peripheral Vascular Disease 
• Ischemic bowel disease 
• Hypertension (greater than or equal to 140/90 mmHg at either the screening or 
admission/baseline visit 
• Any history of hepatic impairment defined as ALT > 150 U/L, AST > 130 U/L or 
bilirubin > 2 times the ULN 
4. History of contact dermatitis or known dermatological disorders that would interfere with the 
study procedures or assessments  
5. Planned participation in activities which cause inflammation, irritation, sunburn, lesions, or 
tattoos at the intended application sites from 2 weeks prior to dosing through their last day of 
study participation 
6. Use of any prescription anticoagulant within 1 month prior to the first dose  
7. Use of prescription and over the counter medications within one week of dosing other than 
the following: 
• Hormone Replacement Therapy (HRT) 


 
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• Birth control pills, patches, IUD, rings, injections, or implants (all hormonal 
contraceptives) are allowed provided the dose has been stable for at least three months 
prior to screening and may be continued throughout the study 
• Proton Pump Inhibitors (PPIs) 
• Antihistamines 
• Intermittently used NSAIDS 
• Acetaminophen if medically necessary (not more than 1000 mg/day) 
• Exceptions may be allowed on a case by case basis 
8. Subject has a known allergy or sensitivity to zolmitriptan or its derivatives or formulations 
9. Subject has a known allergy or sensitivity to tapes or adhesives 
10. Use of any other investigational compound within 30 days of planned study drug dosing  
11. Current use or history of drug and/or alcohol abuse within 6 months of screeningand deemed 
to be clinically significant by the investigator  
12. History of nasal pathology (e.g., polyps) or abnormal nasal exam deemed to be clinically 
significant by the investigator 
13. Body Mass Index (BMI) lower than 18 kg/m2 or greater than 35 kg/m2 
14. If, in the opinion of the investigator, the subject is not suitable for the study 
15. Any positive urine drug screen result or alcohol test 
16. Subject currently smokes or is a nicotine a user 
4.5 
Early Termination 
Participation in the study is completely voluntary and a subject can choose to withdraw from the 
study at any time.  In addition, a subject can be withdrawn for any of the following reasons: the 
Principal Investigator decides that continuing the drug may have an increased or unforeseen risk 
to the subject, a subject is non-compliant with the protocol, a subject has a serious reaction to the 
treatment, or the study is stopped by the Independent Ethics Committee, US Food and Drug 
Administration (FDA), or Zosano Pharma. 
In order to complete all treatments for each dose, additional subjects may be enrolled to account 
for subjects who withdraw or are discontinued from the study.  If a subject does not complete all 
planned treatments, the reason and date of withdrawal from the study must be recorded in the 
CRF.  Zosano Pharma should be notified immediately if a subject withdraws prematurely from 
the study. 


 
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5 
STUDY TREATMENTS 
5.1 
Study Drug Treatments 
The treatments are: 
• Treatment A: M207 3.8 mg administered as two 1.9 mg patches 30 min wear time (upper 
arm application) - made on a “Sled” coater and packaged in foil pouches 
• Treatment B: M207 3.8 mg administered as two 1.9 mg patches 30 min wear time (upper 
arm application) - made on a “MACAP” coater and packaged in foil cups 
• Treatment C: M207 3.8 mg administered as two 1.9 mg patches 30 min wear time (upper 
arm application) - made on a “MiniMac” coater and packaged in foil cups 
• Treatment D: zolmitriptan nasal 2.5 mg/0.1 ml (single dose) 
Depending on the treatment assignment, two M207 patches will be applied to the upper arm by 
means of a handheld reusable applicator with an application energy of 0.26 Joules.  Used patches 
will be removed 30 minutes after application of the second patch.  The patches will be collected 
and frozen in storage until shipped for analysis of remaining drug.  
The applicator systems and unused patches should be stored at room temperature, not to exceed 
15-30°C (59-86°F).  Unused patches should not be refrigerated or frozen. 
5.2 
Study Treatment Assignment and Schedule 
The 24 subjects are planned to receive each of the four treatments (A, B, C, D) 48 hours apart.  
Subjects will be randomly assigned to one of 4 treatment sequences. 
At the end of each dosing day, the safety data from the subjects will be evaluated.  If tolerability 
is deemed to be acceptable by the Principal Investigator, a decision will be made to proceed to 
the next dosing day. 
5.3 
Study Treatment Accountability Procedures 
All transdermal M207 Patch System components are to be used only in accordance with this 
protocol under the supervision of the Investigator.  The Investigator will maintain detailed and 
verifiable records that document the receipt, storage, dispensing, and return of all M207 Patch 
System components provided by Zosano Pharma.  These records will include a listing of which 
study drug supplies were dispensed for particular subjects treated in the study, by whom, when, 
and the specific quantities dispensed and remaining at the completion of the subject’s 
investigational treatment.  Reasons for departure from the expected dispensing and dosing 
regimen will also be documented.  All left over used and unused study patches should be 
retained for drug accountability auditing to be performed by Zosano Pharma or its 
representatives.  At the conclusion of the study, the study drug accountability records must 
accurately reflect the receipt and final disposition of all study drug shipped to the site.  
Destruction or return of remaining used and unused drug supplies by the study site will occur 
only upon receipt of written authorization by Zosano Pharma or its representatives. 


 
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5.4 
Prior and Concomitant Medications Allowed and Prohibited During the Study 
Subjects will be asked to refrain from taking either prescription or OTC (inclusive of herbal) 
medications within one week prior to dosing until the completion of the study, except for those 
discussed in this section.  All concomitant medications taken during the study will be recorded 
on the concomitant medications case report form (CRF) with indication for use, totally daily 
dosage, and dates of drug administration. 
Allowed prescription and over the counter medications: 
• Hormone Replacement Therapy (HRT) 
• Birth control pills, patches, IUD, rings, injections, or implants (all hormonal 
contraceptives) are allowed provided the dose has been stable for at least three months 
prior to screening and may be continued throughout the study 
• Proton Pump Inhibitors (PPIs) 
• Intermittently used NSAIDS 
• Acetaminophen may be administered if medically necessary (not more than 1000mg/day) 
• Antihistamines 
All other concomitant medications will be prohibited, except as specifically exempted by the 
Sponsor on a case-by-case basis. 


 
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6 
STUDY VISIT SCHEDULE AND GENERAL CONSIDERATIONS  
Following review of all Screening procedures, eligible subjects will be enrolled into the dosing 
phase of the study.  The interval between screening and first treatment may be up to 30 days.  
Eligible subjects will be admitted into the clinic on the day beforethe first dosing.   The washout 
period following each dose must be a minimum of 48 hours (from time 0 = application of 
patches) until the next dose.  Subjects will be required to stay in the clinic for the entire duration 
of the study (unless medically necessary to leave the clinic as instructed by the principal 
investigator and/or for non-medically related reasons considered on a case by case basis). 
The PK samples should be drawn as close as possible to the specified time. When multiple 
procedures are scheduled for the same time point, PK samples will be taken at the protocol 
assigned time point within plus or minus 1 minute of the specified time points for the first hour 
and within plus or minus 5 minutes of the specified time points after one hour.  The other 
measurements (i.e., vital signs, ECG, skin assessments) will be taken before or after the protocol-
specified time point within an interval of plus or minus 5 minutes. 
Subjects will refrain from smoking or using tobacco products during the clinic stay.  
Standardized meals and beverages will be served the evening prior to dosing and will be 
provided by the clinical site.   Water is allowed ad libitum, as well as tea and coffee in moderate 
amounts.  Breakfast can be served approximately two hours post-dosing, lunch approximately 4-
6 hours after dosing, the last evening meal of the day will be served approximately 8-10 hours 
post dosing, and an evening snack is permitted no later than 13 hours post dose.  The evening 
prior to dosing, subjects will fast overnight and receive only clear liquids. 
Alcohol is prohibited 24 hours before study drug administration until discharge from the clinic. 
Subject will not engage in any activity that may cause inflammation, irritation, sunburn, lesions 
or tattoos at the intended application sites from two weeks prior to screening through their last 
day of study participation.   
Subjects will not engage in strenuous activity at any time during their stay at the clinical unit.   
No lotions, ointments, or powders may be applied to the upper arm where M207 will be applied 
for 12 hours before or after applying M207.  
6.1 
Screening 
All Screening procedures will be performed after obtaining informed consent and should be 
completed within 30 days prior to admission for the first of four sequential treatments within the 
study.  The screening procedures include: 
6.1.1 Screening Visit (Up to 30 days prior to the Admission/Baseline Visit) 
Subjects who are considered to be good candidates for the study will be seen in the clinic and 
have the following procedures performed: 
• Obtain informed consent 


 
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• Obtain a medical history and demographics 
• Record concomitant medications 
• Perform a physical examination 
• Measure Vital signs (inclusive of temperature) 
• Measure height 
• Measure body weight and calculate BMI 
• Confirm eligibility 
• Collect blood and urine samples for clinical laboratory tests 
• Perform serum pregnancy test (for all females) 
• Collect blood for serology (HIV, Hepatitis B, Hepatitis C) 
• Perform urine drug and alcohol testing 
• Record a 12-lead ECG 
Medical history, physical examination, ECG and laboratory findings are to be reviewed, and 
eligibility determined.  The sponsor must approve any exception to the inclusion or exclusion 
criteria before planned admission for dosing. 
A subject number will be assigned when the subject signs the informed consent.  Only subject 
number, initials and date of birth will identify subjects to the Sponsor.  In the event that a subject 
who has signed the informed consent but did not receive a dose of study medication experiences 
an SAE, the following information will be captured: demographic data (initials, age, and race), 
all other Screening assessments that have been completed, AE(s), and concomitant 
medication(s). 
6.2 
Admission/Baseline Visit (Day Before the first Dose) 
If subjects continue to meet all entry criteria on the day prior to the first dosing, the subject will 
stay in the clinic overnight and through the final discharge.  The following procedures will be 
performed the day prior to  the first dosing only: 
• Record concomitant medications 
• Perform urine drug and alcohol testing 
• Serum pregnancy test (all women) 
• Collect vital signs (inclusive of temperature) 
• Confirm eligibility 


 
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6.3 
Study Dosing Days 
General Considerations 
Subjects will fast for at least 10 hours during the night preceding dosing and until at least 2 hours 
after dosing.  Water is allowed ad libitum, as well as tea and coffee in moderate amounts.  The 
following morning (between 0630 and 0930), subjects will receive that day’s scheduled 
treatment (A, B, C or D).  Breakfast should be withheld until at least two hours post patch 
application.   
No lotions, ointments, or powders may be applied to the upper arm where M207 will be applied 
for 12 hours before or after applying M207.  
All AEs, including any skin irritations and sensations as well as concomitant medication usage 
will be documented. 
When multiple assessments are required at the same time point, they will be conducted in the 
order as specified in the footnotes of the Schedule of Assessment.  All procedures should be 
performed relative to “Time 0” (M207 application) when a time is listed. 
6.3.1 Dosing Visit (all Periods) – All Treatments 
The following procedures will be performed on each of the four dosing days.  The actual 
procedures will be identical at each of the dosing days, only the study drug administered on each 
of the treatment days will vary. 
6.3.1.1 Pre-Dose - Before treatment Administration on the Day of Dosing 
• Record concomitant medications 
• Confirm eligibility 
• Measure vital signs 
• Record a 12-Lead ECG 
• Investigator visual skin assessment 
•  Nasal assessment (visual inspection) for treatment D assignment only 
• Determine that subject is stable and in good health and appropriate for dosing 
• Collect blood for a PK sample within 15 minutes prior to administering study drug 


 
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6.3.1.2 Treatment Administration (time 0 is application of second patch) 
• Apply patches or administer intranasal zolmitriptan (see Appendix 1 for instructions on 
patch administration) 
• Begin recording all AEs, whether observed by investigator, reported by the subject, 
observed in laboratory findings, or discovered by other means, on the AE CRF through 
the End of Study (or Early Termination) final visit.  All adverse events must be followed 
to resolution. 
6.3.1.3 2 Minutes after Treatment Administration 
• Collect blood for a PK sample 
• Record concomitant medications 
6.3.1.4 5 Minutes after Treatment Administration 
• Collect blood for a PK sample 
• Record concomitant medications  
6.3.1.5 10 Minutes after Treatment Administration 
• Collect blood for a PK sample 
• Measure vital signs 
• Record concomitant medications  
6.3.1.6 15 Minutes after Treatment Administration 
• Collect blood for a PK sample 
• Record a 12-Lead ECG 
• Record concomitant medications  
6.3.1.7 20 Minutes after Treatment Administration 
• Collect blood for a PK Sample 
• Record concomitant medications  
6.3.1.8 30 Minutes after Treatment Administration 
• Collect blood for a PK sample following removal of the second patch 
• Record concomitant medications and adverse events 
• Remove patches and perform the following procedures in the order listed below: 
• Investigator visual skin assessment of the patch application sites within one minute of 
removing both patches and prior to swabbing  
• Retain and package patches for freezing. Refer to full instructions in Appendix 3.  


 
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• Application site swabbing. Refer to full instructions in Appendix 3.  
6.3.1.9 45 Minutes after Treatment Administration 
• Collect blood for a PK sample 
• Record concomitant medications  
6.3.1.10 60 Minutes after Treatment Administration 
• Collect blood for a PK sample 
• Measure vital signs 
• Record concomitant medications and adverse events 
6.3.1.11 90 Minutes after Treatment Administration 
• Collect blood for a PK sample 
• Record concomitant medications  
6.3.1.12 Two Hours after Treatment Administration 
• Collect blood for a PK sample 
• Measure vital signs 
• Record concomitant medications  
6.3.1.13 Four Hours after Treatment Administration 
• Collect blood for a PK sample 
• Measure vital signs 
• Record concomitant medications  
6.3.1.14 Eight Hours after Treatment Administration 
• Collect blood for a PK Sample 
• Record concomitant medications  
• Investigator visual skin assessment of the application sites 
• Perform a physical examination 
6.3.1.15 Twelve Hours after Treatment Administration 
• Collect blood for a PK Sample 
• Measure vital signs 
• Record a 12-Lead ECG 
• Determine if subject is stable for the next dosing period  


 
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• Record concomitant medications and adverse events 
6.3.1.16 Twenty Four Hours after Treatment Administration 
• Collect blood for a PK Sample 
• Record concomitant medications and adverse events 
• Investigator visual skin assessment of the application sites 
6.3.1.17 Zolmitriptan PK Sample Handling 
Details related to zolmitriptan PK sample collection and shipment is provided in Appendix 2. 
6.4 
End of Study Visit/or Early Termination  
• Within 48 hours after completion of all protocol required procedures on the last dosing 
day, subjects will complete an End of Study Visit.  At that time, the following 
assessments will be performed: 
• Record all AEs, whether observed by investigator, reported by the subject, observed in 
laboratory findings, or discovered by other means, on the AE CRF through the end of 
study final visit. 
• Record a 12-Lead ECG 
• Record any new concomitant medications and adverse events 
• Measure vital signs (inclusive of temperature) 
• Perform a physical examination 
• Measure body weight 
• Investigator visual skin assessment of the application sites 
• Collect blood and urine for laboratory tests and serum pregnancy test (for all females) 
• Discharge subject from the study 
6.5 
Post Study Phone Call - Follow-up on Adverse Events 
Subjects must be called within 5-10 days following the day of discharge to follow-up on 
resolution of all ongoing AEs.  
6.6 
Early Termination 
Subjects who terminate early will complete the assessments normally scheduled for the End of 
Study Visit and a post study phone call is required if any adverse events are ongoing at the time 
of discharge. 


 
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7 
STUDY PROCEDURES 
7.1 
General Confinement Restrictions 
Subjects will be required to stay in the clinic for the entire duration of the study (unless 
medically necessary to leave the clinic as instructed by the principal investigator and/or for non-
medically related reasons considered on a case by case basis). 
7.2 
Collection, Processing and Assay of Samples 
Each of the plasma samples collected for pharmacokinetic analysis will be separated into two 
containers.  One of the samples will be sent to the analytical laboratory for analysis and one 
sample will be maintained at the investigative site until authorization is received form the 
sponsor to send the remaining samples to the bioanalytical lab.  The plasma sample retained at 
the site may be used for further analysis (additional metabolites, etc.) at some future timepoint. 
Subjects who complete all four treatments will have a blood draw volume of approximately 
279 mL for the entire duration of the study (See Table below). 
Blood Volume Requirements (mL) 
Purpose 
Expected Number 
Sample Amount 
(in mL) 
Total Amount 
(in mL) 
Clinical laboratory tests 
(Chemistry, Serology, 
and Serum Pregnancy) 
2 
12 
24.0 
Serum Pregnancy 
(Admission/baseline and 
end of study) 
2 
3.5 
7.0 
Hematology 
2 
4.0 
8.0 
PK 
60 (15 samples per period x 
4 periods) 
4.0 
240.0 
GRAND TOTAL  
279 ml 
 
7.3 
Assessment Details 
7.3.1 Clinical Laboratory Tests 
Standard clinical laboratory tests (serum pregnancy for all women, chemistry, hematology, and 
urinalysis) will be performed at Screening and End of Study (or Early Termination) visit.  A 
serum pregnancy test will also be completed for all women at the Admission/baseline visit. 
Screening serological tests for HIV, Hepatitis B and Hepatitis C will be performed. 


 
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Hematology will include the following: Hematocrit, hemoglobin, red blood cell count, white 
blood cell count with differential, platelets, mean corpuscular volume, mean corpuscular 
hemoglobin, and mean corpuscular hemoglobin concentration. 
Blood chemistry will include the following: Urea, glucose, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), alkaline phosphatase (AP), lactate dehydrogenase (LDH), 
sodium, phosphate, potassium, chloride, creatinine phosphokinase (CPK), globulin, cholesterol, 
creatinine, serum calcium, total bilirubin, triglyceride, cholesterol (HDL and LDL), gamma 
glutamyl transpeptidase (GGT) and uric acid. 
Urinalysis will include the following: bilirubin, blood, glucose, ketones, leuokocyte esterase, 
nitrite, pH, protein, specific gravity, and urobilinogen.  Microscopic examination will be 
conducted if protein, leukocyte esterase, nitrite and/or blood are detected.  
Urine drug screen and alcohol  testing will be performed at screening and the Admission/baseline 
visit.  Urine drug screen will test for amphetamine, barbituates, cocaine, cannabinoids, 
phencyclidine (PCP), opioids, and methamphetamines. 
Samples will be analyzed by a local laboratory.  After reviewing the laboratory reports and 
evaluating the results, the Investigator must review, sign/date the laboratory report.  
7.3.2 Vital Signs 
Vital signs include pulse, respiratory rate, as well as systolic and diastolic arterial pressure.  Vital 
signs will be recorded after subjects have been in the seated resting position for 2 minutes.  
Temperature will be taken at Screening, admission/baseline, and at end of study visit/or early 
termination only. 
7.3.3 Electrocardiograms 
A standard 12-lead ECG will be performed by a qualified individual at the site.  General 
morphology and intervals [Heart rate, QRS, PR interval, QRS, QTn, QTcf], of interest will be 
assessed with each tracing.  The principal or sub-investigator must review the tracing and assess 
it for any clinically significant abnormality.  Any clinically significant ECG abnormality noted at 
the time of screening and/or pre-dose will be recorded in the appropriate source document and 
may result in the exclusion of the subject from the study. 
7.3.4 Investigator Visual Skin Assessments of the Application Sites 
Each M207 patch site (where a patch has been removed) will be observed for the following skin 
assessments pre-dose and immediately after removal of the patches from the subject’s skin (and 
before swabbing) at 30 min, 60 min, 8 hr, 24 hr and at the End of Study/or Early Termination 
visit. 
7.3.4.1 Erythema 
The erythema evaluations will be performed using the following scale: 


 
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• 0 = None 
• 1 = Mild redness 
• 2 = Moderate colored redness 
• 3 = Beet colored redness 
7.3.4.2 Edema 
The edema evaluations will be performed using the following scale: 
• 0 = None 
• 1 = Slight edema 
• 2 = Moderate edema 
• 3 = Severe edema 
7.3.4.3 Bruising  
Bruising assessments (visual rating) will be performed using the following scale: 
• 0 = None 
• 1 = ≤ 25% application site has bruising spots 
• 2 = ≥ 26 to ≤ 50% application site has bruising spots 
• 3 = > 50% application site has bruising spots 
7.3.4.4 Bleeding  
Bleeding will be assessed using the following scale: 
• 0 = None 
• 1 = Pink color on skin 
• 2 = Visible blood drop 
• 3 = Active bleeding 
7.3.5 Residual Drug on Used M207 Patches 
The used patches should be placed in the proper cryovial tube provided by Zosano and 
immediately placed on dry ice or frozen at approximately -80°C (plus or minus 10°C) and kept 
frozen until shipment to the bioanalytical lab.  Used patches may be assayed for residual 
zolmitriptan if considered relevant after review of the pharmacokinetic results.  Instructions for 
removing and storing the patches are provided in Appendix 3. 


 
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7.3.6 Residual Drug on Skin after M207 Patch Removal 
At the time patches are removed and after the investigator skin assessment (for all patch 
treatment groups), the M207 patch skin sites will be swabbed to collect any residual drug that 
may be on the skin surface where a transdermal M207 patch has been applied.  The process 
consists of using 3 swabs to capture the drug residual for each patch site.  The procedure is 
described in Appendix 3.   
7.3.7 Recording Adverse Events 
Adverse events are collected from the time of of first patch application until the end of the study 
(discharge from the clinic).  A detailed discussion regarding the collection and reporting of 
adverse events is provided in Section 8.  


 
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8 
ADVERSE EVENTS 
All skin and systemic AEs, regardless of treatment group or suspected causal relationship to the 
investigational products, will be reported as described in the following sections. 
For all AEs, the Investigator must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
requiring immediate notification of the Sponsor.  For all skin and systemic AEs, sufficient 
information should be obtained by the Investigator to determine the causality of the AE.  The 
Investigator is required to assess causality.  For skin and systemic AEs with a causal relationship 
to the investigational product, follow-up by the Investigator is required until the event or its 
sequelae resolve or stabilize at a level acceptable to the Investigator, and Zosano Pharma concurs 
with that assessment. 
Reporting Period 
Collection of skin and systemic AEs will be initiated from the time of treatment application and 
will conclude when the end of study procedures for the fouth treatment are completed (or Early 
Termination).  The Investigator will also report to the Sponsor all SAEs that come to his/her 
attention after the study termination within 30 days of the last dose of study drug. 
Any SAE occurring any time after the reporting period must be promptly reported if a causal 
relationship to the investigational product is suspected. 
8.1 
Adverse Event Definitions 
An AE is any untoward medical event that occurs in a clinical investigation, where a subject is 
administered a product or medical device, without regard to causal relationship between the 
event and the treatment.  An AE can be any unfavorable and unintended sign or symptom, 
including clinically significant laboratory values and test results, concomitant illness, accident, or 
worsening of an existing medical condition. 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory or other means, 
will be collected and recorded on the Adverse Event CRF using the signs, symptoms or diagnosis 
associated with them and followed until resolution or, in the Investigator’s opinion, a stable 
condition is reached, or until the patient is lost to follow up. 
Medical conditions/diseases present before starting study treatment are only considered adverse 
events if they worsen after starting study treatment. 
In the event of a clinically important AE, a blood sample may be collected as soon as possible 
after the occurrence of the event for drug assay or for additional laboratory tests.  The 
Investigator will ensure that the serum sample is properly labeled and stored.  The Investigator 
and other study personnel responsible for the care of the patient will institute any supplementary 
investigations of significant AEs based on the clinical judgment of the likely causative factor(s).  
This may include seeking further opinion of a specialist in the field of the AE. 


 
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Any abnormal lab tests starting from the day of study patch application 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 a change in study dosing or 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 
Documentation and Reporting of Adverse Events By the Investigator 
All adverse events (AEs) occurring after the application of the first dose through the End of 
study visit/or early termination, will be reported on the AE CRF pages.  Based on the medical 
judgement of the investigator, all non-serious systemic and skin AEs will be followed until 
30 days after the final end of study visit.  All non-resolved, non-serious systemic and skin AEs 
beyond such date will be recorded as ‘ongoing’ without further follow up. 
However, an AE form will not be filled out for subjects who sign the ICF but fail the entry 
criteria (Screening failures) during the Screening process and experience a non-serious AE. 
Application site reactions will be reported on a dedicated assessment form for the visual skin 
assessment of the application sites.  The regular AE form does not have to be completed for such 
events unless the events are not covered by the questions on the visual skin assessment form or 
are reported outside their time window.  However, all such events will be included in the 
analyses of adverse event incidence. 
Each AE, including skin AEs, 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 (See Section 8.4).  It should be noted that the form for collection of SAE information 
is not the same as the AE CRF.  Where the same data are collected, the forms must be completed 
in a consistent manner.  For example, the same AE term should be used on both forms.  Systemic 
and skin AEs should be reported using concise medical terminology on the CRF pages as well as 
on the form for collection of SAE information. 
In addition to recording the signs, symptoms or diagnosis associated with them to describe the 
adverse event, the following will also be assessed and recorded: 
8.2.1 Duration 
Record the start date and time of the event, and, if applicable, the end date and time.  If the event 
is still ongoing at the final or early termination visit or after the end of follow-up, this should also 
be recorded. 


 
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8.2.2 Severity Ratings 
The Investigator will evaluate the severity of each AE using the following definitions: 
• Mild - event may be noticeable to patient; does not influence daily activities; usually does 
not require intervention. 
• Moderate - event may be of sufficient severity to make patient uncomfortable; 
performance of daily activities may be influenced; intervention may be needed. 
• Severe - event may cause severe discomfort; usually interferes with daily activities; 
patient may not be able to continue in the study; treatment or other intervention usually 
needed. 
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 
patient's usual function) but would not be classified as serious unless it met one of the criteria for 
SAEs, listed above. 
8.2.3 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 that the investigational product caused or 
contributed to an AE.  If the Investigator’s final determination of causality is unknown and the 
Investigator does not know whether or not the investigational product caused the event, then the 
event will be handled as “related to investigational product” for reporting purposes.  If the 
Investigator's causality assessment is "unknown but not related to investigational product", this 
should be clearly documented on study records. 
In addition, if the Investigator determines an SAE is associated with study procedures, the 
Investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting requirements, 
if applicable. 
After careful medical consideration, the Investigator will evaluate the relationship of each AE to 
study drug applying the following definitions: 
Probably Related: 
An AE that is likely due to the use of the study drug.  The relationship in 
time may be suggestive.  An alternative explanation is less likely, 
e.g., concomitant drug(s), concurrent disease(s). 
Possibly Related: 
An AE that may or may not be due to the use of the study drug.  The 
relationship in time is reasonable; therefore, a causal relationship cannot 
be excluded.  An alternative explanation is inconclusive, e.g., concomitant 
drug(s), concurrent disease(s). 


 
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Not Related: 
An AE that is judged to be clearly due only to extraneous causes (disease, 
environment, etc.).  The cause must be noted on the AE CRF page. 
8.3 
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; 
• Results in persistent or significant disability/incapacity; or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Definition of disability: A substantial disruption of a person’s ability to conduct normal life 
functions. 
Life-threatening SAE: Any AE that places the patient, 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 trials associated with hospitalization or prolongation 
of hospitalization is 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); 


 
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• Social admission (e.g., patient 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 patient. 
Pregnancies, though not expected in this subject population, are not reported as SAEs.  
Pregnancy follow-up should describe the outcome of the pregnancy, including any voluntary or 
spontaneous termination, details of the birth, the presence or absence of any congenital 
abnormalities, birth defects, maternal or newborn complications and their relation to the study 
treatment. 
Unexpected Adverse Events 
An unexpected AE is any AE, the specificity or severity of which is not consistent with the 
current Investigator brochure; or if an Investigator 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. “Unexpected,” 
as used in this definition, refers to an AE that has not been previously observed (i.e., is not 
included in the Investigator brochure) rather than an event that is not anticipated based on the 
pharmacological properties of the pharmaceutical product. 
8.4 
Reporting Requirements For Serious Adverse Events 
ALL SERIOUS ADVERSE EVENTS, REGARDLESS OF CAUSE(S) OR RELATIONSHIP 
TO STUDY DRUG MUST BE REPORTED IMMEDIATELY TO THE SPONSOR BY 
TELEPHONE AND FAX. 
8.4.1 Sponsor SAE Contact Information 
Pete Schmidt, MD, MSc 
Phone/fax: 510-745-1251 
If an SAE occurs, the Sponsor 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 Sponsor 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. 
The Investigator must complete the SAE Report Form and send it along with other relevant 
source documents to the medical monitor within 24 hours.  For all SAEs, the Investigator is 
obligated to pursue and provide information to the medical monitor in accordance with the 
timeframes for reporting specified above.  The Investigator (or a physician on the investigational 
staff) must provide relationship to study drug as soon as possible and sign the SAE forms.  The 
Investigator must also provide any relevant information regarding the SAE and respond to 
requests for follow-up in a timely manner.  All SAEs will also be reported on the AE CRF page 
and CM administered in association with the SAE will be documented on the CRF. 


 
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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. 
8.4.2 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 patient is lost to follow up.  Based on the medical judgment of 
the Investigator, all non-serious systemic and skin AEs will be followed until 30 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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9 
DATA MANAGEMENT 
9.1 
Data Collection 
Designated investigator staff must enter the information required by the protocol into the study 
CRF on an ongoing basis.  The completed CRF pages will be reviewed against source documents 
by the monitor at each monitoring visit.  If any data, signatures, or forms are missing or 
incorrect, the Investigator will be informed and corrections made.   Celerion standard CRFs will 
be supplied. CRFs are produced, stored electronically, and are available to the designated study 
team members. Each CRF is reviewed and signed by the PI. The final signed CRFs are provided 
to the Sponsor on CD.  
 
9.2 
Database Management and Quality Control 
Study auditing, data entry, verification and validation of the database, and subsequent analysis 
will be performed by any or all of the sponsor's Clinical Research and Development, Clinical 
Pharmacology, Statistics, and Regulatory Compliance Departments or the sponsor’s 
representatives for these functions according to current GCP requirements.  In addition, 
computerized data entries will be checked against paper CRF if used.  If electronic CRFs are 
used, the system will meet all GCP/ICH-R requirements for database integrity, including 
21 CFR, Part 11. 


 
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10 
STATISTICAL METHODS AND DATA ANALYSIS 
10.1 Sample Size Considerations 
No formal sample size calculation was performed.  In previous studies of Zosano Pharma 
transdermal products in healthy volunteers, a sample size of 24 was sufficient to provide 
directional information on tolerability, as well as adequate information on pharmacokinetics, and 
comparative pharmacokinetics for various regimens.  
10.2 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized descriptively. 
10.3 Analysis Population and Handling of Drop-Outs 
All subjects who receive any amount of study drug will be included in the safety analyses (Safety 
Population).  The PK population will include all subjects who receive any amount of study drug 
and for whom the PK profile can be adequately characterized.  Drop-outs within a 24-hour 
period are not anticipated; however should they occur prior to 2 hours after patch application 
then additional eligible subjects may be enrolled. 
10.4 Zolmitriptan Pharmacokinetics 
The following pharmacokinetic parameters will be calculated for each treatment and subject with 
samples analyzed using each assay. 
• Cmax - maximum observed plasma concentrations 
• Tmax - time to maximum concentration 
• AUC0-t - the area under the plasma concentration time profile from hour 0 to the last 
detectable concentration at time t determined by the linear trapezoidal method. 
• AUC0-30min - the area under the plasma concentration time profile from minute 0 to 
minute 30 determined by the linear trapezoidal method. 
• AUC0-60min - the area under the plasma concentration time profile from minute 0 to 
minute 60 determined by the linear trapezoidal method. 
• AUC0-120min - the area under the plasma concentration time profile from minute 0 to 
minute 120 determined by the linear trapezoidal method 
• k - apparent elimination rate constant will be estimated by linear regression of the 
log-transformed plasma concentrations during the terminal log-linear decline phase. 
• t1/2 - apparent half-life (t1/2) values will be calculated as 0.693/k. 
• AUC0-inf - the AUC value extrapolated to infinity will be calculated as the sum of AUCt, 
and the area extrapolated to infinity, calculated by the concentration at time t (Ct) divided 
by k. 
• Frel - bioavailability relative to each treatment group 


 
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PK parameters (Cmax, Tmax, and AUCs) and plasma and n-desmethyl zolmitriptan concentrations 
for M207 and intranasal zolmitriptan will be summarized using descriptive statistics (arithmetic 
and geometric mean, standard deviation, coefficient of variation, minimum, maximum, and 
median) as applicable.  Individual and mean plasma zolmitriptan and n-desmethyl zolmitriptan 
concentrations as a function of time following M207 patch administration and intranasal 
zolmitriptan administration will be plotted by treatment.   Calculation of Tmax will start from the 
time of study drug administration.  Further details on the analysis of PK parameters can be found 
in the statistical analsyis plan. 
10.5 Analyses of Safety Data 
AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion and summarized by treatment for the number of 
subjects reporting the treatment emergent adverse event (TEAE) and the number of TEAEs 
reported. A by-subject AE data listing including verbatim term, coded term, treatment, severity, 
and relationship to treatment will be provided.  
Concomitant medications will be listed by subject and coded using the most current version of 
the World Health Organization (WHO) drug dictionary available at Celerion. 
Scores from the investigator skin assessment of the application sites at 30 minutes, 60 minutes, 8 
hours and 24 hours post-dose will be summarized by treatment group using frequency tables. 
Descriptive summaries of actual values and changes from pre-dose to 10 minutes, 60 minutes, 2 
hours, 4 hours, and 12 hours post-dose will be calculated for vital signs including heart rate, 
respiratory rate, systolic blood pressure, and diastolic blood pressure and presented by treatment 
group.   
Descriptive summaries of actual values and changes from pre-dose to 15 minutes and 12 hours 
post-dose will also be provided by treatment group for the quantitative ECG parameters of 
rhythm, heart rate, PR interval, QRS interval, QT, and QTcF (Fridericia’s formula correction). 
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.  
10.6 Analyses of Residual Drug 
Analyses may be performed to quantify the amount of drug remaining on the M207 patch system 
and the amount of drug recovered from the skin of the subject following removal of each of the 
patches.  In that case, a description of the disposition of the remaining drug will be presented.  
The results from analysis of residual zolmitriptan on the skin and the residual zolmitriptan on the 
used patches will provide a basis for the calculation of the total amount of drug delivered from 
each treatment. 


 
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11 
ADMINISTRATIVE PROCEDURES 
11.1 Changes to the Protocol 
Any change or addition to the protocol requires a written protocol amendment initiated and 
approved by the sponsor, Zosano Pharma and the IRB/IEC and any applicable regulatory 
authority. 
Amendments of an administrative nature do not require formal protocol amendments or approval 
by the IRB/IEC, but the IRB/IEC must be informed in writing of such administrative changes.  
Examples include changes in the staff used to monitor the trial, editorial corrections and 
clarifications. 
11.2 Investigator Reporting Responsibilities to the Independent Ethics Committee and 
Other Agencies 
The Investigator must promptly report to the IRB all changes in the research activity and all 
unanticipated problems involving risk to human patients or others.  This includes all SAEs (as 
required by the IRB) that have occurred at the study site and all study-related SAEs that have 
resulted in an expedited safety report to regulatory authorities (serious, unexpected SAEs 
possibly or probably related to study drug).  Concurrently, the Investigator must send 
documentation to the Sponsor of such IRB notification.  The Investigator must not make any 
changes in the research without IRB approval, except where necessary to eliminate apparent 
immediate hazards to human patient. 
11.3 Withdrawal and Study Termination 
Subjects will be informed that they are free to withdraw from the study at any time.  The 
Investigator, the Investigator in consultation with the Medical Monitor, or the Medical Monitor 
may exercise his/her medical judgment to terminate a participant’s participation in the study due 
to clinically significant changes in any clinical or laboratory parameter (See Section 4.3). 
Zosano Pharma reserves the right to terminate the study at any time.  All data normally collected 
at completion of the study must be collected either at the time of the subject’s early termination, 
or on or before the scheduled study close out. Subjects with ongoing AEs at termination will be 
followed until all significant changes have resolved or become medically stable. 
11.4 Monitoring 
The clinical site will permit trial-related monitoring, audits, IRB review and regulatory 
inspections by providing direct access to source data/documentation. 
The sponsor's representatives will monitor the study at all stages of study conduct from inception 
to completion in accordance with current GCPs/ICH-R and a study monitoring plan.  This 
monitoring will be in the form of site visits and other communication and will include review of 
original source documents and CRF.  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, 


 
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and required certifications, IRB notifications and approvals, equipment, recruiting, record-
keeping, protocol adherence, data collection, adverse event reporting and other factors. 
11.5 Retention of Documents 
The Investigator will retain all study documents for at least two years after the approval date for 
marketing the product or until 2 years after the investigational use of the study drug is 
discontinued.  The Investigator must obtain written permission from Zosano Pharma before 
destroying any study documents. 
11.6 Publicaton 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 M207, 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.  
11.7 Auditing Procedures 
Zosano Pharma or their agents and contractors may conduct audits of clinical research activities 
in accordance with applicable Standard Operating Procedures.  A regulatory authority may also 
wish to conduct an inspection (during the study or even after its completion).  If an inspection is 
requested by a regulatory authority, the investigator must inform Zosano Pharma immediately 
that this request has been made. 


 
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12 
REFERENCES 
Dahlöf, C, Solomon G. The burden of migraine to the individual suffer: a review. Eur J Neurol. 
1998;5: 525–33. 
Guidance for Industry: Migraine: Developing Drugs for Acute Treatment. 2014 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75:800-2. 
Lipton R, Scher A, Kolodner K, et al. Migraine in the United States: epidemiology and patterns 
of health care use. Neurol. 2002;58(6):885-94. 
Rapoport A, Ramadan N, Adelman J, et al. Optimizing the dose of zolmitriptan (Zomig, 
311C90) for the acute treatment of migraine. A multicenter, double-blind, placebo-controlled, 
dose range-finding study. Neurology. 1997;49(5):1210-18. 
Schoenen J, Caekebeke P, Louis, G, et al. An open study to investigate the absorption and 
tolerability of oral 311C90 and to obtain a preliminary indication of efficacy in migraine 
patients. Proceedings of the 10th Migraine Trust Symposium. New advances in headache 
research. 1994;vol. 4:11-2. 
Seaber E, Peck R, Smith D, et al. The absolute bioavailability and effect of food on the 
pharmacokinetics of zolmitriptan in healthy volunteers. Br J Clin Pharmacol. 1998 
Nov;46(5): 433–9.  
Visser W, Klein K, Cox R, et al. 311C90, a new central and peripherally acting 5-HT1D receptor 
agonist in the acute oral treatment of migraine: a double-blind, placebo-controlled, dose-range 
finding study. Neurology. 1996 Feb;46(2):522-6. 


 
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13 
SCHEDULE OF ASSESSMENTS 
Assessment* 
Screening 
Visit** 
Admission/
baseline 
Dosing Visit*** 
End of 
Study/Early 
Termination 
 
Screening 
Day Prior 
to first 
Dose 
Pre-
dose 
0 
mn 
2 
mn 
5 
mn 
10 
mn 
15 
mn 
20 
mn 
30 
mn 
45 
mn 
60 
mn 
90 
mn 
2 
hr 
4 
hr 
8 
hr 
12 
hr 
24 
hr 
Approximately 
48 hours after 
completion of all 
procedures on 
final dosing day 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/ 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Serum pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Confirm eligibility 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
tests chemisty, 
hematology, UA) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug & Alcohol 
Testing 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect PK samples 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug 
administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (inclusive 
of temperature at 
screening, admission, 
and end of study/or 
ET only) 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
X 
ECG 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Remove and retain 
(freeze) patches  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 


 
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Assessment* 
Screening 
Visit** 
Admission/
baseline 
Dosing Visit*** 
End of 
Study/Early 
Termination 
 
Screening 
Day Prior 
to first 
Dose 
Pre-
dose 
0 
mn 
2 
mn 
5 
mn 
10 
mn 
15 
mn 
20 
mn 
30 
mn 
45 
mn 
60 
mn 
90 
mn 
2 
hr 
4 
hr 
8 
hr 
12 
hr 
24 
hr 
Approximately 
48 hours after 
completion of all 
procedures on 
final dosing day 
Nasal Assessment for 
Treatment D only 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator skin 
assessment of the 
application sites **** 
 
 
X 
 
 
 
 
 
 
 X 
 
X 
 
 
 
X 
 
X 
 
X 
Swabbing 
 
 
 
 
 
 
 
 
 
  X 
 
 
 
 
 
 
 
 
 
Record Adverse 
events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* When multiple procedures are scheduled for the same time point, PK samples will be taken at the protocol assigned time point within plus or minus 1 minute of the 
specified time points for the first hour and within plus or minus 5 minutes of the specified time points after one hour.  The other measurements (i.e., vital signs, ECG, 
skin assessments) will be taken before or after the protocol-specified time point within an interval of plus or minus 5 minutes. 
** Screening Visit – Up to 30 days prior to the Admission/Baseline visit. 
*** The washout period following each dose must be a minimum of 48 hours post removal of the second patch (in each treatment A, B, and C dosing period) until the 
next dose is administered. 
**** Investigator skin assessment at 30 minutes to be completed within one minute of M207 removal. 
 
 


 
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APPENDIX 1: 
M207 PATCH ADMINISTRATION 
 
TABLE OF CONTENTS 
I. 
INTRODUCTION 
II. 
GENERAL DESCRIPTION 
1. The Patch 
2. The Applicator 
3. Storage 
III. 
PRECAUTIONS AND OTHER NOTES  
IV. 
INSTRUCTIONS FOR USE 
1. Before You Apply the Patch 
2. Opening the Packaging 
3. Attaching the Patch Ring to the Applicator and Applying the Patch 
4. After Applying the Patch 
5. Removing the Patch 
 
 


 
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I. 
INTRODUCTION 
The M07 patches and a specially designed applicator are made by Zosano Pharma.  This User’s 
Guide provides instructions for the clinical staff on how to apply patches to subjects.  The 
patches look like round adhesive Band-Aids and have study drug on tiny metal points on one 
side.  Patches are applied to the subject’s skin using a spring-loaded applicator specially designed 
for these patches.  Each patch is used only once.  The applicator can be reused. 
II. 
GENERAL DESCRIPTION 
The M207 (Zolmitriptan Microneedle System) has two parts: a patch attached to a plastic 
supporting ring, and an applicator. 
1. The Patch: The patch comes attached to a plastic supporting ring that allows you to attach it 
to the applicator.  When you apply the patch to the skin, the patch stays on the skin and the 
plastic ring stays on the applicator and is later thrown away. 
 
Top 
Bottom 
 
There is study drug on the shiny metal on the sticky side of the patch.  You can touch the 
supporting plastic ring, but do not touch the sticky side of the adhesive patch or the shiny metal 
piece with your fingers.  Touching this may damage the patch. 
Patch 
backing 
Plastic support ring 
Shiny metal 
surface 
Plastic 
support ring 
Adhesive 
Patch with 
drug 


 
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2. The Applicators 
Applicator 0.26J 
 
 
Use the applicator to apply the patch for treatments A-C to the skin.  Hold the applicator in 
your hand to apply the patch.  The patch cannot be applied without the applicator.  The ring and 
patch attach to the bottom of the applicator.  The applicator cap is twisted to unlock the 
applicator.  When the applicator is pressed against the skin, a plunger pushes the patch out of the 
support ring and applies it to the skin. 
3. Storage of Supplies (patches and applicators): 
Room temperature storage: Store the patches in their pouches and cups at room temperature.  
Store the applicator at room temperature in its box between uses. 
III. 
PRECAUTIONS AND OTHER NOTES 
Lotions, Ointments, or Powders: Ensure no lotions, ointments, or powders have been 
applied to the patch application sites 12 hours before or after applying the patches. 
Wash Hands: Always wash your hands before applying a patch. 
 


 
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IV. INSTRUCTIONS FOR USE 
1. Before You Apply the Patch 
• Check the skin at the upper arm to be sure that it is not irritated from rash, inflammation, 
redness, or other skin problems such as cuts or open wounds.  In addition, the application 
area must be free of tatoos, scars, birthmarks, and/or any skin abnormalities. 
• Clean the the skin area upper arm where the patches will be applied with an alcohol wipe.  
Only wipe with alcohol prior to the first patch application for each dose. 
2. Opening the Foil Pouch (Treatment A) or Cup (Treatment B and C) Containing the 
Patch and Plastic Ring 
Patch and Ring in Package 
Pouch: 
 
 
 
 
 
Cup: 
 
 
 
 
• Each patch is individually sealed in its own protective outer foil pouch or cup.  
• DO NOT USE the patch if its cup has a hole in it, has already been torn open, or is 
otherwise damaged. 
• With the tab pointing towards you, to open the foil pouch or cup, lay the pouch or cup flat 
with printed side up.  Using the notches provided, slowly peel back the top layer of the 
cup to open with “This side up” facing up.  If the cup is difficult to open, you can use 
scissors to cut along the dotted line. 
 


 
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Pouch: 
 
 
 
 
 
 
Cup: 
       
                
                
 
• Leave the patch on the bottom side of the cup.  You can touch the white plastic patch ring 
with your fingers.  However, do not touch the patch or shiny metal surface of the patch 
with your fingers.  This may damage or contaminate the patch. If you accidentally touch 
the shiny metal surface with your finger, return the patch to the original pouch or cup, 
write the date on the pouch or cup, and start over with a new patch. 
Pouch: 
 
 
 
 
 
 
Cup: 
 
                                  
 
 


 
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3. Attaching the Patch Ring to the Applicator, and Applying the Patch to the Skin 
(see Figure 1) 
 
1. 
Prepare the patch and applicator 
o 
Open the applicator box and remove the applicator from its box 
o 
Ensure the applicator is set to ‘1’.  The applicator is ready to attach a patch 
when in the number ‘1’ position.  If the number ‘2’ is showing in the window, 
change it to ‘1’ by depressing the applicator onto your palm or other soft 
surface until it activates. 
o 
Ensure the patch is sitting shiny metal side down.  If not, gently pick up the 
patch ring assembly by touching only the plastic support ring and flip it over.  
The shiny metal side should now be face down. 
2. Attach the patch and ring to the applicator by placing the applicator directly on top of 
the patch ring and push down gently until the patch clicks into place.  You will likely 
hear or feel a “click.” The patch is now attached to the applicator. 
3. Holding the bottom half of the applicator with one hand, unlock the applicator by 
twisting the top half of the applicator clockwise until it clicks into the “2” position. 
The patch and applicator are now ready for application. 
4. Ensure the number shows ‘2’ in the window, indicating the applicator is unlocked.  If 
not, go back to step 4 to change it from ‘1’ to ‘2’. 
5. Place the applicator on the skin and push the applicator against the skin. 
6. When you have pushed against the skin hard enough, you will hear the plunger push the 
patch from the ring onto the skin.  Continue to hold the applicator down against the skin 
for 3 seconds.  The patch is now applied and the medicine is now being delivered through 
the patch.  You may now remove the applicator.  You will see the patch sticking to the 
skin.  The empty plastic ring will still be attached to the applicator. 
7. If edges of the patch are lifted or curled, lightly press down WITH THE FLAT OF 
YOUR PALM to make the patch stick to the skin better. 
8. DO NOT USE YOUR FINGERTIPS to press the edges of the patch because your 
fingertips may push one side down but pull the other side loose. 
9. With your forefinger and thumb, remove the ring from the bottom of the applicator by 
pulling it out.  You may discard the ring in the rubbish bin. 
10. Leave the patches on the subject’s skin for the duration assigned in accordance with the 
protocol treatment assignment (30 minutes). 


 
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Figure 1: 
M207 Patch Application 
 
 
 
 
 
1. Snap patch-ring assembly onto 
applicator 
 
 
 
2. Twist applicator cap clockwise from  
Position 1 to Position 2 to unlock for 
patch application 


 
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3. Place applicator against cleaned area 
and press applicator downward to apply 
patch to skin until you hear a click then 
HOLD for 3 seconds.  Patch is applied. 
Ring assembly remains attached to the 
applicator 
 
 
 
4. Remove the outer ring in order to load 
and apply the second patch. 
 
 
 
5. Repeat all of the above steps to apply 
second patch next to the first patch 
 


 
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4. After Applying the Patch 
Leave the patches on the subject’s skin for the duration assigned in accordance with the protocol. 
Before applying the second patch, remove the used plastic support ring from the applicator and 
discard it.  Use your finger to pull the used patch ring off the applicator.  Throw away the patch 
ring. 
 
 
5. Removing the Patch 
After the appropriate assigned time of patch application, peel the edge of the patch back and 
remove the patches from the subject’s skin as you would remove a Band-Aid.  Refer to 
Appendix 3 for handling and processing of used patches, storage, and return instructions. 


 
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APPENDIX 2: 
ZOLMITRIPTAN PK SAMPLE HANDLING 
1. 
Plasma Zolmitriptan Sample Collection 
Approximately 4 ml of blood will be collected into a labeled K2 EDTA blood collection tubes at 
each pharmacokinetic time point as specified in the the schedule of events.  The actual date and 
time of blood collection will be recorded for each subject.    
The blood samples will be maintained in a chilled ice bath prior to centrifuging.  The samples 
will be centrifuged for 10 minutes at 4○C at 2000 x g and the aliquots will be placed in the 
freezer within 60 minutes of sample collection.  The plasma supernatant will be transferred to 
polypropylene tubes and labeled identically to the original sample container.  Two aliquots will 
be prepared.  Plasma will be aliquoted into a separate LDPE containers labeled (at minimum) 
with the study number, subject’s identification number, date and time of collection, and analyte 
(zolmitriptan).  Aliquot 1 will contain 1 mL of plasma, and Aliquot 2 will contain the rest of the 
plasma (approximately 1 mL). After processing, the tubes will be sealed and the plasma will be 
frozen in an upright position (to avoid frozen plasma in the caps) and stored in a -80 °C 
(+/- 10 °C) freezer in an upright position until shipped for analysis.   
Each sample will be labeled or barcoded (at minimum) with the study number, subject 
identification number, actual date and time of collection, analyte (zolmitripan). 
2. 
Plasma Zolmitriptan Sample Shipment 
Securely pack the frozen samples in Styrofoam freezer boxes with sufficient dry ice to ensure the 
samples remain frozen for at least 72 hours.  Samples will be transported to the bioanalytical 
facility in at least two separate shipments, with each set of aliquots in separate shipments.  Once 
the bioanalytical laboratory confirms receipt of the first shipment, the second set of aliquots 
may be sent upon approval by Zosano.  The shipping container will include TempTale 
temperature monitoring device provided by World Courier.  


 
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APPENDIX 3: 
HANDLING AND PROCESSING OF USED PATCHES AND SKIN 
SWABS  
Delivery performance of M207 patches is determined by drug residual analysis.  The amounts of 
zolmitriptan left on the microneedle array and skin surface after each application are compared 
against the original coated amount on the array, allowing total amount delivered or delivery 
efficiency to be determined by mass balance.  This Appendix 3 provides detailed procedures for 
used patch removal and subsequent swabbing of the treated skin surface.  The collected used 
patches and skin swabs (in swab buffer) will be shipped to the site where plasma samples are 
analyzed.  
MATERIALS:  
A. Content of Used Patches and Skin Swabbing Kits 
Figure 1 outlines the materials provided by Zosano to perform the used patch collection and skin 
swabbing procedures.  The materials for both procedures will be combined into one kit (for each 
dosing period) and designated as the Used Patch/Skin Swab Kit.  Note that materials similar to 
what are shown in Figure 1 may be used as substitutes. Each kit contains materials (Table 1) to 
collect from one dosed patient: 2 used patches and two skin swabbing for each dosing period.   
 
 


 
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PROCEDURE: 
USED PATCH REMOVAL PROCEDURE FROM SKIN AND PROCESSING 
Refer to Figure 1 (above) for material identification and Figure 2 (below) for used patch removal 
procedure.  Note the following procedural highlights:  
1. Do not touch or contaminate the patch-treated skin sites after patch removal.   
2. Since each patient has two patches applied, remove one patch at a time and note the skin 
area where the patch was removed for subsequent skin swabbing in Section B.  
3. Try to perform used patch removal and skin swabbing, for the first and second patches, 
within 5 minutes of the removal of the first used patch. 
 
A minimum of 80 kits will be provided by Zosano and of the 80, 8 (10%) kits are allotted for 
backups and 72 are allotted for 24 subjects with 3 treatments.  Once the used patch collection and 
skin swabbing are completed for all subjects, there should be in total 144 used patch vials and 
144 swab buffer vials to be processed and shipped to Syneos Health.  


 
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Table 1. 
Tally/Labeling of Materials Included in each Used Patch/Skin Swab Kit 
Item # 
Description 
Quantity 
Labeling 
1* 
Orange-cap cryovial with 1-mL swab buffer 
2 
#1 to 144 (sequentially) with 
“1-mL Swab Buffer” 
2** 
Swab buffer vial with 1 dry swab 
2 
**For Items # 2 and 4 include 
at least the following: 
- Subject ID 
- Patch location, ie, upper arm 
and number or side (e.g., 1 
and 2, or left and right)  
- Sample collection date and 
time 
- Protocol number  
3 
Sterile forceps, individually packaged 
2 
4** 
Used patch collection vial 
2 
5 
Ziploc bag for Item 4 
2 
6 
Vial with 4 dry swabs 
1 
7 
Purple-top 50-mL tube 
2 
8** 
White tub with yellow lid to contain Items 1-7 
1 
*This orange-cap cryovial containing buffer will be stored in refrigeration at approximately 0-4°C and 
removed several hours before swabbing. 
 
Labeling: *Item #1 will be numbered from 1 to 144 by Zosano.  **Items # 2, 4 and 8 will need 
to be labeled prior to use with a minimum of the following: Subject ID, patches location (upper 
arm), and numbering or position (e.g., site 1 or 2 or left/right), sample collection date and time, 
and protocol number. 
B. Skin Swabbing After Each Used Patch Removal 
Refer to Figure 1 for material identification and Figure 3 for skin swabbing procedure. 
For each separate patch, the patch-treated skin surface is swabbed using three polyurethane 
swabs: 1 wetted and 2 dry.  The first swab is soaked in 1.0-mL of  0.05% Tween 20 (in phosphate 
buffer saline).  The 0.05% Tween 20 in phosphate buffer saline is also referred to as “swab 
buffer” and shown in Figure 1, Item 1.  The wetted swab is applied over the skin site by rolling 
the swab with slight pressure in several directions (e.g., left to right and up and down) and around 
the periphery of the treatment site.  Two additional swabs, dry, are applied sequentially over the 
wetted skin site using the same rolling motions to absorb all residual buffer.  Make sure to absorb 
all residual buffer on the skin since this is the medium used to capture the residual zolmitriptan 
from the skin.  Once used, all three swabs are placed in the swab buffer vial and sent Syneos 
Health for zolmitriptan analysis. 
Note the following procedural highlights: 
1) Cryovials with swab buffer: 1-mL of the swab buffer aliquot is contained in each orange-cap 
cryovial (Item #1) and 144 will be sent from Zosano and should be stored at 0-4°C prior to use.  
Two cryovials (containing buffer) are allotted for each of the two used patches and should be 
removed from refrigeration and placed with Kit several hours before swabbing.  At least 1 hour 
before swabbing, pour the content of one cryovial into one swab buffer vial with dry swab 
(Item # 2) and repeat for the other set.  Place both swab buffer vials into the Kit tub to keep them 
slightly upright as shown in figure 3B. 


 
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2) Start skin swabbing procedure immediately after patch removal. 
3) Try to complete used patch removal and skin swabbing, for first and second patch, within 
5 minutes of the removal of the first used patch. 
4) Wetted swab should not be dripping with excess buffer when pulled out for swabbing. Keep 
all swabs clean until used. 
5) Apply the wetted swab over the treated skin site by rolling (back-and-forth) the swab with 
slight pressure in several directions (e.g., left to right and up and down) and around the periphery 
of the treatment site.  Once swabbing is done, place the wetted swab back into the swab buffer 
vial. 
6) Apply two additional swabs (dry), one at a time, over the wetted skin site using the same 
rolling motions to absorb all residual buffer on the skin. Once swabbing is done, place both 
swabs into the same swab buffer vial. 
 


 
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C. Packing of Used Patches and Skin Swabs  
Refer to Figure 4 for packing illustration.  Use the Kit tub to pack the used patch vials (2) and 
swab buffer vials (2) collected from each dosed patient.  Pack all tubs in dry ice for shipping and 
ship upon authorization from Zosano Pharma. 
 
 


 
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APPENDIX 4: 
SHIPPING PROCEDURES FOR UNUSED PATCHES 
AND NEW APPLICATORS 
1. Unused Patch Collection and Shipment 
Collection: All unused systems should be stored in their original pouches or cups and shipping 
box, at room temperature until shipment to Zosano Pharma. 
Shipment: All unused systems should be combined into one shipment and shipped at room 
temperature - upon authorization from Zosano Pharma. 
Shipments should be made via World Courier using the Zosano Pharma World Courier 
Account number 13334. 
All returned packages should contain the statement: “For research purposes only.  Not for human 
use.” 
Complete the Product Return Form (provided by Sponsor) and include with each return 
shipment: 
• Insert 1 copy in a separate plastic bag in the sample container box which will act as a 
packing slip. 
• Keep 1 copy in the Regulatory binder  
• Fax or email one copy to Zosano Pharma, Lu Liu (LuLiu@zosanopharma.com) and 
Whitney Halladay (whalladay@zosanopharma.com), Fax: +1-510-952-4632, 
Phone: +1-510-745-1289 
 
Unused Patch shipments to Zosano Pharma should be addressed to: 
Zosano Pharma 
ATTN: Lu Liu 
Senior Director, Manufacturing and Supply Chain 
34790 Ardentech Court 
Fremont, CA 94555 USA 
Phone: + 1 510-745-1289 
Fax: +1-510-952-4632 
 


 
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2. New Applicator Collection and Shipment 
Collection: At the completion of the study, place the used applicators back into the original 
applicator box or equivalent.  Place the applicator boxes into a Ziploc bag and label bag with 
“Used Applicators.”  Place all unused applicators into another Ziploc bag and label bag with 
“Unused Applicators.”  Store used and unused applicators at room temperature until shipment to 
Zosano Pharma.  All samples should be shipped in one shipment. 
Shipment: Securely pack the bags of used and/or unused applicators into suitable boxes 
containing shipping materials (e.g., Styrofoam “popcorn” or bubble-wrap).  Both used and 
unused applicators may be shipped back to Zosano Pharma at ambient temperature. 
Shipments should be made via World Courier using the Zosano Pharma World Courier 
Account 13334.  
All returned packages should contain the statement: “For research purposes only.  Not for human 
use.” 
Complete the Product Return Form (provided by Sponsor) and include with each return 
shipment: 
• Keep 1 copy in the Regulatory binder 
• Place another copy of the Form in a Ziploc back and place the Ziploc bag inside the 
shipping container; this copy will be used as the packing slip for the shipment.   
• Fax or email one copy to Zosano Pharma, Lu Liu (LuLiu@zosanopharma.com) and 
Whitney Halladay (whalladay@zosonopharma.com), Fax: +1-510-952-4632, 
Phone +1-510-745-1289 
 
Applicator shipments to Zosano Pharma Corporation: 
Zosano Pharma Corporation 
ATTN: Lu Liu 
Senior Director, Manufacturing and Supply Chain 
34790 Ardentech Court 
Fremont, CA 94555 USA 
Phone: +1510-745-1289 
Fax: +1-510-952-4632 
 


 
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APPENDIX 5: 
DECLARATION OF HELSINKI 
 
WORLD MEDICAL ASSOCIATION DECLARATION 
OF HELSINKI Ethical Principles for Medical Research 
Involving Human Subjects 
 
Adopted by the 18th WMA General 
Assembly 
Helsinki, Finland, June 1964 and 
amended by the 
29th WMA General Assembly, Tokyo, Japan, 
October 1975 
35th WMA General Assembly, Venice, Italy, 
October 1983 
41st WMA General Assembly, Hong Kong, 
September 1989 
48th WMA General Assembly, Somerset West, Republic of South 
Africa, October 
1996and the52nd WMA General Assembly, Edinburgh, Scotland, 
October 2000 
 
INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other subjects in medical research 
involving human subjects.  Medical research involving human subjects include research on 
identifiable human material or identifiable data. 
It is the duty of the physician to promote and safeguard the health of the people.  The physician’s 
knowledge and conscience are dedicated to the fulfillment of this duty. 
The Declaration of Geneva of the World Medical Association binds the physician with the words, 
“The health of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, “A physician shall act only in the patient’s interest when providing medical 
care which might have the effect of weakening the physical and mental condition of the patient.” 
Medical progress is based on research that ultimately must rest in part on experimentation 
involving human subjects. 
In medical research on human subjects, considerations related to the well being of the human 
subjects should take precedence over the interests of science and society. 


 
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The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic and therapeutic procedures and the understanding of the etiology and pathogenesis of 
disease.  Even the best-proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, efficiency, accessibility and 
quality. 
In current medical practice and medical research, most prophylactic, diagnostic and therapeutic 
procedures involve risks and burdens. 
Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights.  Some research populations are vulnerable and need special 
protection.  The particular needs of the economically and medically disadvantaged must be 
recognized.  Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care. 
Research Investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal or regulatory requirement should be allowed to reduce or 
eliminate any of the protections for human subjects set forth in this Declaration. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity 
of the human subjects. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and on adequate laboratory and, where appropriate, animal experimentation. 
Appropriate caution must be exercised in the conduct of research that may affect the 
environment, and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human subjects should be 
dearly formulated in an experimental protocol.  This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed 
ethical review committee, which must be independent of the Investigator, the sponsor or any 
other kind of undue influence.  This independent committee should be in conformity with the 
laws and regulations of the county in which the research experiment is performed.  The 
committee has the right to monitor ongoing trials.  The researcher has the obligation to provide 
monitoring information to the committee, especially any serious adverse events.  The researcher 
should also submit to the committee, for review, information regarding funding, sponsors, 
institutional affiliations, other potential conflicts of interest and incentives for subjects. 
The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that there is compliance with the principles enunciated in this Declaration. 


 
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Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person.  The responsibility 
for the human subject must always rest with a medically qualified person and never rest on the 
subject of the research, even thought the subject has given consent. 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 
subject or to others.  This does not preclude the participation of healthy volunteers in medical 
research.  The design of all studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed.  Physicians should cease any investigation if the risks are found to outweigh the 
potential benefit or if there is conclusive proof of positive and beneficial results. 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject.  This is especially important 
when the human subjects are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations in which 
the research is carried out stand to benefit from the results of the research. 
The subjects must be volunteers and informed subjects in the research project. 
The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
patient’s information and to minimize the impact of the study on the subject’s physical and 
mental integrity and on the personality of the subject. 
In any research on human beings, each potential subject must be adequately informed to the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of 
the researcher, the anticipated benefits and potential risks of the study and the discomfort it may 
entail.  The subject should be informed of the right to abstain from participation in the study or to 
withdraw consent to participate at any time without reprisal.  After ensuring that the subject has 
understood the information, the physician should then obtain the subject’s freely given informed 
consent, preferably in writing.  If consent cannot be obtained in writing, non-written consent 
must be formally documented and witnessed. 
When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress.  In that case the informed consent should be obtained by a well-informed physician who 
is not engaged in the investigation and who is completely independent of this relationship. 


 
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For research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the Investigator must obtain informed consent from 
the legally authorized representative in accordance with applicable law.  These groups should not 
be included in research unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent persons. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the Investigator must obtain that assent in addition to 
the consent of the legally authorized representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 
informed consent is a necessary characteristic of the research population.  The specific reasons 
for involving research subjects with a condition that renders them unable to give informed 
consent should be stated in the experimental protocol for consideration and approval of the 
review committee.  The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate. 
Both authors and publishers have ethical obligations. In publication of the results of research, the 
Investigators are obliged to preserve the accuracy of the results.  Negative as well as positive 
results should be published or otherwise publicly available.  Sources of funding, institutional 
affiliations and any possible conflicts of interest should be declared in the publication.  Reports 
of experimentation not in accordance with the principles laid down in this Declaration should not 
be accepted for publication. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE. 
The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic or therapeutic value.  When medical 
research is combined with medical care, additional standards apply to protect the patients who 
are research subjects. 
The benefits, risks, burdens and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic and therapeutic methods.  This does not exclude the use 
of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic 
method exists. 
At the conclusion of the study, every patient entered into the study should be assured of access to 
the best-proven prophylactic, diagnostic and therapeutic methods identified by the study. 
The physician should fully inform the patient which aspects of the care are related to the 
research.  The refusal of a patient to participate in a study must never interfere with the patient-
physician relationship.  In the treatment of a patient, where proven prophylactic, diagnostic and 
therapeutic methods do not exist or have been ineffective, the physician, with informed consent 
from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic 
measures, if in the physician’s judgment it offers hope of saving life, re-establishing health or 


 
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alleviating suffering.  Where possible, these measures should be made the object of research, 
designed to evaluate their safety and efficacy. In all cases, new information should be recorded 
and, where appropriate, published.  The other relevant guidelines of this Declaration should be 
followed. 

SAP_001.pdf: