A Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Safety and Efficacy of Staccato Granisetron (AZ-010) for the Acute Treatment of Moderate to Severe Cyclic Vomiting Syndrome
Phase: PHASE2
Conditions: Cyclic Vomiting Syndrome
Sponsor: Alexza Pharmaceuticals, Inc.

NCT04645953 
STATISTICAL ANALYSIS PLAN 
Protocol ID: AMDC-010-201 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY TO EVALUATE THE SAFETY AND EFFICACY OF 
STACCATO® GRANISETRON (AZ-010) FOR THE ACUTE 
TREATMENT OF MODERATE TO SEVERE CYCLIC 
VOMITING SYNDROME 
ALEXZA PHARMACEUTICALS, INC. 
March 3, 2022

CONFIDENTIAL 
  Alexza Pharmaceuticals, Inc. 
    Protocol AMDC 010-201 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
Page | 1 
STATISTICAL ANALYSIS PLAN 
PROTOCOL: AMDC 010-201 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF STACCATO® GRANISETRON (AZ- 010) FOR 
THE ACUTE TREATMENT OF MODERATE TO SEVERE 
CYCLIC VOMITING SYNDROME
SPONSOR: 
Alexza Pharmaceuticals, Inc. 
2091 Stierlin Court 
Mountain View, CA 94043 
PRODUCT : 
AMDC 010 
AUTHORS: 
Brenda Krogen. M.S. 
Manager, Biometrics 
Cognitive Research Corporation 
200 Central Ave. Suite 1230 
Saint Petersburg, FL 33701 
Jeffrey S. Finman, Ph.D. 
Chief of Biostatistics 
Cognitive Research Corporation 
200 Central Ave. Suite 1230 
Saint Petersburg, FL 33701 
DATE: 
03 March 2022 
STATUS: 
Final Version 1.0 

CONFIDENTIAL 
Alexza Pharmaceuticals, lnc.
ProtocolAMDC 010-201
Statistical Analysis Plan
Protocol: AMDC 010-201
FinalVersion: 1.0 
Date: 03 March 2022
CRC REPRESENTATIVE
DOCUMENT REVIEWED AND APPROVED BY:
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NAME: Jeffrey Finman, Ph.6.
DEPARTMENT/TITLE: Chief of Biostatistics
SPONSOR COMPANY REPRESENTATIVE
DOCUMENT REVIEWED AND APPROVED BY:
SIGNATURE:
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| oare: /fuaarz2ozz
NAME: Mike Nel6on
DEPARTM ENT/TITLE: Senior Director, Clinical Operations
STATISTICAL CRC REPRESENTATIVE
DOCUMENT REVIEWED AND APPROVED BY:
srGNAruRE: W 
Wu?Z
NAME: Brenda Krogen
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DEPARTMENTITITLE: Manager, Biometrics
Statistical Analysis Plan: Final Version 1.0, 03 March 2O2Z
Page | 2

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  Alexza Pharmaceuticals, Inc. 
    Protocol AMDC 010-201 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
Page | 3 
TABLE OF CONTENTS 
1 AMENDMENT HISTORY ..................................................................................... 5 
2 LIST OF ABBREVIATIONS ................................................................................. 6 
3 INTRODUCTION .................................................................................................. 8 
4 STUDY OBJECTIVES .......................................................................................... 8 
5 STUDY DESIGN ................................................................................................... 8 
5.1 
DURATION OF STUDY ............................................................................................. 8 
5.2 
NUMBER OF PARTICIPANTS .................................................................................. 8 
5.3 
DESIGN..................................................................................................................... 8 
5.4 
STUDY SCHEMA .................................................................................................... 11 
5.5 
SCHEDULE OF EVENTS ........................................................................................ 11 
5.6 
TREATMENT .......................................................................................................... 14 
5.7 
RANDOMIZATION .................................................................................................. 14 
5.8 
EFFICACY ............................................................................................................... 14 
5.8.1 
EFFICACY ASSESSMENTS .................................................................................................... 14 
5.8.2 
PRIMARY ENDPOINT .............................................................................................................. 15 
5.8.3 
SECONDARY ENDPOINTS ..................................................................................................... 15 
5.9 
SAFETY .................................................................................................................. 16 
5.9.1 
ADVERSE EVENTS ................................................................................................................. 16 
5.9.2 
LABORATORY ASSESSMENTS ............................................................................................. 16 
5.9.3 
VITAL SIGNS............................................................................................................................ 18 
5.9.4 
ELECTROCARDIOGRAM ........................................................................................................ 18 
5.9.5 
PHYSICAL EXAMINATION ...................................................................................................... 18 
5.10 COVID TESTING AND IMPACT .............................................................................. 18 
6 STATISTICAL ANALYSES ................................................................................ 18 
6.1 
GENERAL CONSIDERATIONS .............................................................................. 18 
6.2 
SAMPLE SIZE DETERMINATION ........................................................................... 19 
6.3 
STUDY DATA .......................................................................................................... 19 
6.4 
ANALYSIS SETS ..................................................................................................... 19 
6.5 
TREATMENT GROUPS .......................................................................................... 19 
6.6 
STATISTICAL HYPOTHESIS TESTS ...................................................................... 19 
6.7 
MULTIPLICITY ADJUSTMENT ............................................................................... 20 
6.8 
DEFINITION OF SUBGROUPS ............................................................................... 20 
6.9 
ENDPOINTS AND ESTIMANDS ............................................................................. 20 
6.9.1 
PRIMARY ENDPOINT AND ESTIMAND ................................................................................. 20 
6.9.2 
SECONDARY ENDPOINTS AND ESTIMANDS ...................................................................... 21 
6.10 MAIN ANALYTICAL APPROACH ............................................................................ 22 
7 PLANNED INTERIM ANALYSIS........................................................................ 22 
8 PARTICIPANT INFORMATION ......................................................................... 22 
8.1 
DISPOSITION INFORMATION ................................................................................ 22 
8.2 
PROTOCOL DEVIATIONS ...................................................................................... 23 
8.3 
DEMOGRAPHICS AND SCREENING CHARACTERISTICS .................................. 23 
8.3.1 
DEMOGRAPHIC PARAMETERS AT SCREENING ................................................................ 23 
8.4 
MEDICAL HISTORY ................................................................................................ 23 
8.4.1 
CVS HISTORY ......................................................................................................................... 23 
8.5 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................ 24 

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8.6 
STUDY DRUG ADMINISTRATION .......................................................................... 24 
9 SAFETY ............................................................................................................. 24 
9.1 
ADVERSE EVENTS ................................................................................................ 24 
9.1.1 
CODING OF ADVERSE EVENTS............................................................................................ 25 
9.2 
CLINICAL LABORATORY EVALUATIONS ............................................................. 25 
9.3 
VITAL SIGNS .......................................................................................................... 25 
9.4 
ELECTROCARDIOGRAM ....................................................................................... 25 
9.5 
PHYSICAL EXAMINATIONS ................................................................................... 26 
9.6 
DRUG, ALCOHOL, HIV, HEPATITIS B & C, AND PREGNANCY SCREEN ............ 26 
10 COVID TESTING AND IMPACT ........................................................................ 26 
11 EXPLORATORY ................................................................................................ 26 
12 CHANGES FROM PROTOCOL ......................................................................... 26 
13 TABLES, LISTINGS, AND FIGURES ................................................................ 26 
 

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1 
AMENDMENT HISTORY 
Not applicable 

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2 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic-Chemical 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CI 
Confidence interval 
Cl 
Chloride 
COVID 
Coronavirus Disease 2019 
CRF 
Case report form 
CS 
Clinically significant 
CSR 
Clinical study report 
CVS 
Cyclic Vomiting Syndrome 
ECG 
Electrocardiography 
ePD 
Electronic Patient Diary 
GI 
Gastrointestinal 
GGT 
Gamma-glutamyl transferase 
HbsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
hr 
Hour 
HR 
Heart rate 
IAS 
Intensity of Attack Scale 
LDH 
Lactic dehydrogenase 
LS 
Least-squares 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
mL 
Milliliter 
MMRM 
Mixed model for repeated measures 
N 
Sample size 
Na 
Sodium 
NCS 
Not clinically significant 
P 
Inorganic phosphate 
PES 
Prior Episode Questionnaire 
QTcF 
Fridericia’s QT correction 
RBC 
Red blood cell count 
RINVR 
Rhodes Index of Nausea, Vomiting, and Retching 
RR 
Respiratory rate 
SAP 
Statistical analysis plan 

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                                                                                  Protocol AMDC 010-201 
 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
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Abbreviation 
Term 
SAS 
Statistical Analysis Software 
SD 
Standard deviation 
SEM 
Standard error of the mean 
T 
Temperature 
TEAE 
Treatment-emergent AEs 
TFLs 
Tables, Figures, and Listings 
VAS 
Visual Analog Scale 
WBC 
White blood cell count 
WHO-DD 
World Health Organization-Drug Dictionary 

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        Alexza Pharmaceuticals, Inc. 
                                                                                  Protocol AMDC 010-201 
 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
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3 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analysis for the 
study entitled “A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety and Efficacy of Staccato® Granisetron (AZ- 010) for the Acute Treatment 
of Moderate to Severe Cyclic Vomiting Syndrome” (Amendment 2 dated 28 APR 
2021). Mock shells will be produced as a separate working document to facilitate 
programming of Tables, Figures, and Listings (TFLs) according to the SAP. The 
SAP is to be interpreted in conjunction with the protocol, and supersedes the 
statistical considerations identified in the protocol. If the final clinical study report 
contains changes to any planned statistical analyses, the justification for any such 
differences will be fully documented in the clinical study report (CSR). 
4 
STUDY OBJECTIVES 
The primary objectives for this study are to: 
• Assess the efficacy of AZ-010 as an acute treatment for moderate to 
severe cyclic vomiting syndrome (CVS) in adult patients 
• Assess the safety of AZ-010 in adult patients with moderate to severe 
CVS. 
5 
STUDY DESIGN 
5.1 DURATION OF STUDY 
The total period of the study will be up to approximately 15 weeks, including up to 2 
weeks for Screening, 12 weeks for the home treatment period, and a post-dose visit 
3-5 days following the last dose of the home treatment period.  
5.2 NUMBER OF PARTICIPANTS 
Approximately 150 participants are planned to be randomized at approximately 15 
study centers. 
5.3 DESIGN 
This is a multicenter, randomized, double-blind, parallel group, placebo-controlled, 
efficacy and safety study of adult outpatients diagnosed with CVS and experiencing 
recurring episodes of stereotypical vomiting. Participants meeting all inclusion 
criteria and none of the exclusion criteria will be randomized to treatment with either 
1 mg AZ-010, 3 mg AZ-010, or placebo in a 1:1:1 ratio (active:active:placebo). Each 
randomized participant will receive training in the use of the Staccato device and 
detailed instructions for the use of the ePD in the clinic as well as undergo a pre-test 
self-administration of their randomized study medication. Each participant will be 
monitored during a 2 hr. observation period and have 12-lead ECG (triplicate) 
assessments at pre-dose and 2, 30, 60, 90, and 120 minutes post dose. If there are 
no clinically-significant observations or abnormalities on the ECG, including QT 
prolongation, the participant will be provided with their Patient Kit that contains the 
remaining 5 unused Staccato devices in addition to the 1 Staccato device that they 

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                                                                                  Protocol AMDC 010-201 
 
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used in the clinic. Up to 5 administrations of study medication will be allowed in an At 
Home environment. CVS patients between 18 and 60 years of age who have 
experienced at least 3 episodes of recurrent vomiting in the last 12 months and 2 
episodes in the last 6 months (with stereotypical episodes of acute onset vomiting 
lasting <1 week and absence of vomiting between episodes) are eligible for 
participation. Approximately 50 participants will be randomized to each of 3 
treatment groups: 1 mg AZ-010, 3 mg AZ-010, or matching Staccato Placebo 
(Staccato device without drug coating). Randomization will be stratified by duration 
of the participant’s typical CVS episode into one of the following two categories: 1) 
Typical episode of CVS lasts 24 hrs. or less from the first vomiting/retching event; 2) 
Typical episode of CVS lasts greater than 24 hrs. from the first vomiting/retching 
event. 
There will be 3 Research Clinic visits and a home treatment period, as indicated in 
the Study Schema (5.4). 
Participants will be screened at the Research Clinic to determine if they are eligible 
for study participation no more than 14 days prior to Visit 2. After the study is 
explained to the participant and the participant has signed an informed consent form 
(ICF), the investigator will establish the participant’s eligibility according to the 
inclusion and exclusion criteria via the following assessments: Medical history (with 
particular reference to history of vomiting symptoms, CVS diagnosis, typical duration 
of CVS episode (hrs. vs days), average number of vomiting/retching events in typical 
CVS episode, frequency of CVS episodes per year, any triggers for CVS episode, 
other GI conditions that may cause similar symptoms, treatment history, and current 
medications); full physical examination (including height, weight); vital signs (heart 
rate, blood pressure while sitting, respiratory rate, temperature); 12-lead 
electrocardiogram (ECG); blood draw and urine sample for routine clinical labs 
(chemistry, hematology, urinalysis); and serum pregnancy test (in female 
participants of child-bearing potential). In light of the COVID-19 pandemic, 
participants will also be screened for COVID-19 infection and appropriate social 
distancing and contact procedures should be taken to ensure participant safety 
when in the clinic. 
Participants who continue to be eligible for the study will be asked to return to the 
Research Clinic for Visit 2. Participants meeting all inclusion criteria and none of the 
exclusion criteria will be randomized to treatment with either 1mg AZ-010, 3 mg AZ-
010, or placebo in a 1:1:1 ratio (active:active:placebo). Each randomized participant 
will be provided with a Patient Kit that contains 6 Staccato devices, other study 
materials, and an electronic Patient Diary (ePD) to be used for at-home treatment. 
They will also receive training in the use of the Staccato device and detailed 
instructions for the use of the ePD in the clinic as well as undergo a pre-test self- 
administration of their randomized study medication. Each participant will be 
monitored during a 2 hr. observation period and have 12-lead ECG (triplicate) 
assessments at pre-dose and 2, 30, 60, 90, and 120 minutes post dose. If there are 
no clinically-significant observations or abnormalities on the ECG, including QT 
prolongation, the participant will continue in the study. 

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Randomized participants without clinical observations in the 2-hour observation 
period will be asked to treat a subsequent CVS episode (with single daily dosing up 
to 5 consecutive days) within 12 weeks after the randomization date. Enrolled 
participants will self-administer the study medication when they know their CVS 
episode is imminent or as soon as possible after a CVS-related vomiting episode 
has begun. Participants will interact with their ePD prior to initiation of treatment (if 
possible) and to capture the study data. The ePD will be used to record the date and 
time of study medication administration, the number of vomiting and retching events, 
and the participant reported outcome measures (including the intensity and duration 
of the CVS episode, severity of abdominal pain, nausea, and anxiety/panic, and 
characteristics of the nausea, vomiting and retching over defined time periods) 
(section 5.8). Participants will also record the number of vomiting and retching 
events in the 24 hours after dosing on a paper questionnaire. 
Participants will be instructed to contact the Research Clinic at the earliest possible 
time after initiation of dosing and at any time should they require rescue medication, 
medical assistance or experience an intolerable AE at home during the treatment 
period. Participants will record rescue medications taken after administration of 
study medication in their ePD and on a paper concomitant medications form. 
Rescue medication may include any agent(s) from the list described in Section 9.8 of 
the protocol. Participants are encouraged to avoid rescue medication for the first 2 
hrs. following treatment with the study medication.  
Participants will be required to return to the Research Clinic (Visit 3) within 3-5 days 
from the last study medication administration for final in-clinic assessments, to return 
the Patient Kit containing the used and unused study medication, ePD, and any 
other unused supplies. Conversely, participants will be asked to return to the 
Research Clinic after 12 weeks with their unused Patient Kit if they did not treat a 
CVS episode within this time period.  
Visit 3 will include the following assessments: Vital signs; full physical examination; 
assessment for treatment emergent adverse events; 12- lead ECG, concomitant 
medications (including rescue medication taken), and clinical labs. 

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5.4 STUDY SCHEMA 
 
5.5 SCHEDULE OF EVENTS 
Table 1 presents the schedule of study events. 
 

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Table 1: 
Schedule of Events 
 
Event 
Screening 
Randomization1 
Home Treatment Period2 
(Up to 12 Weeks Post Randomization) 
Follow-Up 
/Termination 
Visit 1 
(Up to Day -14) 
Visit 2 
(Day 1) 
Schedule of Assessments for each Dosing Day (Up to 5 days) 
Visit 3 
Pre-0 
0 
2 h 
post dose 
6 h 
post dose 
12 h 
post dose 
24 h 
post dose 
Informed consent 
X 
Eligibility assessment 
X 
X 
Demographics 
X 
Medical history 
X 
X 
Urine Drug and alcohol breath screen 
X 
Complete Physical Examination 
X 
X3 
Brief Physical Exam4 
X 
X 
Height 
X 
Weight 
X 
X 
X 
Pregnancy test5 
X 
X 
Clinical laboratory testing6 
X 
X 
Serology (HIV, HBV, HCV) 
X 
COVID -19 test 
X 
X 
12-lead electrocardiogram 
X 
X7 
X 
Vital signs 
X 
X 
X 
Device Training 
X 
ePD Instructions 
X 
Randomization and assign Patient Kit 
X 
Study Medication Administration8 
X 
X 
Patient activates ePD and study clock 
X 
Patient records number of discrete 
vomiting/retching events (ePD) 
X --------- X 
VAS Assessments (ePD)9 
X 
X 
X 
X 
RINVR Assessment (ePD) 
X 
X 
X 
Intensity of Attack Scale (ePD) 
X 
X 
X 
X 

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Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
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Event 
Screening 
Randomization1 
Home Treatment Period2 
(Up to 12 Weeks Post Randomization) 
Follow-Up 
/Termination 
Visit 1 
(Up to Day -14) 
Visit 2 
(Day 1) 
Schedule of Assessments for each Dosing Day (Up to 5 days) 
Visit 3 
Pre-0 
0 
2 h 
post dose 
6 h 
post dose 
12 h 
post dose 
24 h 
post dose 
Prior Episode Questionnaire ePD 
X 
24 Hour Vomiting and Retching 
Questionnaire 
X ---------------------------------------------- X 
Reconciliation of Patient Kit 
X 
Adverse events 
X 
X ---------------------------------------------- X 
X 
Rescue Med or HCP Visit 
X ---------------------------------------------- X 
Concomitant medications 
X 
X 
X ------------------------------------------------------------ X 
X 
HBV = hepatitis B virus; HCV = hepatitis C virus 
1 
Randomization/Day 1 may occur any time after eligibility has been confirmed at Screening. The Home Treatment Period cannot begin until the 
triplicate ECG and adverse event assessments are evaluated from Visit 2. 
2 
Participants will be asked to enter responses into the ePD daily during the Home Treatment Period to ensure the device is charged and working. 
3 
Conducted upon return to clinic and prior to pre-test Study Medication administration only 
4 
Brief Physical exam will be symptom directed prior to participant discharge from the clinic 
5 
Serum pregnancy test only for females of childbearing potential 
6 
Includes hematology, serum chemistry, and urinalysis performed by the central lab. 
7 
ECG in triplicate at pre-dose and 2, 30, 60, 90, and 120 min post dosing with Study Medication 
8 
Study medication should be administered as closely as possible to start of vomiting; once per day up to 5 consecutive daily doses can be administered as 
long as the participant is still experiencing the same CVS episode 
9 
Includes separate scales for abdominal pain, nausea, and anxiety/panic 

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5.6 TREATMENT 
Participants will be allocated to each treatment group according to the randomization 
scheme. 
5.7 RANDOMIZATION 
Participants will be randomized in a 1:1:1 ratio to 1 mg AZ-010, 3 mg AZ-010, or 
matching Staccato Placebo (Staccato device without drug coating). Randomization will 
be stratified by duration of the participant’s typical CVS episode into one of the following 
two categories: 
1. Typical episode of CVS lasts 24 hrs. or less from the first vomiting/retching event 
2. Typical episode of CVS lasts greater than 24 hrs. from the first vomiting/retching 
event. 
The randomization schedule will be generated prior to study start. All study participants, 
Investigators, and site study staff will be blinded to study medication assignment. 
Devices and packaging of AZ-010 and placebo are identical in appearance. 
5.8 EFFICACY 
5.8.1 EFFICACY ASSESSMENTS 
5.8.1.1 
NUMBER OF VOMITING AND RETCHING EVENTS IN THE FIRST 2 
HOURS AFTER TREATMENT 
The primary endpoint in the study is the number of vomiting and retching events in the 
first 2 hours following treatment based on patient-reported data entered into the ePD. 
Participants will record the number of vomiting and retching events that they experience 
within the first 30, 60, 90, and 120 minutes on the ePD. Each of these entries in the ePD 
are cumulative from the time of treatment, so the primary endpoint is the assessment at 
120 minutes. 
5.8.1.2 
24 HOUR VOMITING AND RETCHING QUESTIONNAIRE 
The 24 hour vomiting and retching questionnaire is a paper questionnaire on which 
participants will record the date of dosing with study medication and the total number 
vomiting and retching events that occurred within the first 24 hours after dosing. A 
vomiting or retching event is defined as one or more continuous episodes of vomiting 
(expulsion of stomach contents through the mouth) or retching/dry heaves (an attempt 
to vomit that is not productive of stomach contents). If there is a break of at least 1 
minute between vomiting and retching events, those should be considered two different 
events.  
5.8.1.3 
VISUAL ANALOG SCALE (VAS) 
The visual analog scale is a scale of continuous measure initially developed for pain 
that has been used in a variety of clinical settings where the endpoint of interest is 
based on a subjective perception. The visual analog scale is a distinct 100-millimeter 
line anchored on the left end (0) at no degree of impairment and on the right end (100) 
at full degree of impairment, where indication of the degree of impairment perceived at 
the time of assessment is captured by marking the appropriate position on the line 

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between the anchor points. The measured distance of the mark from the left anchor is 
recorded in millimeters and this scale is adapted for the ePD. 
There are 3 different VAS scales assessed in the study. In each case the participant is 
asked to rate the appropriate variable in relation to their last vomiting/retching episode: 
• The assessment of abdominal pain whereby 0 = no pain and 100 = worst 
possible pain; 
• The assessment of nausea whereby 0 = no nausea and 100 = worst possible 
nausea; 
• The assessment of anxiety/panic whereby 0 = no anxiety/panic and 100 = 
worst possible anxiety/panic. 
5.8.1.4 
RHODES INDEX OF NAUSEA, VOMITING, AND RETCHING (RINVR) 
The RINVR is designed to assess the degree of nausea distress and vomiting distress 
in patients. It is composed of 8 questions and each question has 5 choices (see protocol 
Appendix, Section 17.4). Questions 1, 4, 6, 7, and 8 deal with symptom occurrence and 
Questions 2, 3, 5 deal with degree of discomfort of the individual symptoms. Individual 
questions can be tracked over time, or a composite score can be formed by adding the 
total of the symptom occurrence and degree of discomfort questions together. This 
scale is adapted for the ePD and participants are prompted to answer the questions 
according to the Schedule of Events. 
5.8.1.5 
INTENSITY OF ATTACK SCALE 
The Intensity of Attack scale is designed to assess the severity of the last 
vomiting/retching episode at the time of assessment. Severity ranges from Mild to 
Excruciating on a 4 point scale. This scale is administered on the ePD and participants 
are prompted to answer the questions according to the Schedule of Events. 
5.8.1.6 
PRIOR EPISODE QUESTIONNAIRE 
The Prior Episode Questionnaire is designed to compare the overall intensity and 
duration of the current CVS episode with CVS episodes that the participant has typically 
experienced in the past. For both Intensity and Duration, the participant responds 
whether the current episode overall was Less than, the Same as, or Greater than their 
typical previous CVS episodes. The questions are prompted approximately 24 hours 
after each dose of study medication is administered. 
 
5.8.2 PRIMARY ENDPOINT 
Number of vomiting/retching episodes within two hours following initial treatment, during 
the Home Treatment Period. 
5.8.3 SECONDARY ENDPOINTS 
All secondary endpoints will be evaluated based on the first vomiting/retching episode. 
 
 

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• The percentage of participants with no vomiting or retching events and no anti-
emetic benzodiazepine, or triptan rescue medication use in the first 24 hours 
following treatment. This endpoint will use incorporate data as captured in the 24 
hour vomiting and retching questionnaire and the ePD.   
• The intensity of the vomiting/retching attack (Intensity of Attack Scale) at 2, 6, 12, 
and 24 hours following treatment. 
• The Rhodes Index of nausea, vomiting, and retching (RINVR) at 6, 12, and 24 
hours following treatment. 
• The assessment of abdominal pain at 2, 6, 12, and 24 hours following treatment 
(VAS 1-100; 0 = no pain and 100 = worst possible pain) 
• The assessment of nausea at 2, 6, 12, and 24 hours following treatment (VAS 1-
100; 0 = no nausea and 100 = worst possible nausea) 
• The assessment of anxiety/panic at 2, 6, 12, and 24 hours following treatment 
(VAS 1-100; 0 = no anxiety/panic and 100 = worst possible anxiety/panic) 
• The duration of the CVS episode at 24 hours in relation to their typical CVS 
episodes (Prior Episode Questionnaire) 
• The intensity of the CVS episode at 24 hours in relation to their typical CVS 
episodes (Prior Episode Questionnaire) 
• Use of rescue medication within the 24 hours following treatment with the study 
medication 
• Visit to urgent care, emergency department, or physician’s office for care related 
to the treated episode of CVS within the 24 hours following treatment with the 
study medication 
5.9 SAFETY 
Safety and tolerability of AZ-010 will be assessed by evaluating adverse events, vital 
signs, clinical laboratories, ECG results, as well as physical examinations. 
5.9.1 ADVERSE EVENTS 
An adverse event is any untoward medical occurrence that may appear or worsen in a 
participant during the course of a study. It may be a new intercurrent illness, a 
worsening concomitant illness, an injury, or any concomitant impairment of the 
participant’s health, including laboratory test values, regardless of etiology. Any 
worsening (i.e., any clinically significant adverse change in the frequency or intensity of 
a pre-existing condition) should be considered an adverse event.  
All participants will be monitored for adverse events during the study. Assessments may 
include monitoring of the following parameters: the participant’s clinical symptoms, 
laboratory, physical examination findings, or findings from other tests and/or 
procedures. 
5.9.2 LABORATORY ASSESSMENTS 
The following laboratory parameters will be collected at timepoints specified in the 
Schedule of Events. 
 
 

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HEMATOLOGY 
CLINICAL CHEMISTRY 
URINALYSIS 
Haemoglobin [including 
Mean Corpuscular volume 
(MCV); Mean corpuscular 
haemoglobin (MCH); Mean 
corpuscular haemoglobin 
concentration (MCHC)]; 
haematocrit; red cell count 
(RBC); total white cell count 
(WBC) and Differential blood 
count, including: basophils, 
eosinophils, neutrophils, 
lymphocytes, and 
monocytes; Platelet count 
Alanine aminotransaminase 
(ALT; SGPT); Albumin (ALB); 
Alkaline phosphatase (ALK-
P) Aspartate 
aminotransaminase (AST; 
SGOT); Total bilirubin 
Conjugated bilirubin; Blood 
urea nitrogen (BUN) Calcium 
(Ca); Chloride (Cl) Total 
cholesterol Creatinine; 
Gamma-glutamyl transferase 
(GGT) Lactic dehydrogenase 
(LDH); Total protein; 
Inorganic phosphate (P) 
Potassium (K); Sodium (Na); 
Uric Acid 
Bilirubin, Glucose, Ketones, 
Nitrates, Occult, Blood 
Protein; Specific gravity, 
Urobilinogen, pH; 
Leukocytes; Microscopic 
urine analysis if dipstick is 
positive AND a physician 
classifies it as clinically 
significant        
DRUG SCREEN 
SEROLOGY  
(SCREENING ONLY) 
Amphetamines (Urine); 
Barbiturates (Urine); Cocaine 
metabolites (Urine); Opiates 
(Urine); Benzodiazepines 
(Urine); Ethyl alcohol 
(Breath) 
Human immunodeficiency 
virus antibody (HIV1+2-Ab) 
and antigen; Hepatitis B 
surface; antigen (HBsAg); 
Hepatitis C virus antibody 
(HCV- Ab)   
  
PREGNANCY 
  
  
Serum Pregnancy testing 
  
  
 
The approximate total blood volume drawn in the trial is shown below. 
 
Sample 
# Samples Taken 
Sample Volume (mL) 
Blood 
Volume 
Hematology 
2 
X 
4 mL 
= 
8mL 
Serology 
1 
5 mL 
5 mL 
Serum Pregnancy 
2 
5 mL 
10 mL 
Chemistry 
2 
8.5 mL 
17 mL 
Total 
40 mL 
 

CONFIDENTIAL 
 
Alexza Pharmaceuticals, Inc. 
Protocol AMDC 010-201 
 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
Page | 18 
5.9.3 VITAL SIGNS 
Vital signs will include blood pressure, pulse rate, pulse oximetry, respiratory rate, and 
temperature.  
5.9.4 ELECTROCARDIOGRAM 
Twelve-lead electrocardiograms will be performed after the participant has rested in a 
supine or semi-supine position for at least 5 minutes. Individual parameters including 
heart rate, PR, QT, QTcF, QRS, and RR intervals will be collected. Repeat 
electrocardiograms (if deemed necessary) should be performed at least 5 minutes 
apart. ECGs performed on Day 1 for pre-test assessment will be collected in triplicate 
for the pre-dose and post-dose collection times. 
5.9.5 PHYSICAL EXAMINATION 
A complete physical examination will include an examination of all major organ systems 
to include, but not be limited to, chest auscultation, abdominal auscultation and 
palpation, head, eyes, ears, nose and throat, and will exclude urinary and reproductive 
systems. A brief physical examination will be symptom directed. 
5.10 COVID TESTING AND IMPACT 
COVID testing, including date and time of test, will be administered per participant, with 
results reported as positive or negative.  
Information regarding the impact of COVID on visits, assessments, or participant 
participation will also be collected. 
6 
STATISTICAL ANALYSES 
6.1 GENERAL CONSIDERATIONS 
All analysis dataset preparations and statistical analyses will be performed using SAS® 
version 9.4 or higher. No imputation will be performed for missing data unless stated 
otherwise.  
Data will be summarized by dosing group (1 mg AZ-010, 3 mg AZ-010, placebo). All 
data for analysis will be listed by participant. 
The same number of decimal places as in the raw data will be presented when reporting 
minimum and maximum, 1 more decimal place than in the raw data will be presented 
when reporting mean and standard deviation. 
Continuous variables will be summarized by treatment using descriptive statistics (n, 
mean, median, standard deviation, minimum, and maximum). For categorical variables, 
frequencies and percentages will be presented by treatment. Baseline is defined as the 
last observation prior to initiation of Study Medication.  
Listings for CSR Appendix 16.2 will include all the participant data points being collected 
or derived for analyses. Data listings will be provided for all participants up to the point 
of study completion or withdrawal. 
All statistical tests will be 2-sided with a significance value of 0.05. Participants will 
generally be summarized by actual treatment received.  

CONFIDENTIAL 
 
Alexza Pharmaceuticals, Inc. 
Protocol AMDC 010-201 
 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
Page | 19 
If the 12-week treatment period has expired and participants have not yet treated a CVS 
episode, they will be excluded from efficacy analyses since they did not receive any 
study medication specifically in anticipation of a CVS episode. 
6.2 SAMPLE SIZE DETERMINATION 
This is a proof-of-concept study. There are no studies in the literature to provide reliable 
estimates of active treatment or placebo response rates using vomiting/retching events, 
or the estimate of variances around these measures, in participants with CVS being 
treated acutely with an abortive therapy. Consequently, sample size was not based on 
power calculations. 
Approximately 150 participants will be randomized to 1 of 3 treatment groups. An N of 
50 per group should be sufficient to describe and compare across the efficacy 
parameters.  
6.3 STUDY DATA 
The study data to be analyzed include all clinical data captured by the case report form 
(eCRF) or otherwise centrally, including safety lab data and ECGs. The database will be 
locked for the final analyses.  
6.4 ANALYSIS SETS 
The following analysis populations are defined.    
• Efficacy Population - All participants who receive study medication and treated at 
least 1 episode of vomiting/retching due to their CVS, analyzed according to 
randomized treatment 
• Safety Population - All participants who receive study drug 
• Per Protocol (PP) Population – A PP population (subset of the Efficacy 
Population) may be decided upon which will exclude participants with important 
protocol deviations thought to potentially impact conclusions, if a sufficient 
number of participants with such deviations exist. If so, this population will be 
defined prior to breaking the blind.       
6.5 TREATMENT GROUPS 
The analyses will be conducted by treatment group: 
• 1 mg AZ-010 
• 3 mg AZ-010 
• matching Staccato Placebo (Staccato device without drug coating) 
6.6 STATISTICAL HYPOTHESIS TESTS 
H0: There will be no difference between AZ-010 (1 mg or 3 mg) and placebo in the 
mean number of vomiting/retching events in the 2 hours following treatment. 

CONFIDENTIAL 
 
Alexza Pharmaceuticals, Inc. 
Protocol AMDC 010-201 
 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
Page | 20 
H1: Treatment with AZ-010 (1 mg or 3 mg) will result in a statistically significant different 
mean number of vomiting/retching events versus placebo in the 2 hours following 
treatment.  
6.7 MULTIPLICITY ADJUSTMENT 
No adjustments will be made for multiple comparisons for this proof-of-concept study. 
6.8 DEFINITION OF SUBGROUPS 
No subgroup analyses are planned. 
6.9 ENDPOINTS AND ESTIMANDS 
6.9.1 PRIMARY ENDPOINT AND ESTIMAND 
The mean number of vomiting/retching events in the 2 hours following treatment among 
those treated for a CVS episode (imminent or otherwise). 
6.9.1.1 
TARGET POPULATION 
The target populations are given by the Efficacy Population which include all 
participants treated during the Home Treatment Period for a CVS episode (imminent or 
otherwise). If a PP Population is defined, the primary analysis will be repeated for the 
PP Population. 
6.9.1.2 
PRIMARY ENDPOINT 
Number of vomiting/retching episodes within two hours following initial treatment, during 
the Home Treatment Period as assessed at the designated planned two-hour timepoint. 
6.9.1.3 
HANDLING OF INTERCURRENT EVENTS 
1. Clinically significant ECG abnormality during the pre-test self-administration 
which preclude further participation - Principal Stratum Strategy: 
 
• Participants who are excluded from further participation are not included in 
efficacy analyses, with the population for anticipated use consistent with 
this exclusion.  An underlying assumption is that potential treatment 
benefit is independent of the likelihood of exclusion for this reason. 
 
2. Participant experiences a CVS episode (imminent or otherwise) requiring 
treatment during the home treatment period - Principal Stratum Strategy: 
 
• The principal stratum of interest is restricted to those participants 
experiencing at least one episode of CVS (imminent or otherwise) requiring 
treatment. An underlying assumption is that likelihood of experiencing at 
least one episode during the Home Treatment Period and severity of CVS 

CONFIDENTIAL 
 
Alexza Pharmaceuticals, Inc. 
Protocol AMDC 010-201 
 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
Page | 21 
episodes is independent of randomized treatment assignment (and 
subsequent qualification for the Home Treatment Period). 
 
3. Use of rescue medication prior to 2 hours - Treatment Policy Strategy: 
 
• Participants are encouraged not to use rescue prior to 2 hours, however 
vomiting retching episodes prior to 2 hours will be counted, irrespective of 
the use of rescue. 
6.9.1.4 
POPULATION-LEVEL SUMMARY 
Mean number of vomiting retching events in the first 2 hours following the initial 
treatment (during the Home Treatment Period) from an analysis of variance model, with 
treatment group and randomization strata in the model.  
6.9.1.5 
MISSING DATA  
The necessity and approach to handling missing data for the primary endpoint is 
dependent upon the extent of missing data and potential reasons for missingness as 
well as imbalance which may be observed with respect to missing data across 
treatment groups.  A such, post-hoc exploratory analyses may be conducted for this 
proof-of-concept study to address missing data, including the use of non-missing data 
from CVS episodes after the first episode to assess treatment benefit.  
     
6.9.2 SECONDARY ENDPOINTS AND ESTIMANDS  
Secondary endpoints and associated estimands target the Efficacy Population and PP 
Population (if defined) and handle intercurrent events 1 and 2 as for the primary 
estimand and intercurrent event number 3 as for primary (except as noted). Secondary 
endpoints are described in section 5.8, and population-level summaries are as noted 
below.  
6.9.2.1 
POPULATION-LEVEL SUMMARY 
The population-level summary for secondary endpoints are defined as follows: 
• The intensity of the vomiting/retching attack (Intensity of Attack Scale [IAS]) at 2, 
6, 12, and 24 hours following treatment. Participants rate the intensity of their last 
vomiting/retching episode on a scale of 1 (mild) to 4 (excruciating). 
• The Rhodes Index of nausea, vomiting, and retching (RINVR) total score at 6, 
12, and 24 hours following treatment. 
• The assessment of abdominal pain at 2, 6, 12, and 24 hours following treatment 
(visual analog scale [VAS] 1-100; 0 = no pain and 100 = worst possible pain). 
• The assessment of nausea at 2, 6, 12, and 24 hours following treatment (VAS 1-
100; 0 = no nausea and 100 = worst possible nausea). 
• The assessment of anxiety/panic at 2, 6, 12, and 24 hours following treatment 
(VAS 1-100; 0 = no anxiety/panic and 100 = worst possible anxiety/panic). 
• The duration of the CVS episode at 24 hours in relation to their typical CVS 
episodes (Prior Episode Questionnaire [PES]), on a scale where 1=shorter, 
2=same duration, and 3=longer. 

CONFIDENTIAL 
 
Alexza Pharmaceuticals, Inc. 
Protocol AMDC 010-201 
 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
Page | 22 
• The intensity of the CVS episode at 24 hours in relation to their typical CVS 
episodes (Prior Episode Questionnaire), on a scale where 1=less intense, 
2=same intensity, and 3=more intense. 
• The proportion of participants requiring rescue medication (anti-emetics, 
benzodiazapines and triptans) within the 24 hours following treatment with the 
study medication, as reported either in the ePD or as a concomitant medication.  
• The proportion of participants requiring a visit to urgent care, emergency 
department, or physician’s office for care related to the treated episode of CVS 
within the 24 hours following treatment with the study medication. 
6.10 MAIN ANALYTICAL APPROACH 
Data from the RINVR, IAS, VAS, and PES will be analyzed using a mixed model for 
repeated measures (MMRM). Fixed effects will include treatment group, timepoint, 
randomization strata, and a treatment-by-timepoint interaction. Timepoint will be fit as a 
repeated effect using the repeated statement in SAS. An unstructured covariance 
structure and Kenward-Roger degrees of freedom will be used. In the event an 
unstructured covariance structure fails to converge, a Toeplitz structure will be used.  
Least squares means will be presented for treatment*timepoint, with the significance 
level of the treatment-by-timepoint interaction presented in summary tables. Pair-wise 
comparisons of differences in LS means, two-sided 95% confidence intervals (CIs) on 
differences, and p-values will be provided for each active treatment versus placebo for 
each timepoint. 
Proportion data (ie, rescue medication or visits to urgent care/ER/doctor will be 
analyzed using a Mantel-Haenszel test, stratifying on randomization strata, in a pairwise 
fashion of each dose versus placebo. 
7 
PLANNED INTERIM ANALYSIS 
No interim analyses are planned for this study. 
8 
PARTICIPANT INFORMATION 
In general, all participant-level parameters will be summarized for the Safety and the 
Efficacy populations by treatment group, unless stated otherwise. 
8.1 DISPOSITION INFORMATION  
Disposition will be summarized for the Safety Population. The number and percentage 
of participants, who are randomized, treated, who enter the At Home treatment phase, 
who are treated in the At Home treatment phase, who prematurely discontinue, and 
complete will be summarized. The reasons of discontinuations include following 
categories: 
• Adverse Event 
• Death 
• Lost to Follow-up 
• Non-Compliance 

CONFIDENTIAL 
 
Alexza Pharmaceuticals, Inc. 
Protocol AMDC 010-201 
 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
Page | 23 
• Investigator Decision 
• Pregnancy 
• Study Terminated by Sponsor 
• Withdrawal of Consent by Participant 
• Other 
8.2 PROTOCOL DEVIATIONS  
All reported, important protocol deviations will be documented and included in the CSR. 
8.3 DEMOGRAPHICS AND SCREENING CHARACTERISTICS  
Descriptive statistics or frequency tabulation will be provided for the Safety Population 
for the following parameters. 
8.3.1 DEMOGRAPHIC PARAMETERS AT SCREENING 
• Age (years) 
• Sex (Male, Female) 
• Race (White, Black or African American, American Indian or Alaska Native, 
Asian, Native Hawaiian or Other Pacific Islander, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, 
Unknown) 
• Weight at Screening (kg) 
• Height at Screening (cm) 
• Body Mass Index (BMI) = Weight (kg) / [Height (m)]2 rounded to 1 decimal.  
8.4 MEDICAL HISTORY  
All reported medical history will be coded by Medical Dictionary for Regulatory Activities 
(MedDRA, version 23.1), and summarized by MedDRA system organ class and 
preferred term, in order of descending overall frequency for the Safety Population. 
8.4.1 CVS HISTORY 
CVS history, including history of vomiting symptoms, CVS diagnosis, typical duration of 
CVS episode (hrs. vs days), average number of vomiting/retching events in typical CVS 
episode, frequency of CVS episodes per year, any triggers for CVS episode, other GI 
conditions that may cause similar symptoms, treatment history, and current medications 
and co-morbidities, will be summarized as well as provided in a listing.  
The summary tabulation for CVS episodes history will include frequencies and 
percentages based on the following two categories of usual duration: 
1. Typical episode of CVS lasts 24 hrs. or less from the first vomiting/retching event; 
2. Typical episode of CVS lasts greater than 24 hrs. from the first vomiting/retching 
event. 

CONFIDENTIAL 
 
Alexza Pharmaceuticals, Inc. 
Protocol AMDC 010-201 
 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
Page | 24 
8.5 PRIOR AND CONCOMITANT MEDICATIONS 
All reported medications will be coded using the World Health Organization-Drug 
Dictionary (WHODrug version B3, September 2020). A frequency tabulation will be 
shown by WHO-DD ATC class level 4 and preferred term for the Safety Population for 
each of following two categories: 
1) Prior medication: medication received during the 4 weeks (30 days) prior to 
Screening but is no longer being taken, collected on the CRF page “Prior 
Medication” at Screening. 
2) Concomitant medication: medication received during the study, collected on the 
CRF page “Concomitant Medication”. 
Concomitant and prior medications will be included in the participant data listing. 
8.6 STUDY DRUG ADMINISTRATION  
Study drug administration, including dose, will be listed by participant for each treatment 
group.  
9 
SAFETY  
All safety analyses will be conducted on the Safety Population. All safety parameters 
will be summarized based on the actual treatment group. All safety summaries will be 
descriptive.  
9.1 ADVERSE EVENTS 
An adverse event reported after informed consent, but before the first dose of study 
medication, will be considered a pre-treatment adverse event (or interim medical event). 
Treatment-emergent adverse events (TEAEs) will be defined as any adverse event that 
occurs after administration of the first dose of study medication until the Follow Up Visit 
or the Early Termination Visit. The number and percentage of participants who report 
TEAEs will be summarized by system organ class and preferred term. 
Treatment emergent adverse events will also be summarized by intensity as well as 
relationship to study drug. 
Participants who report the same preferred term on multiple occasions will be counted 
once for the preferred term: under the highest severity when summarized by severity 
and under the closest relationship to study medication when summarized by 
relationship. If a participant reports multiple preferred terms for a system organ class, 
the participant will be counted only once for that system organ class. 
The number and percentage of participants who experience TEAEs will be summarized 
by dosing regimen for the following: 
• By system organ class and preferred term 
• By severity/intensity, system organ class, and preferred term 
• By relationship to study drug, system organ class, and preferred term 
• Serious adverse events by system organ class and preferred term 

CONFIDENTIAL 
 
Alexza Pharmaceuticals, Inc. 
Protocol AMDC 010-201 
 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
Page | 25 
• Serious adverse events by relationship to study drug, system organ class, and 
preferred term 
• Adverse events resulting in discontinuation of study medication by system organ 
class and preferred term 
• Adverse events that result in study medication dose interruption by system organ 
class and preferred term 
Clinically significant deteriorations in physical examination findings (in the opinion of the 
investigator) are captured and summarized as adverse events. 
By-participant listings will be provided for any deaths, serious adverse events, and 
adverse events leading to discontinuation of treatment. 
9.1.1 CODING OF ADVERSE EVENTS 
The verbatim terms of adverse events (AEs) will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA, version 23.1 or newer). Events are summarized by 
system organ class and preferred term. 
9.2 CLINICAL LABORATORY EVALUATIONS 
Laboratory values will be converted to the project-defined unit of measurement, as 
applicable, before analysis. Abnormal, clinically significant laboratory values will be 
reported and summarized as adverse events. Clinical laboratory tests (including re-
check values if present) will be listed chronologically. ‘H’ and ‘L’, denoting values above 
or below the reference range (when present), will flag out-of-range results. At each time 
point, absolute values and change from baseline of the hematology and chemistry 
variables will be summarized by treatment and time with n, mean, SD, SEM, median, 
Min, and Max values. The categorical data of the urinalysis will be summarized by 
treatment and time in frequency tables by variable. Note, in some cases, baseline (the 
last assessment prior to dosing with randomized treatment) is obtained at the Screening 
visit.   
9.3 VITAL SIGNS 
The mean change from baseline to each scheduled assessment will be summarized 
descriptively by dose group for each vital sign variable specified in the protocol. 
Baseline will be defined as the last vital sign value obtained on Visit 2 and prior to any 
study medication administration. 
9.4 ELECTROCARDIOGRAM 
The change from baseline in electrocardiogram intervals (PR, QT, QTcF, QRS, and RR) 
to each scheduled assessment will be summarized descriptively by dose group.  
Baseline will be defined as the last ECG obtained on Visit 2 and prior to any study 
medication administration. The number and percentage of participants who have a 
clinically notable ECG interval abnormality or other clinically significant ECG finding will 
be summarized. In addition to descriptive statistics of change from baseline, the number 
and percentage of participants with QTcF intervals > 450, > 480 and > 500 msec. as 
well as those with changes from baseline > 30 msec. and >60 msec. will be provided for 

CONFIDENTIAL 
 
Alexza Pharmaceuticals, Inc. 
Protocol AMDC 010-201 
 
Statistical Analysis Plan: Final Version 1.0, 03 March 2022 
Page | 26 
each treatment group at each timepoint. A listing of abnormal ECG values will also be 
provided. For ECGs collected in triplicate, the average value will be used.  
9.5 PHYSICAL EXAMINATIONS 
The number (N and %) of participants with abnormal physical examinations will be 
tabulated at each timepoint for each treatment. 
When calculating the percentage reporting each category, the “Not Done” category will 
not be included in the denominator. 
9.6 DRUG, ALCOHOL, HIV, HEPATITIS B & C, AND PREGNANCY SCREEN  
Drug, alcohol, HIV, Hepatitis B & C, and pregnancy screen data will be included in the 
participant data listing. 
10 COVID TESTING AND IMPACT 
By-participant results from COVID testing and impact on study procedures will be 
provided in a listing. 
11 EXPLORATORY 
Potential exploratory analyses to assess the impact of missing data are discussed in 
section 6.9.1.5.   
 
12 CHANGES FROM PROTOCOL 
Additions exist with respect to analysis populations and potential (post-hoc) exploratory 
analyses which may be conducted depending on the extent of missing data. 
 
13 TABLES, LISTINGS, AND FIGURES 
A separate document containing the list of tables, listings, and figures (TFLs) to be 
included in the post-text Appendix 14 of the CSR will be provided. TFLs may be 
modified with Sponsor’s approval and as deemed necessary without update to the SAP. 
 

NCT04645953 
Protocol ID: AMDC-010-201 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY TO EVALUATE THE SAFETY AND EFFICACY OF 
STACCATO® GRANISETRON (AZ-010) FOR THE ACUTE 
TREATMENT OF MODERATE TO SEVERE CYCLIC 
VOMITING SYNDROME 
ALEXZA PHARMACEUTICALS, INC. 
April 28, 2021

Staccato Granisetron (AZ-010) 
28 APR 2020 
Protocol AMDC 010-201 Amendment 2 
Alexza Pharmaceuticals, Inc. 
 
 
CONFIDENTIAL 
Page 1 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY TO EVALUATE THE SAFETY AND EFFICACY OF 
STACCATO® GRANISETRON (AZ-010) FOR THE ACUTE 
TREATMENT OF MODERATE TO SEVERE CYCLIC 
VOMITING SYNDROME 
 
 
 
 
INVESTIGATIONAL PRODUCT: 
 
Staccato® Granisetron (AZ-010) 
PROTOCOL NUMBER: 
 
AMDC 010-201 
ORIGINAL PROTOCOL:  
AMENDMENT 1 
AMENDMENT 2 
 
28 SEP 2020 
21 DEC 2020 
28 APR 2021 
IND NUMBER: 
 
145487  
SPONSOR NAME / ADDRESS: 
 
Alexza Pharmaceuticals, Inc. 
2091 Stierlin Court 
Mountain View, CA 94043 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This document is a confidential communication of Alexza Pharmaceuticals, Inc. (Alexza). The 
recipient agrees that no information contained herein will be published or disclosed without prior 
written approval of Alexza, except that this document may be disclosed to appropriate institutional 
review boards or duly authorized representatives of the US Food and Drug Administration (FDA) 
under the condition that they are asked to maintain confidentiality. 
 

Staccato Granisetron (AZ-010) 
28 APR 2020 
Protocol AMDC 010-201 Amendment 2 
Alexza Pharmaceuticals, Inc. 
 
 
CONFIDENTIAL 
Page 2 
STUDY MONITORS / EMERGENCY CONTACT INFORMATION 
Medical Monitor name and contact information will be provided separately. 

Staccato Granisetron (AZ-010) 
28APR 2020 
Protocol AMDC 010-201 Amendment 2 
Alexza Pharmaceuticals Inc. 
ALEXZA SIGNATURE PAGE 
PROTOCOL TITLE: A Randomized, Double-Blind, Placebo Controlled Study to Evaluate the 
Safety and Efficacy of Staccato Granisetron (AZ-0 I 0) for the Acute Treatment of Moderate to 
Severe Cyclic Vomiting Syndrome 
Protocol Number AMDC 0 I 0-20 I 
Sponsor Representative Signature 
dd mmm yyyy 
Printed Name of Sponsor Representative 
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable. 
CONFIDENTIAL 
Page 3 

Staccato Granisetron (AZ-010) 
28 APR 2020 
Protocol AMDC 010-201 Amendment 2 
Alexza Pharmaceuticals, Inc. 
 
 
CONFIDENTIAL 
Page 4 
1 
SYNOPSIS 
Name of Sponsor/Company: 
Alexza Pharmaceuticals, Inc. 
Name of Investigational Product: 
AZ-010 (Staccato® Granisetron) 
Name of Active Ingredient: 
Granisetron  
Protocol Number: AMDC-010-201 
Title of Study: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety and Efficacy of Staccato Granisetron (AZ-010) for the Acute Treatment of Moderate to 
Severe Cyclic Vomiting Syndrome 
Study Center(s): Multicenter study; approximately 15 sites; US 
Study Period (years): 
Estimated Date of First Subject Enrollment: February 2021 
Estimated Date of Last Subject Completed:  December 2021 
Phase of Development: 2 
Objectives:  
The primary objectives of the study are to assess:  
• The efficacy of AZ-010 as an acute treatment for moderate to severe cyclic vomiting 
syndrome (CVS) in adult patients. 
• The safety of AZ-010 in adult patients with moderate to severe CVS. 
Methodology:  
This is a multicenter, randomized, double-blind, parallel group, placebo-controlled, efficacy 
and safety study of adult outpatients diagnosed with CVS and experiencing recurring episodes 
of stereotypical vomiting. Up to 5 administrations of study medication will be studied in an At 
Home environment. CVS patients between 18 and 60 years of age who have experienced at 
least 3 episodes of recurrent vomiting in the last 12 months are eligible for participation. 
Approximately 50 patients will be randomized to each of 3 treatment groups: 1 mg AZ-010, 
3 mg AZ-010, or matching Staccato Placebo (Staccato device without drug coating). 
Randomization will be stratified by duration of the patient’s typical CVS episode into one of 
the following two categories: 1) Typical episode of CVS lasts 24 hrs or less from the 
first vomiting/retching event; 2) Typical episode of CVS lasts greater than 24 hrs from the 
first vomiting/retching event. 
I 
I 
I 
I 

Staccato Granisetron (AZ-010) 
28 APR 2020 
Protocol AMDC 010-201 Amendment 2 
Alexza Pharmaceuticals, Inc. 
 
 
CONFIDENTIAL 
Page 5 
There will be 3 Research Clinic visits and a home treatment period: 
 
Patients will be screened at the Research Clinic to determine if they are eligible for study 
participation no more than 14 days prior to Visit 2. After the study is explained to the patient 
and the patient has signed an informed consent form (ICF), the investigator will establish the 
patient’s eligibility according to the inclusion and exclusion criteria via the following 
assessments: Medical history (with particular reference to history of vomiting symptoms, CVS 
diagnosis, typical duration of CVS episode (hrs, days, etc), average number of 
vomiting/retching events in typical CVS episode, frequency of CVS episodes per year, any 
triggers for CVS episode, other GI conditions that may cause similar symptoms, treatment 
history, and current medications); full physical examination (including height, weight); vital 
signs (heart rate, blood pressure while sitting, respiratory rate, temperature); 12-lead 
electrocardiogram (ECG); blood draw and urine sample for routine clinical labs (chemistry, 
hematology, urinalysis); and serum pregnancy test (in female participants of child-bearing 
potential). In light of the COVID-19 pandemic, patients will also be screened for COVID-19 
infection and appropriate social distancing and contact procedures should be taken to ensure 
patient safety when in the clinic.  
Patients who continue to be eligible to participate in the study will be asked to return to the 
Research Clinic for Visit 2. Patients meeting all inclusion criteria and none of the exclusion 
criteria will be randomized to treatment with either 1mg AZ-010, 3 mg AZ-010, or placebo in 
a 1:1:1 ratio (active:active:placebo). Each randomized patient will receive training in the use 
of the Staccato device and detailed instructions for the use of the ePD in the clinic as well as 
undergo a pre-test self-administration of their randomized study medication. Each patient will 
be monitored during a 2 hr observation period and have 12-lead ECG (triplicate) assessments 
at pre-dose and 2, 30, 60, 90, and 120 minutes post dose. If there are no clinically-significant 
observations or abnormalities on the ECG, including QT prolongation, the patient will be 
provided with their Patient Kit that contains the remaining 5 unused Staccato devices in 
addition to the 1 Staccato device that they used in the clinic.  
AD01O 1mg 
. 0 
r< 
AZ 001O 3 mg 
0 
•I'-
. 
\ 
I 
' 
Placebo 
1Jpto14 Days 
~o 
I 
• 
I 
At Home Tr,eatment 
I 
lU1p to 12 weeks) 
Visit 1 
Vrisirt 2 
Vi,sit 3 
Scr,eening 
Pre-TesU 
Post-Dose 
Randomi1zati:on 
IYJ.i1t!lo. 3-5 days 
of l'.a.st dose) 

Staccato Granisetron (AZ-010) 
28 APR 2020 
Protocol AMDC 010-201 Amendment 2 
Alexza Pharmaceuticals, Inc. 
 
 
CONFIDENTIAL 
Page 6 
Randomized patients will be asked to treat a subsequent CVS episode (with single daily 
dosing up to 5 consecutive days) within 12 weeks after the randomization date. Enrolled 
patients will self-administer the study medication when they know their CVS episode is 
imminent or as soon as possible after a CVS-related vomiting episode has begun. Patients will 
interact with their ePD prior to initiation of treatment (if possible) and to capture the study 
data. The ePD will be used to record the date and time of study medication administration, the 
number of vomiting and retching events, and the patient reported outcome measures 
(including the intensity and duration of the CVS episode, severity of abdominal pain, nausea, 
and anxiety/panic, and characteristics of the nausea, vomiting and retching over defined time 
periods). In addition, patients will complete a paper questionnaire to record the total number 
of vomiting and retching events within the first 24 hours after dosing. Patients will be 
instructed to contact the Research Clinic at the earliest possible time after initiation of dosing 
and any time should they require rescue medication, medical assistance or experience an 
intolerable AE at home during the treatment period. If the number of vomiting and retching 
events are not recorded on the ePD or the 24 hour vomiting and retching questionnaire and the 
patient has unused study medication, that patient may be allowed to continue participation in 
the 12-week Home Treatment Period in order to treat a second CVS episode during this time. 
Patients will also record in a paper diary the use of any medications taken during the Home 
Treatment period. Rescue medications may include any of the agent(s) from the list described 
in Section 9.8; however for the purpose of defining the responder endpoint, only anti-emetic 
medications, benzodiazepines, and triptans will be considered rescue medications. Patients are 
encouraged to avoid rescue medication use for the first 2 hrs following treatment with the 
study medication.  
Patients will be required to return to the Research Clinic (Visit 3) within 3–5 days from the 
last study medication administration for final in-clinic assessments, to return the Patient Kit 
containing the used and unused study medication, ePD, and any other unused supplies. 
Conversely, patients will be asked to return to the Research Clinic after 12 weeks with their 
unused Patient Kit if they did not treat a CVS episode within this time period. Visit 3 will 
include the following assessments: Vital signs; full physical examination; assessment for 
treatment emergent adverse events; 12-lead ECG, concomitant medications (including rescue 
medication taken), and clinical labs. 
Number of Subjects (planned): 
Approximately 150 patients are planned to be randomized in the study. Patients will be 
randomized to treatment with either 1mg AZ-010, 3 mg AZ-010, or placebo in a 1:1:1 ratio 
(active:active:placebo). 

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Main Criteria for Inclusion:  
Subjects eligible for enrollment in the study must meet all of the following inclusion criteria 
and none of the exclusion criteria. 
Inclusion Criteria: 
1. Adult males and females between 18 and 60 years of age, inclusive at the time of signing 
the informed consent document. 
2. Understand and voluntarily sign an informed consent document prior to any study related 
assessments/procedures being conducted.  
3. Diagnosis of cyclic vomiting syndrome (CVS) using the Rome IV diagnostic criteria and 
must have: 
• Stereotypical episodes of acute onset vomiting lasting < 1 week; 
• At least 3 discrete episodes of vomiting in the prior year and 2 episodes in the past 
6 months, occurring at least 1 week apart;  
• Absence of vomiting between episodes (but milder symptoms may be present); 
• Symptoms must be present for the past 3 months with onset at least 6 months prior 
4. Has a prodrome or pre-emetic symptoms associated with approximately half of their 
“typical” CVS episodes 
5. If of reproductive age, female participants and female partners of male participants, 
willing and able to use a medically highly effective form of birth control from at least 
4 weeks prior to Baseline until at least 30 days following last dose of study drug. 
Examples of medically highly effective forms of birth control are: 
• Surgical sterility (hysterectomy or bilateral ligation) or post-menopausal (cessation of 
menses for at least 12 months prior to screening)  
• Sexual partner is sterile, or of the same sex 
• Implants of levonorgestrel in females 
• Oral contraceptive (combined, patch, vaginal ring, injectable, implant) in females 
• Double-barrier method (any combination of physical and chemical methods) 
• Intrauterine device with a failure rate less than 1% per year 
6. Male participants must: 
• Agree to use, with their partners, one of the highly effective contraceptive methods 
listed in Inclusion Criterion 5, from Baseline until at least 30 days following last dose 
of study drug. 
• Refrain from donating sperm during the study and for at least 30 days after the end of 
the study.  
7. Otherwise healthy, as determined by the responsible physician, based on a medical 
evaluation including history, physical examination, vital signs, electrocardiograms (ECGs) 
and laboratory tests assessed at the screening visit.  
8. Negative urine tests for selected drugs of abuse and alcohol breath test at Screening. 
Note: Patients with a positive urine drug screen for benzodiazepines or opioids may be 
allowed in the study provided the drug was prescribed by a physician. 

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9. Willing and able to adhere to overall study visit schedule, procedures and other protocol 
requirements. 
 
Exclusion Criteria: 
1. Any significant medical or psychiatric condition that could, in the Investigator’s opinion, 
compromise the subject’s safety or interfere with the completion of this protocol. 
2. Any condition, including the presence of laboratory abnormalities or pulmonary condition, 
which according to the Investigator places the subject at unacceptable risk if he/she were 
to participate in the study. 
3. A diagnosis of any gastrointestinal disorder other than CVS that in the judgement of the 
Investigator could compromise the subject’s safety or interfere with the interpretation of 
safety or efficacy data. 
4. Current history of clinically significant neurologic (e.g., seizures), cardiac, pulmonary 
(e.g., asthma, COPD), metabolic, renal, or hepatic conditions. 
5. Use of drugs known to prolong the QTc interval with known risk of Torsade de Pointes. 
ECG findings of QTcF interval > 450 msec for men and > 470 msec for women obtained 
at screening visit or prior to the first dose of study drug. 
6. Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase 
(GGT), serum creatinine, or total bilirubin > 1.5 upper limit of normal (ULN) at screening 
or prior to the first dose of study drug. These laboratory tests may be repeated once, if they 
are abnormal on first screening, and if there is a medical reason to believe the results may 
be inaccurate. If the repeat test is within the reference range, the subject may be included 
only if the Investigator considers that the previous finding will not compromise the 
subject’s safety and will not interfere with the interpretation of safety data. 
7. Positive blood screen for human immunodeficiency virus (HIV antibody), hepatitis B virus 
surface antigen, or hepatitis C virus antibody at screening. 
8. History of alcohol or illicit drug abuse within 1 year before the first dose of study drug. 
9. Daily use of marijuana. 
Note: Occasional use of THC/cannabinoid products is allowed in the study 
10. Participation in a clinical trial and receipt of an investigational medication or a new 
chemical entity within 90 days, 5 half-lives, if known, or twice the duration of the 
biological effect of any medication (whichever is longer) prior to the first dose of current 
study drug. 
11. Donation of blood, plasma or other blood products or blood collection in excess of 470 mL 
within 8 weeks prior to dosing. 
12. Known history of sensitivity to any of the study drugs or components thereof, or to other 
5-HT3 receptor antagonists, or a history of medication allergy or other allergy that, in the 
opinion of the Investigator, contraindicates study participation. 
13. Major surgery within 4 weeks of screening that could interfere with, or for which the 
treatment might interfere with, the conduct of the study, or that would pose an 
unacceptable risk to the subject in the opinion of the Investigator. 
14. Uncontrolled current illness (i.e., active infection). 
15. Has a current or a history of cancer, with the exception of basal cell carcinoma. 

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Investigational Product, Dosage and Mode of Administration: 
AZ-010 (Staccato granisetron) is a hand-held, single dose, single-use drug-device 
combination product using the Staccato delivery system. Oral inhalation through the product 
is detected by the breath sensor, which in turn results in rapid heating of a thin film of 
granisetron causing the formation of a thermally generated drug vapor. The vapor condenses 
into aerosol particles with a particle size distribution appropriate for efficient delivery to the 
deep lung. The rapid absorption of the drug provides peak plasma levels in the systemic 
circulation within minutes after administration. 
Each product is packaged inside a sealed foil pouch. Upon removing the product from the 
pouch, pulling the tab connected to the device renders it ready for use, as indicated by 
illumination of a green light on top of the device. Successful dosing is signaled by the 
extinguishing of the green light. 
AZ-010 is administered as a single dose via inhalation, available as 1 mg or 3 mg per device. 
Reference Therapy, Dosage and Mode of Administration:  
Matching placebo which is the same Staccato inhalation device without coated granisetron 
film 
Duration of Study Participation:  
The Screening phase will last up to 14 days. Eligible subjects will be provided with a 
multipack of study medication and instructed to self-medicate upon occurrence of their next 
CVS episode within the next 12-week period. Up to 5 daily doses will be administered when a 
CVS episode occurs. Consequently, subject participation will range from approximately 
1−4 months, depending on the timing of the Screening visit in relation to treatment. 
Criteria for Evaluation: 
Primary Efficacy Endpoint 
• The number of vomiting/retching events in the 2 hours following treatment. 
 
Secondary Endpoints 
• The percentage of patients with no vomiting or retching events and no anti-emetic, 
benzodiazepine, or triptan rescue medication use in the first 24 hours following treatment. 
• The intensity of the vomiting/retching attack (Intensity of Attack Scale) at 2, 6, 12, and 
24 hours following treatment. 
• The Rhodes Index of nausea, vomiting, and retching (RINVR) at 6, 12, and 24 hours 
following treatment.  
• The assessment of abdominal pain at 2, 6, 12, and 24 hours following treatment 
(VAS 1−100; 0 = no pain and 100 = worst possible pain) 
• The assessment of nausea at 2, 6, 12, and 24 hours following treatment (VAS 1–100; 
0 = no nausea and 100 = worst possible nausea) 
• The assessment of anxiety/panic at 2, 6, 12, and 24 hours following treatment 
(VAS 1−100; 0 = no anxiety/panic and 100 = worst possible anxiety/panic) 

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• The duration of the CVS episode at 24 hours in relation to their typical CVS episodes 
(Prior Episode Questionnaire) 
• The intensity of the CVS episode at 24 hours in relation to their typical CVS episodes 
(Prior Episode Questionnaire) 
• Use of rescue medication within the 24 hours following treatment with the study 
medication 
• Visit to urgent care, emergency department, or physician’s office for care related to the 
treated episode of CVS within the 24 hours following treatment with the study medication 
 
All statistical tests will be 2-sided with a significance value of ≤ 0.05. There is no control for 
Type-1 error for the analyses.  
Additional exploratory statistical analyses to further assess for treatment effect will be 
outlined in the Statistical Analysis Plan finalized prior to database lock. 
Safety 
Safety and tolerability of AZ-010 will be assessed by evaluating adverse events, vital signs, 
12-lead ECG, clinical laboratory results, and physical examination. 
 

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2 
TABLE OF CONTENTS 
STUDY MONITORS / EMERGENCY CONTACT INFORMATION ...................................2 
ALEXZA SIGNATURE PAGE ................................................................................................3 
1 
SYNOPSIS ...............................................................................................................4 
2 
TABLE OF CONTENTS .......................................................................................11 
LIST OF TABLES ...................................................................................................................13 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................14 
4 
INTRODUCTION AND RATIONALE ................................................................16 
4.1 
Background Information ..................................................................................16 
4.2 
Study Medication Description .........................................................................17 
4.3 
Preclinical Information for Staccato Granisetron ............................................19 
4.4 
Clinical Information for Staccato Granisetron ................................................19 
5 
ETHICS..................................................................................................................20 
5.1 
Institutional Review Board (IRB) ....................................................................20 
5.2 
Written Informed Consent ...............................................................................20 
6 
STUDY OBJECTIVES ..........................................................................................22 
6.1 
Primary Objectives ...........................................................................................22 
7 
OVERALL STUDY DESIGN ...............................................................................23 
7.1 
Study Design ....................................................................................................23 
7.2 
Number of Patients and Sites ...........................................................................25 
7.3 
Method of Treatment Assignment and Blinding .............................................25 
7.4 
Rationale for Study Design, Doses, and Primary Endpoint .............................25 
7.5 
Schedule of Events ...........................................................................................27 
7.6 
Procedures for Protocol ....................................................................................30 
8 
SELECTION AND WITHDRAWAL OF PATIENTS .........................................34 
8.1 
Inclusion Criteria .............................................................................................34 
8.2 
Exclusion Criteria ............................................................................................35 
8.3 
Patient Withdrawal Criteria .............................................................................36 
8.4 
Emergency Unblinding of Treatment Assignment ..........................................36 
8.5 
Individual or Study Stopping Criteria ..............................................................37 
9 
DESCRIPTION OF STUDY TREATMENT ........................................................38 
9.1 
Description of Investigational Products (Study Medication) ...........................38 
9.2 
Dose-Adjustment Criteria ................................................................................38 
9.3 
Packaging and Labeling ...................................................................................38 
9.4 
Investigational Product Accountability and Disposal ......................................38 
9.5 
Study Medication Preparation ..........................................................................39 
9.6 
Investigational Product Compliance ................................................................39 
9.7 
Concomitant Medications and Procedures .......................................................39 

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9.8 
Permitted Rescue Medications .........................................................................39 
10 
STUDY ASSESSMENTS AND PROCEDURES .................................................40 
10.1 
Demographic Characteristics and Medical History .........................................40 
10.2 
Vital Signs, Weight, and Height ......................................................................40 
10.3 
Physical Examination.......................................................................................40 
10.4 
Electrocardiogram ............................................................................................40 
10.5 
Clinical Laboratory Assessments .....................................................................41 
10.6 
24 Hour Vomiting and Retching Questionnaire ..............................................41 
10.7 
Visual Analog Scale (VAS) .............................................................................41 
10.8 
Rhodes Index of Nausea, Vomiting, and Retching (RINVR) ..........................42 
10.9 
Intensity of Attack Scale ..................................................................................42 
10.10 
Prior Episode Questionnaire ............................................................................42 
11 
ADVERSE EVENTS .............................................................................................43 
11.1 
Definition of Adverse Events ...........................................................................43 
11.2 
Evaluation of Adverse Events ..........................................................................43 
11.3 
Follow-Up ........................................................................................................47 
11.4 
Pregnancy .........................................................................................................47 
11.5 
Recording Adverse Events ...............................................................................47 
11.6 
Reporting Adverse Events ...............................................................................47 
12 
STATISTICAL ANALYSES ................................................................................49 
12.1 
Overview ..........................................................................................................49 
12.2 
Interim Analysis ...............................................................................................49 
12.3 
Determination of Sample Size .........................................................................49 
12.4 
Endpoints .........................................................................................................49 
12.5 
Analysis Populations ........................................................................................50 
12.6 
Analyses ...........................................................................................................50 
13 
REGULATORY CONSIDERATIONS .................................................................53 
13.1 
Good Clinical Practice .....................................................................................53 
13.2 
Sponsor’s Responsibilities ...............................................................................53 
13.3 
Investigator’s Responsibilities .........................................................................54 
13.4 
Protocol Amendments ......................................................................................55 
13.5 
Audits and Inspections .....................................................................................55 
13.6 
Quality Control and Quality Assurance ...........................................................56 
14 
DATA HANDLING AND RECORDKEEPING ..................................................57 
14.1 
Confidentiality .................................................................................................57 
14.2 
Patient Data Protection ....................................................................................57 
14.3 
Data Collection ................................................................................................57 
14.4 
Case Report Form Completion ........................................................................58 

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14.5 
Database Management, Data Clarification, and Quality Assurance ................58 
14.6 
Inspection of Records ......................................................................................58 
14.7 
Retention of Records ........................................................................................59 
15 
PUBLICATION .....................................................................................................60 
16 
REFERENCES ......................................................................................................61 
17 
APPENDICES .......................................................................................................63 
17.1 
Laboratory Assessments ..................................................................................64 
17.2 
Staccato Instructions for Use ...........................................................................65 
17.3 
Rhodes Index of Nausea, Vomiting and Retching ...........................................68 
17.4 
Intensity of Attack Scale ..................................................................................69 
17.5 
VAS Scales ......................................................................................................70 
17.6 
Prior Episode Questionnaire ............................................................................71 
17.7 
24 Hour Vomiting and Retching Questionnaire ..............................................72 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................28 
 

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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Special Term 
Explanation 
AE  
Adverse Event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of Variance 
AR 
Adverse Reaction 
AST 
Aspartate aminotransferase 
AUC0-24h 
Area under the plasma concentration-time curve from time 0 to 24 hours 
post-dose 
AUC0-tlast 
Area under the plasma concentration-time curve from time 0 to the last 
measurable concentration; calculated using linear trapezoid rule 
AUC0-inf 
Area under the plasma concentration-time curve from time 0 to infinity 
BMI 
Body Mass Index 
BP 
Blood pressure 
CBC 
Complete Blood Count  
CFR 
Code of Federal Regulations 
Cmax 
Maximum plasma concentration  
CL/F 
Oral clearance 
CRA 
Clinical Research Associate 
eCRF 
Electronic Case Report Form 
CRO 
Clinical Research Organization  
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMP 
Data Management Plan 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EC  
Ethics Committee 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
HBsAg 
Hepatitis B surface antigen 
HCV  
Hepatitis C Virus  
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
IB 
Investigator’s Brochure 

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Abbreviation or 
Special Term 
Explanation 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
IRB 
Institutional Review Board 
LC/MS/MS 
Liquid Chromatography Tandem Mass Spectrometry 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliters 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PR 
Pulse Rate 
RR 
Respiration Rate 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2  
Apparent terminal half-life 
Tmax  
Time to reach peak plasma concentration 
ULN 
Upper Limit of Normal 
US 
United States 
WBC  
White Blood Cell 
 

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4 
INTRODUCTION AND RATIONALE 
4.1 
Background Information 
Cyclic vomiting syndrome (CVS) is an idiopathic chronic disorder characterized by sudden 
episodes of nausea and rapid-fire vomiting lasting for 1–5 days followed by symptom-free 
periods (Hayes et al, 2018). This alternating pattern of disease and disease-free periods 
distinguishes CVS from other gastrointestinal disorders. There is no current drug therapy 
approved for treatment of CVS.  
CVS is generally described as consisting of four phases. The inter-episodic phase occurs 
between attacks and patients remain relatively asymptomatic. This phase can last for several 
months. During the prodromal phase, some patients describe an ‘aura’ that lasts for minutes to 
hours. This phase usually consists of lethargy, anorexia, pallor or abdominal pain or autonomic 
symptoms such as sweating or salivation. The hyperemesis phase usually starts from the early 
hours of the morning to noon, and is characterized by intense persistent nausea and repeated 
vomiting. Typically, vomiting peaks in the first hour and then declines lasting at least 24 hours 
with episodes commonly occurring in the early morning or upon awakening. The vomiting 
frequency can be up to eight times every hour (Fleisher et al, 2005). This can last for 1–7 days. 
Finally, the recovery phase begins with the cessation of vomiting and ends when energy levels 
and appetite recover. Antiemetic agents have been reported to be a key component of support 
care for acute abortive treatment during the prodromal and emetic phases of CVS in adults 
(Abell et al, 2008). Abortive IV antiemetic agents such as the 5-HT3 antagonist ondansetron at 
high doses and granisetron were reported for supportive treatment of acute vomiting episodes in 
CVS patients (Li and Misiewicz et al, 2003; Yang, 2010; Venkatasubramani, 2007).  
Treatment of CVS remains largely based on real-world clinical experience. There is no current 
drug therapy approved for treatment of CVS. According to guidelines on management of cyclic 
vomiting syndrome in adults by the American Neurogastroenterology and Motility Society and 
the Cyclic Vomiting Syndrome Association (Venkatesan et al, 2019), treatment of CVS should 
be based on a biopsychosocial care model, integrating lifestyle modification, prophylactic and/or 
abortive medications, and evidenced-based psychotherapy to address psychiatric comorbidity. 
The guideline recommends using prophylactic medications in moderate-to-severe CVS and 
offering abortive medications to all patients to terminate an acute attack. For acute attacks, the 
committee conditionally recommends using serotonin antagonists, such as ondansetron, and/or 
triptans, such as sumatriptan or aprepitant to abort symptoms. Antiemetic intravenous therapy 
was reported to be effective for treatment of nausea and vomiting for CVS acute episodes 
(Jensen, 2015; Moses et al, 2014). Granisetron was reported to be an effective pharmacologic 
approach used for abortive and supportive care in CVS (Li and Balint, 2000; Li et al, 2008; 
Li and Misiewicz, 2003). 
Granisetron is a highly selective and potent 5-hydroxyltryptamine type 3 (5-HT3) receptor 
antagonist widely used for over twenty years as an effective antiemetic treatment 
(Blower, 2003). The efficacy of granisetron in the prevention of nausea and vomiting has been 
extensively studied in clinical trials and is approved for chemotherapy-induced nausea and 
vomiting (CINV), radiation-induced nausea and vomiting (RINV), and for postoperative nausea 
and vomiting (PONV) (Kytril (granisetron hydrochloride) Prescribing Information 2011, 

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Aapro, 2004; Spartinou et al, 2017; Gilmore et al, 2018). Granisetron has also been shown to be 
effective and well tolerated in special populations, such as patients refractory to antiemetic 
treatment for gastroparesis (Simmons and Parkman, 2014), bulimia nervosa, cyclic vomiting 
syndrome, HIV (Evans, 2016) and patients with hepatic or renal impairment with minimal 
potential for drug-drug interactions (Aapro, 2004). 
Antiemetic agents have been reported to be a key component of support care for acute abortive 
treatment during the prodromal and emetic phases of CVS in adults (Abell et al, 2008). Abortive 
IV antiemetic agents such as the 5-HT3 antagonist ondansetron at high doses (0.3–0.4 mg/kg up 
to 24 mg, q. 4–6 hours) and granisetron (10 µg/kg, q 4–6 hours) were reported for supportive 
treatment of acute vomiting episodes in CVS patients (Li and Misiewicz et al, 2003; Yang, 2010; 
Venkatasubramani, 2007). Despite the widespread use of 5-HT3 antagonists in the treatment of 
CVS, there have been no definitive clinical trials conducted to date.  
Alexza Pharmaceuticals (Alexza) is currently developing Staccato® Granisetron for Inhalation 
(Staccato Granisetron; AZ-010) as an acute treatment of CVS. Staccato Granisetron represents a 
new dosage form of granisetron. It is a single-use, hand-held, drug-device combination product 
that delivers aerosolized granisetron. From a drug development perspective, one of the most 
compelling characteristics of Staccato Granisetron is that the drug can be delivered 
non-invasively with rapid IV-like pharmacokinetics to individuals. In previous clinical studies 
with Staccato Granisetron and a number of drugs using the Staccato technology, mean peak 
plasma concentration was achieved within minutes following inhalation. In a first-in-human, 
single ascending dose study with Staccato Granisetron (AMDC 010-101; refer to CSR: 
IND 145,487 SN 0009), the median time to maximum plasma concentration was approximately 
2 minutes for doses ranging from 0.5–3 mg.  
Staccato Granisetron may provide significant benefit for the treatment of CVS since it has rapid 
pharmacokinetics and bypasses GI absorption of the drug. Because of the simplicity of the 
delivery, the patient is only required to take a normal breath for delivery of the aerosolized drug. 
Consequently, inhalation via Staccato delivery could provide a non-invasive, rapid delivery of 
granisetron and lead to a more rapid and effective control of acute vomiting episodes, 
representing an improvement to existing patient care. Consequently, this study (AMDC 010-201) 
is designed to assess the effects of Staccato Granisetron as an acute treatment during an episode 
of CVS in patients with moderate to severe disease.  
4.2 
Study Medication Description 
4.2.1 
Staccato Granisetron for Inhalation 
Staccato granisetron is a hand-held, single dose, single-use drug-device combination product 
using Alexza’s proprietary Staccato delivery system. Oral inhalation through the product initiates 
the controlled rapid heating of a thin film of excipient-free granisetron to form a thermally 
generated, highly pure drug vapor. The vapor condenses into aerosol particles with a particle size 
distribution appropriate for efficient delivery to the deep lung. The rapid absorption of the drug 
provides peak plasma levels in the systemic circulation within minutes after administration. 

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The principal components of Staccato Granisetron (shown schematically below) are as follows: 
• Breath sensor: The breath-activation mechanism that initiates actuation of the heat source  
• Heat source (i.e., heat package): The mechanism comprised of a reactant coating on the 
interior surface of a stainless-steel substrate that generates heat to vaporize the drug and 
produce the aerosol 
• Drug coating: The thin film of excipient-free granisetron on the exterior surface of the 
stainless-steel substrate 
• Airway: The medical-grade plastic housing surrounding the heat package; it controls and 
directs the airflow over the vaporizing drug.  
 
Schematic Side-View of Staccato Granisetron 
 
 
 
The interior surface of the stainless-steel substrate of the heat package is coated with a mixture of 
zirconium and molybdenum trioxide powder with a clay binder. When activated, this undergoes 
a controlled, gasless, oxidation-reduction (redox) reaction that liberates heat. The redox reaction 
is initiated by a battery-activated starter inserted into the heat package. Inhalation through the 
product is detected by the breath sensor, causing the starter to initiate the redox reaction and 
subsequent rapid heating of the substrate to approximately 400°C. Heat then transfers into the 
film of granisetron that is coated on the exterior surface of the substrate. The granisetron 
vaporizes in < 1 second, thereby limiting thermal decomposition. The vapor cools in the airflow 
and condenses to form aerosol particles that are characterized by a mass median aerodynamic 
diameter in the range of 1.0 to 3.5μm. The aerosolized granisetron is delivered to the lung within 
seconds of inhalation through the device. 
Each product is packaged inside a sealed foil pouch. Removal of a pull tab from the product 
renders it ready for use, as indicated by illumination of a green light. Successful dosing is 
signaled by the extinguishing of the green light. 
Heat Source
Drug Coating
Drug Coating
Aerosol Inhaled
by Patient
Inlet Air
Breath Sensor
Airway
Heat Source
Drug Coating
Drug Coating
Aerosol Inhaled
by Patient
Inlet Air
Breath Sensor
Airway
<=== 
<=== 

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4.3 
Preclinical Information for Staccato Granisetron 
For a full discussion of the preclinical data generated to date with Staccato Granisetron, please 
see the Investigator Brochure (m1.14.4.1). 
4.4 
Clinical Information for Staccato Granisetron 
While granisetron has been available worldwide in various formulations for many years, AZ-010 
has been administered to healthy volunteers in a single ascending dose Phase 1 study 
(AMDC 010-101) and a multiple ascending dose study (AMDC 010-102). Study 
AMDC 010-101 was designed in 2 parts in separate cohorts of healthy volunteers. The primary 
objectives for each part are as follows. For Part A the purpose was to examine the tolerability, 
safety, and pharmacokinetics of single ascending doses of 0.5, 1, and 3 mg of AZ 010 in healthy 
volunteers. The purpose of Part B was to compare the pharmacokinetics and safety of a single 
dose of 1 mg of AZ-010 with that of 1 mg granisetron hydrochloride intravenous (IV) injection 
in healthy volunteers. The study was conducted in a total of 36 subjects at a single clinical 
research unit. Across the 3 doses of Part A, the drug was generally well tolerated with 
3 of 8 subjects (6 AEs in total) in the 0.5 mg cohort, 3 of 8 subjects (6 AEs in total) in the 1 mg 
cohort, and 0 of 8 subjects in the 3 mg cohort reporting at least 1 adverse event. All adverse 
events were mild to moderate in severity and there were no serious adverse events (SAE). 
Study AMDC 010-102 was designed to examine the tolerability, safety, and pharmacokinetics 
(PK) of AZ-010 following 7 days of dosing (up to 3 mg) in healthy volunteers. The data obtained 
from this study were intended to guide selection of safe and tolerable doses for the Phase 2 
clinical trial. The study was conducted in a total of 30 subjects (8 for each of the AZ-010 dose 
groups and 6 for placebo) at a single clinical research unit. Across the 3 doses the drug was 
generally well tolerated with a total of 13 of 30 subjects (43%) experiencing an AE 
(7 of 8 subjects for 0.5 mg; 0 of 8 subjects for 1.0 mg; 4 of 8 subjects for 3.0 mg of AZ-010 and 
2 of 6 subjects for placebo) There were a total of 30 AEs reported with the most reported for 
Gastrointestinal disorders (n = 9) and Nervous System disorders (n = 9). There were no clinical 
laboratory changes for serum chemistry or hematology or any changes in urinalysis between 
baseline and discharge that were notable. There were no serious adverse events (SAE). 
For a full discussion of the clinical data generated to date with Staccato granisetron, please see 
the Investigator Brochure (m1.14.4.1). 

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5 
ETHICS 
The procedures set out in this study protocol, pertaining to the conduct, evaluation and 
documentation of this study, are designed to ensure that the Sponsor and the Investigator abide 
by Good Clinical Practice (GCP), including but not limited to Title 21 Code of Federal 
Regulations (CFR) Parts 50, 56, and 312, and the International Council on Harmonization (ICH) 
guidelines and directives. Compliance with these regulations also constitutes compliance with 
the ethical principles described in the current revision of the Declaration of Helsinki and 
applicable local regulatory requirements and law. 
The Principal Investigator is responsible for protecting the rights, safety, and welfare of patients 
under his/her care, and for the control of the medications under investigation. All ethical, 
regulatory, and legal requirements must be met before the first patient is enrolled in the study. 
The Principal Investigator will ensure that all persons assisting with the study are adequately 
informed about the protocol, any amendments to the protocol, the study drug, and their 
study-related duties and functions. The Investigator will maintain a list of sub-Investigators and 
other appropriately qualified persons to whom he or she has delegated significant study-related 
duties. Individuals ineligible from conducting or working on clinical studies, including those 
ineligible as a result of debarment under the Generic Drug Enforcement Act of 1992, will not be 
allowed to conduct or work on studies sponsored by Alexza Pharmaceuticals. The Investigator is 
required to immediately disclose to Alexza Pharmaceuticals in writing, if any person involved in 
the conduct of the study is debarred pursuant to a hearing by US FDA under this anti-fraud law, 
or if any proceeding for debarment is pending, or is (to the best of the Investigator’s knowledge) 
threatened.  
5.1 
Institutional Review Board (IRB) 
The Institutional Review Board (IRB) will meet all FDA requirements governing IRBs according 
to CFR, Title 21, Part 56. The Investigator (or designee) must submit this study protocol and any 
amendments, the Sponsor’s approved informed consent form(s) (ICF), patient information 
sheets, patient recruitment materials, and other appropriate documents to the IRB for review and 
approval. Following review of the submitted materials a copy of the written and dated 
approval/favorable opinion will be forwarded to the Sponsor (or designee).  
Any advertisements used to recruit patients for the study will be reviewed by the Sponsor and the 
IRB prior to use. 
5.2 
Written Informed Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the patient. 
Pre-screening for potential eligibility in person or by telephone may be conducted with an 
IRB-approved pre-screen script after a patient provides their consent. 
The ICF, as specified by the clinical site’s IRB, must follow the Protection of Human Subjects 
regulations listed in the Code of Federal Regulations, Title 21, Part 50. The background of the 
proposed study, the procedures, the benefits and risks of the study, and that study participation is 

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voluntary must be explained to the patient. The patient must be given sufficient time to consider 
whether to participate in the study.  
A copy of the ICF, signed and dated by the patient, must be given to the patient. Confirmation of 
a patient’s informed consent must also be documented in the patient’s source documentation 
prior to any testing under this protocol, including screening tests and assessments. The original 
signed consent form will be retained with the study records. 
All ICFs used in this study must be approved by the appropriate IRB and by the Sponsor. The 
ICF must not be altered without the prior agreement of the relevant IRB and the Sponsor. 

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6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
Objectives: 
The primary objectives of the study are to assess:  
• The efficacy of AZ-010 as an acute treatment for cyclic vomiting syndrome (CVS) in adult 
patients. 
• The safety of AZ-010 in adult patients with CVS. 
 

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7 
OVERALL STUDY DESIGN 
7.1 
Study Design 
This is a multicenter, randomized, double-blind, parallel group, placebo-controlled, efficacy and 
safety study of adult outpatients diagnosed with CVS and experiencing recurring episodes of 
stereotypical vomiting. Up to 5 administrations of study medication will be allowed in an At 
Home environment. CVS patients between 18 and 60 years of age who have experienced at least 
3 episodes of recurrent vomiting in the last 12 months and 2 episodes in the last 6 months are 
eligible for participation. Approximately 50 patients will be randomized to each of 3 treatment 
groups: 1 mg AZ-010, 3 mg AZ-010, or matching Staccato Placebo (Staccato device without 
drug coating). Randomization will be stratified by duration of the patient’s typical CVS episode 
into one of the following two categories: 1) Typical episode of CVS lasts 24 hrs or less from the 
first vomiting/retching event; 2) Typical episode of CVS lasts greater than 24 hrs from the 
first vomiting/retching event. 
There will be 3 Research Clinic visits and a home treatment period:  
 
 
Patients will be screened at the Research Clinic to determine if they are eligible for study 
participation no more than 14 days prior to Visit 2. After the study is explained to the patient and 
the patient has signed an informed consent form (ICF), the investigator will establish the 
patient’s eligibility according to the inclusion and exclusion criteria via the following 
assessments: Medical history (with particular reference to history of vomiting symptoms, CVS 
diagnosis, typical duration of CVS episode (hrs vs days), average number of vomiting/retching 
events in typical CVS episode, frequency of CVS episodes per year, any triggers for CVS 
episode, other GI conditions that may cause similar symptoms, treatment history, and current 
medications); full physical examination (including height, weight); vital signs (heart rate, blood 
pressure while sitting, respiratory rate, temperature); 12-lead electrocardiogram (ECG); blood 
draw and urine sample for routine clinical labs (chemistry, hematology, urinalysis); and serum 
pregnancy test (in female participants of child-bearing potential). In light of the COVID-19 
Vr.sirt 1 
Vi,sirt 2 
Scr,eening 
Pm-f,estJ 
Rando11i1i1za1i:on 
AZJ010 1mg 
- --------------
0 
AZJ010 3 mg 
-1-----------='------_. o 
At Horne l reatment 
{Up to 12 weeks> 
0 • 
Visiil: 3 
Post -Dose 
•IW.i1l!Jn 3,-5 days 
of hist dos·e> 

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pandemic, patients will also be screened for COVID-19 infection and appropriate social 
distancing and contact procedures should be taken to ensure patient safety when in the clinic.  
Patients who continue to be eligible to participate in the study will be asked to return to the 
Research Clinic for Visit 2. Patients meeting all inclusion criteria and none of the exclusion 
criteria will be randomized to treatment with either 1 mg AZ-010, 3 mg AZ-010, or placebo in a 
1:1:1 ratio (active:active:placebo). Each randomized patient will receive training in the use of the 
Staccato device and detailed instructions for the use of the ePD in the clinic as well as undergo a 
pre-test self-administration of their randomized study medication. Each patient will be monitored 
during a 2 hr observation period and have 12-lead ECG (triplicate) assessments at pre-dose and 
2, 30, 60, 90, and 120 minutes post dose. If there are no clinically-significant observations or 
abnormalities on the ECG, including QT prolongation, the patient will be provided with their 
Patient Kit that contains the remaining 5 unused Staccato devices in addition to the 1 Staccato 
device that they used in the clinic.  
Randomized patients will be asked to treat a subsequent CVS episode (with single daily dosing 
up to 5 consecutive days) within 12 weeks after the randomization date. Enrolled patients will 
self-administer the study medication when they know their CVS episode is imminent or as soon 
as possible after a CVS-related vomiting episode has begun. Patients will interact with their ePD 
prior to initiation of treatment (if possible) and to capture the study data. The ePD will be used to 
record the date and time of study medication administration, the number of vomiting and 
retching events, and the patient reported outcome measures (including the intensity and duration 
of the CVS episode, severity of abdominal pain, nausea, and anxiety/panic, and characteristics of 
the nausea, vomiting and retching over defined time periods). In addition, patients will complete 
a paper questionnaire to record the number of vomiting and retching events within the 
first 24 hours after dosing. Patients will be instructed to contact the Research Clinic at the 
earliest possible time after initiation of dosing and at any time should they require rescue 
medication, medical assistance, or experience an intolerable AE at home during the treatment 
period. If the number of vomiting and retching events are not recorded on the ePD or the 24 hour 
vomiting and retching questionnaire and the patient has unused study medication, that patient 
may be allowed to continue participation in the 12-week Home Treatment Period in order to treat 
a second CVS episode during this period. Patients will also record in their diary any medications 
taken during the Home Treatment period. Rescue medications may include any agent(s) from the 
list described in Section 9.8; however for the purpose of defining the responder endpoint, only 
anti-emetic medications, benzodiazepines, and triptans will be considered a rescue medication. 
Patients are encouraged to avoid rescue medication use for the first 2 hrs following treatment 
with the study medication. The patient will be required to return to the Research Clinic (Visit 3) 
within 3–5 days from the last study medication administration for final in-clinic assessments, to 
return the Patient Kit containing the used and unused study medication, ePD, and any other 
unused supplies. Conversely, patients will be asked to return to the Research Clinic after 
12 weeks with their unused Patient Kit if they did not treat a CVS episode within this time 
period. Visit 3 will include the following assessments: Vital signs; full physical examination; 
assessment for treatment emergent adverse events; 12-lead ECG, concomitant medications 
(including rescue medication taken), and clinical labs. 

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Safety 
Patient safety will be monitored throughout the trial by the Investigator and supported by regular 
review by the Medical Monitor. The subject will be tested to ensure they do not have the 
Hepatitis B or C virus, HIV, or COVID-19 during the screening period. Chemistry and 
hematology laboratory values will be assessed prior and subsequent to treatment of the CVS 
episode. Patients who experience intolerable symptoms during treatment may discontinue the 
study at the judgement of the Investigator. Patients may withdraw consent at any time. 
All safety assessments will be carried out according to the study Schedules of Events (Table 1). 
Laboratory assessments are listed in the Appendix, Section 17.1 of the protocol. The 
approximate total blood volume drawn is the trial is shown below. 
Sample 
# Samples Taken 
Sample Volume (mL) 
Blood Volume 
Hematology 
2 
X 
4 mL 
= 
8mL 
Serology 
1 
5 mL 
5 mL 
Serum Pregnancy 
2 
5 mL 
10 mL 
Chemistry 
2 
8.5 mL 
17 mL 
Total 
 
40 mL 
 
7.2 
Number of Patients and Sites 
Approximately 150 patients are planned to be randomized at approximately 15 study centers. 
7.3 
Method of Treatment Assignment and Blinding 
Patients will be randomized in a 1:1:1 ratio to 1 mg AZ-010, 3 mg AZ-010, or matching Staccato 
Placebo (Staccato device without drug coating). Randomization will be stratified by duration of 
the patient’s typical CVS episode into one of the following two categories: 
1. Typical episode of CVS lasts 24 hrs or less from the first vomiting/retching event;  
2. Typical episode of CVS lasts greater than 24 hrs from the first vomiting/retching event. 
 
The randomization schedule will be generated prior to study start. All study patients, 
Investigators, and site study staff will be blinded to study medication assignment. Devices and 
packaging of AZ-010 and placebo be identical in appearance. 
7.4 
Rationale for Study Design, Doses, and Primary Endpoint 
Double-blind, randomized, placebo-controlled studies are considered optimal for obtaining 
unbiased estimates of the efficacy and safety of investigational products. There have been no 
double-blind, randomized, placebo-controlled studies assessing the acute treatment of CVS in 
adults prior to this trial. 

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CVS is generally described as consisting of four phases. The hyperemesis phase usually starts 
from the early hours of the morning to noon, and is characterized by intense persistent nausea 
and repeated vomiting. The vomiting frequency can be up to eight times every hour 
(Fleisher et al, 2005). This can last for 1–7 days. Antiemetic agents have been reported to be a 
key component of support care for acute abortive treatment during the prodromal and emetic 
phases of CVS in adults (Abell et al, 2008). Abortive IV antiemetic agents such as the 5-HT3 
antagonists ondansetron at high doses and granisetron were reported for supportive treatment of 
acute vomiting episodes in CVS patients (Li and Misiewicz et al, 2003; Yang, 2010; 
Venkatasubramani, 2007). 
Granisetron is a highly selective and potent 5-HT3 receptor antagonist widely used for over 
twenty years as an effective antiemetic treatment (Blower, 2003). Because of its demonstrated 
effectiveness as an antiemetic treatment, granisetron was selected as the drug for development 
using the Staccato technology. One of the potential advantages of Staccato Granisetron 
(AZ-010) is rapid IV-like pharmacokinetics. In Phase 1 clinical trials with Staccato granisetron, 
mean peak plasma levels were achieved within minutes following inhalation. Because of this 
property, Staccato Granisetron offers flexibility compared to the IV route of administration since 
the patient can take the medication at home and achieve rapid drug exposure in a non-invasive 
way. In addition, as an abortive therapy, Staccato Granisetron offers an advantage to oral 
treatments that may be difficult to administer to an individual with uncontrolled vomiting. 
IV administered granisetron at doses of 1 and 3 mg have been shown to be effective in treating 
nausea and vomiting. For example, a randomized, double-blind dose-ranging study for IV 
granisetron in the prevention of PONV found that a single dose of 1 mg or 3 mg resulted in a 
significant reduction in the numbers of patients experiencing postoperative nausea or vomiting 
during postoperative periods of 0–6 h and 0–24 h (78% and 77% of patients, respectively) 
(Wilson et al, 1996). Granisetron was well tolerated and the optimum dose was 1 mg. Consensus 
guidelines for the prevention of PONV in adults recommend treatment with 0.35–3 mg IV 
granisetron or 4 mg IV ondansetron at the end of surgery (Gan et al, 2014).  
The selection of the 1 mg and 3 doses of AZ-010 for this study is supported by a Phase 1 study 
(AMDC 010-101) demonstrating the equivalence of PK exposure between 1 mg AZ-010 and 
1 mg IV granisetron. In this crossover study conducted in healthy volunteers, mean peak and 
total granisetron exposure (Cmax and AUC) were similar for both routes of administration with 
both treatments yielding peak exposure within 2 minutes. The half-life was the same with the IV 
and Staccato treatments at 10 hr. Consequently, given the importance of the 1 and 3 mg IV doses 
for granisetron in treating nausea and vomiting noted above and the PK equivalence of IV and 
Staccato granisetron, doses of 1 mg and 3 mg AZ-010 were selected for this study. 
CVS is characterized by intense vomiting. The primary endpoint for this study is aimed at 
capturing the number of times the patient has vomited or retched (which will be considered the 
same as vomiting in the enumeration of events) in the time period specified post dosing. This 
endpoint is the most direct assessment of the primary symptom and will be recorded by the 
patient in the ePD. 

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7.5 
Schedule of Events 
The schedule of events is provided in Table 1. 

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Table 1: 
Schedule of Events 
Event 
Screening 
Randomization1 
Home Treatment Period2 
(Up to 12 Weeks Post Randomization) 
Follow-Up 
/Termination 
Visit 1 
(Up to Day -14) 
Visit 2 
(Day 1) 
Schedule of Assessments for each Dosing Day (Up to 5 days) 
Visit 3 
Pre-0 
0 
2 h 
post dose 
6 h 
post dose 
12 h 
post dose 
24 h 
post dose 
Informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
Urine Drug and alcohol breath screen 
X 
 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
X3 
 
 
 
 
 
 
 
Brief Physical Exam4 
 
X 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
X 
Pregnancy test5 
X 
 
 
 
 
 
 
 
X 
Clinical laboratory testing6 
X 
 
 
 
 
 
 
 
X 
Serology (HIV, HBV, HCV) 
X 
 
 
 
 
 
 
 
 
COVID -19 test 
X 
X 
 
 
 
 
 
 
 
12-lead electrocardiogram 
X 
X7 
 
 
 
 
 
 
X 
Vital signs 
X 
X 
 
 
 
 
 
 
X 
Device Training 
 
X 
 
 
 
 
 
 
 
ePD Instructions 
 
X 
 
 
 
 
 
 
 
Randomization and assign Patient Kit 
 
X 
 
 
 
 
 
 
 
Study Medication Administration8 
 
X 
 
X 
 
 
 
 
 
Patient activates ePD and study clock  
 
 
 
X 
 
 
 
 
 
Patient records number of discrete 
vomiting/retching events (ePD) 
 
 
 
X----------X 
 
 
VAS Assessments (ePD)9 
 
 
 
 
X 
X 
X 
X 
 
RINVR Assessment (ePD) 
 
 
 
 
 
X 
X 
X 
 
Intensity of Attack Scale (ePD) 
 
 
 
 
X 
X 
X 
X 
 

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Event 
Screening 
Randomization1 
Home Treatment Period2 
(Up to 12 Weeks Post Randomization) 
Follow-Up 
/Termination 
Visit 1 
(Up to Day -14) 
Visit 2 
(Day 1) 
Schedule of Assessments for each Dosing Day (Up to 5 days) 
Visit 3 
Pre-0 
0 
2 h 
post dose 
6 h 
post dose 
12 h 
post dose 
24 h 
post dose 
Prior Episode Questionnaire ePD 
 
 
 
 
 
 
 
X 
 
24 Hour Vomiting and Retching 
Questionnaire 
 
 
 
X-----------------------------------------------X 
 
Reconciliation of Patient Kit 
 
 
 
 
X 
Adverse events 
 
X 
 
X-----------------------------------------------X 
X 
Rescue Med or HCP Visit 
 
 
 
X-----------------------------------------------X 
 
Concomitant medications 
X 
X 
X-------------------------------------------------------------X 
X 
HBV = hepatitis B virus; HCV = hepatitis C virus 
1 
Randomization/Day 1 may occur any time after eligibility has been confirmed at Screening. The Home Treatment Period cannot begin until the 
triplicate ECG and adverse event assessments are evaluated from Visit 2. 
2 
Patients will be asked to enter responses into the ePD daily during the Home Treatment Period to ensure the device is charged and working. 
3 
Conducted upon return to clinic and prior to pre-test Study Medication administration only  
4 
Brief Physical exam will be symptom directed prior to patient discharge from the clinic  
5 
Serum pregnancy test only for females of childbearing potential  
6 
Includes hematology, serum chemistry, and urinalysis performed by the central lab. 
7 
ECG in triplicate at pre-dose and 2, 30, 60, 90, and 120 min post dosing with Study Medication 
8 
Study medication should be administered as closely as possible to start of vomiting; once per day up to 5 consecutive daily doses can be administered as 
long as the patient is still experiencing the same CVS episode 
9 
Includes separate scales for abdominal pain, nausea, and anxiety/panic 

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7.6 
Procedures for Protocol 
The following sections provide details regarding the procedures to be performed at each study 
visit. All of the following assessments should be made according to the Schedule of Events 
(Table 1). 
7.6.1 
Visit 1: Screening Visit 
Patients will report to the clinical site for a screening examination between Day -14 and Day -1 
and the patient and clinical staff will follow all appropriate COVID-19 safety procedures. 
Prior to performing any study-related activities or evaluations, the patient must be thoroughly 
informed about all aspects of the study and sign the Informed Consent Form (ICF). Patients will 
sign the study-specific consent form prior to any screening procedure. A signed copy of the ICF 
should be provided to each consenting patient and with the original to be retained in the patient’s 
study records.  
For all study procedures, see the Schedule of Events (Table 1). The following information and 
procedures will be performed and documented as part of the Screening assessment: 
• COVID-19 testing. 
• Assessment of eligibility according to inclusion/exclusion criteria. 
• Demographics, including sex, ethnic origin, date of birth. 
• Medical history (with emphasis on history of CVS noted above) including query for baseline 
signs/symptoms. 
• Review of prior and ongoing concomitant medications (taken in previous 30 days). 
• Complete physical examination plus height and weight. 
• Vital signs measured with the subject in a seated position (for at least 2 minutes prior), 
including blood pressure, pulse rate, respiration rate, pulse oximetry, and temperature. 
• Standard 12-lead ECG. 
• Blood samples for routine clinical labs (clinical chemistry, hematology). 
• Blood samples for serology (HIV, and hepatitis B and C evaluations). 
• Urine samples for urinalysis and drugs of abuse screen. 
• Alcohol breath test. 
• Serum pregnancy test (females of childbearing potential only). 
 

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Compliance with inclusion criteria (listed in Section 8.1) and exclusion criteria (listed in 
Section 8.2) will be verified against information collected and documented in the case report 
form (eCRF). 
Once all inclusion criteria are met, exclusion criteria ruled out, and laboratory measurements 
obtained and reviewed, consenting patients are eligible for randomization into the study. 
7.6.2 
Visit 2: Randomization and Pre-test Study Medication Administration 
On arrival at the clinical site, all patients will follow the appropriate COVID-19 procedures and 
undergo the following assessments, which will be documented: 
• COVID-19 testing. 
• Confirmation of eligibility according to inclusion/exclusion criteria.  
• Update of medical history including query for any pre-treatment adverse events. 
• Concomitant medication use since the Screening visit. 
• Physical examination plus weight. 
• Vital signs measured with the subject in a seated position (for at least 2 minutes prior), 
including blood pressure, pulse rate, respiration rate, pulse oximetry, and temperature. 
•  Randomization and assignment of Patient Kit. 
• Staccato device training. 
• ePD instructions and training. 
 
Upon determination of continued eligibility from above, the patient will undergo procedures to 
determine the safety and tolerability of their assigned (randomized) study medication. Patients 
will be instructed to take a pouch from their assigned Patient Kit, open it and self –administer the 
medication in the clinic. The patient should administer the dose while sitting or in a semi-supine 
position. They will be assessed and monitored pre-dose and following dosing for the next 2 hours 
as follows: 
• 12-lead ECG in triplicate at pre-dose and 2, 30, 60, 90, and 120 min post dose 
• Adverse Event assessment  
• Brief Physical examination at 120 min post dose 
 
Patients who meet all inclusion criteria and none of the exclusion criteria and have no 
clinically-significant observations or abnormalities on the ECG following administration of 
Study Medication (either 1 mg AZ-010, 3 mg AZ-010, or placebo) will be provided with their 
Patient Kit that contains 5 unused Staccato devices in addition to the 1 Staccato device that was 
used in the clinic. 

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7.6.3 
Home Treatment Period 
Randomized patients will be asked to treat a subsequent CVS episode within 12 weeks from the 
date that a patient receives their study medication for the Home Treatment Period. Enrolled 
patients will self-administer the study medication when they know their CVS episode is 
imminent or as soon as possible after a vomiting episode has begun. Patients will interact with 
their ePD CVS-related prior to initiation of treatment (if possible) and to capture the study data. 
The ePD will be used to record the date and time of study medication. Prior to dosing, the patient 
will engage the ePD to mark the dosing and onset of episode. If the patient has an episode that 
does not resolve within 1 day of dosing then they may administer another study medication for 
up to a total of 5 consecutive days. As soon as possible, they should contact the clinical site to 
inform them of the onset of the episode and treatment with study medication. 
Patients will use the ePD and paper diaries to capture the study data. The ePD will be used to 
record the date and time of study medication administration, use of rescue medication, the 
number of vomiting and retching events at various time points, and the patient reported outcome 
measures (including the intensity and duration of the CVS episode, severity of abdominal pain, 
nausea, and anxiety/panic, and characteristics of the nausea, vomiting and retching over defined 
time periods). In order to keep the patient practiced in using the ePD over the possible 12-week 
period and to maintain charge of the device, the patient will be required to interact daily with the 
device. Full details will be provided with the ePD training. Patients will use paper diaries/logs to 
record additional details regarding the timing of vomiting/retching events, concomitant 
medication use, and adverse events. 
Patients will be instructed to contact the Research Clinic at the earliest possible time after 
initiation of dosing and any time should they require rescue medication, medical assistance or 
experience an intolerable AE at home during the treatment period. Adverse events will be 
recorded separately by the patient in a paper diary. In the case of intolerable symptoms following 
study medication administration, the patient may take a rescue medication. Permitted rescue 
medications will not be provided to the patient, but it may include any agent(s) defined in the list 
in Section 9.8. Patients will record in their paper diary any medications taken during the Home 
Treatment period. Patients are encouraged to avoid rescue medication use for the first 2 hrs 
following treatment with the study medication. In the case of extreme distress, the patient should 
contact the clinical site and/or receive treatment from a health care facility. 
Patients will be instructed to contact the study site when a CVS episode and dosing occurs (and 
study sites should try to contact a patient when they receive a notification that that patient has 
dosed) so that the study site may schedule the Follow up Visit to the clinic within 3–5 days after 
the last dose of study medication is taken (or if the 12-week treatment period has expired and the 
patient has not yet treated a CVS episode). These latter patients will be excluded from the 
efficacy analyses since they did not take any study medication to treat a CVS episode. 
If the number of vomiting and retching events are not recorded on the ePD or the 24 hour 
vomiting and retching questionnaire and the patient has unused study medication, that patient 
may be allowed to continue participation in the 12-week Home Treatment Period in order to treat 
a second CVS episode during this period. 

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7.6.4 
Visit 3: Follow up and Termination 
The following assessments will be performed and documented for all patients completing the 
study. If a patient discontinues from the study prematurely during the Home Treatment Period, 
they should complete all assessments according to the Schedule of Events (Table 1) summarized 
below, if possible. The reason for discontinuation must be fully documented in the subject’s 
source documentation and in the database: 
• Symptom directed (brief) physical examination plus weight. 
• Vital signs measured with the subject in a seated position (for at least 2 minutes prior), 
including blood pressure, pulse rate, respiration rate, pulse oximetry, and temperature. 
• Blood samples for routine clinical labs. 
• Adverse events: Subjects will be instructed to report AEs during the study.  
• Concomitant medications: All concomitant medications, including rescue medications, will 
be documented in the database. 
• Standard 12-lead ECG 
• Urine samples for urinalysis  
• Serum pregnancy test (females of childbearing potential only) 
 
Subjects may be discharged from the clinic when all final procedures have been completed. 

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8 
SELECTION AND WITHDRAWAL OF PATIENTS 
Patients eligible for enrollment in the study must meet all of the following inclusion criteria and 
none of the exclusion criteria. 
8.1 
Inclusion Criteria  
1. Adult males and females between 18 and 60 years of age, inclusive at the time of signing the 
informed consent document. 
2. Understand and voluntarily sign an informed consent document prior to any study related 
assessments/procedures being conducted.  
3. Diagnosis of cyclic vomiting syndrome (CVS) using the Rome IV diagnostic criteria and 
must have: 
• Stereotypical episodes of acute onset vomiting lasting < 1 week; 
• At least 3 discrete episodes of vomiting in the prior year and 2 episodes in the past 
6 months, occurring at least 1 week apart; 
• Absence of vomiting between episodes (but milder symptoms may be present); 
• Symptoms must be present for the past 3 months with onset at least 6 months prior 
4. Has a prodrome or pre-emetic symptoms associated with approximately half of their 
“typical” CVS episodes 
5. If of reproductive age, female participants and female partners of male participants, willing 
and able to use a medically highly effective form of birth control from at least 4 weeks prior 
to Baseline until at least 30 days following last dose of study drug. Examples of medically 
highly effective forms of birth control are: 
• Surgical sterility (hysterectomy or bilateral ligation) or post-menopausal (cessation of 
menses for at least 12 months prior to screening)  
• Sexual partner is sterile, or of the same sex 
• Implants of levonorgestrel in females 
• Oral contraceptive (combined, patch, vaginal ring, injectable, implant) in females 
• Double-barrier method (any combination of physical and chemical methods) 
• Intrauterine device with a failure rate less than 1% per year 
6. Male participants must: 
• Agree to use, with their partners, one of the highly effective contraceptive methods listed 
in Inclusion Criterion 5, from Baseline until at least 30 days following last dose of study 
drug. 
• Refrain from donating sperm during the study and for at least 30 days after the end of the 
study.  

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7. Otherwise healthy, as determined by the responsible physician, based on a medical 
evaluation including history, physical examination, vital signs, electrocardiograms (ECGs) 
and laboratory tests assessed at the screening visit. 
8. Negative urine tests for selected drugs of abuse and alcohol breath test at Screening. 
Note: Patients with a positive urine drug screen for benzodiazepines or opioids may be 
allowed in the study provided the drug was prescribed by a physician. 
9. Willing and able to adhere to overall study visit schedule, procedures and other protocol 
requirements.  
 
8.2 
Exclusion Criteria 
1. Any significant medical or psychiatric condition that could, in the Investigator’s opinion, 
compromise the subject’s safety or interfere with the completion of this protocol. 
2. Any condition, including the presence of laboratory abnormalities or pulmonary condition, 
which according to the Investigator places the subject at unacceptable risk if he/she were to 
participate in the study. 
3. A diagnosis of any gastrointestinal disorder other than CVS that in the judgement of the 
Investigator could compromise the subject’s safety or interfere with the interpretation of 
safety or efficacy data. 
4. Current history of clinically significant central nervous system (e.g., seizures), cardiac, 
pulmonary (e.g., asthma, COPD), metabolic, renal, or hepatic conditions. 
5. Use of drugs known to prolong the QTc interval with known risk of Torsade de Pointes. ECG 
findings of QTcF interval > 450 msec for men and > 470 msec for women obtained at 
screening visit or prior to the first dose of study drug. 
6. Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase 
(GGT), serum creatinine, or total bilirubin > 1.5 upper limit of normal (ULN) at screening or 
prior to the first dose of study drug. These laboratory tests may be repeated once, if they are 
abnormal on first screening, and if there is a medical reason to believe the results may be 
inaccurate. If the repeat test is within the reference range, the subject may be included only if 
the Investigator considers that the previous finding will not compromise the subject’s safety 
and will not interfere with the interpretation of safety data. 
7. Positive blood screen for human immunodeficiency virus (HIV antibody), hepatitis B virus 
surface antigen, or hepatitis C virus antibody at screening. 
8. History of alcohol or illicit drug abuse within 1 year before the first dose of study drug. 
9. Daily use of marijuana. 
Note: Occasional use of THC/cannabinoid products is allowed in the study 
10. Participation in a clinical trial and receipt of an investigational medication or a new chemical 
entity within 90 days, 5 half-lives, if known, or twice the duration of the biological effect of 
any medication (whichever is longer) prior to the first dose of current study drug. 

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11. Donation of blood, plasma or other blood products or blood collection in excess of 470 mL 
within 8 weeks prior to dosing. 
12. Known history of sensitivity to any of the study drugs or components thereof, or to other 
5-HT3 receptor antagonists, or a history of medication allergy or other allergy that, in the 
opinion of the Investigator, contraindicates study participation. 
13. Major surgery within 4 weeks of screening that could interfere with, or for which the 
treatment might interfere with, the conduct of the study, or that would pose an unacceptable 
risk to the subject in the opinion of the Investigator. 
14. Uncontrolled current illness (i.e., active infection). 
15. Has a current or a history of cancer, with the exception of basal cell carcinoma. 
 
8.3 
Patient Withdrawal Criteria 
All patients are free to withdraw from participation in the study at any time, for any reason, and 
without prejudice. The Investigator must withdraw any patient from the study if the patient 
requests to stop participating in the study. The Investigator, Sponsor, or its designee may remove 
a patient from the study at any time and for any reason. 
Patients who withdraw or are withdrawn from the study will not be replaced. 
8.3.1 
Patient Withdrawal Procedures 
A patient who prematurely discontinues study participation should have all Visit 3 assessments 
performed as an Early Termination Visit, (See Table 1).  
If a patient terminates early from the study, the Investigator will record the reason(s) for early 
termination on the relevant electronic case report form (eCRF). The specific reason for the 
withdrawal should be carefully documented on the eCRF. 
8.4 
Emergency Unblinding of Treatment Assignment 
In the case of a medical requirement to break the blind to determine appropriate treatment for an 
adverse event, unblinding of a patient’s treatment assignment can be achieved through the 
study-specific Interactive Web Response System. If possible, the Investigator should discuss the 
circumstances with the Medical Monitor(s) prior to accessing unblinding information. In the 
event of a blind break, the Medical Monitor(s) will be notified through the electronic data 
capture system. The patient for whom the blind is broken should be subsequently withdrawn 
from the study. The details regarding the process of breaking the blind are outlined in the 
Medical Monitoring Plan. 

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8.5 
Individual or Study Stopping Criteria 
1. Individual Stopping Criteria 
Patients experiencing a CTCAE Grade 3 or higher AE may be discontinued from the trial 
regardless of the assessment of attribution to the study drug (eg, potential relatedness) following 
review by the PI and Medical Monitor. 
2. Study Stopping Criteria 
The study should be stopped and the data reviewed if 2 or more patients develop the same 
CTCAE Grade 3 event or 1 patient develops a CTCAE Grade 4 or higher event. 
Any termination required by the Sponsor must be implemented by the Investigator, if instructed 
to do so, in a time frame that is compatible with the patient’s well-being. 

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9 
DESCRIPTION OF STUDY TREATMENT 
9.1 
Description of Investigational Products (Study Medication) 
Study Medication will be administered once per day for up to 5 days. 
Study Medication 
 
Study Medication 
Product Name: 
AZ-010 
Staccato Placebo 
Dose/Dosage Form:  
1 mg and 3 mg 
Staccato 
No active drug 
Staccato 
Route of 
Administration:  
Oral inhalation 
Oral inhalation 
Physical Description:  
White plastic Staccato 
device 
Matching white plastic Staccato 
device 
 
9.2 
Dose-Adjustment Criteria 
No individualized dose adjustment is allowed during the study. 
9.3 
Packaging and Labeling 
AZ-010 and Staccato placebo devices will be packaged inside a sealed foil pouch. Each patient 
will receive a kit containing 6 blinded study devices. 
The label(s) for the study medication and placebo will include Sponsor name and address, the 
protocol number, investigational product name, dosage form, storage conditions, and required 
caution statements and/or regulatory statements, as applicable. Additional information may be 
included on the label as applicable per local regulations. 
Adequate supplies of study medication will be provided to each site by the sponsor or designee. 
Study medication should be stored as stated on the product label, in a secure, 
temperature-monitored, locked area, under the responsibility of the Investigator or other 
authorized individual until dispensed to the patients. 
Study medication dispensed to patients should be stored in the original sealed foil pouch at room 
temperature as stated on the package label. No special handling procedures are required. 
9.4 
Investigational Product Accountability and Disposal  
To satisfy regulatory requirements regarding drug accountability, all study medication will be 
reconciled in full. The clinical site must maintain accurate records of the receipt of all study 
drug, including date received, lot number, expiration date if applicable, amount received, 
condition of the package, and the disposition of all study drug. 
Current dispensing records will also be maintained, including the date and amount of medication 
dispensed and the identity of the subject receiving the medication. Any device used by the 

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patient at home should be returned to the foil pouch from which it came and returned to the 
clinical site and held until the study monitor has completed product accountability. 
9.5 
Study Medication Preparation 
Study Medication will be packaged and labeled by a vendor selected by the Sponsor and 
dispensed to the site for distribution to the patients. Patients will be instructed in the use of the 
Staccato device at the clinical research center. Instructions for use will be provided to the patient 
for home use.  
9.6 
Investigational Product Compliance 
All investigational products used in this study will be monitored for compliant usage throughout 
the trial by Alexza or their designee. All Staccato devices not used in the study must be returned 
to the Sponsor facility after the study is completed. 
9.7 
Concomitant Medications and Procedures  
Medications, including over the counter therapies (e.g., vitamins, herbal and nutritional 
supplements), taken during the At-Home Treatment Period dosing should be recorded. 
Medications indicated for treatment of AEs will be permitted during the study if they are not 
interfering with study outcomes or subject safety in the opinion of the Investigator, and if they do 
not fall under the list of prohibited medications. Their use must be documented in the subject’s 
eCRF. Any medication taken as a rescue medication following dosing with study medication 
must be recorded with time and dose in the ePD (patient’s electronic diary). 
9.8 
 Permitted Rescue Medications 
The clinical site will discuss with the patient what they typically use to treat or abort their CVS 
episode. The site and the patient will agree in advance at Visit 2 what possible rescue 
medications will be used in the study. The PI will choose the rescue medication(s) consistent 
with the patient’s preference and experience from the list below. Patients in distress and 
requiring the use of rescue medication should contact the clinical center prior to dosing if 
possible. Only anti-emetic medications, benzodiazepines, and triptans will be considered “rescue 
medications” for the purpose of characterizing participants who meet the responder endpoint. 
Allowed rescue medications during emetic phase: 
1. Anti-emetics: Prochlorperazine, Metoclopramide, or Aprepitant 
2. Antihistamine: Diphenhydramine 
3. Benzodiazepine: Lorazepam 
4. Analgesics: Ibuprofen or Ketorolac 
5. Gastric acid suppressants: Omeprazole or Ranitidine 
6. Antimigraine: Sumatriptan, Zolmitriptan, and Frovatriptan  
 

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10 
STUDY ASSESSMENTS AND PROCEDURES 
All assessments and procedures will be performed according to the Schedule of Events (Table 1). 
10.1 
Demographic Characteristics and Medical History 
Demographic characteristics [i.e., sex, ethnic origin, date of birth, and height and weight will be 
collected at the Screening Visit and detailed on the eCRF. 
Prior to randomization. the patient’s typical CVS episode will be classified by usual duration into 
one of the following two categories: 
1. Typical episode of CVS lasts 24 hrs or less from the first vomiting/retching event; 
2. Typical episode of CVS lasts greater than 24 hrs from the first vomiting/retching event. 
 
A thorough medical history with particular reference to history of vomiting symptoms, CVS 
diagnosis, typical duration of CVS episode (hrs vs days), average number of vomiting/retching 
events in typical CVS episode, frequency of CVS episodes per year, any triggers for CVS 
episode, other GI conditions that may cause similar symptoms, treatment history, and current 
medications and co-morbidities will be collected at the Screening Visit and Randomization Visit 
for each dose group. 
10.2 
Vital Signs, Weight, and Height 
Vital signs will be measured after the patient has been in a seated position for at least 2 minutes 
and will include blood pressure, pulse rate, respiratory rate, and temperature. 
Patients should wear light clothing, empty pockets of heavy objects, and remove his/her shoes 
before weight is measured. Height will be measured after the patient has removed his/her shoes. 
Height will only be measured at the Screening Visit. 
10.3 
Physical Examination 
A complete physical examination will include an examination of all major organ systems to 
include, but not be limited to, chest auscultation, abdominal auscultation and palpation, head, 
eyes, ears, nose and throat, and will exclude urinary and reproductive systems. A brief physical 
examination will be symptom directed. 
10.4 
Electrocardiogram 
Twelve-lead electrocardiograms will be performed after the patient has rested in a supine or 
semi-supine position for at least 5 minutes. Individual parameters including heart rate, PR, QT, 
QTcF, QRS, and RR intervals will be collected. Repeat electrocardiograms (if deemed 
necessary) should be performed at least 5 minutes apart. The Investigator should indicate review 
of the electrocardiogram report by signing and dating the report. ECGs performed on Day 1 for 
pre-test assessment will be collected in triplicate for the pre-dose and post-dose collection times. 
The initial ECGs should be performed in a semi-supine position to accommodate appropriate 
dosing of the product. 

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10.5 
Clinical Laboratory Assessments 
The list of clinical laboratory assessments to be performed is included in the 
Appendix, Section 17.1. Specific days for clinical laboratory assessments can be found in the 
Schedule of Events (Table 1). 
The results of clinical laboratory tests conducted at the Screening Visit must be assessed by the 
Investigator to determine each subject’s eligibility for participation in the study. The Investigator 
should indicate review of the laboratory reports by adding their initials to the report.  
Any significant abnormalities should be fully investigated. Whenever possible, the etiology of 
the abnormal findings will be documented. Laboratory results with significantly abnormal values 
should be investigated as such and checked for verification. Additional tests and other 
evaluations required to establish the significance or etiology of an abnormal result or to monitor 
the course of an AE should be obtained when clinically indicated. In particular, if a clinically 
significant abnormal result is observed that is not resolved by the final study visit, repeat tests 
will be performed if possible and resolution or stability of the abnormality will be recorded in the 
source documentation. 
Any significant laboratory abnormalities that are either serious or unexpected will be promptly 
reported to Alexza’s Medical Monitor. Any additional relevant laboratory results obtained by the 
Investigator during the course of this study will be reported to Alexza Pharmaceuticals or its 
representative. 
10.6 
24 Hour Vomiting and Retching Questionnaire 
The 24 hour vomiting and retching questionnaire is a paper questionnaire on which patients will 
record the date of dosing with study medication and the total number vomiting and retching 
events that occurred within the first 24 hours after dosing. A vomiting or retching event is 
defined as one or more continuous episodes of vomiting (expulsion of stomach contents through 
the mouth) or retching/dry heaves (an attempt to vomit that is not productive of stomach 
contents). If there is a break of at least 1 minute between vomiting and retching events, those 
should be considered two different events. In addition to the 24 hour vomiting and retching 
questionnaire, patients will record the number of vomiting and retching events that they 
experience within the first 30, 60, 90, and 120 minutes on the ePD. 
10.7 
Visual Analog Scale (VAS) 
The visual analog scale is a scale of continuous measure initially developed for pain that has 
been used in a variety of clinical settings where the endpoint of interest is based on a subjective 
perception. The visual analog scale is a distinct 100-millimeter line anchored on the left end (0) 
at no degree of impairment and on the right end (100) at full degree of impairment, where 
indication of the degree of impairment perceived at the time of assessment is captured by 
marking the appropriate position on the line between the anchor points. The measured distance 
of the mark from the left anchor will be recorded in millimeters and this scale will be adapted for 
the ePD. 

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There will be 3 different VAS scales assessed in the study. In each case the patient will be asked 
to rate the appropriate variable in relation to their last vomiting/retching episode:  
• The assessment of abdominal pain whereby 0 = no pain and 100 = worst possible pain; 
• The assessment of nausea whereby 0 = no nausea and 100 = worst possible nausea; 
• The assessment of anxiety/panic whereby 0 = no anxiety/panic and 100 = worst possible 
anxiety/panic. 
 
10.8 
Rhodes Index of Nausea, Vomiting, and Retching (RINVR) 
The RINVR is designed to assess the degree of nausea distress and vomiting distress in patients. 
It is composed of 8 questions and each question has 5 choices (see Appendix, Section 17.4). 
Questions 1, 4, 6, 7, and 8 deal with symptom occurrence and Questions 2, 3, 5 deal with degree 
of discomfort of the individual symptoms. Individual questions can be tracked over time or a 
composite score can be formed by adding the total of the symptom occurrence and degree of 
discomfort questions together. This scale will be adapted for the ePD and patients will be 
prompted to answer the questions according to the Schedule of Events (Table 1). 
10.9 
Intensity of Attack Scale 
The Intensity of Attack scale is designed to assess the severity of the last vomiting/retching 
episode at the time of assessment. Severity ranges from Mild to Excruciating on a 4 point scale. 
This scale will be adapted for the ePD and patients will be prompted to answer the questions 
according to the Schedule of Events (Table 1). 
10.10 
Prior Episode Questionnaire 
The Prior Episode Questionnaire is designed to compare the overall intensity and duration of the 
current CVS episode with CVS episodes that the patient has typically experienced in the past. 
For both Intensity and Duration, the patient will respond whether the current episode overall was 
Less than, the Same as, or Greater than their typical previous CVS episodes. The questions will 
be prompted approximately 24 hours after each dose of study medication is administered. 

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11 
ADVERSE EVENTS 
11.1 
Definition of Adverse Events 
An adverse event is any untoward medical occurrence that may appear or worsen in a patient 
during the course of a study. It may be a new intercurrent illness, a worsening concomitant 
illness, an injury, or any concomitant impairment of the patient’s health, including laboratory test 
values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in 
the frequency or intensity of a pre-existing condition) should be considered an adverse event. A 
diagnosis or syndrome should be recorded on the adverse event page of the eCRF rather than the 
individual signs or symptoms of the diagnosis or syndrome. 
All patients will be monitored for adverse events during the study. Assessments may include 
monitoring of the following parameters: the patient’s clinical symptoms, laboratory, physical 
examination findings, or findings from other tests and/or procedures. 
An adverse event reported after informed consent, but before the first dose of study medication, 
will be considered a pretreatment adverse event (or interim medical event) and will be captured 
on the eCRF. Adverse events will be considered treatment-emergent if the onset is after the first 
dose of study drug.  
An abnormal laboratory value is considered to be an adverse event if the abnormality: 
• Is considered clinically significant; OR 
• results in discontinuation from the study; OR 
• is judged by the Investigator to be of significant clinical importance requiring treatment, 
modification/interruption of investigational product dose, or any other therapeutic 
intervention. 
 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the adverse event eCRF. If the abnormality was not a part of 
a diagnosis or syndrome, then the laboratory abnormality should be recorded as the adverse 
event. If possible, the laboratory abnormality should be recorded as a medical term and not 
simply as an abnormal laboratory result (e.g., record thrombocytopenia rather than decreased 
platelets). 
11.2 
Evaluation of Adverse Events  
A qualified Investigator will evaluate all adverse events as to seriousness, severity/intensity, and 
relationship to Study Medication, duration, action taken, and outcome. 

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11.2.1 
Serious Adverse Event (SAE) 
A serious adverse event is an adverse event, as per Title 21 CFR 312.32 and ICH E2A.II.B that 
fulfills the following criteria: 
• Is fatal (results in death); 
• Is life-threatening (Note: the term "life-threatening" refers to an event in which the patient 
was at risk of death at the time of the event; it does not refer to an event that could 
hypothetically have caused death had it been more severe); 
• Requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization 
is defined as an inpatient admission, regardless of length of stay); 
• Results in persistent or significant disability/incapacity (a substantial disruption of the 
patient's ability to conduct normal life functions); 
• Is a congenital anomaly/birth defect; or 
• Constitutes an important medical event that may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed above. 
 
Important medical events are defined as those occurrences that may not be immediately 
life-threatening or result in death, hospitalization, or disability, but may jeopardize the patient or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization.  
Events not considered to be serious adverse events are hospitalizations for: 
• A procedure for protocol/disease-related investigations (e.g., sampling for laboratory tests). 
However, hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable serious adverse event. 
• Hospitalization or prolongation of hospitalization for technical, practical, or social reasons, in 
absence of an adverse event. 
• A procedure that is planned (i.e., planned prior to the starting of treatment on study); must be 
documented in the source document and the eCRF. Hospitalization or prolonged 
hospitalization for a complication remains a reportable serious adverse event. 
• An elective treatment of or an elective procedure for a pre-existing medical condition that 
does not worsen.  
• Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above. 
 

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If an adverse event is considered serious, the adverse event eCRF must be completed. 
For each serious adverse event, the Investigator will provide information on severity, start and 
stop dates, relationship to investigational product, action taken regarding investigational product, 
and outcome. 
Queries pertaining to serious adverse events will be handled through the electronic data capture 
system or other appropriate means. Urgent queries (e.g., missing causality assessment) may be 
handled by telephone. 
11.2.2 
Severity/Intensity 
For both adverse events and serious adverse events, the Investigator must assess the 
severity/intensity of the event. 
The National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0 should be used to grade the severity/intensity of all events. These criteria will be 
provided in a study manual. If a CTCAE criterion does not exist, the Investigator should grade 
the severity according to the following criteria:  
• Grade 1 (mild): does not interfere with the patient’s usual function 
• Grade 2 (moderate): interferes to some extent with patient's usual function 
• Grade 3 (severe): interferes significantly with patient's usual function 
• Grade 4 (life-threatening): results in a threat to life or in an incapacitating disability 
• Grade 5 (death): results in death 
 
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This criterion is not the same as “serious” which is based 
on patient/event outcome or action criteria associated with events that pose a threat to a patient’s 
life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
11.2.3 
Relationship to Study Medication 
Relationship should be assessed and provided for every adverse event/serious adverse event 
based on currently available information. Relationship is to be reassessed and provided as 
additional information becomes available. Adverse events will be classified by the Investigator 
as follows: 

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Related for Regulatory Reporting Assessment: 
Definitely Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The event resolves or improves upon withdrawal 
of drug (de-challenge). The event would be considered as definitely related to the Study 
Medication upon results of a positive re-challenge procedure. 
Probably Related: There is evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the trial medication). However, the influence of 
other factors that may have contributed to the event (e.g., the patient’s clinical condition, other 
concurrent disease, concomitant medications or events) is unlikely, and the event follows a 
clinically reasonable response upon withdrawal of drug (de-challenge).  
Possibly Related: There is evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the Study Medication). However, the influence 
of other factors may have contributed to the event (e.g., the patient’s clinical condition, other 
concurrent disease, concomitant medications or events).  
Unrelated for Regulatory Reporting Assessment: 
Unlikely Related: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event did 
not occur within a reasonable time after administration of the trial medication) and in which 
other drugs or concurrent or underlying disease provide plausible explanations (e.g., the patient’s 
clinical condition, other concomitant treatments). 
Not related: The adverse event is completely independent of Study Medication administration, 
and/or evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
11.2.4 
Duration 
For all adverse events whether or not considered serious, the Investigator will provide a record of 
the start and stop dates of the event. Every effort should be made to resolve all adverse events 
with continued follow-up with the patient until appropriate resolution can be achieved. If an 
event is unresolved at the end of the study it will be recorded as ongoing.  
11.2.5 
Action Taken 
The Investigator will record the action taken with investigational product as a result of an 
adverse event or serious adverse event on the eCRF, as applicable (e.g., discontinuation, or 
interruption of investigational product, as appropriate) and record if concomitant and/or 
additional treatments were given for the event. 
11.2.6 
Outcome 
The Investigator will record the outcome of adverse events on the eCRF, as applicable 
(e.g., recovered, recovered with sequelae, not recovered, or death (due to the adverse event)). 

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11.3 
Follow-Up 
Adverse events assessed as not related to Study Medication, including clinically significant 
laboratory tests, ECGs, or physical examination findings, must be followed until the event 
resolves, the condition stabilizes, the event is otherwise explained, or the final study visit occurs, 
whichever comes first.  
Adverse events assessed as related to Study Medication and serious adverse events will be 
followed for as long as necessary to adequately evaluate the patient’s safety, or until the event 
stabilizes, is otherwise explained, death occurs, or the patient is lost to follow-up. If resolved, a 
resolution date should be provided. The Investigator is responsible for ensuring that follow-up 
includes any supplemental investigations indicated to elucidate the nature and/or causality of the 
adverse event. This may include additional clinical laboratory testing or investigations, 
examinations, or consultation with other health care professionals as is practical. 
11.4 
Pregnancy 
The Sponsor must be informed within 24 hours upon learning that a patient, or male patient’s 
partner, has become pregnant any time after the first dose of Study Medication until 4 weeks 
after the last dose of Study Medication. Patient pregnancies (or pregnancy of a male patient’s 
partner) must be followed until termination of pregnancy or the birth of the child.  
If a female partner of a male patient taking investigational product becomes pregnant, the male 
patient taking the investigational product should notify the Investigator, and the pregnant female 
partner should be advised to call her healthcare provider immediately. 
11.5 
Recording Adverse Events 
All adverse events (regardless of seriousness or relationship to Study Medication) including 
those from the time informed consent is obtained through to the final study visit are to be 
recorded in the eCRF. Each individual adverse event is to be listed as a separate entry. The 
Investigator will provide information about dates of onset and resolution, seriousness, severity, 
action(s) taken, outcome, and relationship to the Study Medication. All adverse events should be 
documented in the patient’s source documents. 
11.6 
Reporting Adverse Events 
The Investigator must report to Sponsor or its designee all adverse events that occur during the 
study from the time written informed consent is given until the final study visit or early 
termination, regardless of their relationship to the Study Medication. Serious adverse events and 
pregnancies will be reported from the time written informed consent is given through 30 days 
beyond the last dose of Study Medication. 
11.6.1 
Reporting Serious Adverse Events 
The Investigator is required to notify the Sponsor, and the Sponsor’s designated Drug Safety 
Unit within 24 hours after becoming aware of the occurrence of a serious adverse event. All 
serious adverse events will be reported through completion of the adverse event eCRF. The 
Investigator will be responsible for reporting serious adverse events to the IRB. 

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Medical Monitor and Emergency Contact Information: 
Dr. Lawrence Blob, Medical Director, Cognitive Research Corporation 
200 Central Avenue, Suite 1230, St. Petersburg, FL33701 
Phone: 410-262-1908 
Fax: 727-897-9009 
e-mail: lblob@cogres.com 
 
If an Investigator becomes aware of a serious adverse event within 30 days after the last dose of 
Study Medication and it is considered by him/her to be caused by the Study Medication with a 
reasonable possibility, the event must be documented and reported through completion of the 
adverse event eCRF. 
11.6.2 
Reporting Urgent Safety Issues 
If the study site staff becomes aware of an actual or potential urgent safety issue, then the 
Sponsor and Medical Monitor must be immediately contacted so that appropriate urgent safety 
measures can be agreed upon. An urgent safety issue is defined as: 
• An immediate hazard to the health or safety of patients participating in a clinical study 
• A serious risk to human health or potentially a serious risk to human health 
 
An urgent safety issue may include: (1) issues with an investigational drug or comparators; 
(2) study procedures; (3) intercurrent illness (including pandemic infections); (4) concomitant 
medications; (5) concurrent medical conditions; or (6) any other issues related to the safe 
conduct of the study or that pose a risk to study patients. 
In exceptional circumstances of imminent hazard and in order to safeguard the health or safety of 
individuals, the Investigators may take urgent safety measures before informing the Sponsor, but 
the Sponsor must be informed immediately after the hazard has resolved.  

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12 
STATISTICAL ANALYSES 
12.1 
Overview 
Full details for statistical methods will be provided in the Statistical Analysis Plan. 
12.2 
Interim Analysis 
No formal statistical interim analysis is planned.  
12.3 
Determination of Sample Size 
This is a proof of concept study. There are no studies in the literature to provide reliable 
estimates of active treatment or placebo response rates using vomiting/retching events, or the 
estimate of variances around these measures, in patients with CVS being treated acutely with an 
abortive therapy. Consequently, sample size was not based on power calculations. 
Approximately 150 patients will be randomized to 1 of 3 treatment groups. An N of 50 per group 
should be sufficient to describe and compare across the efficacy parameters. 
12.4 
Endpoints 
12.4.1 
Efficacy 
Primary Efficacy Endpoint 
• The number of vomiting/retching events in the 2 hours following treatment. 
 
Secondary Endpoints 
• The percentage of patients with no vomiting or retching events and no anti-emetic 
benzodiazepine, or triptan rescue medication use in the first 24 hours following treatment. 
• The intensity of the vomiting/retching attack (Intensity of Attack Scale) at 2, 6, 12, and 
24 hours following treatment. 
• The Rhodes Index of nausea, vomiting, and retching (RINVR) at 6, 12, and 24 hours 
following treatment.  
• The assessment of abdominal pain at 2, 6, 12, and 24 hours following treatment (VAS 1–100; 
0 = no pain and 100 = worst possible pain). 
• The assessment of nausea at 2, 6, 12, and 24 hours following treatment (VAS 1–100; 
0 = no nausea and 100 = worst possible nausea). 
• The assessment of anxiety/panic at 2, 6, 12, and 24 hours following treatment (VAS 1–100; 
0 = no anxiety/panic and 100 = worst possible anxiety/panic). 
• The duration of the CVS episode at 24 hours in relation to their typical CVS episodes (Prior 
Episode Questionnaire). 

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• The intensity of the CVS episode at 24 hours in relation to their typical CVS episodes (Prior 
Episode Questionnaire). 
• Use of anti-emetic, benzodiazepine, or triptan rescue medication within the 24 hours 
following treatment with the study medication. 
• Visit to urgent care, emergency department, or physician’s office for care related to the 
treated episode of CVS within the 24 hours following treatment with the study medication. 
 
12.4.2 
Safety 
Safety and tolerability of AZ-010 will be assessed by evaluating adverse events, vital signs, 
clinical laboratories, ECG results, as well as physical examinations. 
12.5 
Analysis Populations 
The Efficacy Population will include all patients who receive study medication and treated at 
least 1 episode of vomiting/retching due to their CVS. The Safety Population will include all 
patients who receive study drug. Patients will be summarized according to study medication dose 
received (i.e., as treated) should it differ from the randomized arm. 
12.6 
Analyses 
For the study, data will be summarized by dosing group (1 mg AZ-010, 3 mg AZ-010, placebo). 
All data for analysis will be listed by patient. 
Continuous measures will be summarized descriptively (mean, standard deviation, median, 
minimum value, and maximum value) and categorical measures will be presented as number and 
percentage. 
12.6.1 
Disposition and Baseline Characteristics 
Disposition will be summarized by randomized dose group. The number and percentage of 
patients, who are randomized, treated, prematurely discontinued, and completers will be 
summarized.  
Baseline characteristics will be summarized by dose group for patients participating in the 
Treatment Period. 
Medical history will be coded with the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. Concomitant medications will be summarized by World Health Organization Drug 
Dictionary Anatomical-Therapeutic-Chemical classification and preferred term. 
Concomitant medications will be summarized by World Health Organization Drug Dictionary 
for Anatomical-Therapeutic-Chemical classification and preferred term.  

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12.6.2 
Efficacy 
All efficacy tests will be described in detail in the Statistical Analysis Plan (SAP) The SAP will 
be finalized prior to database lock. 
12.6.3 
Safety 
All safety summaries will be descriptive with no statistical hypothesis testing and based on the 
Safety Population. All safety endpoints will be listed in by-patient data listings. 
Adverse events will be coded using MedDRA and summarized by system organ class and 
preferred term. Clinically significant deteriorations in physical examination findings will be 
reported and summarized as adverse events. 
Laboratory values will be converted to the project-defined unit of measurement, as applicable, 
before analysis. Abnormal, clinically significant laboratory values will be reported and 
summarized as adverse events. 
Adverse Events 
An adverse event reported after informed consent, but before the first dose of study medication, 
will be considered a pre-treatment adverse event (or interim medical event). Treatment-emergent 
adverse events (TEAEs) will be defined as any adverse event that occurs after administration of 
the first dose of study medication until the Follow Up Visit or the Early Termination Visit. The 
number and percentage of patients who report TEAEs will be summarized by system organ class 
and preferred term. 
Treatment emergent adverse events will also be summarized by intensity as well as relationship 
to study drug. 
Patients who report the same preferred term on multiple occasions will be counted once for the 
preferred term: under the highest severity when summarized by severity and under the closest 
relationship to study medication when summarized by relationship. If a patient reports multiple 
preferred terms for a system organ class, the patient will be counted only once for that system 
organ class. 
The number and percentage of patients who experience TEAEs will be summarized by dosing 
regimen for the following: 
• By system organ class and preferred term 
• By severity/intensity, system organ class, and preferred term 
• By relationship to study drug, system organ class, and preferred term 
• Serious adverse events by system organ class and preferred term 
• Serious adverse events by relationship to study drug, system organ class, and preferred term 

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• Adverse events resulting in discontinuation of study medication by system organ class and 
preferred term 
• Adverse events that result in study medication dose interruption by system organ class and 
preferred term 
 
By-patient listings will be provided for any deaths, serious adverse events, and adverse events 
leading to discontinuation of treatment. 
Clinical Laboratory 
Clinical laboratory tests (including re-check values if present) will be listed chronologically. ‘H’ 
and ‘L’, denoting values above or below the reference range (when present), will flag 
out-of-range results. At each time point, absolute values and change from baseline of the 
hematology and chemistry variables will be summarized by treatment and time with n, mean, 
SD, SEM, median, Min, and Max values. The categorical data of the urinalysis will be 
summarized by treatment and time in frequency tables by variable. 
Vital Signs 
The mean change from Baseline to each scheduled assessment will be summarized descriptively 
by dose group for each vital sign variable specified in this protocol. Baseline will be defined as 
the last vital sign value obtained on Visit 2 and prior to any study medication administration. 
Electrocardiogram 
The change from Baseline in electrocardiogram intervals (PR, QT, QTcF, QRS, and RR) to each 
scheduled assessment will be summarized descriptively by dose group. Baseline will be defined 
as the last ECG obtained on Visit 2 and prior to any study medication administration. The 
number and percentage of patients who have a clinically notable ECG interval abnormality or 
other clinically significant ECG finding will be summarized. A listing of abnormal ECG values 
will also be provided. 
12.6.4 
Concomitant Medications  
All concomitant medications will be displayed in a listing. 

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13 
REGULATORY CONSIDERATIONS 
It is the responsibility of the clinical site and staff to notify the Sponsor and Sponsor’s designee 
immediately upon becoming aware of a serious breach of GCP or of the study protocol. It is the 
responsibility of the Sponsor or its designee to notify appropriate regulatory authorities of any 
serious breach which is likely to effect, to a significant degree, the safety or mental integrity of 
the patients of the study or the scientific value of the study. 
13.1 
Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator abide by GCP, as described in ICH Guideline E6 and in 
accordance with the general ethical principles outlined in the Declaration of Helsinki. The study 
will receive approval from the IRB prior to commencement. The Investigator will conduct all 
aspects of this study in accordance with applicable national, state, and local laws of the pertinent 
regulatory authorities. 
13.2 
Sponsor’s Responsibilities 
The Sponsor or its designee is responsible for the following: 
• Selecting qualified Investigators 
• Providing Investigators with the information they need to properly conduct an investigation 
• Ensuring proper monitoring of the investigation 
• Ensuring that the applicable regulatory authorities, and all participating Investigators are 
properly informed of significant new information regarding adverse events or risks 
associated with the medication being studied 
 
If required by standard operating procedures, a representative of the Sponsor may visit the 
investigational study site before entering a patient into the study to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of the Sponsor or its representatives. This will be 
documented in a Clinical Study Agreement between the Sponsor and the Investigator. 
 
During the study, a monitor from Alexza Pharmaceuticals or its representative will have regular 
contacts with the investigational site, for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 

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• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product accountability 
checks are being performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the patient’s medical records at the hospital or practice, and other records relevant 
to the study. This will require direct access to all original records for each patient (e.g., clinic 
charts). 
• Record and report any protocol deviations. 
• Confirm adverse events and serious adverse events have been properly documented on 
eCRFs and confirm any serious adverse events have been forwarded to the Sponsor and those 
serious adverse events that met criteria for reporting have been forwarded to the IRB. 
 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
As the Sponsor, Alexza Pharmaceuticals has delegated some responsibilities to a designee, or 
Contract Research Organization. 
13.3 
Investigator’s Responsibilities 
Investigator responsibilities are set out in the ICH Guideline for GCP and in the local 
regulations. Each Investigator participating in this study is required to maintain complete and 
accurate study documentation in compliance with current GCP standards and all applicable local 
regulations related to the conduct of a clinical study. 
The Principal Investigator will ensure that all persons assisting with the study are adequately 
informed about the protocol, any amendments to the protocol, the Study Medication, and their 
study-related duties and functions. The Principal Investigator will maintain a list of 
sub-Investigators and other appropriately qualified persons to whom he or she has delegated 
significant study-related duties. Individuals ineligible from conducting or working on clinical 
studies, including those ineligible as a result of debarment under the Generic Drug Enforcement 
Act of 1992, will not be allowed to conduct or work on studies sponsored by Alexza 
Pharmaceuticals. The Investigator is required to immediately disclose to the Sponsor in writing, 
if any person involved in the conduct of the study is debarred pursuant to a hearing by the FDA 
under this anti-fraud law, or if any proceeding for debarment is pending, or is (to the best of the 
Investigator’s knowledge) threatened.  
The Investigator is responsible for keeping a record of all patients who sign an informed consent 
document and are screened for entry into the study. Patients who fail screening must have the 
reason(s) recorded in the patient’s source documents. 
The Investigator should inform the IRB of any event likely to affect the safety of patients or the 
continued conduct of the study, in particular any change in safety. Additionally, all updates to the 
Investigator’s Brochure will be sent to the IRB. A progress report will be sent to the IRB and the 

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protocol will be reviewed annually (e.g., re-approved) or more frequently, as required by the IRB 
or local regulations.  
The Investigator will maintain a copy of all correspondence with the IRB, including copies of 
approved documents. The Investigator will also maintain a copy of the IRB membership list with 
occupation and qualification (or a statement confirming compliance with GCP requirements for 
committee composition).  
The Investigator will notify the IRB of the conclusion of the clinical study within 1 month of 
completion or termination of the study. The final report sent to the IRB will also be sent to the 
Sponsor along with the completed electronic case report forms (eCRFs) and all necessary 
regulatory documents, thereby fulfilling the Investigator’s regulatory responsibility. 
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to patient records (e.g., 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The Investigator must ensure timely and accurate completion of eCRFs and queries. 
13.4 
Protocol Amendments 
Any change to the protocol, whether it is an overall change or a change for specific study 
center(s), must be handled as a protocol amendment. All amendments to the protocol will be 
written by the Sponsor. Except for deviations that are necessary to protect the health or safety of 
the participants, Investigators must await IRB approval of protocol amendments before deviating 
from an IRB-approved protocol. A protocol change intended to eliminate an apparent immediate 
hazard to patients should be implemented immediately, and the IRB notified within 5 days. The 
Sponsor will ensure submission of any protocol amendments to the appropriate regulatory 
agencies. 
When the amendment to the protocol substantially alters the study design and/or increases the 
potential risk to the patient, the currently approved written ICF will require similar modification. 
In such cases, repeat informed consent will be obtained from patients enrolled in the study before 
continued participation under the new amendment. 
13.5 
Audits and Inspections 
The Sponsor’s Quality Assurance Unit (or representative) may conduct audits at the study site(s). 
Audits will include, but are not limited to: drug supply, presence of required documents, the 
informed consent process, laboratory specimen processing, and comparison of eCRFs with 
source documents. The Investigator agrees to cooperate with audits conducted at a reasonable 
time and in a reasonable manner. 
Regulatory authorities worldwide may also audit the Investigator during or after the study. The 
Investigator should contact the Sponsor immediately if this occurs, and must fully cooperate with 
the audits conducted at a reasonable time in a reasonable manner. 
The Investigator is required to make all study documentation promptly available for inspection, 
review or audit at the study site upon request by Sponsor, its representatives, or any appropriate 
regulatory agencies. 

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13.6 
Quality Control and Quality Assurance 
All aspects of the study will be carefully monitored by the Sponsor or its authorized 
representative for compliance with applicable government regulations with respect to current 
GCP and standard operating procedures.  
A quality control and quality assurance plan addressing aspects of the study that may impact data 
integrity or the protection of human subjects may be instituted for this study. All audit findings 
will be summarized and placed on file with appropriate 

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14 
DATA HANDLING AND RECORDKEEPING 
14.1 
Confidentiality 
All information disclosed or provided by the Sponsor (or designee), or generated or produced 
during the study including, but not limited to, the protocol, the eCRFs, the Investigator’s 
Brochure, and the results obtained during the course of the study, are confidential. The 
Investigator or any person under his/her authority agrees to keep confidential and not to disclose 
the information to any third party without the prior written approval of the Sponsor. 
Submission of this protocol and any other necessary documentation to the IRB is expressly 
permitted, IRB members having the same obligation of confidentiality. Authorized regulatory 
officials and Sponsor personnel (or designee) will be allowed full access to inspect and copy the 
records. The copied and inspected records will remain at the site and will not be transmitted or 
removed from the site. Study Medication, patient bodily fluids, and/or other materials collected 
shall be used solely in accordance with this protocol, unless otherwise agreed to in writing by the 
Sponsor and responsible ethics committee(s) or regulatory authorities. 
Patients’ names may, however, be made known to a regulatory agency or other authorized 
officials in the event of inspections. Documents containing the full name or other personally 
identifiable information of the patient are to remain at the site. This information will not be 
transferred to the Sponsor nor be contained in regulatory filings.  
14.2 
Patient Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., protected health information 
authorization).  
Patients will be identified only by unique patient numbers in eCRFs and other datasets generated 
for this study. The patient will not be identified by name in the eCRF, in any study samples or 
study reports. All data generated in this study is for research purposes only. The Sponsor, its 
partner(s) and designee(s), and various government health agencies may inspect the records of 
this study. Every effort will be made to keep the patient’s personal medical data confidential.  
The Sponsor will protect individual patient information to the fullest extent possible during this 
study. At no time will a patient become identified in any publication or presentation. However, 
the patient may have to become identified in the event of a regulatory authority audit or 
inspection in order to verify the accuracy of the data. Access to patient information is at the 
discretion of the Sponsor and cannot occur prior to database lock or other specified events as 
determined solely by the discretion of the Sponsor. 
14.3 
Data Collection 
All data obtained for analysis in the clinical study described in this protocol will use an 
electronic data capture system. Data reported in the eCRFs should be consistent with and 
substantiated by the patient’s medical record and original source documents. Any discrepancies 
must be explained.  

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Prior to the start of the study, the Principal Investigator will complete a Delegation of Authority 
form (Site Signature and Delegation Log), showing the signatures and handwritten initials of all 
individuals and the delegation of responsibilities, such as identifying those individuals who are 
authorized to make or change entries on eCRFs. 
14.4 
Case Report Form Completion 
Data within the eCRF will be monitored by a Clinical Research Associate according to the 
Monitoring Plan. Queries will be generated based on discrepancies found while monitoring. Site 
personnel will review and respond to these queries appropriately. Additionally, the Sponsor’s 
designee and the Sponsor may periodically perform aggregate data reviews, which could result in 
queries being generated for site personnel resolution. The completed eCRF for each patient must 
be signed and dated by the Principal Investigator to signify that the Principal Investigator has 
reviewed the eCRF and certifies it to be complete and accurate. 
14.5 
Database Management, Data Clarification, and Quality Assurance 
The Sponsor’s designee (i.e., a designated Contract Research Organization) will be responsible 
for data management. Data Management will develop a Data Management Plan (DMP) 
document, and provide it to the Sponsor for approval. The DMP document will define all 
activities in the data collection and cleaning process. The detailed DMP will be based on the 
protocol, work scope, contract, analysis plans, data-flows, eCRFs, data cleaning procedures, 
other supporting documents, and data management standards and practices. 
The programmed data validations will be run to check for database completeness and 
consistency, and queries will be generated upon data entry or via review by a Clinical Data 
Manager after entry. The sites will respond to the data queries in a timely manner. 
Quality control procedures will be conducted prior to database lock according to the designated 
Contract Research Organization standard operating procedures. 
When the database has been declared to be complete and accurate, it will be locked. Any changes 
to the database after that time will only be made by joint written agreement between the Sponsor, 
Statistician, Data Manager, and Quality Assurance Auditor according to designated standard 
operating procedures of the Contract Research Organization. 
14.6 
Inspection of Records 
According to the ICH guidelines for GCP, the Sponsor or designee must verify data entered in 
the eCRF entries against the source documents. The objective of source document verification is 
to comply with GCP and international regulatory requirements and to reduce the risks of fraud. 
Source document verification means ensuring that source documents are an accurate and 
confirmable reflection of the patient’s evaluations during participation in the study and that all 
relevant information recorded in the source document is accurately entered into the eCRF. All 
source documents should be correctly labeled and filed and associated with a single, verifiable 
patient. 
All data required for this study should be captured in source notes. No data obtained by the 
Investigator or other study personnel should be captured directly in the eCRF. All source 

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documents pertaining to this study will be maintained by the Investigator and made available for 
inspection by authorized persons. If electronic progress notes and other electronic source 
documents are not compliant with applicable regulatory guidance, they are not considered a valid 
source for this study. All patient progress notes must be dated and signed at the time of the visit. 
The Sponsor reserves the right to terminate the study for refusal of the Investigator to supply 
original source documentation for this clinical study. 
The Investigator will note in a source independent from the eCRF the following information: 
• Information to confirm that the patient exists (e.g., initials, date of birth, and sex); 
• Confirmation that the patient satisfies the inclusion/exclusion criteria; 
• Confirmation that the patient is taking part in the clinical study; 
• Confirmation of the informed consent process; 
• Visit dates and documentation of protocol assessments and procedures; 
• Information concerning all adverse events; 
• Details of concomitant and investigational medications. 
 
Source document verification is not a substitute for clinical study monitoring, the purpose of 
which is to ensure that the protocol has been followed correctly, the eCRF has been fully and 
accurately completed, source document verification has been carried out, and the study timelines 
and enrollment goals and requirements have been met. 
14.7 
Retention of Records 
For investigational drug studies, clinical Investigators must retain study records for a period of 
2 years following the date a marketing application is approved for the drug for the indication for 
which it is being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until two years after the investigation is discontinued and FDA is 
notified. 
The Investigator must maintain all study documentation as confidential, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator must notify the Sponsor prior to destroying any study essential documents. 
If the Investigator can no longer ensure archiving, he/she shall inform the Sponsor. The relevant 
records shall be transferred to a mutually agreed upon designee. 

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15 
PUBLICATION 
All information concerning the product as well as any information such as clinical indications for 
the study drugs, their formula, their formulation, methods of manufacture and other scientific 
data relating to it, that have been provided by Alexza Pharmaceuticals or designee, and are 
unpublished, are confidential and must remain the sole property of Alexza Pharmaceuticals. The 
Investigator will agree to use the information only for the purposes of carrying out this study and 
for no other purpose unless prior written permission from Alexza Pharmaceuticals is obtained. 
Alexza Pharmaceuticals has full ownership of the data collected as part of the study. 
The results of this study will be published in a medical publication, journal, or another public 
dissemination, or may be presented at a medical conference or used for teaching purposes. 
Additionally, this study and its results will be submitted for inclusion in all appropriate health 
authority study registries, as well as publication on health authority study registry websites, as 
required by local health authority regulations.  
By signing the study protocol, the Investigator agrees that the results of the study may be used 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals by Alexza Pharmaceuticals. If necessary, the 
authorities will be notified of the Investigator’s name, address, qualifications, and extent of 
involvement. 

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16 
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Simmons K and Parkman HP (2014). Granisetron transdermal system improves refractory 
nausea and vomiting in gastroparesis. Dig. Dis. Sci., 59(6): 1231-1234. 
Spartinou A, Nyktari V and Papaioannou A (2017). Granisetron: a review of pharmacokinetics 
and clinical experience in chemotherapy induced nausea and vomiting. Expert Opinion on Drug 
Metabolism and Toxicology, 13(12): 1289-1297 
Venkatasubramani N, Venkatesan T and Li BUK (2007). Extreme Emesis: Cyclic Vomiting 
Syndrome. Practical Gasteroenterology, 9: 21-34. 
Venkatesan T, Levinthal DJ, Tarbell SE, Jaradeh SS, Hasler WL, Issenman RM, Adams KA, 
Sarosiek I, Stave CD, Sharaf RN, Siltan S and Li BUK (2019). Guidelines on management of 
cyclic vomiting syndrome in adults by the American Neurogastroenterology and Motility Society 
and the Cyclic Vomiting Syndrome Association. Neurogastroenterol Motil, 31 (Suppl 2): 13605-
13634. 
Wilson AJ, Diemunsch D, Lindeque BG, Scheinin H, Helbo-Hansen HS, Krroeks MVAM and 
Kong KL (1996). Single-dose i.v. granisetron in the prevention of postoperative nausea and 
vomiting. British J. Anaesthesia, 76: 515-518. 
Yang HR (2010). Recent Concepts on Cyclic Vomiting Syndrome in Children. J. 
Neurogastroenterol Motil., 16(2): 139-147. 

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17 
APPENDICES 
 
 

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17.1 
Laboratory Assessments 
HEMATOLOGY 
CLINICAL CHEMISTRY 
URINALYSIS 
Haemoglobin [including 
Mean Corpuscular 
volume (MCV),  
Mean corpuscular 
haemoglobin (MCH),  
Mean corpuscular 
haemoglobin 
concentration (MCHC)],  
haematocrit,  
red cell count (RBC),  
total white cell count 
(WBC) and Differential 
blood count, including: 
basophils, eosinophils, 
neutrophils, 
lymphocytes, and 
monocytes. 
Platelet count.  
Alanine aminotransaminase (ALT; 
SGPT) 
Albumin (ALB) 
Alkaline phosphatase (ALK-P) 
Aspartate aminotransaminase (AST; 
SGOT) 
Total bilirubin 
Conjugated bilirubin 
Blood urea nitrogen (BUN) 
Calcium (Ca) 
Chloride (Cl) 
Total cholesterol  
Creatinine 
Gamma-glutamyl transferase (GGT) 
Lactic dehydrogenase (LDH) 
Total protein 
Inorganic phosphate (P) 
Potassium (K) 
Sodium (Na) 
Uric Acid 
Bilirubin 
Glucose 
Ketones 
Nitrates 
Occult Blood 
Protein 
Specific gravity 
Urobilinogen 
pH 
Leukocytes 
Microscopic urine analysis 
if dipstick is positive AND 
a physician classifies it as 
clinically significant. 
DRUG SCREEN 
SEROLOGY 
(SCREENING ONLY) 
 
Amphetamines (Urine) 
Barbiturates (Urine) 
Cocaine metabolites 
(Urine) 
Opiates (Urine) 
Benzodiazepines (Urine) 
Ethyl alcohol (Breath) 
Human immunodeficiency virus 
antibody (HIV1+2-Ab) and antigen, 
Hepatitis B surface 
antigen (HBsAg) 
Hepatitis C virus antibody (HCV-
Ab) 
 
PREGNANCY 
 
 
Serum Pregnancy testing   
 
 
 

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Alexza Pharmaceuticals, Inc. 
 
 
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17.2 
Staccato Instructions for Use 
 
Becoming Familiar with Staccato® for Inhalation 
 
Read all instructions before use. 
 
Staccato for Inhalation is a single dose, single-use inhaler for oral inhalation only.  
The pictures below show the features of Staccato for Inhalation: 
 
 
The indicator light conveys important information about dose delivery: 
• The indicator light is off when Staccato for Inhalation is removed from the 
pouch. 
• The indicator light turns on (green) when the tab is pulled out. The inhaler is 
then ready for use. 
• The indicator light turns off after the patient inhales. This indicates the dose 
has been delivered. 
• If the indicator light does NOT turn off, the dose has NOT been delivered. See 
Instructions for Use. 
 
indicator 
light 
mouthpiece 
LJ 
tab ____---7 

Staccato Granisetron (AZ-010) 
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Protocol AMDC 010-201 Amendment 2 
Alexza Pharmaceuticals, Inc. 
 
 
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Staccato For Inhalation Instructions for Use 
Read the following 6 steps before administering Staccato for Inhalation to a 
subject. Do not open the pouch until ready to use. 
 
 
1. Open pouch 
Tear open the foil pouch and remove the inhaler from the 
package.  
 
2. Pull tab 
Firmly pull the plastic tab from the rear of the inhaler.  
 
 
IMPORTANT: Check that the green light turns on. This 
indicates that the inhaler is ready for use. 
 
 
Use inhaler within 15 minutes after removing the tab or else 
the green light will turn off indicating the inhaler is not 
usable. 
 
3. Explain Procedures to Subject 
Explain the administration procedures to the subject prior 
to use and let patients know it is important to follow the 
instructions. Advise subjects that the inhaler may produce 
a flash of light or a clicking sound, or become warm during 
use. These are normal.  
 
Instruct the Subject to: 
 
4. Inhale  
Inhale through the mouthpiece with a steady deep breath.  
 
IMPORTANT: Check that the green light turns off after the 
patient inhales. The light will turn off indicating that the 
dose has been delivered. 
_____ 
I 
___ 
I 

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Alexza Pharmaceuticals, Inc. 
 
 
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5. Hold breath 
Remove the mouthpiece from the mouth and hold breath 
for as long as possible, up to 10 seconds. 
Important: If the green light stays on after the subject inhales, the dose has NOT 
been delivered. Instruct the subject to repeat steps 4, and 5 up to 2 additional times.  
If the green light still does not turn off, discard the inhaler and use a new one. 
 
 

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Protocol AMDC 010-201 Amendment 2 
Alexza Pharmaceuticals, Inc. 
 
 
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17.3 
Rhodes Index of Nausea, Vomiting and Retching 
(Sample, NOT to be used in trial) 
NOTE: 
For 6 hr assessment the reference should be “in the last 4 hours…”; for 12 hr assessment the 
reference should be “in the last 6 hours…”, for the 24 hr assessment the reference will be as 
shown below 
 
 
 
Instructions: 
Please mark the box for each question that most dear1y corresponds to your experience. Please do not miss 
out a question and place only one X in a box for each question. e.g. ml 
The __ in statements represents 
the selected phrase. 
1. In the last 12 hours I threw up __ times: 
7 or 
5-6 0 
3-40 
1-2 
I did not throw up 
3. In the last 12 hours, from vomiting or 
throwing up, I have felt __ distress: 
5. In the last 12 hours, from nausea/sickness 
to my stomach, I have felt __ distress: 
7. In the last 12 hours, I have felt nauseated 
or sick to my stomach __ times: 
7 or 
5-6 0 
3-4 0 
2. In the last 12 hours, from retching and 
dry heaves, I have felt __ distress: 
4. In the last 12 hours, I have felt nauseated 
or sick to my stomach: 
not at 
1 hour or less D 
2-3 
4-6 
more than 6 
6. In the last 12 hours, each time I threw 
up I produced a __ amount: 
very large (3 cups or 
large (2-3 cups) 
moderate (1/2-2 
small (up to 1/2 
I did not throw up 
8. In the last 12 hours, I have had periods of retching or 
dry heaves without bringing anything up __ times: 
1-2 D 

Staccato Granisetron (AZ-010) 
28 APR 2020 
Protocol AMDC 010-201 Amendment 2 
Alexza Pharmaceuticals, Inc. 
 
 
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17.4 
Intensity of Attack Scale 
 
Rate the Intensity of your last vomiting/retching episode: 
1. Mild 
2. Moderate 
3. Severe 
4. Excruciating 
 
 

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Alexza Pharmaceuticals, Inc. 
 
 
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17.5 
VAS Scales 
17.5.1 
Abdominal Pain VAS 
Place a vertical line reflecting the Abdominal Pain associated with your last vomiting/retching 
episode  
No Pain (0) -----------------------------------------------------------(100) Worst Possible Pain 
 
17.5.2 
Nausea VAS 
Place a vertical line reflecting the Nausea associated with your last vomiting/retching episode 
No Nausea (0) --------------------------------------------------------(100) Worst Possible Nausea 
 
17.5.3 
Anxiety/Panic VAS 
Place a vertical line reflecting the Anxiety/Panic associated with your last vomiting/retching 
episode  
No Anxiety/Panic (0) -----------------------------------------------(100) Worst Possible Anxiety/Panic 
 
 

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28 APR 2020 
Protocol AMDC 010-201 Amendment 2 
Alexza Pharmaceuticals, Inc. 
 
 
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17.6 
Prior Episode Questionnaire 
1. Compared to my “typical” CVS episode, the Intensity of this current CVS episode was: 
1. Less Intense than my “typical” CVS episode 
2. The Same Intensity as my “typical” CVS episode 
3. More Intense than my “typical” CVS episode 
 
2.  Compared to my “typical” CVS episode, the Duration of this current CVS episode was: 
1. Shorter than my “typical” CVS episode 
2. The Same Duration as my “typical” CVS episode 
3. Longer than my “typical” CVS episode 
 
 

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Protocol AMDC 010-201 Amendment 2 
Alexza Pharmaceuticals, Inc. 
 
 
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17.7 
24 Hour Vomiting and Retching Questionnaire 
 
 
AMDC-010-201 
24 HOUR VOM ITING AND RETCHING QUESTIONNAIRE 
INVESTIGATOR: 
SITE PHONE NUMBER: 
SITE ADDRESS: 
SUBJECT NUMBER: 
INSTRUCTIONS: Please record the number of vomit ing and retching events within 24 hours after you 
take a dose of study medication at home on this form. Record the date t hat you took a dose of study 
medication in the left column. Record the total number of vomiting or retching events in t he 24 hours 
after taking that dose of study medication in the right column. If you take more than one dose of study 
medication on another day, record the date and number of events on the next row. If you have no 
vomiting or retching events in the 24 hours after dosing, write O in the right column. 
Reminders: 
1. 
2. 
3. 
4. 
5. 
• 
A vomiting or retching event is defined as one or more episodes of vomiting (expulsion of 
stomach contents through the mouth) or retch ing/dry heaves (an attempt to vomit that is not 
productive of stomach contents) 
• 
If there is a break of at least 1 minute between vomiting and retching events, those should be 
considered two different events 
• 
Please t ry to avoid taking any rescue medications (to treat nausea and vomiting) in t he first 2 
hours after dosing with study medication 
Date I took a dose of study medication 
Number of vomiting or retching events in the 24 
hours after dosing