Conditions: Asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 841
Healthy volunteers: no

Brief summary:
This study is to evaluate the safety and efficacy of fluticasone propionate and fluticasone propionate salmeterol in pediatric participants with a documented history of persistent asthma.

Detailed description:

Arms:
arm 1: Participants received matching placebo via multidose dry powder inhaler (MDPI) for 12 weeks. arm 2: Participants received 1 inhalation of 25 mcg fluticasone propionate (Fp) via MDPI twice daily (BID) (total daily dose: 50 mcg) for 12 weeks. arm 3: Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks. arm 4: Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol (FS) via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.

Interventions: intervention 1: Fluticasone Propionate intervention 2: Fluticasone Propionate/Salmeterol intervention 3: Placebo MDPI
Intervention descriptions: intervention 1: Fluticasone propionate was administered via MDPI per the dose and schedule specified in the arm. intervention 2: Fluticasone propionate/salmeterol was administered via MDPI per the dose and schedule specified in the arm. intervention 3: Matching placebo was administered via MDPI per the schedule specified in the arm.

Protocol document:
Prot_000.pdf: 
 
 
 
 
Clinical Study Protocol with Amendment 02 
 
 
A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of 
Fluticasone Propionate Multidose Dry Powder Inhaler Compared with Fluticasone 
Propionate/Salmeterol Multidose Dry Powder Inhaler in Patients Aged 4 Through 11 
Years with Persistent Asthma 
 
 
Study Number FSS-AS-30003 
 
NCT02980133 
 
Protocol with Amendment 02 Approval Date: 5 June 2018  
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
1 
 
 
Clinical Study Protocol with Amendment 02 
Study Number FSS-AS-30003 
A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of 
Fluticasone Propionate Multidose Dry Powder Inhaler Compared with Fluticasone 
Propionate/Salmeterol Multidose Dry Powder Inhaler in Patients Aged 4 Through 
11 Years with Persistent Asthma 
Efficacy and Safety Study (Phase 3) 
IND number: 108,838 and 72,240; EudraCT number: 2016-003835-39 
Article 45 or 46 of 1901/2006 does not apply 
 
Protocol Approval Date: 13 September 2016 
Protocol with Amendment 02 Approval Date: 05 June 2018 
 
Sponsor 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States of America 
 
Information regarding clinical laboratories and other departments and institutions is 
found in Appendix A 
 
Confidentiality Statement 
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Council for Harmonisation (ICH); United States (US) Code of 
Federal Regulations (CFR), and European Union (EU) Directives (as applicable in the region of the 
study); national country legislation; and the sponsor’s Standard Operating Procedures (SOPs). 
This document contains confidential and proprietary information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded 
Pharmaceutical Products R&D. The recipient agrees that no information contained herein may be 
published or disclosed without written approval from the sponsor. 
© 2018 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
2 
AMENDMENT HISTORY 
The protocol for Study FSS-AS-30003 (original protocol dated 13 September 2016) has been 
amended and reissued as follows: 
Amendment 02 
05 June 2018 
572 patients randomized/enrolled to date 
Letter of Clarification 02 
21 February 2018 
Letter of Clarification 01 
21 September 2017 
Local Protocol Amendment 01 
for Russia 
22 May 2017 
126 patients randomized/enrolled to date 
Amendment 01 
31 October 2016 
0 patients randomized/enrolled to date 
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 16. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
3 
INVESTIGATOR AGREEMENT 
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
4 
COORDINATING INVESTIGATOR AGREEMENT 
Original Protocol Dated 13 September 2016 
Clinical Study Protocol with Amendment 02 
IND number: 108,838 and 72,240 
Article 45 or 46 of 1901/2006 does not apply 
 
A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of 
Fluticasone Propionate Multidose Dry Powder Inhaler Compared with Fluticasone 
Propionate/Salmeterol Multidose Dry Powder Inhaler in Patients Aged 4 Through 
11 Years with Persistent Asthma 
I have read the protocol with Amendment 02 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes approval of this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national and local legal and regulatory requirements and applicable regulations and guidelines. 
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
responsible to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, IMPs shipment and return forms, and all other information 
collected during the study, in accordance with national and local Good Clinical Practice (GCP) 
regulations. In addition I will assume the responsibility of the coordinating investigator 
according to a separate contract. 
Coordinating Investigator: 
 
Address of Investigational Center: 
 
 
 
 
Coordinating Investigator 
 
 
Signature 
Date 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
5 
CLINICAL STUDY PROTOCOL SYNOPSIS 
with Amendment 02 
Study FSS-AS-30003 
Title of Study: A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Efficacy and 
Safety Study of Fluticasone Propionate Multidose Dry Powder Inhaler Compared with 
Fluticasone Propionate/Salmeterol Multidose Dry Powder Inhaler in Patients Aged 4 Through 
11 Years with Persistent Asthma 
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. 
Investigational New Drug (IND) Number: 108,838 and 72,240 
Article 45 or 46 of 1901/2006 does not apply 
Name of Test Investigational Medicinal Product (IMP): fluticasone propionate (Fp) multidose 
dry powder inhaler (MDPI), fluticasone propionate/salmeterol (FS) MDPI 
EudraVigilance (EV) code for the IMP: SUB02241MIG (fluticasone propionate), 
SUB04314MIG (salmeterol xinafoate) 
Type of the Study: Efficacy and Safety Study (Phase 3) 
Indication: Asthma 
Is this study conducted to investigate the New Use of an approved, marketed product? No 
Number of Investigational Centers Planned: Approximately 130 investigational centers 
Countries Planned: United States (US) and ex-US 
Planned Study Period: Q4/2016 (first patient in) to Q2/2019 (last patient last visit) 
Number of Patients Planned (total): A total of approximately 824 male and female patients, 
206 patients in each of 4 treatment groups will be enrolled. Assuming a dropout rate of 12%, 
approximately 181 evaluable patients in each treatment group (724 total patients) will complete 
the 12-week treatment period. 
Study Population: The population planned to be enrolled in this study comprises male and 
female patients 4 through 11 years of age who have a documented history of persistent asthma. 
The asthma diagnosis must be in accordance with the National Institutes of Health (NIH) 
definition. 
Primary and Secondary Objectives and Endpoints: 
The primary objective of this study is to evaluate the efficacy of Fp MDPI and FS MDPI when 
administered over 12 weeks in patients 4 through 11 years of age with persistent asthma. 
The secondary objective of this study is to evaluate the safety and tolerability of Fp MDPI and 
FS MDPI. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
6 
Primary Efficacy Endpoints:  
The primary efficacy endpoints are as follows: 
• For Fp MDPI versus placebo: the change from baseline in weekly average of the 
percent predicted trough morning forced expiratory volume in 1 second (FEV1) at 
week 12 
• For FS MDPI versus Fp MDPI: the change from baseline in 1-hour postdose percent 
predicted morning FEV1 at week 12 
Secondary Efficacy Endpoints:  
The secondary efficacy endpoints are as follows: 
• Change from baseline in the weekly average of daily trough morning (predose and 
pre-rescue bronchodilator) peak expiratory flow (PEF) over the 12-week treatment 
period 
• Change from baseline in the weekly average of total daily (24-hour) use of 
albuterol/salbutamol inhalation aerosol (number of inhalations) over 
weeks 1 through 12 
• Change from baseline in the weekly average of the total daily asthma symptom score 
(defined as the average of the daytime and nighttime scores) over weeks 1 through 12 
• Change from baseline in asthma control (measured by Childhood Asthma Control 
Test [C-ACT]) score over the 12-week treatment period 
• Time to first onset of effect defined as the first decrease from baseline in daily rescue 
medication use  
• Proportion of patients discontinued from IMP for asthma exacerbation during the 
12-week treatment period 
The sequential order of the secondary endpoints for multiplicity will be described in the 
statistical analysis plan. 
Other Efficacy and Safety Endpoints: 
The other efficacy endpoints are as follows: 
• Change from baseline in the weekly average of total daily (24-hour) use of 
albuterol/salbutamol inhalation aerosol (number of inhalations) at weeks 4, 8, and 12  
• Change from baseline in the percentage of rescue-free days (defined as 24-hour 
periods with no rescue medication usage) during the 12-week treatment period 
• Change from baseline in the percentage of symptom-free days (defined as 24-hour 
periods with asthma symptom score of 0) during the 12-week treatment period 
• Change from baseline in the percentage of asthma-control days (defined as 24-hour 
periods with asthma symptom score of 0 and no rescue medication usage) during the 
12-week treatment period 
• Change from baseline in 1-hour postdose percent predicted morning FEV1 at week 1 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
7 
• Change from baseline in the weekly average of daily evening PEF over the 12-week 
treatment period 
• Change from baseline in the weekly average of the percent predicted trough morning 
FEV1 at weeks 1, 2, 4, and 8 
• Proportion of patients who achieve at least a 15% increase in morning FEV1 at 1 hour 
postdose at day 1 (the randomization visit [RV]/treatment visit [TV] 1), week 1, and 
week 12 
• Change from baseline in asthma control (measured by C-ACT) score at weeks 4, 8, 
and 12 
• Time to consistent onset of effect defined as the decrease from baseline in daily 
rescue medication use on 3 consecutive days 
The safety endpoints are as follows: 
• Incidence of adverse events throughout the study 
• Vital signs assessments throughout the study 
• Oropharyngeal examination findings at each visit 
• Physical examination findings at baseline and at week 12 or at the IMP 
discontinuation visit (IMPDV) 
General Design: Patients meeting all of the inclusion criteria and none of the exclusion criteria 
at the screening visit (SV) will begin a 14- to 30-day run-in period. An albuterol/salbutamol 
hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (a short-acting β2 agonist [SABA] 
inhaler) will be provided to replace the patient’s current rescue medication and is to be used as 
needed for relief of asthma symptoms during the run-in and treatment periods, with a maximum 
of 12 inhalations permitted per day. Starting on day 1 of the run-in period, patients must 
discontinue all nonstudy asthma-related drugs and instead take a patient-blinded MDPI placebo 
device (1 inhalation twice daily).  
The study consists of 3 periods as follows: 
• Patient-blinded run-in period: SV to RV, up to 30 days 
• Double-blind, randomized treatment period: RV through the TV6, approximately 
12 weeks  
• Follow-up period: TV6 through the follow-up visit (FV), approximately 7 days after 
TV6 
A prescreening visit may be conducted, if needed, before the SV to discuss study procedures 
and/or provide patient instructions about any required washout periods for prohibited 
medications. The SV may take place during several investigational center visits.  
At the prescreening or SV, the patient or parent/legal guardian must provide informed consent, 
and patients must give assent (as applicable) before any study procedures are performed. At the 
time of informed consent, the parent/legal guardian will be counseled that, once randomized to 
treatment, patients are to remain in the study and complete all study procedures unless the choice 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
8 
is made to withdraw consent. This includes patients who may require alternative asthma therapy, 
experience an adverse event, violate the protocol, or fail to comply with study procedures. 
Continued patient participation is important to contribute to the scientific investigation. Patients 
who are being treated with an inhaled corticosteroid (ICS) with or without a long-acting 
β2-agonist (LABA) and/or with a noncorticosteroid (NCS) therapy are eligible to be included in 
the study. Patients must meet washout period requirements at the SV for their asthma and 
non-asthma disallowed medications according to Appendix H. The patient’s asthma medication 
regimen must be stable for 30 days prior to the SV (except as adjusted at an optional 
prescreening visit to wash out prohibited medications). If the patient has taken asthma 
maintenance medication the morning of the SV or SABA within 6 hours of lung function 
assessments (FEV1 and PEF) by handheld device, the visit must be rescheduled so that lung 
function assessments and response to bronchodilator testing can be completed as described (other 
assessments not involving lung function may be completed that day). 
Patients will be provided with a handheld device at the SV, which will be used to measure lung 
function assessments (FEV1 and PEF) and will serve as an electronic patient diary to collect 
asthma symptom scores, rescue medication use, and IMP use. Screening lung function 
assessments (FEV1 and PEF) by handheld device should be performed at the investigational 
center between the hours of 0530 and 1100. Patients will be permitted 8 attempts per test. The 
highest FEV1 value from 3 technically acceptable and 2 repeatable maneuvers will be used to 
qualify patients for the placebo run-in period. Patients who have failed screening for inability to 
perform lung function assessments (FEV1 and PEF) in a technically acceptable manner or due to 
FEV1 not meeting the inclusion criterion or demonstrated <10% response to a bronchodilator 
may retest once within 7 days of their initial SV provided that they have met all other inclusion 
criteria and none of the exclusion criteria at the SV. The handheld device should be kept at the 
clinic for these patients until they meet the requirements to enter the run-in period. 
At retest, patients (or patient’s parent/legal guardian/caregiver) will report if there have been any 
adverse events, changes in medications, or changes in medical history since providing 
consent/assent (as applicable). Patients who fail again to demonstrate technically acceptable lung 
function assessments (FEV1 and PEF) or due to FEV1 not meeting the inclusion criterion or who 
demonstrate <10% response to a bronchodilator will be considered screen failures. The run-in 
period will not start until patients have met all inclusion criteria and none of the exclusion 
criteria. Patients who fail to meet the requirements to enter the run-in period at this visit will be 
considered screen failures and will not be allowed to be rescreened. 
Patients who qualify for entry into the placebo run-in period must discontinue all currently 
administered asthma medications (including leukotriene modifiers prescribed for other 
conditions) until completion of the TV6 (week 12) visit or IMPDV if, in the investigator’s 
judgment, there would be no inherent harm in changing the patient’s treatment and the patient or 
parent/legal guardian provides consent/assent (as applicable). Patients will be provided with 
albuterol/salbutamol HFA MDI (90 mcg ex-actuator) or equivalent as rescue medication. During 
the run-in period (SV to RV), in addition to the above rescue medication, patients will be 
provided with a patient-blinded placebo MDPI device for twice-daily use after appropriate 
training and demonstration of proper technique. 
All patients who enter the placebo run-in period will perform daily morning and evening lung 
function assessments (FEV1 and PEF) by handheld device at home and assess and record 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
9 
daytime and nighttime asthma symptom scores, rescue albuterol/salbutamol HFA MDI use, and 
morning and evening IMP dosing in the patient diary built into the handheld device.  
Patients who experience an upper respiratory infection (URI) or lower respiratory infection (LRI) 
during the run-in period should be classified as randomization failures and be discontinued from 
the study but may be rescreened 2 weeks after resolution of the infection. Patients who are 
rescreened will need to repeat all screening procedures and evaluations. Only 1 rescreening for 
each patient will be permitted. 
Patients who entered the run-in period with response to a bronchodilator ≥10% and <14.50% 
must present for repeat lung function assessments and another bronchodilator test within 
14±2 days, during which they must demonstrate at least a 15% response to a bronchodilator. If 
the criteria are not met, patients may continue in the run-in period for up to 14 additional days to 
meet the lung function assessment and response to bronchodilator criteria (1 final attempt) for 
randomization. Patients may only continue in the run-in period if the investigator determines, by 
assessing the patient’s asthma status (at each investigational center visit), that it is safe for the 
patient to continue. Patients who have entered the run-in period but fail to demonstrate 
technically acceptable lung function assessments and response to a bronchodilator (as described) 
will be considered to have failed randomization. All patients must demonstrate at least a 
15% response to a bronchodilator at the SV or during the run-in period. Patients who 
demonstrate the response to bronchodilator during the run-in period may present for 
randomization the following day at the earliest or at another later time as long as it is within the 
30-day allowance for the run-in period. Responses to a bronchodilator of 14.50% to 14.99% will 
be rounded to 15%.  
At the RV (end of run-in period, TV1), patients will be assessed for randomization. Patients who 
meet all randomization inclusion criteria and continue meeting all inclusion criteria and none of 
the exclusion criteria will be stratified by previous therapy (ICS or NCS) and randomly assigned 
into the double-blind treatment period of the study in a 1:1:1:1 ratio to Fp MDPI 25 mcg, 
Fp MDPI 50 mcg, FS MDPI 50/12.5 mcg, or placebo MDPI, twice daily (see Table 1). Patients 
will be instructed to take 1 inhalation from the assigned device twice daily approximately 
12 hours apart.  
Table 1: 
Treatment Group Description 
Treatment group 
Active devices 
Total daily dose (mcg) 
Blinding 
A 
Fp MDPI 25 mcg 
50 
Double-blind 
B 
Fp MDPI 50 mcg 
100 
Double-blind 
C 
FS MDPI 50/12.5 mcg 
100/25 
Double-blind 
D 
Placebo MDPI 
0 
Double-blind 
Fp=fluticasone propionate; FS=fluticasone propionate/salmeterol; MDPI=multidose dry powder inhaler. 
During the treatment period (RV through TV6 [week 12] or IMPDV), daily in the morning and 
evening at approximately the same time each day, patients will use the handheld device at home 
to record asthma symptom scores and rescue albuterol/salbutamol HFA MDI use, after which 
they will perform lung function assessments (FEV1 and PEF) and then will take their dose of the 
IMP and record IMP dosing in the patient diary built into the handheld device. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
10 
On the morning of each TV, patients will be instructed to record their asthma symptom score and 
rescue albuterol/salbutamol HFA MDI use and complete their morning lung function 
assessments (FEV1 and PEF) by handheld device as usual, but to delay IMP dosing until they get 
to the investigational center. Patients are also to withhold their rescue SABA for a minimum of 6 
hours prior to obtaining lung function assessments. If the patient inadvertently takes the morning 
IMP dose or rescue medication within 6 hours of the planned lung function assessments, the visit 
must be rescheduled. Similarly, patients who have been withdrawn from IMP but remain in the 
study should withhold their alternative asthma therapy dosing until after treatment visit 
assessments and avoid rescue medication for a minimum of 6 hours prior to clinic lung function 
assessments. The treatment visit should be rescheduled if either or both occur. 
At the investigational center, after appropriate instruction and training (competent handheld 
device use and dosing technique using the training devices provided), patients will perform their 
lung function assessment (FEV1 and PEF) under the supervision of the investigational center 
staff. They will then take their morning dose of the IMP unless IMP has been withdrawn. IMP 
administration at the investigational center should be timed so that lung function assessments 
will be approximately 12 hours following the doses taken the previous evening. Patients will 
then perform 1-hour postdose FEV1 measurements using the handheld device. Patients who have 
been withdrawn from IMP will be asked to perform 1-hour postdose lung function assessments; 
although the patients will not be taking a dose of IMP, the assessment should be approximately 
1 hour after the predose lung function assessments were obtained. The highest FEV1 value from 
3 acceptable and 2 repeatable maneuvers (maximum of 8 attempts per test) will be obtained 
before and 1-hour after the morning dose.  
At each visit, the investigational center staff will determine if patients have experienced any 
adverse events, changes in medical history, changes in medication, or any difficulty following 
study procedures. The C-ACT will be completed by the patient and the patient’s parent/legal 
guardian/caregiver (as applicable) at the investigational center, before any other assessments are 
performed, at specified visits. The same parent/legal guardian/caregiver should complete the 
assessments at each visit, if possible.  
A telephone call may be conducted as needed during the alternate, non-visit weeks (weeks 5, 7, 
etc) to monitor the patients’ safety and to assess their asthma status or for any other relevant 
reason.  
At the end of the study, a FV (which may be a follow-up investigational center visit or telephone 
call) will be conducted 7±2 days after TV6 (week 12) to monitor safety of the patients.  
Patients who meet the alert criteria for worsening asthma as defined for this study or experience 
worsening of asthma including asthma exacerbation will present to the investigational center for 
an investigator assessment as soon as possible. If possible and when it is judged safe to do so, 
this visit should be conducted before a change in asthma therapy takes place. Following 
investigator assessment of the patient’s asthma status a decision will be made whether or not it is 
safe for a patient to continue the IMP. In cases where the IMP is to be withdrawn and alternative 
therapy started, the investigational center staff should contact the medical monitor to confirm the 
findings. In the event that it is considered in the best interest of a patient to stop the IMP and 
initiate an alternative asthma therapy, the patient will undergo all visit procedures required for 
the IMPDV. After the IMPDV, IMP dosing will not occur. The investigator should discuss and 
implement alternative asthma treatment that is appropriate for the patient. These patients will 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
11 
continue to participate in all study visits as scheduled and continue to complete all morning and 
evening study procedures except for the IMP dosing. Patients will be asked to perform 1-hour 
postdose lung function assessments at the remaining treatment visits; although the patients will 
not be taking a dose of IMP, the assessment should be approximately 1 hour after the predose 
lung function assessments were obtained. If a patient or patient’s parent/legal guardian/caregiver 
elects to completely withdraw from the study (ie, withdraw consent) prior to the investigator 
assessment or investigational center visit, irrespective of the reason for the study discontinuation, 
every attempt will be made to conduct the IMPDV subsequent to the patient’s withdrawal from 
the IMP. 
Asthma exacerbation that requires a change in medication or worsening of asthma that requires 
the patient to be treated with alternative therapy will be entered into the case report form (CRF), 
including the date at which any medication change was made and whether this medication 
change was implemented prior to or after the IMPDV lung function assessments (FEV1 and PEF) 
were completed. Asthma worsening including asthma exacerbations with a change to alternative 
asthma therapy will not be considered an adverse event for this study since it is an expected 
outcome for this study in an asthmatic patient population. Asthma exacerbations that meet the 
criteria for a serious adverse event will be recorded as adverse events.  
At TV6 (week 12), or the IMPDV as applicable, the investigator will discuss asthma treatment 
with the patient after safety assessments have been completed, and any medication started for the 
purpose of newly recommended asthma treatment will not be considered a protocol violation. 
This asthma therapy will be recorded in the CRF following IMP discontinuation (planned or 
unplanned). Additionally, an investigational center visit may be conducted at any time at the 
request of the patient or parent/legal guardian/caregiver, as applicable or at the discretion of the 
investigator. 
Safety will be monitored by vital signs, physical examination, oropharyngeal examination, and 
recording of adverse events. In addition, during the study, PEF and FEV1 will be monitored as 
part of safety monitoring (alert criteria for worsening asthma). Any visual evidence of oral 
candidiasis during the treatment period will be confirmed by obtaining a swab for culture of the 
suspect area. Patients and parents/legal guardians/caregivers will be provided with guidelines for 
when to contact the investigational center in case of worsening asthma symptoms or rescue 
inhaler use. Patients who meet predefined alert criteria should be evaluated by the investigator to 
determine if the IMP should be discontinued. If a patient discontinues the IMP prematurely but 
remains in the study, all subsequent visits will include all assessments according to the study 
procedures and assessments table except for IMP dosing. Patients will be asked to perform 1-
hour postdose lung function assessments at the remaining treatment visits; although the patients 
will not be taking a dose of IMP, the assessment should be approximately 1 hour after the 
predose lung function assessments were obtained. 
Alert criteria for individual patients have been designed to ensure patient safety. If any of the 
criteria listed below are met, during a scheduled or unplanned study visit, the investigator (after 
discussion with the sponsor) will determine whether the patient’s overall clinical picture is 
consistent with worsening asthma and if the patient should be withdrawn from IMP (but not the 
study) to be placed on alternative asthma therapy in the interest of patient safety. Meeting 1 of 
these alert criteria does not automatically require a patient to be withdrawn from IMP, rather it 
requires a clinical evaluation to determine if the patient’s asthma can continue to be managed in 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
12 
a blinded manner per the study or necessitates a change in asthma therapy. All attempts will be 
made to safely continue to manage a patient in a blinded manner. 
• Morning FEV1 by handheld device measured at home falls below the FEV1 stability 
limit (see Section 6.1.3) calculated at the SV for the run-in period and at baseline for 
the treatment period on 4 or more days (do not have to be consecutive) out of any 
7-day period (7-day period is defined as any consecutive 7 days following the RV and 
can overlap with scheduled study investigational center visits).  
• Based upon a review of patient data from the patient diary built into the handheld 
device, the patient has experienced any of the following during a 7-day period (7-day 
period is defined as any consecutive 7 days following a previous TV; 7 days can 
overlap with scheduled study investigational center visits): 
− 3 or more days in which 8 or more inhalations/day of rescue medication 
(albuterol/salbutamol HFA MDI [90 mcg ex-actuator] or equivalent) were used 
(any 3 days in the consecutive 7-day period) 
− 3 or more days in which the patient experienced a nighttime asthma symptom 
score of more than 2 (any 3 days in the consecutive 7-day period) 
Patients who meet the alert criteria and/or who experience a clinically meaningful worsening of 
their asthma will be assessed by the investigator. If the investigator considers it is not possible to 
safely manage a patient in a blinded manner as patient’s asthma warrants a change in his/her 
asthma treatment, the IMP will be stopped, and appropriate treatment (based on the 
investigator’s judgment) should be offered. The medical monitor should be contacted to confirm 
the findings when alternative therapy is to be instituted. The patient should continue in the study 
until the patient has completed all remaining study visits and the FV.  
• For the purpose of this study, an asthma exacerbation is defined as worsening of 
asthma requiring any significant treatment other than IMP and study rescue 
medication. Significant treatment includes the use of systemic corticosteroids and/or 
the addition of other ICS-containing asthma medications, LABAs, or other NCS 
asthma medications, for example, inhaled short-acting muscarinic antagonist; 
emergency room (ER)/urgent care clinic visit; or hospitalization. Note: A single dose 
of nebulized albuterol/salbutamol would not meet the criteria for an asthma 
exacerbation. ER/urgent care clinic visits where the treatment is limited to a single 
dose of nebulized albuterol/salbutamol will not meet the criteria of an asthma 
exacerbation. 
After the last TV (TV6, week 12), the patient will enter the follow-up period. One week 
(±2 days) after the last TV, the patient will have a FV. This FV may be in person or over the 
telephone. The patient will be deemed to have completed the treatment period if they have 
completed all periods of the study, including screening, run-in, and all TVs. The patient will be 
deemed to have completed the study period if they have completed all periods of the study, 
including FV in addition to screening, run-in, and all TVs. Patients who stop IMP and return for 
safety evaluation at week 12 will not be considered to have completed the treatment period. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
13 
Brief Summary of Study Design for the Trial Registry(s): This study will evaluate the 
efficacy and safety of Fp MDPI and FS MDPI in pediatric patients with a documented history of 
persistent asthma. 
Method of Randomization and Blinding: This is a double-blind, parallel-group, 
placebo-controlled, randomized clinical study. Patients who meet all randomization criteria at the 
RV will be stratified by previous therapy (ICS or NCS) and randomly assigned into a 
1:1:1:1 ratio to receive Fp MDPI 25 mcg, Fp MDPI 50 mcg, FS MDPI 50/12.5 mcg, or placebo 
MDPI, twice daily, for the entire treatment period. Randomization will be assigned via 
Interactive Response Technology (IRT). Patients being treated with a combination of ICS/NCS 
will be stratified as an ICS patient. Approximately 206 patients will be randomized into each 
treatment group. After the run-in period, patients and parents/legal guardians/caregivers will 
remain blinded to randomized treatment assignment during the study. In addition, the 
investigator and the sponsor’s clinical personnel involved in the study will be blinded to the IMP 
identity after the run-in period until the database is locked for analysis and the treatment 
assignment is revealed. 
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate 
Test IMP: Fp MDPI, 25 mcg, 1 inhalation twice daily; Fp MDPI, 50 mcg, 1 inhalation twice 
daily; FS MDPI, 50/12.5 mcg, 1 inhalation twice daily 
Placebo IMP: Placebo MDPI, 1 inhalation twice daily 
Duration of Patient Participation and Maximal Exposure to IMP: The total duration of 
patient participation in this study is approximately 15 to 17 weeks, which includes a 
patient-blinded run-in period (up to 30 days), a double-blind, randomized treatment period 
(12 weeks±2 days), and a follow-up period (7±2 days). Patients may also participate in an 
optional prescreening period for up to 15 days before the SV, during which no IMP will be 
administered. 
Study Duration: Approximately from Q4 of 2016 to Q2 of 2019 
End of Study: End of study is defined as the last visit of the last patient. 
Plans for Treatment or Care after the Patient Has Ended Participation in the Study: No 
IMP will be provided beyond completion of the study. Patients should return to their primary 
care physician for treatment after study completion. 
Inclusion Criteria: The SV can be broken into more than 1 visit. Patients may be included in the 
study run-in period if they meet all of the following inclusion criteria at screening:  
a. The patient is a male or female patient 4 through 11 years of age, inclusive, when 
informed consent/assent (as applicable) is signed. 
b. Written informed consent must be signed and dated by parent/legal guardian and the 
written informed assent form must be signed and dated by the patient (as applicable, 
per local regulations) before any study-related procedures are conducted. 
c. The patient has a diagnosis of asthma as defined by the NIH. The asthma diagnosis 
has been present for a minimum of 3 months before SV. 
d. The patient has persistent asthma with a FEV1 ≥50% and ≤90% of the value predicted 
for age, height, sex, and race at the SV as measured by handheld device.  


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
14 
e. The patient’s persistent asthma is stable and is currently being treated with stable 
asthma therapy (eg, ICS, ICS/LABA, leukotriene receptor antagonist, etc.) for at least 
30 days before the SV. Patients who are currently on SABA regimen only or PRN 
only are not eligible for the study. 
f. The patient has demonstrated ≥10% response to a bronchodilator from screening 
FEV1 within 30 minutes (±5 min) after 2 to 4 inhalations of albuterol/salbutamol 
HFA MDI (90 mcg ex-actuator) or equivalent at SV as measured by handheld device. 
Patients who demonstrated <10% response to a bronchodilator may retest within 7 
days of their initial SV. 
− Patients who demonstrate response to a bronchodilator ≥10% and <14.50% may 
enter the run-in period (provided that they meet the other inclusion and none of 
the exclusion criteria) and may present for repeat lung function assessments by 
handheld device and another bronchodilator test within 14±2 days, during which 
they must demonstrate at least a 15% response to a bronchodilator. If the criteria 
are not met, patients may continue in the run-in period for up to 14 additional 
days to meet the lung function assessment and response to bronchodilator criteria 
(1 final attempt) for randomization. Patients may only continue in the run-in 
period if the investigator determines, by assessing the patient’s asthma status (at 
each investigational center visit), that it is safe for the patient to continue. 
g. The patient (with assistance from parents/legal guardians/caregivers, as needed) is 
able to perform technically acceptable lung function assessments by handheld device. 
Patients who fail to demonstrate technically acceptable lung function assessments 
may retest within 7 days of their initial SV. 
h. The patient (with assistance from parents/legal guardians/caregivers, as needed) is 
able to use an MDI device and an MDPI device.  
i. The patient is able to withhold (as judged by the investigator) his/her rescue 
medication for at least 6 hours before SV and all TVs where lung function 
assessments are performed.  
j. The patient is assessed as otherwise healthy, with clinically acceptable medical 
history, physical examination, and vital signs within acceptable ranges for children 
with asthma as assessed by the investigator.  
k. All patients must be able to replace their current SABA with albuterol/salbutamol 
HFA MDI inhalation aerosol at the SV for use as needed for the duration of the study.  
l. Female patients who have reached puberty and achieved menarche (as determined by 
the investigator) must be counseled regarding the possible unknown risks associated 
with IMP during pregnancy following permission of the parents/legal guardians. A 
urine pregnancy test must be negative for these patients at SV. Eligible female 
patients who are known to be sexually active will be excluded.  
m. Eligible male patients who are known to be sexually active will be excluded. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
15 
Exclusion Criteria: Patients will be excluded from participating in this study if they meet any of 
the following criteria: 
a. The patient has a history of life-threatening asthma exacerbation that is defined for 
this protocol as an asthma episode that required intubation and/or was associated with 
hypercapnia, respiratory arrest, or hypoxic seizures. 
b. The patient is pregnant or lactating or plans to become pregnant during the study 
period or within 30 days after the patient’s last study-related visit (for eligible patients 
only and if applicable).  
c. The patient has participated as a randomized patient in any investigational drug study 
within the 30 days or within 5 half-lives (starting from the final FV of that study) 
preceding the SV (or prescreening visit, as applicable) or plans to participate in 
another investigational drug study at any time during this study.  
d. The patient has a known hypersensitivity to any corticosteroid, salmeterol, or any of 
the excipients in the IMP or rescue medication formulation (ie, lactose). Dietary 
lactose intolerance does not exclude the patient from inclusion into the study or as per 
the investigator’s medical discretion. 
e. The patient has been treated with any known strong cytochrome P450 (CYP) 3A4 
inhibitors (eg, ketoconazole, ritonavir, clarithromycin) within 30 days before the SV 
or plans to be treated with any strong CYP3A4 inhibitor during the study.  
f. The patient has been treated with any of the prohibited medications during the 
prescribed (per protocol) washout periods before the SV.  
g. The patient currently smokes or has a smoking history. The patient must not have 
used tobacco products within the past year (eg, cigarettes, cigars, chewing tobacco, or 
pipe tobacco).  
h. The patient has a culture-documented or suspected bacterial or viral infection of the 
upper or lower respiratory tract, sinus, or middle ear that has not resolved at least 
2 weeks before the SV (note: patients who develop a URI or LRI during the run-in 
period may be rescreened 2 weeks after symptoms resolve).  
i. The patient has had an asthma exacerbation requiring systemic corticosteroids within 
30 days before the SV or has had any hospitalization for asthma within 2 months 
before the SV.  
j. Initiation or dose escalation of immunotherapy (administered by any route) is planned 
during the study period. However, patients who initiated immunotherapy 90 days or 
more before the SV and have been on a stable (maintenance) dose for 30 days or 
more before the SV may be considered for inclusion.  
k. The patient has used immunosuppressive medications within 30 days before the SV.  
l. The patient is unable to tolerate or unwilling to comply with the appropriate washout 
periods and withholding of all applicable medications.  


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
16 
m. The patient has untreated oral candidiasis at the SV. Patients with clinical visual 
evidence of oral candidiasis who agree to receive treatment and comply with 
appropriate medical monitoring may enter the run-in period. 
n. The patient has a history of a positive test for human immunodeficiency virus, active 
hepatitis B virus, or hepatitis C infection.  
o. The patient is an immediate relative of an employee of the clinical investigational 
center.  
p. A member of the patient’s household is participating in the study at the same time. 
However, after the enrolled patient completes or discontinues participation in the 
study, another patient from the same household may be screened.  
q. The patient has a disease/condition that, in the medical judgment of the investigator, 
would put the safety of the patient at risk through participation or that could affect the 
efficacy or safety analysis if the disease/condition worsened during the study. 
Examples include, but are not limited to, the following: 
− cardiovascular conditions including clinically significant cardiac arrhythmia, 
known aortic aneurysm, congenital heart disease, coronary heart disease, or vital 
signs clinically unacceptable for ranges in children with asthma as assessed by the 
investigator 
− hepatic, renal, hematologic, neuropsychologic, or endocrine conditions (eg, sickle 
cell disease, uncontrolled diabetes mellitus, uncontrolled thyroid disorder, 
Addison’s disease, Cushing’s syndrome, stroke within 3 months before the SV) 
− gastrointestinal conditions (eg, poorly controlled peptic ulcer disease, poorly 
controlled gastroesophageal reflux disease)  
− infectious/immunologic conditions including untreated tuberculosis (a history of 
tuberculosis is acceptable only if a patient has received an approved prophylactic 
treatment regimen or an approved active treatment regimen and has had no 
evidence of active disease for a minimum of 2 years) and immunologic 
compromise 
− ocular conditions including glaucoma, ocular herpes simplex, or cataracts 
− oncologic conditions including any current malignancy, excluding basal cell 
carcinoma. History of malignancy is acceptable only if the patient has been in 
remission for 1 year before the SV. Remission is defined as no current evidence 
of malignancy and no treatment for the malignancy in the 12 months before the 
SV. 
− pulmonary conditions including chronic bronchitis, emphysema, chronic 
bronchiectasis, cystic fibrosis, chronic lung disease, or chronic obstructive 
pulmonary disease 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
17 
− renal conditions including chronic renal failure or ongoing dialysis 
− history of or planned solid organ transplant 
r. Vulnerable patients (ie, people kept in detention) are excluded from participation. 
Randomization Criteria:  
The following criteria must be fulfilled at the RV: 
a. The patient continues to be in general good health, meeting the entry criteria.  
n. The average of the 5 highest values for trough morning FEV1 obtained at home (by 
handheld device) out of the last 7 days prior to RV is within 40% to 85% predicted 
for age, height, sex, and race (Quanjer et al 2012). 
o. The patient’s C-ACT score at the RV is ≤19. 
p. The patient has demonstrated at least a 15% response to a bronchodilator from 
baseline FEV1 within 30 minutes after 2 to 4 inhalations of albuterol/salbutamol HFA 
MDI (90 mcg ex-actuator) or equivalent at SV or during the run-in period as 
measured by handheld device. Note: The RV may not be conducted on the same day 
as the response to bronchodilator testing. 
q. The patient has had no significant changes in asthma medications during run-in, 
excluding the albuterol/salbutamol HFA MDI (90 mcg ex-actuator) or equivalent 
used as rescue medication or run-in placebo MDPI as supplied per protocol.  
r. The patient has not had a URI or LRI during the run-in period. Patients who develop 
a URI or LRI during the run-in period may be discontinued from the study and 
allowed to rescreen 2 weeks after resolution of symptoms.  
s. The patient has had no asthma exacerbation during the run-in period, defined as any 
worsening of asthma requiring any significant treatment other than rescue 
albuterol/salbutamol HFA MDI (90 mcg ex-actuator) or equivalent or the patient’s 
run-in MDPI. This includes requiring the use of systemic corticosteroids, inhaled 
corticosteroids or other medications used to control asthma or are prohibited 
medications (Appendix H), and/or ER/urgent care clinic visit or hospitalization. Note: 
A single dose of nebulized albuterol/salbutamol will not meet the criteria for an 
asthma exacerbation. Emergency room/urgent care clinic visits where the treatment is 
limited to a single dose of nebulized albuterol/salbutamol will not meet the criteria of 
an asthma exacerbation. 
t. The patient has no clinical visual evidence (on oropharyngeal examination) of 
oropharyngeal candidiasis.  
u. The patient has not experienced an adverse event that would result in failure to 
continue to meet selection criteria.  
v. The patient has not used any of the prohibited concomitant medications during the 
run-in period.  


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
18 
w. The patient has complied with home lung function assessments and patient diary 
(built into the handheld device) entry on at least 5 of the last 7 days prior to RV, 
including the following: 
− completion of daytime and nighttime asthma symptom scores 
− completion of daytime and nighttime rescue medication (albuterol/salbutamol 
HFA MDI) use (whether used or not) 
− completion of the morning and evening lung function assessments (FEV1 and 
PEF) by handheld device on 5 or more of the 7 days immediately preceding the 
RV 
− recording of morning and evening IMP use on 5 or more of the 7 days 
immediately preceding RV 
Statistical Considerations:  
Sample Size Rationale: Sample size and power calculations are driven by demonstrating 
superiority of FS MDPI 50/12.5 mcg twice daily over Fp MDPI 50 mcg twice daily in change 
from baseline in 1-hour postdose percent predicted morning FEV1 at week 12 and the superiority 
of Fp MDPI 50 mcg twice daily over placebo in change from baseline in percent predicted 
trough morning FEV1 at week 12.  
For the superiority comparison of FS MDPI 50/12.5 mcg twice daily versus Fp MDPI 50 mcg 
twice daily, assuming that the change from baseline in 1-hour postdose percent predicted 
morning FEV1 at week 12 is analyzed using an ANOVA model with only a single factor of 
treatment group, the following assumptions were made: 
• The initial assumed common standard deviation (SD) was 9.3% and the true 
treatment difference was 4.5% between FS MDPI 50/12.5 mcg twice daily and Fp 
MDPI 50 mcg twice daily. This assumption was based on data collected in previous 
Teva studies with the same Fp MDPI and FS MDPI products in adult asthma patients 
who completed the 12-week treatment period and based on office-based spirometry.  
• The initial power was 97% at a 2-sided significance level of 5%.  
For the superiority comparison of Fp MDPI 50 mcg twice daily versus placebo, assuming that 
the change from baseline in percent predicted trough morning FEV1 at week 12 is analyzed using 
an analysis of variance (ANOVA) model with only a single factor of treatment group, the 
following assumptions were made: 
• The initial assumed common standard deviation (SD) was 13.25% and the true 
treatment difference was 5% between Fp MDPI 50 mcg twice daily and placebo. This 
assumption was based on data collected in previous Teva studies with the same 
Fp MDPI product in adult asthma patients and based on office-based spirometry 
• The initial power was 85% at a 2-sided significance level of 5%.  
This study FSS-AS-30003 is the first Teva's study in which the handheld spirometry is utilized as 
an endpoint and this hanheld device is being used in a pediatric asthma patient population, the 
target population of this study. A blinded sample size reassessment was not planned for this 
study. However, routine blinded data monitoring of this study FSS-AS-30003 revealed that a few 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
19 
patietnts showed nonphysiologic (~200% of percent predicted FEV1) changes from baseline. 
This triggered a blinded sample size reassessment that showed that the overall mean change from 
baseline and SD for the overall study population is higher than the initial assumptions based on 
the office spirometry in adult asthma patients. In addition, monitoring of FEV1 stability 
throughout the study revealed challenges in obtaining consistent morning trough FEV1 values 
with best efforts in this young patient population, despite the rigorous training and coaching 
provided by the investigators. Therefore, some of the initial assumptions and the sample size 
described above were revised to the following: 
• For the superiority comparison of FS MDPI 50/12.5 mcg twice daily versus Fp MDPI 
50 mcg twice daily, the SD was revised to 22% and the overall mean change from 
baseline was revised to 6.5% (blinded SD observed after 427 patients completed 
week 12 of this study (excluding IMPD)) and the power down to 80%.  
• With these assumptions, 181 patients per treatment group are required for the 2-sided 
test of FS MDPI 50/12.5 mcg twice daily and Fp MDPI 50 mcg twice daily. 
• For the superiority comparison of Fp MDPI 50 mcg twice daily versus placebo, the 
SD was revised to 17% and overall mean change from baseline was 5% (blinded SD 
observed after 434 patients completed week 12 of this study (excluding IMPD)) and 
the power was revised to 80%.  
• With these assumptions, 181 patients per treatment group are required for the 2-sided 
test of Fp MDPI 50 mcg twice daily versus placebo. 
Assuming a dropout rate of 12%, then 206 patients per treatment group in the 4 treatment groups, 
for a total of 824 patients, will be randomized (initial assumption for dropout rate was 15%).  
Primary Estimands and Efficacy Analysis:  
The specific estimands selected for the 2 primary endpoints will assess the change from baseline 
due to the initially randomized treatment as actually taken. These estimands assess the 
effectiveness at week 12, focusing on the causal effects attributable to the initially randomized 
medication. The sponsor will make all efforts to avoid study withdrawal in this 12-week study. 
In instances where a patient decides to discontinue IMP or, more importantly, requires 
alternative therapy for worsening asthma or an asthma exacerbation, the investigators will be 
instructed to encourage the patient to continue in the study and return for planned visits in order 
to collect data after IMP discontinuation.  
It is expected that patients randomized to placebo would discontinue IMP due to worsening 
asthma at a higher rate than those randomized to active treatment, which is known to be an 
efficacious drug as established by multiple studies. The inclusion of patients who failed therapy 
and who were then treated with alternative medication would blunt the treatment effect, 
potentially causing the study to fail due to the analysis rather than the effectiveness of the 
treatment given during the study. These patients no longer represent a true placebo population 
and including them in the population for the primary outcome is not consistent with treatment by 
placebo. In light of this, retrieved dropout data will be used only for sensitivity analyses. Missing 
data for patients who discontinue IMP will be imputed using reference-based multiple 
imputations representing a missing not at random (MNAR) mechanism.  


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
20 
Analysis of the change from baseline in weekly average of the percent predicted trough 
morning FEV1 at week 12 
The baseline percent predicted FEV1 will be the weekly average of the morning FEV1 prior to 
the first IMP dose. The first day before randomization consists of the entry on the morning of the 
RV in the patient diary built into the handheld device. The weekly average of the percent 
predicted FEV1 at week 12 will be the average values based on the available data at that week. 
The primary analysis of the change from baseline in weekly average of percent predicted 
morning FEV1 at week 12 due to the initially randomized treatment as actually taken will be 
analyzed using an analysis of covariance (ANCOVA) model with effects due to baseline percent 
predicted trough morning FEV1, sex, age, (pooled) investigational center, previous therapy (ICS 
or NCS), and IMP treatment group. Contrasts for pairwise treatment comparisons of interest will 
be constructed. The estimated treatment difference between each IMP treatment group and the 
placebo group will be presented together with the 2-sided 95% confidence interval (CI) for the 
difference and the p-value.  
In this analysis, missing data that are caused by early dropouts from the study or from IMP 
(regardless of availability of retrieved dropout data) will be imputed using reference-based 
multiple imputations. Details on the implementation of the multiple imputations will be provided 
in the statistical analysis plan. 
Analysis of the change from baseline in 1-hour postdose percent predicted morning FEV1 
at week 12 
For the endpoint of change from baseline in 1-hour postdose percent predicted morning FEV1 
(measured at the clinic) at week 12, baseline is defined as predose FEV1 measurements obtained 
at the clinic at the RV with the handheld device immediately prior to the IMP administration.   
The primary analysis of the change from baseline in 1-hour postdose percent predicted morning 
FEV1 at week 12 due to the initially randomized treatment as actually taken will be analyzed 
using an ANCOVA model with effects due to baseline percent predicted trough morning FEV1, 
sex, age, (pooled) investigational center, previous therapy (ICS or NCS), and IMP treatment 
group. Contrasts for pairwise treatment comparisons of interest will be constructed. The 
estimated treatment difference between each IMP treatment group and the placebo group will be 
presented together with the 2-sided 95% CI for the difference and the p-value. Missing data 
caused by early dropouts will be handled similarly to the above analysis. 
Sensitivity Analysis 
To assess the impact of missing data, several sensitivity analyses will be conducted for the 
2 endpoints by evaluating alternative estimands. More details will be provided in Section 9 of the 
protocol and the statistical analysis plan. 
• The primary analysis for the 2 endpoints will be repeated using data collected after IMP 
discontinuation (retrieved dropout data). Reference-based imputation will be used only 
for patients with no retrieved dropout data. This analysis estimates different estimands, 
namely the change from baseline as actually taken. 
• The primary analysis for the 2 endpoints will be repeated on completers with no major 
protocol violations. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
21 
• A tipping point analysis will be performed as a sensitivity analysis to missing data by 
utilizing multiple imputations assuming MNAR for the active arms. Only data collected 
prior to IMP discontinuation will be utitlized in this analysis. 
• “2-dimensional tipping point” will also be performed to assess shifts to the distribution 
apply to both placebo and active arms. 
• The primary analysis for the 2 endpoints will be repeated when missing data will be 
imputed using a mixed approach of last observation carried forward and baseline 
observation carried forward (see Section 9.5.4.2 of the protocol).  
• For the first primary endpoint of change from baseline in the weekly average of percent 
predicted trough morning FEV1 over the 12-week treatment period, analysis will be 
performed using a mixed model for repeated measures (MMRM). This analysis will not 
use retrieved dropout data. This analysis represents a missing at random assumption. 
Secondary Efficacy Analysis:  
For all secondary endpoints, analyses will be performed using the ITT analysis set and will not 
include retrieved dropout data in the analysis. 
Analyses of change from baseline in weekly average of daily trough morning PEF, total daily use 
of albuterol/salbutamol, total daily asthma symptom score, and C-ACT score over the 12-week 
treatment period will be analyzed using an MMRM analysis with effects due to baseline, sex, 
age, (pooled) investigational center, previous therapy (ICS or NCS), treatment, time, and time-
by-treatment interaction. For all of these endpoints, the MMRM will use only observations 
collected until IMP discontinuation. 
The time to first onset of effect, defined as the first decrease from baseline in daily rescue 
medication use, will be analyzed using a log-rank test. Median and mean time to first onset of 
effect and associated 95% CIs will be estimated. Time to first onset of effect will also be 
displayed graphically with a Kaplan-Meier figure. 
The proportion of patients who discontinued from IMP for asthma exacerbation during the 
12-week treatment period will be analyzed using a logistic regression model with effects due to 
previous therapy (ICS or NCS) and treatment. These patients will be considered as 
nonresponders in this analysis. 
Other Efficacy Analysis: Statistical methods to be used for other efficacy endpoints will be 
described and detailed in the statistical analysis plan. 
Multiple Comparisons and Multiplicity: A fixed-sequence testing procedure will be employed 
to control the overall Type I error rate at the 2-sided 0.05 level for the co-primary endpoints. The 
sequential order of comparisons will be as follows:  
1. 1-hour postdose percent predicted FEV1 comparing FS MDPI 50/12.5 mcg versus Fp 
MDPI 50 mcg 
2. Trough percent predicted FEV1 comparing Fp MDPI 50 mcg versus placebo 
3. Trough percent predicted FEV1 comparing Fp MDPI 25 mcg versus placebo 
Each test will be 2-sided and performed at the 0.05 level of significance. However, if a test is not 
significant at the 2-sided 0.05 level, no further tests will be performed. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
22 
Taking into consideration that this is the very first study that utilizes the handheld device in a 
large Phase 3 study in a pediatric asthma patient population (4 to 11 years of age), an unplanned 
blinded sample size reassement was conducted. Since the adjustment to sample size was based 
on blinded standard deviation, no adjustment to the multiplicity control is warrented. 
Multiplicity control for the secondary endpoints and the sequential order of the secondary 
endpoints will be described in the statistical analysis plan. 
No multiplicity adjustments will be made for other efficacy analyses.  
Safety Analyses: Safety data will be summarized using descriptive statistics by treatment group. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
23 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
AMENDMENT HISTORY .............................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
COORDINATING INVESTIGATOR AGREEMENT ...................................................................4 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................5 
LIST OF ABBREVIATIONS ........................................................................................................30 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ..................................33 
1.1. 
Introduction .................................................................................................................33 
1.2. 
Findings from Nonclinical and Clinical Studies .........................................................35 
1.2.1. 
Nonclinical Studies .....................................................................................................35 
1.2.2. 
Clinical Studies ...........................................................................................................35 
1.2.2.1. 
Fluticasone Propionate Efficacy .................................................................................35 
1.2.2.2. 
Fluticasone Propionate/Salmeterol Efficacy ...............................................................36 
1.3. 
Known and Potential Benefits and Risks to Patients ..................................................36 
1.3.1. 
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) ..................................................................................................36 
1.3.1.1. 
Benefits of Test Investigational Medicinal Product Treatment ..................................36 
1.3.1.2. 
Risks of Test Investigational Medicinal Product Treatment ......................................37 
1.3.2. 
Overall Benefit and Risk Assessment for This Study ................................................38 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................40 
2.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................40 
2.1.1. 
Justification of Primary Endpoint ...............................................................................41 
2.2. 
Other Efficacy and Safety Endpoints .........................................................................41 
2.2.1. 
Other Efficacy Endpoints ...........................................................................................41 
3. 
STUDY DESIGN .......................................................................................................42 
3.1. 
General Design and Study Schematic Diagram ..........................................................42 
3.2. 
Planned Number of Patients and Countries ................................................................48 
3.3. 
Justification for Study Design and Selection of Population .......................................48 
3.4. 
Stopping Rules for the Study ......................................................................................49 
3.5. 
Schedule of Study Procedures and Assessments ........................................................49 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................53 
4.1. 
Patient Inclusion Criteria ............................................................................................53 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
24 
4.2. 
Patient Exclusion Criteria ...........................................................................................54 
4.3. 
Withdrawal Criteria and Procedures for the Patient ...................................................56 
4.3.1. 
Withdrawal for Worsening Asthma ............................................................................57 
4.3.2. 
Alert Criteria for Worsening Asthma .........................................................................57 
4.4. 
Replacement of Patients .............................................................................................58 
4.5. 
Rescreening .................................................................................................................58 
4.6. 
Screening Failure ........................................................................................................58 
5. 
TREATMENTS ..........................................................................................................59 
5.1. 
Investigational Medicinal Products Used in the Study ...............................................59 
5.1.1. 
Test Investigational Medicinal Product ......................................................................59 
5.1.2. 
Placebo Investigational Medicinal Product ................................................................59 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products ............................................................................60 
5.2.1. 
Storage and Security ...................................................................................................60 
5.2.2. 
Labeling ......................................................................................................................60 
5.2.3. 
Accountability .............................................................................................................60 
5.3. 
Justification for Investigational Medicinal Products ..................................................61 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product ..............................61 
5.3.2. 
Justification for Use of Placebo Investigational Medicinal Product ..........................61 
5.4. 
Other Medicinal Products/Non-Investigational Medicinal Products ..........................61 
5.5. 
Treatment After the End of the Study .........................................................................61 
5.6. 
Restrictions .................................................................................................................61 
5.7. 
Prior and Concomitant Medication or Therapy ..........................................................62 
5.8. 
Procedures for Monitoring Patient Compliance .........................................................62 
5.9. 
Randomization and Blinding ......................................................................................63 
5.10. 
Maintenance of Randomization and Blinding ............................................................64 
5.10.1. 
Maintenance of Randomization ..................................................................................64 
5.10.2. 
Blinding and Unblinding ............................................................................................64 
5.10.3. 
Data Monitoring Committee .......................................................................................65 
5.11. 
Total Blood Volume ...................................................................................................65 
6. 
ASSESSMENT OF EFFICACY ................................................................................66 
6.1. 
Primary Efficacy Measure and Justification ...............................................................66 
6.1.1. 
Lung Function Assessments (FEV1 and PEF) by Handheld Device ..........................66 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
25 
6.1.2. 
Response to a Bronchodilator .....................................................................................67 
6.1.3. 
FEV1 Stability Limit ...................................................................................................67 
6.2. 
Secondary Efficacy Measures .....................................................................................68 
6.2.1. 
Weekly Average of Daily Trough Morning Peak Expiratory Flow ...........................68 
6.2.2. 
Weekly Average of Total Daily Rescue Medication Use ...........................................68 
6.2.3. 
Weekly Average of the Total Daily Asthma Symptom Score ....................................69 
6.2.4. 
Change from Baseline in Asthma Control (measured by C-ACT) Score ...................69 
6.2.5. 
Time to First Onset of Effect ......................................................................................70 
6.2.6. 
Proportion of Patients who Discontinued from IMP for Asthma Exacerbation 
During the 12-week Treatment Period .......................................................................70 
6.3. 
Other Efficacy Measures ............................................................................................70 
6.3.1. 
Change from Baseline in Weekly Average of Total Daily Rescue Medication 
Use ..............................................................................................................................71 
6.3.2. 
Change from Baseline in Percentage of Rescue-Free Days .......................................71 
6.3.3. 
Change from Baseline in Percentage of Symptom-Free Days ...................................71 
6.3.4. 
Change from Baseline in Percentage of Asthma-Control Days .................................71 
6.3.5. 
Change from Baseline in 1-hour Postdose Percent Predicted Morning FEV1 
at Week 1 ....................................................................................................................71 
6.3.6. 
Change from Baseline in Weekly Average of Daily Evening Peak Expiratory 
Flow ............................................................................................................................71 
6.3.7. 
Change from Baseline in Weekly Average of Percent Predicted Trough 
Morning FEV1 ............................................................................................................72 
6.3.8. 
Proportion of Patients Who Achieve At Least a 15% Increase in Morning 
FEV1 ...........................................................................................................................72 
6.3.9. 
Change from Baseline in Asthma Control (measured by C-ACT) Score ...................72 
6.3.10. 
Time to Consistent Onset of Effect ............................................................................72 
6.4. 
Safety Measures and Time Points ...............................................................................72 
7. 
ASSESSMENT OF SAFETY .....................................................................................73 
7.1. 
Adverse Events ...........................................................................................................73 
7.1.1. 
Definition of an Adverse Event ..................................................................................73 
7.1.2. 
Recording and Reporting of Adverse Events .............................................................74 
7.1.3. 
Severity of an Adverse Event .....................................................................................75 
7.1.4. 
Relationship of an Adverse Event to the Test Investigational Medicinal 
Product ........................................................................................................................75 
7.1.5. 
Serious Adverse Events ..............................................................................................76 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
26 
7.1.5.1. 
Definition of a Serious Adverse Event .......................................................................76 
7.1.5.2. 
Expectedness ...............................................................................................................77 
7.1.5.3. 
Reporting a Serious Adverse Event ............................................................................77 
7.1.6. 
Protocol-Defined Adverse Events not for Expedited Reporting ................................79 
7.1.7. 
Protocol-Defined Adverse Events of Special Interest ................................................79 
7.1.8. 
Protocol Deviations Because of an Adverse Event ....................................................79 
7.2. 
Pregnancy ...................................................................................................................79 
7.3. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products .....................................................................................................80 
7.4. 
Clinical Laboratory Tests ...........................................................................................81 
7.4.1. 
Human Chorionic Gonadotropin Tests .......................................................................81 
7.5. 
Physical Examinations ................................................................................................81 
7.6. 
Vital Signs ..................................................................................................................81 
7.7. 
Oropharyngeal Examinations .....................................................................................82 
8. 
ASSESSMENT OF PHARMACOKINETICS / PHARMACODYNAMICS / 
BIOMARKERS / PHARMACOGENOMICS / IMMUNOGENICITY / 
ANCILLARY STUDIES ............................................................................................83 
8.1. 
Pharmacokinetic Assessment ......................................................................................83 
8.2. 
Pharmacodynamics Assessment .................................................................................83 
8.3. 
Assessment of Exploratory Biomarkers .....................................................................83 
9. 
STATISTICS ..............................................................................................................84 
9.1. 
Sample Size and Power Considerations .....................................................................84 
9.2. 
Analysis Sets ...............................................................................................................85 
9.2.1. 
Intent-to-Treat Analysis Set ........................................................................................85 
9.2.2. 
Safety Analysis Set .....................................................................................................85 
9.2.3. 
Per-Protocol Analysis Set ...........................................................................................85 
9.3. 
Data Handling Conventions ........................................................................................86 
9.4. 
Study Population .........................................................................................................86 
9.4.1. 
Patient Disposition ......................................................................................................86 
9.4.2. 
Demographic and Baseline Characteristics ................................................................86 
9.5. 
Efficacy Analysis ........................................................................................................86 
9.5.1. 
Primary Endpoint ........................................................................................................86 
9.5.2. 
Secondary Endpoints ..................................................................................................86 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
27 
9.5.3. 
Other Efficacy Endpoints ...........................................................................................87 
9.5.4. 
Planned Method of Analysis .......................................................................................87 
9.5.4.1. 
Primary Estimands and Efficacy Analysis .................................................................88 
9.5.4.2. 
Sensitivity Analysis to Missing Data ..........................................................................89 
9.5.4.3. 
Secondary Efficacy Analysis ......................................................................................90 
9.5.4.4. 
Other Efficacy Analysis ..............................................................................................90 
9.6. 
Multiple Comparisons and Multiplicity......................................................................91 
9.7. 
Safety Analysis ...........................................................................................................91 
9.8. 
Tolerability Analysis ..................................................................................................92 
9.9. 
Planned Interim Analysis ............................................................................................92 
9.10. 
Reporting Deviations from the Statistical Plan ..........................................................92 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................93 
11. 
COMPLIANCE STATEMENT ..................................................................................93 
12. 
DATA MANAGEMENT AND RECORD KEEPING ..............................................93 
13. 
FINANCING AND INSURANCE .............................................................................94 
14. 
PUBLICATION POLICY ..........................................................................................94 
15. 
REFERENCES ...........................................................................................................95 
16. 
SUMMARY OF CHANGES TO PROTOCOL .........................................................97 
16.1. 
Amendment 02 Dated 05 June 2018 ...........................................................................97 
16.2. 
Letter of Clarification 02 Dated 21 February 2018 ..................................................108 
16.3. 
Letter of Clarification 01 Dated 21 September 2017 ................................................110 
16.4. 
Country-specific (Russia) Amendment 01 Dated 22 May 2017 ..............................112 
16.5. 
Amendment 01 Dated 31 October 2016 ...................................................................114 
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS .......................................................................................................138 
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT .........................140 
APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE ..............................147 
APPENDIX D. ETHICS ...........................................................................................................149 
APPENDIX E. LOST TO FOLLOW-UP .................................................................................150 
APPENDIX F. INSTRUCTIONS FOR USE OF MEDICAL DEVICES ................................151 
APPENDIX G. HANDLING, LABELING, STORAGE, AND ACCOUNTABILITY 
FOR IMPS ................................................................................................................152 
APPENDIX H. LIST OF PROHIBITED MEDICATIONS .....................................................154 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
28 
APPENDIX I. PHARMACOGENETIC ASSESSMENTS ......................................................156 
APPENDIX J. PRODUCT COMPLAINTS .............................................................................157 
APPENDIX K. DOCUMENTING A PRODUCT COMPLAINT............................................159 
APPENDIX L. DOCUMENTING A PRODUCT COMPLAINT ............................................162 
APPENDIX M. DOCUMENTING A PRODUCT COMPLAINT ...........................................163 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
29 
LIST OF TABLES 
Table 1: 
Treatment Group Description .......................................................................................9 
Table 2: 
Treatment Group Description .....................................................................................44 
Table 3: 
Study Procedures and Assessments ............................................................................50 
Table 4: 
Investigational Medicinal Products Used in the Study ...............................................59 
Table 5: 
The Relationship of an Adverse Event to the Test Investigational Medicinal 
Product ........................................................................................................................76 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Schematic Diagram .............................................................................48 
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
30 
LIST OF ABBREVIATIONS 
List of Abbreviations 
Abbreviation 
Term 
ADL 
activities of daily living 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AUC0-t 
area under the concentration-time curve from time 0 to the time of the last measurable drug 
concentration 
BOCF 
baseline observation carried forward 
BP 
blood pressure 
C-ACT 
Childhood Asthma Control Test 
CDC 
Centers for Disease Control and Prevention 
CDMS 
clinical data management system 
CFR 
Code of Federal Regulations (US) 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum observed plasma drug concentration 
CRF 
case report form (refers to any media used to collect study data [ie, paper or electronic]) 
CI 
confidence interval 
CRO 
contract research organization 
CSR 
clinical study report 
CYP 
cytochrome P450 
ePRO 
electronic patient-reported outcome 
ER 
emergency room 
EU 
European Union 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
Fp 
fluticasone propionate 
Fp MDPI 
fluticasone propionate multidose dry powder inhaler 
FS 
fluticasone propionate/salmeterol 
FS MDPI 
fluticasone propionate/salmeterol multidose dry powder inhaler 
FSH 
follicle stimulating hormone 
FV 
follow-up visit 
GCP 
Good Clinical Practice 
GPSP 
Global Patient Safety and Pharmacovigilance 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
31 
Abbreviation 
Term 
GQA 
Global Quality Assurance 
HFA 
hydrofluoroalkane 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICS 
inhaled corticosteroid 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IMPDV 
investigational medicinal product discontinuation visit 
IND 
Investigational New Drug 
INN 
international nonproprietary name 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IUD 
intrauterine device 
LABA 
long-acting β2 agonist 
LOCF 
last observation carried forward 
LRI 
lower respiratory infection 
LSO 
local safety officer 
MA 
Marketing Authorisation 
MAR 
missing at random 
MDI 
metered-dose inhaler 
MDPI 
multidose dry powder inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
n 
number 
NAEPP 
National Asthma Education and Prevention Program 
NCS 
noncorticosteroid 
NDA 
New Drug Application 
NIH 
National Institutes of Health 
PEF 
peak expiratory flow 
PP 
per-protocol 
PT 
preferred term 
PRN 
Pro re nata/when needed 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
32 
Abbreviation 
Term 
RSI 
reference safety information 
RV 
randomization visit 
SABA 
short-acting β2 agonist 
SD 
standard deviation 
SmPC 
Summary of Product Characteristics 
SOC 
system organ class 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
SV 
screening visit 
Sx 
salmeterol xinafoate 
TV 
treatment visit 
ULN 
upper limit of normal 
URI 
upper respiratory infection 
US 
United States 
XML 
Extensible Markup Language 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
33 
1. 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1. 
Introduction 
An estimated 300 million people worldwide suffer from asthma, with the prevalence of asthma 
increasing in industrialized countries and in developing countries (Beasley et al 2000, Masoli et 
al 2004). The number of persons with asthma is estimated to reach 400 million by the year 2025, 
and the estimated worldwide death rate from asthma is 1 in every 250 deaths (Masoli et al 2004). 
In the United States (US), research by the National Center for Health Statistics, Centers for 
Disease Control and Prevention (CDC) shows that asthma has been diagnosed in more than 
39 million people at some time (National Health Interview Survey 2011), and in 2010, 
25.7 million residents have asthma (Akinbami et al 2012). In “Asthma’s Impact on the Nation,” 
the CDC estimates that in 2010 over 7 million children in the USA had asthma, equal to 1 in 
11 children; there were 10.5 million missed days of school due to asthma in 2008; and nearly 
1 in 5 children went to an emergency department for care in 2009. Estimates in the adult 
population for 2010 were over 18.7 million adults with asthma, equal to 1 in 12 adults, with 
14.2 million missed days of work due to asthma in 2008. Asthma limits daily activity for 
3 in 5 persons with asthma, and about 9 people die from asthma each day (CDC 2012). 
The characteristic feature of asthma is chronic airway inflammation. This inflammatory process 
includes mast cells, eosinophils, macrophages, neutrophils, lymphocytes, and epithelial cells 
(National Asthma Education and Prevention Program [NAEPP] 2007). Symptoms of asthma 
include wheezing, shortness of breath, chest tightness, and coughing, with symptoms often worse 
at night and in the early morning. The main pathological features of asthma are airway 
inflammation and airway smooth muscle dysfunction resulting in airway hyperresponsiveness 
with the predominant physiological feature being episodes of airway obstruction with limited 
expiratory airflow (NAEPP 2007). Chronic inflammation in the airways may lead to permanent 
alterations to the airway structure, a process known as airway remodeling (NAEPP 2007). 
The goal of pharmacologic therapy in asthma is to control chronic and nocturnal symptoms, 
maintain normal activity levels (including exercise), maintain near-normal pulmonary function, 
prevent acute episodes of asthma, minimize emergency room (ER) visits and hospitalizations, 
and avoid adverse effects of asthma medications (NAEPP 2007). Quick relief medications, such 
as short-acting β2 agonists (SABAs) and anticholinergics are used to treat acute symptoms by 
rapidly reversing airflow limitation and bronchoconstriction. Long-term control medications 
such as inhaled corticosteroids (ICSs), cromolyn, immunomodulators, leukotriene modifiers, and 
long-acting β2 agonists (LABAs) are used to achieve daily control of persistent asthma 
symptoms. Because of the complementary mechanisms of action of ICSs and LABAs, many 
asthma patients require treatment with both for optimal control of their asthma. Clinical 
programs conducted with currently marketed combination products have demonstrated that 
ICS/LABA combination products provide greater improvement in forced expiratory volume in 
1 second (FEV1), peak expiratory flow (PEF), and decreased exacerbations than either individual 
component alone in patients older than 12 years with persistent asthma (Shrewsbury et al 2000). 
The rationale for use of such a combination therapy for the treatment of asthma is that it is 
scientifically sound (counteracting airway inflammation and smooth muscle dysfunction), 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
34 
justifiable on therapeutic grounds (potential for improved compliance and convenience), and 
offers significant clinical benefits. 
Teva Branded Pharmaceutical Products R&D, Inc. (Teva) is developing fluticasone propionate 
(Fp) inhalation powder products and a fixed-dose combination of fluticasone 
propionate/salmeterol (FS) inhalation powder products, using Teva’s proprietary multidose dry 
powder inhaler (MDPI). Fluticasone propionate is a synthetic trifluorinated corticosteroid with 
potent anti-inflammatory activity. Salmeterol xinafoate (Sx) is a LABA. Inflammation is an 
important component of the pathophysiology of asthma, and corticosteroids have been shown to 
inhibit multiple inflammatory cells and mediators involved in the pathophysiology of asthma. 
The fluticasone propionate multidose dry powder inhaler (Fp MDPI) is supplied in multiple 
dosage strengths of Fp (25, 50, and 100 mcg twice daily) for doses of 50, 100, and 200 mcg daily 
to patients ages 12 years and older requiring ICS therapy for treatment of asthma. The Fp MDPI 
contains the same active ingredient as FLOVENT® DISKUS® (GlaxoSmithKline plc1), which is 
marketed at strengths of 50, 100, and 250 mcg for doses of 100 to 1000 mcg twice daily 
(adolescents and adults) and is the reference drug. The proposed Fp dose for study in patients 
4 through 11 years of age is based on the adult dose-ranging study demonstrating efficacy of the 
25 and 50 mcg twice daily doses that are the same or lower than the currently approved doses of 
FLOVENT DISKUS and ADVAIR® DISKUS® (GlaxoSmithKline plc2) in pediatric patients. 
Similarly, the proposed dose for salmeterol is based on the adult Phase 2 study, which 
demonstrated that the dose of 12.5 mcg twice daily was the optimal dose and resulted in less 
systemic exposure. Based on the results from the adult and adolescent Phase 3 clinical trials 
(New Drug Applications [NDAs] submitted for Food and Drug Administration [FDA] review in 
March 2016), the 25- and 50-mcg twice daily doses (50/12.5 and 100/12.5 mcg, respectively) of 
fluticasone propionate/salmeterol multidose dry powder inhaler (FS MDPI) were confirmed as 
appropriate for studies in patients 4 through 11 years of age. 
The fixed-dose combination product, FS MDPI, is supplied in multiple dosage strengths of Fp 
with a fixed dosage of salmeterol (50/12.5, 100/12.5, and 200/12.5 mcg) to allow for treatment of 
the entire spectrum of asthma patients ages 12 years and older for whom combination therapy is 
appropriate. The FS MDPI contains the same active ingredients as ADVAIR DISKUS, which is 
marketed at doses of 100/50, 250/50, and 500/50 mcg and is the reference drug. Exposure to Fp 
and salmeterol is similar or lower for the FS MDPI doses to the higher doses administered for the 
marketed product ADVAIR DISKUS. The salmeterol in FS MDPI and ADVAIR DISKUS is Sx 
(the conversion factor from salmeterol xinafoate salt to salmeterol free base is 0.6883). 
Salmeterol xinafoate will dissolve and dissociate into salmeterol free base (active moiety) in the 
lung to exert a therapeutic effect. 
The Teva device-formulation combination allows for concentrations of drug in the formulation to 
be significantly lower than ADVAIR DISKUS while achieving similar systemic exposure and 
clinical benefits. 
                                                 
1 FLOVENT® DISKUS® is a trademark, the property of the GlaxoSmithKline group of companies. 
2 ADVAIR® DISKUS® is a trademark, the property of the GlaxoSmithKline group of companies. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
35 
The 100/12.5-cg dose of FS MDPI provides approximately twice the exposure to Fp than the 
100/50-mcg dose of ADVAIR DISKUS. The availability of the lowest FS MDPI dose, 
50/12.5 mcg (which corresponds to the commonly used 100/50-mcg ADVAIR DISKUS dose), 
allows for lower exposure to Fp, as well as considerably less exposure to salmeterol. In a Phase 2 
clinical study evaluating the dose response, efficacy, and safety of FS MDPI, the Teva 
formulation of FS MDPI demonstrated lower Sx exposure when compared with ADVAIR 
DISKUS (FS MDPI 100/12.5 mcg area under the concentration-time curve from time 0 to the 
time of the last measurable drug concentration [AUC0-t]=69.9 pg•hr/mL and maximum observed 
plasma drug concentration [Cmax]=35.8 pg/mL versus ADVAIR DISKUS 100/50 mcg 
AUC0-t=173.5 pg•hr/mL and Cmax=42.3 pg/mL; Study FSS-AS-201).  
Multiple FS doses, with increasing levels of Fp, allow for treatment of patients with varying 
asthma severities and is consistent with asthma guidelines recommending a stepwise approach to 
ongoing asthma treatment; treatment is stepped up in patients with persistent symptoms or 
exacerbations and is stepped down once good asthma control is achieved and maintained (eg, the 
optimal step-up from Fp MDPI 50 mcg would be FS MDPI 50/12.5 mcg). 
The availability of multiple dose levels is therefore advantageous to allow for adjustment of 
treatment in a stepwise approach across a spectrum of asthma patients and symptoms, and helps 
to avoid underdosing or overdosing with ICS in the presence of a LABA. The goal of this study 
is to confirm the optimal dose of Fp MDPI and demonstrate the superiority of FS MDPI versus 
Fp MDPI on bronchodilation in patients 4 through 11 years old with persistent asthma. 
1.2. 
Findings from Nonclinical and Clinical Studies 
Brief summaries of nonclinical pharmacology, pharmacokinetics, and toxicology studies and 
clinical studies are provided in the following sections. More detailed information is provided in 
the Fp MDPI and FS MDPI Investigator’s Brochures (IBs). 
1.2.1. 
Nonclinical Studies 
Information about nonclinical findings may be found in the current IBs for Fp MDPI and FS 
MDPI. 
1.2.2. 
Clinical Studies 
1.2.2.1. 
Fluticasone Propionate Efficacy 
The efficacy of Fp in asthma is due, in part, to its local anti-inflammatory activity. Specifically, 
these effects include inhibition of multiple cell types (mast cells, eosinophils, basophils, 
lymphocytes, macrophages, and neutrophils) and inhibition of mediator production/secretion 
(histamine, eicosanoids, leukotrienes, and cytokines). 
Clinical studies on Fp, marketed as FLOVENT, have shown the benefit of Fp in the maintenance 
treatment of all severities of persistent asthma. For pediatric asthmatic patients ages 4 through 
11 years, the recommended starting dosage is 1 inhalation of the 50-mcg strength product twice 
daily. Information about these studies is contained in the FLOVENT prescribing information. 
The Fp MDPI IB contains information about previous Teva clinical studies performed to 
determine the optimal dose of Fp using the Teva MDPI versus FLOVENT. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
36 
1.2.2.2. 
Fluticasone Propionate/Salmeterol Efficacy 
Salmeterol (SEREVENT® DISKUS®3) is a selective LABA that has demonstrated a prolonged 
duration of bronchodilator action. As a class, LABAs have been widely used in combination with 
ICS for the long-term maintenance treatment of asthma. Salmeterol inhalation aerosol was 
approved in 1994 for the long-term maintenance treatment of asthma and the prevention of 
bronchospasm in adolescent and adult patients with reversible airway obstruction. As a result of 
the chlorofluorocarbon phase out, only a dry powder formulation of salmeterol as a monoproduct 
is currently available in the US. 
In the NDA submitted in March 2016, the proposed indication for Teva’s FS MDPI is for the 
treatment of asthma in patients aged 12 years and older. FS (ADVAIR DISKUS) is indicated for 
the long-term, twice-daily, maintenance treatment of asthma in patients 4 years of age and older. 
For pediatric asthmatic patients ages 4 through 11 years, the recommended starting dosage is 
1 inhalation of the 100/50-mcg strength product twice daily. ADVAIR DISKUS is not indicated 
for the relief of acute bronchospasm. 
Teva has conducted a dose-ranging study in asthmatic patients to determine the optimal dose of 
salmeterol in FS MDPI. This study, FSS-AS-201, was performed in patients with mild asthma. 
Study FSS-AS-201 was performed as a blinded, single-dose, crossover study with 4 different 
strengths of salmeterol (all with 100 mcg of Fp) in the Teva MDPI device compared with Fp 
100 mcg in the Teva MDPI device and ADVAIR DISKUS 100/50 mcg. Results showed that the 
12.5- and 25-mcg strengths of salmeterol in Teva’s FS MDPI device were comparable in clinical 
efficacy (as determined by serial spirometry) with 50 mcg of salmeterol in ADVAIR DISKUS 
100/50 mcg. The peak salmeterol concentration and exposure for FS MDPI 100/12.5 mcg was 
lower than ADVAIR DISKUS 100/50 mcg (data on file). 
Additional information about clinical studies with ADVAIR DISKUS in asthma patients is 
provided in the prescribing information, which is included as an appendix in the Teva FS MDPI 
IB. 
1.3. 
Known and Potential Benefits and Risks to Patients 
1.3.1. 
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product(s) 
Additional information regarding benefits and risks to patients may be found in the Fp MDPI and 
FS MDPI IBs. 
In summary, the benefit and risk assessment for Fp MDPI and FS MDPI is favorable following 
review of the outlined data. 
1.3.1.1. 
Benefits of Test Investigational Medicinal Product Treatment 
These known and potential risks described below are balanced against known benefits. Clinical 
data demonstrate that use of Fp and salmeterol in combination in both adults and children with 
                                                 
3 SEREVENT® DISKUS® is a trademark, the property of the GlaxoSmithKline group of companies. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
37 
persistent asthma provides greater improvement in pulmonary function and overall asthma 
control than either component alone. The use of such a combination is recommended for the 
maintenance treatment of asthma in children, adolescents, and adults who remain symptomatic 
despite low-to-medium doses of an ICS in accordance with current guidelines for the 
management of asthma. 
1.3.1.2. 
Risks of Test Investigational Medicinal Product Treatment 
The class effects of systemic and local corticosteroids include Candida albicans infection, 
immunosuppression, hypercorticism and adrenal suppression, paradoxical bronchospasm, growth 
effects, and glaucoma and cataracts.  
The class of LABAs, such as salmeterol, increases the risk of asthma-related death. Data from a 
large placebo-controlled study that compared the safety of salmeterol (SEREVENT Inhalation 
Aerosol [GlaxoSmithKline plc]) or placebo added to usual asthma therapy showed an increase in 
asthma-related deaths in patients receiving salmeterol. Currently available data are inadequate to 
determine whether concurrent use of ICSs with other long-term asthma control drugs mitigates 
the increased risk of asthma-related death from LABAs. Available data from controlled clinical 
trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and 
adolescent patients. Excessive beta-adrenergic stimulation has been associated with 
cardiovascular and central nervous system (CNS) effects, such as seizures, angina, hypertension 
or hypotension, tachycardia, arrhythmia, nervousness, headache, tremor, palpitation, nausea, 
dizziness, fatigue, malaise and insomnia. 
Based on extensive clinical experience with Fp alone and in combination with salmeterol, 
Fp MDPI and FS MDPI are expected to have safety profiles (incidence, severity, and 
seriousness) that are comparable to those of FLOVENT DISKUS and ADVAIR DISKUS, 
respectively. However, Teva is developing Fp MDPI and FS MDPI for use at lower dose 
strengths of both active ingredients, but with comparable efficacy, relative to these currently 
marketed products.  
In studies in which all patients were ≥12 years of age the most common treatment-emergent 
adverse events in ≥3% of patients in the Fp MDPI and FS MDPI groups (Teva Studies 
FpS-AS-101, FpS-AS-102, FpS-AS-201, FpS-AS-202, and FSS-AS-201) included 
nasopharyngitis, upper respiratory infection (URI), headache, and nasal congestion.  
The most common adverse reactions (≥3%) in Phase 3, placebo-controlled clinical trials with 
Fp MDPI and FS MDPI products in adults included nasopharyngitis, oral candidiasis, back pain, 
headache, and cough.  
In Studies FSS-AS-301 and FSS-AS-30017, asthma exacerbations were reported at a similar 
frequency among patients treated with Fp MDPI and FS MDPI treatment groups (<1% to 4%), 
while the incidence of asthma exacerbation was 11% in patients treated with placebo. 
For Study FSS-AS-305 in the ICS cohort, the incidence of asthma exacerbations was balanced 
between the mid-strength groups, while the incidence of severe asthma exacerbations was 6% for 
Fp MDPI and 0 for FLOVENT hydrofluoroalkane (HFA). For Study FSS-AS-305 in the 
ICS/LABA cohort, the incidence of asthma exacerbations was 15% in the 
FS MDPI 200/12.5 mcg group and 7% in the ADVAIR DISKUS group, while the incidence of 
severe asthma exacerbations was 6% and 5%, respectively. Four patients had treatment 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
38 
discontinued, 3 patients were hospitalized in response to a severe asthma exacerbation, and 
5 patients had an ER/urgent care clinic visit (but were not hospitalized) because of an asthma 
exacerbation. There was no apparent relationship with treatment group for these events. This 
open-label safety study was not designed to evaluate treatment differences in asthma 
exacerbation incidence. Prior history of asthma exacerbations was not collected and was not used 
to ensure proper balance in randomization across the treatment groups. Ad hoc statistical 
analyses were performed and confirmed the incidences were not different among all groups. The 
most likely explanation for the apparent differences are the rarity of the events and the smaller 
numbers of patients in the active comparator groups relative to the study drug groups 
(3:1 randomization ratio).  
The most common adverse events noted in adult and adolescent asthmatic patients receiving 
ADVAIR DISKUS in repeat-dose, controlled clinical trials included URI, pharyngitis, 
headaches, upper respiratory inflammation, bronchitis, cough, and nausea and vomiting.  
In a study of pediatric patients randomly assigned to either ADVAIR DISKUS 100/50 mcg or Fp 
inhalation powder 100 mcg twice daily, aged 4 through 11 years who were receiving ICS at 
study entry, common adverse reactions (≥3% and greater than placebo) seen in the pediatric 
patients receiving ADVAIR DISKUS but not reported in the adult and adolescent clinical trials 
included throat irritation and ear, nose, and throat infections.  
Complete safety information is available in the Fp MDPI and FS MDPI IBs. 
1.3.2. 
Overall Benefit and Risk Assessment for This Study 
Based on extensive clinical experience with Fp and FS, Fp MDPI and FS MDPI are expected to 
have safety profiles (incidence, severity, and seriousness) that are comparable to those of 
ADVAIR DISKUS. However, Teva is developing Fp MDPI and FS MDPI for use at lower dose 
strengths of both active ingredients, but with comparable efficacy, relative to these currently 
marketed products. 
The most common adverse events noted in adult and adolescent asthmatic patients receiving 
ADVAIR DISKUS in repeat-dose, controlled clinical trials included URI, pharyngitis, 
headaches, upper respiratory inflammation, bronchitis, cough, and nausea and vomiting. The 
most common adverse reactions noted in pediatric patients aged 4 through 11 years receiving 
ADVAIR DISKUS 100/50 mcg or Fp 100 mcg twice daily but not in adults or adolescents were 
throat irritation, and ear, nose, and throat infections. The most common adverse events noted in 
asthmatic patients 4 years and older receiving FLOVENT DISKUS included URI, throat 
irritation, sinusitis, rhinitis, oral candidiasis, nausea and vomiting, gastrointestinal discomfort, 
fever, cough, bronchitis, and headache. The safety profile in the pediatric population is similar to 
that of adults. 
The most common adverse reactions (≥3%) in Phase 3, placebo-controlled clinical trials with 
Fp MDPI and FS MDPI products in adults and adolescents included nasopharyngitis, oral 
candidiasis, back pain, headache, and cough. The safety profile is consistent with the known 
class of drugs and underlying diseases. 
The potential benefits will likely outweigh the risks for this study. Efficacy results of the 
well-controlled Phase 3 and Phase 2 studies demonstrated that Fp MDPI (50, 100, and 
200 mcg bid) and FS MDPI (50/12.5, 100/12.5, and 200/12.5 mcg bid) significantly improved 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
39 
lung function, reduced rescue bronchodilator use, and improved asthma symptoms and quality of 
life in patients with asthma 12 years of age and older. Thus, Fp MDPI and FS MDPI represent 
effective, easily administered treatment options for these patients. 
Use of placebo-controlled study design in evaluating ICSs and other molecules is commonly 
used in developing these drug products and is required by FDA towards supporting the efficacy 
of the molecule (eg, Kerwin et al 2008, Woodcock et al 2013). The design of this study is very 
similar to other pediatric placebo-controlled trials where adverse events in the placebo arm were 
similar to those in the treatment arms. The study has been designed to minimize the risks of 
placebo use to the intended population of patients 4 through 11 years of age. The patient 
inclusion and exclusion criteria were selected to ensure that patients with severe asthma or 
history of life-threatening exacerbations would not be eligible. In this study, the patients’ lung 
function, symptom scores, and rescue medication use will be monitored daily with use of a 
handheld device/electronic diary. The handheld device/electronic diary will provide alerts to the 
study center and medical monitor for the trial so that patients whose asthma status may be 
deteriorating will be captured early (Section 4.3.2). This will minimize the risk and asthma 
exacerbation as well as any discomfort that might come from an exacerbation. Additionally, use 
of the handheld device/electronic diary minimizes the burden of requiring patients to travel to the 
study center for monitoring. Patients assigned to placebo therapy often demonstrate improvement 
in lung function, suggesting that frequent contact with medical providers may be of benefit. 
Additionally, all patients are provided with rescue albuterol/salbutamol for use as needed. 
Rescue albuterol/salbutamol usage will be followed closely for signs of deterioration. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
40 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Primary and Secondary Study Objectives and Endpoints 
The primary and secondary study objectives and endpoints are: 
Objectives 
Endpoints 
The primary objective of the study 
is to evaluate the efficacy of Fp 
MDPI and FS MDPI when 
administered over 12 weeks in 
patients 4 through 11 years of age 
with persistent asthma. 
The primary efficacy endpoints are as follows: 
• For Fp MDPI versus placebo: the change from baseline in 
weekly average of the percent predicted trough morning FEV1 
at week 12 
• For FS MDPI versus Fp MDPI: the change from baseline in 
1-hour postdose percent predicted morning FEV1 at week 12 
The secondary efficacy endpoints are as follows: 
• Change from baseline in the weekly average of daily trough 
morning (predose and pre-rescue bronchodilator) PEF over the 
12-week treatment period 
• Change from baseline in the weekly average of total daily 
(24-hour) use of albuterol/salbutamol inhalation aerosol 
(number of inhalations) over weeks 1 through 12 
• Change from baseline in the weekly average of the total daily 
asthma symptom score (defined as the average of the daytime 
and nighttime scores) over weeks 1 through 12 
• Change from baseline in asthma control (measured by 
Childhood Asthma Control Test [C-ACT]) over the 12-week 
treatment period 
• Time to first onset of effect defined as the first decrease from 
baseline in daily rescue medication use 
• Proportion of patients discontinued from IMP for asthma 
exacerbation during the 12-week treatment period 
The sequential order of the secondary endpoints for multiplicity will be 
described in the statistical analysis plan. 
The secondary objective of this 
study is to evaluate the safety and 
tolerability of Fp MDPI and FS 
MDPI. 
The safety endpoints are as follows: 
• Incidence of adverse events throughout the study 
• Vital signs assessments throughout the study 
• Oropharyngeal examination findings at each visit 
• Physical examination findings at baseline and at week 12 or at 
the IMP discontinuation visit (IMPDV) 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
41 
2.1.1. 
Justification of Primary Endpoint 
The co-primary endpoints selected for this study are consistent with those previously used in the 
selected population by other combination products and in the Fp MDPI and FS MDPI program in 
the adult and adolescent asthma population. They reflect the distinct mechanism of action of the 
2 different drug components. 
2.2. 
Other Efficacy and Safety Endpoints 
2.2.1. 
Other Efficacy Endpoints 
The other efficacy endpoints are as follows: 
• Change from baseline in the weekly average of total daily (24-hour) use of 
albuterol/salbutamol inhalation aerosol (number of inhalations) at weeks 4, 8, and 12  
• Change from baseline in the percentage of rescue-free days (defined as 24-hour 
periods with no rescue medication usage) during the 12-week treatment period 
• Change from baseline in the percentage of symptom-free days (defined as 24-hour 
periods with asthma symptom score of 0) during the 12-week treatment period 
• Change from baseline in the percentage of asthma-control days (defined as 24-hour 
periods with asthma symptom score of 0 and no rescue medication usage) during the 
12-week treatment period 
• Change from baseline in 1-hour postdose percent predicted morning FEV1 at week 1 
• Change from baseline in the weekly average of daily evening PEF over the 12-week 
treatment period 
• Change from baseline in the weekly average of the percent predicted trough morning 
FEV1 at weeks 1, 2, 4, and 8 
• Proportion of patients who achieve at least a 15% increase in morning FEV1 at 1 hour 
postdose at day 1 (randomization visit [RV]/treatment visit [TV] 1), week 1, and 
week 12 
• Change from baseline in asthma control (measured by C-ACT) score at weeks 4, 8, 
and 12  
• Time to consistent onset of effect defined as the decrease from baseline in daily 
rescue medication use on 3 consecutive days 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
42 
3. 
STUDY DESIGN 
3.1. 
General Design and Study Schematic Diagram 
This is a Phase 3, 12-week, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled study to evaluate the safety and efficacy of Fp MDPI and FS MDPI 
administered twice daily at doses of Fp MDPI 25 mcg, Fp MDPI 50 mcg, and FS MDPI 
50/12.5 mcg in pediatric patients with asthma. The total duration of patient participation in this 
study is approximately 15 to 17 weeks depending on the duration of the placebo run-in period.  
Patients meeting all of the inclusion criteria and none of the exclusion criteria at the screening 
visit (SV) will begin a 14- to 30-day run-in period. An albuterol/salbutamol 
hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (a SABA inhaler) will be provided to 
replace the patient’s current rescue medication and is to be used as needed for relief of asthma 
symptoms during the run-in and treatment periods, with a maximum of 12 inhalations permitted 
per day. Starting day 1 of the run-in period, patients must discontinue all nonstudy 
asthma-related drugs and instead take a patient-blinded MDPI placebo device (1 inhalation 
twice daily).  
The study consists of 3 periods as follows: 
• Patient-blinded run-in period: SV to RV, up to 30 days 
• Double-blind, randomized treatment period: RV through the TV6, approximately 
12 weeks  
• Follow-up period: TV6 through the follow-up visit (FV), approximately 7 days after 
TV6 
A prescreening visit may be conducted, if needed, before the SV to discuss study procedures 
and/or provide patient instructions about any required washout periods for prohibited 
medications. SV may take place during several investigational center visits.  
At the prescreening or SV, the patient or parent/legal guardian must provide informed consent, 
and patients must give assent (as applicable) before any study procedures are performed. At the 
time of informed consent, the parent/legal guardian will be counseled that, once randomized to 
treatment, patients are to remain in the study and complete all study procedures unless the choice 
is made to withdraw consent. This includes patients who may require alternative asthma therapy, 
experience an adverse event, violate the protocol, or fail to comply with study procedures. 
Continued patient participation is important to contribute to the scientific investigation. Patients 
who are being treated with an ICS with or without a LABA and/or with a noncorticosteroid 
(NCS) therapy are eligible to be included in the study. Patients must meet washout period 
requirements at the SV for their asthma and non-asthma disallowed medications according to 
Appendix H. The patient’s asthma medication regimen must be stable for 30 days prior to the SV 
(except as adjusted at an optional prescreening visit to wash out prohibited medications). If the 
patient has taken asthma maintenance medication the morning of the SV or SABA within 
6 hours of lung function assessments (FEV1 and PEF) by handheld device, the visit must be 
rescheduled so that lung function assessments and response to bronchodilator testing can be 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
43 
completed as described (other assessments not involving lung function may be completed that 
day). 
Patients will be provided with a handheld device at the SV, which will be used to measure lung 
function assessments (FEV1 and PEF) and will serve as an electronic patient diary to collect 
asthma symptom scores, rescue medication use, and IMP use. Screening lung function 
assessments (FEV1 and PEF) by handheld device should be performed at the investigational 
center between the hours of 0530 and 1100. Patients will be permitted 8 attempts per test. The 
highest FEV1 value from 3 technically acceptable and 2 repeatable maneuvers will be used to 
qualify patients for the placebo run-in period. Patients who have failed screening for inability to 
perform lung function assessments (FEV1 and PEF) in a technically acceptable manner or due to 
FEV1 not meeting the inclusion criterion or demonstrated <10% response to a bronchodilator 
may retest once within 7 days of their initial SV provided that they have met all other inclusion 
criteria and none of the exclusion criteria at the SV. The handheld device should be kept at the 
clinic for these patients until they meet the requirements to enter the run-in period. 
At retest, patients (or patient’s parent/legal guardian/caregiver) will report if there have been any 
adverse events, changes in medications, or changes in medical history since providing 
consent/assent. Patients who fail again to demonstrate technically acceptable lung function 
assessments (FEV1 and PEF) or due to FEV1 not meeting the inclusion criterion or who 
demonstrate <10% response to a bronchodilator will be considered screen failures. The run-in 
period will not start until patients have met all inclusion criteria and none of the exclusion 
criteria. Patients who fail to meet the requirements to enter the run-in period at this visit will be 
considered screen failures and will not be allowed to be rescreened. 
Patients who qualify for entry into the placebo run-in period must discontinue all currently 
administered asthma medications (including leukotriene modifiers prescribed for other 
conditions) until completion of the TV6 (week 12) visit or IMPDV if, in the investigator’s 
judgment, there would be no inherent harm in changing the patient’s treatment and the patient or 
parent/legal guardian provides consent/assent (as applicable). Patients will be provided with 
albuterol/salbutamol HFA MDI (90 mcg ex-actuator) or equivalent as rescue medication. During 
the run-in period (SV to RV), in addition to the above rescue medication, patients will be 
provided with a patient-blinded placebo MDPI device for twice-daily use after appropriate 
training and demonstration of proper technique. 
All patients who enter the placebo run-in period will perform daily morning and evening lung 
function assessments (FEV1 and PEF) by handheld device at home and assess and record 
daytime and nighttime asthma symptom scores, rescue albuterol/salbutamol HFA MDI use, and 
morning and evening IMP dosing in the patient diary built into the handheld device.  
Patients who experience an URI or lower respiratory infection (LRI) during the run-in period 
should be classified as randomization failures and be discontinued from the study but may be 
rescreened 2 weeks after resolution of the infection. Patients who are rescreened will need to 
repeat all screening procedures and evaluations. Only 1 rescreening for each patient will be 
permitted. 
Patients who entered the run-in period with response to a bronchodilator ≥10% and <14.50% 
must present for repeat lung function assessments and another bronchodilator test within 
14±2 days, during which they must demonstrate at least a 15% response to a bronchodilator. If 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
44 
the criteria are not met, patients may continue in the run-in period for up to 14 additional days to 
meet the lung function assessment and response to bronchodilator criteria (1 final attempt) for 
randomization. Patients may only continue in the run-in period if the investigator determines, by 
assessing the patient’s asthma status (at each investigational center visit), that it is safe for the 
patient to continue. Patients who have entered the run-in period but fail to demonstrate 
technically acceptable lung function assessments and response to a bronchodilator (as described) 
will be considered to have failed randomization. All patients must demonstrate at least a 
15% response to a bronchodilator at the SV or during the run-in period. Patients who 
demonstrate the response to bronchodilator during the run-in period may present for 
randomization the following day at the earliest or at another later time as long as it is within the 
30-day allowance for the run-in period. Responses to a bronchodilator of 14.50% to 14.99% will 
be rounded to 15%. 
At the RV (end of run-in period, TV1), patients will be assessed for randomization. Patients who 
meet all randomization inclusion criteria and continue meeting all inclusion criteria and none of 
the exclusion criteria will be stratified by previous therapy (ICS or NCS) and randomly assigned 
into the double-blind treatment period of the study in a 1:1:1:1 ratio to Fp MDPI 25 mcg, Fp 
MDPI 50 mcg, FS MDPI 50/12.5 mcg, or placebo MDPI, twice daily (see Table 2). Patients will 
be instructed to take 1 inhalation from the assigned device twice daily approximately 12 hours 
apart.  
Table 2: 
Treatment Group Description 
Treatment group 
Active devices 
Total daily dose (mcg) 
Blinding 
A 
Fp MDPI 25 mcg 
50 
Double-blind 
B 
Fp MDPI 50 mcg 
100 
Double-blind 
C 
FS MDPI 50/12.5 mcg 
100/25 
Double-blind 
D 
Placebo MDPI 
0 
Double-blind 
Fp=fluticasone propionate; FS=fluticasone propionate/salmeterol; MDPI=multidose dry powder inhaler. 
During the treatment period (RV through TV6 [week 12] or IMPDV), daily in the morning and 
evening at approximately the same time each day, patients will use the handheld device at home 
to record asthma symptom scores and rescue albuterol/salbutamol HFA MDI use, after which 
they will perform lung function assessments (FEV1 and PEF) and then will take their dose of the 
IMP and record IMP dosing in the patient diary built into the handheld device.  
On the morning of each TV, patients will be instructed to record their asthma symptom score and 
rescue albuterol/salbutamol HFA MDI use and complete their morning lung function 
assessments (FEV1 and PEF) by handheld device as usual, but to delay IMP dosing until they get 
to the investigational center. Patients are also to withhold their rescue SABA for a minimum of 
6 hours prior to obtaining lung function assessments. If the patient inadvertently takes the 
morning IMP dose or rescue medication within 6 hours of the planned lung function 
assessments, the visit must be rescheduled. Similarly, patients who have been withdrawn from 
IMP but remain in the study should withhold their alternative asthma therapy dosing until after 
treatment visit assessments and avoid rescue medication for a minimum of 6 hours prior to clinic 
lung function assessments. The treatment visit should be rescheduled if either or both occur. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
45 
At the investigational center, after appropriate instruction and training (competent handheld 
device use and dosing technique using the training devices provided), patients will perform their 
lung function assessment (FEV1 and PEF) under the supervision of the investigational center 
staff. They will then take their morning dose of the IMP unless IMP has been withdrawn. IMP 
administration at the investigational center should be timed so that lung function assessments 
will be approximately 12 hours following the doses taken the previous evening. Patients will 
then perform 1-hour postdose FEV1 measurements using the handheld device. Patients who have 
been withdrawn from IMP will be asked to perform 1-hour postdose lung function assessments; 
although the patients will not be taking a dose of IMP, the assessment should be approximately 
1 hour after the predose lung function assessments were obtained. The highest FEV1 value from 
3 acceptable and 2 repeatable maneuvers (maximum of 8 attempts per test) will be obtained 
before and 1-hour after the morning dose.  
At each visit, the investigational center staff will determine if patients have experienced any 
adverse events, changes in medical history, changes in medication, or any difficulty following 
study procedures. The C-ACT will be completed by the patient and the patient’s parent/legal 
guardian/caregiver (as applicable) at the investigational center, before any other assessments are 
performed, at specified visits. The same parent/legal guardian/caregiver should complete the 
assessments at each visit, if possible.  
A telephone call may be conducted as needed during the alternate, non-visit weeks (weeks 5, 7, 
etc) to monitor the patients’ safety and to assess their asthma status or for any other relevant 
reason.  
At the end of the study, a FV (which may be a follow-up investigational center visit or telephone 
call) will be conducted 7±2 days after TV6 (week 12) to monitor safety of the patients.  
Patients who meet the alert criteria for worsening asthma as defined for this study or experience 
worsening of asthma including asthma exacerbation will present to the investigational center for 
an investigator assessment as soon as possible. If possible and when it is judged safe to do so, 
this visit should be conducted before a change in asthma therapy takes place. Following 
investigator assessment of the patient’s asthma status, a decision will be made whether or not it 
is safe for a patient to continue the IMP. In cases where the IMP is to be withdrawn and 
alternative therapy started, the investigational center staff should contact the medical monitor to 
confirm the findings. In the event that it is considered in the best interest of a patient to stop the 
IMP and initiate an alternative asthma therapy, the patient will undergo all visit procedures 
required for the IMPDV. After the IMPDV, IMP dosing will not occur. The investigator should 
discuss and implement alternative asthma treatment that is appropriate for the patient. These 
patients will continue to participate in all study visits as scheduled and continue to complete all 
morning and evening study procedures except for IMP dosing. Patients will be asked to perform 
1-hour postdose lung function assessments at the remaining treatment visits; although the 
patients will not be taking a dose of IMP, the assessment should be approximately 1 hour after 
the predose lung function assessments were obtained. If a patient or patient’s parent/legal 
guardian elects to completely withdraw from the study (ie, withdraw consent) prior to the 
investigator assessment or investigational center visit, irrespective of the reason for the study 
discontinuation, every attempt will be made to conduct the IMPDV subsequent to the patient’s 
withdrawal from the IMP.  


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
46 
Asthma exacerbation that requires a change in medication or worsening of asthma that requires 
the patient to be treated with alternative therapy will be entered into the case report form (CRF), 
including the date at which any medication change was made and whether this medication 
change was implemented prior to or after the IMPDV lung function assessments (FEV1 and PEF) 
were completed. Asthma worsening including asthma exacerbations with a change to alternative 
asthma therapy will not be considered an adverse event for this study since it is an expected 
outcome for this study in an asthmatic patient population. Asthma exacerbations that meet the 
criteria for a serious adverse event will be recorded as adverse events.  
At TV6 (week 12), or the IMPDV as applicable, the investigator will discuss asthma treatment 
with the patient after safety assessments have been completed, and any medication started for the 
purpose of newly recommended asthma treatment will not be considered a protocol violation. 
This asthma therapy will be recorded in the CRF following IMP discontinuation (planned or 
unplanned). Additionally, an investigational center visit may be conducted at any time at the 
request of the patient or parent/legal guardian/caregiver, as applicable or at the discretion of the 
investigator. 
Safety will be monitored by vital signs, physical examination, oropharyngeal examination, and 
recording of adverse events. In addition, during the study, PEF and FEV1 will be monitored as 
part of safety monitoring (alert criteria for worsening asthma). Any visual evidence of oral 
candidiasis during the treatment period will be confirmed by obtaining a swab for culture of the 
suspect area. Patients and parents/legal guardians/caregivers will be provided with guidelines for 
when to contact the investigational center in case of worsening asthma symptoms or rescue 
inhaler use. Patients who meet predefined alert criteria should be evaluated by the investigator to 
determine if the IMP should be discontinued. If a patient discontinues the IMP prematurely but 
remains in the study, all subsequent visits will include all assessments according to Table 3 
except for IMP dosing. Patients will be asked to perform 1-hour postdose lung function 
assessments at the remaining treatment visits; although the patients will not be taking a dose of 
IMP, the assessment should be approximately 1 hour after the predose lung function assessments 
were obtained. 
Alert criteria for individual patients have been designed to ensure patient safety. If any of the 
criteria listed below are met, during a scheduled or unplanned study visit, the investigator (after 
discussion with the sponsor) will determine whether the patient’s overall clinical picture is 
consistent with worsening asthma and if the patient should be withdrawn from IMP (but not the 
study) to be placed on alternative asthma therapy in the interest of patient safety. Meeting 1 of 
these alert criteria does not automatically require a patient to be withdrawn from IMP, rather it 
requires a clinical evaluation to determine if the patient’s asthma can continue to be managed in 
a blinded manner per the study or necessitates a change in asthma therapy. All attempts will be 
made to safely continue to manage a patient in a blinded manner. 
• Morning FEV1 by handheld device measured at home falls below the FEV1 stability 
limit (see Section 6.1.3) calculated at the SV for the run-in period and at baseline for 
the treatment period on 4 or more days (do not have to be consecutive) out of any 
7-day period (7-day period is defined as any consecutive 7 days following the RV and 
can overlap with scheduled study investigational center visits). 
• Based upon a review of patient data from the patient diary built into the handheld 
device, the patient has experienced any of the following during a 7-day period (7-day 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
47 
period is defined as any consecutive 7 days following a previous TV; 7 days can 
overlap with scheduled study investigational center visits): 
− 3 or more days in which 8 or more inhalations/day of rescue medication 
(albuterol/salbutamol HFA MDI [90 mcg ex-actuator] or equivalent) were used 
(any 3 days in the consecutive 7-day period) 
− 3 or more days in which the patient experienced a nighttime asthma symptom 
score of more than 2 (any 3 days in the consecutive 7-day period) 
Patients who meet the alert criteria and/or who experience a clinically meaningful worsening of 
their asthma will be assessed by the investigator. If the investigator considers it is not possible to 
safely manage a patient in a blinded manner as patient’s asthma warrants a change in his/her 
asthma treatment, the IMP will be stopped, and appropriate treatment (based on the 
investigator’s judgment) should be offered. The medical monitor should be contacted to confirm 
the findings when alternative therapy is to be instituted. The patient should continue in the study 
until the patient has completed all remaining study visits and the FV.  
• For the purpose of this study, an asthma exacerbation is defined as worsening of 
asthma requiring any significant treatment other than IMP and study rescue 
medication. Significant treatment includes the use of systemic corticosteroids and/or 
the addition of other ICS-containing asthma medications, LABAs, or other NCS 
asthma medications, for example, inhaled short-acting muscarinic antagonist; 
ER/urgent care clinic visit(s); or hospitalization. Note: A single dose of nebulized 
albuterol/salbutamol would not meet the criteria for an asthma exacerbation. 
ER/urgent care clinic visits where the treatment is limited to a single dose of 
nebulized albuterol/salbutamol will not meet the criteria of an asthma exacerbation. 
After the last TV (TV6, week 12), the patient will enter the follow-up period. One week 
(±2 days) after the last TV, the patient will have a FV. This FV may be in person or over the 
telephone. The patient will be deemed to have completed the treatment period if they have 
completed all periods of the study, including screening, run-in, and all TVs. The patient will be 
deemed to have completed the study period if they have completed all periods of the study, 
including FV in addition to screening, run-in, and all TVs. Patients who stop IMP and return for 
safety evaluation at week 12 will not be considered to have completed the treatment period. 
The assessments and procedures performed during each study visit are detailed in Table 3 and 
Appendix B. 
The study schematic diagram is presented in Figure 1. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
48 
Figure 1: 
Overall Study Schematic Diagram 
 
Fp=fluticasone propionate; FS=fluticasone propionate/salmeterol; IMPDV=investigational medicinal product 
discontinuation visit; MDPI=multidose dry powder inhaler; RV=randomization visit; SV=screening visit; 
TV=treatment visit.  
3.2. 
Planned Number of Patients and Countries 
The population planned to be enrolled in this study comprises male and female patients 
4 through 11 years of age who have a documented history of persistent asthma. Approximately 
824 male and female patients, 206 patients in each of 4 treatment group, will be enrolled. 
Assuming a dropout rate of 12%, approximately 181 evaluable patients in each treatment group 
(724 total patients) will complete the 12-week treatment period. 
Details on the definition of evaluable patients and sample size are given in Section 9. 
The study is planned to be conducted in the US and ex-US in approximately 130 investigational 
centers. The study is expected to start in the fourth quarter of 2016 (first patient in) and last until 
approximately the second quarter of 2019 (last patient last visit). 
3.3. 
Justification for Study Design and Selection of Population 
This is a standard study design used to determine the safety and efficacy of 3 investigational 
treatments in pediatric patients aged 4 through 11 years old with persistent asthma. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
49 
The study is part of a pediatric program to investigate the efficacy and safety in pediatric 
patients. This study follows completion of a pharmacokinetic study with Fp MDPI and FS MDPI 
in the target study population of asthmatic patients 4 through 11 years of age. The population 
planned to be enrolled in this study comprises male and female patients 4 through 11 years of 
age who have a documented history of persistent asthma. The asthma diagnosis must be in 
accordance with the National Institutes of Health (NIH) definition. 
3.4. 
Stopping Rules for the Study 
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed (see Section7.1.5) as they are reported from the 
investigational centers to identify safety concerns. 
The study may be terminated by the sponsor for any reason at any time.  
A patient may discontinue participation in the study at any time for any reason by withdrawal of 
consent; every effort should be undertaken to find out the reason for discontinuation. The 
investigator or sponsor can withdraw a patient from the study IMP at any time for any reason 
(eg, protocol violation or deviation as defined in Appendix C, noncompliance, or adverse event). 
However, patients that do not withdraw consent should remain in the study (as counseled during 
the informed consent process) and complete the remaining study procedures and visits, with the 
exception of IMP dosing. Patients will be asked to perform 1-hour postdose lung function 
assessments at the remaining treatment visits; although the patients will not be taking a dose of 
IMP, the assessment should be approximately 1 hour after the predose lung function assessments 
were obtained. 
3.5. 
Schedule of Study Procedures and Assessments 
Study procedures and assessments with their time points are summarized in Table 3. Detailed 
by-visit information is provided starting with Appendix B, Part 11. Detailed descriptions of each 
assessment are provided in Section 6 (efficacy assessments) and Section 7 (safety assessments). 
Study procedures and assessments by visit are listed in Appendix B. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
50 
Table 3: 
Study Procedures and Assessments 
Study period 
Placebo run-in 
Double-blind treatment period (visit week) 
Follow-up 
Visit number 
SVa 
RV/TV1b 
TV2 
TV3 
TV4 
TV5 
TV6 
IMPDV 
FV 
Procedures and assessments 
Screening Baseline 
W1 
W2 
W4 
W8 
W12 
IMP discontinuation 
W13 
Allowed time windows 
-30 to  
-14 days 
Day 1 
Day 8 
±2 days 
Day 15 
±2 days 
Day 29 
±2 days 
Day 57 
±2 days 
Day 85 
±2 days 
±2 days 
Day 92 
±2 days 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
Medical historyc 
X 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Begin run-in 
X 
 
 
 
 
 
 
 
 
Perform randomization and treatment assignment in IRTb 
 
X 
 
 
 
 
 
 
 
Randomization criteria 
 
X 
 
 
 
 
 
 
 
Adverse event inquiry and recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs measurementd 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full physical examination, including weight and height 
X 
 
 
 
 
 
X 
X 
 
Directed cardiopulmonary examination 
 
X 
 
 
 
 
 
 
 
Oropharyngeal examinatione  
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine pregnancy test (female patients of childbearing potential) 
X 
X 
X 
X 
X 
X 
X 
X 
 
Perform lung function assessments (FEV1 and PEF) by handheld 
device with response to bronchodilator testingf 
X 
 
 
 
 
 
 
 
 
Perform lung function assessments (FEV1 and PEF) by handheld 
device predose g 
X 
X 
X 
X 
X 
X 
X  
(morning only) 
X  
 
Perform lung function assessments (FEV1) by handheld device 
1-hour postdose at the investigational centerh 
 
X 
X 
X 
X 
X 
X  
(morning only) 
X  
 
Conduct training for use of handheld device 
X 
X 
X 
X 
X 
X 
 
X 
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
51 
Study period 
Placebo run-in 
Double-blind treatment period (visit week) 
Follow-up 
Visit number 
SVa 
RV/TV1b 
TV2 
TV3 
TV4 
TV5 
TV6 
IMPDV 
FV 
Procedures and assessments 
Screening Baseline 
W1 
W2 
W4 
W8 
W12 
IMP discontinuation 
W13 
Allowed time windows 
-30 to  
-14 days 
Day 1 
Day 8 
±2 days 
Day 15 
±2 days 
Day 29 
±2 days 
Day 57 
±2 days 
Day 85 
±2 days 
±2 days 
Day 92 
±2 days 
Asthma control questionnaire (C-ACT) 
 
X 
 
 
X 
X 
X 
X 
 
Dispense/collect run-in IMP kit 
X 
X 
 
 
 
 
 
X 
 
Conduct training for IMP administration and have patient 
demonstrate proper technique using the provided training inhaleri 
X 
X 
X 
X 
X 
X 
 
 
 
Observe patient dosing with IMP 
 
X 
X 
X 
X 
X 
X 
 
 
Dispense/collect rescue medicationj 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense/collect double-blind IMP kit 
 
X 
 
X 
X 
X 
X 
X 
 
Assess alert criteria for worsening asthma  
 
X 
X 
X 
X 
X 
X 
X 
 
Distribute/collect handheld devicek 
X 
X 
X 
X 
X 
X 
X 
X 
 
Discuss and record recommended asthma therapyl 
 
 
 
 
 
 
X 
X 
 
End IMP in IRT system 
 
 
 
 
 
 
X 
X 
 
End study participation in IRT systemm 
 
 
 
 
 
 
X 
Xl 
 
a Patients may attend a prescreening visit up to 15 days before the SV. The SV may occur up to 30 days prior to the RV. Patients who fail to meet baseline lung 
function assessments by handheld device requirements may retest within 7 days of their initial SV. Patients who demonstrate a response to a bronchodilator 
≥10% and <14.50% may enter the run-in period but must undergo repeat lung function assessments and another bronchodilator test in 14±2 days and may 
attempt lung function assessments and response to a bronchodilator within 14 more days if needed (as applicable). Patient-blinded drug should be dispensed at 
each visit until the patient qualifies for or fails randomization. Informed consent/assent should be done at the SV unless already completed at a prescreening 
visit. 
b The RV may occur up to 30 days following the SV. The patient’s home FEV1 by handheld device should be reviewed, and the average of the 5 highest daily 
values (3 attempts) for trough morning FEV1 out of the last 7 days prior to RV must be 40% to 85% predicted for age, height, sex and race (Quanjer et al 2012) 
with asthma symptom criteria, the C-ACT score must be ≤19 to be eligible for randomization. The patient must also meet the lung function assessment 
requirements at the investigational center and all other study criteria. Eligible patients will be assigned a patient randomization identification number via the 
IRT system that is different than the one received at screening. 
c The medical history is to be obtained by the investigator or designated study personnel. If there are no prior medical records available, the investigator must 
document the history of asthma, as reported by the patient, in the source document. Prior medical records must be requested, or the reason if not requested must 
be documented in the source documents. This will be considered adequate history if it meets the inclusion criteria. 
d Vital signs (BP and pulse rate) should be obtained with the patient in the sitting position after a 5-minute rest period. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
52 
e An oropharyngeal examination is to be conducted by a qualified medical provider (as required by local regulation) at each visit. Clinical visual evidence of 
oropharyngeal candidiasis at the RV will exclude the patient from participating in the treatment period. Evidence of oropharyngeal candidiasis at any study TV 
or end of study TV should be evaluated by obtaining a swab for culture. Patients who agree to treatment may continue to receive IMP. Treatment should not be 
delayed for results of the culture. 
f Lung function assessments (FEV1 and PEF) by handheld device and response to bronchodilator testing should be conducted. Patients unable to perform lung 
function assessments will be allowed to retest once within 7 days. Patients who meet lung function assessment and response to a bronchodilator requirements 
may enter the run-in period. Patients who entered the run-in period with response to a bronchodilator ≥10% and <14.50% must present for repeat lung function 
assessments and another bronchodilator test within 14±2 days, during which they must demonstrate at least a 15% response to a bronchodilator. Responses to 
bronchodilator of 14.50% to 14.99% will be rounded to 15%. If the criteria are not met, patients may continue in the run-in period for up to 14 additional days 
to meet the lung function assessment and response to a bronchodilator criteria (1 final attempt) for randomization. Patients who have failed screening for 
inability to perform lung function assessments in a technically acceptable manner or due to FEV1 not meeting the inclusion criterion or demonstrated <10% 
response to a bronchodilator may retest once within 7 days of their initial SV provided that they have met all other inclusion criteria and none of the exclusion 
criteria at the SV. Patients who enter the run-in period with response to a bronchodilator ≥15% do not need to retest at the RV. For patients who need to 
demonstrate the response to bronchodilator during the run-in, the RV must be on another day. 
g Daily morning and evening lung function assessments (FEV1 and PEF) by handheld device (after the patient is trained on its use and has demonstrated proper 
technique using the provided training device) will be performed, except as indicated. The patient will be instructed to perform 3 trough morning FEV1 
maneuvers and 3 evening FEV1 maneuvers at home each day during participation in the run-in period and the treatment period (morning only on the final TV 
[TV6 (week 12)]). The highest FEV1 obtained at the SV will be used to calculate the home FEV1 stability limit, which will be used for review of alert criteria 
during the run-in period. The average FEV1 over 5 days prior to RV will be used to calculate the alert criteria for the treatment period.  
h 60-minute (±10 minutes) postdose lung function assessments will be performed at the investigational center at all visits (excluding patients placed on 
alternative therapy where the patient will not dose but a 1-hour assessment will still be collected). 
i  Except patients who have been placed on alternative therapy. 
j Rescue medication will be dispensed for all patients entering the run-in period. At each visit, the study personnel should determine if the patient has adequate 
rescue medication remaining (based on current use) or dispense a new albuterol/salbutamol HFA MDI. A second inhaler may be provided for use at school or 
camp, as applicable. Rescue medication dispensed at SV will be used for response to a bronchodilator test. 
k The investigational center staff must verify that the information from the patient diary built into the handheld device is up to date and identify any potential 
missing data or deviations upon review of the patient diary built into the handheld device at that visit. The device will be collected and inspected to make sure it 
is not damaged and the data will be downloaded at each clinic visit. Once inspected, the same handheld device will be redispensed to the patient unless it needs 
to be replaced. 
l The investigator will discuss ongoing asthma treatment with the patient after lung function assessments have been completed, and any medication started for 
the purpose of ongoing asthma treatment will not be considered a protocol violation. This treatment, if instituted, should be entered in the CRF as ongoing 
therapy. 
m End of study participation in the IRT system will take place at the last visit during the treatment period (ie, at TV6 for patients who complete the treatment 
period, or at the IMPDV for patients who discontinue the study prematurely [patients who withdraw consent]). 
BP=blood pressure; C-ACT=Childhood Asthma Control Test; CRF=case report form; FEV1=forced expiratory volume in 1 second; FV=follow-up visit; HFA 
MDI=hydrofluoroalkane metered-dose inhaler; IMP=investigational medicinal product; IMPDV=investigational medicinal product discontinuation visit; 
IRT=Interactive Response Technology; PEF=peak expiratory flow; RV=randomization visit; SV=screening visit; TV=treatment visit. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
53 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be enrolled are not granted by Teva (Appendix C). 
4.1. 
Patient Inclusion Criteria 
The SV can be broken into more than 1 visit. Patients may be included in the study run-in period 
if they meet all of the following inclusion criteria at screening:  
a. The patient is a male or female patient 4 through 11 years of age, inclusive, when 
informed consent/assent (as applicable) is signed. 
b. Written informed consent must be signed and dated by parent/legal guardian and the 
written informed assent form must be signed and dated by the patient (as applicable, 
per local regulations) before any study-related procedures are conducted. 
c. The patient has a diagnosis of asthma as defined by the NIH. The asthma diagnosis 
has been present for a minimum of 3 months before SV. 
d. The patient has persistent asthma with a FEV1 ≥50% and ≤90% of the value predicted 
for age, height, sex, and race at the SV as measured by handheld device.  
e. The patient’s persistent asthma is stable and is currently being treated with stable 
asthma therapy (eg, ICS, ICS/LABA, leukotriene receptor antagonist, etc.) for at least 
30 days before the SV. Patients who are currently on SABA regimen only or PRN 
only are not eligible for the study.  
f. The patient has demonstrated ≥10% response to a bronchodilator from screening 
FEV1 within 30 minutes (±5 min) after 2 to 4 inhalations of albuterol/salbutamol 
HFA MDI (90 mcg ex-actuator) or equivalent at SV as measured by handheld device. 
Patients who demonstrated <10% response to a bronchodilator may retest within 7 
days of their initial SV. 
− Patients who demonstrate response to a bronchodilator ≥10% and <14.50% may 
enter the run-in period (provided that they meet the other inclusion and none of 
the exclusion criteria) and may present for repeat lung function assessments by 
handheld device and another bronchodilator test within 14±2 days, during which 
they must demonstrate at least a 15% response to a bronchodilator. If the criteria 
are not met, patients may continue in the run-in period for up to 14 additional 
days to meet the lung function assessment and response to bronchodilator criteria 
(1 final attempt) for randomization. Patients may only continue in the run-in 
period if the investigator determines, by assessing the patient’s asthma status (at 
each investigational center visit), that it is safe for the patient to continue. 
g. The patient (with assistance from parents/legal guardians/caregivers, as needed) is 
able to perform technically acceptable lung function assessments by handheld device. 
Patients who fail to demonstrate technically acceptable lung function assessments 
may retest within 7 days of their initial SV. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
54 
h. The patient (with assistance from parents/legal guardians/caregivers, as needed) is 
able to use an MDI device and an MDPI device.  
i. The patient is able to withhold (as judged by the investigator) his/her rescue 
medication for at least 6 hours before SV and all TVs where lung function 
assessments are performed.  
j. The patient is assessed as otherwise healthy, with clinically acceptable medical 
history, physical examination, and vital signs within acceptable ranges for children 
with asthma as assessed by the investigator.  
k. All patients must be able to replace their current SABA with albuterol/salbutamol 
HFA MDI inhalation aerosol at the SV for use as needed for the duration of the study.  
l. Female patients who have reached puberty and achieved menarche (as determined by 
the investigator) must be counseled regarding the possible unknown risks associated 
with IMP during pregnancy following permission of the parents/legal guardians. A 
urine pregnancy test must be negative for these patients at SV. Eligible female 
patients who are known to be sexually active will be excluded.  
m. Eligible male patients who are known to be sexually active will be excluded. 
4.2. 
Patient Exclusion Criteria 
Patients will be excluded from participating in this study if they meet any of the following 
criteria: 
a. The patient has a history of life-threatening asthma exacerbation that is defined for 
this protocol as an asthma episode that required intubation and/or was associated with 
hypercapnia, respiratory arrest, or hypoxic seizures. 
b. The patient is pregnant or lactating or plans to become pregnant during the study 
period or within 30 days after the patient’s last study-related visit (for eligible patients 
only and if applicable).  
c. The patient has participated as a randomized patient in any investigational drug study 
within the 30 days or within 5 half-lives (starting from the final FV of that study) 
preceding the SV (or prescreening visit, as applicable) or plans to participate in 
another investigational drug study at any time during this study.  
d. The patient has a known hypersensitivity to any corticosteroid, salmeterol, or any of 
the excipients in the IMP or rescue medication formulation (ie, lactose). Dietary 
lactose intolerance does not exclude the patient from inclusion into the study or as per 
the investigator’s medical discretion. 
e. The patient has been treated with any known strong cytochrome P450 (CYP) 3A4 
inhibitors (eg, ketoconazole, ritonavir, clarithromycin) within 30 days before the SV 
or plans to be treated with any strong CYP3A4 inhibitor during the study.  
f. The patient has been treated with any of the prohibited medications during the 
prescribed (per protocol) washout periods before the SV.  


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
55 
g. The patient currently smokes or has a smoking history. The patient must not have 
used tobacco products within the past year (eg, cigarettes, cigars, chewing tobacco, or 
pipe tobacco).  
h. The patient has a culture-documented or suspected bacterial or viral infection of the 
upper or lower respiratory tract, sinus, or middle ear that has not resolved at least 
2 weeks before the SV (note: patients who develop a URI or LRI during the run-in 
period may be rescreened 2 weeks after symptoms resolve).  
i. The patient has had an asthma exacerbation requiring systemic corticosteroids within 
30 days before the SV or has had any hospitalization for asthma within 2 months 
before the SV.  
j. Initiation or dose escalation of immunotherapy (administered by any route) is planned 
during the study period. However, patients who initiated immunotherapy 90 days or 
more before the SV and have been on a stable (maintenance) dose for 30 days or 
more before the SV may be considered for inclusion.  
k. The patient has used immunosuppressive medications within 30 days before the SV.  
l. The patient is unable to tolerate or unwilling to comply with the appropriate washout 
periods and withholding of all applicable medications.  
m. The patient has untreated oral candidiasis at the SV. Patients with clinical visual 
evidence of oral candidiasis who agree to receive treatment and comply with 
appropriate medical monitoring may enter the run-in period. 
n. The patient has a history of a positive test for human immunodeficiency virus, active 
hepatitis B virus, or hepatitis C infection.  
o. The patient is an immediate relative of an employee of the clinical investigational 
center.  
p. A member of the patient’s household is participating in the study at the same time. 
However, after the enrolled patient completes or discontinues participation in the 
study, another patient from the same household may be screened.  
q. The patient has a disease/condition that, in the medical judgment of the investigator, 
would put the safety of the patient at risk through participation or that could affect the 
efficacy or safety analysis if the disease/condition worsened during the study. 
Examples include, but are not limited to, the following: 
− cardiovascular conditions including clinically significant cardiac arrhythmia, 
known aortic aneurysm, congenital heart disease, coronary heart disease, or vital 
signs clinically unacceptable for ranges in children with asthma as assessed by the 
investigator 
− hepatic, renal, hematologic, neuropsychologic, or endocrine conditions (eg, sickle 
cell disease, uncontrolled diabetes mellitus, uncontrolled thyroid disorder, 
Addison’s disease, Cushing’s syndrome, stroke within 3 months before the SV) 
− gastrointestinal conditions (eg, poorly controlled peptic ulcer disease, poorly 
controlled gastroesophageal reflux disease)  


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
56 
− infectious/immunologic conditions including untreated tuberculosis (a history of 
tuberculosis is acceptable only if a patient has received an approved prophylactic 
treatment regimen or an approved active treatment regimen and has had no 
evidence of active disease for a minimum of 2 years) and immunologic 
compromise 
− ocular conditions including glaucoma, ocular herpes simplex, or cataracts 
− oncologic conditions including any current malignancy, excluding basal cell 
carcinoma. History of malignancy is acceptable only if the patient has been in 
remission for 1 year before the SV. Remission is defined as no current evidence 
of malignancy and no treatment for the malignancy in the 12 months before the 
SV. 
− pulmonary conditions including chronic bronchitis, emphysema, chronic 
bronchiectasis, cystic fibrosis, chronic lung disease, or chronic obstructive 
pulmonary disease 
− renal conditions including chronic renal failure or ongoing dialysis 
− history of or planned solid organ transplant 
r. Vulnerable patients (ie, people kept in detention) are excluded from participation. 
4.3. 
Withdrawal Criteria and Procedures for the Patient 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each patient (parent/legal guardian) is free to withdraw from the study at any time. 
The investigator also has the right to withdraw a patient from the study in the event of serious 
intercurrent illness, pregnancy (see Section 7.2), or other reasons concerning the health or 
well-being of the patient, or in the event of repeated and documented lack of cooperation. 
Patients who are withdrawn from IMP may choose not to withdraw consent and to continue their 
participation in the study. These patients should complete the remaining study procedures and 
visits, with the exception of IMP dosing. Patients will be asked to perform 1-hour postdose lung 
function assessments at the remaining treatment visits; although the patients will not be taking a 
dose of IMP, the assessment should be approximately 1 hour after the predose lung function 
assessments were obtained.  
In addition, a patient may be withdrawn from the study as described in Section 3.4. 
Should a patient (parent/legal guardian) decide to withdraw after administration of IMP, all 
efforts will be made to complete and report all observations up to the time of withdrawal. A 
complete final evaluation at the time of the patient’s withdrawal should be made and an 
explanation given as to why the patient is withdrawing from the study. 
The reason for and date of withdrawal from the study must be recorded on the source 
documentation and transcribed to the CRF. If a patient withdraws consent, every attempt will be 
made to determine the reason. If consent is withdrawn because of an adverse event, monitoring 
will be continued at the discretion of the investigator (eg, until the event has resolved or 
stabilized, until the patient is referred to the care of a health care professional, or until a 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
57 
determination of a cause unrelated to the IMP or study procedure is made). The specific event or 
test result must be recorded on the source documentation and transcribed to the CRF. 
All assessments should be performed according to the protocol on the last day the patient takes 
IMP, or as soon as possible thereafter. 
If the final visit is conducted more than 7 ±2 days after the last dose of IMP, all safety 
assessments will be performed, but efficacy assessments will not be made (see Appendix B, 
Part 16). 
4.3.1. 
Withdrawal for Worsening Asthma 
Patients who meet the alert criteria and/or who experience a clinically meaningful worsening of 
their asthma will be assessed by the investigator. If the investigator considers it is not possible to 
safely manage a patient in a blinded manner as patient’s asthma warrants a change in his/her 
asthma treatment, the IMP will be stopped, and appropriate treatment (based on the 
investigator’s judgment) should be offered. The medical monitor should be contacted to confirm 
the findings when alternative therapy is to be instituted. The patient should continue in the study 
until the patient has completed all remaining study visits and the FV.  
• For the purpose of this study, an asthma exacerbation is defined as worsening of 
asthma requiring any significant treatment other than IMP and study rescue 
medication. Significant treatment includes the use of systemic corticosteroids and/or 
the addition of other ICS-containing asthma medications, LABAs, or other NCS 
asthma medications, for example, inhaled short-acting muscarinic antagonist; 
ER/urgent care clinic visit; or hospitalization. Note: A single dose of nebulized 
albuterol/salbutamol would not meet the criteria for an asthma exacerbation. 
ER/urgent care clinic visits where the treatment is limited to a single dose of 
nebulized albuterol/salbutamol will not meet the criteria of an asthma exacerbation. 
4.3.2. 
Alert Criteria for Worsening Asthma 
Alert criteria for individual patients with worsening asthma have been designed to ensure patient 
safety. If any of the criteria listed below are met, during scheduled or unplanned study visit, the 
investigator will determine whether the patient’s overall clinical picture is consistent with 
worsening asthma and if the patient should be withdrawn from IMP (but not the study) to be 
placed on alternative asthma therapy in the interest of patient safety. In cases where the IMP is to 
be withdrawn and alternative therapy started, the investigational center staff should contact the 
medical monitor to confirm the findings. Meeting 1 of these alert criteria does not automatically 
require a patient to be withdrawn from IMP, rather it requires a clinical evaluation to determine 
if the patient’s asthma can continue to be managed in a blinded manner per the study or 
necessitates a change in asthma therapy. All attempts will be made to safely continue to manage 
a patient in a blinded manner. 
• Morning FEV1 by handheld device measured at home falls below the FEV1 stability 
limit (see Section 6.1.3) calculated at the SV for the run-in period and at baseline for 
the treatment period on 4 or more days (do not have to be consecutive) out of any 
7-day period (7-day period is defined as any consecutive 7 days following the RV and 
can overlap with scheduled study investigational center visits). 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
58 
• Based upon a review of patient data from the patient diary built into the handheld 
device, the patient has experienced any of the following during a 7-day period (7-day 
period is defined as any consecutive 7 days following a previous TV; 7 days can 
overlap with scheduled study investigational center visits): 
− 3 or more days in which 8 or more inhalations/day of rescue medication 
(albuterol/salbutamol HFA MDI [90 mcg ex-actuator] or equivalent) were used 
(any 3 days in the consecutive 7-day period) 
− 3 or more days in which the patient experienced a nighttime asthma symptom 
score of more than 2 (any 3 days in the consecutive 7-day period) 
4.4. 
Replacement of Patients 
A patient who is randomized but does not complete the treatment period will not be replaced. 
4.5. 
Rescreening 
Patients who have not met inclusion criteria for response to a bronchodilator and cannot return 
within 7 days for a retest should be classified as screen failures but may be rescreened. Patients 
who experience an URI or LRI during the run-in period should be classified as randomization 
failures and be discontinued from the study, but may be rescreened 2 weeks after resolution of 
the infection. Patients who are rescreened will need to repeat all screening procedures and 
evaluations. Only 1 retest and 1 rescreening for each patient will be permitted.  
The decision to retest or rescreen patients will be based on the investigator’s judgment and the 
study protocol. In cases of rescreening, the sponsor or designee should be notified of the pending 
rescreening. Patients may retest/rescreen for lung function assessments and response to a 
bronchodilator only if they meet all other nonspirometric inclusion/exclusion criteria. At the 
retest, patients will be asked if they have had any adverse events, changes in medications, or 
changes in medical history. Patients will not be eligible to enter the run-in period until all 
inclusion/exclusion criteria are met. 
4.6. 
Screening Failure 
Screening failures are defined as participants who consent to participate in the clinical study but 
do not subsequently enter the placebo run-in period. Minimal information includes but is not 
limited to demography, screening failure details, eligibility criteria, and any serious adverse 
events. 
Randomization failures are defined as participants who enter the placebo run-in period but are 
not subsequently randomized (ie, do not meet the randomization criteria). 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
59 
5. 
TREATMENTS 
5.1. 
Investigational Medicinal Products Used in the Study 
IMP is defined as the test IMPs, reference IMPs, and matching placebo IMPs to the respective 
test and reference IMPs. Details for each IMP are provided below and in Table 4. (Note: The use 
of spacers or chambers for inhalers is not permitted with IMP inhalers [test or placebo] or rescue 
inhalers.) 
5.1.1. 
Test Investigational Medicinal Product 
The investigation products include the following: 
• Treatment A: Fp MDPI 25 mcg, 1 inhalation twice daily 
• Treatment B: Fp MDPI 50 mcg, 1 inhalation twice daily 
• Treatment C: FS MDPI 50/12.5 mcg, 1 inhalation twice daily 
5.1.2. 
Placebo Investigational Medicinal Product 
The placebo used in this study includes the following: 
• Treatment D: Placebo MDPI 0 mcg, 1 inhalation twice daily 
Table 4: 
Investigational Medicinal Products Used in the Study 
IMP Name 
Fp MDPI 
FS MDPI 
Placebo IMP 
Trade name and INN, if 
applicable, or 
company-assigned number 
Fluticasone Propionate 
Inhalation Powder 
Fluticasone 
Propionate/Salmeterol 
Inhalation Powder 
Placebo inhalation 
powder 
Formulation 
Inhalation powder 
Inhalation powder 
Inhalation powder 
Unit dose strength(s)/Dosage 
level(s) 
25 mcg or 50 mcg 
50/12.5 mcg 
0 mcg 
Route of administration 
Inhalation 
Inhalation 
Inhalation 
Dosing instructions 
1 inhalation twice daily 
approximately 12 hours 
apart 
1 inhalation twice daily 
approximately 12 hours apart 
1 inhalation twice daily 
approximately 12 hours 
apart 
Packaging 
Inhaler device 
Inhaler device 
Inhaler device 
Manufacturer 
 
 
 
 
Fp=fluticasone propionate; FS=fluticasone propionate/salmeterol; IMP=investigational medicinal product; 
INN=international nonproprietary name; MDPI=multidose dry powder inhaler. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
60 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products 
5.2.1. 
Storage and Security 
For the purposes of the study, test IMPs (Fp MDPI, FS MDPI) and placebo with Teva MDPI 
devices must be stored between 15° and 25°C (59° and 77°F) in a dry place away from direct 
heat and sunlight, and in a securely locked, substantially constructed cabinet or enclosure. All 
rescue medication (albuterol/salbutamol HFA) will be stored according to the manufacturer’s 
drug product stipulation, in a dry place, and in a securely locked, substantially constructed 
cabinet or enclosure. Maintenance of a daily temperature log (manual or automated) is required. 
Each IMP shipment will include a packing slip listing the contents of the shipment and a device 
for monitoring and recording temperatures. The investigator is responsible for ensuring that 
deliveries of IMP and other study materials from the sponsor are treated as follows: 
• correctly received and recorded 
• handled and stored safely and properly in accordance with the Code of Federal 
Regulations (CFR) or local regulations 
• used in accordance with this protocol 
The investigational center personnel are responsible for the acknowledgement of the receipt 
using the interactive response technology (IRT). 
Detailed instructions regarding labeling (eg, investigational centers indicating the use by date) of 
the IMP are provided in the study operations manual. 
5.2.2. 
Labeling 
Supplies of IMPs will be labeled according to the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements. If necessary, labels will be translated 
into the local language. 
5.2.3. 
Accountability 
Each IMP shipment will include a packing slip listing the contents of the shipment, drug return 
instructions, and any applicable forms. 
The investigator is responsible for ensuring that deliveries of IMP and other study materials from 
the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the CFR or national and local regulations, and used in accordance with this 
protocol. 
The IMP for this study must be used in accordance with the protocol and may be dispensed to 
patients only by authorized study investigational center personnel. The investigator is responsible 
for drug accountability, reconciliation, and record maintenance. In accordance with applicable 
regulatory requirements, the investigator or designated study investigational center personnel 
must maintain IMP accountability records. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
61 
A record of IMP accountability (ie, IMP and other materials received, used, retained, returned, or 
destroyed) should be documented in the IRT and signed by the principal investigator or designee, 
with an account given for any discrepancies. Empty, partially used, and unused IMP will be 
returned to the sponsor or designee. 
5.3. 
Justification for Investigational Medicinal Products 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product 
The Fp MDPI doses to be evaluated in this study (25 mcg twice daily and 50 mcg twice daily) 
were selected for study in patients 4 through 11 years of age based on the adult dose-ranging 
study. Based on the results from the adult and adolescent Phase 3 clinical trials (submitted for 
FDA review in March 2016), the 25- and 50-mcg twice-daily doses were confirmed as 
reasonable for studies in patients 4 through 11 years of age. 
The FS MDPI dose to be evaluated in this study (50/12.5 mcg twice daily) was selected for study 
in patients 4 through 11 years of age based on the adult and adolescent dose-ranging study, 
which showed that FS MDPI at a total daily dose of 100/50 mcg was superior to ADVAIR 
DISKUS in its effects on FEV1 over the 12 hours after a single dose, while lower doses of FS 
MDPI were generally comparable.  
A detailed description of IMP administration is presented in Section 5.1. 
5.3.2. 
Justification for Use of Placebo Investigational Medicinal Product 
A placebo was elected to be used in this study in order to evaluate the efficacy of treatment with 
Fp MDPI or FS MDPI versus rescue treatment only in patients with persistent asthma. 
5.4. 
Other Medicinal Products/Non-Investigational Medicinal Products 
Not applicable. 
5.5. 
Treatment After the End of the Study 
No IMP will be provided beyond completion of the study. Patients should return to their primary 
care physician for treatment after study completion. 
5.6. 
Restrictions 
Medication restrictions are described in Section 5.7 and Appendix H. Patients will be required to 
comply with the following activity restrictions: 
• Patients are not to engage in strenuous exercise on the mornings of any scheduled 
investigational center visits. 
• If possible, patients should avoid cold air exposure on the mornings of any scheduled 
investigational center visits. Patients who experience bronchial symptoms related to 
exposure to cold air should be adequately stabilized at room temperature before 
performance of any study-related lung function assessments. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
62 
5.7. 
Prior and Concomitant Medication or Therapy 
All patients will be required to be on a stable dose of asthma therapy for a minimum of 30 days 
before the SV. At the SV, all nonstudy asthma-related medications will be discontinued and 
replaced with placebo run-in medication and rescue medication for use during the run-in period. 
At the RV (TV1), these medications will be replaced with double-blind IMP and rescue 
medication for randomized patients for use during the double-blind period.  
Allowed Medications: In addition to rescue medication use (albuterol/salbutamol inhalation 
aerosol), the following medications will be permitted, but with restrictions, during the study: 
• Chronic and as-needed doses of low potency topical corticosteroids 
(eg, 1% hydrocortisone cream, desonide, fluocinolone cream 0.01%) are permitted for 
dermatologic diseases, not to exceed 20% of the body surface area; no occlusive 
dressing is permitted. 
• Short-acting or long-acting antihistamine use (with a washout period of 24 hours 
before any visit) is permitted for the treatment of allergic rhinitis, as needed. 
• Chronic stable doses of intranasal corticosteroids of at least 7 days’ duration before 
the SV and stable throughout the study duration for the treatment of allergic rhinitis 
are allowed throughout the study. 
• Chronic stable doses of ocular steroids of at least 7 days duration, with doses 
expected to remain stable throughout the study, are allowed. 
• Immunotherapy for the treatment of allergies by any route is permitted as long as 
therapy was initiated 90 days or more before the SV and the patient has been on a 
stable dose for 30 days or more before the SV. The regimen must remain stable 
throughout the study. 
Prohibited/Disallowed Medications:  
The medications in Appendix H are not allowed during the study. The washout period is also 
defined. Initiation of immunotherapy (administered by any route) during this study is prohibited, 
as is the escalation of the dose of maintenance immunotherapy (administered by any route). 
Patients who require continuous treatment with β-blockers, monoamine oxidase inhibitors, 
tricyclic antidepressants, anticholinergics, and/or systemic corticosteroids are excluded. 
5.8. 
Procedures for Monitoring Patient Compliance 
The investigator will be responsible for monitoring patient compliance. A check of IMP 
compliance will be performed during each visit after the initial dispensation of IMP; and IMP 
accountability records will be completed. If the investigator or the sponsor determines that the 
patient is not in compliance with the study protocol, the investigator and the sponsor should 
determine whether the patient should be withdrawn. The Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) should be notified. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
63 
5.9. 
Randomization and Blinding 
This is a double-blind, parallel-group, placebo-controlled, randomized clinical study. Patients 
who meet all randomization criteria at the RV will be stratified by previous therapy (ICS or 
NCS) and randomly assigned into a 1:1:1:1 ratio to receive Fp MDPI 25 mcg, Fp MDPI 50 mcg, 
FS MDPI 50/12.5 mcg, or placebo MDPI, twice daily, for the entire treatment period. 
Randomization will be assigned via IRT. Patients being treated with a combination of ICS/NCS 
will be stratified as an ICS patient. Approximately 206 patients will be randomized into each 
treatment group. After the run-in period, patients and parents/legal guardians/caregivers will 
remain blinded to randomized treatment assignment during the study. In addition, the 
investigator and the sponsor’s clinical personnel involved in the study will be blinded to the IMP 
identity after the run-in period until the database is locked for analysis and the treatment 
assignment is revealed. 
No effort will be made to maintain a balance among treatment groups within an investigational 
center. 
Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list. The specifications for randomization will be under the responsibility and 
oversight of Teva Global Statistics. The output of the randomization process will be a patient 
randomization list. 
The sponsor’s clinical personnel involved in the study will be blinded to the identity of the 
treatment until the database is locked for analysis and the treatment assignment revealed. 
The following criteria must be fulfilled at the RV: 
a. The patient continues to be in general good health, meeting the entry criteria.  
n. The average of the 5 highest values for trough morning FEV1 obtained at home (by 
handheld device) out of the last 7 days prior to RV is within 40% to 85% predicted 
for age, height, sex, and race (Quanjer et al 2012). 
o. The patient’s C-ACT score at the RV is ≤19. 
p. The patient has demonstrated at least a 15% response to a bronchodilator from 
baseline FEV1 within 30 minutes after 2 to 4 inhalations of albuterol/salbutamol HFA 
MDI (90 mcg ex-actuator) or equivalent at SV or during the run-in period as 
measured by handheld device. Note: The RV may not be conducted on the same day 
as the response to bronchodilator testing. 
q. The patient has had no significant changes in asthma medications during run-in, 
excluding the albuterol/salbutamol HFA MDI (90 mcg ex-actuator) or equivalent 
used as rescue medication or run-in placebo MDPI as supplied per protocol.  
r. The patient has not had a URI or LRI during the run-in period. Patients who develop 
a URI or LRI during the run-in period may be discontinued from the study and 
allowed to rescreen 2 weeks after resolution of symptoms.  
s. The patient has had no asthma exacerbation during the run-in period, defined as any 
worsening of asthma requiring any significant treatment other than rescue 
albuterol/salbutamol HFA MDI (90 mcg ex-actuator) or equivalent or the patient’s 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
64 
run-in MDPI. This includes requiring the use of systemic corticosteroids, inhaled 
corticosteroids or other medications used to control asthma or are prohibited 
medications (Appendix H), and/or ER/urgent care clinic visit or hospitalization. Note: 
A single dose of nebulized albuterol/salbutamol will not meet the criteria for an 
asthma exacerbation. Emergency room/urgent care clinic visits where the treatment is 
limited to a single dose of nebulized albuterol/salbutamol will not meet the criteria of 
an asthma exacerbation. 
t. The patient has no clinical visual evidence (on oropharyngeal examination) of 
oropharyngeal candidiasis.  
u. The patient has not experienced an adverse event that would result in failure to 
continue to meet selection criteria.  
v. The patient has not used any of the prohibited concomitant medications during the 
run-in period (see Section 5.7 and Appendix H).  
w. The patient has complied with home lung function assessments and patient diary 
(built into the handheld device) entry on at least 5 of the last 7 days prior to RV, 
including the following: 
− completion of daytime and nighttime asthma symptom scores 
− completion of daytime and nighttime rescue medication (albuterol/salbutamol 
HFA MDI) use (whether used or not) 
− completion of the morning and evening lung function assessments (FEV1 and 
PEF) by handheld device on 5 or more of the 7 days immediately preceding the 
RV 
− recording of morning and evening IMP use on 5 or more of the 7 days 
immediately preceding RV 
5.10. 
Maintenance of Randomization and Blinding 
5.10.1. 
Maintenance of Randomization 
Patient randomization codes will be maintained in a secure location at the service provider. At 
the time of analysis (after the end of study), after receiving unblinding request from the Teva 
statistician, the service provider will provide the unblinded treatment assignment according to 
the processes defined in the relevant Standard Operating Procedure (SOP). 
5.10.2. 
Blinding and Unblinding 
For information about personnel who may be aware of treatment assignments, see Section 5.9. 
These individuals will not be involved in conduct of any study procedures or assessment of any 
adverse events. 
In case of a serious adverse event, pregnancy, or in cases when knowledge of the treatment 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
treatment assignment as deemed necessary, mainly in emergency situations, through specialized 
access in the IRT system. If possible, the sponsor should be notified of the event before breaking 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
65 
of the code. If this is not possible, the sponsor should be notified immediately afterwards, and the 
patient’s treatment code should not be revealed. Breaking of the treatment code can always be 
performed by the investigational center without prior approval by the sponsor. 
When a blind is broken, the patient will be withdrawn from the study and the event will be 
recorded on the CRF. The circumstances leading to the breaking of the code should be fully 
documented in the investigator’s study files and in the patient’s source documentation. 
Treatment assignment should not be recorded in any study documents or source document. 
In blinded studies, for an adverse event defined as a suspected unexpected serious adverse 
reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety and 
Pharmacovigilance (GPSP) may independently request that the treatment code be broken (on a 
case-by-case basis) to comply with regulatory requirements. The report will be provided in an 
unblinded manner for regulatory submission. If this occurs, blinding will be maintained for the 
investigator and for other personnel involved in the conduct of the study, and analysis and 
reporting of the data. 
5.10.3. 
Data Monitoring Committee 
There will be no Data Monitoring Committee in this study. 
5.11. 
Total Blood Volume 
No laboratory tests or serum pregnancy tests will be performed in this study unless clinically 
indicated, and no blood is planned to be collected. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
66 
6. 
ASSESSMENT OF EFFICACY 
6.1. 
Primary Efficacy Measure and Justification 
The primary efficacy measures are as follows: 
• For Fp MDPI versus placebo: the change from baseline in weekly average of the 
percent predicted trough morning FEV1 at week 12 
• For FS MDPI versus Fp MDPI: the change from baseline in 1-hour postdose percent 
predicted morning FEV1 at week 12 
6.1.1. 
Lung Function Assessments (FEV1 and PEF) by Handheld Device 
Preferably, all lung function assessment (FEV1 and PEF) are to be conducted consistently, using 
standardized equipment, time of day (±1 hour), and posture. Patients will be provided with a 
handheld device at the SV, which will be used to measure lung function assessments and will 
serve as an electronic patient diary to collect asthma symptom scores, rescue medication, and 
IMP use. The same handheld device should be used for a patient throughout the study, whenever 
possible. The device will be collected and inspected to make sure it is not damaged and the data 
will be downloaded at each clinic visit. Once inspected, the same handheld device will be 
redispensed to the patient unless it needs to be replaced. 
During the treatment period (RV through TV6 [week 12] or IMPDV), daily in the morning and 
evening at approximately the same time each day, patients will use the handheld device at home 
to record asthma symptom scores and rescue albuterol/salbutamol HFA MDI use, after which 
they will perform lung function assessments (FEV1 and PEF) and then will take their dose of the 
IMP and record IMP dosing in the patient diary built into the handheld device.  
On the morning of each TV, patients will be instructed to record their asthma symptom score and 
rescue albuterol/salbutamol HFA MDI use and complete their morning lung function 
assessments (FEV1 and PEF) by handheld device as usual, but to delay IMP dosing until they get 
to the investigational center. Patients are also to withhold their rescue SABA for a minimum of 
6 hours prior to obtaining lung function assessments. If the patient inadvertently takes the 
morning IMP dose or rescue medication within 6 hours of the planned lung function 
assessments, the visit must be rescheduled. Similarly, patients who have been withdrawn from 
IMP but remain in the study should withhold their alternative asthma therapy dosing until after 
treatment visit assessments and avoid rescue medication for a minimum of 6 hours prior to clinic 
lung function assessments. The treatment visit should be rescheduled if either or both occur. 
At the investigational center, after appropriate instructions and training (competent handheld 
device use and dosing technique using the training devices provided), patients will repeat their 
lung function assessment (FEV1 and PEF) under the supervision of the investigational center 
staff. They will then take their morning dose of the IMP. IMP administration at the 
investigational center should be timed so that lung function assessments will be approximately 
12 hours following the doses taken the previous evening. Patients will then perform a 1-hour 
postdose FEV1 measurement using the handheld device. The 1-hour postdose assessment should 
be conducted 60 ±10 minutes after IMP dosing (or as described for patients on alternative asthma 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
67 
treatment; see Section 3.1). The highest FEV1 value from 3 acceptable and 2 repeatable 
maneuvers (maximum of 8 attempts per test) will be obtained before and 1-hour after the 
morning dose. The acceptability and repeatability of each maneuver will be automatically 
determined as programmed by the handheld device. Patients will be allowed 1 retest for 
screening lung function assessments. Predicted FEV1 will be computed and adjusted for age, 
height, race, and sex using the criteria of Quanjer (Quanjer et al 2012). A standard method for 
calculating FEV1 will be provided to all investigational centers. 
In cases of lung function assessment-induced bronchospasm (ie, successively lower values with 
good technique), the largest valid FEV1 may be used.  
The baseline lung function assessments are defined as the weekly average of the morning FEV1 
prior to the RV. 
6.1.2. 
Response to a Bronchodilator 
At SV, FEV1 will be measured immediately before and within 30 minutes after administration of 
2 to 4 inhalations of albuterol/salbutamol HFA MDI (90 mcg ex-actuator) or equivalent. 
Nebulized albuterol/salbutamol at a total dose of 2.5 mg may be used at the investigator’s 
discretion. Spacers are also allowed during this time, but their use is only allowed for the test of 
response to bronchodilator. Patients who meet the criteria to enter the run-in but who have not 
demonstrated the required response to bronchodilator my repeat this testing 14 ±2 days after the 
SV and may have 1 final attempt if needed within 14 days. The run-in period should not exceed 
30 days. Responses to a bronchodilator of 14.50% to 14.99% will be rounded to 15%. The 
percent response to a bronchodilator is calculated using the following equations, as applicable: 
(Post-bronchodilator FEV1 –Pre-bronchodilator FEV1) × 100% 
Pre-bronchodilator FEV1 
6.1.3. 
FEV1 Stability Limit 
At SV, the FEV1 stability limit will be calculated for patients who qualify to enter the run-in 
period as 80% of the highest acceptable pre-albuterol/salbutamol FEV1. This value will be used 
during the run-in period. 
The FEV1 stability limit for the treatment period will be calculated for each patient at the RV, as 
applicable, using the following equation: 
Mean best pre-albuterol/salbutamol FEV1 available from 5 of 7 days (the baseline value) 
preceding RV × 80% 
This value will be used for the remainder of the study and will be used to determine alert criteria 
for worsening asthma, as applicable. The FEV1 stability limit is automatically calculated and 
stored in the handheld device software. If a patient falls below the FEV1 stability limit, an alert 
will appear on the handheld device screen. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
68 
6.2. 
Secondary Efficacy Measures 
The secondary efficacy measures and time points for this study are as follows: 
• PEF will be measured by the patient (with assistance from the parents/legal 
guardians/caregivers, as needed) with a handheld device in the morning and evening 
before administration of IMP or rescue medications. The time points for assessment 
of PEF as a secondary efficacy endpoint are specifically the morning (predose and 
pre-rescue bronchodilator) evaluation over the 12-week treatment period.  
• The total daily (24-hour) use of albuterol/salbutamol inhalation aerosol will be 
calculated based on information recorded in the daily patient diary built into the 
handheld device by the patient (with assistance from the parents/legal 
guardians/caregivers, as needed) over weeks 1 through 12. 
• Daytime and nighttime asthma symptom scores will be recorded in the daily patient 
diary built into the handheld device by the patient (with assistance from the 
parents/legal guardians/caregivers, as needed) over weeks 1 through 12. 
• The C-ACT will be completed at weeks 4, 8, and 12 and at the IMPDV. 
• The time to first onset of effect, defined as the first decrease from baseline in daily 
rescue medication use, will be calculated based on information recorded in the daily 
patient diary built into the handheld device by the patient (with assistance from the 
parents/legal guardians/caregivers, as needed). 
• The proportion of patients who discontinued from IMP for asthma exacerbation 
during the 12-week treatment period will be evaluated over the 12-week treatment 
period. 
6.2.1. 
Weekly Average of Daily Trough Morning Peak Expiratory Flow 
Peak expiratory flow will be determined twice daily, in the morning before administration of 
IMP or rescue medications and in the evening. A handheld device will be provided to patients at 
the SV and used to determine the morning and evening PEF throughout the course of the study. 
The patient will record the highest value of 3 measurements obtained in the morning in the 
patient diary built into the handheld device. 
On mornings for which a TV is scheduled (RV through TV6/IMPDV), patients will perform 
their morning PEF measurement as usual using the handheld device at home and will then repeat 
their PEF measurement (using the handheld device) at the investigational center. Symptom 
scores should always be assessed before any PEF measurements are obtained. The morning 
administration of IMP will take place and be recorded at the visit. 
6.2.2. 
Weekly Average of Total Daily Rescue Medication Use 
The patients will record the number of inhalations of rescue medication (albuterol/salbutamol 
HFA MDI [90 mcg ex-actuator] or equivalent) each morning and evening in the patient diary 
built into the handheld device. If there is no rescue medication usage, patients should enter 0 in 
the patient diary built into the handheld device. The average number of daily inhalations over the 
7 days before the RV will be the baseline value and will be compared to the rescue aerosol over 
weeks 1 through 12. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
69 
6.2.3. 
Weekly Average of the Total Daily Asthma Symptom Score 
The change from baseline in the weekly average of the total daily asthma symptom score will be 
assessed over weeks 1 through 12. The total daily asthma symptom score is the average of the 
daytime and nighttime scores. 
Asthma symptom scores will be recorded in the patient diary built into the handheld device each 
morning and each evening before determining PEF and FEV1 and before administration of study 
or rescue medications. 
Each patient will assess the symptoms of cough, wheeze, shortness of breath, and chest tightness 
and enter a single score that is inclusive of all symptoms. 
On mornings for which a TV is scheduled (SV through TV6), the symptom scores and recording 
of the morning administration of IMP will be completed at the investigational center visit. 
Symptom scores should always be assessed before lung function assessments (FEV1 and PEF) by 
handheld device are obtained. 
Daytime Symptom Score (determined in the evening) 
 
0=No symptoms during the day 
 
1=Symptoms for 1 short period during the day 
 
2=Symptoms for 2 or more short periods during the day 
 
3=Symptoms for most of the day, which did not affect my normal daily activities 
 
4=Symptoms for most of the day, which did affect my normal daily activities 
 
5=Symptoms so severe that I could not go to school or perform normal daily activities 
Nighttime Symptom Score (determined in the morning) 
 
0=No symptoms during the night 
 
1=Symptoms causing me to wake once (or wake early) 
 
2=Symptoms causing me to wake twice or more (including waking early) 
 
3=Symptoms causing me to be awake for most of the night 
 
4=Symptoms so severe that I did not sleep at all 
6.2.4. 
Change from Baseline in Asthma Control (measured by C-ACT) Score 
The C-ACT is a simple, patient-completed tool used for the assessment of overall asthma 
control. The first 4 items of the test are completed by the patient, while the last 3 items are 
completed by the patient’s parents/legal guardians/caregivers. The first 4 questions are scored on 
a 3-point scale (0 to 3) and the last 3 questions are scored on a 5-point scale (0 to 5), with 
summation of all items providing scores ranging from 0 to 27. These scores span the continuum 
of poor control of asthma (score ≤5) to complete control of asthma (score ≥25), with a cutoff 
score of 19 indicating patients with poorly controlled asthma. 
The C-ACT will be completed by the patient and the patient’s parent/legal guardian/caregiver (as 
applicable) at the investigational center, before any other assessments are performed, at the 
specified visits. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
70 
The investigators and personnel will be provided with detailed instructions for administering the 
C-ACT (in the study reference manual) in order to achieve maximum compliance in a clinical 
study environment and maximum data quality. After completion of the C-ACT, investigational 
center personnel will check the questionnaires for completeness and legibility. 
The C-ACT should be completed during a study visit and should precede any discussion of 
asthma status between the patient/parent/caregiver and investigational center personnel. 
6.2.5. 
Time to First Onset of Effect  
The time to first onset of effect, defined as the first decrease from baseline in daily rescue 
medication use, will be calculated based on the number of inhalations of rescue medication 
(albuterol/salbutamol HFA MDI [90 mcg ex-actuator] or equivalent) recorded by the patient each 
morning and evening in the patient diary built into the handheld device. 
6.2.6. 
Proportion of Patients who Discontinued from IMP for Asthma Exacerbation 
During the 12-week Treatment Period  
The proportion of patients who discontinued from IMP for asthma exacerbation during the 
12-week treatment period will be assessed.  
6.3. 
Other Efficacy Measures 
The other efficacy measures for this study are as follows: 
• The total daily (24-hour) use of albuterol/salbutamol inhalation aerosol will be 
calculated based on information recorded in the daily patient diary built into the 
handheld device by the patient (with assistance from the parents/legal 
guardians/caregivers, as needed) at weeks 4, 8, and 12. 
• The percentage of rescue-free days and symptom-free days will be calculated based 
on information recorded in the daily patient diary built into the handheld device by 
the patient (with assistance from the parents/legal guardians/caregivers, as needed) 
over the 12-week treatment period. 
• The percentage of asthma-control days will be calculated based on information 
recorded in the daily patient diary built into the handheld device by the patient (with 
assistance from the parents/legal guardians/caregivers, as needed) over the 12-week 
treatment period. 
• FEV1 will be measured by the patient (with assistance from the clinic staff) with a 
handheld device in the clinic before administration of IMP or rescue medications at 
the morning evaluation on weeks 1, 2, 4, 8, and 12. The change from baseline in 
1-hour postdose percent predicted morning FEV1 at week 1 and in the weekly average 
of percent predicted trough morning FEV1 will be based on the measurements 
obtained in the clinic. 
• PEF will be measured by the patient (with assistance from the parents/legal 
guardians/caregivers, as needed) with a handheld device before administration of IMP 
or rescue medications at the evening evaluation over the 12-week treatment period. 
The change from baseline in the weekly average of daily evening PEF will be 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
71 
calculated based on information recorded in the daily patient diary built into the 
handheld device by the patient (with assistance from the parents/legal 
guardians/caregivers, as needed). 
• The change from baseline in asthma control (measured by C-ACT) score will be 
evaluated over the 12-week treatment period. C-ACT will be completed at weeks 4, 8, 
and 12. 
• The time to consistent onset of effect defined as the decrease from baseline in daily 
rescue medication use on 3 consecutive days will be calculated based on the number 
of inhalations of rescue medication recorded by the patient each morning and evening 
in the patient diary built into the handheld device. 
6.3.1. 
Change from Baseline in Weekly Average of Total Daily Rescue Medication Use 
The change from baseline in the weekly average of total daily use of albuterol/salbutamol 
inhalation aerosol will be assessed at weeks 4, 8, and 12. 
6.3.2. 
Change from Baseline in Percentage of Rescue-Free Days 
The change from baseline in the percentage of rescue-free days (defined as 24-hour periods with 
no use of rescue medication recorded in the morning and the evening) as recorded in the patient 
diary built into the handheld device during the 12-week treatment period will be summarized. 
6.3.3. 
Change from Baseline in Percentage of Symptom-Free Days 
The change from baseline in the percentage of symptom-free days (defined as 24-hour periods 
with asthma symptom score of 0) as recorded in the patient diary built into the handheld device 
during the 12-week treatment period will be summarized. 
6.3.4. 
Change from Baseline in Percentage of Asthma-Control Days 
The change from baseline in the percentage of asthma-control days (defined as 24-hour periods 
with asthma symptom score of 0 and no rescue medication use) as recorded in the patient diary 
built into the handheld device during the 12-week treatment period will be summarized. 
6.3.5. 
Change from Baseline in 1-hour Postdose Percent Predicted Morning FEV1 at 
Week 1 
The change from baseline in 1-hour postdose percent predicted morning FEV1 at week 1 will be 
assessed at TV2. 
6.3.6. 
Change from Baseline in Weekly Average of Daily Evening Peak Expiratory 
Flow 
The change from baseline in the weekly average of daily evening PEF over the 12-week 
treatment period will be assessed. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
72 
6.3.7. 
Change from Baseline in Weekly Average of Percent Predicted Trough Morning 
FEV1 
The change from baseline in weekly average of the percent predicted trough morning FEV1 will 
be assessed at weeks 1, 2, 4, and 8. 
6.3.8. 
Proportion of Patients Who Achieve At Least a 15% Increase in Morning FEV1 
The proportion of patients who achieve at least a 15% increase in FEV1 at 1-hour postdose at 
day 1 (the RV/TV1), week 1 (TV2), and week 12 (TV6) will be assessed. 
6.3.9. 
Change from Baseline in Asthma Control (measured by C-ACT) Score  
The change from baseline in C-ACT score at weeks 4, 8, and 12 will be assessed. 
6.3.10. 
Time to Consistent Onset of Effect 
The time to consistent onset of effect (defined as the decrease from baseline in daily rescue 
medication use on 3 consecutive days) will be calculated based on the number of inhalations of 
rescue medication recorded by the patient each morning and evening in the patient diary built 
into the handheld device and will be summarized. 
6.4. 
Safety Measures and Time Points 
Safety measures and time points for this study are as follows: 
• inquiries about adverse events at all visits 
• vital signs measurements at all visits 
• oropharyngeal examinations at all visits 
• physical examinations at baseline and week 12 or at the IMPDV 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
73 
7. 
ASSESSMENT OF SAFETY 
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, vital signs measurements, physical examination findings (including body weight 
measurements), and oropharyngeal examination findings. In addition, during the study, PEF and 
FEV1 will be monitored as part of safety monitoring (alert criteria for worsening asthma). Any 
visual evidence of oral candidiasis during the treatment period will be confirmed by obtaining a 
swab for culture of the suspect area. Patients and parents/legal guardians/caregivers will be 
provided with guidelines for when to contact the investigational center in case of worsening 
asthma symptoms or rescue inhaler use. Patients who meet predefined alert criteria should be 
evaluated by the investigator. The investigator will determine whether the patient’s overall 
clinical picture is consistent with worsening asthma and if the patient should be withdrawn from 
IMP (but not the study) to be placed on alternative asthma therapy in the interest of patient 
safety. 
7.1. 
Adverse Events 
7.1.1. 
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
In this study, any adverse event occurring after the clinical study patient has signed the informed 
consent form/assent form (as applicable) should be recorded and reported as an adverse event. 
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to the IMP. (Note: Asthma exacerbations in this study will not be considered 
adverse events unless they meet the criteria for serious adverse events.) A new condition or the 
worsening of a pre-existing condition will be considered an adverse event. Stable chronic 
conditions (such as arthritis) that are present before study entry and do not worsen during this 
study will not be considered adverse events (but should be recorded as medical history). 
Accordingly, an adverse event can include any of the following: 
• intercurrent illnesses 
• physical injuries 
• events possibly related to concomitant medication 
• significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions 
• drug interactions 
• events occurring during diagnostic procedures or during any washout phase of this 
study 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
74 
• laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, require medical treatment or further diagnostic work-up, or are considered by 
the investigator to be clinically significant (Note: Abnormal laboratory test results at 
the SV that preclude a patient from entering the study or receiving IMP are not 
considered adverse events.) 
For the purpose of this study, an asthma exacerbation is defined as worsening of asthma 
requiring any significant treatment other than IMP and study rescue medication. Significant 
treatment includes the use of systemic corticosteroids and/or the addition of other ICS-containing 
asthma medications, LABAs, or other NCS asthma medications, for example, inhaled 
short-acting muscarinic antagonist, ER/urgent care clinic visit(s), or hospitalization. Note: A 
single dose of nebulized albuterol/salbutamol would not meet the criteria for an asthma 
exacerbation. ER/urgent care clinic visits where the treatment is limited to a single dose of 
nebulized albuterol/salbutamol will not meet the criteria of an asthma exacerbation. 
Asthma exacerbation that requires a change in medication or worsening of asthma that requires 
the patient to be treated with alternative therapy will be entered into the case report form (CRF), 
including the date at which any medication change was made and whether this medication 
change was implemented prior to or after the IMPDV lung function assessments (FEV1 and PEF) 
were completed. Asthma worsening, including asthma exacerbations with a change to alternative 
asthma therapy will not be considered an adverse event for this study since it is an expected 
outcome for this study in an asthmatic patient population. Asthma exacerbations that meet the 
criteria for a serious adverse event will be recorded as adverse events. 
Any occurrence of oropharyngeal candidiasis that is confirmed by culture during the study will 
be reported as an adverse event. A patient who agrees to be treated may continue in the study at 
the discretion of the investigator. 
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the clinical study report (CSR). 
7.1.2. 
Recording and Reporting of Adverse Events 
For recording of adverse events, the study period is defined for each patient as that time period 
from signature of the informed consent/assent form (as applicable) to the end of the follow-up 
period. The follow-up period is defined as 7±2 days after the last dose of IMP. 
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed to the CRF, regardless of the severity of the event or judged 
relationship to the IMP. For serious adverse events, the Serious Adverse Event Form must be 
completed and the serious adverse event must be reported immediately. The investigator does not 
need to actively monitor patients for adverse events once the study has ended. Serious adverse 
events occurring in a patient (after the treatment of that patient has ended) should be reported to 
the sponsor if the investigator becomes aware of them, following the procedures described in 
Section 7.1.5.3.1. 
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe”. All reported or observed signs 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
75 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event, on the 
serious adverse event form. 
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; or until the patient is referred for continued care to a health 
care professional; or until a determination of a cause unrelated to the IMP or study procedure is 
made. 
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding IMP, treatment administered, and outcome for each adverse event must be 
recorded on the source documentation and transcribed to the CRF. 
The relationship of each adverse event to IMP and study procedures, and the severity and 
seriousness of each adverse event as judged by the investigator, must be recorded as described 
below. 
7.1.3. 
Severity of an Adverse Event 
The severity of each adverse event must be recorded as 1 of the following: 
Mild: 
No limitation of usual activities 
Moderate: Some limitation of usual activities 
Severe: 
Inability to carry out usual activities 
7.1.4. 
Relationship of an Adverse Event to the Test Investigational Medicinal Product 
The relationship of an adverse event to the test IMP is characterized in Table 5. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
76 
Table 5: 
The Relationship of an Adverse Event to the Test Investigational Medicinal 
Product 
Term 
Definition 
Clarification 
No reasonable 
possibility 
(not related) 
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the IMP. 
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply: 
• 
It does not follow a reasonable temporal sequence 
from the administration of the IMP. 
• 
It could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the patient. 
• 
It does not follow a known pattern of response to the 
IMP. 
• 
It does not reappear or worsen when the IMP is 
re-administered. 
Reasonable 
possibility 
(related) 
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the administration of IMP cannot be 
ruled out with certainty. 
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply: 
• 
It follows a reasonable temporal sequence from 
administration of the IMP. 
• 
It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient. 
• 
It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear after 
discontinuation of the IMP, yet an IMP relationship 
clearly exists. 
• 
It follows a known pattern of response to the IMP. 
IMP=investigational medicinal product. 
7.1.5. 
Serious Adverse Events 
For recording of serious adverse events, the study period is defined for each patient as that time 
period from signature of the informed consent form to the end of the follow-up period. Serious 
adverse events occurring in a patient after the end of the follow-up period should be reported to 
the sponsor if the investigator becomes aware of them, following the procedures described in 
Section 7.1.5.3.1. 
7.1.5.1. 
Definition of a Serious Adverse Event 
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions: 
• death 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
77 
• is life-threatening adverse event (ie, the patient was at risk of death at the time of the 
event); it does not refer to an event which hypothetically might have caused death if it 
were more severe 
• requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission or prolongation of hospital stay were required 
for treatment of an adverse event, or that they occurred as a consequence of the event 
Hospitalizations scheduled before the patient signed the informed consent form will 
not be considered serious adverse events, unless there was worsening of the 
pre-existing condition during the patient’s participation in this study. 
• persistent or significant disability/incapacity (refers to a substantial disruption of 
one’s ability to conduct normal life functions) 
• is a congenital anomaly/birth defect 
• an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition 
Examples of such events are intensive treatment in an ER or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or the development of drug dependency or drug abuse. Note: Any suspected 
transmission of an infectious agent via a medicinal product is considered an important 
medical event. 
7.1.5.2. 
Expectedness 
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this study are the Teva Fp MDPI and 
FS MDPI IBs. 
The sponsor’s GPSP will determine the expectedness for all serious adverse events. 
For the purpose of SUSAR reporting, the version of the IB at the time of occurrence of the 
SUSAR applies. 
7.1.5.3. 
Reporting a Serious Adverse Event 
7.1.5.3.1. Investigator Responsibility 
To satisfy regulatory requirements, all serious adverse events that occur during the study, 
regardless of judged relationship to administration of the test IMP, must be reported to the 
sponsor by the investigator. The event must be reported within 24 hours of when the investigator 
learns about it. Completing the serious adverse event form and reporting the event must not be 
delayed, even if not all the information is available. The investigator does not need to actively 
monitor patients for adverse events once this study has ended. 
Serious adverse events occurring to a patient after the last administration of IMP of that patient 
has ended should be reported to the sponsor if the investigator becomes aware of them. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
78 
The serious adverse event form should be sent to the local safety officer (LSO) or designee (a 
contract research organization [CRO] in a country without a sponsor LSO) (contact information 
is in the Clinical Study Personnel Contact Information section); the LSO will forward the report 
to the sponsor’s GPSP. 
The following information should be provided to record the event accurately and completely: 
• study number 
• investigator and investigational center identification 
• patient number 
• onset date and detailed description of adverse event 
• investigator’s assessment of the relationship of the adverse event to the test IMP (no 
reasonable possibility, reasonable possibility) 
Additional information includes: 
• age and sex of patient 
• date of first dose of IMP 
• date and amount of last administered dose of IMP 
• action taken 
• outcome, if known 
• severity 
• explanation of assessment of relatedness 
• concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event 
• pertinent laboratory or other diagnostic test data 
• medical history 
• results of dechallenge/rechallenge, if known 
• for an adverse event resulting in death 
− cause of death (whether or not the death was related to IMP) 
− autopsy findings (if available) 
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the test IMP, study 
procedures, and to underlying disease. 
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator within 24 hours of when it becomes known to 
the same address as the initial report. 
For all countries, the sponsor’s GPSP will distribute the Council for International Organizations 
of Medical Sciences (CIOMS) form/Extensible Markup Language (XML) file to the LSO/CRO 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
79 
for submission to the competent authorities, IEC/IRBs, and investigators, according to 
regulations. The investigator is responsible for ensuring that the IEC/IRB is also informed of the 
event, in accordance with national and local regulations. 
For double-blind studies, blinding will be maintained for all study personnel. Therefore, in case 
of a SUSAR, only the LSO/CRO will receive the unblinded report for regulatory submission; the 
others will receive a blinded report. 
7.1.5.3.2. Sponsor Responsibility 
If a SUSAR is believed to be related to the IMP or study procedures, the sponsor will take 
appropriate steps to notify all investigators participating in sponsored clinical studies of 
Fp MDPI and FS MDPI and the appropriate competent authorities (and IEC/IRB, as 
appropriate). 
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other measures may be required, including: 
• altering existing research by modifying the protocol 
• discontinuing or suspending the study 
• altering the process of informed consent by modifying the existing consent form and 
informing all study participants of new findings 
• modifying listings of expected toxicities to include adverse events newly identified as 
related to Fp MDPI and FS MDPI 
7.1.6. 
Protocol-Defined Adverse Events not for Expedited Reporting 
No protocol-defined adverse events not for expedited reporting were identified for this study. 
7.1.7. 
Protocol-Defined Adverse Events of Special Interest 
No protocol-defined adverse events of special interest were identified for this study. 
7.1.8. 
Protocol Deviations Because of an Adverse Event 
If a patient experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure patient safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 
contact the physician identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to receive study IMP, continue in 
the study on alternative treatment, or be withdrawn from the study in the interest of patient 
safety. 
7.2. 
Pregnancy 
All pregnancies of females participating in the study that occur during the study, or within 
30 days of completion of the study, are to be reported immediately to the physician identified in 
the Clinical Study Personnel Contact Information section of this protocol, and the investigator 
must provide the LSO/CRO with the pregnancy form. The process for reporting a pregnancy is 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
80 
the same as that for reporting a serious adverse event but using the pregnancy form (see 
Section 7.1.5.3.1 ). 
Any female patient becoming pregnant during the study will discontinue treatment. All patients 
who become pregnant will be monitored for the outcome of the pregnancy (including 
spontaneous or voluntary termination). If the pregnancy continues to term, the outcome (health 
of the infant up to 8 weeks of age), including details of birth and presence or absence of any birth 
defect, congenital abnormalities, or maternal and newborn complications, will be reported to the 
sponsor. Any complication of pregnancy during the study and any complication of pregnancy 
that the investigator becomes aware of after withdrawal from the study will be reported as an 
adverse event or serious adverse event, as appropriate. 
If the pregnancy does not continue to term, 1 of the following actions will be taken: 
• For a spontaneous abortion, report as a serious adverse event. 
• For an elective abortion due to developmental anomalies, report as a serious adverse 
event. 
• For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event. 
7.3. 
Medication Error and Special Situations Related to the 
Investigational Medicinal Products 
Any administration of IMP that is not in accordance with the study protocol should be reported 
either as a violation, if it meets the violation criteria specified in the protocol (Appendix C), or as 
a deviation, in the patient’s source documents, regardless of whether or not an adverse event 
occurs as a result. When meeting protocol violation criteria, all instances of incorrect IMP 
administration should be categorized as “Non-Compliance to investigational medicinal product 
(IMP).”   
The following are types of medication errors and special situations, as reported by the 
investigator: 
1. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
patient, or consumer. 
4. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. Any dose of 
IMP (whether the test IMP, reference IMP, or placebo IMP), whether taken intentionally 
or unintentionally, in excess of that prescribed must be immediately reported to the 
sponsor. 
5. Abuse: Persistent or sporadic, intentional excessive use of IMP which is accompanied by 
harmful physical or psychological effects. 
6. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
81 
7. Occupational exposure: Exposure to an IMP as a result of one’s professional or 
nonprofessional occupation. 
8. Breastfeeding: Suspected adverse reactions which occur in infants following exposure to 
a medicinal product from breast milk. 
When the identification of the IMP is required, the investigator must follow the procedures for 
unblinding outlined in Section 5.10.2. 
7.4. 
Clinical Laboratory Tests 
Since the IMPs in this trial are well-established molecules and are not known to influence 
clinical laboratory tests at doses to be studied in this trial, optional clinical laboratory evaluation, 
if needed at the discretion of the investigator, may be performed during the study at a local 
laboratory. These clinical laboratory tests may be performed to ensure the health and wellbeing 
of the patients but will not be used to assess the safety of the IMP. 
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to one of the following categories: 
• abnormal but not clinically significant  
• abnormal and clinically significant  
A laboratory test result that is judged by the investigator as clinically significant will be recorded 
on the source documentation, transcribed to the CRF as an adverse event, and monitored as 
described in Section 7.1.2. An event may include a laboratory or diagnostic test abnormality 
(once confirmed by repeated testing) that results in patient continuing study participation, the 
withdrawal of the patient from the study, the temporary or permanent cessation of treatment with 
IMP or medical treatment, or further diagnostic work-up. 
7.4.1. 
Human Chorionic Gonadotropin Tests 
Human chorionic gonadotropin tests in urine will be performed for all female patients who have 
reached puberty and achieved menarche at the SV and, if clinically indicated, thereafter. Any 
female patient who becomes pregnant during the study will be withdrawn. Procedures for 
reporting the pregnancy are provided in Section 7.2. 
7.5. 
Physical Examinations 
Physical examinations, including weight and height, will be performed at the time points detailed 
in Table 3. Any physical examination finding that is judged by the investigator as clinically 
significant will be considered an adverse event, recorded on the CRF, and monitored as 
described in Section 7.1.2. 
7.6. 
Vital Signs 
Vital signs (blood pressure [BP] and pulse) will be measured at the time points detailed in 
Table 3. All vital signs results outside of the reference ranges will be judged by the investigator 
as belonging to 1 of the following categories: 
• abnormal but not a clinically significant worsening from baseline 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
82 
• abnormal and a clinically significant worsening from baseline 
Before BP and pulse are measured, the patient must be in a supine or semi-erect/seated position 
and resting for at least 5 minutes (the same position and arm should be used each time vital signs 
are measured for a given patient). For any abnormal vital sign finding, the measurement should 
be repeated as soon as possible. Any vital sign value that is judged by the investigator as 
clinically significant will be recorded on the source documentation, transcribed to the CRF as an 
adverse event, and monitored as described in Section 7.1.2. 
In addition, potentially clinically significant values may be predefined by the sponsor for 
selected vital signs (see Section 9.7) and, if so, will be documented in the statistical analysis plan 
or other relevant documents (eg, medical monitoring plan). 
7.7. 
Oropharyngeal Examinations 
Oropharyngeal examinations will be performed at every visit (SV through TV6). The 
examination must be performed by a qualified healthcare professional. Whenever possible, the 
same qualified healthcare professional should complete the assessment for the same patient 
throughout that patient’s participation in the study.  
Patients with clinical visual evidence of oral candidiasis at SV who agree to receive treatment 
and comply with appropriate medical monitoring may participate in the run-in period and may 
return for randomization. However, if the oral candidiasis is not controlled at that time, the 
patient will not be allowed to enter the study treatment period.  
Any visual evidence of oral candidiasis during the treatment period of the study (after RV 
through TV6, inclusive) will be evaluated by obtaining and analyzing a swab of the suspect area. 
Appropriate therapy should be initiated immediately at the discretion of the investigator and 
should not be delayed for culture confirmation.  
Patients with a culture-positive infection may continue participation in the study on appropriate 
anti-infective therapy, provided this therapy is not prohibited by the protocol. If a patient requires 
a protocol-prohibited medication for therapy, the patient will be discontinued from the study and 
provided appropriate therapy.  


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
83 
8. 
ASSESSMENT OF PHARMACOKINETICS / 
PHARMACODYNAMICS / BIOMARKERS / 
PHARMACOGENOMICS / IMMUNOGENICITY / ANCILLARY 
STUDIES 
8.1. 
Pharmacokinetic Assessment 
Pharmacokinetic parameters are not evaluated in this study. 
8.2. 
Pharmacodynamics Assessment 
Pharmacodynamic parameters are not evaluated in this study. 
8.3. 
Assessment of Exploratory Biomarkers 
Biomarkers are not evaluated in this study. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
84 
9. 
STATISTICS 
This section describes the statistical analysis planned for this study. Changes, additions, and 
further details about the analyses will be described in the statistical analysis plan (SAP). After 
finalization of the statistical analysis plan, any additional analyses or changes to analyses that 
may be required will be fully disclosed in the CSR. 
9.1. 
Sample Size and Power Considerations 
Sample size and power calculations are driven by demonstrating superiority of FS MDPI 50/12.5 
mcg twice daily over Fp MDPI 50 mcg twice daily in change from baseline in 1-hour postdose 
percent predicted morning FEV1 at week 12 and the superiority of Fp MDPI 50 mcg twice daily 
over placebo in change from baseline in percent predicted trough morning FEV1 at week 12.  
For the superiority comparison of FS MDPI 50/12.5 mcg twice daily versus Fp MDPI 50 mcg 
twice daily, assuming that the change from baseline in 1-hour postdose percent predicted 
morning FEV1 at week 12 is analyzed using an ANOVA model with only a single factor of 
treatment group, the following assumptions were made: 
• The initial assumed common standard deviation (SD) was 9.3% and the true 
treatment difference was 4.5% between FS MDPI 50/12.5 mcg twice daily and Fp 
MDPI 50 mcg twice daily. This assumption was based on data collected in previous 
Teva studies with the same Fp MDPI and FS MDPI products in adult asthma patients 
who completed the 12-week treatment period and based on office-based spirometry.  
• The initial power was 97% at a 2-sided significance level of 5%.  
For the superiority comparison of Fp MDPI 50 mcg twice daily versus placebo, assuming that 
the change from baseline in percent predicted trough morning FEV1 at week 12 is analyzed using 
an analysis of variance (ANOVA) model with only a single factor of treatment group, the 
following assumptions were made: 
• The initial assumed common standard deviation (SD) was 13.25% and the true 
treatment difference was 5% between Fp MDPI 50 mcg twice daily and placebo. This 
assumption was based on data collected in previous Teva studies with the same 
Fp MDPI product in adult asthma patients and based on office-based spirometry 
• The initial power was 85% at a 2-sided significance level of 5%.  
This study FSS-AS-30003 is the first Teva's study in which the handheld spirometry is utilized as 
an endpoint and this hanheld device is being used in a pediatric asthma patient population, the 
target population of this study. A blinded sample size reassessment was not planned for this 
study. However, routine blinded data monitoring of this study FSS-AS-30003 revealed that a few 
patietnts showed nonphysiologic (~200% of percent predicted FEV1) changes from baseline. 
This triggered a blinded sample size reassessment that showed that the overall mean change from 
baseline and SD for the overall study population is higher than the initial assumptions based on 
the office spirometry in adult asthma patients. In addition, monitoring of FEV1 stability 
throughout the study revealed challenges in obtaining consistent morning trough FEV1 values 
with best efforts in this young patient population, despite the rigorous training and coaching 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
85 
provided by the investigators. Therefore, some of the initial assumptions and the sample size 
described above were revised to the following: 
• For the superiority comparison of FS MDPI 50/12.5 mcg twice daily versus Fp MDPI 
50 mcg twice daily, the SD was revised to 22% and the overall mean change from 
baseline was revised to 6.5% (blinded SD observed after 427 patients completed 
week 12 of this study (excluding IMPD)) and the power down to 80%.  
• With these assumptions, 181 patients per treatment group are required for the 2-sided 
test of FS MDPI 50/12.5 mcg twice daily and Fp MDPI 50 mcg twice daily. 
• For the superiority comparison of Fp MDPI 50 mcg twice daily versus placebo, the 
SD was revised to 17% and overall mean change from baseline was 5% (blinded SD 
observed after 434 patients completed week 12 of this study (excluding IMPD)) and 
the power was revised to 80%.  
• With these assumptions, 181 patients per treatment group are required for the 2-sided 
test of Fp MDPI 50 mcg twice daily versus placebo. 
Assuming a dropout rate of 12%, then 206 patients per treatment group in the 4 treatment groups, 
for a total of 824 patients, will be randomized (initial assumption for dropout rate was 15%). 
9.2. 
Analysis Sets 
9.2.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all randomized patients. 
In the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received.  
The ITT analysis set will serve as the primary analysis set for efficacy analyses. 
9.2.2. 
Safety Analysis Set 
The safety analysis set will include all randomized patients who receive at least 1 dose of IMP. 
In the safety analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized, unless otherwise specified. 
The safety analysis set will be used for all analyses of safety data. 
9.2.3. 
Per-Protocol Analysis Set 
The per-protocol (PP) analysis set is a subset of the ITT analysis set including only patients 
without major protocol violations and who have >80% compliance to the IMP over the entire 
treatment period. Treatment compliance during the study will be assessed based on both data 
collected in the IMP dose counter and diary. Details will be provided in the SAP. Major protocol 
violations will be determined before unblinding. Note that since the use of incorrect IMP will be 
considered a major protocol violation, for treatment assignment in the PP analysis set, “as 
randomized” will coincide with “as treated.” 
The PP analysis set will serve as the supportive population for the primary efficacy analysis only. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
86 
9.3. 
Data Handling Conventions 
Data imputation rules will be described in the statistical analysis plan, as appropriate for each 
endpoint. 
9.4. 
Study Population 
The ITT analysis set (Section 9.2.1) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented by treatment group and for all patients. 
9.4.1. 
Patient Disposition 
The following data will be summarized using descriptive statistics: patients screened; patients 
screened but not enrolled (and reason); patients enrolled in the run-in period; patients enrolled in 
the run-in period but not randomized (and reason); patients randomized; patients randomized but 
not treated; patients in the ITT, safety, and PP analysis sets; patients who complete the study; and 
patients who withdraw from the treatment period of the study and the reason for withdrawal. 
9.4.2. 
Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including medical history, and prior 
medications and therapies will be examined to assess the comparability of the treatment groups 
and will be summarized using descriptive statistics. For continuous variables, descriptive 
statistics (number [n], mean, SD, median, minimum, and maximum) will be provided. For 
categorical variables, patient counts and percentages will be provided. Categories for missing 
data will be presented if necessary. 
Patient demographics will be presented for all 3 analysis sets defined in Section 9.2. 
9.5. 
Efficacy Analysis 
9.5.1. 
Primary Endpoint 
The primary efficacy endpoints are as follows: 
• For Fp MDPI versus placebo: the change from baseline in weekly average of the 
percent predicted trough morning FEV1 at week 12 
• For FS MDPI versus Fp MDPI: the change from baseline in 1-hour postdose percent 
predicted morning FEV1 at week 12 
9.5.2. 
Secondary Endpoints 
The secondary efficacy endpoints are as follows: 
• Change from baseline in the weekly average of daily trough morning (predose and 
pre-rescue bronchodilator) PEF over the 12-week treatment period 
• Change from baseline in the weekly average of total daily (24-hour) use of 
albuterol/salbutamol inhalation aerosol (number of inhalations) over weeks 
1 through 12 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
87 
• Change from baseline in the weekly average of the total daily asthma symptom score 
(defined as the average of the daytime and nighttime scores) over weeks 1 through 12 
• Change from baseline in asthma control (measured by C-ACT) score over the 
12-week treatment period  
• Time to first onset of effect defined as the first decrease from baseline in daily rescue 
medication use 
• Proportion of patients who discontinued from IMP for asthma exacerbation during the 
12-week treatment period 
The sequential order of the secondary endpoints for multiplicity will be described in the 
statistical analysis plan. 
9.5.3. 
Other Efficacy Endpoints 
The other efficacy endpoints include the following: 
• Change from baseline in the weekly average of total daily (24-hour) use of 
albuterol/salbutamol inhalation aerosol (number of inhalations) at weeks 4, 8, and 12  
• Change from baseline in the percentage of rescue-free days (defined as 24-hour 
periods with no rescue medication usage) during the 12-week treatment period 
• Change from baseline in the percentage of symptom-free days (defined as 24-hour 
periods with asthma symptom score of 0) during the 12-week treatment period 
• Change from baseline in the percentage of asthma-control days (defined as 24-hour 
periods with asthma symptom score of 0 and no rescue medication usage) during the 
12-week treatment period 
• Change from baseline in 1-hour postdose percent predicted morning FEV1 at week 1 
• Change from baseline in the weekly average of daily evening PEF over the 12-week 
treatment period 
• Change from baseline in weekly average of the percent predicted trough morning 
FEV1 at weeks 1, 2, 4, and 8 
• Proportion of patients who achieve at least a 15% increase in morning FEV1 at 1-hour 
postdose at day 1 (the RV/TV1), week 1, and week 12 
• Change from baseline in asthma control (measured by C-ACT) score at weeks 4, 8, 
and 12 
• Time to consistent onset of effect defined as the decrease from baseline in daily 
rescue medication use on 3 consecutive days 
9.5.4. 
Planned Method of Analysis 
The ITT analysis set (Section 9.2.1) will be the primary analysis set to be used for all efficacy 
analyses. The PP analysis set will serve as the sensitivity analysis set for primary efficacy 
analyses only. Details will be provided in the statistical analysis plan. Subgroup (sex, age group, 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
88 
previous therapy [ICS or NCS], and race) analyses will be provided for the primary efficacy 
endpoints. 
9.5.4.1. 
Primary Estimands and Efficacy Analysis 
The specific estimands selected for the 2 primary endpoints will assess the change from baseline 
due to the initially randomized treatment as actually taken. These estimands assess the 
effectiveness at week 12, focusing on the causal effects attributable to the initially randomized 
medication. The sponsor will make all efforts to avoid study withdrawal in this 12-week study. 
In instances where a patient decides to discontinue IMP or, more importantly, requires 
alternative therapy for worsening asthma or an asthma exacerbation, the investigators will be 
instructed to encourage the patient to continue in the study and return for planned visits in order 
to collect data after IMP discontinuation.  
The question of whether to use data collected after IMP discontinuation is an ongoing debate in 
statistical literature, in particular for studies with symptomatic endpoints and when it is common 
for patients who dropout to switch therapies (Little and Kang 2015, Mallinckrodt et al 2016, 
Mallinckrodt 2013, O’Neill and Temple 2012). This study is designed as a placebo-controlled 
study and it is expected that patients randomized to placebo would discontinue IMP due to 
worsening asthma at a higher rate than those randomized to active treatment, which is known to 
be an efficacious drug as established by multiple studies. After a patient discontinues IMP due to 
worsening asthma, the patient will be placed on alternative asthma therapies, such as systemic 
corticosteroids, additional medications containing ICS, or both, which would alter the spirometry 
collected after that point and therefore not be appropriate for assessment of IMP effectiveness. 
Improvement of asthma would be expected as rapidly and early as 1 week for FEV1 for placebo 
patients placed on ICS (Szefler et al 1999). It has also been shown that patients placed on ICS 
with long acting beta-agonists can have significant improvement in serial FEV1 measurements on 
the same day (Corren et al 2007, Pearlman et al 1999). Therefore, any patient who discontinued 
IMP and was placed on alternative therapies would be expected to have rapid and demonstrable 
improvements in lung function approximating or exceeding the levels measured at screening.  
The inclusion of patients who failed therapy and who were then treated with alternative 
medication would blunt the treatment effect, potentially causing the study to fail due to the 
analysis rather than the effectiveness of the treatment given during the study. These patients no 
longer represent a true placebo population and including them in the population for the primary 
outcome is not consistent with treatment by placebo. In light of this, retrieved dropout data will 
be used only for sensitivity analyses. Missing data for patients who discontinue IMP will be 
imputed using reference-based multiple imputations representing a missing not at random 
(MNAR) mechanism. This approach is discussed in Mallinckrodt et al 2016 (Sections 3.2 and 
3.4 for estimand 2 in the paper). 
Analysis of the change from baseline in weekly average of the percent predicted trough 
morning FEV1 at week 12 
The baseline percent predicted FEV1 will be the weekly average of the morning FEV1 prior to 
the first IMP dose. The first day before randomization consists of the entry on the morning of the 
RV in the patient diary built into the handheld device. The weekly average of the percent 
predicted FEV1 at week 12 will be the average values based on the available data at that week. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
89 
The primary analysis of the change from baseline in weekly average of percent predicted 
morning FEV1 at week 12 due to the initially randomized treatment as actually taken will be 
analyzed using an analysis of covariance (ANCOVA) model with effects due to baseline percent 
predicted trough morning FEV1, sex, age, (pooled) investigational center, previous therapy (ICS 
or NCS), and IMP treatment group. Contrasts for pairwise treatment comparisons of interest will 
be constructed. The estimated treatment difference between each IMP treatment group and the 
placebo group will be presented together with the 2-sided 95% confidence interval (CI) for the 
difference and the p-value.  
In this analysis, missing data that are caused by early dropouts from the study or from IMP 
(regardless of availability of retrieved dropout data) will be imputed using reference-based 
multiple imputations. Details on the implementation of the multiple imputations will be provided 
in the statistical analysis plan. 
Analysis of the change from baseline in 1-hour postdose percent predicted morning FEV1 
at week 12 
For the endpoint of change from baseline in 1-hour postdose percent predicted morning FEV1 
(measured at the clinic) at week 12, baseline is defined as predose FEV1 measurements obtained 
at the clinic at the RV with the handheld device immediately prior to the IMP administration. 
The primary analysis of the change from baseline in 1-hour postdose percent predicted morning 
FEV1 at week 12 due to the initially randomized treatment as actually taken will be analyzed 
using an ANCOVA model with effects due to baseline percent predicted trough morning FEV1, 
sex, age, (pooled) investigational center, previous therapy (ICS or NCS), and IMP treatment 
group. Contrasts for pairwise treatment comparisons of interest will be constructed. The 
estimated treatment difference between each IMP treatment group and the placebo group will be 
presented together with the 2-sided 95% CI for the difference and the p-value. Missing data 
caused by early dropouts will be handled similarly to the above analysis. 
9.5.4.2. 
Sensitivity Analysis to Missing Data 
To assess the impact of missing data, several sensitivity analyses will be conducted for the 
2 endpoints by evaluating alternative estimands. More details will be provided in the statistical 
analysis plan. 
• The primary analysis for the 2 endpoints will be repeated when using data collected after 
IMP discontinuation (retrieved dropout data). Reference-based imputation will be used 
only for patients with no retrieved dropout data. This analysis estimates different 
estimands, namely the change from baseline as actually taken (see estimand 1 in 
Mallinckrodt et al 2016).  
• The primary analysis for the 2 endpoints will be repeated on completers with no major 
protocol violations (see estimand 3 in Mallinckrodt et al 2016). 
• A tipping point analysis will be performed as a sensitivity analysis to missing data by 
utilizing multiple imputations under different missing mechanism. For placebo patients, 
in all applications of multiple imputations, missing at random (MAR) will be assumed. 
For the active arms, in the first application, MAR will be assumed and the imputations 
will be drawn from data in the corresponding active arms. In subsequent applications, 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
90 
shifts to the distribution of the active arms will be applied to represent different degrees 
of effect loss, ie, MNAR will be assumed. This analysis will utilize only data collected 
prior to IMP discontinuation. Additional details will be provided in the SAP.  
• “2-dimensional tipping point” multiple imputation will be performed similar to above, the 
shifts to the distribution will apply to both placebo and active arms, to represent different 
degrees of effect loss. This analysis will utilize only data collected prior to IMP 
discontinuation. Additional details will be provided in the SAP. 
• The primary analysis for the 2 endpoints will be repeated when missing data will be 
imputed using a mixed approach of last observation carried forward (LOCF) and baseline 
observation carried forward (BOCF) as follows: BOCF will be used for patients who had 
a positive change from baseline at the time of study or IMP discontinuation (ie, a change 
of 0), while LOCF will be used for patients that have negative change from baseline. In 
this imputation method, the imputed value is the lower between LOCF and BOCF for 
each patient. No adjustments will be made to other patients.  
• For the first primary endpoint of change from baseline in the weekly average of percent 
predicted trough morning FEV1 over the 12-week treatment period, analysis will be 
performed using a mixed model for repeated measures (MMRM). This analysis will not 
use retrieved dropout data. This analysis represents a MAR assumption. 
9.5.4.3. 
Secondary Efficacy Analysis 
For all secondary endpoints, analyses will be performed using the ITT analysis set and will not 
include retrieved dropout data in the analysis. 
Analysis of change from baseline in weekly average of daily trough morning PEF, total daily use 
of albuterol/salbutamol, total daily asthma symptom score, and C-ACT score over the 12-week 
treatment period will be analyzed using an MMRM analysis with effects due to baseline, sex, 
age, (pooled) investigational center, previous therapy (ICS or NCS), treatment, time, and time-
by-treatment interaction. For all of these endpoints, the MMRM will use only observations 
collected until IMP discontinuation. 
The time to first onset of effect, defined as the first decrease from baseline in daily rescue 
medication use, will be analyzed using a log-rank test. Median and mean time to first onset of 
effect and associated 95% Cis will be estimated. Time to first onset of effect will also be 
displayed graphically with a Kaplan-Meier figure. 
The proportion of patients who discontinued from IMP for asthma exacerbation during the 
12-week treatment period will be analyzed using a logistic regression model with effects due to 
previous therapy (ICS or NCS) and treatment. These patients will be considered as 
nonresponders in this analysis. 
9.5.4.4. 
Other Efficacy Analysis 
Statistical methods to be used for other efficacy endpoints will be described and detailed in the 
statistical analysis plan. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
91 
9.6. 
Multiple Comparisons and Multiplicity 
A fixed-sequence testing procedure will be employed to control the overall Type I error rate at 
the 2-sided 0.05 level for the co-primary endpoints. The sequential order of comparisons will be 
as follows:  
1. 1-hour postdose percent predicted FEV1 comparing FS MDPI 50/12.5 mcg versus Fp 
MDPI 50 mcg 
9. Trough percent predicted FEV1 comparing Fp MDPI 50 mcg versus placebo 
10. Trough percent predicted FEV1 comparing Fp MDPI 25 mcg versus placebo 
Each test will be 2-sided and performed at the 0.05 level of significance. However, if a test is not 
significant at the 2-sided 0.05 level, no further tests will be performed. 
Taking into consideration that this is the very first study that utilizes the handheld device in a 
large Phase 3 study in a pediatric asthma patient population (4 to 11 years of age), an unplanned 
blinded sample size reassement was conducted. Since the adjustment to sample size was based 
on blinded standard deviation, no adjustment to the multiplicity control is warrented. 
Multiplicity control for the secondary endpoints and the sequential order of the secondary 
endpoints will be described in the statistical analysis plan. 
No multiplicity adjustments will be made for other efficacy analyses.  
9.7. 
Safety Analysis 
Safety analyses will be performed on the safety analysis set (Section 9.2.2). 
Safety assessments and time points are provided in Table 3. 
Safety data will be summarized using descriptive statistics by treatment group. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term (PT) or system organ 
class (SOC) category for the analyses of safety. Summaries will be presented for all treatment-
emergent adverse events (overall and by severity), treatment-emergent adverse events 
determined by the investigator to be related to IMP (ie, reasonable possibility; see Section 7.1.4) 
(defined as related or with missing relationship, overall and by severity), serious treatment-
emergent adverse events, and treatment-emergent adverse events causing withdrawal from the 
study.  
Summaries will be presented by treatment group and for all patients. Incidence and event counts 
will be summarized for the SOC and PT summary table. Patient listings of serious adverse events 
and treatment-emergent adverse events leading to withdrawal will be presented. 
Shifts from baseline to the final TV (TV6/IMPDV) in physical examination findings will be 
summarized descriptively. 
Changes in vital signs measurement data will be summarized descriptively. All values will be 
compared with predefined criteria to identify potentially clinically significant values or changes, 
and such values will be summarized and listed in separate tables and listings. Although such 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
92 
values will be summarized and listed, clinical significance will be determined independently by 
the investigator. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is being 
treated with IMP. 
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) 
will be provided for actual values and changes from baseline to each time point. For categorical 
variables, patient counts and percentages will be provided. Descriptive summaries of serious 
adverse events, patient withdrawals due to adverse events, and potentially clinically significant 
abnormal values (vital signs) based on predefined criteria will be provided as well. 
If any patient dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the patient narrative included in the CSR. 
9.8. 
Tolerability Analysis 
Tolerability will be assessed via other endpoints. 
9.9. 
Planned Interim Analysis 
There will be no interim analysis. 
9.10. 
Reporting Deviations from the Statistical Plan 
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the CSR, or any combination of these, as 
appropriate, and in accordance with applicable national, local, and regional requirements and 
regulations. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
93 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Refer to Appendix C for information regarding quality control and quality assurance. This 
includes information about protocol amendments, deviations and violations, responsibilities of 
the investigator to study personnel, study monitoring, and audit and inspection. 
Refer to Error! Reference source not found. for the definition of a clinical product complaint 
and investigator responsibilities in the management of a clinical product complaint. 
Details are given in a Study Manual. 
11. 
COMPLIANCE STATEMENT 
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline 
for GCP E6 and any applicable national and local laws and regulations (eg, Title 21 CFR 
Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC of the European Parliament and of the 
Council on the approximation of the laws, regulations and administrative provisions of the 
Member States relating to the implementation of good clinical practice in the conduct of clinical 
trials on medicinal products for human use). Any episode of noncompliance will be documented. 
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable GCP guidelines referenced above for collecting, recording, and reporting the 
data accurately and properly. Agreement of the investigator to conduct and administer this 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent authorities in the 
country where each investigational center is located. 
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study; and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study; and with the properties of 
the IMPs as described in the IB or prescribing information. 
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the clinical study at that investigational center and for contacts 
with study management, with the IEC/IRB, and with competent authorities. 
See Appendix D for the ethics expectations of informed consent or assent, competent authorities 
and IEC/IRB, confidentiality regarding study patients, and requirements for registration of the 
clinical study. 
12. 
DATA MANAGEMENT AND RECORD KEEPING 
See Error! Reference source not found. for information regarding data management and record 
keeping. This includes direct access to source data and documents, data collection, data quality 
control, and archiving of CRFs and source documents. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
94 
13. 
FINANCING AND INSURANCE 
A separate clinical study agreement, including a study budget, will be signed between each 
principal investigator and the sponsor (or the CRO designated by the sponsor) before the IMP is 
delivered. 
The patients in this clinical study are insured in accordance with applicable legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance coverage are inter alia, damages to health, and worsening of 
previous existing disease that would have occurred or continued if the patient had not taken part 
in the clinical study. 
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor. 
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete FDA 3454 form. Each investigator will notify the 
sponsor of any relevant changes during the conduct of the study and for 1 year after the study has 
been completed. 
14. 
PUBLICATION POLICY 
See Error! Reference source not found. for information regarding the publication policy. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
95 
15. 
REFERENCES 
Akinbami LJ, Moorman JE, Bailey C, Zahran HS, King M, Johnson CA, et al. Trends in asthma 
prevalence, health care use, and mortality in the United States, 2001-2010. NCHS Data Brief. 
2012 May;(94):1-8. 
Beasley R, Crane J, Lai CK, Pearce N. Prevalence and etiology of asthma. J Allergy Clin 
Immunol 2000;105(2 Pt 2):S466-72. 
Centers for Disease Control and Prevention. Asthma’s impact on the nation: data from the CDC 
National Asthma Control Program. 
http://www.cdc.gov/asthma/impacts_nation/asthmafactsheet.pdf. 2012. Accessed [April 2014]. 
Corren J, Korenblat PE, Miller CJ, O’Brien CD, Mezzanotte WS. Twelve-week, randomized, 
placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and 
formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in 
adolescents and adults with asthma. Clin Ther 2007;29(5):823–43. 
Kerwin EM, Pearlman DS, de Guia T, Carlsson LG, Gillen M, Uryniak T, et al. Evaluation of 
efficacy and safety of budesonide delivered via two dry powder inhalers. Curr Med Res Opin. 
2008;24(5):1497–510. 
Little R, Kang S. Intention-to-treat analysis with treatment discontinuation and missing data in 
clinical trials. Stat Med 2015;34(16):2381–90. 
Mallinckrodt C. Choosing primary estimands and analyses. In: Preventing and treating missing 
data in longitudinal clinical trials: A practical guide. New York: Cambridge University Press, 
2013. 
Mallinckrodt C, Molenberghs G, Rathmann S. Choosing estimands in clinical trials with missing 
data. Pharm Stat 2016. 
Masoli M, Fabian D, Holt S, Beasley R for the Global Initiative for Asthma (GINA) Program. 
The global burden of asthma: executive summary of the GINA Dissemination Committee report. 
Allergy 2004;59(5):469-78. 
National Health Interview Survey (NHIS), National Center for Health Statistics, Centers for 
Disease Control and Prevention. Data: 2011 Lifetime Asthma, Current Asthma, Asthma Attacks 
among those with Current Asthma. Available at 
http://www.cdc.gov/asthma/nhis/2011/table1-1.htm. Accessed 25 August 2013.  
National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program 
(NAEPP). Expert Panel Report 3: Guidelines for the diagnosis and management of asthma—full 
report 2007, August 28 2007. National Institutes of Health publication 07-4051. Available at 
http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed 26 September 2013. 
O’Neill RT, Temple R. The prevention and treatment of missing data in clinical trials: an FDA 
perspective on the importance of dealing with it. Clin Pharmacol Ther 2012;91(3):550–4. 
Pearlman DS, Stricker W, Weinstein S, Gross G, Chervinsky P, Woodring A, et al. Ann Allergy 
Asthma Immunol 1999;82(3):257–65. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
96 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J 2012;40(6):1324-43. 
Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition 
of salmeterol in symptomatic asthma (MIASMA). BMJ 2000;320(7246):1368-73. 
Szefler SJ, Boushey HA, Pearlman DS, Togias A, Liddle R, Furlong A, et al. Time to onset of 
effect of fluticasone propionate in patients with asthma. J Allergy Clin Immunol 
1999;103(5):780–8. 
Woodcock A, Bleecker ER, Lötvall J, O’Byrne PM, Bateman ED, Medley H, et al. Efficacy and 
safety of fluticasone furoate/vilanterol compared with fluticasone propionate/salmeterol 
combination in adult and adolescent patients with persistent asthma. Chest 2013;144(4):1222–9. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
97 
16. 
SUMMARY OF CHANGES TO PROTOCOL 
16.1. 
Amendment 02 Dated 05 June 2018 
The primary reason for this amendment is to address the observed larger variability in the overall 
blinded patient population in morning trough FEV1 at home values than the initial protocol 
assumptions.  
The initial assumptions of the treatment effect and variability were based on data collected in 
previous Teva studies with the same Fp MDPI and FS MDPI product in adult asthma patients. 
The relationship between the handheld and clinic-based spirometry was analysed using data from 
a previous Teva study (a double-blinded, placebo controlled study of beclomethasone 
diproprionate via breath-actuated inhaler for persisten asthma in adults and adolescents aged ≥12 
yeas) in which both handheld and clinic-based spirometry were used to measure FEV1. Analysis 
of the relationship between handheld and clinic-based spirometry demonstrated that handheld 
spirometery provided consistent and reliable results with reduced placebo response in the home 
setting. 
However, this study FSS-AS-30003 is the very first study in which handheld spirometry is 
utilized 1) as the primary endpoint in a Phase 3 study and 2) in a pediatric asthma patient 
population for a pivotal study of this scale. This made it difficult to predict the actual variability 
of the data. A blinded sample size reassessment was not planned. Routine blinded data 
monitoring of this study FSS-AS-30003 revealed that the SD for the overall study population is 
indeed higher than the initial assumptions. In addition, FEV1 stability has been monitored closely 
throughout this study (see Section 6.1.3 for a description of how FEV1 stability alert criteria were 
used to monitor patient safety related to worsening of asthma). A number of alerts were 
determined by the investigators as not related to worsening asthma but rather due to poor 
patients’ effort, which has been challenging in this patient population as young as 4 years of age, 
despite the rigorous training and coaching provided by the investigators.  
To ensure the high quality of the FEV1 data and integrity of the study, an unplanned blinded data 
quality evaluation and sample size reassessment was conducted. Based on the observed blinded 
410 completed patients, the initial assumptions for SD and power calculation and the sample size 
have been revised as detailed in Section 9.  
Other minor or editorial changes have been made to the protocol (and protocol synopsis, as 
appropriate). These changes are unlikely to affect the safety or rights (physical or mental 
integrity) of the patients in this clinical study or the scientific value of the clinical study. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
98 
Original text with changes shown 
New wording 
Reason/justification for 
change 
Section 3.1 affected by this change: 
On the morning of each TV, patients will be instructed to 
record their asthma symptom score and rescue 
albuterol/salbutamol HFA MDI use and complete their morning 
lung function assessments (FEV1 and PEF) by handheld device 
as usual, but to delay IMP dosing until they get to the 
investigational center. 
On the morning of each TV, patients will be instructed to 
record their asthma symptom score and rescue 
albuterol/salbutamol HFA MDI use and complete their 
morning lung function assessments (FEV1 and PEF) by 
handheld device as usual, but to delay IMP dosing until they 
get to the investigational center. 
Adding IMP for clarity 
Section 3.2 affected by this change: 
The population planned to be enrolled in this study comprises 
male and female patients 4 through 11 years of age who have a 
documented history of persistent asthma. Approximately 600 
824 male and female patients, 150 206 patients in each of 4 
treatment group, will be enrolled. Assuming a dropout rate of 
1512%, approximately 127 181 evaluable patients in each 
treatment group (508 724 total patients) will complete the 12-
week treatment period.  
The population planned to be enrolled in this study 
comprises male and female patients 4 through 11 years of 
age who have a documented history of persistent asthma. 
Approximately 824 male and female patients, 206 patients in 
each of 4 treatment group, will be enrolled. Assuming a 
dropout rate of 12%, approximately 181 evaluable patients in 
each treatment group (724 total patients) will complete the 
12-week treatment period. 
Increase in number of patients 
enrolled (for details, see 
above) 
The study is expected to start in the fourth quarter of 2016 (first 
patient in) and last until approximately the thirdsecond quarter 
of 20182019 (last patient last visit). 
The study is expected to start in the fourth quarter of 2016 
(first patient in) and last until approximately the second 
quarter of 2019 (last patient last visit). 
Increase in number of patients 
enrolled (for details, see 
above) 
Section 3.5 “Table 3 Study Procedures and Assessments” affected by this change: 
Row: allowed time windows 
Column: RT/TV1 
Day 01 
Row: allowed time windows 
Column: RT/TV1 
Day 01 
Letter of Clarification 01 
Row: Perform lung function assessments (FEV1) by handheld 
device 1 hour postdose at the investigational center 
Column: SV 
X 
Row: Perform lung function assessments (FEV1) by handheld 
device 1 hour postdose at the investigational center 
Column: SV 
 
Letter of Clarification 01 
Row: End study participation in IRT system 
Column: TV6 
Xn 
Row: End study participation in IRT system 
Column: TV6 
X 
Letter of Clarification 01 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
99 
Original text with changes shown 
New wording 
Reason/justification for 
change 
Table 3: Study Procedures and Assessments; footnote a 
Patients who fail to meet baseline lung function assessments by 
handheld device requirements may retest after within 7 days of 
their initial SV. 
Table 3: Study Procedures and Assessments; footnote a 
Patients who fail to meet baseline lung function assessments 
by handheld device requirements may retest within 7 days of 
their initial SV. 
Letter of Clarification 01 
Table 3 Study Procedures and Assessments; footnote b 
The patient’s home FEV1 by handheld device should be 
reviewed, and the average of the 5 most recent highest daily 
values (3 attempts) for trough morning FEV1 over out of the 
last 7 days prior to RV must be 40% to 85% predicted for age, 
height, sex and race 
Table 3: Study Procedures and Assessments; footnote a 
The patient’s home FEV1 by handheld device should be 
reviewed, and the average of the 5 highest daily values (3 
attempts) for trough morning FEV1 out of the last 7 days 
prior to RV must be 40% to 85% predicted for age, height, 
sex and race 
Letter of Clarification 02 
Section 4.1 affected by this change: 
The patient’s persistent asthma is stable and is currently being 
treated with stable asthma therapy (eg, ICS, ICS/LABA, 
leukotriene receptor antagonist, etc.) for at least 30 days before 
the SV. Patients who are currently on SABA regimen only or 
PRN only are not eligible for the study. 
The patient’s persistent asthma is stable and is currently 
being treated with stable asthma therapy (eg, ICS, 
ICS/LABA, leukotriene receptor antagonist, etc.) for at least 
30 days before the SV. Patients who are currently on SABA 
regimen only or PRN only are not eligible for the study. 
Letter of Clarification 02 
The patient has demonstrated ≥10% response to a 
bronchodilator from screening FEV1 within 30 minutes (±5 
min) after 2 to 4 inhalations of albuterol/salbutamol HFA MDI 
(90 mcg ex actuator) or equivalent at SV as measured by 
handheld device. 
The patient has demonstrated ≥10% response to a 
bronchodilator from screening FEV1 within 30 minutes (±5 
min) after 2 to 4 inhalations of albuterol/salbutamol HFA 
MDI (90 mcg ex actuator) or equivalent at SV as measured 
by handheld device. 
Adding time window 
Section 5.7 affected by this change: 
Chronic stable doses of ocular steroids of at least 307 days 
duration, with doses expected to remain stable throughout the 
study, are allowed. 
Chronic stable doses of ocular steroids of at least 7 days 
duration, with doses expected to remain stable throughout 
the study, are allowed. 
Letter of Clarification 01 
Section 5.9 affected by this change 
Approximately 150 206 patients will be randomized into each 
treatment group. 
Approximately 206 patients will be randomized into each 
treatment group. 
Increase in number of patients 
enrolled (for details, see 
above) 
The average of the 5 most recent highest daily values for trough 
morning FEV1 obtained at home (by handheld device) over 5 
out of the last 7 days prior to RV is within 40% to 85% 
The average of the 5 highest values for trough morning FEV1 
obtained at home (by handheld device) out of the last 7 days 
prior to RV is within 40% to 85% predicted for age, height, 
Letter of Clarification 02 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
100 
Original text with changes shown 
New wording 
Reason/justification for 
change 
predicted for age, height, sex, and race 
sex, and race 
Section 7.7 affected by this change: 
Patients with a culture positive infection may continue 
participation in the study on appropriate anti infective therapy, 
provided this therapy is not prohibited by the protocol. Azole 
antifungal medications are prohibited. If a patient requires a 
protocol prohibited medication for therapy, the patient will be 
discontinued from the study and provided appropriate therapy. 
Patients with a culture positive infection may continue 
participation in the study on appropriate anti infective 
therapy, provided this therapy is not prohibited by the 
protocol. If a patient requires a protocol prohibited 
medication for therapy, the patient will be discontinued from 
the study and provided appropriate therapy. 
Letter of Clarification 01 
Section 9 affected by this change: 
This section describes the statistical analysis as foreseen at the 
time of planning theplanned for this study. Changes, additions, 
and further details about the analyses will be described in the 
statistical analysis plan. (SAP). 
This section describes the statistical analysis planned for this 
study. Changes, additions, and further details about the 
analyses will be described in the statistical analysis plan 
(SAP). 
Increase in number of patients 
enrolled (for details, see 
above) 
Section 9.1 affected by this change: 
 
 
Sample size and power calculations are driven by 
demonstrating superiority of Fp MDPI 50 mcg twice daily over 
placebo in change from baseline in percent predicted trough 
morning FEV1 at week 12 and the superiority of FS MDPI 
50/12.5 mcg twice daily over Fp MDPI 50 mcg twice daily in 
change from baseline in 1-hour postdose percent predicted 
morning FEV1 at week 12. and the superiority of Fp MDPI 50 
mcg twice daily over placebo in change from baseline in 
percent predicted trough morning FEV1 at week 12.  
For the superiority comparison of Fp MDPI 50 mcg twice daily 
versus placebo, assuming that the change from baseline in 
percent predicted trough morning FEV1 at week 12 is analyzed 
using an analysis of variance (ANOVA) model with only a 
single factor of treatment group, that a true treatment difference 
is 5% between Fp MDPI 50 mcg twice daily and placebo, and 
that a common standard deviation (SD) is 13.25%, then 127 
Sample size and power calculations are driven by 
demonstrating superiority of FS MDPI 50/12.5 mcg twice 
daily over Fp MDPI 50 mcg twice daily in change from 
baseline in 1-hour postdose percent predicted morning FEV1 
at week 12 and the superiority of Fp MDPI 50 mcg twice 
daily over placebo in change from baseline in percent 
predicted trough morning FEV1 at week 12.  
For the superiority comparison of FS MDPI 50/12.5 mcg 
twice daily versus Fp MDPI 50 mcg twice daily, assuming 
that the change from baseline in 1-hour postdose percent 
predicted morning FEV1 at week 12 is analyzed using an 
ANOVA model with only a single factor of treatment group, 
the following assumptions were made: 
• 
The initial assumed common standard deviation 
(SD) was 9.3% and the true treatment 
Increase in number of patients 
enrolled (for details, see 
above) 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
101 
Original text with changes shown 
New wording 
Reason/justification for 
change 
patients per treatment group will yield an approximate 
statistical power of 85%, at a significance level of 0.05, for the 
2 sided test of Fp MDPI 50 mcg twice daily versus placebo. 
The treatment effect and variability assumptions made for this 
power calculation are based on data collected in Teva studies. 
For the superiority comparison of FS MDPI 50/12.5 mcg twice 
daily versus Fp MDPI 50 mcg twice daily, assuming that the 
change from baseline in 1-hour postdose percent predicted 
morning FEV1 at week 12 is analyzed using an ANOVA model 
with only a single factor of treatment group, that a true 
treatment difference is 4.5% between FS MDPI 50/12.5 mcg 
twice daily and Fp MDPI 50 mcg twice daily, and that a 
common SD is 9.3%, then 127 patients per treatment group will 
yield a statistical power of 97%, at a significance level of 0.05, 
for the 2 sided test of FS MDPI 50/12.5 mcg twice daily versus 
Fp MDPI 50 mcg twice daily. The treatment effect and 
variability assumptions made for this power calculation are 
based on data collected in studies conducted by Teva.the 
following assumptions were made: 
• 
The initial assumed common standard deviation 
(SD) was 9.3% and the true treatment difference 
was 4.5% between FS MDPI 50/12.5 mcg twice 
daily and Fp MDPI 50 mcg twice daily. This 
assumption was based on data collected in 
previous Teva studies with the same Fp MDPI 
and FS MDPI products in adult asthma patients 
who completed the 12-week treatment period and 
based on office-based spirometry.  
• 
The initial power was 97% at a 2-sided 
difference was 4.5% between FS MDPI 50/12.5 
mcg twice daily and Fp MDPI 50 mcg twice 
daily. This assumption was based on data 
collected in previous Teva studies with the 
same Fp MDPI and FS MDPI products in adult 
asthma patients who completed the 12-week 
treatment period and based on office-based 
spirometry.  
• 
The initial power was 97% at a 2-sided 
significance level of 5%.  
For the superiority comparison of Fp MDPI 50 mcg twice 
daily versus placebo, assuming that the change from baseline 
in percent predicted trough morning FEV1 at week 12 is 
analyzed using an analysis of variance (ANOVA) model 
with only a single factor of treatment group, the following 
assumptions were made: 
• 
The initial assumed common standard deviation 
(SD) was 13.25% and the true treatment 
difference was 5% between Fp MDPI 50 mcg 
twice daily and placebo. This assumption was 
based on data collected in previous Teva 
studies with the same Fp MDPI product in adult 
asthma patients and based on office-based 
spirometry 
• 
The initial power was 85% at a 2-sided 
significance level of 5%.  
This study FSS-AS-30003 is the first Teva's study in which 
the handheld spirometry is utilized as an endpoint and this 
hanheld device is being used in a pediatric asthma patient 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
102 
Original text with changes shown 
New wording 
Reason/justification for 
change 
significance level of 5%.  
For the superiority comparison of Fp MDPI 50 mcg twice daily 
versus placebo, assuming that the change from baseline in 
percent predicted trough morning FEV1 at week 12 is analyzed 
using an analysis of variance (ANOVA) model with only a 
single factor of treatment group, the following assumptions 
were made: 
• 
The initial assumed common standard deviation 
(SD) was 13.25% and the true treatment 
difference was 5% between Fp MDPI 50 mcg 
twice daily and placebo. This assumption was 
based on data collected in previous Teva studies 
with the same Fp MDPI product in adult asthma 
patients and based on office-based spirometry 
• 
The initial power was 85% at a 2-sided 
significance level of 5%.  
This study FSS-AS-30003 is the first Teva's study in which the 
handheld spirometry is utilized as an endpoint and this hanheld 
device is being used in a pediatric asthma patient population, 
the target population of this study. A blinded sample size 
reassessment was not planned for this study. However, routine 
blinded data monitoring of this study FSS-AS-30003 revealed 
that a few patietnts showed nonphysiologic (~200% of percent 
predicted FEV1) changes from baseline. This triggered a 
blinded sample size reassessment that showed that the overall 
mean change from baseline and SD for the overall study 
population is higher than the initial assumptions based on the 
office spirometry in adult asthma patients. In addition, 
monitoring of FEV1 stability throughout the study revealed 
population, the target population of this study. A blinded 
sample size reassessment was not planned for this study. 
However, routine blinded data monitoring of this study 
FSS-AS-30003 revealed that a few patietnts showed 
nonphysiologic (~200% of percent predicted FEV1) changes 
from baseline. This triggered a blinded sample size 
reassessment that showed that the overall mean change from 
baseline and SD for the overall study population is higher 
than the initial assumptions based on the office spirometry in 
adult asthma patients. In addition, monitoring of FEV1 
stability throughout the study revealed challenges in 
obtaining consistent morning trough FEV1 values with best 
efforts in this young patient population, despite the rigorous 
training and coaching provided by the investigators. 
Therefore, some of the initial assumptions and the sample 
size described above were revised to the following: 
• 
For the superiority comparison of FS MDPI 
50/12.5 mcg twice daily versus Fp MDPI 50 
mcg twice daily, the SD was revised to 22% 
and the overall mean change from baseline was 
revised to 6.5% (blinded SD observed after 427 
patients completed week 12 of this study 
(excluding IMPD)) and the power down to 
80%.  
• 
With these assumptions, 181 patients per 
treatment group are required for the 2-sided test 
of FS MDPI 50/12.5 mcg twice daily and Fp 
MDPI 50 mcg twice daily. 
• 
For the superiority comparison of Fp MDPI 50 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
103 
Original text with changes shown 
New wording 
Reason/justification for 
change 
challenges in obtaining consistent morning trough FEV1 values 
with best efforts in this young patient population, despite the 
rigorous training and coaching provided by the investigators. 
Therefore, some of the initial assumptions and the sample size 
described above were revised to the following: 
• 
For the superiority comparison of FS MDPI 
50/12.5 mcg twice daily versus Fp MDPI 50 mcg 
twice daily, the SD was revised to 22% and the 
overall mean change from baseline was revised to 
6.5% (blinded SD observed after 427 patients 
completed week 12 of this study (excluding 
IMPD)) and the power down to 80%.  
• 
With these assumptions, 181 patients per 
treatment group are required for the 2-sided test 
of FS MDPI 50/12.5 mcg twice daily and Fp 
MDPI 50 mcg twice daily. 
• 
For the superiority comparison of Fp MDPI 50 
mcg twice daily versus placebo, the SD was 
revised to 17% and overall mean change from 
baseline was 5% (blinded SD observed after 434 
patients completed week 12 of this study 
(excluding IMPD)) and the power was revised to 
80%.  
• 
With these assumptions, 181 patients per 
treatment group are required for the 2-sided test 
of Fp MDPI 50 mcg twice daily versus placebo. 
Assuming a dropout rate of 1512%, then 150206 patients per 
treatment group in the 4 treatment groups, for a total of 
600824 patients, will be randomized. (initial assumption for 
mcg twice daily versus placebo, the SD was 
revised to 17% and overall mean change from 
baseline was 5% (blinded SD observed after 
434 patients completed week 12 of this study 
(excluding IMPD)) and the power was revised 
to 80%.  
• 
With these assumptions, 181 patients per 
treatment group are required for the 2-sided test 
of Fp MDPI 50 mcg twice daily versus placebo. 
Assuming a dropout rate of 12%, then 206 patients per 
treatment group in the 4 treatment groups, for a total of 
824 patients, will be randomized (initial assumption for 
dropout rate was 15%).  


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
104 
Original text with changes shown 
New wording 
Reason/justification for 
change 
dropout rate was 15%). 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
105 
Original text with changes shown 
New wording 
Reason/justification for 
change 
Section 9.2.3 affected by this change: 
The per-protocol (PP) analysis set is a subset of the ITT 
analysis set including only patients without major protocol 
violations and who have >80% compliance to the IMP over the 
entire treatment period. Treatment compliance during the study 
will be assessed based on both data collected in the IMP dose 
counter and diary. Details will be provided in the SAP. Major 
protocol violations will be determined before unblinding. Note 
that since the use of incorrect IMP will be considered a major 
protocol violation, for treatment assignment in the PP analysis 
set, “as randomized” will coincide with “as treated.” 
The per-protocol (PP) analysis set is a subset of the ITT 
analysis set including only patients without major protocol 
violations and who have >80% compliance to the IMP over 
the entire treatment period. Treatment compliance during the 
study will be assessed based on both data collected in the 
IMP dose counter and diary. Details will be provided in the 
SAP. Major protocol violations will be determined before 
unblinding. Note that since the use of incorrect IMP will be 
considered a major protocol violation, for treatment 
assignment in the PP analysis set, “as randomized” will 
coincide with “as treated.” 
Patients compliance might not 
be captured accurately by 
using data from the diary 
alone. Therefore, treatment 
compliance will be assessed 
on both data from the dose 
counter and the diary.  
Section 9.5.4.2 affected by this change: 
•A tipping point analysis will be performed as a sensitivity 
analysis to missing data by utilizing multiple imputations under 
different missing mechanism. For placebo patients, in all 
applications of multiple imputations, missing at random (MAR) 
will be assumed. For the active arms, in the first application, 
MAR will be assumed and the imputations will be drawn from 
data in the corresponding active arms. In subsequent 
applications, shifts to the distribution of the active arms will be 
applied to represent different degrees of effect loss, ie, MNAR 
will be assumed. This analysis will utilize only data collected 
prior to IMP discontinuation. Additional details will be 
provided in the SAP. 
•A tipping point analysis will be performed as a sensitivity 
analysis to missing data by utilizing multiple imputations 
under different missing mechanism. For placebo patients, in 
all applications of multiple imputations, missing at random 
(MAR) will be assumed. For the active arms, in the first 
application, MAR will be assumed and the imputations will 
be drawn from data in the corresponding active arms. In 
subsequent applications, shifts to the distribution of the 
active arms will be applied to represent different degrees of 
effect loss, ie, MNAR will be assumed. This analysis will 
utilize only data collected prior to IMP discontinuation. 
Additional details will be provided in the SAP. 
In response to FDA feedback 
•“2-dimensional tipping point” multiple imputation will be 
performed similar to above, the shifts to the distribution will 
apply to both placebo and active arms, to represent different 
degrees of effect loss. This analysis will utilize only data 
collected prior to IMP discontinuation. Additional details will 
be provided in the SAP. 
•“2-dimensional tipping point” multiple imputation will be 
performed similar to above, the shifts to the distribution will 
apply to both placebo and active arms, to represent different 
degrees of effect loss. This analysis will utilize only data 
collected prior to IMP discontinuation. Additional details 
will be provided in the SAP. 
Adding the 2-dimensional 
tipping point in response to 
FDA feedback   
Section 9.5.4.3 affected by this change: 
Analysis of change from baseline in weekly average of daily 
trough morning PEF, total daily use of albuterol/salbutamol, 
Analysis of change from baseline in weekly average of daily 
trough morning PEF, total daily use of albuterol/salbutamol, 
Text was change to include the 
appropriate statistical analysis. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
106 
Original text with changes shown 
New wording 
Reason/justification for 
change 
and total daily asthma symptom score, and C-ACT score over 
the 12-week treatment period will be analyzed using an 
MMRM analysis with effects due to baseline, sex, age, 
(pooled) investigational center, previous therapy (ICS or NCS), 
treatment, time, and time-by-treatment interaction. 
The change from baseline in C ACT score over the 12 week 
treatment period will be analyzed using an ANCOVA model 
with effects due to sex, age, (pooled) investigational center, 
previous therapy (ICS or NCS), and treatment. Patients who 
drop out or discontinue IMP will be considered as 
nonresponders in this analysis. 
total daily asthma symptom score, and C-ACT score over the 
12-week treatment period will be analyzed using an MMRM 
analysis with effects due to baseline, sex, age, (pooled) 
investigational center, previous therapy (ICS or NCS), 
treatment, time, and time-by-treatment interaction. 
Section 9.6 affected by this change: 
Taking into consideration that this is the very first study that 
utilizes the handheld device in a large Phase 3 study in a 
pediatric asthma patient population (4 to 11 years of age), an 
unplanned blinded sample size reassement was conducted. 
Since the adjustment to sample size was based on blinded 
standard deviation, no adjustment to the multiplicity control is 
warrented. 
Taking into consideration that this is the very first study that 
utilizes the handheld device in a large Phase 3 study in a 
pediatric asthma patient population (4 to 11 years of age), an 
unplanned blinded sample size reassement was conducted. 
Since the adjustment to sample size was based on blinded 
standard deviation, no adjustment to the multiplicity control 
is warrented. 
Increase in number of patients 
enrolled (for details, see 
above) 
 
Appendix A affected by this change: 
 
 
  
Teva Pharmaceuticals 
 
  
Teva Pharmaceuticals 
 
Update title and phone number 
 
 
 
Teva Pharmaceuticals 
 
 
Teva Pharmaceuticals 
 
Update of study personnel 
 
Merckle GmbH 
 
Merckle GmbH 
Updated legal representative 
of the sponsor in the EU 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
107 
Original text with changes shown 
New wording 
Reason/justification for 
change 
Graf-Arco-Str. 3 
89079 Ulm 
Germany 
 
Teva GmbH 
Graf Arco Str. 3 
89079 Ulm 
Germany 
Graf-Arco-Str. 3 
89079 Ulm 
Germany 
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
108 
16.2. 
Letter of Clarification 02 Dated 21 February 2018 
 
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
109 
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
110 
16.3. 
Letter of Clarification 01 Dated 21 September 2017 
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
111 
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
112 
16.4. 
Country-specific (Russia) Amendment 01 Dated 22 May 2017 
The primary reason for this amendment is to respond to feedback from the Ministry of Health 
(MOH) of the Russian Federation. This amendment is considered to be nonsubstantial by the 
sponsor’s Authorized Representative. The protocol is being locally amended to include safety 
and efficacy data on Fp MDPI and FS MDPI in children 12 years of age and older. These 
changes are unlikely to affect the safety or rights (physical or mental integrity) of the patients in 
this clinical study or the scientific value of the clinical study. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
113 
Original text with changes shown 
New wording 
Reason/Justification for change 
APPENDIX B EFFICACY AND SAFETY DATA FOR PHASE 2 AND 3 STUDIES FOR ADOLESCENT PATIENTS (Other section affected by this 
change: Section 1.2) 
New appendix added. 
New appendix added. 
This appendix was added in response to feedback 
from the MOH of the Russian Federation. 
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
114 
16.5. 
Amendment 01 Dated 31 October 2016 
The primary reason for this amendment is to respond to FDA feedback. This amendment is 
considered to be substantial (ie, requires approval by CA, IEC, and/or IRB) by the sponsor’s 
Authorized Representative. Other nonsubstantial changes have been made to the protocol (and 
protocol synopsis, as appropriate). These changes are unlikely to affect the safety or rights 
(physical or mental integrity) of the patients in this clinical study or the scientific value of the 
clinical study. 
Table 3 (Study Procedures and Assessments) has been revised to reflect changes described 
below.


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
115 
Changes to the Protocol 
Original text with changes shown 
New wording 
Reason/justification for 
change 
SECTION 1.1 INTRODUCTION (Other sections affected by this change: Section 3.2, Section 3.3, and Section 5.3.1) 
The proposed Fp dose for study in childrenpatients 4 through 
11 years of age is based on the adult dose-ranging study 
demonstrating efficacy of the 25 and 50 mcg twice daily doses 
that are the same or lower than the currently approved doses of 
FLOVENT DISKUS and ADVAIR® DISKUS® 
(GlaxoSmithKline plc) in pediatric patients. 
The proposed Fp dose for study in patients 4 through 11 
years of age is based on the adult dose-ranging study 
demonstrating efficacy of the 25 and 50 mcg twice daily 
doses that are the same or lower than the currently approved 
doses of FLOVENT DISKUS and ADVAIR® DISKUS® 
(GlaxoSmithKline plc) in pediatric patients. 
This change was made in 
order to use uniform language 
throughout the protocol. 
SECTION 1.3.2 OVERALL BENEFIT AND RISK ASSESSMENT FOR THIS STUDY 
Use of placebo-controlled study design in evaluating ICSs and 
other molecules is commonly used in developing these drug 
products and is required by FDA towards supporting the 
efficacy of the molecule (eg, Kerwin et al 2008, Woodcock et 
al 2013). The design of this study is very similar to other 
pediatric placebo-controlled trials where adverse events in the 
placebo arm were similar to those in the treatment arms. The 
study has been designed to minimize the risks of placebo use to 
the intended population of patients 4 through 11 years of age. 
The patient inclusion and exclusion criteria were selected to 
ensure that patients with severe asthma or history of life-
threatening exacerbations would not be eligible. In this study, 
the patients’ lung function, symptom scores, and rescue 
medication use will be monitored daily with use of a handheld 
device/electronic diary. The handheld device/electronic diary 
will provide alerts to the study center and medical monitor for 
the trial so that patients whose asthma status may be 
deteriorating will be captured early (Section 4.3.2). This will 
minimize the risk and asthma exacerbation as well as any 
discomfort that might come from an exacerbation. 
Additionally, use of the handheld device/electronic diary 
minimizes the burden of requiring patients to travel to the study 
center for monitoring. Patients assigned to placebo therapy 
often demonstrate improvement in lung function, suggesting 
that frequent contact with medical providers may be of benefit. 
Additionally, all patients are provided with rescue 
Use of placebo-controlled study design in evaluating ICSs 
and other molecules is commonly used in developing these 
drug products and is required by FDA towards supporting 
the efficacy of the molecule (eg, Kerwin et al 2008, 
Woodcock et al 2013). The design of this study is very 
similar to other pediatric placebo-controlled trials where 
adverse events in the placebo arm were similar to those in 
the treatment arms. The study has been designed to minimize 
the risks of placebo use to the intended population of patients 
4 through 11 years of age. The patient inclusion and 
exclusion criteria were selected to ensure that patients with 
severe asthma or history of life-threatening exacerbations 
would not be eligible. In this study, the patients’ lung 
function, symptom scores, and rescue medication use will be 
monitored daily with use of a handheld device/electronic 
diary. The handheld device/electronic diary will provide 
alerts to the study center and medical monitor for the trial so 
that patients whose asthma status may be deteriorating will 
be captured early (Section 4.3.2). This will minimize the risk 
and asthma exacerbation as well as any discomfort that 
might come from an exacerbation. Additionally, use of the 
handheld device/electronic diary minimizes the burden of 
requiring patients to travel to the study center for monitoring. 
Patients assigned to placebo therapy often demonstrate 
improvement in lung function, suggesting that frequent 
contact with medical providers may be of benefit. 
This change was made to 
elaborate and expand on the 
benefit-risk text in the 
protocol. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
116 
Original text with changes shown 
New wording 
Reason/justification for 
change 
albuterol/salbutamol for use as needed. Rescue 
albuterol/salbutamol usage will be followed closely for signs of 
deterioration. 
Additionally, all patients are provided with rescue 
albuterol/salbutamol for use as needed. Rescue 
albuterol/salbutamol usage will be followed closely for signs 
of deterioration. 
SECTION 2.2.1 OTHER EFFICACY ENDPOINTS (Other sections affected by this change: Section 6.3, Section 6.3.1, Section 6.3.7, Section 6.3.8, 
Section 6.3.9, and Section 9.5.3) 
• 
Change from baseline in the weekly average of total 
daily (24-hour) use of albuterol/salbutamol inhalation 
aerosol (number of inhalations) at weeks 4, 8, and 12 
and at the last postbaseline observation 
• 
Change from baseline in the weekly average of the 
percent predicted trough morning FEV1 at weeks 1, 2, 
4, and 8, and at the last postbaseline observation  
• 
Proportion of patients who achieve at least a 15% 
increase in morning FEV1 at 1 hour postdose at day 1 
(randomization visit [RV]/treatment visit [TV] 1), 
week 1, and week 12, and at the last postbaseline 
observation 
• 
Change from baseline in asthma control (measured 
by C-ACT) score at weeks 4, 8, and 12 and at the last 
postbaseline observation 
• Change from baseline in the weekly average of total 
daily (24-hour) use of albuterol/salbutamol 
inhalation aerosol (number of inhalations) at weeks 
4, 8, and 12  
• 
Change from baseline in weekly average of the 
percent predicted trough morning FEV1 at 
weeks 1, 2, 4, and 8 
• 
Proportion of patients who achieve at least a 15% 
increase in morning FEV1 at 1-hour postdose at 
day 1 (the RV/TV1), week 1, and week 12 
• 
Change from baseline in asthma control (measured 
by C-ACT) score at weeks 4, 8, and 12 
This change was made to 
remove the last postbaseline 
observation as a time point for 
these other efficacy endpoints 
since it is not a meaningful 
time point for this evaluation. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
117 
Original text with changes shown 
New wording 
Reason/justification for 
change 
SECTION 3.1 GENERAL DESIGN AND STUDY SCHEMATIC DIAGRAM (Other section affected by this change: Appendix B) 
An albuterol/salbutamol hydrofluoroalkane (HFA) metered-
dose inhaler (MDI) (a SABA inhaler) will be provided to 
replace the patient’s current rescue medication and is to be used 
as needed for relief of asthma symptoms during the run-in and 
treatment periods, with a maximum of 812 inhalations 
permitted per day. 
An albuterol/salbutamol hydrofluoroalkane (HFA) metered-
dose inhaler (MDI) (a SABA inhaler) will be provided to 
replace the patient’s current rescue medication and is to be 
used as needed for relief of asthma symptoms during the run-
in and treatment periods, with a maximum of 12 inhalations 
permitted per day. 
This change was made to 
correct the maximum amount 
of inhalations permitted per 
day. 
SECTION 3.1 GENERAL DESIGN AND STUDY SCHEMATIC DIAGRAM (Other section affected by this change: Appendix B) 
At the prescreening or SV, the patient or parent/legal guardian 
must provide informed consent, and patients must give assent 
(as applicable) before any study procedures are performed. At 
the time of informed consent, the parent/legal guardian will be 
counseled that, once randomized to treatment, patients are to 
remain in the study and complete all study procedures unless 
the choice is made to withdraw consent. This includes patients 
who may require alternative asthma therapy, experience an 
adverse event, violate the protocol, or fail to comply with study 
procedures. Continued patient participation is important to 
contribute to the scientific investigation. 
At the prescreening or SV, the patient or parent/legal 
guardian must provide informed consent, and patients must 
give assent (as applicable) before any study procedures are 
performed. At the time of informed consent, the parent/legal 
guardian will be counseled that, once randomized to 
treatment, patients are to remain in the study and complete 
all study procedures unless the choice is made to withdraw 
consent. This includes patients who may require alternative 
asthma therapy, experience an adverse event, violate the 
protocol, or fail to comply with study procedures. Continued 
patient participation is important to contribute to the 
scientific investigation. 
This change was made to 
emphasize that after providing 
consent, patients are expected 
to complete all study 
procedures and visits (unless 
they choose to withdraw 
consent). 
SECTION 3.1 GENERAL DESIGN AND STUDY SCHEMATIC DIAGRAM (Other sections affected by this change: Section 6.1.1 and Appendix B) 
If the patient inadvertently takes the morning IMP dose or 
rescue medication within 6 hours of the planned lung function 
assessments, the visit must be rescheduled so that lung function 
assessments and response to bronchodilator testing can be 
completed as described (other assessments not involving lung 
function may be completed that day). Similarly, patients who 
have been withdrawn from IMP but remain in the study should 
withhold their alternative asthma therapy dosing until after 
treatment visit assessments and avoid rescue medication for a 
minimum of 6 hours prior to clinic lung function assessments. 
The treatment visit should be rescheduled if either or both 
occur. 
If the patient inadvertently takes the morning IMP dose or 
rescue medication within 6 hours of the planned lung 
function assessments, the visit must be rescheduled. 
Similarly, patients who have been withdrawn from IMP but 
remain in the study should withhold their alternative asthma 
therapy dosing until after treatment visit assessments and 
avoid rescue medication for a minimum of 6 hours prior to 
clinic lung function assessments. The treatment visit should 
be rescheduled if either or both occur. 
Text was removed to correct 
that if a patient takes the 
morning IMP dose or rescue 
medication within 6 hours of 
the planned lung function 
assessments, the entire 
treatment visit must be 
rescheduled. 
Text was also added to 
provide instructions on taking 
other medications prior to 
treatment visit assessments for 
patients who have been 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
118 
Original text with changes shown 
New wording 
Reason/justification for 
change 
withdrawn from IMP. 
SECTION 3.1 GENERAL DESIGN AND STUDY SCHEMATIC DIAGRAM (Other sections affected by this change: Section 3.4, Section 3.5 [Table 3, 
footnote h] Section 4.3, Section 6.1.1, and Appendix B) 
At the investigational center, after appropriate instruction and 
training (competent handheld device use and dosing technique 
using the training devices provided), patients will perform their 
lung function assessment (FEV1 and PEF) under the 
supervision of the investigational center staff. They will then 
take their morning dose of the IMP. unless IMP has been 
withdrawn. IMP administration at the investigational center 
should be timed so that lung function assessments will be 
approximately 12 hours following the doses taken the previous 
evening. Patients will then perform 1-hour postdose FEV1 
measurements using the handheld device. Patients who have 
been withdrawn from IMP will be asked to perform 1-hour 
postdose lung function assessments; although the patients will 
not be taking a dose of IMP, the assessment should be 
approximately 1 hour after the predose lung function 
assessments were obtained. For patients who need to 
demonstrate the response to bronchodilator during the run in, 
the RV must be on another day. 
At the investigational center, after appropriate instruction 
and training (competent handheld device use and dosing 
technique using the training devices provided), patients will 
perform their lung function assessment (FEV1 and PEF) 
under the supervision of the investigational center staff. They 
will then take their morning dose of the IMP unless IMP has 
been withdrawn. IMP administration at the investigational 
center should be timed so that lung function assessments will 
be approximately 12 hours following the doses taken the 
previous evening. Patients will then perform 1-hour postdose 
FEV1 measurements using the handheld device. Patients who 
have been withdrawn from IMP will be asked to perform 1-
hour postdose lung function assessments; although the 
patients will not be taking a dose of IMP, the assessment 
should be approximately 1 hour after the predose lung 
function assessments were obtained. 
Text was added to provide 
instructions for performing 
lung function assessments for 
patients who have been 
withdrawn from IMP. 
Text was also removed for 
better flow and to avoid 
redundancy with other 
paragraphs in this section. 
SECTION 3.1 GENERAL DESIGN AND STUDY SCHEMATIC DIAGRAM (Other sections affected by this change: Section 3.5 [Table 3, footnote k], 
Section 4.3.2, Appendix B, and Appendix E) 
In cases where the IMP is to be withdrawn and alternative 
therapy started, the siteinvestigational center staff should 
contact the medical monitor to confirm the findings. 
In cases where the IMP is to be withdrawn and alternative 
therapy started, the investigational center staff should contact 
the medical monitor to confirm the findings. 
This change was made 
because “investigational 
center” is the term preferred 
by the sponsor, rather than 
“site.”  
The term “staff” was added for 
clarity. 
SECTION 3.1 GENERAL DESIGN AND STUDY SCHEMATIC DIAGRAM  
If a patient or patient’s parent/legal guardian elects to 
completely withdraw from the study (ie, withdraw consent) 
prior to the investigator assessment or investigational center 
If a patient or patient’s parent/legal guardian elects to 
completely withdraw from the study (ie, withdraw consent) 
prior to the investigator assessment or investigational center 
This text was added to clarify 
that withdrawing completely 
from the study involves 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
119 
Original text with changes shown 
New wording 
Reason/justification for 
change 
visit, irrespective of the reason for the study discontinuation, 
every attempt will be made to conduct the IMPDV subsequent 
to the patient’s withdrawal from the IMP. 
visit, irrespective of the reason for the study discontinuation, 
every attempt will be made to conduct the IMPDV 
subsequent to the patient’s withdrawal from the IMP. 
withdrawing consent. 
SECTION 3.1 GENERAL DESIGN AND STUDY SCHEMATIC DIAGRAM (Other section affected by this change: Section 7.1.1) 
Asthma worsening including asthma exacerbations with a 
change to alternative asthma therapy, will be recorded as an 
efficacy endpoint and will not be considered an adverse event 
for this study since it is an expected outcome for this study in 
an asthmatic patient population. 
Asthma worsening including asthma exacerbations with a 
change to alternative asthma therapy will not be considered 
an adverse event for this study since it is an expected 
outcome for this study in an asthmatic patient population. 
This text was changed to 
remove incorrect wording. 
SECTION 3.1 GENERAL DESIGN AND STUDY SCHEMATIC DIAGRAM 
This asthma therapy will be recorded in the CRF as 
recommended asthma therapy following IMP discontinuation 
(planned or unplanned). 
This asthma therapy will be recorded in the CRF following 
IMP discontinuation (planned or unplanned). 
This change was made to 
clarify the procedure for 
recording asthma therapy in 
the CRF following IMP 
discontinuation. 
SECTION 3.1 GENERAL DESIGN AND STUDY SCHEDMATIC DIAGRAM (Other sections affected by this change: Section 3.5 [Table 3, foonote g], 
and Appendix B) 
After the last TV (TV6, week 12), the patient will enter the 
follow-up period. One week (±2 days) after the last TV or the 
IMPDV, the patient will have a FV. This FV may be in person 
or over the telephone. The patient will be deemed to have 
completed the treatment period if they have completed all 
periods of the study, including screening, run-in, and all TVs. 
The patient will be deemed to have completed the study period 
if they have completed all periods of the study, including FV in 
addition to screening, run-in, and all TVs. Patients who stop 
IMP and return for safety evaluation at week 12 but who do not 
complete the FV will stillnot be considered to have completed 
the treatment period for the purposes of primary analysis. 
After the last TV (TV6, week 12), the patient will enter the 
follow-up period. One week (±2 days) after the last TV, the 
patient will have a FV. This FV may be in person or over the 
telephone. The patient will be deemed to have completed the 
treatment period if they have completed all periods of the 
study, including screening, run-in, and all TVs. The patient 
will be deemed to have completed the study period if they 
have completed all periods of the study, including FV in 
addition to screening, run-in, and all TVs. Patients who stop 
IMP and return for safety evaluation at week 12 will not be 
considered to have completed the treatment period. 
This change was made to 
reflect that patients who 
discontinue IMP are still 
expected to attend treatment 
visits (although they will not 
be given IMP).  
Text was also revised to 
correct which patients will not 
be considered to have 
completed the treatment 
period. 
SECTION 3.4 EARLY STOPPING RULES  
A patient may discontinue participation in the study at any time 
for any reason (eg, lack of efficacy,by withdrawal of consent, 
and adverse event); every effort should be undertaken to find 
A patient may discontinue participation in the study at any 
time for any reason by withdrawal of consent; every effort 
should be undertaken to find out the reason for 
These changes were made to 
correct the reasons for 
discontinuing participation in 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
120 
Original text with changes shown 
New wording 
Reason/justification for 
change 
out the reason for discontinuation.  
discontinuation.  
the study. 
SECTION 3.4 EARLY STOPPING RULES (Other section affected by these changes: Section 4.3) 
The investigator or sponsor can withdraw a patient from the 
study IMP at any time for any reason (eg, protocol violation or 
deviation as defined in Appendix C, noncompliance, or adverse 
event). However, patients that do not withdraw consent should 
remain in the study (as counseled during the informed consent 
process) and complete the remaining study procedures and 
visits, with the exception of IMP dosing.  
The investigator or sponsor can withdraw a patient from the 
study IMP at any time for any reason (eg, protocol violation 
or deviation as defined in Appendix C, noncompliance, or 
adverse event). However, patients that do not withdraw 
consent should remain in the study (as counseled during the 
informed consent process) and complete the remaining study 
procedures and visits, with the exception of IMP dosing.  
These changes were made to 
emphasize that patients who 
discontinue study IMP should 
still participate in study 
procedures and visits. 
SECTION 3.5 SCHEDULE OF STUDY PROCEDURES AND ASSESSMENTS (TABLE 3) 
Allowed time windows: 
TV2: Day 8±2 days 
TV3: Day 15±2 days 
TV4: Day 29±2 days 
TV5: Day 57±2 days 
TV6: Day 85±2 days 
FV: Day 92±2 days 
Allowed time windows: 
TV2: Day 8±2 days 
TV3: Day 15±2 days 
TV4: Day 29±2 days 
TV5: Day 57±2 days 
TV6: Day 85±2 days 
FV: Day 92±2 days 
This change was made to 
include the days of the study 
visits, where applicable. 
SECTION 3.5 SCHEDULE OF STUDY PROCEDURES AND ASSESSMENTS (TABLE 3) 
Perform lung function assessments (FEV1 and PEF) by 
handheld device 1-hour postdose at the investigational center 
Perform lung function assessments (FEV1) by handheld 
device 1-hour postdose at the investigational center 
This change was made to 
correct that PEF will not be 
performed as a 1-hour 
postdose lung function 
assessment. 
SECTION 3.5 SCHEDULE OF STUDY PROCEDURES AND ASSESSMENTS (TABLE 3, FOOTNOTE B) 
The RV may occur up to 30 days following the SV. The 
patient’s home FEV1 by handheld device should be reviewed, 
and the average of the 5 most recent highest daily values (3 
attempts) for trough morning FEV1 over the 7 days prior to RV 
must be 40% to 85% predicted for age, height, sex and race 
(Quanjer et al 2012) with asthma symptom criteria, the C-ACT 
score must be ≤19 to be eligible for randomization. The patient 
The RV may occur up to 30 days following the SV. The 
patient’s home FEV1 by handheld device should be 
reviewed, and the average of the 5 most recent highest daily 
values (3 attempts) for trough morning FEV1 over the 7 days 
prior to RV must be 40% to 85% predicted for age, height, 
sex and race (Quanjer et al 2012) with asthma symptom 
criteria, the C-ACT score must be ≤19 to be eligible for 
This change was made to 
clarify that 2 different 
randomization identification 
numbers will be assigned at 
SV and at RV. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
121 
Original text with changes shown 
New wording 
Reason/justification for 
change 
must also meet the lung function assessment requirements at 
the investigational center and all other study criteria. Assign 
Eligible patients will be assigned a patient randomization 
identification number via the IRT system unless already 
completedthat is different than the one received at a 
prescreening visitscreening. 
randomization. The patient must also meet the lung function 
assessment requirements at the investigational center and all 
other study criteria. Eligible patients will be assigned a 
patient randomization identification number via the IRT 
system that is different than the one received at screening. 
SECTION 3.5 SCHEDULE OF STUDY PROCEDURES AND ASSESSMENTS (TABLE 3, FOOTNOTE E) 
Evidence of oropharyngeal candidiasis at any study TV or end 
of study TV should be evaluated by obtaining a swab for 
culture. Patients who agree to treatment may continue in the 
study.to receive IMP. 
Evidence of oropharyngeal candidiasis at any study TV or 
end of study TV should be evaluated by obtaining a swab for 
culture. Patients who agree to treatment may continue to 
receive IMP. 
This change was made to 
clarify that patients who 
receive treatment for 
oropharyngeal candidiasis 
may continue receiving IMP. 
SECTION 3.5 SCHEDULE OF STUDY PROCEDURES AND ASSESSMENTS (TABLE 3, FOOTNOTE G) 
The patient will be instructed to perform 3 trough morning 
FEV1 maneuvers and 3 evening FEV1 maneuvers at home each 
day during participation in the run-in period and the treatment 
period (morning only on the final TV [TV6 (week 12) or 
IMPDV]).)]). The highest FEV1 obtained at the SV will be used 
to calculate the home FEV1 stability limit, which will be used 
for review of alert criteria during the run-in period. The average 
FEV1 over 5 days prior to RV will be used to calculate the alert 
criteria for the treatment period. 
The patient will be instructed to perform 3 trough morning 
FEV1 maneuvers and 3 evening FEV1 maneuvers at home 
each day during participation in the run-in period and the 
treatment period (morning only on the final TV [TV6 (week 
12)]). The highest FEV1 obtained at the SV will be used to 
calculate the home FEV1 stability limit, which will be used 
for review of alert criteria during the run-in period. The 
average FEV1 over 5 days prior to RV will be used to 
calculate the alert criteria for the treatment period. 
This text was changed to 
clarify that patients will 
continue to participate in study 
visits and procedures even 
after discontinuing IMP. 
Text was also added to clarify 
how the alert criteria will be 
calculated. 
SECTION 3.5 SCHEDULE OF STUDY PROCEDURES AND ASSESSMENTS (TABLE 3, FOOTNOTE M) 
End of study participation in the IRT system will take place at 
the last visit during the treatment period (ie, at TV6 for patients 
who complete the treatment period, or at the IMPDV for 
patients who discontinue the study prematurely [patients who 
withdraw consent]). 
End of study participation in the IRT system will take place 
at the last visit during the treatment period (ie, at TV6 for 
patients who complete the treatment period, or at the IMPDV 
for patients who discontinue the study prematurely [patients 
who withdraw consent]). 
This change was made to 
clarify the reason for 
discontinuing the study. 
SECTION 4.2 PATIENT EXCLUSION CRITERIA 
b. The patient is pregnant or lactating or plans to 
become pregnant during the study period or within 30 
days after the patient’s last study-related visit (for 
b. 
The patient is pregnant or lactating or plans to 
become pregnant during the study period or within 
30 days after the patient’s last study-related visit 
These changes were made to 
remove exclusion criterion 
that are not relevant. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
122 
Original text with changes shown 
New wording 
Reason/justification for 
change 
eligible patients only and if applicable). Any patient 
who becomes pregnant during the study will be 
withdrawn from the study.  
d. The patient has previously participated as a 
randomized patient in an Fp MDPI or FS MDPI 
study.  
(for eligible patients only and if applicable). 
SECTION 4.2 PATIENT EXCLUSION CRITERIA  
k. The patient has used immunosuppressive medications 
within 4 weeks30 days before the SV. 
k. 
The patient has used immunosuppressive 
medications within 30 days before the SV. 
This change was made for 
consistency throughout the 
protocol. 
SECTION 4.3 WITHDRAWAL CRITERIA AND PROCEDURES FOR THE PATIENT 
In accordance with the Declaration of Helsinki (in accordance 
with the applicable country’s acceptance), each patient 
(parent/legal guardian) is free to withdraw from the study at 
any time. The investigator also has the right to withdraw a 
patient from the study in the event of serious intercurrent 
illness, adverse events, pregnancy (see Section 7.2), or other 
reasons concerning the health or well-being of the patient, or in 
the event of repeated and documented lack of cooperation 
In accordance with the Declaration of Helsinki (in 
accordance with the applicable country’s acceptance), each 
patient (parent/legal guardian) is free to withdraw from the 
study at any time. The investigator also has the right to 
withdraw a patient from the study in the event of serious 
intercurrent illness, pregnancy (see Section 7.2), or other 
reasons concerning the health or well-being of the patient, or 
in the event of repeated and documented lack of cooperation 
This change was made to 
clarify that the parent/legal 
guardian of the patient may 
withdraw the patient from the 
study. 
Changes were also made to the 
text to clarify the 
circumstances under which the 
investigator may wish to 
withdraw a patient from the 
study. 
SECTION 4.3 WITHDRAWAL CRITERIA AND PROCEDURES FOR THE PATIENT 
Should a patient (parent/legal guardian) decide to withdraw 
after administration of IMP(s), or should the investigator decide 
to withdraw the patient, all efforts will be made to complete 
and report all observations up to the time of withdrawal. A 
complete final evaluation at the time of the patient’s 
withdrawal should be made and an explanation given as to why 
the patient is withdrawing or being withdrawn from the study. 
The reason for and date of withdrawal from the study must be 
recorded on the source documentation and transcribed to the 
Should a patient (parent/legal guardian) decide to withdraw 
after administration of IMP, all efforts will be made to 
complete and report all observations up to the time of 
withdrawal. A complete final evaluation at the time of the 
patient’s withdrawal should be made and an explanation 
given as to why the patient is withdrawing from the study. 
The reason for and date of withdrawal from the study must 
be recorded on the source documentation and transcribed to 
the CRF. If a patient withdraws consent, every attempt will 
These changes to the text were 
made to clarify the 
circumstances under which a 
patient may withdraw from the 
study. 
This text was also changed to 
reflect that laboratory tests 
will not be performed during 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
123 
Original text with changes shown 
New wording 
Reason/justification for 
change 
CRF. If a patient withdraws consent, every attempt will be 
made to determine the reason. If the reason for 
withdrawalconsent is withdrawn because of an adverse event or 
a clinically significant abnormal laboratory test result, 
monitoring will be continued at the discretion of the 
investigator (eg, until the event has resolved or stabilized, until 
the patient is referred to the care of a health care professional, 
or until a determination of a cause unrelated to the IMP or 
study procedure is made). 
be made to determine the reason. If consent is withdrawn 
because of an adverse event, monitoring will be continued at 
the discretion of the investigator (eg, until the event has 
resolved or stabilized, until the patient is referred to the care 
of a health care professional, or until a determination of a 
cause unrelated to the IMP or study procedure is made). 
this study. 
SECTION 5.9 RANDOMIZATION AND BLINDING 
Patients who meet all randomization criteria at the RV will be 
stratified by previous therapy (ICS or NCS) and randomly 
assigned into a 1:1:1:1 ratio to receive Fp MDPI 25 mcg, Fp 
MDPI 50 mcg, FS MDPI 50/12.5 mcg, or placebo MDPI, twice 
daily, for the entire treatment period. Randomization will be 
assigned via IRT. Patients being treated with a combination of 
ICS/NCS will be stratified as an ICS patient. 
Patients who meet all randomization criteria at the RV will 
be stratified by previous therapy (ICS or NCS) and randomly 
assigned into a 1:1:1:1 ratio to receive Fp MDPI 25 mcg, Fp 
MDPI 50 mcg, FS MDPI 50/12.5 mcg, or placebo MDPI, 
twice daily, for the entire treatment period. Randomization 
will be assigned via IRT. Patients being treated with a 
combination of ICS/NCS will be stratified as an ICS patient. 
This change was made to add 
detail about stratification 
procedures. 
SECTION 5.10.1 MAINTENANCE OF RANDOMIZATION 
Patient randomization codes will be maintained in a secure 
location at the service provider contracted to generate the 
codes. 
Patient randomization codes will be maintained in a secure 
location at the service provider. 
This change was made to 
clarify the location of the 
patient randomization codes. 
SECTION 6.3 OTHER EFFICACY MEASURES 
• 
FEV1 will be measured by the patient (with assistance 
from the parents/legal guardians/caregivers, as 
neededclinic staff) with a handheld device in the clinic 
before administration of IMP or rescue medications at the 
morning evaluation on weeks 1, 2, 4, and 8 and the last 
postbaseline observation.8, and 12. The change from 
baseline in 1-hour postdose percent predicted morning 
FEV1 at week 1 and in the weekly average of percent 
predicted trough morning FEV1 will be calculated based on 
information recorded in the daily patient diary built into 
the handheld device by the patient (with assistance from 
the parents/legal guardians/caregivers, as needed).based on 
• 
FEV1 will be measured by the patient (with assistance 
from the clinic staff) with a handheld device in the clinic 
before administration of IMP or rescue medications at 
the morning evaluation on weeks 1, 2, 4, 8, and 12. The 
change from baseline in 1-hour postdose percent 
predicted morning FEV1 at week 1 and in the weekly 
average of percent predicted trough morning FEV1 will 
be based on the measurements obtained in the clinic. 
These changes were made to 
clarify the procedures for 
measuring FEV1 and to 
emphasize that the endpoints 
involving FEV1 will be based 
on measurements taken in the 
clinic. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
124 
Original text with changes shown 
New wording 
Reason/justification for 
change 
the measurements obtained in the clinic. 
SECTION 7.1.1 DEFINITION OF AN ADVERSE EVENT 
AsthmaFor the purpose of this study, an asthma exacerbation is 
defined as any worsening of asthma requiring any significant 
treatment other than IMP and study rescue albuterol 
(salbutamol) or the patient’s regular ICS 
maintenancemedication. Significant treatment. As includes the 
use of systemic corticosteroids and/or the addition of other 
ICS-containing asthma medications, LABAs, or other NCS 
asthma medications, for example, inhaled short-acting 
muscarinic antagonist, ER/urgent care clinic visit(s), or 
hospitalization. Note: A single dose of nebulized 
albuterol/salbutamol would not meet the criteria for an asthma 
exacerbation. ER/urgent care clinic visits where the treatment is 
limited to a single dose of nebulized albuterol/salbutamol will 
not meet the criteria of an asthma exacerbation. 
Asthma exacerbation that requires a change in medication or 
worsening of asthma that requires the patient to be treated with 
alternative therapy will be entered into the case report form 
(CRF), including the date at which any medication change was 
made and whether this medication change was implemented 
prior to or after the IMPDV lung function assessments (FEV1 
and PEF) were completed. Asthma worsening, including 
asthma exacerbations arewith a change to alternative asthma 
therapy, will be recorded separately in the CRFs,as an asthma 
exacerbation isefficacy endpoint and will not be considered an 
adverse event unlessfor this study since it meets the definition 
ofis an expected outcome for this study in an asthmatic patient 
population. Asthma exacerbations that meet the criteria for a 
serious adverse event. will be recorded as adverse events.  
Any occurrence of oropharyngeal candidiasis that is confirmed 
by culture during the study will be reported as an adverse 
event. A patient who agrees to be treated may continue in the 
study at the discretion of the investigator. 
For the purpose of this study, an asthma exacerbation is 
defined as worsening of asthma requiring any significant 
treatment other than IMP and study rescue medication. 
Significant treatment includes the use of systemic 
corticosteroids and/or the addition of other ICS-containing 
asthma medications, LABAs, or other NCS asthma 
medications, for example, inhaled short-acting muscarinic 
antagonist, ER/urgent care clinic visit(s), or hospitalization. 
Note: A single dose of nebulized albuterol/salbutamol would 
not meet the criteria for an asthma exacerbation. ER/urgent 
care clinic visits where the treatment is limited to a single 
dose of nebulized albuterol/salbutamol will not meet the 
criteria of an asthma exacerbation. 
Asthma exacerbation that requires a change in medication or 
worsening of asthma that requires the patient to be treated 
with alternative therapy will be entered into the case report 
form (CRF), including the date at which any medication 
change was made and whether this medication change was 
implemented prior to or after the IMPDV lung function 
assessments (FEV1 and PEF) were completed. Asthma 
worsening, including asthma exacerbations with a change to 
alternative asthma therapy, will be recorded as an efficacy 
endpoint and will not be considered an adverse event for this 
study since it is an expected outcome for this study in an 
asthmatic patient population. Asthma exacerbations that 
meet the criteria for a serious adverse event will be recorded 
as adverse events.  
Any occurrence of oropharyngeal candidiasis that is 
confirmed by culture during the study will be reported as an 
adverse event. A patient who agrees to be treated may 
continue in the study at the discretion of the investigator. 
These changes were made so 
that the language describing 
asthma exacerbation in this 
section is consistent with 
Section 3.1. 
Text was also added to discuss 
the occurrence of 
oropharyngeal candidiasis in 
greater detail. 
SECTION 7.1.3 SEVERITY OF ADVERSE EVENT 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
125 
Original text with changes shown 
New wording 
Reason/justification for 
change 
The severity of each adverse event must be recorded as 1 of the 
following: 
Mild: 
No limitation of usual activities 
Moderate: Some limitation of usual activities 
Severe: Inability to carry out usual activities 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not indicated 
Grade 2: 
Moderate; minimal, local intervention or 
noninvasive intervention indicated; limiting age appropriate 
instrumental activities of daily living (ADL) (eg, preparing 
meals, shopping for groceries or clothes, using the telephone, 
managing money) 
Grade 3: 
Severe or medically significant but not 
immediately life threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self care ADL 
(eg, bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden) 
Grade 4: 
Life threatening consequences; urgent 
intervention indicated 
Grade 5: 
Death related to adverse event 
 
The severity of each adverse event must be recorded as 1 of 
the following: 
Mild: 
No limitation of usual activities 
Moderate: Some limitation of usual activities 
Severe: Inability to carry out usual activities 
 
This change was made to 
remove text that is not relevant 
to this study. 
SECTION 7.1.8 PROTOCOL DEVIATIONS BECAUSE OF AN ADVERSE EVENT 
The investigator, in consultation with the sponsor, will decide 
whether the patient should continue to participatereceive study 
IMP, continue in the study on alternative treatment, or be 
withdrawn from the study in the interest of patient safety. 
The investigator, in consultation with the sponsor, will 
decide whether the patient should continue to receive study 
IMP, continue in the study on alternative treatment, or be 
withdrawn from the study in the interest of patient safety. 
These changes were made to 
clarify the options available to 
the investigator for patients 
who experience a protocol 
deviation because of an 
adverse event. 
SECTION 7.3 MEDICATION ERROR AND SPECIAL SITUATIONS RELATED TO THE INVESTIGATIONAL MEDICINAL PRODUCT (Other 
section affected by these changes: Appendix C) 
Any administration of IMP that is not in accordance with the 
study protocol should be reported on the CRF either as a 
violation, if it meets the violation criteria specified in the 
Any administration of IMP that is not in accordance with the 
study protocol should be reported either as a violation, if it 
meets the violation criteria specified in the protocol 
This text was changed to 
reflect that protocol violations 
will no longer be captured in 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
126 
Original text with changes shown 
New wording 
Reason/justification for 
change 
protocol (Appendix C), or as a deviation, in the patient’s source 
documents, regardless of whether or not an adverse event 
occurs as a result. When meeting protocol violation criteria, all 
instances of incorrect IMP administration should be categorized 
on the CRF as “Non-Compliance to investigational medicinal 
product (IMP).”  
The following are types of medication errors and special 
situations, as reported by the investigator: 
1. Medication error: Any unintentional error in 
the prescribing, dispensing, or administration 
of a medicinal product while in the control of 
the healthcare professional, patient, or 
consumer. 
2. Overdose: Administration of a quantity of a medicinal 
product given per administration or cumulatively 
which is above the maximum recommended dose 
according to the authorized product information. 
Clinical judgment should always be applied. Any dose 
of IMP (whether the test IMP, reference IMP, or 
placebo IMP), whether taken intentionally or 
unintentionally, in excess of that prescribed must be 
immediately reported to the sponsor. 
When the identification of the IMP is required, the 
investigator must follow the procedures for unblinding 
outlined in Section . 
3. Misuse: Situations where the IMP is intentionally and 
inappropriately used not in accordance with the 
authorized product information. 
4. Abuse: Persistent or sporadic, intentional excessive 
use of IMP which is accompanied by harmful physical 
or psychological effects. 
5. Off-label use: Situations where an IMP is intentionally 
used for a medical purpose not in accordance with the 
(Appendix C), or as a deviation, in the patient’s source 
documents, regardless of whether or not an adverse event 
occurs as a result. When meeting protocol violation criteria, 
all instances of incorrect IMP administration should be 
categorized as “Non-Compliance to investigational 
medicinal product (IMP).” 
The following are types of medication errors and special 
situations, as reported by the investigator: 
1. Medication error: Any unintentional error in 
the prescribing, dispensing, or administration 
of a medicinal product while in the control of 
the healthcare professional, patient, or 
consumer. 
2. Overdose: Administration of a quantity of a 
medicinal product given per administration or 
cumulatively which is above the maximum 
recommended dose according to the authorized 
product information. Clinical judgment should 
always be applied. Any overdose of IMP (whether 
the test IMP, reference IMP, or placebo IMP), 
whether taken intentionally or unintentionally, in 
excess of that prescribed must be immediately 
reported to the sponsor. 
3. Abuse: Persistent or sporadic, intentional excessive 
use of IMP which is accompanied by harmful 
physical or psychological effects. 
4. Off-label use: Situations where an IMP is 
intentionally used for a medical purpose not in 
accordance with the authorized product information. 
5. Occupational exposure: Exposure to an IMP as a 
result of one’s professional or nonprofessional 
occupation. 
6. Breastfeeding: Suspected adverse reactions which 
the CRF. 
This text was also changed to 
incorporate updated template 
language from the sponsor 
regarding medication errors. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
127 
Original text with changes shown 
New wording 
Reason/justification for 
change 
authorized product information. 
6. Occupational exposure: Exposure to an IMP as a 
result of one’s professional or non professional 
occupation. 
7. Breastfeeding: Suspected adverse reactions which 
occur in infants following exposure to a medicinal 
product from breast milk. 
When the identification of the IMP is required, the investigator 
must follow the procedures for unblinding outlined in 
Section 5.10.2. 
occur in infants following exposure to a medicinal 
product from breast milk. 
When the identification of the IMP is required, the 
investigator must follow the procedures for unblinding 
outlined in Section 5.10.2. 
SECTION 7.4.1 SERUM CHEMISTRY, HEMATOLOGY, AND URINALYSIS 
Clinical laboratory tests (serum chemistry, hematology and 
coagulation, urinalysis), if needed at the discretion of the 
investigator, may be performed during the trial.  
None 
This section was removed 
from the protocol because it is 
not relevant to the study. 
SECTION 7.4.2. OTHER CLINICAL LABORATORY TESTS 
Other clinical laboratory tests will be performed as needed to 
ensure the safety of the patients. 
None 
This section was removed 
from the protocol because it is 
not relevant to the study. 
SECTION 7.7 OROPHARYNGEAL EXAMINATIONS 
Oropharyngeal examinations will be performed at every visit 
(SV through TV6). The examination must be performed by a 
qualified healthcare professional. Whenever possible, the same 
qualified healthcare professional should complete the 
assessment for the same patient throughout that patient’s 
participation in the study.  
Patients with clinical visual evidence of oral candidiasis at SV 
who agree to receive treatment and comply with appropriate 
medical monitoring may participate in the run-in period and 
may return for randomization. However, if the oral candidiasis 
is not controlled at that time, the patient will not be allowed to 
enter the study treatment period.  
Any visual evidence of oral candidiasis during the treatment 
period of the study (after RV through TV6, inclusive) will be 
Oropharyngeal examinations will be performed at every visit 
(SV through TV6). The examination must be performed by a 
qualified healthcare professional. Whenever possible, the 
same qualified healthcare professional should complete the 
assessment for the same patient throughout that patient’s 
participation in the study.  
Patients with clinical visual evidence of oral candidiasis at 
SV who agree to receive treatment and comply with 
appropriate medical monitoring may participate in the run-in 
period and may return for randomization. However, if the 
oral candidiasis is not controlled at that time, the patient will 
not be allowed to enter the study treatment period.  
Any visual evidence of oral candidiasis during the treatment 
period of the study (after RV through TV6, inclusive) will be 
This text was added to provide 
a detailed description of 
oropharyngeal examinations to 
the protocol. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
128 
Original text with changes shown 
New wording 
Reason/justification for 
change 
evaluated by obtaining and analyzing a swab of the suspect 
area. Appropriate therapy should be initiated immediately at the 
discretion of the investigator and should not be delayed for 
culture confirmation.  
Patients with a culture-positive infection may continue 
participation in the study on appropriate anti-infective therapy, 
provided this therapy is not prohibited by the protocol. Azole 
antifungal medications are prohibited. If a patient requires a 
protocol-prohibited medication for therapy, the patient will be 
discontinued from the study and provided appropriate therapy.  
 
evaluated by obtaining and analyzing a swab of the suspect 
area. Appropriate therapy should be initiated immediately at 
the discretion of the investigator and should not be delayed 
for culture confirmation.  
Patients with a culture-positive infection may continue 
participation in the study on appropriate anti-infective 
therapy, provided this therapy is not prohibited by the 
protocol. Azole antifungal medications are prohibited. If a 
patient requires a protocol-prohibited medication for therapy, 
the patient will be discontinued from the study and provided 
appropriate therapy.  
SECTION 9.2.2 Modified Intent-to-Treat Analysis Set (Other section affected by these changes: Section 9.4.1) 
The modified intent to treat (mITT) analysis set will include all 
patients in the ITT population and will include the available 
data for those patients until they discontinue IMP.  
The mITT analysis set will serve as the main analysis set for 
the primary, secondary, and other efficacy endpoints. 
None 
This section was removed 
because the mITT analysis set 
will no longer be used for 
analysis in this study. 
SECTION 9.4.2 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Patient demographics will be presented for all 43 analysis sets 
defined in Section 9.2. 
Patient demographics will be presented for all 3 analysis sets 
defined in Section 9.2. 
The number of analysis sets 
was corrected. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
129 
Original text with changes shown 
New wording 
Reason/justification for 
change 
SECTION 9.5.4 PLANNED METHOD OF ANALYSIS (Other section affected by these changes: Section 9.2.1) 
The mITTITT analysis set (Section 9.2.1) will be the primary 
analysis set to be used for all efficacy analyses. The ITT 
analysis set will serve as the supportive analysis set for all 
efficacy analyses. The PP analysis set will serve as the 
supportivesensitivity analysis set for primary efficacy analyses 
only. Details will be provided in the statistical analysis plan. 
Subgroup (sex, age group, previous therapy [ICS or NCS], and 
race) analyses will be provided for the primary efficacy 
endpoints. 
The ITT analysis set (Section 9.2.1) will be the primary 
analysis set to be used for all efficacy analyses. The PP 
analysis set will serve as the sensitivity analysis set for 
primary efficacy analyses only. Details will be provided in 
the statistical analysis plan. Subgroup (sex, age group, 
previous therapy [ICS or NCS], and race) analyses will be 
provided for the primary efficacy endpoints. 
This text was revised to reflect 
that the ITT analysis set will 
be the primary analysis set for 
efficacy analyses, since the 
mITT analysis set will no 
longer be used in this study. 
SECTION 9.5.4.1 PRIMARY ESTIMANDS AND EFFICACY ANALYSIS 
The specific estimands selected for the 2 primary endpoints 
will assess the change from baseline due to the initially 
randomized treatment as actually taken. These estimands assess 
the effectiveness at week 12, focusing on the causal effects 
attributable to the initially randomized medication. The sponsor 
will make all efforts to avoid study withdrawal in this 12-week 
study. In instances where a patient decides to discontinue IMP 
or, more importantly, requires alternative therapy for worsening 
asthma or an asthma exacerbation, the investigators will be 
instructed to encourage the patient to continue in the study and 
return for planned visits in order to collect data after IMP 
discontinuation.  
The question of whether to use data collected after IMP 
discontinuation is an ongoing debate in statistical literature, in 
particular for studies with symptomatic endpoints and when it 
is common for patients who dropout to switch therapies (Little 
and Kang 2015, Mallinckrodt et al 2016, Mallinckrodt 2013, 
O’Neill and Temple 2012). This study is designed as a placebo-
controlled study and it is expected that patients randomized to 
placebo would discontinue IMP due to worsening asthma at a 
higher rate than those randomized to active treatment, which is 
known to be an efficacious drug as established by multiple 
studies. After a patient discontinues IMP due to worsening 
asthma, the patient will be placed on alternative asthma 
The specific estimands selected for the 2 primary endpoints 
will assess the change from baseline due to the initially 
randomized treatment as actually taken. These estimands 
assess the effectiveness at week 12, focusing on the causal 
effects attributable to the initially randomized medication. 
The sponsor will make all efforts to avoid study withdrawal 
in this 12-week study. In instances where a patient decides to 
discontinue IMP or, more importantly, requires alternative 
therapy for worsening asthma or an asthma exacerbation, the 
investigators will be instructed to encourage the patient to 
continue in the study and return for planned visits in order to 
collect data after IMP discontinuation.  
The question of whether to use data collected after IMP 
discontinuation is an ongoing debate in statistical literature, 
in particular for studies with symptomatic endpoints and 
when it is common for patients who dropout to switch 
therapies (Little and Kang 2015, Mallinckrodt et al 2016, 
Mallinckrodt 2013, O’Neill and Temple 2012). This study is 
designed as a placebo-controlled study and it is expected that 
patients randomized to placebo would discontinue IMP due 
to worsening asthma at a higher rate than those randomized 
to active treatment, which is known to be an efficacious drug 
as established by multiple studies. After a patient 
discontinues IMP due to worsening asthma, the patient will 
These changes were made to 
update the primary efficacy 
analysis in response to FDA 
feedback. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
130 
Original text with changes shown 
New wording 
Reason/justification for 
change 
therapies, such as systemic corticosteroids, additional 
medications containing ICS, or both, which would alter the 
spirometry collected after that point and therefore not be 
appropriate for assessment of IMP effectiveness. Improvement 
of asthma would be expected as rapidly and early as 1 week for 
FEV1 for placebo patients placed on ICS (Szefler et al 1999). It 
has also been shown that patients placed on ICS with long 
acting beta-agonists can have significant improvement in serial 
FEV1 measurements on the same day (Corren et al 2007, 
Pearlman et al 1999). Therefore, any patient who discontinued 
IMP and was placed on alternative therapies would be expected 
to have rapid and demonstrable improvements in lung function 
approximating or exceeding the levels measured at screening.  
The inclusion of patients who failed therapy and who were then 
treated with alternative medication would blunt the treatment 
effect, potentially causing the study to fail due to the analysis 
rather than the effectiveness of the treatment given during the 
study. These patients no longer represent a true placebo 
population and including them in the population for the primary 
outcome is not consistent with treatment by placebo. In light of 
this, retrieved dropout data will be used only for sensitivity 
analyses. Missing data for patients who discontinue IMP will 
be imputed using reference-based multiple imputations 
representing a missing not at random (MNAR) mechanism. 
This approach is discussed in Mallinckrodt et al 2016Change 
from Baseline in Weekly Average of the Percent Predicted 
Trough Morning FEV1 at Week 12 (Sections 3.2 and 3.4 for 
estimand 2 in the paper). 
Analysis of the change from baseline in weekly average of 
the percent predicted trough morning FEV1 at week 12 
The baseline percent predicted FEV1 will be the weekly 
average of the morning FEV1 prior to the first IMP dose. The 
first day before randomization consists of the entry on the 
morning of the RV in the patient diary built into the handheld 
device. The weekly average of the percent predicted FEV1 at 
week 12 will be the average values based on the available data 
at that week. 
be placed on alternative asthma therapies, such as systemic 
corticosteroids, additional medications containing ICS, or 
both, which would alter the spirometry collected after that 
point and therefore not be appropriate for assessment of IMP 
effectiveness. Improvement of asthma would be expected as 
rapidly and early as 1 week for FEV1 for placebo patients 
placed on ICS (Szefler et al 1999). It has also been shown 
that patients placed on ICS with long acting beta-agonists 
can have significant improvement in serial FEV1 
measurements on the same day (Corren et al 2007, Pearlman 
et al 1999). Therefore, any patient who discontinued IMP 
and was placed on alternative therapies would be expected to 
have rapid and demonstrable improvements in lung function 
approximating or exceeding the levels measured at 
screening.  
The inclusion of patients who failed therapy and who were 
then treated with alternative medication would blunt the 
treatment effect, potentially causing the study to fail due to 
the analysis rather than the effectiveness of the treatment 
given during the study. These patients no longer represent a 
true placebo population and including them in the population 
for the primary outcome is not consistent with treatment by 
placebo. In light of this, retrieved dropout data will be used 
only for sensitivity analyses. Missing data for patients who 
discontinue IMP will be imputed using reference-based 
multiple imputations representing a missing not at random 
(MNAR) mechanism. This approach is discussed in 
Mallinckrodt et al 2016 (Sections 3.2 and 3.4 for estimand 2 
in the paper). 
Analysis of the change from baseline in weekly average of 
the percent predicted trough morning FEV1 at week 12 
The baseline percent predicted FEV1 will be the weekly 
average of the morning FEV1 prior to the first IMP dose. The 
first day before randomization consists of the entry on the 
morning of the RV in the patient diary built into the 
handheld device. The weekly average of the percent 
predicted FEV1 at week 12 will be the average values based 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
131 
Original text with changes shown 
New wording 
Reason/justification for 
change 
The primary analysis of the change from baseline in weekly 
average of percent predicted morning FEV1 at week 12 due to 
the initially randomized treatment as actually taken will be 
analyzed using an analysis of covariance (ANCOVA) model 
with effects due to baseline percent predicted trough morning 
FEV1, sex, age, (pooled) investigational center, previous 
therapy (ICS or NCS), and IMP treatment group. Contrasts for 
pairwise treatment comparisons of interest will be constructed. 
The estimated treatment difference between each IMP 
treatment group and the placebo group will be presented 
together with the 2-sided 95% confidence interval (CI) for the 
difference and the p-value.  
In this analysis, missing data for the primary endpoint that are 
caused by early dropouts from the study or from IMP 
(regardless of availability of retrieved dropout data) will be 
handled by penalizing a positive imputed using reference-based 
multiple imputations. Details on the implementation of the 
multiple imputations will be provided in the statistical analysis 
plan. 
Analysis of the change from baseline in 1-hour postdose 
percent predicted FEV1 score using a baseline observation 
carried forward method. This method will assign these patients 
a change from baseline percent predicted FEV1 score of 0; thus, 
the discontinued patients are treated as failures and are assigned 
a poor score. Discontinued patients that have negative change 
from baseline with last nonmissing percent predicted FEV1 
score will not have their results adjusted, since their scores are 
already poor. The same adjustment will be made for patients 
who discontinue IMP but continued the study assessment using 
the last assessment prior to discontinuation of IMPmorning 
FEV1 at week 12. No adjustments will be made to other 
patients.  
A supporting analysis of change from baseline in the weekly 
average of percent predicted trough morning FEV1 over the 
12 week treatment period will be performed using a mixed 
model for repeated measures (MMRM). 
Change from Baseline in 1 hour Postdose Percent Predicted 
on the available data at that week. 
The primary analysis of the change from baseline in weekly 
average of percent predicted morning FEV1 at week 12 due 
to the initially randomized treatment as actually taken will be 
analyzed using an analysis of covariance (ANCOVA) model 
with effects due to baseline percent predicted trough morning 
FEV1, sex, age, (pooled) investigational center, previous 
therapy (ICS or NCS), and IMP treatment group. Contrasts 
for pairwise treatment comparisons of interest will be 
constructed. The estimated treatment difference between 
each IMP treatment group and the placebo group will be 
presented together with the 2-sided 95% confidence interval 
(CI) for the difference and the p-value.  
In this analysis, missing data that are caused by early 
dropouts from the study or from IMP (regardless of 
availability of retrieved dropout data) will be imputed using 
reference-based multiple imputations. Details on the 
implementation of the multiple imputations will be provided 
in the statistical analysis plan. 
Analysis of the change from baseline in 1-hour postdose 
percent predicted morning FEV1 at week 12 
The co-primary For the endpoint of change from baseline in 
1-hour postdose percent predicted morning FEV1 (measured 
at the clinic) at week 12, baseline is defined as predose FEV1 
measurements obtained at the clinic at the RV with the 
handheld device immediately prior to the IMP 
administration. 
The primary analysis of the change from baseline in 1-hour 
postdose percent predicted morning FEV1 at week 12 due to 
the initially randomized treatment as actually taken will be 
analyzed using an ANCOVA model with effects due to 
baseline percent predicted trough morning FEV1, sex, age, 
(pooled) investigational center, previous therapy (ICS or 
NCS), and IMP treatment group. Contrasts for pairwise 
treatment comparisons of interest will be constructed. The 
estimated treatment difference between each IMP treatment 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
132 
Original text with changes shown 
New wording 
Reason/justification for 
change 
Morning FEV1 at Week 12 
The co primary For the endpoint of change from baseline, in 1-
hour postdose percent predicted morning FEV1 (measured at 
the clinic) at week 12, baseline is defined as pre dosepredose 
FEV1 measurements obtained at the clinic at the RV with the 
handheld device immediately prior to the IMP administration,. 
The primary analysis of the change from baseline in 1-hour 
postdose percent predicted morning FEV1 (measured at the 
clinic) at week 12 due to the initially randomized treatment as 
actually taken will be analyzed using an ANCOVA model with 
effects due to baseline percent predicted trough morning FEV1, 
sex, age, (pooled) investigational center, previous therapy (ICS 
or NCS), and IMP treatment group. Contrasts for pairwise 
treatment comparisons of interest will be constructed. The 
estimated treatment difference between each IMP treatment 
group and the placebo group will be presented together with the 
2-sided 95% CI for the difference and the p-value. Missing data 
caused by early dropouts will be handled similarly to the above 
analysis. 
group and the placebo group will be presented together with 
the 2-sided 95% CI for the difference and the p-value. 
Missing data caused by early dropouts will be handled 
similarly to the above analysis. 
 
SECTION 9.5.4.2 SENSITIVITY ANALYSIS TO MISSING DATA 
To assess the impact of missing data, several sensitivity 
analyses will be conducted for the 2 endpoints by evaluating 
alternative estimands. More details will be provided in the 
statistical analysis plan. 
• 
The primary endpointanalysis for the 2 endpoints will 
be repeated when using data collected after IMP 
discontinuation and penalizing(retrieved dropout 
data). Reference-based imputation will be used only 
for patients for whomwith no retrieved dropout data. 
This analysis estimates different estimands, namely 
the change from baseline as actually taken (see 
estimand 1 in Mallinckrodt et al 2016). 
• 
The primary analysis for the 2 endpoints will be 
repeated on completers with no major protocol 
violations (see estimand 3 in Mallinckrodt et al 
To assess the impact of missing data, several sensitivity 
analyses will be conducted for the 2 endpoints by evaluating 
alternative estimands. More details will be provided in the 
statistical analysis plan. 
• 
The primary analysis for the 2 endpoints will be 
repeated when using data collected after IMP 
discontinuation (retrieved dropout data). Reference-
based imputation will be used only for patients with 
no retrieved dropout data. This analysis estimates 
different estimands, namely the change from 
baseline as actually taken (see estimand 1 in 
Mallinckrodt et al 2016).  
• 
The primary analysis for the 2 endpoints will be 
repeated on completers with no major protocol 
violations (see estimand 3 in Mallinckrodt et al 
These changes were made to 
update the handling of missing 
data in response to FDA 
feedback. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
133 
Original text with changes shown 
New wording 
Reason/justification for 
change 
2016assessment after IMP discontinuation is 
available. In addition, a). 
• 
A tipping point analysis will be performed as a 
sensitivity analysis to missing data by utilizing 
multiple imputations under the missing not at random 
(MNAR) assumption. different missing mechanism. 
For placebo patients, in all applications of multiple 
imputations, missing at random (MAR) will be 
assumed. For the active arms, in the first application, 
MAR will be assumed and the imputations will be 
drawn from data in the corresponding active arms. In 
subsequent applications, shifts to the distribution of 
the active arms will be applied to represent different 
degrees of effect loss, ie, MNAR will be assumed. 
An additional analysis to assess the robustness of the results 
will be conducted by applying the primary efficacy analysis to 
the PP analysis set. 
• 
The primary analysis for the 2 endpoints will be 
repeated when missing data will be imputed using a 
mixed approach of last observation carried forward 
(LOCF) and baseline observation carried forward 
(BOCF) as follows: BOCF will be used for patients who
had a positive change from baseline at the time of study 
or IMP discontinuation (ie, a change of 0), while LOCF 
will be used for patients that have negative  
change from baseline. In this imputation method, the 
imputed value is the lower between LOCF  
and BOCF for each patient. No adjustments will  
be made to other patients. 
• 
For the first primary endpoint of change from baseline 
in the weekly average of percent  
predicted trough morning FEV1 over the 12-week 
treatment period, analysis will be performed using a 
mixed model for repeated measures (MMRM). This 
analysis will not use retrieved dropout data. This 
analysis represents a MAR assumption. 
2016). 
• 
A tipping point analysis will be performed as a 
sensitivity analysis to missing data by utilizing 
multiple imputations under different missing 
mechanism. For placebo patients, in all applications 
of multiple imputations, missing at random (MAR) 
will be assumed. For the active arms, in the first 
application, MAR will be assumed and the 
imputations will be drawn from data in the 
corresponding active arms. In subsequent 
applications, shifts to the distribution of the active 
arms will be applied to represent different degrees 
of effect loss, ie, MNAR will be assumed. 
• 
The primary analysis for the 2 endpoints will be 
repeated when missing data will be imputed using a 
mixed approach of last observation carried forward 
(LOCF) and baseline observation carried forward 
(BOCF) as follows: BOCF will be used for patients 
who had a positive change from baseline at the time 
of study or IMP discontinuation (ie, a change of 0), 
while LOCF will be used for patients that have 
negative change from baseline. In this imputation 
method, the imputed value is the lower between 
LOCF and BOCF for each patient. No adjustments 
will be made to other patients.  
• 
For the first primary endpoint of change from 
baseline in the weekly average of percent predicted 
trough morning FEV1 over the 12-week treatment 
period, analysis will be performed using a mixed 
model for repeated measures (MMRM). This 
analysis will not use retrieved dropout data. This 
analysis represents a MAR assumption. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
134 
Original text with changes shown 
New wording 
Reason/justification for 
change 
SECTION 9.5.4.3 SECONDARY EFFICACY ANALYSIS 
For all secondary endpoints, analyses will be performed using 
the ITT analysis set and will not include retrieved dropout data 
in the analysis. 
For all secondary endpoints, analyses will be performed 
using the ITT analysis set and will not include retrieved 
dropout data in the analysis. 
Text was added to clarify the 
analyses of the secondary 
endpoints. 
SECTION 15 REFERENCES 
Corren J, Korenblat PE, Miller CJ, O’Brien CD, Mezzanotte 
WS. Twelve-week, randomized, placebo-controlled, 
multicenter study of the efficacy and tolerability of budesonide 
and formoterol in one metered-dose inhaler compared with 
budesonide alone and formoterol alone in adolescents and 
adults with asthma. Clin Ther 2007;29(5):823–43. 
Kerwin EM, Pearlman DS, de Guia T, Carlsson LG, Gillen M, 
Uryniak T, et al. Evaluation of efficacy and safety of 
budesonide delivered via two dry powder inhalers. Curr Med 
Res Opin. 2008;24(5):1497–510. 
Little R, Kang S. Intention-to-treat analysis with treatment 
discontinuation and missing data in clinical trials. Stat Med 
2015;34(16):2381–90. 
Mallinckrodt C. Choosing primary estimands and analyses. In: 
Preventing and treating missing data in longitudinal 
clinical trials: A practical guide. New York: Cambridge 
University Press, 2013. 
Mallinckrodt C, Molenberghs G, Rathmann S. Choosing 
estimands in clinical trials with missing data. Pharm Stat 2016. 
O’Neill RT, Temple R. The prevention and treatment of 
missing data in clinical trials: An FDA perspective on the 
importance of dealing with it. Clin Pharmacol Ther 
2012;91(3):550–4. 
Pearlman DS, Stricker W, Weinstein S, Gross G, Chervinsky P, 
Woodring A, et al. Ann Allergy Asthma Immunol 
1999;82(3):257–65. 
Szefler SJ, Boushey HA, Pearlman DS, Togias A, Liddle R, 
Furlong A, et al. Time to onset of effect of fluticasone 
propionate in patients with asthma. J Allergy Clin Immunol 
Corren J, Korenblat PE, Miller CJ, O’Brien CD, Mezzanotte 
WS. Twelve-week, randomized, placebo-controlled, 
multicenter study of the efficacy and tolerability of 
budesonide and formoterol in one metered-dose inhaler 
compared with budesonide alone and formoterol alone in 
adolescents and adults with asthma. Clin Ther 
2007;29(5):823–43. 
Kerwin EM, Pearlman DS, de Guia T, Carlsson LG, Gillen 
M, Uryniak T, et al. Evaluation of efficacy and safety of 
budesonide delivered via two dry powder inhalers. Curr Med 
Res Opin. 2008;24(5):1497–510. 
Little R, Kang S. Intention-to-treat analysis with treatment 
discontinuation and missing data in clinical trials. Stat Med 
2015;34(16):2381–90. 
Mallinckrodt C. Choosing primary estimands and analyses. 
In: Preventing and treating missing data in longitudinal 
clinical trials: A practical guide. New York: Cambridge 
University Press, 2013. 
Mallinckrodt C, Molenberghs G, Rathmann S. Choosing 
estimands in clinical trials with missing data. Pharm Stat 
2016. 
O’Neill RT, Temple R. The prevention and treatment of 
missing data in clinical trials: An FDA perspective on the 
importance of dealing with it. Clin Pharmacol Ther 
2012;91(3):550–4. 
Pearlman DS, Stricker W, Weinstein S, Gross G, Chervinsky 
P, Woodring A, et al. Ann Allergy Asthma Immunol 
1999;82(3):257–65. 
Szefler SJ, Boushey HA, Pearlman DS, Togias A, Liddle R, 
Additional references were 
inserted into the list of 
references as additional 
sources were included in the 
text. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
135 
Original text with changes shown 
New wording 
Reason/justification for 
change 
1999;103(5):780–8. 
Woodcock A, Bleecker ER, Lötvall J, O’Byrne PM, Bateman 
ED, Medley H, et al. Efficacy and safety of fluticasone 
furoate/vilanterol compared with fluticasone 
propionate/salmeterol combination in adult and adolescent 
patients with persistent asthma. Chest 2013;144(4):1222–9. 
Furlong A, et al. Time to onset of effect of fluticasone 
propionate in patients with asthma. J Allergy Clin Immunol 
1999;103(5):780–8. 
Woodcock A, Bleecker ER, Lötvall J, O’Byrne PM, 
Bateman ED, Medley H, et al. Efficacy and safety of 
fluticasone furoate/vilanterol compared with fluticasone 
propionate/salmeterol combination in adult and adolescent 
patients with persistent asthma. Chest 2013;144(4):1222–9. 
APPENDIX A CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS 
Not applicable Q Squared Solutions LLC 
27027 Tourney Road, Suite 2E 
Valencia, CA 91355 
USA 
 
Q Squared Solutions Limited 
The Alba Campus (Rosebank) 
Livingston 
West Lothian EH54 7EG 
Scotland, United Kingdom 
Q Squared Solutions LLC 
27027 Tourney Road, Suite 2E 
Valencia, CA 91355 
USA 
 
Q Squared Solutions Limited 
The Alba Campus (Rosebank) 
Livingston 
West Lothian EH54 7EG 
Scotland, United Kingdom 
The information for the central 
clinical laboratories was 
inserted into the document. 
APPENDIX B STUDY PROCEDURES AND ASSESSMENTS BY VISIT 
The intent of the run-in period is to complete baseline safety 
evaluations, establish patient compliance, and obtain baseline 
measures of asthma symptoms, rescue use, and PEFlung 
function assessment values. Patients (with assistance from 
parents/legal guardians/caregivers, as needed) will record 
symptoms, rescue use, and PEFlung function assessments 
(FEV1 and PEF) in the patient diary built into the handheld 
device throughout the 14- to 30-day run-in period to establish 
their baseline profiles. 
The intent of the run-in period is to complete baseline safety 
evaluations, establish patient compliance, and obtain baseline 
measures of asthma symptoms, rescue use, and lung function 
assessment values. Patients (with assistance from 
parents/legal guardians/caregivers, as needed) will record 
symptoms, rescue use, and lung function assessments (FEV1 
and PEF) in the patient diary built into the handheld device 
throughout the 14- to 30-day run-in period to establish their 
baseline profiles. 
This change was made to 
correct which lung function 
assessments should be 
recorded in the patient diary 
during the run-in period. 
APPENDIX B STUDY PROCEDURES AND ASSESSMENTS BY VISIT (Other section affected by these changes: Section 3.5 [Table 3, footnote i]) 
The training inhaler is to be kept at the clinic and not provided 
to the patient to keep at home. Inhaler device training is not 
The training inhaler is to be kept at the clinic and not 
provided to the patient to keep at home. Inhaler device 
This text was added to exempt 
patients who discontinue the 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
136 
Original text with changes shown 
New wording 
Reason/justification for 
change 
required for patients placed on alternative asthma therapy and 
who are no longer taking IMP per protocol. 
training is not required for patients placed on alternative 
asthma therapy and who are no longer taking IMP per 
protocol. 
study IMP from inhaler device 
training. 
APPENDIX D ETHICS 
The investigator, or a qualified person designated by the 
investigator, should fully inform the patient of all pertinent 
aspects of the study, including the written information 
approved by the IEC/IRB. All written and oral information 
about the study will be provided in a language as nontechnical 
as practical to be understood by the patient. The patient should 
be given ample time and opportunity to inquire about details of 
the study and to decide whether or not to participate in the 
study. The above should be detailed in the source documents. 
Written informed consent will be obtained from each patient 
before any study specific procedures or assessments are done 
and after the aims, methods, anticipated benefits, and potential 
hazards are explained. The patient’s willingness to participate 
in the study will be documented in the informed consent form, 
which will be signed and personally dated by the patient and by 
the person who conducted the informed consent discussion. 
The investigator will keep the original informed consent forms, 
and copies will be given to the patients. It will also be 
explained to the patients that the patient is free to refuse 
participation in the study and free to withdraw from the study at 
any time without prejudice to future treatment. 
The investigator, or a qualified person designated by the 
investigator, should fully inform the patient and each 
parent/legal guardian of all pertinent aspects of the study, 
including the written information approved by the IEC/IRB. All 
written and oral information about the study will be provided in 
a language as nontechnical as practical to be understood by the 
each parent/legal guardian and the patient. The patient and each 
parent/ legal guardian should be given ample time and 
opportunity to inquire about details of the study and to decide 
whether or not to participate in the study. The above should be 
detailed in the source documents. 
The investigator, or a qualified person designated by the 
investigator, should fully inform the patient and each 
parent/legal guardian of all pertinent aspects of the study, 
including the written information approved by the IEC/IRB. 
All written and oral information about the study will be 
provided in a language as nontechnical as practical to be 
understood by the parent/legal guardian and the patient. The 
patient and each parent/legal guardian should be given ample 
time and opportunity to inquire about details of the study and 
to decide whether or not to participate in the study. The 
above should be detailed in the source documents. 
A personally signed and dated informed consent form will be 
obtained from the parent/legal guardian, and a signed and 
dated assent form will be obtained from each patient (as 
applicable and as may be specified by local regulations) 
before any study specific procedures or assessments are done 
and after the aims, methods, anticipated benefits, and 
potential hazards are explained; according to IEC/IRB 
requirements. The forms will be signed and dated also by the 
person who conducted the informed consent discussion. The 
investigator will keep the original informed consent and 
assent forms, and copies will be given to the patients (and 
each parent/legal guardian). It will also be explained to the 
patients (and each parent/legal guardian) that they are free to 
refuse participation in the study and free to withdraw from 
the study at any time without prejudice to future treatment. 
The first 2 paragraphs of this 
text were deleted to avoid 
redundancy with the next 2 
paragraphs. 
The text was also changed to 
modify the circumstances 
under which a signed and 
dated assent form may be 
collected from each patient. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
137 
Original text with changes shown 
New wording 
Reason/justification for 
change 
A personally signed and dated informed consent form will be 
obtained from the parent/legal guardian, and a signed and dated 
assent form will be obtained from each patient (if the patient is 
ableas applicable and as may be specified by local regulations) 
before any study specific procedures or assessments are done 
and after the aims, methods, anticipated benefits, and potential 
hazards are explained; according to IEC/IRB requirements. The 
forms will be signed and dated also by the person who 
conducted the informed consent discussion. The investigator 
will keep the original informed consent and assent forms, and 
copies will be given to the patients (and each parent/legal 
guardian). It will also be explained to the patients (and each 
parent/legal guardian) that they are free to refuse participation 
in the study and free to withdraw from the study at any time 
without prejudice to future treatment. 
APPENDIX E LOST TO FOLLOW-UP 
• 
The investigational center must attempt to contact the 
patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of 
maintaining the assigned visit schedule and ascertain 
whether or not the patient wishes to and/or should 
continue in the study. This includes using alternative 
contact information supplied by the parent/legal 
guardian as outlined in the informed consent (as 
allowed by local regulation). 
• 
The investigational center must attempt to contact 
the patient and reschedule the missed visit as soon 
as possible and counsel the patient on the 
importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient 
wishes to and/or should continue in the study. This 
includes using alternative contact information 
supplied by the parent/legal guardian as outlined 
in the informed consent (as allowed by local 
regulation). 
This text was added to specify 
the manner in which the 
investigational center will 
attempt to contact patients 
who do not return to the 
investigational center for a 
required study visit. 
.


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
138 
APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS 
Sponsor’s Authorized Representative 
 
 
  
Teva Pharmaceuticals 
 
Legal Representative of the sponsor in the EU 
 
Merckle GmbH 
Graf-Arco-Str. 3 
89079 Ulm 
Germany 
Sponsor’s Medical Expert/Contact Point designated by the 
sponsor for Further Information on the Study 
 
Teva Pharmaceuticals 
 
Coordinating Principal Investigator 
 
 
 
 
 
Sponsor’s Representative of Global Patient Safety and 
Pharmacovigilance 
For serious adverse events: 
Send by email to the LSO/CRO. The email address will be 
provided in the serious adverse event report form. In the event of 
difficulty transmitting the form, contact the sponsor’s study 
personnel identified above for further instruction. 
 
Teva Pharmaceuticals 
 
 
Contract Research Organization 
PRA Health Sciences 
4130 Parklake Ave, #400 
Raleigh, NC 27612 
Central Clinical Laboratory 
Q Squared Solutions LLC 
27027 Tourney Road, Suite 2E 
Valencia, CA 91355 
USA 
 
Q Squared Solutions Limited 
The Alba Campus (Rosebank) 
Livingston 
West Lothian EH54 7EG 
Scotland, United Kingdom 
Central Electrocardiogram Evaluation 
Not applicable 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
139 
Bioanalytical Pharmacokinetics Evaluation 
Not applicable 
Bioanalytical Immunogenicity Evaluation 
Not applicable 
Pharmacogenomics/Biomarker Evaluation 
Not applicable 
Randomization and Trial Supply Management (RTSM) 
vendor 
Y-Prime 
263 Great Valley Parkway 
Malvern, PA 19355 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
140 
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT 
1. Procedures for Optional Prescreening Visit 
An optional prescreening visit may be scheduled up to 15 days prior to the screening visit (SV). 
During this visit and after informed consent/assent (as applicable) is obtained, the investigator 
will discuss with the patient and parents/legal guardians/caregivers study procedures and 
potential study-specific changes to the patient’s current asthma therapy if a patient decides to 
participate in the study and qualifies for study entry; the investigator will also discuss any 
required washout periods for prohibited medications before the SV.  
At the time of informed consent (at the prescreening visit or SV), the parent/legal guardian will 
be counseled that, once randomized to treatment, patients are to remain in the study and 
complete all study procedures unless the choice is made to withdraw consent. This includes 
patients who may require alternative asthma therapy, experience an adverse event, violate the 
protocol, or fail to comply with study procedures. Continued patient participation is important to 
contribute to the scientific investigation. 
An SV will be scheduled, which should occur in the morning (0530 to 1100) and instruct patients 
to refrain from taking their morning inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) 
and to avoid taking rescue medication for at least 6 hours before the appointment time on the day 
of the SV. 
11. Procedures for Screening and Enrollment (Visit 1) 
A signed and dated informed consent form (unless already obtained at a prescreening visit) will 
be obtained from the parent/legal guardian, and a signed and dated assent form will be obtained 
from each patient (as applicable) before any screening procedures commence, according to 
national laws and local Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
requirements. Each parent/legal guardian will acknowledge and agree to the possible use of this 
information for the study by giving informed consent. 
After informed consent is obtained, interactive response technology (IRT) will be used to assign 
screened patients an 8-digit permanent identification.  
Note that if the patient has a prescreening visit, a permanent identification number would have 
been assigned at that time. 
Lung function assessments by handheld device at the SV are to be performed a minimum of 
6 hours after the last SABA use and should not be conducted if the patient has taken routine 
maintenance asthma medication on that day. Screening lung function assessments should be 
performed at the investigational center between the hours of 0530 and 1100. Patients will be 
permitted 8 attempts per test. The highest forced expiratory volume in 1 second (FEV1) value 
from 3 technically acceptable and 2 repeatable maneuvers will be used. Patients who have failed 
screening for FEV1 or response to a bronchodilator may retest once within 7 days of the SV 
provided that they have met all other inclusion criteria and none of the exclusion criteria. At 
retest, patients will report if there have been any adverse events, changes in medications, or 
changes in medical history since providing consent/assent (as applicable). The run-in period will 
not start until patients have passed all screening procedures (including a retest, if needed).  


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
141 
Patients who have not met inclusion criteria for response to a bronchodilator and cannot return 
within 7 days for a retest should be classified as screen failures but may be rescreened. Patients 
who experience an upper respiratory infection (URI) or lower respiratory infection (LRI) during 
the run-in period should be classified as randomization failures and be discontinued from the 
study, but may be rescreened 2 weeks after resolution of the infection. Patients who are 
rescreened will need to repeat all screening procedures and evaluations. Only 1 retest and 
1 rescreening for each patient will be permitted.  
The SV will take place up to 30 days before the RV. The following procedures will be performed 
at SV: 
• obtain written informed consent/assent (as applicable) before any study-related 
procedures are performed (unless already obtained at a prescreening visit) 
• review medical history 
• collect prior medication history 
• review inclusion and exclusion criteria 
• collect demographic data 
• inquire and record adverse events and concomitant medications 
• perform vital signs measurements 
• perform full physical examination (including weight and height) 
• perform oropharyngeal examination 
• perform urine pregnancy test (for females of childbearing potential, as applicable) 
• perform predose lung function assessments (FEV1 and peak expiratory flow [PEF]) 
by handheld device, followed by response to a bronchodilator test within 30 minutes 
after 2 to 4 inhalations of albuterol/salbutamol HFA. Patients who fail to meet lung 
function assessments or response to a bronchodilator requirements may retest once 
within 7 days. 
• dispense run-in drug kit 
• dispense rescue medication 
• provide training on handheld device 
• provide patient handheld device 
• provide training on investigational medicinal product (IMP) and have patient 
demonstrate proper technique using the provided training device. The training inhaler 
is to be kept at the clinic and not provided to the patient to keep at home. 
Patients will be provided with a handheld device at the SV, which will be used to measure lung 
function assessments (FEV1 and PEF) and will serve as an electronic patient diary to collect 
asthma symptom scores, rescue medication use, and IMP use throughout the course of the study. 
A single training inhaler will be assigned to each patient at the SV and will be kept at the 
investigational center for use at each investigational center visit. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
142 
12. Retesting and Rescreening 
Patients who have not met inclusion criteria for response to a bronchodilator and cannot return 
within 7 days for a retest should be classified as screen failures but may be rescreened. Patients 
who experience an URI or LRI during the run-in period should be classified as randomization 
failures and be discontinued from the study, but may be rescreened 2 weeks after resolution of 
the infection. Patients who are rescreened will need to repeat all screening procedures and 
evaluations. Only 1 retest and 1 rescreening for each patient will be permitted.  
The decision to retest or rescreen patients will be based on the investigator’s judgement and the 
study protocol. In cases of rescreening, the sponsor or designee should be notified of the pending 
rescreening. Patients may retest/rescreen for lung function assessments and response to a 
bronchodilator only if they meet all other nonspirometric inclusion/exclusion criteria. At the 
retest, patients will be asked if they have had any adverse events, changes in medications, or 
changes in medical history. Patients will not be eligible to enter the run-in period until all 
inclusion/exclusion criteria are met. 
13. Run-in Period (Between Screening Visit and Treatment Visit [TV] 1) 
Patients meeting all of the inclusion criteria and none of the exclusion criteria at the SV will 
begin a 14- to 30-day run-in period. Albuterol/salbutamol hydrofluoroalkane (HFA) 
metered-dose inhaler (MDI; a SABA inhaler) will be provided to replace the patient’s current 
rescue medication, and is to be used as needed for symptomatic relief of asthma symptoms 
during the run-in and treatment periods, with a maximum of 12 inhalations permitted per day. 
Starting day 1 of the run-in period, patients must discontinue their current ICS or ICS/LABA 
therapy and all other nonstudy asthma-related drugs and instead take a patient-blinded MDPI 
placebo device (1 inhalation twice daily). 
The intent of the run-in period is to complete baseline safety evaluations, establish patient 
compliance, and obtain baseline measures of asthma symptoms, rescue use, and lung function 
assessment values. Patients (with assistance from parents/legal guardians/caregivers, as needed) 
will record symptoms, rescue use, and lung function assessments (FEV1 and PEF) in the patient 
diary built into the handheld device throughout the 14- to 30-day run-in period to establish their 
baseline profiles. Patients and parents/legal guardians/caregivers will be instructed to contact 
their investigator if they have met predefined asthma alert criteria.  
14. Procedures Before Investigational Medicinal Product Treatment (Baseline 
[Randomization Visit (RV)/TV1]) 
Patients who meet the inclusion and exclusion criteria at visit SV will continue to RV/TV1. At 
the RV/TV1, patient will be assessed for randomization. Patients who meet all of the 
randomization criteria will be randomized into the double-blind treatment period of the study. 
Note: response to bronchodilator testing may not be conducted on the same day as the 
randomization visit. 
The following procedures will be performed at the RV/TV1: 
• review randomization criteria 
• inquire about adverse events and concomitant medications 
• perform vital signs measurements 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
143 
• perform directed cardiopulmonary examination 
• perform oropharyngeal examination 
• perform urine pregnancy test (for females of childbearing potential, as applicable) 
• perform predose lung function assessments (FEV1 and PEF) by handheld device 
• provide training on IMP and have patient demonstrate proper technique using the 
provided training device before dosing with IMP. The training inhaler is to be kept at 
the clinic and not provided to the patient to keep at home. 
• dispense IMP 
• observe patient dosing with IMP 
• perform 1-hour postdose lung function assessments (FEV1 and PEF) by handheld 
device 
• collect Childhood Asthma Control Test (C-ACT) asthma questionnaire 
• collect run-in drug kit 
• dispense/collect rescue medication (if needed) 
• dispense and provide training on handheld device 
• assess alert criteria for worsening asthma 
A patient who is not enrolled in the study on the basis of results of baseline assessments 
(eg, because inclusion and exclusion criteria were not met or enrollment did not occur within the 
specified time) may be considered for screening again if there is a change in the patient’s 
medical background, a modification of study inclusion and exclusion criteria, or other relevant 
change. (Note: Details of rescreening criteria and procedures are included in the monitoring 
plan.) 
Patients who continue to meet the inclusion and exclusion criteria will be assigned a permanent 
unique randomization number. 
15. Procedures During Investigational Medicinal Product Treatment 
a. Double-Blind Treatment Period (TV1 to TV6) 
During the treatment period (TV1 though TV6), daily in the morning and evening at 
approximately the same time each day, patients (with assistance from parents/legal 
guardians/caregivers, as needed) will use the handheld device at home to record asthma symptom 
scores and rescue albuterol/salbutamol HFA MDI use, after which they will perform lung 
function assessments (FEV1 and PEF) and then will take their dose of the IMP and record IMP 
dosing in the patient diary built into the handheld device.  
On the morning of each TV, patients will be instructed to record their asthma symptom score and 
rescue albuterol/salbutamol HFA MDI use and complete their morning lung function 
assessments (FEV1 and PEF) by handheld device as usual, but to delay dosing until they get to 
the investigational center. Patients are also to withhold their rescue SABA for a minimum of 
6 hours prior to obtaining lung function assessments. If the patient inadvertently takes the 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
144 
morning IMP dose or rescue medication within 6 hours of the planned lung function 
assessments, the visit must be rescheduled. Similarly, patients who have been withdrawn from 
IMP but remain in the study should withhold their alternative asthma therapy dosing until after 
treatment visit assessments and avoid rescue medication for a minimum of 6 hours prior to clinic 
lung function assessments. The treatment visit should be rescheduled if either or both occur. 
At the investigational center, after appropriate instructions and training (competent handheld 
device use and dosing technique using the training devices provided), patients will repeat their 
lung function assessment (FEV1 and PEF) under the supervision of the investigational center 
staff. They will then take their morning dose of the IMP unless IMP has been withdrawn. IMP 
administration at the investigational center should be timed so that lung function assessments 
will be approximately 12 hours following the doses taken the previous evening. Patients will 
then perform a 1-hour postdose FEV1 measurements using the handheld device. Patients who 
have been withdrawn from IMP will be asked to perform 1-hour postdose lung function 
assessments; although the patients will not be taking a dose of IMP, the assessment should be 
approximately 1 hour after the predose lung function assessments were obtained. The highest 
FEV1 value from 3 acceptable and 2 repeatable maneuvers (maximum of 8 attempts per test) will 
be obtained before and 1-hour after the morning dose. The postdose measurements should be 
taken at 60 minutes ±10 minutes from the time of IMP dosing. 
The C-ACT will be completed by the patient and the patient’s parent/legal guardian/caregiver (as 
applicable) at the investigational center, before any other assessments are performed, at specified 
visits. The same parent or caregiver should complete assessments at each visit. Specific 
instructions are provided in the study reference manual. 
Safety will be monitored by physical examination, oropharyngeal examination, vital signs, lung 
function assessments, and recording of adverse events. Any visual evidence of oral candidiasis 
during the treatment period will be confirmed by obtaining a swab for culture of the suspect area. 
Patients and parents/legal guardians/caregivers will be provided with guidelines for when to 
contact the investigational center in case of worsening asthma symptoms or rescue inhaler use. 
Patients who meet predefined alert criteria should be evaluated by the investigator to determine if 
they should be withdrawn from the study either at the next scheduled TV or an IMP 
discontinuation visit (IMPDV). In cases where the IMP is to be withdrawn and alternative 
therapy started, the investigational center staff should contact the medical monitor to confirm the 
findings. If a patient discontinues the study prematurely but remains in the study, all subsequent 
visits will include all assessments according to Table 3. 
− Treatment Visits 2, 3, 4, 5, and 6 (Weeks 1, 2, 4, 8, and 12) and IMPDV 
Patients will attend the investigational center at weeks 1, 2, 4, 8, and 12. The following 
procedures/assessments will be performed at these visits: 
• inquiry and recording of adverse events and concomitant medications 
• measurements of vital signs 
• perform oropharyngeal examination 
• perform urine pregnancy test (for females of childbearing potential, as applicable) 
• perform predose lung function assessments (FEV1 and PEF) by handheld device 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
145 
• provide training on IMP (at all but TV6 and the IMPDV) and have patient 
demonstrate proper technique using the provided training inhaler. The training inhaler 
is to be kept at the clinic and not provided to the patient to keep at home. Inhaler 
device training is not required for patients placed on alternative asthma therapy and 
who are no longer taking IMP per protocol. 
• observe patient dosing with IMP 
• perform 1-hour postdose lung function assessments (FEV1 and PEF) by handheld 
device (morning only at TV6) 
• provide handheld device training (at all but TV6) 
• collect C-ACT asthma questionnaire (at TV4, TV5, TV6, and IMPDV only) 
• dispense/collect rescue medication (as needed) 
• dispense/collect IMP (at TV3, TV4, TV5, TV6, and the IMPDV only) 
• assess alert criteria for worsening asthma 
• discuss and record recommended asthma therapy (TV6 and the IMPDV only) 
• end IMP in IRT system (TV6 and the IMPDV only) 
• end study participation in IRT system (IMPDV only) 
16. Procedures After Investigational Medicinal Product Treatment 
Patients who participate in the study in compliance with the protocol for the entire duration of 
the study (screening, run-in, and all TVs) will be considered to have completed the study.  
a. Follow-up 
For patients who complete the study or withdraw prematurely, final evaluations will be 
performed at the IMPDV or on the last day the patient receives the IMP, or as soon as possible 
thereafter. Procedures for patients who withdraw prematurely from the study are described in 
Section 4.3. Patients should be treated with standard of care after termination of the study as 
appropriate. 
Patients may attend a follow-up visit one week (±2 days) after the last TV. The follow-up visit 
may be in person or over the telephone. The following assessments will be performed during the 
follow-up visit: 
• inquiry of adverse events 
• inquiry of concomitant medication 
The patients will be deemed to have completed the treatment period if they have completed all 
periods of treatment, including screening, run-in, and all treatments visits. The patient will be 
deemed to have completed the study period if they have completed all periods of the study, 
including FV in addition to screening, run-in, and all TVs. Patients who stop IMP and return for 
safety evaluation at week 12 will not be considered to have completed the treatment period. 
Patients with ongoing adverse events will be monitored as described in Section 7.1.2. Otherwise, 
the follow-up visit will be the last study visit. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
146 
17. Unscheduled Visits 
An unscheduled visit may be performed at any time during the study at the patient’s request and 
as deemed necessary by the investigator. The date and reason for the unscheduled visit will be 
recorded on the case report form as well as any other data obtained (eg, adverse events, 
concomitant medications and treatments, and results from procedures or tests). 
Procedures performed during unscheduled visits include the following: 
• concomitant medication inquiry 
• vital signs measurements 
• adverse event inquiry 
Other procedures may be performed at the discretion of the investigator. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
147 
APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE 
Protocol Amendments and Protocol Deviations and Violations 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB and national and local 
competent authorities, as applicable, except when necessary to address immediate safety 
concerns to the patients or when the change involves only nonsubstantial logistics or 
administration. The principal investigator at each investigational center, the coordinating 
investigator (if applicable), and the sponsor will sign the protocol amendment. 
Protocol Violations 
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered a protocol violation. Protocol violations may include nonadherence on the part of the 
patient, the investigator, or the sponsor to protocol-specific inclusion and exclusion criteria, 
primary objective variable criteria, or GCP guidelines; noncompliance to IMP administration; 
and use of prohibited medications. All protocol violations will be reported to the responsible 
IEC/IRB, as required. 
When a protocol violation is reported, the sponsor will determine whether to discontinue the 
patient from the study or permit the patient to continue in the study, with documented approval 
from the medical expert. The decision will be based on ensuring the safety of the patient and 
preserving the integrity of the study. 
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the protocol violation. If such patient has already completed the study or has 
withdrawn early, no action will be taken but the violation will be recorded. 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all personnel members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel member’s 
responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study personnel, including the 
investigator, and for ensuring they comply with the protocol. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
148 
Study Monitoring 
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable SOPs, the protocol, and other written instructions and regulatory 
guidelines. 
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor(s) are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals. 
The study monitor(s) will contact the investigator and visit the investigational center according 
to the monitoring plan. The study monitor will be permitted to review and verify the various 
records (CRFs and other pertinent source data records, including specific electronic source 
document relating to the study) to verify adherence to the protocol and to ensure the 
completeness, consistency, and accuracy of the data being recorded. 
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting personnel must agree to cooperate with the study monitor to resolve any problems, 
errors, or possible misunderstandings concerning the findings detected during the course of these 
monitoring visits or provided in follow-up written communication. 
Audit and Inspection 
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCP guidelines, and applicable regulatory requirements. The sponsor’s Global 
Clinical Quality Assurance, independent of Global Specialty Development, is responsible for 
determining the need for (and timing of) an investigational center audit. 
The investigator must accept that competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
149 
APPENDIX D. ETHICS 
Informed Consent/Assent 
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient and each parent/legal guardian of all pertinent aspects of the study, including the written 
information approved by the IEC/IRB. All written and oral information about the study will be 
provided in a language as nontechnical as practical to be understood by the parent/legal guardian 
and the patient. The patient and each parent/legal guardian should be given ample time and 
opportunity to inquire about details of the study and to decide whether or not to participate in the 
study. The above should be detailed in the source documents. 
A personally signed and dated informed consent form will be obtained from the parent/legal 
guardian, and a signed and dated assent form will be obtained from each patient (as applicable 
and as may be specified by local regulations) before any study specific procedures or 
assessments are done and after the aims, methods, anticipated benefits, and potential hazards are 
explained; according to IEC/IRB requirements. The forms will be signed and dated also by the 
person who conducted the informed consent discussion. The investigator will keep the original 
informed consent and assent forms, and copies will be given to the patients (and each 
parent/legal guardian). It will also be explained to the patients (and each parent/legal guardian) 
that they are free to refuse participation in the study and free to withdraw from the study at any 
time without prejudice to future treatment. The parent/legal guardian will be counseled about the 
importance of the patient completing all visits even if the patient is withdrawn from IMP but 
chooses to continue their participation in the study (ie, does not withdraw consent). The 
parent/legal guardian will be asked to provide alternative contact information (as allowed by 
local regulation) in the event that the study center is unable to contact the parent/legal guardian 
to encourage continued participation in the study. 
Competent Authorities and Independent Ethics Committees/Institutional Review Boards 
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start at a given investigational 
center before the IEC/IRB and competent authority (as applicable) for the investigational center 
give written approval or a favorable opinion. 
Confidentiality Regarding Study Patients 
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification number. 
Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and the CRF. This review may be conducted by the study monitor, properly 
authorized persons on behalf of the sponsor, Global Quality Assurance (GQA), or competent 
authorities. Personal medical information will always be treated as confidential. 
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study will be registered on trials registry websites. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
150 
APPENDIX E. LOST TO FOLLOW-UP 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the investigational center. 
The following actions must be taken if a patient fails to return to the investigational center for a 
required study visit: 
• The investigational center staff must attempt to contact the patient and reschedule the 
missed visit as soon as possible and counsel the patient on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the patient 
wishes to and/or should continue in the study. This includes using alternative contact 
information supplied by the parent/legal guardian as outlined in the informed consent 
(as allowed by local regulation). 
• In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of ‘lost to follow-up’. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
151 
APPENDIX F. INSTRUCTIONS FOR USE OF MEDICAL DEVICES 
All patients will be provided training on use of the Teva MDPI device during the SV. The 
training will be done after all screening procedures and lung function assessments have been 
completed and the patient has been deemed eligible for inclusion. Directions for use of the 
device will be reviewed with each patient. Patients will then be provided with a Teva MDPI 
training device. The training devices are empty and do not contain active medication. Patients 
will practice using the device and will be required to demonstrate their understanding of correct 
technique. Directions for use of each device should be reviewed with each patient at 
randomization and at each TV. Training procedures should be repeated at each TV to ensure that 
patients continue to use correct technique for the device over the duration of the study. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
152 
APPENDIX G. HANDLING, LABELING, STORAGE, AND 
ACCOUNTABILITY FOR IMPS 
Storage and Security 
For the purposes of the study, test IMPs (Fp MDPI, Fs MDPI) and placebo with Teva MDPI 
devices must be stored between 15°C and 25°C (59°F and 77°F) in a dry place away from direct 
heat and sunlight, and in a securely locked, substantially constructed cabinet or enclosure. All 
rescue medication (albuterol/salbutamol HFA) will be stored according to the manufacturer’s 
drug product stipulation, in a dry place, and in a securely locked, substantially constructed 
cabinet or enclosure. Maintenance of a daily temperature log (manual or automated) is required. 
Each IMP shipment will include a packing slip listing the contents of the shipment and a device 
for monitoring and recording temperatures. The investigator is responsible for ensuring that 
deliveries of IMP and other study materials from the sponsor are treated as follows: 
• Correctly received and recorded 
• Handled and stored safely and properly in accordance with the Code of Federal 
Regulations (CFR) or local regulations 
• Used in accordance with this protocol 
The investigational center personnel are responsible for the acknowledgement of the receipt 
using the IRT. 
Labeling 
Detailed instructions regarding labeling (eg, investigational centers indicating the use by date) of 
the investigational product are provided in the study operations manual. 
Supplies of IMPs will be labeled in accordance with the current ICH guidelines on GCP and 
Good Manufacturing Practice and will include any locally required statements. If necessary, 
labels will be translated into the local language. 
Accountability 
Each IMP shipment will include a packing slip listing the contents of the shipment, return 
instructions, and any applicable forms. 
The investigator is responsible for ensuring that deliveries of IMPs and other study materials 
from the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the CFR or national and local regulations, and used in accordance with this 
protocol. 
Only patients enrolled in the study may receive IMPs and only authorized staff at the 
investigational center may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the investigator and 
authorized staff at the investigational center. 
The investigator (or designee) will instruct the patient to store the IMP according to the 
instructions on the label, if applicable; or will give instructions in an appropriate form. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
153 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
A record of IMP accountability (ie, IMP and other study materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. Empty, partially used, and unused IMP will be 
returned to the sponsor or designee. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
154 
APPENDIX H. LIST OF PROHIBITED MEDICATIONS 
Type of medication 
Washout period before the screening visit (unless 
otherwise specified) 
Anti-immunoglobulin E therapy (omalizumab)  
5 half-lives 
Any other investigational drug  
30 days or 5 half-lives, whichever is longer 
Aspirina  
1 day 
Beta-adrenergic receptor blocking agents 
30 days 
Bisphosphonates oral or intravenous (eg, alendronate, 
ibandronate) 
30 days 
Corticosteroids (oral, intravenous, intra-articular, or 
intramuscular)b 
30 days 
Cromones 
14 days 
Decongestants (eg, pseudoephedrine, 
phenylpropanolamine, phenylephrine) 
Discontinue 24 hours before SV, RV, and TV1 to TV6 
(week 12) and resume use after the visit 
Immunologically active biologic medications (eg, anti-
tumor necrosis factor alpha, abatacept) 
5 half-lives 
Immunosuppressive therapy (eg, methotrexate, gold, 
azathioprine)  
30 days 
Immunotherapyc 
Initiation within 90 days or change in dose within 30 
days 
Inhaled anticholinergic medication (eg, tiotropium 
bromide) 
7 days 
ICSs other than IMP 
Permitted at SV, but discontinue upon entering run-in 
Inhaled LABA 
Permitted at SV, but discontinue upon entering run-in 
Leukotriene modifiers 
Permitted at SV, but discontinue upon entering run-in 
Monoamine oxidase inhibitors 
14 days 
Oral β2-agonists (tablets, syrup)  
7 days 
Oral or nasal antihistamines (eg, loratadine, 
diphenhydramine, cetirizine) 
Discontinue 24 hours before SV, RV, and TV1 to TV6 
(week 12) and resume use after completion of the visit  
Strong CYP3A4 inhibitors (eg, oral ketoconazole, 
itraconazole, ritonavir, clarithromycin) 
30 days 
Theophyllines  
Permitted at SV, but discontinue upon entering run-in 
Topical dermatologic corticosteroids (intermediate to 
high potency; eg, CUTIVATE® [PharmaDerm], 
ELOCON® [Schering Corporation])d 
14 days 
Marijuana (medical, legal, and illegal)  
30 days before the SV and throughout the study 
Electronic cigarettes  
Discontinue 24 hours before the SV and do not resume 
use during the study 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
155 
Type of medication 
Washout period before the screening visit (unless 
otherwise specified) 
Tricyclic antidepressants  
14 days 
a Chronic stable doses of aspirin (≤325 mg/day) for cardiovascular prophylaxis are allowed. 
b Chronic stable doses of ocular steroids of at least 7 days duration, with doses expected to remain stable throughout 
the study, are allowed. 
c Immunotherapy for the treatment of allergies by any route is permitted as long as therapy was initiated 90 days or 
more before the SV and the patient has been on a stable dose for 30 days or more before the SV. The patient must 
remain on this stable regimen throughout the study. 
d Chronic and as-needed doses of low potency topical corticosteroids (eg, 1% hydrocortisone cream, desonide, 
fluocinolone cream 0.01%) covering <20% of body surface area are allowed; no occlusive dressings are allowed. 
CYP=cytochrome P450; ICS=inhaled corticosteroid; IMP=investigational medicinal product; LABA=long-acting 
β2-agonist; RV=randomization visit; SV=screening visit; TV=treatment visit.  
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
156 
APPENDIX I. PHARMACOGENETIC ASSESSMENTS 
Pharmacogenomics is not evaluated in this study. 
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
157 
APPENDIX J. PRODUCT COMPLAINTS 
Clinical Product Complaints 
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical IMP supplies or clinical device supplies used in a clinical 
research study sponsored by Teva. Examples of a product complaint include but are not limited 
to: 
• suspected contamination 
• questionable stability (eg, color change, flaking, crumbling, etc) 
• defective components 
• missing or extra units (eg, primary container is received at the investigational center 
with more or less than the designated number of units inside) 
• incorrect packaging, or incorrect or missing labeling/labels 
• unexpected or unanticipated taste or odor, or both 
• device not working correctly or appears defective in some manner 
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the product complaint form provided by Teva and emailing it to 
 within 48 hours of becoming aware of the issue. 
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the sponsor for investigative testing whenever possible. For complaints 
involving an IMP, all relevant samples (eg, the remainder of the patient’s IMP supply) should be 
sent back to the sponsor for investigative testing whenever possible. 
2. Product Complaint Information Needed from the Investigational Center 
In the event that the product complaint form cannot be completed, the investigator will provide 
the following information, as available: 
• investigational center number and principal investigator name 
• name, phone number, and address of the source of the complaint 
• clinical protocol number 
• patient identifier (patient study number) and corresponding visit numbers, if 
applicable 
• product name and strength for open label studies 
• patient number, bottle, and kit numbers (if applicable) for double blind or open label 
studies 
• product available for return (Yes/No) 
• product was taken or used according to protocol (Yes/No) 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
158 
• description or nature of complaint 
• associated serious adverse event (Yes/No) 
• clinical supplies unblinded (for blinded studies) [Yes/No] 
• date and name of person receiving the complaint 
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information. 
2. Handling of Investigational Medicinal Product(s) at the Investigational Center(s) 
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the IMP. 
If it is determined that the investigational center must return all IMP, the sponsor will provide the 
information needed to handle the return. 
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient. 
3. Adverse Events or Serious Adverse Events Associated with a Product Complaint 
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section Section 7.1.2 and Section 
Section 7.1.5.3, respectively). 
4. Documenting a Product Complaint 
The investigator will record in the source documentation a description of the product complaint, 
and any actions taken to resolve the complaint and to preserve the safety of the patient. Once the 
complaint has been investigated by the sponsor and the investigator, if necessary, an event 
closure letter may be sent to the investigational center where the complaint originated or to all 
investigational centers using the product. 
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study. 
 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
159 
APPENDIX K. DOCUMENTING A PRODUCT COMPLAINT 
Direct Access to Source Data and Documents 
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the CRF. Data may not be recorded directly on the CRF 
and considered as source data unless the sponsor provides written instructions specifying which 
data are permitted to be recorded directly to the CRF. 
If data are processed from other institutions or by other means (eg, clinical laboratory, central 
image center, or data from the patient diary built into the handheld device) the results will be sent 
to the investigational center, where they will be retained but not transcribed to the CRF, unless 
otherwise noted in the protocol. These data may also be sent electronically to the sponsor (or 
organization performing data management). 
The medical experts, study monitors, auditors, IEC/IRB, and inspectors from competent 
authority (or their agents) will be given direct access to source data and documents (eg, medical 
charts/records, laboratory test results, printouts, videotapes) for source data verification, provided 
that patient confidentiality is maintained in accordance with national and local requirements. 
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient. 
Data Collection 
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11 (USA) and documents of other concerned 
competent authorities. Before using the CDMS, it will be fully validated and all users will 
receive training on the system and study specific training. After they are trained, users will be 
provided with individual system access rights. 
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient who provided informed consent. Patient 
identity should not be discernible from the data provided on the CRF. 
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, data from the patient diary built into the handheld device, electronic patient-
reported outcome [ePRO] tablet), these data will be sent to the investigational center, where they 
will be retained but not transcribed to the CRF, unless otherwise noted in the protocol. These 
data may also be sent electronically to the sponsor (or organization performing data 
management). All patient data must have supportive original source documentation in the 
medical records, or equivalent, before they are transcribed to the CRF. Data may not be recorded 
directly on the CRF and considered as source data unless the sponsor provides written 
instructions specifying which data are permitted to be recorded directly to the CRF. 
For patients who enter a study but do not meet entry criteria, at a minimum, data for screening 
failure reason, demography, and adverse events from the time of informed consent will be 
entered in the CRF. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
160 
Data Quality Control 
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Oversight will be carried out as described in the 
sponsor’s SOPs for clinical studies. Day to day data management tasks for this study are 
delegated to a contract organization, and these functions may be carried out as described in the 
SOPs for clinical studies at that organization. These SOPs will be reviewed by the sponsor before 
the start of data management activities. 
Data will be verified by the study monitor using the data source, and reviewed by Data 
Management using both automated logical checks and manual review. Data identified as 
erroneous, or data that are missing, will be referred to the investigational center for resolution 
through data queries. Any necessary changes will be made in the clinical database, and data 
review and validation procedures will be repeated as needed. Data from external sources will be 
compared with the information available in the CDMS and any discrepancies will be queried. 
Applicable terms will be coded according to the coding conventions for this study. 
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate. All data collected will be approved by the 
investigator at the investigational center. This approval acknowledges the investigator’s review 
and acceptance of the data as being complete and accurate. 
Archiving of Case Report Forms and Source Documents 
Sponsor Responsibilities 
The sponsor will have final responsibility for the processing and quality control of the data. Data 
management oversight will be carried out as described in the sponsor’s SOPs for clinical studies. 
Day to day data management tasks for this study are delegated to a contract organization, and 
these functions may be carried out as described in the SOPs for clinical studies at that 
organization. These SOPs will be reviewed by the sponsor before the start of data management 
activities. The original CRFs will be archived by the sponsor. Investigational center specific 
CRFs will be provided to the respective investigational centers for archiving. 
Investigator Responsibilities 
The investigator must maintain all written and electronic records, accounts, notes, reports, and 
data related to the study and any additional records required to be maintained under country, 
state/province, or national and local laws, including, but not limited to: 
• full case histories 
• signed informed consent forms 
• patient identification lists 
• case report forms for each patient on a per visit basis 
• data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, patient diary built into the handheld device) 
• safety reports 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
161 
• financial disclosure reports/forms 
• reports of receipt, use, and disposition of the IMPs 
• copies of all correspondence with sponsor, the IEC/IRB, and any competent authority 
The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the CRO or 
sponsor notifies the institution in writing that records may be destroyed. If, after 25 years from 
study completion, or earlier in the case of the investigational center closing or going out of 
business, the investigator reasonably determines that study record retention has become unduly 
burdensome, and sponsor has not provided written notification of destruction, then the 
investigator may submit a written request to sponsor at least 60 days before any planned 
disposition of study records. After receipt of such request, the sponsor may make arrangements 
for appropriate archival or disposition, including requiring that the investigator deliver such 
records to the sponsor. The investigator shall notify the sponsor of any accidental loss or 
destruction of study records. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
162 
APPENDIX L. DOCUMENTING A PRODUCT COMPLAINT 
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor. 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results: 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (www.ICMJE.org). Publication of the results will occur in a timely manner 
according to applicable regulations. In accordance with standard editorial and ethical practice, 
the sponsor will generally support publication of multicenter studies only in their entirety and not 
as individual investigational center data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements: 
• substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work 
• drafting the work or revising it critically for important intellectual content 
• final approval of the version to be published 
• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved 
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement. 
No patent applications based on the results of the study may be made by the investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor. 


 
Placebo Controlled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study FSS-AS-30003 
163 
APPENDIX M. DOCUMENTING A PRODUCT COMPLAINT 
 

SAP_001.pdf: 
Statistical Analysis Plan 
A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of 
Fluticasone Propionate Multidose Dry Powder Inhaler Compared with Fluticasone 
Propionate/Salmeterol Multidose Dry Powder Inhaler in Patients Aged 4 through 11 Years 
with Persistent Asthma 
Study Number FSS-AS-30003 
NCT02980133 
Statistical Analysis Plan Approval Date: 16 April 2019 


Statistical Analysis Plan 
Study FSS-AS-30003 
1 
 
 
Statistical Analysis Plan 
Study FSS-AS-30003 
 
A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of 
Fluticasone Propionate Multidose Dry Powder Inhaler Compared with Fluticasone 
Propionate/Salmeterol Multidose Dry Powder Inhaler in Patients Aged 4 through 11 Years 
with Persistent Asthma 
Phase 3 
 
 
 
IND number: 108,838 and 72,240; EudraCT number: 2016-003835-39 
 
 
Approval Date: 16 April 2019 
 
Sponsor 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States 
 
 
 
 
 
Prepared by: 
 
  


Statistical A nal ysis Pla n  
St u d y F S S -A S - 3 0 0 0 3 
2 
S T A TI S TI C A L A N A L Y SI S  P L A N A P P R O V A L  
 
St u d y N o.: 
F S S -A S - 3 0 0 0 3 
 
St u d y Title:  A 1 2 -Wee k, R a n d o mize d, D o u ble -Bli n d, Pl ace b o - C o ntr olle d, Effic ac y a n d  
  
 
S af et y St u d y of Fl utic as o ne Pr o pi o n ate M ulti d ose Dr y P o w der I n h aler  
  
 
C o m p are d wit h Fl utic as o ne Pr o pi o n ate/ S al meter ol M ulti d ose Dr y P o w der  
  
  
I n h aler i n P atie nts A ge d 4 t hr o u g h 1 1 Years wit h Persiste nt Ast h m a  
 
 
St atistic al A n al ysis Pl a n f or: 
 
☐ I nteri m A n al ysis    
 
☐ I nte gr ate d S u m m a r y of Effic ac y 
  
 X  X  Fi n al A n al ysis   
  
 
☐ I nte gr ate d S u m m a r y of S afet y 
 
 
 
A ut h or:  
 
  
 
 
 
 
 


Statistical Analysis Plan 
Study FSS-AS-30003 
3 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................8 
INTRODUCTION .........................................................................................................................10 
1. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................11 
1.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................11 
1.2. 
Other Efficacy Endpoints ...........................................................................................11 
2. 
STUDY DESIGN .......................................................................................................13 
2.1. 
General Design ...........................................................................................................13 
2.2. 
Randomization and Blinding ......................................................................................16 
2.3. 
Data Monitoring Committee .......................................................................................17 
2.4. 
Sample Size and Power Considerations .....................................................................17 
2.5. 
Sequence of Planned Analyses ...................................................................................18 
2.5.1. 
Planned Interim Analyses ...........................................................................................18 
2.5.2. 
Final Analyses and Reporting .....................................................................................18 
3. 
ANALYSIS SETS ......................................................................................................19 
3.1. 
Intent-to-Treat Analysis Set ........................................................................................19 
3.2. 
Safety Analysis Set .....................................................................................................19 
3.3. 
Per-Protocol Analysis Set ...........................................................................................19 
4. 
GENERAL ISSUES FOR DATA ANALYSIS ..........................................................20 
4.1. 
General ........................................................................................................................20 
4.2. 
Specification of Baseline Values ................................................................................20 
4.3. 
Handling Withdrawals and Missing Data ...................................................................23 
4.3.1. 
Missing Data Imputation for Efficacy Analysis .........................................................23 
4.3.2. 
Study Days and Visit Windows ..................................................................................23 
5. 
STUDY POPULATION .............................................................................................25 
5.1. 
General ........................................................................................................................25 
5.2. 
Patient Disposition ......................................................................................................25 
5.3. 
Demographics and Baseline Characteristics ...............................................................25 
5.4. 
Medical and Asthma History ......................................................................................25 
5.5. 
Prior Therapy and Medication ....................................................................................26 


Statistical Analysis Plan 
Study FSS-AS-30003 
4 
5.6. 
Physical Examinations ................................................................................................26 
5.7. 
Childbearing Potential and Methods of Contraception ..............................................26 
5.8. 
Study Protocol Violations ...........................................................................................26 
6. 
EFFICACY ANALYSIS ............................................................................................27 
6.1. 
General ........................................................................................................................27 
6.2. 
Primary Estimands and Efficacy Analyses .................................................................27 
6.2.1. 
Variable Definition .....................................................................................................30 
6.2.2. 
Primary Efficacy Analysis ..........................................................................................30 
6.2.2.1. 
For Fp MDPI versus Placebo: Change from Baseline in Weekly Average of 
the Percent Predicted Trough Morning FEV1 at Week 12 .........................................30 
6.2.2.2. 
For FS MDPI versus Fp MDPI: Change from Baseline in 1-hour Postdose 
Percent Predicted Morning FEV1 at Week 12 ............................................................31 
6.2.2.3. 
Sensitivity Analyses ....................................................................................................31 
6.2.3. 
Sub-Group Analyses ...................................................................................................33 
6.3. 
Secondary Efficacy Endpoints and Analysis ..............................................................34 
6.3.1. 
Variable Definitions ....................................................................................................34 
6.3.1.1. 
Weekly Average of the Daily Trough Morning PEF ..................................................34 
6.3.1.2. 
Weekly Average of Total Daily (24-Hour) Use of Albuterol/Salbutamol 
Inhalation Aerosol (Number of Inhalations) ...............................................................34 
6.3.1.3. 
Asthma Symptom Score .............................................................................................35 
6.3.1.4. 
Childhood Asthma Control Test Score .......................................................................35 
6.3.1.5. 
Time to First Onset of Effect ......................................................................................36 
6.3.1.6. 
Proportion of Patients Discontinued From IMP for Asthma Exacerbation 
During the 12-week Treatment Period .......................................................................36 
6.3.2. 
Analysis Methods for Secondary Efficacy Variables .................................................36 
6.3.2.1. 
Change from Baseline in the Weekly Average of Daily Trough Morning 
(Predose and Prerescue Bronchodilator) Peak Expiratory Flow (PEF) Over 
the 12-week Treatment Period ....................................................................................36 
6.3.2.2. 
Change from Baseline in the Weekly Average of Total Daily (24-hour) use 
of Albuterol/Salbutamol Inhalation Aerosol (Number of Inhalations) Over 
Weeks 1 Through 12 ...................................................................................................36 
6.3.2.3. 
Change from Baseline in the Weekly Average of the Total Daily Asthma 
Symptom Score (Defined as the Average of the Daytime and Nighttime 
Scores) Over Weeks 1 Through 12 .............................................................................37 
6.3.2.4. 
Change from Baseline in Asthma Control (Measured by Childhood Asthma 
Control Test [C-ACT] Score Over the 12-week Treatment Period ............................37 


Statistical Analysis Plan 
Study FSS-AS-30003 
5 
6.3.2.5. 
Time to First Onset of Effect in Daily Rescue Medication Use .................................37 
6.3.2.6. 
Proportion of Patients Discontinued From IMP for Asthma Exacerbation 
During the 12-week Treatment Period .......................................................................38 
6.4. 
Other Efficacy Endpoints Analysis ............................................................................38 
6.4.1. 
Definition ....................................................................................................................39 
6.4.1.1. 
Percentage of Rescue-free 24-Hour Periods ...............................................................39 
6.4.1.2. 
Percentage of Symptom-free 24-Hour Periods ...........................................................39 
6.4.1.3. 
Percentage of Asthma-control 24-Hour Periods .........................................................39 
6.4.1.4. 
Weekly Average of the Daily Trough Evening PEF ..................................................39 
6.4.1.5. 
Time to Consistent Onset of Effect ............................................................................40 
6.4.2. 
Analysis Methods for Other Efficacy Variables .........................................................40 
6.4.2.1. 
Change from Baseline in the Weekly Average of the Total Daily (24-hour) 
use of Albuterol/Salbutamol Inhalation Aerosol (Number of Inhalations) at 
Weeks 4, 8, and 12 ......................................................................................................40 
6.4.2.2. 
Change from Baseline in the Percentage of Rescue-free Days (Defined as 
24-hour Periods with no Rescue Medication Usage) During the 12-week 
Treatment Period ........................................................................................................40 
6.4.2.3. 
Change from Baseline in the Percentage of Symptom-free Days (Defined as 
24-hour Periods with Asthma Symptom Score of 0) During the 12-week 
Treatment Period ........................................................................................................41 
6.4.2.4. 
Change from Baseline in the Percentage of Asthma-control Days (Defined as 
24-hour Periods with Asthma Symptom Score of 0 and no Rescue 
Medication usage) During the 12-week Treatment Period .........................................41 
6.4.2.5. 
Change from Baseline in 1-Hour Postdose Percent Predicted Morning FEV1 
at Week 1 ....................................................................................................................41 
6.4.2.6. 
Change from Baseline in the Weekly Average of the Daily Evening PEF 
Over the 12-week Treatment Period ...........................................................................41 
6.4.2.7. 
Change from Baseline in Weekly Average of the Percent Predicted Trough 
Morning FEV1 at weeks 1, 2, 4 and 8 .........................................................................41 
6.4.2.8. 
Proportion of Patients who Achieve at Least a 15% increase in morning 
FEV1 at 1-hour postdose at Day 1 (RV/TV1), Week 1, and Week 12 .......................42 
6.4.2.9. 
Change from Baseline in Asthma Control (measure by C-ACT) score at 
Weeks 4, 8, and 12 ......................................................................................................42 
6.4.2.10. 
Time to Consistent Onset of Effect in Daily Rescue Medication Use .......................42 
7. 
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................43 
7.1. 
Multiple Comparisons for the Primary Analysis ........................................................43 
7.2. 
Multiple Comparisons for the Secondary Analysis ....................................................43 


Statistical Analysis Plan 
Study FSS-AS-30003 
6 
8. 
SAFETY ANALYSIS ................................................................................................46 
8.1. 
General ........................................................................................................................46 
8.2. 
Duration of Exposure to IMP .....................................................................................46 
8.3. 
IMP Compliance .........................................................................................................46 
8.4. 
Adverse Events ...........................................................................................................47 
8.5. 
Deaths .........................................................................................................................48 
8.6. 
Asthma Exacerbations ................................................................................................48 
8.7. 
Clinical Laboratory Tests ...........................................................................................49 
8.8. 
Physical Examinations ................................................................................................49 
8.9. 
Vital Signs ..................................................................................................................49 
8.10. 
Electrocardiography ....................................................................................................50 
8.11. 
Oropharyngeal Examinations .....................................................................................50 
8.12. 
Concomitant Medications or Therapies ......................................................................50 
9. 
TOLERABILITY VARIABLES AND ANALYSIS..................................................51 
10. 
STATISTICAL SOFTWARE ....................................................................................52 
11. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL ..............53 
12. 
REFERENCES ...........................................................................................................54 
APPENDIX A. MULTIPLE IMPUTATION STEPS FOR PRIMARY ENDPOINTS ..............55 
APPENDIX B. SENSITIVITY ANALYSIS: TIPPING POINT ANALYSIS ...........................58 
APPENDIX C. SENSITIVITY ANALYSIS: 2-DIMENSIONAL TIPPING POINT 
ANALYSIS.................................................................................................................62 
APPENDIX D. SENSITIVITY ANALYSIS: MIXED APPROACH OF LOCF AND 
BOCF ..........................................................................................................................67 
APPENDIX E. SENSITIVITY ANALYSIS: MMRM ...............................................................69 
 


Statistical Analysis Plan 
Study FSS-AS-30003 
7 
LIST OF TABLES 
Table 1: Treatment Group Description ..........................................................................................14 
Table 2: An Example of Baseline Electronic Patient Diary Data for Symptom-free Days ...........22 
Table 3: An Example of Baseline Electronic Patient Diary for Asthma-control days ..................23 
Table 4: Analysis Day ....................................................................................................................24 
Table 5: 
Standardized Baseline-adjusted Trough Morning FEV1 Area Under the 
Effect Curve from Time Zero to 6 Weeks for Individual Patient who 
Discontinued IMP with Retrieve Dropout Data .........................................................28 
Table 6: An example of shift amount in percent predicted FEV1 ..................................................32 
Table 7: Multiple Testing Procedures ............................................................................................43 
Table 8: Sequence of Testing Secondary Endpoints for Fp MDPI ................................................44 
Table 9: Sequence of Testing Secondary Endpoints for FS MDPI ...............................................45 
Table 10: Example of Unreturned Device or Dose Counter Error ................................................47 
Table 11: Criteria for Potentially Clinically Significant Vital Signs .............................................50 
Table 12: Changes to the Statistical Analysis Plan ........................................................................53 
 


Statistical Analysis Plan 
Study FSS-AS-30003 
8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
BP 
blood pressure 
BMI 
body mass index 
BOCF 
baseline observation carried forward 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
ECG 
electrocardiogram 
ET 
early termination (visit) 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
Fp MDPI 
fluticasone propionate multidose dry powder inhaler 
FS MDPI 
fluticasone propionate/salmeterol multidose dry powder inhaler 
ICH 
International Conference on Harmonisation 
ICS 
inhaled corticosteroid 
IMP 
investigational medicinal product 
IRT 
interactive response technology 
ITT 
intent-to-treat 
LABA 
long acting β2-agonist 
LOCF 
last observation carried forward 
LS 
least squares 
max 
maximum 
MAR 
missing at random  
MDI 
metered-dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDPI 
multidose dry powder inhaler 
min 
minimum 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
n 
number 


Statistical Analysis Plan 
Study FSS-AS-30003 
9 
NCS 
noncorticosteroid 
PEF 
peak expiratory flow 
PFT 
pulmonary function test(s) 
PP 
per-protocol  
PT 
preferred term 
RV 
randomization visit 
SAS 
statistical analysis system 
SABA 
short-acting β2-agonist 
SD 
standard deviation  
SDR 
statistical data review 
SE 
standard error 
SOC 
system organ class 
SV 
screening visit 
WHO Drug 
World Health Organization dictionary of medical terms 
 


Statistical Analysis Plan 
Study FSS-AS-30003 
10 
INTRODUCTION 
This Statistical Analysis Plan describes the planned analysis and reporting for Teva 
Pharmaceutical Global Respiratory Research and Development, Inc. Study FSS-AS-30003, (A 
12-Week, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of 
Fluticasone Propionate Multidose Dry Powder Inhaler Compared with Fluticasone 
Propionate/Salmeterol Multidose Dry Powder Inhaler in Patients Aged 4 Through 11 Years with 
Persistent Asthma), and was written in accordance with SOP GBP_RD_702 (Statistical Analysis 
Plan). 
The reader of this Statistical Analysis Plan is encouraged to read the study protocol for details on 
the conduct of this study, the operational aspects of clinical assessments, and the timing for 
completing the participation of a patient in this study.  
The Statistical Analysis Plan is intended to be in agreement with the protocol, especially with 
regards to the primary and all secondary endpoints and their respective analyses. However, the 
Statistical Analysis Plan may contain more details regarding these particular points of interest, or 
other types of analyses (e.g. other endpoints). When differences exist in descriptions or 
explanations provided in the study protocol and this Statistical Analysis Plan, the Statistical 
Analysis Plan prevails; the differences will be explained in the Clinical Study Report. 


Statistical Analysis Plan 
Study FSS-AS-30003 
11 
1. 
STUDY OBJECTIVES AND ENDPOINTS 
1.1. 
Primary and Secondary Study Objectives and Endpoints 
The primary objective of this study is to evaluate the efficacy of Fp MDPI and FS MDPI when 
administered over 12 weeks in patients 4 through 11 years of age with persistent asthma. 
The secondary objective of this study is to evaluate the safety and tolerability of Fp MDPI and 
FS MDPI. 
The primary efficacy endpoints are as follows: 
• For Fp MDPI versus placebo: the change from baseline in weekly average of the 
percent predicted trough morning forced expiratory volume in 1 second (FEV1) at 
week 12 
• For FS MDPI versus Fp MDPI: the change from baseline in 1-hour postdose percent 
predicted morning FEV1 at week 12 
The secondary efficacy endpoints are as follows: 
• Change from baseline in the weekly average of daily trough morning (predose and 
pre-rescue bronchodilator) peak expiratory flow (PEF) over the 12-week treatment 
period 
• Change from baseline in the weekly average of total daily (24-hour) use of 
albuterol/salbutamol inhalation aerosol (number of inhalations) over 
weeks 1 through 12 
• Change from baseline in the weekly average of the total daily asthma symptom score 
(defined as the average of the daytime and nighttime scores) over weeks 1 through 12 
• Change from baseline in asthma control (measured by Childhood Asthma Control 
Test [C-ACT]) score over the 12-week treatment period 
• Time to first onset of effect defined as the first decrease from baseline in daily rescue 
medication use  
• Proportion of patients discontinued from investigational medicinal product (IMP) for 
asthma exacerbation during the 12-week treatment period 
The sequential order of the secondary endpoints for multiplicity will be described in Section 7.2. 
1.2. 
Other Efficacy Endpoints 
The other efficacy endpoints are as follows: 
• Change from baseline in the weekly average of total daily (24-hour) use of 
albuterol/salbutamol inhalation aerosol (number of inhalations) at weeks 4, 8, and 12  
• Change from baseline in the percentage of rescue-free days (defined as 24-hour 
periods with no rescue medication usage) during the 12-week treatment period 


Statistical Analysis Plan 
Study FSS-AS-30003 
12 
• Change from baseline in the percentage of symptom-free days (defined as 24-hour 
periods with asthma symptom score of 0) during the 12-week treatment period 
• Change from baseline in the percentage of asthma-control days (defined as 24-hour 
periods with asthma symptom score of 0 and no rescue medication usage) during the 
12-week treatment period 
• Change from baseline in 1-hour postdose percent predicted morning FEV1 at week 1 
• Change from baseline in the weekly average of daily evening PEF over the 12-week 
treatment period 
• Change from baseline in the weekly average of the percent predicted trough morning 
FEV1 at weeks 1, 2, 4 and 8 
• Proportion of patients who achieve at least a 15% increase in morning FEV1 at 1 hour 
postdose at day 1 (randomization visit [RV]/treatment visit [TV] 1), week 1, and 
week 12 
• Change from baseline in asthma control (measured by C-ACT) score at weeks 4, 8, 
and 12  
• Time to consistent onset of effect defined as the decrease from baseline in daily 
rescue medication use on 3 consecutive days 


Statistical Analysis Plan 
Study FSS-AS-30003 
13 
2. 
STUDY DESIGN 
2.1. 
General Design 
This is a Phase 3, 12-week, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled study to evaluate the safety and efficacy of Fp MDPI and FS MDPI 
administered twice daily at doses of Fp MDPI 25 mcg, Fp MDPI 50 mcg, and FS MDPI 
50/12.5 mcg in pediatric patients with asthma. The total duration of patient participation in this 
study is approximately 15 to 17 weeks depending on the duration of the placebo run-in period.  
Patients meeting all of the inclusion criteria and none of the exclusion criteria at the screening 
visit (SV) will begin a 14- to 30-day run-in period. An albuterol/salbutamol 
hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (a SABA inhaler) will be provided to 
replace the patient’s current rescue medication and is to be used as needed for relief of asthma 
symptoms during the run-in and treatment periods, with a maximum of 8 inhalations permitted 
per day. Starting day 1 of the run-in period, patients must discontinue all non-study 
asthma-related drugs and instead take a patient-blinded MDPI placebo device (1 inhalation 
twice daily).  
The study consists of 3 periods as follows: 
• Patient-blinded run-in period: SV to RV, up to 30 days 
• Double-blind, randomized treatment period: RV through the TV6, approximately 
12 weeks  
• Follow-up period: TV6 through the follow-up visit (FV), approximately 7 days after 
TV6 
At the prescreening or SV, the patient or parent/legal guardian must provide informed consent, and 
patients must give assent (as applicable) before any study procedures are performed. At the time of 
informed consent, the parent/legal guardian will be counseled that, once randomized to treatment, 
patients are to remain in the study and complete all study procedures unless the choice is made to 
withdraw consent. This includes patients who may require alternative asthma therapy, experience an 
adverse event, violate the protocol, or fail to comply with study procedures. Continued patient 
participation is important to contribute to the scientific investigation.  
Patients will be provided with a handheld device at the SV, which will be used to measure lung 
function assessments (FEV1 and PEF) and will serve as an electronic patient diary to collect 
asthma symptom scores, rescue medication use, and IMP use. The run-in period will not start 
until patients have met all inclusion criteria and none of the exclusion criteria. 
Patients who qualify for entry into the placebo run-in period must discontinue all currently 
administered asthma medications until completion of the TV6 (week 12) visit or investigational 
medicinal product discontinuation visit (IMPDV) if, in the investigator’s judgment, there would 
be no inherent harm in changing the patient’s treatment and the patient or parent/legal guardian 
provides consent/assent (as applicable). Patients will be provided with albuterol/salbutamol HFA 
MDI or equivalent as rescue medication. During the run-in period (SV to RV), in addition to the 


Statistical Analysis Plan 
Study FSS-AS-30003 
14 
above rescue medication, patients will be provided with a patient-blinded placebo MDPI device 
for twice-daily use after appropriate training and demonstration of proper technique. 
All patients who enter the placebo run-in period will perform daily morning and evening lung 
function assessments (FEV1 and PEF) by handheld device at home and assess and record 
daytime and nighttime asthma symptom scores, rescue albuterol/salbutamol HFA MDI use, and 
morning and evening IMP dosing in the electronic patient diary built into the handheld device.  
At the RV (end of run-in period, TV1), patients will be assessed for randomization. Patients who 
meet all randomization inclusion criteria and continue meeting all inclusion criteria and none of 
the exclusion criteria will be stratified by previous therapy (inhaled corticosteroid [ICS] or 
noncorticosteroid [NCS]) and randomly assigned into the double-blind treatment period of the 
study in a 1:1:1:1 ratio to Fp MDPI 25 mcg, Fp MDPI 50 mcg, FS MDPI 50/12.5 mcg, or 
placebo MDPI, twice daily (see Table 1). Patients will be instructed to take 1 inhalation from the 
assigned device twice daily approximately 12 hours apart.  
Table 1: Treatment Group Description 
Treatment group 
Active devices 
Total daily dose (mcg) 
Blinding 
A 
Fp MDPI 25 mcg 
50 
Double-blind 
B 
Fp MDPI 50 mcg 
100 
Double-blind 
C 
FS MDPI 50/12.5 mcg 
100/25 
Double-blind 
D 
Placebo MDPI 
0 
Double-blind 
Fp=fluticasone propionate; FS=fluticasone propionate/salmeterol; MDPI=multidose dry powder inhaler. 
During the treatment period (RV through TV6 [week 12] or IMPDV), daily in the morning and 
evening at approximately the same time each day, patients will use the handheld device at home 
to record asthma symptom scores and rescue albuterol/salbutamol HFA MDI use, after which 
they will perform lung function assessments (FEV1 and PEF) and then will take their dose of the 
IMP and record IMP dosing in the electronic patient diary built into the handheld device. 
On the morning of each TV, patients will be instructed to record their asthma symptom score and 
rescue albuterol/salbutamol HFA MDI use and complete their morning lung function 
assessments (FEV1 and PEF) by handheld device as usual, but to delay IMP dosing until they get 
to the investigational center. Patients are also to withhold their rescue SABA for a minimum of 6 
hours prior to obtaining lung function assessments. If the patient inadvertently takes the morning 
IMP dose or rescue medication within 6 hours of the planned lung function assessments, the visit 
must be rescheduled. Similarly, patients who have been withdrawn from IMP but remain in the 
study should withhold their alternative asthma therapy dosing until after treatment visit 
assessments and avoid rescue medication for a minimum of 6 hours prior to clinic lung function 
assessments. The treatment visit should be rescheduled if either or both occur. 
At the investigational center, after appropriate instruction and training (competent handheld 
device use and dosing technique using the training devices provided), patients will perform their 
lung function assessment (FEV1 and PEF) under the supervision of the investigational center 
staff. They will then take their morning dose of the IMP unless IMP has been withdrawn. IMP 
administration at the investigational center should be timed so that lung function assessments 
will be approximately 12 hours following the doses taken the previous evening. Patients will 


Statistical Analysis Plan 
Study FSS-AS-30003 
15 
then perform 1-hour postdose FEV1 measurements using the handheld device. Patients who have 
been withdrawn from IMP will be asked to perform 1-hour postdose lung function assessments; 
although the patients will not be taking a dose of IMP, the assessment should be approximately 
1-hour after the predose lung function assessments were obtained. 
At each visit, the investigational center will determine if patients have experienced any adverse 
events, changes in medical history, changes in medication, or any difficulty following study 
procedures. The C-ACT will be completed by the patient and the patient’s parent/legal 
guardian/caregiver (as applicable) at the investigational center, before any other assessments are 
performed, at specified visits. The same parent/legal guardian/caregiver should complete the 
assessments at each visit, if possible. 
After the last TV (TV6, week 12), the patient will enter the follow-up period. One week 
(±2 days) after the last TV or the IMPDV, the patient will have a follow up visit (FV). This FV 
may be in person or over the telephone. The patient will be deemed to have completed the 
treatment period if they have completed all periods of the study, including screening, run-in, and 
all TVs. The patient will be deemed to have completed the study period if they have completed 
all periods of the study, including FV in additional to screening, run-in, and all TVs. Patients 
who stop IMP and return for safety evaluation at week 12 but who do not complete the FV will 
still be considered to have completed the treatment period for the purposes of primary analysis. 
Study procedures and assessments with their time points are summarized in Table 3 of the study 
protocol. 
The study schematic diagram is presented in Figure 1. 


Statistical Analysis Plan 
Study FSS-AS-30003 
16 
Figure 1: 
Overall Study Schematic Diagram 
 
Fp=fluticasone propionate; FS=fluticasone propionate/salmeterol; IMPDV=investigational medicinal product 
discontinuation visit; MDPI=multidose dry powder inhaler; RV=randomization visit; SV=screening visit; 
TV=treatment visit. 
2.2. 
Randomization and Blinding 
This is a double-blind, parallel-group, placebo-controlled, randomized clinical study. Patients 
who meet all randomization criteria at the RV will be stratified by previous therapy (ICS or 
NCS) and randomly assigned into a 1:1:1:1 ratio to receive Fp MDPI 25 mcg, Fp MDPI 50 mcg, 
FS MDPI 50/12.5 mcg, or placebo MDPI, twice daily, for the entire treatment period. 
Randomization will be assigned via IRT. Patients being treated with a combination of ICS/NCS 
will be stratified as an ICS patient.  
Approximately 206 patients will be randomized into each treatment group (approximately 
824 patients in total). After the run-in period, patients and parents/legal guardians/caregivers will 
remain blinded to randomized treatment assignment during the study. In addition, the 
investigator and the sponsor’s clinical personnel involved in the study will be blinded to the IMP 
identity after the run-in period until the database is locked for analysis and the treatment 
assignment is revealed. 
No effort will be made to maintain a balance among treatment groups within an investigational 
center. 


Statistical Analysis Plan 
Study FSS-AS-30003 
17 
Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list. The specifications for randomization will be under the responsibility and 
oversight of Teva Global Statistics. The output of the randomization process will be a patient 
randomization list. 
The sponsor’s clinical personnel involved in the study will be blinded to the identity of the 
treatment until the database is locked for analysis and the treatment assignment revealed. 
2.3. 
Data Monitoring Committee 
There will be no data monitoring committee in this study. 
2.4. 
Sample Size and Power Considerations 
Sample size and power calculations are driven by demonstrating superiority of FS MDPI 
50/12.5 mcg twice daily over Fp MDPI 50 mcg twice daily in change from baseline in 1-hour 
postdose percent predicted morning FEV1 at week 12 and the superiority of Fp MDPI 50 mcg 
twice daily over placebo in change from baseline in percent predicted trough morning FEV1 at 
week 12. 
For the superiority comparison of FS MDPI 50/12.5 mcg twice daily versus Fp MDPI 50 mcg 
twice daily, assuming that the change from baseline in 1-hour postdose percent predicted 
morning FEV1 at week 12 is analyzed using an ANOVA model with only a single factor of 
treatment group, the following assumptions were made: 
• The initial assumed common standard deviation (SD) was 9.3% and the true 
treatment difference was 4.5% between FS MDPI 50/12.5 mcg twice daily and Fp 
MDPI 50 mcg twice daily. This assumption was based on data collected in previous 
Teva studies with the same Fp MDPI and FS MDPI products in adult asthma patients 
who completed the 12-week treatment period and based on office-based spirometry.  
• The initial power was 97% at a 2-sided significance level of 5%.  
For the superiority comparison of Fp MDPI 50 mcg twice daily versus placebo, assuming that 
the change from baseline in percent predicted trough morning FEV1 at week 12 is analyzed using 
an analysis of variance (ANOVA) model with only a single factor of treatment group, the 
following assumptions were made: 
• The initial assumed common standard deviation (SD) was 13.25% and the true 
treatment difference was 5% between Fp MDPI 50 mcg twice daily and placebo. This 
assumption was based on data collected in previous Teva studies with the same 
Fp MDPI product in adult asthma patients and based on office-based spirometry 
• The initial power was 85% at a 2-sided significance level of 5%.  
Study FSS-AS-30003 is the very first study in which a handheld spirometry device is utilized 1) 
as the primary endpoint in a Phase 3 study and 2) in a pediatric asthma patient population for a 
pivotal study of this scale. This made it difficult to predict the actual variability of the data. A 
blinded sample size reassessment was not planned. Routine blinded data monitoring of this study 
FSS-AS-30003 revealed that the SD for the overall study population is indeed higher than the 
initial assumptions. In addition, FEV1 stability has been monitored closely throughout this study 


Statistical Analysis Plan 
Study FSS-AS-30003 
18 
(see Clinical Study Protocol FSS-AS-30003 Section 6.1.3 for detail). A number of alerts were 
determined by the investigators as not related to worsening asthma but rather due to poor 
patients’ effort, which has been challenging in this patient population as young as 4 years of age, 
despite the rigorous training and coaching provided by the investigators. To ensure the high 
quality of the FEV1 data and integrity of the study, an unplanned blinded data quality evaluation 
and sample size reassessment was conducted. Some of the initial assumptions and the sample 
size described above were revised to the following: 
• For the superiority comparison of FS MDPI 50/12.5 mcg twice daily versus Fp MDPI 
50 mcg twice daily, the SD was revised to 22% and the overall mean change from 
baseline was revised to 6.5% (blinded SD observed after 427 patients completed 
week 12 of this study (excluding IMPD)) and the power down to 80%.  
• With these assumptions, 181 patients per treatment group are required for the 2-sided 
test of FS MDPI 50/12.5 mcg twice daily and Fp MDPI 50 mcg twice daily. 
• For the superiority comparison of Fp MDPI 50 mcg twice daily versus placebo, the 
SD was revised to 17% and overall mean change from baseline was 5% (blinded SD 
observed after 434 patients completed week 12 of this study (excluding IMPD) and 
the power was revised to 80%.  
• With these assumptions, 181 patients per treatment group are required for the 2-sided 
test of Fp MDPI 50 mcg twice daily versus placebo. 
Based on current blinded data and assuming a dropout rate of 12%, a total of 824 patients 
(206 patients per treatment group) will be randomized (initial assumption for dropout rate was 
15%). 
2.5. 
Sequence of Planned Analyses 
2.5.1. 
Planned Interim Analyses 
No formal interim analysis was initially planned for this study. However, this study is the very 
first study in which the handheld spirometry device is utilized as the primary endpoint and the 
study is conducted in a pediatric patient population across several age groups; Routine blinded 
data monitoring of this study revealed that the SD for the overall study population is higher than 
the initial assumptions based on the adult asthma patient population. Therefore, some of the 
initial assumptions and the sample size initially used were revised. 
2.5.2. 
Final Analyses and Reporting 
All analyses identified in this statistical analysis plan will be performed only after the last patient 
has completed the study as defined in the study protocol. The statistical analysis plan and any 
corresponding amendments will be approved before database lock, in accordance to SOP 
GBP_RD_702 (Statistical Analysis Plan). The randomization codes will not be unblinded until 
database lock. 
Any exploratory analyses completed to support study analyses, which were not identified in this 
statistical analysis plan, will be documented and reported in the CSR.  


Statistical Analysis Plan 
Study FSS-AS-30003 
19 
3. 
ANALYSIS SETS 
3.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all randomized patients. 
In the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received. 
The ITT analysis set will serve as the primary analysis set for the efficacy analyses. 
3.2. 
Safety Analysis Set 
The safety analysis set will include all randomized patients who receive at least 1 dose of IMP. 
In the safety analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized, unless otherwise specified. 
The safety analysis set will be used for all analyses of safety data. 
3.3. 
Per-Protocol Analysis Set 
The per-protocol (PP) analysis set is a subset of the ITT analysis set including only patients 
without protocol violations that could have an effect on the primary outcome and who have 
greater than or equal to 80% compliance to the IMP over the entire treatment period. The 
compliance rate calculation is detailed in Section 8.3.  
PP analysis set will be determined before unblinding at the Statistical Data Review (SDR) 
meeting and documented in the SDR meeting minutes. Note that since the use of incorrect IMP 
will be considered a protocol violation and will not be included in the PP analysis set, for 
treatment assignment in the PP analysis set, “as randomized” will coincide with “as treated”. 
The PP analysis set will serve as the supportive population for the primary efficacy analysis only. 


Statistical Analysis Plan 
Study FSS-AS-30003 
20 
4. 
GENERAL ISSUES FOR DATA ANALYSIS 
4.1. 
General 
Descriptive statistics for continuous variables include n, mean, SD, standard error (SE), median, 
minimum, and maximum. Descriptive statistics for categorical variables include patient counts 
and percentages, missing category will be displayed as appropriate. 
Inferential statistics for repeated measures and analysis of covariance (ANCOVA) analyses 
include least squares (LS) mean and SE of the LS mean, estimated treatment difference, 95% 
confidence interval (CI), and p-value. 
For patients who prematurely discontinued study IMP participation for any reason but remain in 
the study for their scheduled weekly efficacy evaluation, data collected on other alternative 
therapies received after IMP discontinuation are defined as “retrieved dropout” data. 
Data values which are deemed implausible from a clinical perspective (eg, post-randomization 
pre-bronchodilator percent predicted FEV1 is ≥200% while the baseline FEV1 was <85% as 
required by the protocol Inclusion/Exclusion criteria) will be identified and assessed at the SDR 
meeting and before unblinding of the database. Any percent predicted FEV1 values that are 
≥200% will be treated as missing and excluded from all data analyses. Exclusion of data values 
will be documented and justified in the clinical study report. 
4.2. 
Specification of Baseline Values 
In general, the baseline values for efficacy and safety variables are defined as the last observed 
data before the first dose of study drug, unless otherwise noted.  
For data collected daily in electronic patient diaries (ie, daily FEV1, PEF, asthma symptom 
scores, rescue medication use, etc.), baseline is defined as the average of daily data recorded in 
the 7 days before randomization. The prerandomization day consists of the electronic patient 
diary entries on the evening prior to the RV (TV1) or on the morning of the RV (TV1) for 
evening or morning FEV1 and PEF values, respectively. The first postbaseline record is the data 
collected after the first dose on the evening of the RV (TV1). Patients have to record baseline 
values on at least 5 out of the last 7 days prior to the RV in order to be randomized, nonetheless, 
a few patients who were randomized with less than 5 nonmissing values. To eliminate number of 
missing baseline values, rules for handling missing electronic patient’s diaries are specified 
below. 
Weekly Average Percent Predicted Trough Morning FEV1 and Trough Morning PEF: 
The baseline percent predicted trough morning FEV1 or trough morning PEF is defined as the 
average of recorded (nonmissing) percent predicted trough morning FEV1 or trough morning 
PEF assessments over the 7 days prior to randomization. The first day before randomization 
consists of the electronic patient diary entry at home on the morning of the RV (TV1). A patient 
has to record trough morning FEV1 and trough morning PEF values on at least 5 out of the last 7 
days prior to the RV in order to be randomized. In case there are less than 5 non-missing values, 
the trough morning FEV1 or trough morning PEF record will include days beyond 7 days prior to 
the randomization to ensure that the baseline value can be calculated. If a minimum of 


Statistical Analysis Plan 
Study FSS-AS-30003 
21 
5 nonmissing values cannot be satisfied during the entire run-in period (14-30 days), the patient’s 
percent predicted trough morning FEV1 or trough morning PEF baseline values will be replaced 
by the overall baseline value. 
1-Hour Percent Predicted Trough Morning FEV1: 
The baseline 1-hour percent predicted trough morning FEV1 is defined as the predose percent 
predicted trough morning FEV1 measurement at the RV (TV1) at the investigational center. If 
the predose FEV1 measurement is missing or the value is implausible, the baseline weekly at 
home average percent predicted trough morning FEV1 will be used. If both, the baseline pre-dose 
FEV1 measurement and the baseline weekly average percent predicted trough morning FEV1 are 
missing, the baseline trough morning FEV1 will be replaced by the overall baseline 1-hour value.  
Trough Evening PEF:  
The baseline trough evening PEF is defined as the average of recorded (nonmissing) trough 
evening PEF assessments over the 7 days prior to randomization. The first day before 
randomization consists of the electronic patient diary entry on the evening before the RV (TV1). 
Five out of the last 7 days nonmissing values are required for a patient to be randomized and to 
calculate the baseline value. In case the minimum of 5 nonmissing values cannot be satisfied 
during the entire run-in period (14-30 days), the patient’s evening PEF baseline value will 
include days beyond 7 days prior to the randomization. If a minimum of 5 nonmissing values 
cannot meet, missing baseline value will be replaced by the overall trough evening PEF value. 
Total Daily (24-Hour) Use of Albuterol/Salbutamol Inhalation Aerosol (Number of 
Inhalations):  
Throughout the study albuterol/salbutamol inhalation aerosol will be provided to patients to be 
used as needed for the relief of asthma symptoms. Patients will record intake (number of 
inhalations) of rescue medication each morning and evening in the electronic patient diary. An 
entry of zero inhalations for both morning and evening will indicate a rescue-free 24-hour 
period. 
The baseline value is defined as the average number of inhalations over each 24-hour (day and 
night) period over the 7 days prior to the date of the first dose. Patients should withhold their 
rescue medication for at least 6 hours prior to the morning of the RV (TV1), and all other study 
visits. Five out of last 7 days nonmissing values are required for patient to be randomized. No 
missing data imputation rule will apply. 
Percentage of Rescue-free Days (24-Hour Periods): 
A rescue-free day is defined as a 24-hour period with no use of rescue medication recorded. The 
baseline percentage of rescue-free days is defined as the percentage of rescue-free days over the 
7 days prior to the RV. An entry of zero inhalations for both morning and evening will indicate a 
rescue-free 24-hour period. 
Total Daily (24-Hour) Asthma Symptom Score: 
The total daily asthma symptom score is defined as the average of the daytime and nighttime 
scores. The baseline total daily asthma symptom score is defined as the average of recorded 
(nonmissing) total daily asthma symptom scores over the 7 days prior to randomization. Five out 
of the last 7 nonmissing values are required for a patient to be randomized. If a minimum of 


Statistical Analysis Plan 
Study FSS-AS-30003 
22 
5 nonmissing values cannot be satisfied during the entire run-in period (14-30 days), the patient’s 
asthma symptom score will include days beyond 7 days prior to the randomization or replaced by 
the overall asthma symptom score. No missing data imputation rule will apply. 
Percentage of Symptom-free Days (24-Hour Periods): 
Symptom-free days are defined as 24-hour periods with asthma symptom scores of zero recorded 
on the asthma symptom score electronic patient diary for both morning and evening entries. The 
baseline is defined as the percentage of symptom-free days over the 7 days prior to 
randomization. 
A 24-hour symptom-free period is associated with a score of zero on the asthma symptom score 
diary for both morning and evening entries. Should either the morning or evening entry be 
missing and the other value is equal to zero, the available value will be weighted by half, and 
similarly the denominator will be modified to reflect the missing value. If both, morning and 
evening values, are missing for a particular day, the value will not be used in the calculation of 
percentage. Table 2 illustrates a week of baseline symptom score and imputation rules as 
recorded in the electronic patient diary. 
Table 2: An Example of Baseline Electronic Patient Diary Data for Symptom-free Days 
Analysis Day  
Morning score  
Evening score  
Value used for 
numerator of 
percentage calculation  
Value used for 
denominator of 
percentage calculation  
1  
3  
0  
0  
1  
2  
Missing  
Missing  
Not used in calculations  
Not used in calculations  
3  
0  
0  
1  
1  
4  
1  
3  
0  
1  
5  
Missing  
2  
0  
1/2 
6  
Missing  
0  
1/2  
1/2 
7  
0  
0  
1  
1  
Week’s total  
2.5  
5  
The percent of symptom-free 24-hour periods for this example is derived as 2.5/5*100% = 50%. 
Similar rules apply to on-therapy interval. 
Percentage of Asthma-control Days (24-Hour Periods): 
Asthma-control days are defined as scores of zero recorded on the asthma symptom score diary 
during the 24-hour period and no rescue medication usage during the same 24-hour period. The 
baseline is defined as the percentage of asthma-control days over the 7 days prior to 
randomization. Detailed imputation rules are specified in Table 3. 


Statistical Analysis Plan 
Study FSS-AS-30003 
23 
Table 3: An Example of Baseline Electronic Patient Diary for Asthma-control days 
Analysis 
Day 
Total Daily Asthma Score / Rescue 
Medication Usage 
Value used for 
numerator of percentage 
calculation 
Value used for 
denominator of 
percentage calculation 
-1 
3 / 0 
0 
1 
-2 
Missing / 0 
Not used in calculations 
Not used in calculations 
-3 
0 / 0 
1 
1 
-4 
Missing / 3 
0 
1 
-5 
0 / 3 
0 
1 
-6 
3 / 3  
0 
1 
-7 
Missing / Missing  
Not used in calculations 
Not used in calculations 
Week’s total 
1 
5 
The percent of asthma-control days for this example is derived as 1/5*100% = 20%. Note that if 
a patient’s asthma score is missing, and there is no rescue medication usage during the same 24-
hour period, the asthma-control days will not be used in calculations. 
4.3. 
Handling Withdrawals and Missing Data 
4.3.1. 
Missing Data Imputation for Efficacy Analysis 
The primary analysis and sensitivity analyses for the primary endpoints include reference-base 
multiple imputations for missing data and tipping point approaches as detailed in Section 6 and 
Appendix A.  
For endpoints analyzed using the mixed model for repeated measures (MMRM), there will be no 
imputation for missing data. 
For all other variables, only the observed data from the patients will be used in the statistical 
analyses (ie, there is no plan to estimate missing data). 
4.3.2. 
Study Days and Visit Windows 
Study days are numbered relative to the first day of IMP administration. The start of treatment 
(Day 1) is defined as the date on which a patient takes the first dose of IMP. Days will be 
numbered relative to treatment start (ie, ..., –2, –1, 1, 2, ...; with day 1 being the first day of IMP 
administration and day –1 being the day before the first day of IMP drug administration). 
For data collected at the investigational center visits, such as RV (TV1), TV2 toTV6/IMPDV, 
efficacy and safety data will be analyzed using the visit recorded in the case report forms (CRFs) 
unless otherwise stated for by-visit summaries. If there are multiple assessments at a postbaseline 
visit, then the last nonmissing assessment at that visit will be used for the summary. This 
includes assessments at scheduled and unscheduled visits (the reason for the unscheduled visit 
has to be included for that particular assessment). If there are both scheduled and unscheduled 
visits with nonmissing results at the specific visit, the last nonmissing assessment will be used 
for the summary. For the purpose of the efficacy analysis, assessments collected at the 


Statistical Analysis Plan 
Study FSS-AS-30003 
24 
unscheduled early termination visit will be assigned to the next scheduled visit and also used as 
the final assessment for the final assessment summaries. 
For the analysis of electronic patient diary recorded data (ie, pulmonary function test [PFT], 
rescue medication usage and asthma symptom score, etc.), the day used for analysis consists of 
the evening assessment for the date of the first dose of IMP and the morning assessment for the 
following day as illustrated in Table 4. 
Weekly average data will be generated using 7-day windows based on study days (before and 
after the first dose of double-blind IMP). For example, week 6 will start from day 36 to day 42. 
A summary will be provided using the derived week window. 
Table 4: Analysis Day 
Analysis day 
Study day 
Time point 
-1 
1 (predose) 
AM 
1 
1 
PM 
2 
AM 
2 
2 
PM 
3 
AM 
X 
X 
PM 
X + 1 
AM 
84 
84 
PM 
85 
AM 


Statistical Analysis Plan 
Study FSS-AS-30003 
25 
5. 
STUDY POPULATION 
5.1. 
General 
The ITT analysis set will be used for all study population summaries unless otherwise specified. 
Summaries will be presented by treatment group and for all patients. 
5.2. 
Patient Disposition 
The following data will be summarized using descriptive statistics: patients screened; patients 
screened but not enrolled (and reason); patients enrolled in the run-in period; patients enrolled in 
the run-in period but not randomized (and reason); patients randomized; patients randomized but 
not treated; ITT analysis set, patients in the ITT with retrieved data, ITT without retrieved data, 
safety, and PP analysis sets; patients who complete the treatment, and patients who withdraw 
from the treatment (and reason); patients who complete the study, and patients who withdraw 
from the study (and reason) will be summarized using counts and percentages. The summary will 
include all patients screened. The denominator for calculation of percentages will be the number 
of randomized patients. All disposition information for screened patients will be provided in a 
listing by patient.  
5.3. 
Demographics and Baseline Characteristics 
Demographics variables (age, age group [4-6 years, 7-11 years], ethnicity, race, sex, weight, 
height, and body mass index [BMI]) will be summarized using descriptive statistics (refer to 
section 4.1). Baseline characteristics (baseline percent predicted FEV1, baseline PEF, and 
previous asthma therapy [ICS or NCS], etc.) will also be summarized using descriptive statistics. 
Patient demographics will be presented for both ITT and Safety analysis sets. The PP analysis set 
will be presented if the difference between ITT and PP is more than 5 patients in any of the 
treatment arm.  
A listing for demographics and baseline characteristics in the ITT analysis set will be presented. 
Patient demographic and baseline characteristics, including medical history, and prior 
medications and therapies will be examined to assess the comparability of the treatment groups 
and will be summarized using descriptive statistics (refer to section 4.1). Categories for missing 
data will be presented if necessary. 
5.4. 
Medical and Asthma History 
All medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of medical history abnormalities will be summarized using 
descriptive statistics by system organ class (SOC) and preferred term (PT). Patients are counted 
only once in each PT and SOC category. Patients who have a medical history assessment, with at 
least 1 abnormal finding and abnormal findings for each category will be summarized by 
treatment group and for all patients. 


Statistical Analysis Plan 
Study FSS-AS-30003 
26 
5.5. 
Prior Therapy and Medication 
Any prior therapy and medication before study drug administration will be recorded on the CRF. 
Trade name or international nonproprietary name, indication, and dosage will be recorded. The 
sponsor will encode all therapy and medication according to the World Health Organization 
(WHO) drug dictionary (WHO Drug). 
The incidence of prior therapies and medications will be summarized using descriptive statistics 
(count and percentages) by therapeutic class and PT. Patients are counted only once in each 
therapeutic class category, and only once in each preferred term category. Prior therapies and 
medications will include all medications taken and therapies administered before the first day of 
IMP administration. 
5.6. 
Physical Examinations 
Physical examinations, including height and weight, will be performed at the SV and at the final 
treatment visit (TV6/IMPDV). Patients with a physical examination, patients with at least 1 
abnormal finding, and abnormal findings for each category will be summarized at baseline using 
descriptive statistics (counts and percentages). Abnormal values at or before screening will be 
reported as a part of medical history. 
5.7. 
Childbearing Potential and Methods of Contraception 
For all female patients, childbearing potential and premenarchal status will be listed.  
5.8. 
Study Protocol Violations 
Data from patients with any protocol violation (as recorded in protocol violation CRF) during the 
study will be summarized overall and for each category using descriptive statistics. Of note, 
medication errors, overdose, misuse, abuse, off-label use, and occupational exposure will be 
summarized in category "Non-Compliance to study medication”. 
Patient with at least 1 protocol violation for each category will be summarized using count and 
percentages. 


Statistical Analysis Plan 
Study FSS-AS-30003 
27 
6. 
EFFICACY ANALYSIS 
6.1. 
General 
The ITT analysis set will serve as the primary analysis set for all efficacy analyses, the PP 
population will serve as a supportive population for the primary efficacy analyses, as detailed 
below. Summaries will be presented by treatment group, unless specified otherwise.   
Descriptive statistics (n, mean, SD, SE, median, min, and max) for efficacy variables and change 
from baseline will be provided by visit or week window, as appropriate. Final assessments will 
compare between treatment groups. 
6.2. 
Primary Estimands and Efficacy Analyses 
The estimands selected for the 2 primary endpoints will assess the change from baseline due to 
the initially randomized treatment as actually taken. These estimands assess the effectiveness at 
week 12, focusing on the causal effects attributable to the initially randomized medication. The 
sponsor will make all efforts to avoid study withdrawal in this 12-week study. In instances where 
a patient decides to discontinue IMP or, more importantly, requires alternative therapy for 
worsening asthma or an asthma exacerbation, the investigators will be instructed to encourage 
the patient to continue in the study and return for planned visits until the study completion in 
order to collect data after IMP discontinuation.  
The question of whether to use data collected after IMP discontinuation is an ongoing debate in 
statistical literature, in particular for studies with symptomatic endpoints and when it is common 
for patients who dropout to switch therapies (Mallinckrodt et al 2016, Mallinckrodt 2013, Little 
and Kang 2015, O’Neill and Temple 2012). This study is designed as a placebo-controlled study 
and it is expected that patients randomized to placebo would discontinue IMP due to worsening 
asthma at a higher rate than those randomized to active treatment, which is known to be an 
efficacious drug as established by multiple studies. After a patient discontinues IMP due to 
worsening asthma, the patient will be placed on alternative asthma therapies. The first choice 
will be ICS or a combination of ICS/LABA, exactly the classes of drugs being studied. Other 
therapeutic choices will include systemic corticosteroids, additional medications other than ICS, 
or both. All alternatives are proven to alter the spirometry collected after that point and therefore 
not be appropriate for assessment of IMP effectiveness. Improvement of asthma would be 
expected as rapidly and early as 1 week for FEV1 for placebo patients placed on ICS (Szefler et 
al 1999). It has also been shown that patients placed on ICS with long acting beta-agonists can 
have significant improvement in serial FEV1 measurements on the same day (Corren et al 2007, 
Pearlman et al 1999). Therefore, any patient who discontinued IMP and was placed on 
alternative therapies would be expected to have rapid and demonstrable improvements in lung 
function approximating the levels measured at screening.  
The inclusion of patients who failed therapy and who were then treated with alternative 
medication would blunt the treatment effect, potentially causing the study to fail due to the 
analysis rather than the effectiveness of the treatment given during the study. These patients no 
longer represent a true placebo population and including them in the population for the primary 
outcome is not consistent with treatment by placebo. As a matter of fact, if retrieved drop outs 


Statistical Analysis Plan 
Study FSS-AS-30003 
28 
placed on the alternative therapy such as ICS or ICS/LABA treatments, the efficacy would be 
compared between two identical classes of drugs, making such comparison not appropriate for 
the clinical trial designed and powered as the placebo-controlled trial.  
In a study recently completed by Teva under IND 114865, Study BDB-AS-30039, patients randomized to 
placebo had indeed higher IMP discontinuation rates than patients randomized to either of the 3 active 
treatment arms with beclomethasone dipropionate breath-actuated inhaler (BAI). Study BDB-AS-30039 
was a randomized, double-blind, placebo-controlled, parallel-group trial that investigated the use of 
beclomethasone dipropionate BAI in patients 12 years of age and older with persistent asthma. Data 
from this study indicated that patients receiving placebo placed on alternative asthma therapies after 
IMP discontinuation had marked improvements in spirometry results collected after that IMP 
discontinuation (Table 5). Study BDB-AS-30039 had a shorter duration (6 weeks) than FSS-AS-30003 (12 
weeks) and included adults, but patients were encouraged to attend study visits after discontinuation of 
IMP. 
The study had 4 arms: placebo and 3 active treatment arms. IMP discontinuation rates were 
11.2% in the placebo treatment arm compared to 3.1% in the pooled active treatment arm; 10 of the 
patients treated with placebo (9.3%) withdrew due to worsening asthma, while only 2 patients 
combined from all 3 active groups withdrew due to worsening asthma (0.6%). Table 5 shows the data 
collected for each individual patient after resumption of alternative therapy resulted in large increases 
from baseline for placebo. 
Table 5: 
Standardized Baseline-adjusted Trough Morning FEV1 Area Under the 
Effect Curve from Time Zero to 6 Weeks for Individual Patient who 
Discontinued IMP with Retrieve Dropout Data 
Treatment 
Subject ID 
Including data 
after IMP 
discontinuation 
Excluding data 
after IMP 
discontinuation 
Difference 
(Including – 
Excluding data 
after IMP 
Treatment 
administered to 
patient after 
IMP 
discontinuation 
BAI  
320 mcg/day 
 
-358.3 
0.0 
-358.3 
Budesonide and 
formoterol with 
oral prednisone 
BAI  
320 mcg/day 
 
-181.7 
-125.0 
-56.7 
Oral prednisone 
BAI  
320 mcg/day 
 
-136.7 
-110.0 
-26.7 
Beclomethasone 
and montelukast 
BAI  
640 mcg/day 
 
75.0 
0.0 
75.0 
Oral 
methylprednisol
one 
MDI  
320 mcg/day 
 
-183.3 
-100.0 
-83.3 
Budesonide and 
formoterol 
Placebo 
 
-210.0 
-200.0 
-10.0 
Beclomethasone 
Placebo 
 
-106.7 
-285.0 
178.3 
Budesonide and 
montelukast 


Statistical Analysis Plan 
Study FSS-AS-30003 
29 
Treatment 
Subject ID 
Including data 
after IMP 
discontinuation 
Excluding data 
after IMP 
discontinuation 
Difference 
(Including – 
Excluding data 
after IMP 
Treatment 
administered to 
patient after 
IMP 
discontinuation 
Placebo 
 
-1.7 
-150.0 
148.3 
Oral 
prednisone 
Table 5: 
Standardized Baseline-adjusted Trough Morning FEV1 Area Under the 
Effect Curve from Time Zero to 6 Weeks for Individual Patient who 
Discontinued IMP with Retrieve Dropout Data (Continued) 
Treatment 
Subject ID 
Including data 
after IMP 
discontinuation 
Excluding data 
after IMP 
discontinuation 
Difference 
(Including – 
Excluding data 
after IMP 
Treatment 
administered to 
patient after 
IMP 
discontinuation 
Placebo 
 
143.3 
-155.0 
298.3 
Oral 
prednisone with 
budesonide and 
formoterol 
Placebo 
 
223.3 
-32.5 
255.8 
Oral 
prednisone and 
montelukast 
Placebo 
 
396.7 
0.0 
396.7 
Budesonide and 
formoterol 
Placebo 
 
976.7 
-5.0 
981.7 
Fluticasone and 
salmeterol 
Note: Data were not included for patients who withdrew from the study for worsening asthma for whom data post 
withdrawals was not available, since including and excluding data after IMP have the same value. 
An imbalance in treatment discontinuation rates was also observed in another study conducted by Teva. 
Study BDB-AS-302 was a 12-week randomized, double-blind, double-dummy, placebo-controlled, 
parallel-group trial that investigated the use of beclomethasone dipropionate BAI in pediatric patients 
aged 4 through 11 years with persistent asthma. Patients randomized to placebo had a higher rate of 
discontinuation from IMP (14.2%) compared to patients randomized to active treatment (range from 
7.9% to 10.4%). 
Based upon the experiences with Study BDB-AS-30039 and Study BDB-AS-302, Teva is concerned that an 
imbalance in treatment discontinuation rates coupled with a markedly reduced treatment effect as a 
result of alternative asthma therapies for patients randomized to placebo will likely result in a study that 
fails to show a statistically significant effect of investigational therapy. In light of these issues, retrieved 
dropout data will be used only for sensitivity analyses. Missing data for patients who discontinue IMP 
will be imputed using reference-based multiple imputations representing a missing not at random 
(MNAR) mechanism. This approach is discussed Mallinckrodt et al 2016 (sections 3.2 and 3.4 for 
estimand 2 in the paper). 


Statistical Analysis Plan 
Study FSS-AS-30003 
30 
6.2.1. 
Variable Definition 
A handheld device to measure FEV1 will be provided to patients at the SV and used to determine 
the percent predicted trough morning FEV1 throughout the course of the study. 
Weekly Average Percent Predicted Trough Morning FEV1: 
Baseline percent predicted trough morning FEV1 is defined as the average value of recorded 
(nonmissing) morning assessments 5 out of the last 7 days prior to randomization (Section 4.2 
for details). The first day before randomization consists of the electronic patient diary entry at 
home on the morning of the RV (TV1) and the first day postrandomization consists of electronic 
patient diary entry at home on the morning of the day after the RV (TV1).  
For postdose weekly average of percent predicted trough morning FEV1 measurements, the 
values will be the averages based on the available data for that week. The averages will be 
calculated as the sum of morning FEV1 values divided by the number of nonmissing 
assessments. There will be no imputation applied to postrandomization assessments. 
1-hour Postdose Percent Predicted Morning FEV1 at Week 12: 
The baseline predose FEV1 should be performed at the investigational center between the hours 
of 0530 and 1100 using the handheld device before administration of study drug or rescue 
medications (Section 4.2 for details).  
The IMP dose should be administered right after the predose FEV1 measurement (eg, within a 
10-minute window). The patient will then perform 1-hour (+/-10 minutes) postdose lung function 
assessments on week 12 at the investigational center.  
Electronic patient diary percent predicted FEV1 time will be compared with IMP dose time. If a 
percent predicted FEV1 measurement is performed after the IMP dose, a 10-minute window will 
be allowed and that measurement will be included in the analysis, otherwise the percent 
predicted FEV1 measurement will be ignored.   
Patients who have been withdrawn from IMP will be asked to perform 1-hour postdose lung 
function assessments; although the patients will not be taking a dose of IMP, the assessment 
should be performed approximately 1 hour after the predose lung function assessments were 
obtained. 
6.2.2. 
Primary Efficacy Analysis 
6.2.2.1. 
For Fp MDPI versus Placebo: Change from Baseline in Weekly Average of the 
Percent Predicted Trough Morning FEV1 at Week 12 
For the purpose of the efficacy analysis of weekly average of daily morning FEV1 
measurements, the FEV1 value at week 12 will be the average based on the available data for 
that week. The averages will be calculated as the sum of the morning FEV1 values divided by 
the number of nonmissing assessments. There will be no imputation applied to 
postrandomization daily assessments. 
The primary analysis of the change from baseline in weekly average of percent predicted 
morning FEV1 at week 12 due to the initially randomized treatment as actually taken will be 
analyzed using an ANCOVA model with effects due to baseline percent predicted trough 


Statistical Analysis Plan 
Study FSS-AS-30003 
31 
morning FEV1, sex, age, (pooled) investigational center, previous therapy (ICS or NCS), and 
IMP treatment group. Contrasts for pairwise treatment comparisons of interest will be 
constructed. The estimated treatment difference between each IMP treatment group and the 
placebo group will be presented together with the 2 sided 95% CI for the difference and the 
p-value. 
In this analysis, missing data that are caused by early dropouts from the study or from IMP 
(regardless of availability of retrieved dropout data) will be imputed using reference-based 
multiple imputations which represents a missing not at random (MNAR) mechanism. The 
reference-based multiple imputation method multiply imputes the missing data in treatment 
group based on an imputation model built using data from the placebo group. This will yield a 
conservative treatment effect estimate as compared to the estimate obtained from multiple 
imputations (MI) under a missing at random (MAR) mechanism. The methodology and 
algorithm used for imputation is described in Appendix A. 
6.2.2.2. 
For FS MDPI versus Fp MDPI: Change from Baseline in 1-hour Postdose 
Percent Predicted Morning FEV1 at Week 12 
The baseline predose percent predicted trough morning FEV1 will be performed at the 
investigational center at the RV (TV1) (Section 4.2 for details). The postdose percent predicted 
morning FEV1 (measured at the investigational center) at week 12 with the handheld device will 
be approximately 1-hour after the IMP administration. 
The co-primary endpoint change from baseline in 1-hour postdose percent predicted morning 
FEV1 at week 12 will be analyzed using an ANCOVA model with effects due to baseline trough 
morning percent predicted FEV1, sex, age, (pooled) investigational center, previous therapy (ICS 
or NCS), and IMP treatment group. Contrasts for pairwise treatment comparisons of interest will 
be constructed. The estimated treatment comparisons of interest will be presented together with 
the 2‑sided 95% CI for the difference and the p-value. Missing 1-hour postdose FEV1 data at 
week 12 will be handled similarly to the above (see Appendix A for details). 
For patients who completed the treatment period, but with clinically and physiologically 
implausible data (eg, percent predicted FEV1 values post-randomization is ≥200%), imputation 
will be based on measurements observed at previous weeks and in the same treatment group (this 
represent a MAR mechanism).  
6.2.2.3. 
Sensitivity Analyses 
The following list of sensitivity analyses are prespecified for this study, to evaluate alternative 
estimands and assess the robustness of the primary efficacy results. Each sensitivity analysis will 
be conducted for the 2 primary efficacy endpoints, unless otherwise noted. 
• Effectiveness with retrieved dropout data: to evaluate the estimand of the effect of the 
treatment regimens as actually taken (effectiveness), the analysis will be repeated 
including observed FEV1 data over 12 weeks, for patients who completed the 12-
week treatment period and for patients who discontinued from treatment earlier than 
week 12 but from whom the sponsor was able to collect efficacy data post 
discontinuation. Early withdrawal patients for whom the sponsor fails to retrieve data 
post discontinuation despite all attempts to contact the patient, a reference-based 


Statistical Analysis Plan 
Study FSS-AS-30003 
32 
imputation (RBI), which is an MNAR mechanism, will be utilized. The RBI method 
multiply imputes the missing data in every treatment group based on an imputation 
model built using data from the placebo group. This will yield a conservative 
treatment effect estimate as compared to the estimate obtained from multiple 
imputations (MI) under MAR (see Appendix A for details). 
• Treatment completer analysis: In this completer analysis, the estimand is conditional 
on taking IMP. This estimand applies to all patients in the ITT analysis set who have 
completed the 12-week treatment period; patients who have taken their medication as 
directed without any major protocol violations. Note that since the use of incorrect 
IMP is considered a major treatment administration protocol violation, “as 
randomized” will coincide with “as treated” for the treatment assignment in this 
population. No imputation will be used since this is a completer analysis. 
• “Tipping point” multiple imputations: similar to the primary estimand (change due to 
the initially randomized treatments as actually taken without retrieved dropout data), 
this sensitivity analysis will utilize multiple imputations under the MNAR 
assumption. For placebo patients, MAR will be assumed in all applications of 
multiple imputations. For the active arms, in the first application, MAR will be 
assumed and the imputations will be drawn from data in the corresponding active 
arms. In subsequent applications, shifts to the distribution of the active arms will be 
applied to represent different degrees of effect loss, ie, MNAR will be assumed. In 
this analysis, only data collected before IMP discontinuation will be utilized. If the 
sensitivity analysis reveals that the tipping point consists of unreasonable values, the 
robustness of the study results is supported. The methodology and algorithm used for 
imputations is provided in Appendix B. 
• “2-dimensional tipping point” multiple imputations: similar to above, the shifts to the 
distribution will apply to both placebo and active arms, to represent different degrees 
of effect loss. In this analysis, only data collected before IMP discontinuation will be 
utilized. An example below shows that a specified amount from actives will be 
subtracted from its value and at the same time, another specified amount will be 
added to the placebo. The methodology and algorithm used for imputations is 
provided in Appendix C .  
Table 6: An example of shift amount in percent predicted FEV1 
Placebo 
 
Active 
0 
0 
0 
-5 
0 
-10 
0 
-15 
2 
-5 
2 
-10 
2 
-15 


Statistical Analysis Plan 
Study FSS-AS-30003 
33 
Placebo 
 
Active 
4 
-5 
4 
-10 
4 
-15 
Table 6: An example of shift amount in percent predicted FEV1 (Continued) 
Placebo 
 
Active 
6 
-5 
6 
-10 
6 
-15 
• Mixed approach of LOCF and baseline observation carried forward (BOCF): this 
sensitivity analysis will penalize discontinued patients who have a positive change 
from baseline score to zero by using (BOCF) method, thus these discontinued patients 
are treated as failures. While patients who discontinue IMP who have a negative 
change from baseline score will not have their results adjusted (LOCF) since their 
scores are already poor. In this imputation method, the imputed value is the lower 
between LOCF and BOCF for each patient. No adjustments will be made to the 
results for patients who complete the study. Retrieved dropout data will be included 
for this analysis. Details are provided in Appendix D. 
• MMRM: similar to the primary estimand (change due to the initially randomized 
treatments as actually taken without retrieved dropout data), this sensitivity analysis 
will be performed using a MMRM model. This analysis represents a MAR 
assumption. The sensitivity analysis will be performed for the first primary endpoint, 
ie, change from baseline in the weekly average of percent predicted trough morning 
FEV1 over the 12-week treatment period. Details are provided in Appendix E. 
6.2.3. 
Sub-Group Analyses 
The following subgroup analyses will be provided for the primary efficacy endpoints with ITT 
analysis set without retrieved dropout data: 
• By sex (male and female) 
• By age group (4-8 and 9-11 years) 
• By race (white, black, and other) 
• By region (US and non-US) 
• By previous therapy (ICS and NCS) 
The subgroup analyses will be summarized using descriptive statistics by each week/visit and by 
treatment.  


Statistical Analysis Plan 
Study FSS-AS-30003 
34 
6.3. 
Secondary Efficacy Endpoints and Analysis 
Secondary efficacy endpoints are as follows: 
• Change from baseline in the weekly average of daily trough morning (predose and 
pre-rescue bronchodilator) PEF over the 12-week treatment period 
• Change from baseline in the weekly average of total daily (24-hour) use of 
albuterol/salbutamol inhalation aerosol (number of inhalations) over weeks 1 through 
12 
• Change from baseline in the weekly average of the total daily asthma symptom score 
(defined as the average of the daytime and nighttime scores) over weeks 1 through 12 
• Change from baseline in asthma control (measured by C-ACT) score over the 
12-week treatment period 
• Time to first onset of effect defined as the first decrease from baseline in daily rescue 
medication use 
• Proportion of patients who discontinued from IMP for asthma exacerbation during the 
12-week treatment period. 
The sequential order of the secondary endpoints for multiplicity will be described in Section 7.2. 
6.3.1. 
Variable Definitions 
6.3.1.1. 
Weekly Average of the Daily Trough Morning PEF 
A handheld device will be provided to patients at the SV and used to determine the morning PEF 
throughout the course of the study. 
Morning PEF will be determined in the morning, before administration of IMP or rescue 
medications. Daily PEF time will be compared with IMP dose time.  
If a PEF measurement is performed after the IMP dose, a 10-minute window will be allowed and 
included in the analysis, otherwise the PEF measurement will be ignored. 
The first day postrandomization consists of electronic patient diary entry on the morning of the 
day after the RV (TV1). For the purpose of the efficacy analyses of weekly average of daily 
morning PEF measurements, the values will be the averages based on the available data for that 
week. The averages will be calculated as the sum of morning PEF values divided by the number 
of nonmissing assessments. There will be no imputation applied to postrandomization 
assessments. 
6.3.1.2. 
Weekly Average of Total Daily (24-Hour) Use of Albuterol/Salbutamol 
Inhalation Aerosol (Number of Inhalations) 
Patients will record the number of inhalations of rescue medication (albuterol/salbutamol HFA 
MDI) each morning and evening in the electronic patient diary. An entry of zero inhalations 
indicates no rescue medication is needed. 
To calculate the total daily use of albuterol/salbutamol inhalation aerosol (number of 
inhalations), the electronic patient diary entry on RV (TV1) is defined as the first day of analysis. 


Statistical Analysis Plan 
Study FSS-AS-30003 
35 
The weekly average of the total daily inhalations is the average based on the available data for 
that week. The average will be calculated as the sum of total daily inhalations over the 7 days for 
each analysis week divided by the number of nonmissing assessments. 
6.3.1.3. 
Asthma Symptom Score 
Asthma symptom scores will be recorded in the patient’s electronic patient diary each morning 
and each evening before determining PEF and before administration of IMP or rescue 
medications. 
Daytime Symptom Score (determined in the evening): 
0=No symptoms during the day 
1=Symptoms for 1 short period during the day 
2=Symptoms for 2 or more short periods during the day 
3=Symptoms for most of the day which did not affect my normal daily activities 
4=Symptoms for most of the day which did affect my normal daily activities 
5=Symptoms so severe that I could not go to work or perform normal daily activities 
Nighttime Symptom Score (determined in the morning): 
0=No Symptoms during the night 
1=Symptoms causing me to wake once (or wake early) 
2=Symptoms causing me to wake twice or more (including waking early) 
3=Symptoms causing me to be awake for most of the night 
4=Symptoms so severe that I did not sleep at all 
To calculate total daily asthma symptom score, analysis days are defined in Table 4. The total 
daily asthma symptom score is the average of the daytime and the nighttime scores. The total 
daily asthma symptom score will be considered missing if either the daytime or nighttime score 
is missing. 
The weekly average will be calculated as the sum of total daily asthma symptom scores over the 
7 days for each analysis week divided by the number of nonmissing assessments. 
6.3.1.4. 
Childhood Asthma Control Test Score 
The C-ACT is a simple, patient-completed tool used for the assessment of overall asthma 
control. The first 4 items of the test are completed by the patient, while the last 3 items are 
completed by the patient’s parents/legal guardians/caregivers. The first 4 items are scored on a 
3-point scale (0 to 3) and the last 3 items are scored on a 5-point scale (0 to 5), with summation 
of all items providing scores ranging from 0 to 27. In case of missing item score, the average 
value will be calculated for that particular item and treatment. For the first 4 items, a patient has 
to have a minimum of 2 items in order to replace the mean value and for the last 3 items, a 
minimum of 1 item is required to replace the mean value. 
These scores span the continuum of poor control of asthma (score ≤5) to complete control of 
asthma (score ≥25), with a cutoff score of 19 indicating patients with poorly controlled asthma. 
The C-ACT will be completed by the patient and the patient’s parents/legal guardians/caregivers 
at the investigational center, before any other assessments are performed, at the RV (TV1), TV4, 


Statistical Analysis Plan 
Study FSS-AS-30003 
36 
TV5, and TV6/IMPDV. The same parent/legal guardian/caregiver should complete the 
assessments at each visit, if possible. 
6.3.1.5. 
Time to First Onset of Effect 
Patients will record the number of inhalations of rescue medication (albuterol/salbutamol HFA 
MDI [90 mcg ex-actuator] or equivalent) each morning and evening in the electronic patient 
diary. Total daily use will be calculated after the RV. The time to first onset of effect is defined 
as the first decrease from the weekly average baseline in daily rescue medication use. 
6.3.1.6. 
Proportion of Patients Discontinued From IMP for Asthma Exacerbation 
During the 12-week Treatment Period 
Once the investigator confirms that a case of asthma exacerbation requiring a significant 
alternative treatment has occurred, the event will be entered into the CRF as an asthma 
exacerbation event. Such patients will be discontinued from IMP. The proportion of patients 
discontinued from IMP for asthma exacerbation during the 12-week treatment period will be 
assessed. 
6.3.2. 
Analysis Methods for Secondary Efficacy Variables 
The analysis of the secondary efficacy variables will be performed on the ITT analysis set 
without retrieved dropout data. 
6.3.2.1. 
Change from Baseline in the Weekly Average of Daily Trough Morning (Predose 
and Prerescue Bronchodilator) Peak Expiratory Flow (PEF) Over the 12-week 
Treatment Period 
The analysis of change from baseline in the weekly average of daily morning (predose and pre-
rescue bronchodilator) PEF over the 12-week treatment period will be performed using an 
MMRM with effects due to baseline weekly average of daily morning PEF, sex, age, (pooled) 
investigational center, previous therapy (ICS or NCS), week, treatment, and week-by-treatment 
interaction. No explicit structure will be assumed for the covariance among the repeated 
measures. However, if there is a convergence problem with unstructured covariance, then a 
compound symmetry covariance structure will be assumed. 
6.3.2.2. 
Change from Baseline in the Weekly Average of Total Daily (24-hour) use of 
Albuterol/Salbutamol Inhalation Aerosol (Number of Inhalations) Over Weeks 1 
Through 12 
The change from baseline in the weekly average of total daily (24-hour) use of 
albuterol/salbutamol inhalation aerosol (number of inhalations) over weeks 1 through 12 will be 
analyzed using an MMRM with effects due to baseline value, sex, age, (pooled) investigational 
center, previous therapy (ICS or NCS), week, treatment, and week-by-treatment interaction. No 
explicit structure will be assumed for the covariance among the repeated measures. However, if 
there is a convergence problem with unstructured covariance, then a compound symmetry 
covariance structure will be assumed. 


Statistical Analysis Plan 
Study FSS-AS-30003 
37 
6.3.2.3. 
Change from Baseline in the Weekly Average of the Total Daily Asthma 
Symptom Score (Defined as the Average of the Daytime and Nighttime Scores) 
Over Weeks 1 Through 12 
The change from baseline in the weekly average of the total daily asthma symptom scores over 
weeks 1 through 12 will be analyzed using an MMRM with effects due to baseline score, sex, 
age, (pooled) investigational center, previous therapy (ICS or NCS), week, treatment, and week-
by-treatment interaction. No explicit structure will be assumed for the covariance among the 
repeated measures. However, if there is a convergence problem with unstructured covariance, 
then a compound symmetry covariance structure will be assumed. 
6.3.2.4. 
Change from Baseline in Asthma Control (Measured by Childhood Asthma 
Control Test [C-ACT] Score Over the 12-week Treatment Period  
The change from baseline in C-ACT score over the 12-week treatment period will be analyzed 
using an MMRM with effects due to baseline C-ACT score, sex, age, (pooled) investigational 
center, previous therapy (ICS or NCS), week, treatment, and week-by-treatment interaction. No 
explicit structure will be assumed for the covariance among the repeated measures. However, if 
there is a convergence program with unstructured covariance, then a compound symmetry 
covariance structure will be assumed. 
6.3.2.5. 
Time to First Onset of Effect in Daily Rescue Medication Use 
The time to first onset of effect, defined as the number of days elapsed from the date of 
randomization to the first date of decrease from baseline in daily rescue medication use. Patients 
who first have a decrease of effect will be counted as an event in the analysis; otherwise, patients 
will be right-censored at the date of last IMPDV assessments. 
The analysis of time to first onset of effect will be performed using a log-rank test to compare the 
survival curves. Time to first onset of effect will be displayed graphically with a Kaplan-Meier 
figure, and median time to first onset of effect and associated 95% CIs will be provided. 
Example SAS code for this analysis: 
proc lifetest data=toasm method=KM outsurv=yyy; 
   
where treat in (“A”, “D”); 
   
time aval*cnsr(0); 
   
strata treat; 
   
ods output  CensoredSummary=count  
    
Quartiles=qrt  
productlimitestimates=kmest 
  
 
 
HomTests = pvals(where=(upcase(test) = "LOG-RANK")); 
run; 
where: aval is days from the date of first double-blind study IMP 
to the date of event or censoring. CNSR is the censoring flag (0=no 
event [censored]; 1=event [meet criteria]). The code is executed for 
each pair of treatment comparisons of interest. 


Statistical Analysis Plan 
Study FSS-AS-30003 
38 
6.3.2.6. 
Proportion of Patients Discontinued From IMP for Asthma Exacerbation 
During the 12-week Treatment Period  
The proportion of patients discontinued from IMP for asthma exacerbation during the 12-week 
treatment period will be analyzed using a logistic regression model with effects due to previous 
therapy (ICS or NCS) and treatment. In case the algorithm does not converge, a stratified (based 
on previous therapy [ICS or NCS]) Cochran-Mantel-Haenszel (CMH) test will be used to 
analyze the proportion of patients discontinued from IMP for asthma exacerbation during the 
12-week treatment period. 
Example SAS code for this analysis: 
proc logistic data=proasm descending; 
class treat therapy; 
model flag = treat therapy; 
output out=yyy predicted=pp; 
ods output  oddsratios=oddsratios  
 
 
 
parameterestimates=parameterestimates  
contrastTest=contrast 
 
convergencestatus=convergencestatus; 
run; 
where: flag is either 1 (event) or 0 (no event) 
6.4. 
Other Efficacy Endpoints Analysis 
The other efficacy endpoints are as follows: 
• Change from baseline in weekly average of the total daily (24-hour) use of 
albuterol/salbutamol inhalation aerosol (number of inhalations) at weeks 4, 8, and 12 
• Change from baseline in percentage of rescue-free days (defined as 24-hour periods 
with no rescue medication usage) during the 12-week treatment period 
• Change from baseline in percentage of symptom-free days (defined as 24-hour 
periods with asthma symptom score of 0) during the 12-week treatment period 
• Change from baseline in percentage of asthma-control days (defined as 24-hour 
periods with asthma symptom score of 0 and no rescue medication usage) during the 
12-week treatment period 
• Change from baseline in 1-hour postdose percent predicted morning FEV1 at week 1 
• Change from baseline in weekly average of the daily evening PEF over the 12-week 
treatment period 
• Change from baseline in weekly average of the percent predicted trough morning 
FEV1 at weeks 1, 2, 4 and 8 
• Proportion of patients who achieve at least a 15% increase in morning FEV1 at 1-hour 
postdose at day 1 (the RV/TV1), week 1, and week 12 


Statistical Analysis Plan 
Study FSS-AS-30003 
39 
• Change from baseline in asthma control (measured by C-ACT) score at weeks 4, 8, 
and 12 
• Time to consistent onset of effect defined as the decrease from baseline in daily 
rescue medication use on 3 consecutive days 
6.4.1. 
Definition 
6.4.1.1. 
Percentage of Rescue-free 24-Hour Periods 
Rescue-free days are defined as 24-hour periods with no use of rescue medication. An entry in 
the electronic patient diary of zero inhalations will indicate a rescue-free 24-hour period. The 
percentage of rescue-free 24-hour periods is defined as the percentage of rescue-free days over 
the weekly analysis day during the treatment period. The entry on the day of the RV (TV1) 
excluding records prior to the first IMP dose is defined as day 1. A minimum of 60% of full days 
during the 12-week treatment period (or relative to the number of days that the patient 
participated in the study) cannot be missing in order for a patient to be included in this analysis. 
6.4.1.2. 
Percentage of Symptom-free 24-Hour Periods 
The asthma symptom scores are specified in Section 6.3.1.3. Scores of zero for both morning and 
evening indicate a 24-hour symptom-free period. The calculations of the percentage of symptom-
free 24-hour periods will be based on the weekly analysis day data recorded during the treatment 
period. The missing data will be imputed according to the rules specified in Table 2. A minimum 
of 60% of full days during the 12-week treatment period (or relative to the number of days that 
the patient participated in the study) cannot be missing in order for a patient to be included in this 
analysis. 
6.4.1.3. 
Percentage of Asthma-control 24-Hour Periods 
An asthma-control 24-hour period is defined as a 24-hour period with asthma symptom scores of 
zero and no rescue medication use as recorded in the electronic patient diaries. The calculations 
of the percentage of asthma-control 24-hour periods will be based on the weekly analysis day 
data recorded during the treatment period. The missing data will be imputed according the rules 
specified in Table 3. A minimum of 60% of full days during the 12-week treatment period (or 
relative to the number of days that the patient participated in the study) cannot be missing in 
order for a patient to be included in this analysis. 
6.4.1.4. 
Weekly Average of the Daily Trough Evening PEF 
A handheld spirometry device measuring FEV1 and PEF will be provided to patients at the SV 
and used to determine the evening PEF throughout the course of the study. 
Trough evening PEF will be determined in the evening before administration of IMP. Daily PEF 
time will be compared with IMP dose time. If a PEF measurement is performed after the IMP 
dose, a 10-minute window will be allowed and included in the analysis, otherwise the PEF 
measurement will be ignored. 
The first day postrandomization consists of the electronic patient diary entry on the evening of 
the day of the RV (TV1). For the purpose of the efficacy analyses of weekly average of daily 


Statistical Analysis Plan 
Study FSS-AS-30003 
40 
evening PEF measurements, the values will be the averages based on the available data for that 
week. The averages will be calculated as the sum of evening PEF values divided by the number 
of nonmissing assessments. There will be no imputation applied to postrandomization 
assessments. 
6.4.1.5. 
Time to Consistent Onset of Effect 
Patients will record the number of inhalations of rescue medication (albuterol/salbutamol HFA 
MDI [90 mcg ex-actuator] or equivalent) each morning and evening in the electronic patient 
diary. Total daily use will be calculated after the RV. The time to consistent onset of effect is 
defined as a decrease from baseline in daily rescue medication use on 3 consecutive days. 
6.4.2. 
Analysis Methods for Other Efficacy Variables 
The analysis of the other efficacy variables will be performed on the ITT analysis set without 
retrieved dropout data. 
6.4.2.1. 
Change from Baseline in the Weekly Average of the Total Daily (24-hour) use of 
Albuterol/Salbutamol Inhalation Aerosol (Number of Inhalations) at Weeks 4, 8, 
and 12 
The change from baseline in weekly average of total daily (24-hour) use of albuterol/salbutamol 
inhalation aerosol (number of inhalations) at weeks 4, 8, and 12 will be analyzed using an 
MMRM with effects due to baseline value, sex, age, (pooled) investigational center, previous 
therapy (ICS or NCS), week, treatment, and week-by-treatment interaction. No explicit structure 
will be assumed for the covariance among the repeated measures. However, if there is a 
convergence problem with unstructured covariance, then a compound symmetry covariance 
structure will be assumed. 
6.4.2.2. 
Change from Baseline in the Percentage of Rescue-free Days (Defined as 24-hour 
Periods with no Rescue Medication Usage) During the 12-week Treatment 
Period 
The change from baseline in the percentage of rescue-free days (defined as 24-hour periods with 
no use of rescue medication recorded in the morning and evening) as recorded in the patient 
diaries during the 12-week treatment period will be summarized and compared between 
treatment groups using the Wilcoxon-Mann-Whitney test. 
Example SAS code for this analysis: 
proc npar1way data=salf wilcoxon;  
where treat in (“A”, “D”);  
class treat;  
var change;  
output out=yyy wilcoxon; run;  
where: change is the change from baseline in percentage of rescue-free 
days. The code is executed for each pair of treatment comparisons of 
interest. 


Statistical Analysis Plan 
Study FSS-AS-30003 
41 
6.4.2.3. 
Change from Baseline in the Percentage of Symptom-free Days (Defined as 24-
hour Periods with Asthma Symptom Score of 0) During the 12-week Treatment 
Period 
The change from baseline in the percentage of symptom-free days (defined as 24-hour periods 
with asthma symptom scores of zero) as recorded in the patient diaries during the 12-week 
treatment period will be summarized and will be compared between treatment groups using the 
Wilcoxon-Mann-Whitney test. 
6.4.2.4. 
Change from Baseline in the Percentage of Asthma-control Days (Defined as 24-
hour Periods with Asthma Symptom Score of 0 and no Rescue Medication 
usage) During the 12-week Treatment Period 
The change from baseline in the percentage of asthma-control days (defined as 24-hour periods 
with asthma symptom scores of zero and no rescue medication use) during the 12-week 
treatment period will be summarized and compared between treatment groups using the 
Wilcoxon-Mann-Whitney test. 
6.4.2.5. 
Change from Baseline in 1-Hour Postdose Percent Predicted Morning FEV1 at 
Week 1 
On the morning of the week 1 visit (TV2), patients will perform their predose FEV1 assessment 
at the investigational center. They will take their morning dose of the IMP, and subsequently 
perform the 1-hour postdose FEV1 measurements using the handheld device. Patients, who have 
been withdrawn from IMP but remain in the study, will be asked to perform the 1-hour postdose 
lung function assessments at the visit although patients will not be taking a dose of IMP. The 
assessment should be performed approximately 1 hour after the predose lung function 
assessments were obtained. 
The change from baseline in 1-hour postdose percent predicted morning FEV1 at week 1will be 
analyzed using an ANCOVA model with effects due to baseline percent predicted FEV1, sex, 
age, (pooled) investigational center, previous therapy (ICS or NCS), and treatment. In cases 
where the 1-hour postdose value is missing at week 1, the 1-hour postdose at baseline (RV/TV1) 
will be used. 
6.4.2.6. 
Change from Baseline in the Weekly Average of the Daily Evening PEF Over the 
12-week Treatment Period 
The analysis of change from baseline in weekly average of daily evening PEF over the 12-week 
treatment period will be performed using an MMRM with effects due to baseline weekly average 
of daily evening PEF, sex, age, (pooled) investigational center, previous therapy (ICS or NCS), 
week, treatment, and week-by-treatment interaction. No explicit structure will be assumed for the 
covariance among the repeated measures. However, if there is a convergence problem with 
unstructured covariance, a compound symmetry covariance structure will be assumed. 
6.4.2.7. 
Change from Baseline in Weekly Average of the Percent Predicted Trough 
Morning FEV1 at weeks 1, 2, 4 and 8 
The change from baseline in weekly average of the percent predicted trough morning FEV1 will 
be summarized descriptively by week and treatment. 


Statistical Analysis Plan 
Study FSS-AS-30003 
42 
6.4.2.8. 
Proportion of Patients who Achieve at Least a 15% increase in morning FEV1 at 
1-hour postdose at Day 1 (RV/TV1), Week 1, and Week 12 
The proportion of patients who achieve at least a 15% increase in morning FEV1 at 1-hour 
postdose at day 1 will be analyzed using a logistic regression model with effects due to previous 
therapy (ICS or NCS) and treatment. The proportion of patients who achieve at least a 12% 
increase in FEV1 at 1-hour postdose at week 12 will be analyzed similarly. 
6.4.2.9. 
Change from Baseline in Asthma Control (measure by C-ACT) score at Weeks 
4, 8, and 12 
The change from baseline in C-ACT score at weeks 4, 8 and12 will be summarized descriptively 
by visit and treatment. 
6.4.2.10. Time to Consistent Onset of Effect in Daily Rescue Medication Use 
The time to consistent onset of effect is defined as the number of days elapsed from the date of 
randomization to the first date of 3 consecutive days with a decrease from baseline in daily 
rescue medication use. Patients who have 3 consecutive days with a decrease in effect will be 
counted as an event in the analysis, otherwise, patients will be right-censored at the date of last 
IMPDV assessments. 
The analysis of time to consistent onset of effect will be performed using a log-rank test to 
compare the survival curves. Time to first onset of effect will be graphically displayed with a 
Kaplan-Meier figure and the median time to first onset and associated 95% CIs will be provided. 


Statistical Analysis Plan 
Study FSS-AS-30003 
43 
7. 
MULTIPLE COMPARISONS AND MULTIPLICITY 
7.1. 
Multiple Comparisons for the Primary Analysis 
For the analysis of the co-primary endpoints, a fixed-sequence multiple testing procedure will be 
employed to control the overall Type I error rate at the 0.05 level, as described in Table 7. 
Specifically, treatment comparisons will begin with the first primary endpoint, [1] 1-hour 
postdose percent predicted morning FEV1 at week 12 at the FS MDPI 50/12.5 versus Fp MDPI 
50 mcg. If the resulting p-value is less than 0.05, then the next comparison of interest will be 
made, according to the direction of the arrow. This process will continue until the point where 
the p-value is greater than 0.05 at which no further comparisons will be interpreted inferentially. 
Taking into consideration that this is the very first study that utilizes the handheld device in a 
large Phase 3 study in a pediatric asthma patient population (4 through 11 years of age), an 
unplanned blinded sample size re-assessment was conducted. Since the adjustment to sample 
size was based on blinded standard deviation, no adjustment to the multiplicity control is 
warranted.  
No multiplicity adjustment will be made for sensitivity analyses of the primary endpoints or 
subgroups. 
Table 7: Multiple Testing Procedures 
Sequence 
Primary Endpoint 
Hypothesis Testing 
1 
[1] Change from baseline in1-hour postdose 
percent predicted morning FEV1 at week 12 
FS MDPI 50/12.5 mcg BID vs. 
Fp MDPI 50 mcg BID 
 
 
↓ 
2 
[2] Change from baseline in weekly average of 
the percent predicted trough morning FEV1 at 
week 12 
Fp MDPI 50 mcg BID vs. 
Placebo 
 
 
↓ 
3 
[2] Change from baseline in weekly average of 
the percent predicted trough morning FEV1 at 
week 12 
Fp MDPI 25 mcg BID vs. 
Placebo 
FEV1= forced expiratory volume in 1 second; FS MDPI = fluticasone propionate/salmeterol xinafoate multidose dry 
powder inhaler, Fp MDPI = fluticasone propionate multidose dry powder inhaler. 
7.2. 
Multiple Comparisons for the Secondary Analysis 
If the p-value is less than 0.05 for the 3 inferential comparisons in the primary analysis, 
inferential testing will be extended to the secondary analysis. 
Testing of secondary efficacy variables for the study drugs will be performed in the sequential 
manner described in Table 8 (Fp MDPI) and Table 9 (FS MDPI). 
Treatment comparisons will begin with the change from baseline in weekly average of daily 
trough morning PEF (first secondary endpoint) with Fp MDPI 50 mcg versus placebo for 


Statistical Analysis Plan 
Study FSS-AS-30003 
44 
Fp MDPI, or FS MDPI 50/12.5 mcg versus placebo for FS MDPI. If the resulting p-value is less 
than 0.05, the next comparison(s) of interest will be made according to the direction of the 
arrows. To the right, this will be the same endpoint to compare Fp MDPI 25 mcg versus placebo 
(Fp MDPI), or FS MDPI 50/12.5 mcg versus Fp MPDI 25 mcg (FS MDPI). To the next 
endpoint, this will be the change from baseline in the weekly average of the total daily (24-hour) 
use of albuterol/salbutamol inhalation aerosol (second secondary endpoint) at the 
Fp MDPI 50 mcg versus placebo (Fp MDPI), or FS MDPI 50/12.5 mcg versus placebo (FS 
MDPI). 
This process will continue testing sequentially through the next study drug/strength for each 
variable and at a given strength through the order presented in Table 8 and Table 9 until either all 
comparisons of interest are made, or until the point at which the resulting p-value for a 
comparison is greater than 0.05. At the point where the p-value is greater than 0.05, no further 
comparisons of either that strength or that measure can be made. This procedure allows for 
control of the Type I error for comparisons at a particular study drug/strength over the 6 
secondary endpoints, as well as comparisons over study drugs/strengths within a particular 
endpoint. However, it does not control the overall Type I error, nominal p-value will be reported.  
No multiplicity adjustment will be made for other efficacy analyses. 
Table 8: Sequence of Testing Secondary Endpoints for Fp MDPI 
 
 
Secondary Endpoint 
Hypothesis Testing 
Fp MDPI 50 mcg  
vs. Placebo 
Fp MDPI 25 mcg vs. 
Placebo 
[A] Change from baseline in weekly average of daily 
trough morning PEF over the 12-week treatment period 
 
↓ → 
 
↓  
[B] Change from baseline in the weekly average of total 
daily (24-hour) use of albuterol /salbutomol inhalation 
aerosol (number of inhalations) over weeks 1 through 12 
 
↓ → 
 
↓  
[C] Change from baseline in the weekly average of the 
total daily asthma symptom score over weeks 1 through 
12 
 
↓ → 
 
↓  
[D] Change from baseline in asthma control (measured 
by C-ACT) score over the 12-week treatment period 
 
↓ → 
 
↓  
[E] Time to first onset of effect defined as the first 
decrease from baseline in daily rescue medication use 
 
↓ → 
 
↓  
[F] Proportion of patients discontinued from IMP for 
asthma exacerbation during the 12-week treatment period  
 
→ 
 


Statistical Analysis Plan 
Study FSS-AS-30003 
45 
Table 9: Sequence of Testing Secondary Endpoints for FS MDPI 
 
 
 
 
Secondary Endpoint 
Hypothesis Testing 
FS MDPI 50/12.5 
mcg vs. Placebo 
FS MDPI 50/12.5 
mcg vs. Fp 
MDPI 25 mcg 
FS MDPI 
50/12.5 mcg vs. 
Fp MDPI 50 
mcg 
[A] Change from baseline in weekly average of 
daily trough morning PEF over the 12-week 
treatment period 
 
↓ → 
 
↓ → 
 
↓  
[B] Change from baseline in the weekly average of 
total daily (24-hour) use of albuterol /salbutomol 
inhalation aerosol (number of inhalations) over 
weeks 1 through 12 
 
↓ → 
 
↓ → 
 
↓  
[C] Change from baseline in the weekly average of 
the total daily asthma symptom score over weeks 1 
through 12 
 
↓ → 
 
↓ → 
 
↓  
[D] Change from baseline in asthma control 
(measured by C-ACT) score over the 12-week 
treatment period 
 
↓ → 
 
↓ → 
 
↓  
[E] Time to first onset of effect defined as the first 
decrease from baseline in daily rescue medication 
use 
 
↓ → 
 
↓ → 
 
↓  
[F] Proportion of patients discontinued from IMP 
for asthma exacerbation during the 12-week 
treatment period  
 
→ 
 
→ 
 
 


Statistical Analysis Plan 
Study FSS-AS-30003 
46 
8. 
SAFETY ANALYSIS 
8.1. 
General 
The safety analysis set will be used for all safety analyses. Summaries will be presented by 
treatment group and will represent what treatment was actually received, unless specified 
otherwise. Summaries of clinically significant abnormal values will include all postbaseline 
values (including scheduled, unscheduled, and IMPDV). 
8.2. 
Duration of Exposure to IMP 
Duration of exposure to IMP (days) for the individual patient is the number of days patient 
received drug (last day of IMP – first day of IMP + 1). Duration of treatment (days) will be 
summarized using descriptive statistics. 
The last day of the IMP is determined by the study drug exposure date on patient’s electronic 
diary or the treatment completion/discontinuation date on the disposition page; whichever comes 
first. The reason is that in some cases, the question “It is now time to take your study drug. 
Confirm that it was taken” was continuing showing up on the AM3 device and it caused many 
confusions to patients who were on alternative medication, and should not need to answer this 
question after they were terminated from treatment. 
8.3. 
 IMP Compliance 
IMP compliance during the study will be assessed based on data collected with the dose counter 
device. This will be the primary method to evaluate the patient’s compliance rate. For patients 
who have a compliance rate of <80%, their handheld electronic diary will also be evaluated. A 
routine data monitoring report will be sent to a service provider to further investigate the issue 
(ie, diary data and IMP dose counter data are not consistent). Each of these individual patients 
will then be evaluated during the SDR meeting to determine whether the patient should be 
included in the PP analysis set. 
The degree of IMP compliance will be determined by presenting the number of doses taken as a 
percentage of the number required by the protocol.  
 
Device: % Compliance =  
Actual # of actuations use per dose counter
Expected # of actuations to be used
  𝑥𝑥 100 
 
Diary:% Compliance =  
Actual # of actuations use per diary card
Expected # of actuations to be used
  𝑥𝑥 100 
 
The denominator of “expected # of times study drug was to be taken” will be calculated based on 
patients’ participation in the study (ie, last day of IMP – first day of IMP + 1). For patients who 
complete the study treatment period, the last day of IMP used in the denominator calculation will 


Statistical Analysis Plan 
Study FSS-AS-30003 
47 
be the last expected dosing day. For early termination patients, the last day of IMP used in the 
denominator calculation will be the last expected dosing day before termination day. See 
Section 8.2 for last IMP date definition. 
Patients are supposed to return their devices with dose counters at each visit. However, if there is 
no date for the return of the device in the database or a dose counter error has been reported, the 
treatment duration for that patient will be prorated according to the number and day when the 
device was returned without dose counter error. Table 10 below illustrates as an example for 
patient who has an unreturned device and reported dose counter error. 
Table 10: Example of Unreturned Device or Dose Counter Error 
Dispense Date 
Return Date 
Report Dose 
Counter Error 
# of Days 
# of Doses (total 
count) 
02 April 2018 
09 April 2018 
-- 
7 
12  
09 April 2018 
Device not returned 
-- 
N/A 
N/A 
16 April 2018 
30 April 2018 
Reported on 
20-April-2019 
N/A 
N/A 
30 April 2018 
14 May 2018 
-- 
14 
12  
Overall compliance rate: (12 + 12) / [(7 + 14+1)*2] = 57% 
If a patient has missing electronic patient diary pages, it is assumed that this patient did not take 
the IMP on the days as expected. 
Compliance with IMP will be categorized as <60%, 60% to <80%, 80% to <100%, and ≥100% 
and summarized using descriptive statistics.  
8.4. 
Adverse Events 
All adverse events will be coded using the MedDRA version 19.0. The incidence of adverse 
events will be summarized using descriptive statistics (counts and percentages) by SOC and 
preferred term (PT). Patients are counted only once in each SOC category, and only once in each 
PT category. Treatment-related adverse event summaries will include adverse events with 
missing relationship to study drug. For the summaries by severity, patients are counted at the 
greatest severity. Summaries will be presented for all treatment-emergent adverse events (overall 
and by severity), treatment-emergent adverse events determined by the investigator to be related 
to IMP (see FSS-AS-30003 protocol Section 7.1.4) (defined as related or with missing 
relationship, overall and by severity), serious treatment-emergent adverse events, treatment-
emergent adverse events causing withdrawal from the study, and nonserious adverse events. 
Summaries will be presented by treatment group and for all patients. 
Any event occurring after the patient has signed the study informed consent/assent form should 
be recorded and reported as adverse event. Those events occurring prior to the first dose of IMP 
will be considered as non-treatment-emergent adverse events, and those occurring on or after the 
first dose of IMP drug through 7 days after the last dose of IMP will be considered as treatment-
emergent adverse events. Any events that occurred beyond the 7 days after the last dose of IMP 
will be considered as non-treatment-emergent adverse events. 


Statistical Analysis Plan 
Study FSS-AS-30003 
48 
For all non-treatment-emergent adverse events that occurred during the run-in period, a summary 
and a patient listing will be presented separately. All non-treatment-emergent adverse events that 
occurred 7days after the last dose of IMP, prior to week 12 (mainly for patients who 
discontinued IMP but continued in the study) will be presented similarly. In addition, serious 
adverse events that were reported during the follow up period will be presented.   
For all treatment-emergent adverse events that lead to discontinuation from IMP treatment 
through 7 days after the last dose of IMP will be summarized. 
Patient listings of deaths, serious adverse events, adverse events leading to discontinuation, 
MedDRA dictionary terms for adverse event descriptions, and adverse event PT by patient 
number will be presented. 
8.5. 
Deaths 
If any patient dies during the study, all relevant information will be discussed in the patient’s 
narrative included in the CSR. 
8.6. 
Asthma Exacerbations 
Asthma exacerbations that requires a change in medication or worsening of asthma that requires 
the patient to be treated with alternative therapy will be entered into the case report form (CRF), 
including the date at which any medication change was made and whether this medication 
change was implemented prior to or after the IMPDV lung function assessments (FEV1 and PEF) 
were completed. Asthma worsening including asthma exacerbations with a change to alternative 
asthma therapy will not be considered an adverse event for this study since it is an expected 
outcome for this study in an asthmatic patient population. Asthma exacerbations that meet the 
criteria for a serious adverse event will be recorded as adverse events. For the purpose of this 
study, an asthma exacerbation is defined as worsening of asthma requiring any significant 
treatment other than IMP and study rescue medication. 
The number and percentage (%) of patients experiencing an asthma exacerbation will be 
presented by treatment group. 
A summary of the number and percentage of patients with asthma exacerbations resulting in 
hospitalization, leading to permanent withdrawal of study drug, and other actions will be 
presented by treatment group. 
The number and percentage of patients with asthma exacerbations will be presented by 
maximum severity and treatment group. Severity will be classified as “mild”, “moderate”, or 
“severe”. If a patient experiences more than 1 asthma exacerbations, only the asthma 
exacerbations with the greatest severity will be included in the summary table. 
In all of the above summaries, each patient will be counted only once regardless of the number of 
asthma exacerbations experienced during the study. 


Statistical Analysis Plan 
Study FSS-AS-30003 
49 
8.7. 
Clinical Laboratory Tests 
Clinical laboratory tests of chemistry, hematology, and urinalysis parameters are not collected 
for this study. However, optional clinical laboratory evaluation at the discretion of the 
investigator will be listed. All clinical laboratory tests will be listed (if any) to ensure the safety 
of the patients. 
8.8. 
Physical Examinations 
Physical examinations, including height (to be measured at the screening visit only) and weight, 
will be performed at the SV, RV and at the final treatment visit (TV6 or at the IMPDV). Patients 
with a physical examination, patients with at least 1 abnormal finding, and abnormal findings for 
each category will be summarized at baseline using descriptive statistics. Any physical 
examination finding that is judged by the investigator as a clinically significant change 
(worsening) compared with a baseline value will be considered an adverse event, recorded on the 
CRF, and monitored as described in Section 7.1.2 of the FSS-AS-30003 study protocol. 
Shifts (normal and abnormal) from baseline to final treatment visit will be summarized by 
treatment for each physical examination category. 
Descriptive statistics for weight and height will be provided and a listing of physical 
examinations by patient and all abnormal findings will be provided. 
8.9. 
Vital Signs 
Summary statistics for vital signs (blood pressure and pulse) will be presented at each visit 
throughout the study. Vital signs values and changes from baseline to each visit will be 
summarized using descriptive statistics. Height and weight will be recorded at SV and 
TV6/IMPDV. 
Table 11 specifies the criteria for identifying vital signs as potentially clinically significant 
abnormal values. Note that in order to be identified as potentially clinically significant abnormal, 
a value needs to meet both criteria below: ie, have a value beyond the criterion value and a 
change of at least the magnitude specified in the change relative to baseline column. The 
potentially clinically significant abnormal vital signs values will include all post baseline values 
(including scheduled, unscheduled, and early termination visits) for the summaries. 


Statistical Analysis Plan 
Study FSS-AS-30003 
50 
Table 11: Criteria for Potentially Clinically Significant Vital Signs 
 
Criterion Value 
Change relative to baseline 
Age (years) 
4-5 
6-8 
9-11 
4-5 
6-8 
9-11 
Pulse (bpm) 
>135 
>130 
>110 
Increase of ≥25 
Increase of ≥20 
Increase of ≥20 
<65 
<60 
<60 
Decrease of ≥ 25 
Decrease of ≥20 
Decrease of ≥20 
SBP (mmHg) 
>110 
>120 
>130 
Increase of ≥20 
Increase of ≥20 
Increase of ≥20 
<80 
<80 
<80 
Decrease of ≥20 
Decrease of ≥20 
Decrease of ≥20 
DBP (mmHg) 
>80 
>80 
>80 
Increase of ≥15 
Increase of ≥15 
Increase of ≥15 
<50 
<50 
<50 
Decrease of ≥15 
Decrease of ≥15 
Decrease of ≥15 
Abbreviations: bpm=beats per minute; DBP=diastolic blood pressure; mmHg=mm of mercury; SBP=systolic blood 
pressure. 
Note: All ranges are adapted from The Harriet Lane Handbook of Pediatrics, 20th ed, 2015. Pulse: Table 7-4. Blood 
pressure: Table 7-1. 
8.10. 
Electrocardiography 
Electrocardiography was not collected for this study. 
8.11. 
Oropharyngeal Examinations 
Oropharyngeal examinations for visual evidence of oral candidiasis will be conducted at the 
scheduled investigational center visits. This will be evaluated by obtaining an analyzing a swab 
of the suspect area. Any occurrence of oropharyngeal candidiasis that is confirmed by culture 
during the study will be reported as an adverse event. 
The number and percentage of patients with clinical/visual evidence of oral candidiasis will be 
tabulated for each treatment group at each visit. In addition, the number and percentage of 
patients with a positive swab will be tabulated for each treatment group at each visit. 
A listing of all visual evidence of oral candidiasis will be provided. 
8.12. 
Concomitant Medications or Therapies  
Concomitant therapies and medications, including medications that are taken on an as needed 
basis and occasional therapies, will be monitored during the study. Details of prohibited 
medications may be found in Section 5.7 and Appendix H of the FSS-AS-30003 study protocol. 
All concomitant medications will be coded using the WHO Drug. 
The incidence of concomitant therapies and medications will be summarized using descriptive 
statistics by therapeutic class category and preferred term. Patients are counted only once in each 
therapeutic class, and only once in each preferred term category. Concomitant therapies and 
medications will include all medications taken while the patient is being treated with IMP as 
defined in the FSS-AS-30003 study protocol. In addition, a separate summary table will be 
provided for patients who discontinue IMP but stay in the study. 


Statistical Analysis Plan 
Study FSS-AS-30003 
51 
9. 
TOLERABILITY VARIABLES AND ANALYSIS 
Tolerability will be assessed via other endpoints. 


Statistical Analysis Plan 
Study FSS-AS-30003 
52 
10. 
STATISTICAL SOFTWARE 
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later. 


Statistical Analysis Plan 
Study FSS-AS-30003 
53 
11. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL 
There is no change to the analyses specified in the FSS-AS-30003 clinical study protocol. Only 
one clarification to the PP analysis set has been made. 
Table 12: Changes to the Statistical Analysis Plan 
SAP 
Section 
Protocol Description 
SAP Change 
Rationale 
3.3 
The per-protocol (PP) analysis set is a 
subset of the ITT analysis set including 
only patients without major protocol 
violations and who have >80% 
compliance to the IMP over the entire 
treatment period. Treatment 
compliance during the study will be 
assessed based on data collected in the 
IMP dose counter. In the event the 
IMP isn’t returned by a patient or a 
dose counter is broken, treatment 
compliance will be assessed based on 
the patient’s diary. Major protocol 
violations will be determined before 
unblinding. Note that since the use of 
incorrect IMP will be considered a 
major protocol violation, for treatment 
assignment in the PP analysis set, “as 
randomized” will coincide with “as 
treated.” 
The per-protocol (PP) analysis set 
is a subset of the ITT analysis set 
including only patients without 
protocol violations that could have 
an effect on the primary outcome 
and who have greater than or equal 
to 80% compliance to the IMP 
over the entire treatment period. 
The compliance rate calculation is 
detailed in section 8.3. 
PP analysis set will be determined 
before unblinding at the Statistical 
Data Review (SDR) meeting and 
documented in the SDR meeting 
minutes. Note that since the use of 
incorrect IMP will be considered a 
protocol violation and will not be 
included in the PP analysis set, for 
treatment assignment in the PP 
analysis set, “as randomized” will 
coincide with “as treated”. 
This change 
was made so 
that the 
language is 
consistent 
with SOP 
GBP-RD-312 


Statistical Analysis Plan 
Study FSS-AS-30003 
54 
12. 
REFERENCES 
Mallinckrodt C. Choosing primary estimands and analyses. In: Preventing and treating missing 
data in longitudinal clinical trials: A practical guide. New York: Cambridge University 
Press,2013. 
Mallinckrodt C, Molenberghs G, Rathmann S. Choosing estimands in clinical trials with missing 
data. Pharm Stat 2016. 
Little R, Kang S. Intention-to-treat analysis with treatment discontinuation and missing data in 
clinical trials. Stat Med 2015;34(16):2381–90. 
O’Neill RT, Temple R. The prevention and treatment of missing data in clinical trials: an FDA 
perspective on the importance of dealing with it. Clin Pharmacol Ther 2012;91(3):550–4. 
Szefler SJ, Boushey HA, Pearlman DS, Togias A, Liddle R, Furlong A, et al. Time to onset of 
effect of fluticasone propionate in patients with asthma. J Allergy Clin Immunol 
1999;103(5):780–8. 
Corren J, Korenblat PE, Miller CJ, O’Brien CD, Mezzanotte WS. Twelve-week, 
randomized,placebo-controlled, multicenter study of the efficacy and tolerability of budesonide 
and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol 
alone in adolescents and adults with asthma. Clin Ther 2007;29(5):823–43. 
Pearlman DS, Stricker W, Weinstein S, Gross G, Chervinsky P, Woodring A, et al. Ann Allergy 
Asthma Immunol 1999;82(3):257–65. 


Statistical Analysis Plan 
Study FSS-AS-30003 
55 
APPENDIX A. MULTIPLE IMPUTATION STEPS FOR PRIMARY 
ENDPOINTS 
The following represents an outline of the planned methodology for the multiple imputation (MI) 
procedure for the primary analyses. Minor deviations from this outline will be addressed in the 
CSR. In the situation that more significant updates are warranted, changes will be addressed in a 
SAP amendment to be finalized prior to database lock. 
Change from Baseline in Weekly Average of the Percent Predicted Trough Morning FEV1 
at Week 12: 
Multiple imputation (MI) method will be applied to impute the weekly missing data that are 
caused by early discontinuation from the study or from IMP (regardless of availability of 
retrieved dropout data). The data will be processed by the following steps: 
1. For all patients who prematurely discontinue from IMP, regardless of assigned treatment 
arm, imputation will be based on data from the placebo-treated patients (eg, reference-
based imputation). 
2. For patients who completed the treatment period but with clinically and physiologically 
implausible data (eg, percent predicted FEV1 values postrandomization are ≥200%), 
imputation will be based on data from patients treated with the same treatment.  
3. Assume patients with arbitrary missing data patterns, the fully conditional specification 
statement will be used to impute by using regression with treatment arm and percent 
predicted FEV1 measurements from previous weeks as explanatory variables. 
proc mi data=outmi_mono seed=56789 nimpute=10 out=outmi; 
class sex therapy center trt; 
 
   
fcs nbiter=50 reg(wk1= &covlist / details); 
       
fcs nbiter=50 reg(wk2= &covlist wk1 / details); 
       
fcs nbiter=50 reg(wk3= &covlist wk1 wk2 / details); 
       
fcs nbiter=50 reg(wk4= &covlist wk1 wk2 wk3 / details); 
       
fcs nbiter=50 reg(wk5= &covlist wk1 wk2 wk3  
wk4 / details); 
       
fcs nbiter=50 reg(wk6= &covlist wk1 wk2 wk3  
wk4 wk5 / details); 
       
fcs nbiter=50 reg(wk7= &covlist wk1 wk2 wk3  
wk4 wk5 wk6 / details);        
fcs nbiter=50 reg(wk8= &covlist wk1 wk2 wk3   
wk4 wk5 wk6 wk7 / details); 
       
fcs nbiter=50 reg(wk9= &covlist wk1 wk2 wk3  
wk4 wk5 wk6 wk7 wk8 / details); 


Statistical Analysis Plan 
Study FSS-AS-30003 
56 
       
fcs nbiter=50 reg(wk10= &covlist wk1 wk2 wk3  
wk4 wk5 wk6 wk7 wk8 wk9 / details); 
       
fcs nbiter=50 reg(wk11= &covlist wk1 wk2 wk3 
wk4 wk5 wk6 wk7 wk8 wk9 wk10 / details); 
       
fcs nbiter=50 reg(wk12= &covlist wk1 wk2 wk3  
wk4 wk5 wk6 wk7 wk8 wk9 wk10 wk11 / 
details); 
  
 
var trt &covlist wk1 – wk12; 
 
 
mnar model( wk1 – wk12 / modelobs = (trt = “D”)); 
run; 
where: the order of &covlist includes: sex, (pooled)   
investigational center, previous therapy, base, and age 
Note: wk1 – wk12 is the AVAL raw data, change from baseline  
values should not be used in PROC MI procedure.  
4. The ANCOVA model will be fitted to the above dataset using the model described in 
Section 6.2.2.1. The difference will be estimated in adjusted LS means and p-value will 
be output for each dataset. An example SAS code to the following will be used: 
proc mixed data=fev_model; 
      where week = "week 12"; 
 
 
class sex center therapy trt; 
 
 
model chg= base sex age therapy trt;  
       
lsmeans trt/diff=CONTROL("Placebo") cl alpha=0.05; 
       
ods output Estimates=Est LSMeans=lsmeans Diffs=Diffs; 
   run; 
where: chg is the change from baseline percent predicted FEV1 
value at week 12.  
5. The results from the ANCOVA model will be combined using the following code: 
    
data diff2; 
       
set diff; 
       
comparison=trt||' vs '||left(_trt); 
      run; 
    
proc sort data=diff2; 
       
by comparison; 


Statistical Analysis Plan 
Study FSS-AS-30003 
57 
run; 
6. The SAS® procedure PROC MIANALYZE procedure will be used to generate the final 
LS means for the treatment groups, treatment difference as well as p-values associated 
with treatment differences. The 95% confidence intervals for the treatment differences 
will be also calculated. An example of the SAS code will be used: 
proc mianalyze data=diff2; 
by comparison; 
      modeleffects estimate; 
      stderr stderr; 
 
ods output ParameterEstimates=mianalyzeparm; 
run; 
Change from Baseline in 1-hour Postdose Percent Predicted Morning FEV1 at Week 12: 
The 1-hour postdose percent predicted morning FEV1 measurement will be performed at the 
investigational center at the RV, TV2 (week 1), TV3 (week 2), TV4 (week 4), TV5 (week 8) and 
TV6 (week 12). The MI method will be applied similarly to impute the 1-hour postdose missing 
data that are caused by early dropouts from IMP without including retrieve dropout data. Steps 1 
to 6 will be repeated similarly. 
Sensitivity Analysis: Effectiveness with retrieved dropout data: 
In order to evaluate the estimand of the effect of the treatment regimens as actually taken 
(effectiveness), the above analysis will be repeated including observed FEV1 data over 12 weeks, 
for patients who completed the 12-week treatment period, including clinically and 
physiologically implausible data at week 12, and for patients who discontinued from treatment 
earlier than 12 week but from whom the sponsor was able to collect data post discontinuation. 
The sensitivity analysis will be conducted for both primary efficacy endpoints. 


Statistical Analysis Plan 
Study FSS-AS-30003 
58 
APPENDIX B. SENSITIVITY ANALYSIS: TIPPING POINT ANALYSIS 
The following represents an outline of the planned methodology for the “tipping point” multiple 
imputation sensitivity analysis of the change from baseline in weekly average of the percent 
predicted trough morning FEV1 at week 12. Minor deviations from this outline will be addressed 
in the CSR. In the situation that more significant updates are warranted, changes will be 
addressed in a SAP amendment to be finalized prior to database lock. 
The tipping point analysis evaluates several combinations of imputed missing data values until it 
reaches a “tipping point” or point at which a particular combination of imputed missing data 
changes the study conclusions, as summarized by its p-value. This is a sensitivity analysis 
utilizing MI under the missing not at random (MNAR) assumption, and will only be conducted if 
a significant result (p≤0.05) is observed as part of the primary analysis. If the sensitivity analysis 
reveals that the tipping point consists of unreasonable values, then the robustness of the study 
results is supported. 
Change from Baseline in Weekly Average of the Percent Predicted Trough Morning FEV1 
at Week 12: 
In the tipping point analysis, missing percent predicted FEV1 values will be imputed for patients 
who discontinued treatment before the week 12 visit for weekly average in which FEV1 values 
are missing. MI and associated combining rules will be applied to propagate imputation 
uncertainty. In the placebo group, the missing percent predicted FEV1 values will be imputed 
based on measurements observed at previous weeks and treatment group; that is, the missing 
data in the placebo group are assumed missing at random (MAR). For the active treatment 
groups, missing FEV1 values will be imputed in the same manner, but then a constant (positive 
value) shift will be subtracted from the imputed FEV1 values. The initial shift value will be zero 
(representing MAR) and it will then be increased and the process repeated until the treatment 
effect is no longer significant at the 5% level. The shift point at which the effect is no longer 
significant is the tipping point. 
More specifically, the "tipping point" analysis will be performed using the following steps: 
1. Assume patients with arbitrary missing data patterns, the fully conditional specification 
statement will be used to impute by using regression with treatment arm and percent 
predicted FEV1 measurements from previous weeks as explanatory variables. For the 3 
active treatment groups, MNAR will be assumed using specified shift parameters to 
adjust imputed values. For the placebo group, the imputed values will be generated using 
a zero shift parameter (namely, MAR is assumed for placebo). This will be done using 
code similar to the following:   
  proc mi data= outmi_mono seed=56789 nimpute=10 out=outmi; 
class trt sex therapy center; 
 
fcs nbiter=50 reg(wk1= &covlist trt / details); 
      fcs nbiter=50 reg(wk2= &covlist trt wk1 / details); 
      fcs nbiter=50 reg(wk3= &covlist trt wk1 wk2 / details); 


Statistical Analysis Plan 
Study FSS-AS-30003 
59 
      fcs nbiter=50 reg(wk4= &covlist trt wk1 wk2 wk3 / details); 
      fcs nbiter=50 reg(wk5= &covlist trt wk1 wk2 wk3 wk4 / details); 
      fcs nbiter=50 reg(wk6= &covlist trt wk1 wk2 wk3  
wk4 wk5 /details); 
fcs nbiter=50 reg(wk7= &covlist trt wk1 wk2 wk3   
  
wk4 wk5 wk6 / details); 
      fcs nbiter=50 reg(wk8= &covlist trt wk1 wk2 wk3  
  
wk4 wk5 wk6 wk7 / details); 
      fcs nbiter=50 reg(wk9= &covlist trt wk1 wk2 wk3  
  
wk4 wk5 wk6 wk7 wk8 / details); 
      fcs nbiter=50 reg(wk10= &covlist trt wk1 wk2 wk3  
  
wk4 wk5 wk6 wk7 wk8 wk9 / details); 
      fcs nbiter=50 reg(wk11= &covlist trt wk1 wk2 wk3  
  
wk4 wk5 wk6 wk7 wk8 wk9 wk10 / details); 
      fcs nbiter=50 reg(wk12= &covlist trt wk1 wk2 wk3  
  
wk4 wk5 wk6 wk7 wk8 wk9 wk10 wk11 / details); 
 
mnar adjust( wk1 / shift=&sj  adjustobs=(trt='A' )); 
        
mnar adjust( wk2 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk3 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk4 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk5 / shift=&sj  adjustobs=(trt='A' )); 
mnar adjust( wk6 / shift=&sj  adjustobs=(trt='A' )); 
mnar adjust( wk7 / shift=&sj  adjustobs=(trt='A' )); 
mnar adjust( wk8 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk9 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk10 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk11 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk12 / shift=&sj  adjustobs=(trt='A' )); 
    
       
mnar adjust( wk1 / shift=&sj  adjustobs=(trt='B' )); 
       
mnar adjust( wk2 / shift=&sj  adjustobs=(trt='B' )); 


Statistical Analysis Plan 
Study FSS-AS-30003 
60 
       
mnar adjust( wk3 / shift=&sj  adjustobs=(trt='B' )); 
       
mnar adjust( wk4 / shift=&sj  adjustobs=(trt='B' )); 
       
mnar adjust( wk5 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk6 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk7 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk8 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk9 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk10 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk11 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk12 / shift=&sj  adjustobs=(trt='B' )); 
 
       
mnar adjust( wk1 / shift=&sj  adjustobs=(trt='C' )); 
       
mnar adjust( wk2 / shift=&sj  adjustobs=(trt='C' )); 
       
mnar adjust( wk3 / shift=&sj  adjustobs=(trt='C' )); 
       
mnar adjust( wk4 / shift=&sj  adjustobs=(trt='C' )); 
       
mnar adjust( wk5 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk6 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk7 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk8 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk9 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk10 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk11 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk12 / shift=&sj  adjustobs=(trt='C' )); 
 
var trt &covlist wk1 – wk12; 
run; 
  where: the order of &covlist includes: sex, (pool) investigational  
        center, previous therapy, base, and age  
   
  Note: wk1 – wk12 is the AVAL raw data, change from baseline values 
  should not be used in PROC MI procedure. 
The same shift will be assumed for all weekly average and all active treatments. 


Statistical Analysis Plan 
Study FSS-AS-30003 
61 
2. The MMRM model will be fitted to the completed datasets using the model that was 
used for analysis. The difference will be estimated in adjusted LS means and p-value. 
SAS code similar to the following will be used: 
ods output diffs=middiffs; 
proc mixed data=dateset; 
     by shift; 
     class usubjid sex center therapy visit trt; 
     model chg=base sex age center therapy visit trt visit*trt /   
               ddfm=KR alpha=0.05; 
     repeated visit / type=un sub=usubjid(trt) r; 
                ** repeated visit / type=cs sub=usubjid(trt) r; 
                ** if type=un fails to converge; 
     lsmeans trt / diff cl; 
run; 
3. The results from the MMRM models will be combined using the following code: 
data diffdt; 
       
 
set midiffs; 
       
 
comparison=trt||' vs '||left(_trt); 
run; 
proc sort data=diffdt; 
    
 
 
by comparison shift; 
run; 
ods output parameterestimates=miparm1; 
proc mianalyze data=diffdt alpha=0.05 theta0=0; 
 
 
 
by comparison shift; 
 
 
 
modeleffects estimate; 
 
 
 
stderr stderr; 
run; 
4. Steps 2 through 3 will be repeated using different values for the shift parameter. After 
this step, for each shift parameter, a treatment effect (difference in adjusted means 
from placebo) and associated p-value will be estimated. 
Since the tipping point analysis is to find out how much of a change is required to “tip” the result 
from statistically significant to not statistically significant, it will not be performed for any 
comparison that is not statistically significant at the onset. 
Change from Baseline in 1-hour Postdose Percent Predicted Morning FEV1 at Week 12: 
The 1-hour postdose percent predicted morning FEV1 measurement will be performed at the 
investigational center at the RV, TV2 (week 1), TV3 (week 2), TV4 (week 4), TV5 (week 8) and 
TV6 (week 12). MI method will be applied similarly to impute the 1-hour postdose missing data 
that are caused by early dropouts, then tipping point analysis will be performed. 


Statistical Analysis Plan 
Study FSS-AS-30003 
62 
APPENDIX C. SENSITIVITY ANALYSIS: 2-DIMENSIONAL TIPPING 
POINT ANALYSIS 
The following represents an outline of the planned methodology for the “2-dimensional tipping 
point” multiple imputation sensitivity analysis of the change from baseline in weekly average of 
the percent predicted trough morning FEV1 at week 12. Minor deviations from this outline will 
be addressed in the CSR. In the situation that more significant updates are warranted, changes 
will be addressed in a SAP amendment to be finalized prior to database lock. 
The 2-dimensional tipping point analysis evaluates several combinations of imputed missing data 
values until it reaches a “tipping point” or point at which a particular combination of imputed 
missing data changes the study conclusions, as summarized by its p-value. This is a sensitivity 
analysis utilizing MI under the missing not at random (MNAR) assumption, and will be only 
conducted if a significant result (p≤0.05) is observed as part of the primary analysis. If the 
sensitivity analysis reveals that the tipping point consists of unreasonable values, then the 
robustness of the study results is supported. 
Change from Baseline in Weekly Average of the Percent Predicted Trough Morning FEV1 
at Week 12: 
In the 2-dimensional tipping point analysis, missing percent predicted FEV1 values will be 
imputed for patients who discontinued treatment before the week 12 visit for weekly average in 
which FEV1 values are missing. MI and associated combining rules will be applied to propagate 
imputation uncertainty. In each treatment group, the missing percent predicted FEV1 values will 
be imputed based on measurements observed at previous weeks and in the same treatment group. 
For the active groups, a constant (positive value) shift will be subtracted from the imputed FEV1 
values. For the placebo group, a constant (positive value) shift will be added to the imputed 
FEV1 values. The initial shift values will be zero (representing MAR) and they will then be 
increased and the process repeated until the treatment effect is no longer significant at the 5% 
level. The shift point at which the effect is no longer significant is the tipping point. 
More specifically, the "tipping point" analysis will be performed using the following steps: 
1. Assume patients with arbitrary missing data patterns, the fully conditional specification 
statement will be used to impute by using regression with treatment arm and percent 
predicted FEV1 measurements from previous weeks as explanatory variables. For the 3 
active treatment groups, MNAR will be assumed using specified shift parameters to 
adjust imputed values. For the placebo group, first imputed values will be generated 
using a zero shift parameter (namely, MAR is assumed for placebo). This will be done 
using code similar to the following:   
  proc mi data= outmi_mono seed=56789 nimpute=10 out=outmi; 
class trt sex therapy center; 
 
fcs nbiter=50 reg(wk1= &covlist trt / details); 
      fcs nbiter=50 reg(wk2= &covlist trt wk1 / details); 
      fcs nbiter=50 reg(wk3= &covlist trt wk1 wk2 / details); 


Statistical Analysis Plan 
Study FSS-AS-30003 
63 
      fcs nbiter=50 reg(wk4= &covlist trt wk1 wk2 wk3 / details); 
      fcs nbiter=50 reg(wk5= &covlist trt wk1 wk2 wk3 wk4 / details); 
      fcs nbiter=50 reg(wk6= &covlist trt wk1 wk2 wk3  
wk4 wk5 /details); 
fcs nbiter=50 reg(wk7= &covlist trt wk1 wk2 wk3   
  
wk4 wk5 wk6 / details); 
      fcs nbiter=50 reg(wk8= &covlist trt wk1 wk2 wk3  
  
wk4 wk5 wk6 wk7 / details); 
      fcs nbiter=50 reg(wk9= &covlist trt wk1 wk2 wk3  
  
wk4 wk5 wk6 wk7 wk8 / details); 
      fcs nbiter=50 reg(wk10= &covlist trt wk1 wk2 wk3  
  
wk4 wk5 wk6 wk7 wk8 wk9 / details); 
      fcs nbiter=50 reg(wk11= &covlist trt wk1 wk2 wk3  
  
wk4 wk5 wk6 wk7 wk8 trt wk9 wk10 / details); 
      fcs nbiter=50 reg(wk12= &covlist trt wk1 wk2 wk3  
  
wk4 wk5 wk6 wk7 wk8 wk9 wk10 wk11 / details); 
 
mnar adjust( wk1 / shift=&sj  adjustobs=(trt='A' )); 
        
mnar adjust( wk2 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk3 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk4 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk5 / shift=&sj  adjustobs=(trt='A' )); 
mnar adjust( wk6 / shift=&sj  adjustobs=(trt='A' )); 
mnar adjust( wk7 / shift=&sj  adjustobs=(trt='A' )); 
mnar adjust( wk8 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk9 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk10 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk11 / shift=&sj  adjustobs=(trt='A' )); 
       
mnar adjust( wk12 / shift=&sj  adjustobs=(trt='A' )); 
    
       
mnar adjust( wk1 / shift=&sj  adjustobs=(trt='B' )); 
       
mnar adjust( wk2 / shift=&sj  adjustobs=(trt='B' )); 


Statistical Analysis Plan 
Study FSS-AS-30003 
64 
       
mnar adjust( wk3 / shift=&sj  adjustobs=(trt='B' )); 
       
mnar adjust( wk4 / shift=&sj  adjustobs=(trt='B' )); 
       
mnar adjust( wk5 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk6 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk7 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk8 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk9 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk10 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk11 / shift=&sj  adjustobs=(trt='B' )); 
mnar adjust( wk12 / shift=&sj  adjustobs=(trt='B' )); 
 
       
mnar adjust( wk1 / shift=&sj  adjustobs=(trt='C' )); 
       
mnar adjust( wk2 / shift=&sj  adjustobs=(trt='C' )); 
       
mnar adjust( wk3 / shift=&sj  adjustobs=(trt='C' )); 
       
mnar adjust( wk4 / shift=&sj  adjustobs=(trt='C' )); 
       
mnar adjust( wk5 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk6 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk7 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk8 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk9 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk10 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk11 / shift=&sj  adjustobs=(trt='C' )); 
mnar adjust( wk12 / shift=&sj  adjustobs=(trt='C' )); 
 
       
mnar adjust( wk1 / shift=0  adjustobs=(trt='D' )); 
       
mnar adjust( wk2 / shift=0  adjustobs=(trt='D' )); 
       
mnar adjust( wk3 / shift=0  adjustobs=(trt='D' )); 
       
mnar adjust( wk4 / shift=0  adjustobs=(trt='D' )); 
       
mnar adjust( wk5 / shift=0  adjustobs=(trt='D' )); 
mnar adjust( wk6 / shift=0  adjustobs=(trt='D' )); 
mnar adjust( wk7 / shift=0  adjustobs=(trt='D' )); 
mnar adjust( wk8 / shift=0  adjustobs=(trt='D' )); 


Statistical Analysis Plan 
Study FSS-AS-30003 
65 
mnar adjust( wk9 / shift=0  adjustobs=(trt='D' )); 
mnar adjust( wk10 / shift=0  adjustobs=(trt='D' )); 
mnar adjust( wk11 / shift=0  adjustobs=(trt='D' )); 
mnar adjust( wk12 / shift=0  adjustobs=(trt='D' )); 
 
var trt &covlist wk1 – wk12; 
run; 
  where: the order of &covlist includes: sex, (pooled investigational  
  center, previous therapy, base, and age 
  Note: wk1 – wk12 is the AVAL raw data, change from baseline values  
        should not be used in PROC MI procedure. 
 
The same shift will be assumed for all weekly average and all treatment groups. 
2. The MMRM model will be fitted to the completed datasets using the model that was 
used for analysis. The difference will be estimated in adjusted LS means and p-value. 
SAS code similar to the following will be used: 
ods output diffs=middiffs; 
proc mixed data=dateset; 
     by shift; 
     class usubjid sex center therapy visit trt; 
     model chg=base sex age center therapy visit trt visit*trt /   
               ddfm=KR alpha=0.05; 
     repeated visit / type=un sub=usubjid(trt) r; 
                ** repeated visit / type=cs sub=usubjid(trt) r; 
                ** if type=un fails to converge; 
     lsmeans trt / diff cl; 
run; 
3. The results from the MMRM models will be combined using the following code: 
data diffdt; 
       
 
set midiffs; 
       
 
comparison=trt||' vs '||left(_trt); 
run; 
proc sort data=diffdt; 
    
 
 
by comparison shift; 
run; 
ods output parameterestimates=miparm1; 
proc mianalyze data=diffdt alpha=0.05 theta0=0; 


Statistical Analysis Plan 
Study FSS-AS-30003 
66 
 
 
 
by comparison shift; 
 
 
 
modeleffects estimate; 
 
 
 
stderr stderr; 
run; 
4. Repeat steps 1 through 3 using the same values for the shift parameter for active arms 
but with a different positive value for placebo group. For example, SAS code below 
indicated a shift of 2 for placebo group.  
mnar adjust( wk1 / shift=2  adjustobs=(trt='D' )); 
mnar adjust( wk2 / shift=2  adjustobs-(trt='D' )); 
mnar adjust( wk3 / shift=2  adjustobs-(trt='D' )); 
mnar adjust( wk4 / shift=2  adjustobs=(trt='D' )); 
mnar adjust( wk5 / shift=2  adjustobs-(trt='D' )); 
mnar adjust( wk6 / shift=2  adjustobs-(trt='D' )); 
mnar adjust( wk7 / shift=2  adjustobs=(trt='D' )); 
mnar adjust( wk8 / shift=2  adjustobs-(trt='D' )); 
mnar adjust( wk9 / shift=2  adjustobs-(trt='D' )); 
mnar adjust( wk10 / shift=2  adjustobs-(trt='D' )); 
mnar adjust( wk11 / shift=2  adjustobs-(trt='D' )); 
mnar adjust( wk12 / shift=2  adjustobs-(trt='D' )); 
 
5. Repeat step 6 with a few different positive values for placebo group.  
6. Steps 2 through 5 will be repeated using different values for the shift parameter. After 
this step,, a treatment effect (difference in adjusted means from placebo) and 
associated p-value will be estimated for each shift parameter. 
Since the tipping point analysis is to find out how much of a change is required to “tip” the result 
from statistically significant to not statistically significant, it will not be performed for any 
comparison that is not statistically significant at the onset. 
Change from Baseline in 1-hour Postdose Percent Predicted Morning FEV1 at Week 12: 
The 1-hour postdose percent predicted morning FEV1 measurement will be performed at the 
investigational center at the RV, TV2 (week 1), TV3 (week 2), TV4 (week 4), TV5 (week 8) and 
TV6 (week 12). MI method will be applied similarly to impute the 1-hour postdose missing data 
that are caused by early dropouts, then tipping point analysis will be performed. 


Statistical Analysis Plan 
Study FSS-AS-30003 
67 
APPENDIX D. SENSITIVITY ANALYSIS: MIXED APPROACH OF 
LOCF AND BOCF 
With this approach, missing data caused by early dropouts from the study will be handled by two 
parts: a positive change from baseline score will be penalized by using the BOCF method. This 
will assign patient’s change from baseline score to zero. Discontinued patient that has negative 
change from baseline with last nonmissing score (LOCF) will not have his/her result adjusted, 
since his/her score will be poor already. 
Change from Baseline in Weekly Average of the Percent Predicted Trough Morning FEV1 
at Week 12: 
The approach will be implemented as follows. Let C denote the change from baseline in percent 
predicted trough morning FEV1, then 
 
 
where fi is the last nonmissing FEV1, and f0 is the baseline of percent predicted FEV1. 
The primary analysis variable that accounts for early dropout, S, will be defined as follows: 
 
 
 
where C is given by equation [1], P=1, if a patient completes the study by protocol or if a 
patient’s final FEV1 is measured at week 12, and P=0, otherwise. Note that retrieved dropout 
data will not be used for this analysis. 
The primary analysis of change from baseline in weekly average of percent predicted trough 
morning FEV1 at week 12 of S, as defined in equation [2] above, will be analyzed using an 
analysis of covariance (ANCOVA) model with effects due to baseline percent predicted trough 
morning FEV1, sex, age, (pooled) investigational center, previous therapy (ICS or NCS), and 
treatment. Contrasts for pairwise treatment comparisons of interest will be constructed. The 
estimated treatment difference between each contrast of interest (i.e, Fp MDPI vs Placebo) will 
be presented together with the 2-sided 95% confidence interval (CI) for the difference and the p-
value. The following SAS code pertains to the analysis: 
proc mixed data=fev1cfb;  
class sex center therapy trt; 
model S=bfev sex age center therapy trt; 
 
/* Compare active Fp treatment to Placebo at Week 12 */ 
estimate ‘Fp 25 mcg BID vs Placebo’      trt  1 0 0 -1 /cl; 
estimate ‘Fp 50 mcg BID vs Placebo’      trt  0 1 0 -1 /cl; 
 CP,  if C > 0 
S = 
C,    if C ≤ 0 
C =  fi − f0 
[2] 
[1] 


Statistical Analysis Plan 
Study FSS-AS-30003 
68 
 
lsmeans trt / diff cl; 
ods output Estimates=Est LSMeans=lsmeans Diffs=Diffs; 
run; 
where: S is defined as in equation [2] above; bfev is the baseline  
value of FEV1; and trt is the treatment for the primary analysis:  
A = Fp MDPI 50 mcg BID 
B = Fp MDPI 100 mcg BID 
C = FS MDPI 50/12.5 mcg BID 
D = Placebo 
Change from Baseline in 1-hour Postdose Percent Predicted Morning FEV1 at Week 12: 
The 1-hour postdose percent predicted morning FEV1 measurement will be performed at the 
investigational center at the RV, TV2 (week 1), TV3 (week 2), TV4 (week 4), TV5 (week 8) and 
TV6 (week 12). Mixed approach of LOCF and BOCF method will be applied similarly to impute 
the 1-hour postdose missing data that are caused by early dropouts from the study IMP.   


Statistical Analysis Plan 
Study FSS-AS-30003 
69 
APPENDIX E. SENSITIVITY ANALYSIS: MMRM 
Similar to the primary estimand, retrieved dropout data will not be used in this sensitivity 
analysis. Missing data are not implicitly imputed in the MMRM analysis; however, all 
nonmissing data for a patient will be used within the analysis to estimate the time-averaged 
difference between treatment groups over 12 weeks. This analysis represents a MAR assumption. 
Change from Baseline in Weekly Average of the Percent Predicted Trough Morning FEV1 
Over Week 12: 
The sensitivity analysis will be performed using a MMRM with effects due to baseline FEV1, 
sex, age, (pooled) center, previous therapy (ICS or NCS), week, treatment, and week-by-
treatment interaction. No explicit structure will be assumed for the covariance among the 
repeated measures. However, if there is a convergence problem with unstructured covariance, 
then a compound symmetry covariance structure will be assumed. 
The estimated treatment means and treatment mean difference derived from the MMRM analysis 
between each treatment will be presented together with 2-sided 95% CI for the means and the 
mean difference with corresponding p-value. An example of the SAS codes is as followed: 
proc mixed data=fev1cfb; 
class usubjid sex center therapy week trt; 
model cfev=bfev sex age center therapy week trt week*trt 
/ddfm=KR; 
repeated week / type=un sub=usubjid(trt) r; 
                             ***repeated week / type=cs sub=usubjid(trt) r; 
                             ***If type=un fails to converge; 
 
/* Compare active Fp treatment to Placebo over 12 weeks */ 
estimate ‘Fp 25 mcg BID vs Placebo’    trt  1 0 0 -1 /cl; 
estimate ‘Fp 50 mcg BID vs Placebo’    trt  0 1 0 -1 /cl; 
 
lsmeans trt week*trt / diff cl; 
ods output Estimates=Est LSMeans=lsmeans Diffs=Diffs; 
run; 
where: cfev and bfev denote change from baseline and baseline value of 
percent predicted FEV1 respectively; week = 1, 2, 3, 4, 5, 6, 7, 8, 9, 
10, 11, 12 representing weeks 1 to 12 respectively; and trt is the 
treatment for the primary analysis: 
A = Fp MDPI 25 mcg BID 
B = Fp MDPI 50 mcg BID 


Statistical Analysis Plan 
Study FSS-AS-30003 
70 
C = FS MDPI 50/12.5 mcg BID 
 
D = Placebo