A Randomized, Blinded, Parallel Group, Placebo-Controlled, Multiple Dose, Multicenter, Multinational Study to Compare the Therapeutic Equivalence of a Budesonide 80 μg/Formoterol Fumarate Dihydrate 4.5 μg Inhalation Aerosol (Manufactured by Catalent for Watson Laboratories Inc.) to Symbicort® (Budesonide 80 μg/Formoterol Fumarate Dihydrate 4.5 μg Inhalation Aerosol) (Manufactured by AstraZeneca) in Adolescent and Adult Patients With Asthma
Phase: PHASE3
Conditions: Asthma
Sponsor: Actavis Inc.

 
 
 
 
Clinical Study Protocol with Amendment 01 
 
 
A Randomized, Blinded, Parallel Group, Placebo-Controlled, Multiple Dose, Multicenter, 
Multinational Study to Compare the Therapeutic Equivalence of a Budesonide 80 
mcg/Formoterol Fumarate Dihydrate 4.5 mcg Inhalation Aerosol (manufactured by 
 for Watson Laboratories Inc.) to Symbicort® (Budesonide 80 mcg/Formoterol 
Fumarate Dihydrate 4.5 mcg Inhalation Aerosol) (manufactured by AstraZeneca) in 
Adolescent and Adult Patients with Asthma 
 
 
Study Number ACT-2015-075-0AA 
 
NCT02495168 
 
Protocol with Amendment 01 Approval Date: 24 February 2017  
 

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SPONSOR SIGNATURE PAGE 
 
Declaration of Sponsor 
Title: A Randomized, Blinded, Parallel Group, Placebo-Controlled, Multiple Dose, 
Multicenter, Multinational Study to Compare the Therapeutic Equivalence of a 
Budesonide 80 mcg/Formoterol Fumarate Dihydrate 4.5 mcg Inhalation Aerosol 
(manufactured by
 for Watson Laboratories Inc.) to Symbicort® 
(Budesonide 80 mcg/Formoterol Fumarate Dihydrate 4.5 mcg Inhalation Aerosol) 
(manufactured by AstraZeneca) in Adolescent and Adult Patients with Asthma  
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki and all amendments, the guidelines on Good 
Clinical Practice, and the Code of Federal Regulations. 
 
 
_____________________________________ 
_____________________ 
 
Date 
 
 
 
 

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Declaration of the Investigator and/or Principal/Global Investigator 
Title: A Randomized, Blinded, Parallel Group, Placebo-Controlled, Multiple Dose, 
Multicenter, Multinational Study to Compare the Therapeutic Equivalence of a 
Budesonide 80 mcg/Formoterol Fumarate Dihydrate 4.5 mcg Inhalation Aerosol 
(manufactured by 
 for Watson Laboratories Inc.) to Symbicort® 
(Budesonide 80 mcg/Formoterol Fumarate Dihydrate 4.5 mcg Inhalation Aerosol) 
(manufactured by AstraZeneca) in Adolescent and Adult Patients with Asthma  
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, electronic CRF (eCRF), and other scientific data. 
The study will be performed according to the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki and all amendments, 
the guidelines on Good Clinical Practice, and the Code of Federal Regulations. 
The study will not be commenced without the prior written approval of a properly 
constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). 
No changes will be made to the study protocol without the prior written approval of the 
Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to 
the patients. 
I have read and understood and agree to abide by all the conditions and instructions 
contained in this protocol. 
 
Responsible Investigator  
 
 
 
_____________________________________ 
_____________________ 
Signature 
Date 
 
_____________________________________ 
Name (block letters) 
 
_____________________________________ 
Title (block letters) 
 
_____________________________________ 
Institution (block letters) 
 
_____________________________________ 
Phone number 
  

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sensitivity of 25 IU/L or equivalent units of beta-human chorionic 
gonadotropin (β-hCG) at screening. 
3. Women of childbearing potential (WOCBP) and female partners 
(WOCBP) of male patients participating in the study, must commit 
to consistent and correct use of an acceptable method of birth 
control (at the Investigator’s discretion) throughout the study and 
for 30 days after study drug discontinuation. 
4. Male patients and male partners of female patients (WOCBP) must 
commit to consistent and correct use of an acceptable method of 
birth control (at the Investigator’s discretion) throughout the study 
and for 30 days after the study drug discontinuation. 
5. Diagnosed with asthma as defined by the NAEPP 3 at least 
6 months prior to screening. If the patient is new to the study site, 
the Investigator must confirm the patient’s asthma diagnosis. 
Acceptable means include either medical records or pharmacy 
records. 
6. Moderate to severe asthma with a pre-bronchodilator FEV1 of 
≥45% and ≤85% of the predicted normal value during measured at 
least 6 hours after short-acting β agonist (SABA) and at least 
24 hours after the last dose of long-acting β agonist (LABA) at the 
screening visit (Visit 1) and on the first day of treatment (prior to 
randomization at Visit 2). 
7. Currently non-smoking, negative for urine cotinine at screening, 
having not used tobacco products (i.e., cigarettes, cigars, pipe 
tobacco, electronic cigarettes) within the past year, and had 
≤10 pack-years of historical use. 
8. Body mass index (BMI) between 18 and 40, inclusive, for patients 
≥18 years old. For adolescent patients 12 to 17 years old, BMI 
between 15 and 40 inclusive (in accordance with the BMI range 
typical for the age).  
9. ≥15% and ≥ 0.20 L reversibility of FEV1 within 30 minutes 
following 360 mcg (4 puffs) of albuterol (400 mcg salbutamol) 
inhalation (pMDI). If the patient achieves <15%, but ≥10% 
reversibility at Visit 1, the site may instruct the patient to hold 
LABA and/or inhaled corticosteroids (ICS) and return up to 7 days 
later for a repeat test. Only 1 repeat of the Visit 1 spirometry (to 
retest reversibility) is allowed per screening. 
10. Able to perform valid and reproducible spirometry per American 
Thoracic Society/European Respiratory Society (ATS/ERS) 
standards at screening. 
11. Able to inhale study drug properly. 
12. Willing to discontinue asthma medications (ICS and LABAs) 
during the Run-in Period and for the remainder of the study. 
13. Able to replace current regularly scheduled SABAs with 
albuterol/salbutamol inhaler for use only on as needed basis for the 
duration of the study (patients should be able to withhold all 

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inhaled SABAs for at least 6 hours prior to lung function 
assessments on study visits). 
14. Able to continue the following medications without a significant 
adjustment of dosage, formulation, dosing interval for the duration 
of the study, and judged able by the Investigator to withhold them 
for the specified minimum time intervals prior to each clinic visit, 
if applicable: 
• Short-acting forms of theophylline: 12 hours. 
• Twice-a-day controlled-release forms of theophylline: 
24 hours. 
• Once-a-day controlled-release forms of theophylline: 36 hours. 
15. Able to discontinue the following medications for the specified 
minimum time intervals prior to the Run-in Period and for the 
remainder of the study, if applicable: 
• Oral corticosteroids for 30 days. 
• Parenteral corticosteroids for 30 days. 
• Oral (not inhaled) SABAs for 24 hours. 
16. Clinical laboratory tests (clinical chemistry, hematology, and 
urinalysis) and 12-lead electrocardiogram (ECG) conducted at the 
screening visit within normal limits or abnormal but not clinically 
significant to the Investigator. The QTc should be calculated using 
Bazett’s formula. 
17. Willing to give written informed consent/assent, and willing and 
able to follow the study rules and procedures. 
18. Stable on chronic asthma treatment regimen for at least 4 weeks 
prior to enrollment. 
19. Ability to perform forced expiratory assessments according to ATS 
standards. 
 
Randomization eligibility criteria: 
1. Baseline pre bronchodilator FEV1 should be ≥45% and ≤85% of 
predicted normal value and not vary by more than ±20% from the 
screening visit FEV1 value. 
2. Compliance during the Run-in Period of at least 75% based on 
eDiary entries is required for a patient to qualify for 
randomization. Compliance with the run-in placebo treatment 
must be between 75% and 125%.  
3. Documented total asthma symptom score of ≥1 for at least 2 days 
during the Run-in Period. 
 
Exclusion criteria: 
1. Life-threatening asthma, defined as a history of asthma episode(s) 
requiring intubation, and/or associated with hypercapnea, 
respiratory arrest or hypoxic seizures, asthma-related syncopal 
episode(s), or hospitalizations within the past year or during the 

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Run-in Period. 
2. Exercise-induced asthma as the only asthma-related diagnosis. 
3. Evidence or history of clinically significant disease or abnormality 
including congestive heart failure, uncontrolled hypertension, 
uncontrolled coronary artery disease, myocardial infarction, or 
cardiac dysrhythmia. In addition, historical or current evidence of 
significant hematologic, hepatic, neurologic, psychiatric, renal, or 
other diseases that, in the opinion of the Investigator, would put the 
patient at risk through study participation, or would affect the 
study analyses if the disease exacerbated during the study. Patients 
with well-controlled hypertension, diabetes or 
hypercholesterolemia are not excluded as long as their medication 
does not interfere with the study. 
4. Any other clinically significant pulmonary disease except for 
asthma, including chronic obstructive pulmonary disease (COPD), 
interstitial lung disease, cystic fibrosis, bronchiectasis, chronic 
bronchitis, emphysema, active pulmonary tuberculosis, pulmonary 
carcinoma, pulmonary fibrosis, or pulmonary hypertension. In 
addition, obstructive sleep apnea warranting a prescription for 
continuous or biphasic positive airway pressure (CPAP or BiPAP). 
5. Patients who required systemic corticosteroids (for any reason) 
within the past 4 weeks. 
6. Patients with hypersensitivity to any sympathomimetic drug (e.g., 
formoterol, albuterol/salbutamol, or salmeterol) or any inhaled, 
intranasal, or systemic corticosteroid therapy. 
7. Patients taking medication(s) (either daily or as needed) with the 
potential to affect the course of asthma or to interact with 
sympathomimetic amines, e.g.,: 
• Oral β-blockers. 
• Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir). 
• Monoclonal antibodies/Biologic agents which may affect the 
course of asthma (such as mepolizumab, reslizumab, 
lebrikizumab, and others).  
8. Viral or bacterial, upper or lower respiratory tract infection or 
sinus or middle ear infection within 2 weeks prior to the screening 
visit or during the Run-in Period. 
9. Factors (e.g., infirmity, disability or geographic location) that the 
Investigator feels would likely limit the patient’s compliance with 
the study protocol or scheduled clinic visits. 
10. Anti-IgE (such as omalizumab) within the 6 months prior to 
screening. 
11. History of alcohol or drug abuse within the last 6 months. 
12. A positive urine drug screen at Visit 1. Exceptions are made for a 
positive urine drug screen at Visit 1 for opiates or stimulants if 
there is a documented prescription with supporting medical history 

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and diagnosis, and the Principal Investigator assesses there are no 
safety concerns with patient participation. Screened patients with a 
urine drug screen positive for Marijuana/Tetrahydrocannabinol are 
not eligible for study participation, without exceptions. Repeat 
drug screening is not allowed.  
13. Have received any investigational treatment within 30 days (or 
within 5 terminal half-lives of the investigational drug whichever 
is longer) of the screening visit or plans to receive investigational 
treatment within 30 days after the study is completed. 
14. Be an Investigator, employee, or otherwise be directly affiliated 
with the study site, Watson Laboratories Inc. and affiliates, or 
service provider involved in the study including being an 
immediate family member of an Investigator or site employee 
(where immediate family member is defined as spouse, parent, 
child or sibling, whether biological or legally adopted or in foster 
care). 
15. Non-compliance with the study requirements, rules, and 
procedures. 
Primary 
Endpoints  
• Baseline-corrected (change from baseline) area under the serial 
FEV1-time effect curve calculated from time zero to 12 hours 
(FEV1 AUC0-12) on the first day of the randomized treatment 
(Visit 2, Day 1) to assess equivalence of test drug (from Watson 
Laboratories Inc.) with RLD Symbicort 80/4.5 mcg, and to assess 
superiority over placebo. 
• Baseline-corrected (change from baseline) FEV1 measured in the 
morning prior to the dosing of inhaled medications on the last day 
of a 6-week treatment (Visit 4, Day ~42) to assess equivalence of 
test drug (from Watson Laboratories Inc.) with RLD Symbicort 
80/4.5 mcg, and to assess superiority over placebo. 
Safety 
Measurements 
• Forced vital capacity (FVC) results at the same time points as the 
FEV1 measurements. 
• Daily rescue medication use. 
• Daily peak expiratory flow rate (PEFR) (morning and evening) at 
home. 
• Symptom scores and daily symptoms (to be recorded in the 
electronic diary [eDiary]). 

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• Adverse drug reactions throughout. 
• Concomitant medications at screening and updated with all new 
concurrent medications at all other visits. 
• Daily SABA use recorded at home in the eDiary. 
• Daily PEFR recorded at home in the eDiary. 
• Spirometry (FEV1, FVC, FEV1/FVC) at screening and all other 
visits. 
• Vital signs (blood pressure, pulse, respiratory rate, and body 
temperature) at all visits. 
• Physical examination at screening and Visit 4 (or early 
termination visit). 
• Clinical laboratory investigation (clinical chemistry, hematology, 
urinalysis) at screening. These tests will be repeated at Visit 4 (or 
early termination) and at any time during the study at the 
Investigator’s discretion. Abnormal values which are deemed 
clinically significant will be rechecked at suitable time intervals. 
• Serum pregnancy (β-hCG) test at screening and Visit 4 (or early 
termination); urine pregnancy test at Visit 2. 
• 12-lead ECG at screening and Visit 4 (or early termination). 
Other 
Assessments 
• Demographics and medical history at screening. 
• Height, weight, and BMI at screening. 
• Drug/alcohol/cotinine screen at screening. 
Statistical 
Methods 
For this pivotal study, equivalence will be based on the test/reference 
(T/R) ratio for the 2 co-primary endpoints. The 90% confidence 
intervals (CI) for both T/R ratios for the primary endpoints should fall 
within the limits of 80.00-125.00%. Actual values without the 
logarithms will be used in the models. 
A separate analysis of covariance (ANCOVA) model will be fit to 
each of the primary endpoints. The model will contain a main effect 
for treatment arm (one degree of freedom; DF) and center. The 
baseline FEV1 will be included as a covariate. The corresponding 90% 
CIs for the (T/R) ratios will be calculated using Fieller’s theorem. 
Equivalence analyses will be done on the PPS. 
To ensure adequate study sensitivity, the test and reference products 
should both be statistically superior in terms of differences to placebo 
(p<0.05, 2-sided) with regard to the study primary endpoints. 
Superiority will be assessed using a similar ANCOVA model as 
described above, for both pairs of compared treatments. Analysis of 
study sensitivity will be done on the mITT set. 
The symptom scores and other variables will be collected 
descriptively. 
Vital signs and ECGs will be recorded and tabulated.  
Safety and tolerability data will be recorded and tabulated. The 
number and percentage of patients experiencing at least 

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1 treatment-emergent adverse event (TEAE) will be summarized by 
Medical Dictionary for Regulatory Activities (MedDRA) primary 
system organ class (SOC) and preferred term (PT), by treatment in 
total (N, incidence) and for the different levels of intensity and 
relationship to study drug.  
 
SCHEDULE OF PROCEDURES 
The Schedule of Procedures, as outlined in Table 1, consists of a Run-in Period and a 
Treatment Period. 

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1. During the Run-in Period, patients will perform PEFR measurements and inhale placebo medication at approximately 12-hour intervals for a minimum of 
14 days and maximum of 21 days. 
2. There is NO Day 0. 
3. The patient will be reminded to report any adverse experiences that occur within 30 days after the last visit. 
4. If a patient discontinues the study prematurely, he/she will be invited to undergo an early termination visit with the same procedures as on Visit 4, except for 
inhalation of the study drug. More specifically, a series of at least 3 spirometric measurements will be obtained in the morning with an interval of 
approximately 20 minutes in between. A medical follow-up examination including physical examination, blood pressure, pulse, ECG and clinical laboratoy 
investigation will be done. 
5. Informed consent/assent may be signed up to 14 days prior to Visit 1. Written informed consent/assent must be obtained prior to any study-related procedure 
which includes medication washout and restrictions. 
6. Blood pressure, pulse, respiratory rate, and body temperature. Blood pressure and pulse will be measured at each clinical visit after at least 10 minutes rest in 
supine position. On Visits 2, 3, and 4, measurements will be done in the morning prior to inhalation, and a patient would not be administered study drug if 
his/her blood pressure or pulse is deemed as clinically significant abnormal by the Investigator. 
7. 12-lead ECG to be measured after at least 10 minutes rest in supine position.  
8. Screening spirometry must demonstrate a pre-bronchodilator FEV1 of ≥45% and ≤85% of the predicted value and at least 80% of the Visit 1 value. 
In the morning of the first day of treatment (Visit 2) the FEV1 must also be in the range of ≥45% and ≤85% of the predicted value. 
9. Patients must demonstrate ≥15% reversibility of FEV1 within 30 minutes following 360 mcg of albuterol/400 mcg salbutamol inhalation pMDI. 
If the patient achieves <15%, but ≥10% reversibility at Visit 1, the site may instruct the patient to hold LABA and/or ICS and return up to 7 days later for a 
repeat test. Only 1 repeat of the Visit 1 spirometry (to retest reversibility) is allowed per screening. 
10. Spirometric measurements in the morning prior to the dosing of inhaled medication at 60, 30, and 5 minutes pre-dose. 
11. Must be performed at 60, 30 and 5 minutes pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on the first day of the 6-week Treatment Period 
(Visit 2). 
12. Inhalation training using placebo devices will be performed at the screening visit (Visit 1). Patients will inhale from a placebo pMDI. 
 
 
. Patients will be instructed to use the inhaler in the morning at 
approximately the same time every day between 6:30 am and 11:00 am, and then approximately 12 hours later between 6:30 pm and 11:00 pm every day for 
the full duration of the Run-in Period and the Treatment Period. At each subsequent visit, the correct inhalation technique will be reinforced by the 
Investigator in the morning prior to inhalation. Patients will keep the placebo pMDI for use during the Run-in Period. 
13. If a re-supply is needed. 
14. If needed. 

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15. Open-label placebo medication will be inhaled during the Run-in Period. If a patient is deemed to be suitable to enter the Run-in Period, the first dose of 
placebo medication will be inhaled at the study site at Visit 1, and the correct inhalation technique will be reinforced.  
16. Patients will be instructed to withhold the study drug and not perform morning PEFR measurements until they arrive at the study site. Visits must be 
scheduled to allow completion of the relevant assessments prior to taking study drug at the patient’s regular morning time. The last dose of study drug will 
be inhaled at Visit 4 in the morning. Then, the inhaler will be collected. 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .................................................................................................. 4 
SCHEDULE OF PROCEDURES .................................................................................. 11 
LIST OF STUDY PERSONNEL .................................................................................... 16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 23 
1 
INTRODUCTION................................................................................................ 26 
1.1 
Background ...................................................................................................... 26 
1.2 
Rationale .......................................................................................................... 27 
1.3 
Risk-Benefit Assessment ................................................................................. 27 
2 
STUDY OBJECTIVES ........................................................................................ 29 
2.1 
Primary Objective ........................................................................................... 29 
3 
INVESTIGATIONAL PLAN ............................................................................. 30 
3.1 
Overall Study Design and Plan ...................................................................... 30 
3.2 
Criteria for Evaluation of the Study .............................................................. 32 
3.2.1 
Primary Endpoints ............................................................................... 32 
3.2.2 
Safety Measurements ........................................................................... 33 
3.2.3 
Other Assessments ............................................................................... 33 
3.3 
Justification of the Study Design ................................................................... 33 
4 
STUDY POPULATION ...................................................................................... 34 
4.1 
Inclusion Criteria ............................................................................................ 34 
4.2 
Randomization Eligibility Criteria ................................................................ 35 
4.3 
Exclusion Criteria ........................................................................................... 36 
4.4 
Patient Withdrawal and Replacement .......................................................... 37 
4.4.1 
Withdrawal Criteria for Asthma Exacerbation .................................... 37 
4.4.2 
Additional Withdrawal Criteria ........................................................... 38 
4.4.3 
Withdrawal Procedures ........................................................................ 38 
4.5 
Planned Sample Size and Number of Study Centers ................................... 38 
4.6 
Patient Identification and Randomization .................................................... 38 
4.6.1 
Patient Identification ............................................................................ 38 
4.6.2 
Randomization Scheme ....................................................................... 39 
4.6.3 
Allocation/Randomization of Patients to Treatment............................ 39 
5 
STUDY DRUG ..................................................................................................... 40 
5.1 
Identity ............................................................................................................. 40 
5.1.1 
Test Product ......................................................................................... 40 
5.1.2 
Reference Product ................................................................................ 41 
5.1.3 
Placebo ................................................................................................. 41 
5.1.4 
Rescue Medication ............................................................................... 41 
5.2 
Administration ................................................................................................. 41 
5.2.1 
Run-in Period ....................................................................................... 42 
5.2.2 
Treatment Period .................................................................................. 42 

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5.3 
Device Training ............................................................................................... 43 
5.4 
Packaging, Labeling, and Storage ................................................................. 43 
5.5 
Retention of Samples ....................................................................................... 43 
5.6 
Blinding and Breaking the Blind ................................................................... 44 
5.6.1 
Blinding................................................................................................ 44 
5.6.2 
Breaking the Blind ............................................................................... 45 
5.7 
Drug Accountability ........................................................................................ 45 
5.8 
Compliance ...................................................................................................... 46 
5.8.1 
Study Drug Compliance ....................................................................... 46 
5.9 
Previous and Concomitant Medications ....................................................... 46 
5.9.1 
Rescue Medication ............................................................................... 47 
6 
VARIABLES AND METHODS OF ASSESSMENT ....................................... 48 
6.1 
Lung Function and Reversibility Testing ..................................................... 48 
6.1.1 
Spirometry............................................................................................ 48 
6.1.2 
Reversibility Testing ............................................................................ 49 
6.2 
Daily eDiary Assessments ............................................................................... 49 
6.2.1 
Daily Symptoms................................................................................... 49 
6.2.2 
Asthma Symptom Scores ..................................................................... 50 
6.2.3 
Study Drug Use .................................................................................... 50 
6.2.4 
Rescue Medication Use........................................................................ 51 
6.2.5 
Peak Expiratory Flow Rate Measurements .......................................... 51 
6.3 
Adverse Events ................................................................................................ 51 
6.3.1 
Definitions of Adverse Events ............................................................. 51 
6.3.2 
Recording Adverse Events ................................................................... 52 
6.3.3 
Follow-up of Adverse Events .............................................................. 53 
6.3.4 
Reporting Serious Adverse Events ...................................................... 53 
6.3.5 
Removal of Patients from Study Due to Adverse Events .................... 55 
6.3.6 
Termination of Study Due to Adverse Events ..................................... 55 
6.3.7 
Suspected Unexpected Serious Adverse Reactions ............................. 55 
6.3.8 
Pregnancy ............................................................................................. 56 
6.4 
Laboratory Variables ...................................................................................... 57 
6.5 
Vital Signs ........................................................................................................ 58 
6.6 
Electrocardiograms ......................................................................................... 58 
6.7 
Physical Examinations .................................................................................... 59 
7 
STUDY CONDUCT ............................................................................................. 60 
7.1 
Procedures by Visit ......................................................................................... 60 
7.1.1 
Informed Consent................................................................................. 60 
7.1.2 
Screening (Visit 1) ............................................................................... 60 
7.1.3 
Open Placebo Run-in Period ................................................................ 61 
7.1.4 
Treatment Period .................................................................................. 61 
7.1.4.1 
Visit 2 (Randomization) ................................................................. 61 
7.1.4.2 
Visit 3 ............................................................................................. 62 
7.1.4.3 
Visit 4 ............................................................................................. 62 
7.1.5 
Early Termination Visit ....................................................................... 63 

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8 
STATISTICAL METHODS ............................................................................... 64 
8.1 
Study Patients .................................................................................................. 64 
8.1.1 
Disposition of Patients ......................................................................... 64 
8.1.2 
Protocol Deviations .............................................................................. 64 
8.1.3 
Analysis Sets ........................................................................................ 65 
8.2 
General Considerations .................................................................................. 65 
8.2.1 
Missing Data and Data Conventions: .................................................. 65 
8.3 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications ............................................................................... 65 
8.4 
Lung Function Testing/Spirometry ............................................................... 66 
8.5 
Rescue Medications, Previous and Concomitant Medications ................... 66 
8.6 
Treatment Compliance ................................................................................... 66 
8.7 
Analysis of Primary Endpoints ...................................................................... 66 
8.7.1 
Analysis of Bioequivalence ................................................................. 67 
8.7.2 
Analysis of Assay Sensitivity .............................................................. 67 
8.8 
Safety Analyses ................................................................................................ 67 
8.8.1 
Adverse Events .................................................................................... 67 
8.8.2 
Safety Laboratory Tests, Vital Signs, and ECGs ................................. 68 
8.8.3 
Physical Examination........................................................................... 68 
8.8.4 
Daily Diary Questions.......................................................................... 68 
8.9 
Other Analyses ................................................................................................ 68 
8.10 
Interim Analyses .............................................................................................. 69 
8.11 
Determination of Sample Size ........................................................................ 69 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS .......................... 71 
9.1 
Data Quality Assurance .................................................................................. 71 
9.1.1 
Database Management and Quality Control ........................................ 71 
9.2 
Case Report Forms and Source Documentation .......................................... 71 
9.2.1 
Data Collection .................................................................................... 72 
9.3 
Access to Source Data ..................................................................................... 72 
9.4 
Data Processing ............................................................................................... 73 
9.5 
Archiving Study Records ................................................................................ 73 
9.6 
Good Clinical Practice .................................................................................... 73 
9.7 
Informed Consent ............................................................................................ 73 
9.8 
Protocol Approval and Amendment .............................................................. 74 
9.9 
Duration of the Study ...................................................................................... 74 
9.10 
Premature Termination of the Study ............................................................ 74 
9.11 
Confidentiality ................................................................................................. 75 
9.12 
Other Ethical and Regulatory Issues ............................................................. 75 
9.12.1 
Institutional Review Board/Independent Ethics Committee................ 75 
9.12.2 
Investigator’s Statement....................................................................... 75 
9.13 
Publication Policy ............................................................................................ 76 
10 
REFERENCE LIST ............................................................................................. 77 
11 
APPENDICES ...................................................................................................... 78 

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11.1 
Information on Asthma Medications and Prohibited Concomitant 
Medications ...................................................................................................... 78 
11.2 
Guide to Lower Limits of BMI in Adolescents ............................................. 82 
 
Tables in Text 
Table 1: Schedule of Procedures ..................................................................................... 12 
Table 2: Previous and Concomitant Medications, with Required Washout Periods ....... 47 
Table 3: Reporting Contacts for SAEs ............................................................................ 54 
Table 4: Laboratory Assessments .................................................................................... 58 
Table 5: Sample Size Calculation ................................................................................... 69 
 
Figures in Text 
Figure 1: Overall Study Design ........................................................................................ 32 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
ANCOVA 
Analysis of covariance  
ANDA 
Abbreviated new drug application 
ANOVA 
Analysis of variance  
ATC 
Anatomical Therapeutic Chemical 
ATS 
American Thoracic Society 
AUC 
Area under curve 
AUC0-12 
Area under the serial FEV1 time effect curve calculated from time 
zero to 12 hours (FEV1 AUEC0 -12) 
β-hCG 
Beta-human chorionic gonadotropin 
BDRM 
Blinded Data Review Meeting 
BDS 80/FFD 4.5 
Generic budesonide 80 mcg/formoterol fumarate dihydrate 4.5 mcg  
(as developed by Watson Laboratories Inc.) 
BMI 
Body mass index  
CI 
Confidence interval 
COPD 
Chronic obstructive pulmonary disease  
CRO 
Contract research organization 
CV 
Coefficient variance  
DF 
Degrees of freedom 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
eDiary 
Electronic diary 
ENS 
Enrolled Set 
ERS 
European Respiratory Society  
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle stimulating hormone 
FVC 
Forced vital capacity  
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practices 
hCG 
Human chorionic gonadotropin  
IB 
Investigator’s brochure  

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ICS 
Inhaled corticosteroids  
IEC 
Independent Ethics Committee 
ICH 
International Conference on Harmonization 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System  
LABA 
Long-acting β2-adrenergic agonist 
LOCF 
Last observation carried forward 
MAO 
Monoamine oxidase  
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-To-Treat (set) 
NAEPP 
National Asthma Education and Prevention Program Expert Panel 
Report  
NHANES 
National Health and Nutrition Examination Survey 
PEF 
Peak expiratory flow  
PEFR 
Peak expiratory flow rate  
PID 
Patient identification  
PIF 
Peak inspiratory flow rate 
pMDI 
Pressurized metered dose inhaler  
PT 
Preferred term 
PPS 
Per-Protocol Set 
QTc 
Corrected QT interval 
RiN 
Run-in Set 
RLD 
Reference listed drug 
SABA 
Short-acting β agonist  
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SUSAR 
Suspected unexpected serious adverse reaction 
SOC 
System organ class 
SPC 
Summary of product characteristics  
TEAE 
Treatment-emergent adverse event 

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T/R 
Test/reference ratio 
US 
United States (of America) 
WHO-DRL 
World Health Organization – Drug Reference List 
WOCBP 
Women of childbearing potential  
 

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1 
INTRODUCTION  
1.1 
Background 
Asthma is a serious public health problem throughout the world, affecting about 
300 million individuals of all ages. Asthma is a chronic inflammatory disorder of the 
airways, characterized by recurrent acute attacks of breathlessness and wheezing, in 
which many cells and cellular elements play a role [1]. When uncontrolled, asthma can 
place severe limitations on daily life, and is sometimes fatal. Although there is no cure, 
avoidance of asthma triggers and the use of appropriate long- and short-term medication 
offer patients options for control of their disease [2]. 
Inhaled corticosteroids (ICSs) are recommended as first-line treatment for patients with 
persistent asthma, and the addition of an inhaled long-acting β2-adrenergic agonist 
(LABA) can be considered to improve lung function and symptoms in patients whose 
asthma is not well controlled on ICS alone. Combination therapy has become the 
standard of care for the treatment of mild to moderate persistent asthma [3], [4], [5]. 
Clinical long-term experience over the last decade has shown that regular inhalational 
treatment with fixed combinational ICS/LABA products results in substantial increases in 
relevant lung function parameters (forced expiratory volume in 1 second [FEV1] and peak 
expiratory flow [PEF]) and clinical symptom control [3], [4]. Further it has been shown 
that ICS/LABA combinations do not cause any tolerance development of asthma control, 
rendering fixed ICS/LABA combinations currently the most effective and beneficial 
long-term treatments of asthma available. 
Symbicort® is a combination product containing a corticosteroid (budesonide) and a 
LABA (formoterol fumarate dehydrate), indicated for the treatment of asthma in patients 
12 years of age and older and for maintenance treatment of airflow obstruction in patients 
with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and 
emphysema [6]. It is not indicated for the relief of acute bronchospasm. Symbicort® is 
marketed in the US as Symbicort® and in Europe as Symbicort Turbohaler®. 
Watson Laboratories Inc. is developing a generic form of budesonide/formoterol 
fumarate dihydrate inhalation aerosol delivered via a pressurized metered dose inhaler 
(pMDI) device. The device is a disposable canister containing a combination of 
micronized budesonide (80 mcg per actuation) and micronized formoterol fumarate 
dihydrate (4.5 mcg per actuation) as an oral inhalation aerosol formulation. It is a pMDI 
developed as generic to the United States (US) reference listed drug (RLD) Symbicort® 
for the treatment of asthma and COPD.  
Further details can be found in the Investigator’s Brochure (IB), which contains 
comprehensive information on the investigational product. 
The current study is designed to establish the therapeutic equivalence of Watson 
Laboratories Inc.’s generic formulation to commercially available Symbicort®. It is a 
randomized, multiple-dose, placebo-controlled, parallel group design consisting of a 2-
week open placebo Run-in Period followed by a 6-week randomized Treatment Period 
with either test product, RLD, or placebo. Male and female adolescents and adults who 
have asthma will self-administer study drug twice daily. 

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1.2 
Rationale 
This study is part of a program considered necessary by the US Food and Drug 
Administration (FDA) for getting approval for a generic inhalation product. Generally, in 
the absence of a product specific guidance the FDA suggests that to support the “weight 
of evidence” for approval of an abbreviated new drug application (ANDA) a pivotal 
therapeutic equivalence study with clinical endpoint should be done comparing test 
product and RLD with regard to clinical efficacy. 
This study is designed to evaluate bioequivalence between the test product and RLD in 
accordance with the recommendations outlined in the US FDA Draft Guidance on 
Budesonide; Formoterol fumarate dihydrate (June 2015) [7].  
1.3 
Risk-Benefit Assessment 
The risks of participation in this study are mainly related to the possibility of loss of 
asthma control and resulting morbidity in patients randomized to the placebo group, or 
not responding to therapy, and the adverse effects of budesonide/formoterol fumarate 
therapy.  
The adverse effect profile of generic budesonide/formoterol fumarate therapy is expected 
to be the same as for the RLD, Symbicort®. The adverse effect profile of Symbicort® is 
well established [6]. Symbicort® has a Black Box Warning in the US which states:  
ASTHMA-RELATED DEATH:  
• LABA, such as formoterol one of the active ingredients in Symbicort®, increase the 
risk of asthma-related death. A placebo-controlled study with another LABA 
(salmeterol) showed an increase in asthma-related deaths in patients receiving 
salmeterol. This finding with salmeterol is considered a class effect of LABA, 
including formoterol. Currently available data are inadequate to determine whether 
concurrent use of ICS or other long-term asthma control drugs mitigates the risk of 
asthma-related death from LABA. Available data from controlled clinical trials 
suggest that LABA increase the risk of asthma-related hospitalization in pediatric and 
adolescent patients. 
• When treating patients with asthma, prescribe Symbicort® only for patients not 
adequately controlled on a long-term asthma control medication, such as inhaled 
corticosteroid or whose disease severity clearly warrants initiation of treatment with 
both an inhaled corticosteroid and LABA. Once asthma control is achieved and 
maintained, assess the patient at regular intervals and step down therapy (e.g., 
discontinue Symbicort®) if possible without loss of asthma control, and maintain the 
patient on a long-term asthma control medication, such as an inhaled corticosteroid. 
Do not use Symbicort® for patients whose asthma is adequately controlled on low or 
medium dose ICS. 
The prescribing information [6] also includes the following ICS-related warning: 
• Hypercorticism and adrenal suppression: May occur with very high dosages or at the 
regular dosage in susceptible individuals. If such changes occur, discontinue 
Symbicort® slowly. 
The available information suggests that the present study has a favorable risk-benefit 
ratio. The study design includes strict withdrawal criteria for worsening asthma during 

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both the 2-week placebo Run-in Period and 6-week randomized Treatment Period, and 
the availability of rescue medication ensures that no patient is placed at undue risk. The 
risk of ICS-related effects is minimized because the recommended daily dose will not be 
exceeded. 
 

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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The objective of this pivotal trial is to confirm the therapeutic equivalence of a new 
generic fixed-dose combination product containing budesonide 80 mcg/formoterol 
fumarate dihydrate 4.5 mcg (BDS 80/FFD 4.5) (per actuation) inhalation aerosol pMDI 
manufactured by 
 for Watson Laboratories Inc. and RLD Symbicort® 
(budesonide 80 mcg/formoterol fumarate dihydrate 4.5 mcg inhalation aerosol) 
manufactured by AstraZeneca, in adolescent patients and adult patients with chronic but 
stable asthma as defined in National Asthma Education and Prevention Program Expert 
Panel Report 3 (NAEPP 3) guidelines [8].  
To ensure adequate study sensitivity the test and reference products should both be 
statistically superior to placebo (p<0.05) with regard to the bioequivalence study primary 
endpoints. 

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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a randomized, blinded, parallel group, placebo-controlled, multiple dose, 
multicenter, multinational study to compare the therapeutic equivalence of 
BDS 80/FFD 4.5 (per actuation) inhalation aerosol pMDI manufactured by 
 for 
Watson Laboratories Inc. and RLD Symbicort® manufactured by AstraZeneca, in 
adolescent patients and adult patients with chronic but stable asthma as defined in 
NAEPP 3 guidelines. 
All patients in this study must have a documented diagnosis of moderate to severe 
asthma. Male patients and non-pregnant, nonlactating female patients 12 years to 
75 years of age who meet the entry criteria may be enrolled. 
The study consists of a 2-week open placebo Run-in Period followed by a 6-week 
randomized Treatment Period (test, reference, or placebo).  
Written informed consent/assent must be obtained prior to any study-related procedure 
which includes medication washout and restrictions. Informed consent/assent may be 
signed up to 14 days prior to Visit 1. 
Screening Visit 
Patient demographic information, medical and asthma history, lung function, and clinical 
laboratory assessments will be collected after patients provide informed consent/assent 
(the latter for adolescent patients) and before taking study drug. Laboratory values at 
screening must be normal (or abnormal and not clinically significant) as evaluated by the 
Investigator. 
At Visit 1, patients will perform spirometry to demonstrate a pre-bronchodilator FEV1 of 
≥45% and ≤85% of the predicted normal value using the equations derived from the 
National Health and Nutrition Examination Survey (NHANES) III dataset for adults [9]. 
All lung function tests will be conducted in accordance with current American Thoracic 
Society/European Respiratory Society (ATS/ERS) recommendations [10].  
Patients must demonstrate ≥15% reversibility of FEV1 within 30 minutes following 
360 mcg (4 puffs) of albuterol (free base) or 400 mcg (4 puffs) of salbutamol inhalation 
(pMDI) at screening (Visit 1). Up to 2 spirometry sessions within the time window after 
bronchodilator administration (30 minutes ± 10 minutes) are permitted at Visit 1. If the 
patient achieves <15%, but ≥10% reversibility at Visit 1, the site may instruct the patient 
to hold LABA and/or ICS and return up to 7 days later for a repeat test. Only 1 repeat of 
the Visit 1 spirometry (to retest for reversibility) is allowed per screening.  
Patients will receive instruction on how to measure PEF rate (PEFR) and answer 
electronic diary (eDiary) questions asking the patient about his/her asthma symptoms. 
Patients will also be instructed to measure PEFR and answer the questions before 
self-administering the provided study drug. Patients will also be given an 
albuterol/salbutamol pMDI as rescue medication and instructed to use 2 inhalations of 
albuterol/salbutamol as needed to relieve asthma symptoms. 

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Open Label Placebo Run-in Period 
Eligible patients will enter an open label, placebo Run-in Period of at least 2 weeks in 
duration (but not longer than 21 days) to wash out any pre-study corticosteroids or 
long-acting bronchodilators and to establish FEV1 baseline values.  
Patients will perform PEFR measurements and inhale placebo medication at 
approximately 12 hour intervals for a minimum of 14 days and maximum of 21 days.  
Patients must have placebo inhaler compliance of at least 75% of study drug doses in the 
Run-in Period to proceed into the randomized Treatment Period. Compliance will be 
based on patient eDiary. 
Randomized Treatment Period 
Those continuing to meet entry criteria will enter a 6-week Treatment Period (that begins 
on the following day, Day 1) and be randomly assigned in a 4:4:1 ratio to 1 of 3 treatment 
arms: 
• Test product: BDS 80/FFD 4.5 inhalation aerosol (manufactured by 
for 
Watson Laboratories Inc.) (test) 
• Reference product (RLD): Symbicort® (manufactured by AstraZeneca) (reference) 
• Placebo: To match generic BDS 80/FFD 4.5 inhalation aerosol (manufactured by 
 for Watson Laboratories Inc.) (placebo) 
On the first day of treatment at Visit 2, FEV1 will be determined at 60, 30, and 5 minutes 
pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours post-dose. 
Patients will record PEFR data and the other requested information on their eDiary and 
take test, reference, or placebo at approximately 12 hour intervals for a minimum of 
42 days and maximum of 49 days. 
Patients will be instructed to return to the clinic for Visit 3 at the end of the third 
treatment week (treatment day 21 ± 7 days) and for Visit 4, at the end of the sixth 
treatment week (treatment day 42 + a time window of 7 days). Patients will be instructed 
to withhold the study drug and not perform morning PEFR measurements until they 
arrive at the clinic on the morning of Visit 3 (Day 21 ± 7 days) and Visit 4 (Day 42 + 
7 days. On both visits, FEV1 will be determined at 60, 30, and 5 minutes pre-dose, the 
average of which constitutes the pre-dose (0) value. A minimum of 2 pre-dose values are 
required to estimate the mean/average. 
At the beginning of each visit, the Investigator will thoroughly review the patient’s 
eDiary entries and discuss the results with the patient. The patients will be asked about 
their medication washouts and whether they have experienced any unusual symptoms or 
medical problems since the last visit. Patients will be reminded that they must inhale the 
study drug as instructed. 
Overall, the planned duration of patient participation is 8 weeks comprising 2 weeks for 
the placebo Run-in Period and 6 weeks for the randomized Treatment Period.  
No formal interim analysis with statistical stopping rules will be undertaken, although 
sample size recalculation may be performed per the interim analysis plan (Section 8.10). 
After the end of the study, the patients will revert to their previous care plan. 
A detailed Schedule of Procedures is provided in Table 1. A schematic of the study 
design is provided in Figure 1. 

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pre-dose (the average of which constitutes the pre-dose (0) value), and at 0.5, 1, 2, 3, 4, 6, 
8, 10, and 12 hour post-dose. At the end of the 6-week Treatment Period, FEV1 will be 
determined at 60, 30, and 5 minutes pre-dose on ~Day 42 morning dose (constituting the 
trough values). 
3.2.2 Safety Measurements 
• Forced vital capacity (FVC) results at the same time points as the FEV1 
measurements.  
• Daily rescue medication use. 
• Daily PEFR (morning and evening) at home. 
• Symptom scores and daily symptoms (to be recorded in the eDiary). 
• Adverse reactions throughout. 
• Concomitant medications throughout. 
• Daily short-acting β agonist (SABA) use recorded at home in the eDiary. 
• Daily PEFR recorded at home in the eDiary. 
• Spirometry (FEV1, FVC, FEV1/FVC) at screening and all other visits. 
• Vital signs at all visits. 
• Physical examination at screening and Visit 4 (or early termination visit). 
• Clinical laboratory investigation at screening and Visit 4 (or early termination). 
• Serum pregnancy (β-hCG) test at screening and Visit 4 (or early termination); urine 
pregnancy test at Visit 2. 
• 12-lead electrocardiogram (ECG) at screening and Visit 4 (or early termination). 
 
3.2.3 Other Assessments 
• Demographics and medical history at screening. 
• Height, weight, and BMI at screening. 
• Drug/alcohol/cotinine screen at screening. 
3.3 
Justification of the Study Design 
The design of this study follows the recommendation of the FDA draft guidance 
document on Budesonide; Formoterol fumarate dihydrate (June 2015) [7]. 
This FDA guidance requires that patients discontinue previous asthma-controller therapy 
during the 2-week Run-in Period. After the Run-in Period, patients are randomly assigned 
to either the test, reference, or placebo treatment. Patients continue to use the 
study-supplied rescue medication (i.e., albuterol/salbutamol inhaler) throughout the 
6-week Treatment Period. Patients are also blinded to the identity of the study drug 
during the Treatment Period.  

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4 
STUDY POPULATION 
The study population will consist of male and non-pregnant female patients (≥12 and 
≤75 years of age) with moderate to severe asthma as defined by the NAEPP 3 
guidelines [8]. Patients must be able to provide written consent/assent and meet all the 
inclusion criteria and none of the exclusion criteria. 
4.1 
Inclusion Criteria 
Patients will be entered into this study only if they meet all of the following criteria: 
1. Adolescent and adult male or female patients (≥12 and ≤75 years of age) 
2. Female patients must not be lactating or pregnant at screening, as documented by a 
negative serum pregnancy test with a minimum sensitivity of 25 IU/L or equivalent 
units of beta-human chorionic gonadotropin (β-hCG) at screening. 
3. Women of childbearing potential (WOCBP) and female partners (WOCBP) of male 
patients participating in the study, must commit to consistent and correct use of an 
acceptable method of birth control (at the Investigator’s discretion) throughout the 
study and for 30 days after study drug discontinuation. 
4. Male patients and male partners of female patients (WOCBP) must commit to 
consistent and correct use of an acceptable method of birth control (at the 
Investigator’s discretion) throughout the study and for 30 days after the study drug 
discontinuation. 
5. Diagnosed with asthma as defined by the NAEPP 3 [8] at least 6 months prior to 
screening. If the patient is new to the study site, the Investigator must confirm the 
patient’s asthma diagnosis. Acceptable means include either medical records or 
pharmacy records. 
6. Moderate to severe asthma with a pre-bronchodilator FEV1 of ≥45% and ≤85% of the 
predicted normal value during measured at least 6 hours after SABA and at least 
24 hours after the last dose of LABA at the screening visit (Visit 1) and on the first 
day of treatment (prior to randomization at Visit 2).   
7. Currently non-smoking, negative for urine cotinine at screening, having not used 
tobacco products (i.e., cigarettes, cigars, pipe tobacco, electronic cigarettes) within 
the past year, and had ≤10 pack-years of historical use. 
8. Body mass index (BMI) between 18 and 40, inclusive for patients ≥18 years old. For 
adolescent patients 12 to 17 years old, BMI between 15 and 40 inclusive (in 
accordance with the BMI range typical for the age) (refer to Appendix 11.2 for guide 
to lower limits of BMI in adolescents). 
9. ≥15% and ≥ 0.20 L reversibility of FEV1 within 30 minutes following 360 mcg 
(4 puffs) of albuterol (400 mcg salbutamol) inhalation (pMDI). If the patient achieves 
<15%, but ≥10% reversibility at Visit 1, the site may instruct the patient to hold 
LABA and/or ICS and return in up to 7 days for a repeat test. Only 1 repeat of the 
Visit 1 spirometry (to retest reversibility) is allowed per screening. 

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10. Able to perform valid and reproducible spirometry per ATS/ERS standards [10] at 
screening. 
11. Able to inhale study drug properly. 
12. Willing to discontinue asthma medications (ICS and LABAs) during the Run-in 
Period and for the remainder of the study. 
13. Able to replace current regularly scheduled SABAs with albuterol/salbutamol inhaler 
for use only on as-needed basis for the duration of the study (patients should be able 
to withhold all inhaled SABAs for at least 6 hours prior to lung function assessments 
on study visits). 
14. Able to continue the following medications without a significant adjustment of 
dosage, formulation, dosing interval for the duration of the study, and judged able by 
the Investigator to withhold them for the specified minimum time intervals prior to 
each clinic visit, if applicable: 
• Short-acting forms of theophylline: 12 hours. 
• Twice-a-day controlled-release forms of theophylline: 24 hours. 
• Once-a-day controlled-release forms of theophylline: 36 hours. 
15. Able to discontinue the following medications for the specified minimum time 
intervals prior to the Run-in Period and for the remainder of the study, if applicable: 
• Oral corticosteroids for 30 days. 
• Parenteral corticosteroids for 30 days. 
• Oral (not inhaled) SABAs for 24 hours. 
16. Clinical laboratory tests (clinical chemistry, hematology, and urinalysis) and 12-lead 
ECG conducted at the screening visit within normal limits or abnormal but not 
clinically significant to the Investigator. The QTc should be calculated using Bazett’s 
formula. 
17. Willing to give written informed consent/assent, and willing and able to follow the 
study rules and procedures. 
18. Stable on chronic asthma treatment regimen for at least 4 weeks prior to enrollment 
19. Ability to perform forced expiratory assessments according to ATS standards. 
4.2 
Randomization Eligibility Criteria 
1. Baseline pre bronchodilator FEV1 should be ≥45% and ≤85% of predicted normal 
value and not vary by more than ±20% from the screening visit FEV1 value. 
2. Compliance during the Run-in Period of at least 75% (based on eDiary entries) is 
required for a patient to qualify for randomization. Compliance with the run-in 
placebo treatment must be between 75% and 125%.  
3. Documented total asthma symptom score of ≥1 for at least 2 days during the Run-in 
Period. 

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4.3 
Exclusion Criteria 
Patients will be entered into this study only if they meet none of the following criteria: 
1. Life-threatening asthma, defined as a history of asthma episode(s) requiring 
intubation, and/or associated with hypercapnea, respiratory arrest or hypoxic seizures, 
asthma-related syncopal episode(s), or hospitalizations within the past year or during 
the Run-in Period. 
2. Exercise-induced asthma as the only asthma-related diagnosis. 
3. Evidence or history of clinically significant disease or abnormality including 
congestive heart failure, uncontrolled hypertension, uncontrolled coronary artery 
disease, myocardial infarction, or cardiac dysrhythmia. In addition, historical or 
current evidence of significant hematologic, hepatic, neurologic, psychiatric, renal, or 
other diseases that in the opinion of the Investigator, would put the patient at risk 
through study participation, or would affect the study analyses if the disease 
exacerbated during the study. Patients with well controlled hypertension, diabetes, or 
hypercholesterolemia are not excluded as long as their medication does not interfere 
with the study. 
4. Any other clinically relevant pulmonary disease except for asthma, including COPD, 
interstitial lung disease, cystic fibrosis, bronchiectasis, chronic bronchitis, 
emphysema, active pulmonary tuberculosis, pulmonary carcinoma, pulmonary 
fibrosis, or pulmonary hypertension. In addition, obstructive sleep apnea warranting a 
prescription for continuous or biphasic positive airway pressure (CPAP or BiPAP). 
5. Patients who required systemic corticosteroids (for any reason) within the past 
4 weeks. 
6. Patients with hypersensitivity to any sympathomimetic drug (e.g., formoterol, 
albuterol/salbutamol, or salmeterol) or any inhaled, intranasal, or systemic 
corticosteroid therapy. 
7. Patients taking medication(s) (either daily or as needed) with the potential to affect 
the course of asthma or to interact with sympathomimetic amines, e.g.,: 
• Oral β-blockers. 
• Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir). 
• Monoclonal antibodies/Biologic agents which may affect the course of 
asthma (such as mepolizumab, reslizumab, lebrikizumab, and others).  
Refer to Section 5.9 for relevant washout periods  
8. Viral or bacterial, upper or lower respiratory tract infection or sinus or middle ear 
infection within 2 weeks prior to the screening visit or during the Run-in Period. 
9. Factors (e.g., infirmity, disability or geographic location) that the Investigator feels 
would likely limit the patient’s compliance with the study protocol or scheduled clinic 
visits. 
10. Anti-IgE (such as omalizumab) within the 6 months prior to screening. 
11. History of alcohol or drug abuse within the last 6 months. 

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12. A positive urine drug screen at Visit 1. Exceptions are made for a positive urine drug 
screen at Visit 1 for opiates or stimulants if there is a documented prescription with 
supporting medical history and diagnosis, and the Principal Investigator assesses there 
are no safety concerns with patient participation. Screened patients with a urine drug 
screen positive for Marijuana/Tetrahydrocannabinol (THC) are not eligible for study 
participation, without exceptions. Repeat drug screening is not allowed.  
13. Have received any investigational treatment within 30 days (or within 5 terminal 
half-lives of the investigational drug whichever is longer) of the screening visit or 
plans to receive investigational treatment within 30 days after the study is completed. 
14. Be an Investigator, employee, or otherwise be directly affiliated with the study site, 
Watson Laboratories Inc. and affiliates, or service provider involved in the study 
including being an immediate family member of an Investigator or site employee 
(where immediate family member is defined as spouse, parent, child or sibling, 
whether biological or legally adopted or in foster care). 
15. Non-compliance with the study requirements, rules, and procedures. 
4.4 
Patient Withdrawal and Replacement 
Patients may withdraw from the study at any time without penalty and for any reason 
without prejudice to his or her future medical care. Patients may be required to withdraw 
from study at discretion of the Investigator after discussion with the Sponsor and/or 
Investigator. 
4.4.1 Withdrawal Criteria for Asthma Exacerbation 
Asthma-related Withdrawal Criteria at Visit 2: 
• FEV1 at Visit 2 is less than 80% of the Visit 1 value. 
• Use of rescue inhaler at any point during the post-dose 12-hour spirometry during 
Visit 2. 
Investigators may withdraw patients for overuse of rescue medication that, in their 
opinion, demonstrates inadequate asthma control that could put the patient at risk. 
Asthma Exacerbation: 
Patients who experience a severe asthma exacerbation should be withdrawn from the 
study, and receive treatment according to individual needs. A patient is considered to be 
experiencing a severe exacerbation if one or more of the below conditions is experienced:  
• Need for oral and/or parenteral corticosteroids. 
• Need for medication that’s not allowed by the protocol. 
• Asthma-related unscheduled clinic visit (should only be a cause for withdrawal if 
found to be clinically significant by the Investigator). 
• Asthma-related visits to the emergency department. 
• Need for hospital admission due to asthma. 
Patients who require resumption of their prior ICS controller therapy, introduction of oral 
or injectable corticosteroids and/or a LABA after the onset of an exacerbation should be 
withdrawn.  

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The primary reason for withdrawal for patients who discontinue from the study because 
of asthma symptoms should be entered into the electronic case report form (eCRF) as 
“lack of efficacy”, not an adverse event (AE) or serious AE (SAE). However, severe 
asthma exacerbations occurring during the study should be reported as an AE in the 
eCRF (Section 6.3). 
4.4.2 Additional Withdrawal Criteria 
Patients must be withdrawn at any time during the study under the following 
circumstances: 
• The patient becomes pregnant (see Section 6.3.8). 
• The patient has an AE that would, in the Investigator’s judgment, make continued 
participation an unacceptable risk. 
• The patient is judged by the Investigator to be significantly noncompliant with the 
requirements of the protocol. 
• A patient may also be withdrawn from the study by the Sponsor, Regulatory 
Authorities, or Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC). 
Patients will also be withdrawn if the entire study is terminated prematurely as described 
in Section 9.10. 
4.4.3 Withdrawal Procedures 
If a patient withdraws consent/assent to participate after taking at least 1 dose of 
randomized study drug but agrees to undergo final assessments, this will be documented 
on the eCRF and the Investigator’s copy of the consent/assent document, which will be 
countersigned and dated by the patient or his/her parent or legal guardian (if the patient is 
not of legal age). 
In all cases, the primary reason for withdrawal must be recorded on the eCRF. If a patient 
is prematurely withdrawn from the study drug for any reason, the Investigator must make 
every effort to perform the evaluations described for the End-of-Study visit.  
Patients who do not complete the Run-in Period (i.e., patients who withdraw before 
Visit 2 randomization) will be replaced. Patients who withdraw (or are withdrawn) from 
the study after receiving the first dose of randomized study drug will not be replaced. 
Assessments to be performed in case or early withdrawal are specified in Section 7.1.5. 
4.5 
Planned Sample Size and Number of Study Centers 
Approximately 1130 patients at up to 
 sites in the US will be randomized for this 
study. Sites in Europe may be considered in case recruitment is lower than expected in 
US sites. See Section 8.11 for a discussion of sample size. 
4.6 
Patient Identification and Randomization 
4.6.1 Patient Identification 
Upon enrollment into the study (i.e., Visit 1, Screening), each patient will be sequentially 
assigned a 6-digit patient identification (PID) number that uniquely identifies the patient, 

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with the first three digits identifying the site and the last three digits identifying the 
patient number at the site. The PID number for each patient will be assigned via 
Interactive Web Response System (IWRS).  
Once assigned, the PID number cannot be reused or reassigned even if a patient does not 
enter the randomized Treatment Period or withdraws from the study at any time. Patients 
who remain in the study will retain their PID numbers throughout the study. 
4.6.2 Randomization Scheme 
Patients will be randomly assigned to treatment on a 
 of generic BDS 80/FFD 
4.5 inhalation aerosol manufactured by 
 for Watson Laboratories Inc. (test): 
Symbicort® (RLD): placebo (P) [T:R:P] respectively. 
4.6.3 Allocation/Randomization of Patients to Treatment 
Randomization of patient to treatment will occur at Visit 2 (Day 1) after all screening 
procedures have been performed and eligibility for the study confirmed. Each 
randomized patient will receive a unique randomization number assigned via IWRS. 
Randomized patients who terminate their study participation for any reason, regardless of 
whether study drug was taken or not, will retain their randomization number.  
For the randomization of patients, the Investigator will use an IWRS. Appropriate 
documentation will be filed in the Trial Master File (TMF). IWRS will assign patients to 
a treatment group based on the pre-defined randomization list. 

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5 
STUDY DRUG 
All study drugs required for this study (test product, reference product, placebo, rescue 
medication) will be supplied by the Sponsor. 
 
Run-in Period: 
Placebo: 
Generic inhaler containing placebo aerosol for inhalation (open label). 
Route: 
Oral inhalation. 
Posology: Two inhalations twice daily, with a dosing interval of approximately 12 hours.  
Duration: 14 days (up to 21 days). 
 
Treatment Period: 
Randomized Study Drug: 
Test: 
Generic budesonide 80 mcg/formoterol fumarate dihydrate 4.5 mcg 
(BDS 80/FFD 4.5) inhalation aerosol pMDI, manufactured by
 for 
Watson Laboratories Inc.. 
Reference: Symbicort® (budesonide 80 mcg/formoterol fumarate dihydrate 4.5 mcg 
inhalation aerosol, manufactured by AstraZeneca) 
 
. 
Placebo: 
Generic pMDI inhaler containing placebo to match generic test product, 
aerosol for inhalation 
 
 
Dose Regimen (All Study Drugs): 
Route: 
Oral inhalation. 
Posology: Two inhalations twice daily (such that the cumulative single dose is 
budesonide160 mcg/formoterol fumarate dihydrate 9 mcg twice daily) or 
placebo, with a dosing interval of approximately 12 hours. Last dose on the 
morning of Visit 4. 
Duration: 42 days (35 days to 56 days). 
5.1 
Identity 
5.1.1 Test Product 
The generic test product is a metered dose inhaler (pMDI) with a canister containing a 
combination of budesonide and formoterol fumarate dihydrate as an inhalation aerosol. 
The device contains micronized budesonide and micronized formoterol fumarate as the 
dihydrate salt. The generic formulation is identical in composition to the reference 
product.  
The canister contains a total of 120 pre-metered doses of budesonide/formoterol fumarate 
dihydrate. An “Information For Use” document for the pMDI device will be provided to 
all patients. 

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5.1.2 Reference Product 
The RLD, Symbicort® 80/4.5, is available commercially from AstraZeneca as an 
inhalation aerosol of budesonide (80 mcg) and formoterol fumarate dihydrate (4.5 mcg).  
Symbicort® is a disposable metered dose inhaler (pMDI) device with a canister 
containing a combination of micronized budesonide and micronized formoterol fumarate 
dihydrate as an inhalation aerosol. The lowest dose strength of Symbicort® contains 
budesonide and formoterol fumarate as the dihydrate salt.  
After priming the low dose strength (budesonide 80 mcg and formoterol fumarate 
dehydrate 4.5 mcg; BDS 80/FFD 4.5 mcg), each actuation meters 91/5.1 mcg from the 
value and delivers BDS 80/FFD 4.5 mcg from the actuator. The amount of drug delivered 
to the lungs may depend on patient factors such as coordination between actuation of the 
device and inspiration through the device. 
The formulation contains the following excipients, which are well established 
pharmacopoeial excipients for inhalation products: 
• Povidone (viscosity K-value K25) United States Pharmacopeia convention (USP) 
as suspending agent 
• PEG 1000 National Formulary (NF) as lubricant 
• Hydrofluoroalkane (HFA227) as propellant 
The canister contains a total of 120 pre-metered doses of budesonide/formoterol fumarate 
dihydrate. An “Information For Use” document for the pMDI device will be provided to 
all patients.  
5.1.3 Placebo 
The placebo matches the generic test product and is composed of the inactive excipients 
listed is Section 5.1.2. Placebo will be manufactured by
 for Watson Laboratories 
Inc. 
The placebo inhalation aerosol is administered using a pMDI, which is similar in design 
and operation to the test product and the marketed product Symbicort®. An “Information 
For Use” document for the pMDI device will be provided to all patients. 
5.1.4 Rescue Medication 
Rescue medication is a commercially available albuterol/salbutamol inhaler 100 mcg per 
puff (or equivalent) that will be supplied to all study patients.  
One canister will be dispensed at the screening visit (Visit 1). That canister will also be 
used for the reversibility test. Reserve canister(s) or re-supply will be provided as 
necessary. Refer also to Section 5.9.1. 
5.2 
Administration 
All study drugs will be administered via oral inhalation. Two inhalations will be 
administered twice daily with a dosing interval of approximately 12 hours. Study drug 
doses may be taken without regard to meals. For test product and reference product, the 
cummulative single dose will be budesonide160 mcg/ formoterol fumarate dihydrate 

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5.8 
Compliance 
Patients will be instructed on proper study drug usage by designated site staff. All study 
drug will be self-administered by the patients. The date and time of dosing will be 
recorded by the patient in his or her eDiary. Comments will be recorded if there are any 
deviations from the planned dosing times or procedures. Compliance will be assessed 
separately during the Run-in Period and the Treatment Period. 
5.8.1 Study Drug Compliance 
Compliance with study drug will be determined by the eDiary. 
• Compliance during the Run-in Period of at least 75% (based on eDiary entries) is 
required for a patient to qualify for randomization.  
• Once randomly assigned to study drug at Visit 2, patients must take between 75% and 
125%, inclusive, of planned doses to be considered in compliance with study 
requirements and to be included in the PPS. 
Patients should complete at least 80% of the daily diary pages during the Run-in and 
Treatment Periods.  
5.9 
Previous and Concomitant Medications 
Any medication the patient takes other than the study drug, including herbal and other 
non-traditional remedies, is considered a concomitant medication. All prior medications 
taken within 2 months before study entry and new or changed concomitant medications 
taken during the study must be recorded in the eCRF. The following information must be 
recorded for each medication:  
• Generic name. 
• Route of administration. 
• Start and stop dates. 
• Dosage. 
• Frequency. 
• Indication.  
Any changes in the dosage or regimen of a concomitant medication also must be 
recorded. 
After Visit 1, prohibited concomitant medications include the following: 
• Leukotriene modifiers. 
• Oral or parenteral corticosteroids. 
• LABAs and SABAs (except for study-supplied rescue medication). 
• Any ICS or LABA, other than (blinded) study drug. 
Refer also to inclusion criterion 6 (Section 4.1) and Exclusion Criterion 7 (Section 4.2) 
for excluded medications. 
Table 2 lists previous and concomitant medications with their required washouts prior to 
lung function measurements. 

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6 
VARIABLES AND METHODS OF ASSESSMENT 
Please refer to Table 1, the Schedule of Procedures for the timing of events. Methods of 
analysis of variables are described in Section 8. 
6.1 
Lung Function and Reversibility Testing 
Lung function measurements will be performed at the visits specified in the Schedule of 
Procedures (Table 1). Compliance with concomitant medication and study drug usage is 
critical before lung function tests can be conducted (see Section 5.8) or lung function 
tests will have to be re-scheduled. Each patient must perform spirometry assessments 
while in the same position (either sitting or standing) at each study visit. Every attempt 
should be made to standardize the time of day that a patient undergoes lung function 
testing throughout the study. All lung function tests, except for serial spirometry, will be 
conducted before any administration of study drug or rescue medication. 
6.1.1 Spirometry 
Spirometry will be implemented and analyzed via a central spirometry facility, to ensure 
quality data and to minimize variability between sites. 
Spirometry will be performed using standardized equipment that will be provided by a 
centralized spirometry service 
 that meets or exceeds the ATS/ERS joint 
recommendations [10]. Both absolute and percent of predicted values will be recorded. 
The predicted normal values will be based on the equations derived from the NHANES 
III dataset for adults [9]. Peak expiratory flow rate and FEV1 will be performed to 
measure patient lung function. 
For this study, a spirometry session is defined as a group of flow volume loops from 
which FEV1 data are derived. Within each spirometry session, it is required that patients 
produce flow volume loops of acceptable quality, as per ATS/ERS recommendations. 
Repeat spirometry maneuvers may be performed as necessary, up to a maximum of 
8 efforts per session. Spirometry sessions must be stopped if the patient becomes tired or 
breathless. From each spirometry session, the highest acceptable measurement of FEV1 
will be used for statistical analysis. 
All study visits, during which spirometry is performed, should be initiated in the 
morning, before 11:00 am. Spirometry should be assessed at least 6 hours after the 
patient’s last dose of study-supplied short-acting beta agonist (albuterol/salbutamol). The 
acceptability of the data will be reviewed by blinded over-readers provided by 
. 
Standardized spirometry software will be used to assess the maneuvers and to calculate 
percent predicted values and percent reversibility.  
At Visit 1 (screening), an initial spirometry session is performed, followed by a 
30 (± 10)-minute wait period, during which 360 mcg of albuterol (400 mcg salbutamol) is 
administered. Next, a second spirometry session is performed to evaluate for FEV1 
reversibility (Section 6.1.2).  
At Visit 2 (randomization visit), all patients will perform 3 spirometry sessions, at 60, 30, 
and 5 minutes pre-dose (the average of the highest acceptable FEV1 from each session 
constitutes the baseline FEV1 value). A minimum of 2 observations are required for 
calculation of the baseline value. Patients meeting study requirements will undergo 

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randomization and receive their first dose of study drug. Spirometry sessions will then be 
performed at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hour post-dose. Use of rescue inhaler at any 
point during the post-dose 12-hour spirometry will result in withdrawal of the patient 
from the study. 
Baseline (Visit 2) FEV1 should be ≥45% and ≤85% of predicted normal value and not 
vary by more than ±20% from the screening visit FEV1 value. 
At Visits 3 and 4, patients will be at the study site before 11:00 am for spirometry 
assessments. FEV1 will be determined in spirometry sessions performed at 60, 30, and 
5 minutes pre-dose of study drug. 
6.1.2 Reversibility Testing 
Airflow reversibility is not an outcome variable of this study but it is an inclusion 
criterion applicable to spirometry (see inclusion criterion 8, Section 4.1). Reversibility 
testing will be conducted at Visit 1. FEV1 readings will be taken; then 360 mcg of 
albuterol (or 400 mcg salbutamol) is administered using the rescue medication provided 
to the patient. Thirty minutes later (±10 minutes), 1-2 FEV1 measurements are taken so 
reversibility can be assessed. For this study, FEV1 reversibility is defined as an increase 
in FEV1 (from the highest acceptable flow volume maneuver) of ≥15% and ≥ 0.20 L. If 
the patient achieves <15%, but ≥10% reversibility at Visit 1, the site may instruct the 
patient to hold LABA and/or ICS and return up to 7 days later for a repeat test. Only 
1 repeat of the Visit 1 spirometry (to retest reversibility) is allowed per screening. 
6.2 
Daily eDiary Assessments 
This study will use an eDiary. Patients will be provided with the eDiary at Visit 1 and 
will be shown how to use it. Patients will be expected to complete the eDiary at home on 
a daily basis and to bring it with them to every clinic visit. 
During the Run-in Period and 6-week Treatment Period patients will be asked to perform 
the following in the order listed each day:  
• Record the number of inhalations of rescue medication (albuterol/salbutamol) in 
eDiary card. 
• Perform PEFR measurements in the morning and evening, and record the results in 
the eDiary. 
• Inhale study drug at approximately 12 hour intervals in the morning and evening 
(after the PEFR measurements), and record the intake in the eDiary. 
6.2.1 Daily Symptoms 
Patients will record whether they have experienced any symptoms during the day or 
during the night in a eDiary. Twice each day, before taking any study drug, patients will 
answer Yes or No to the following questions: 

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6.2.4 Rescue Medication Use 
The patient will also record in his/her eDiary the number of inhalations of rescue 
medication (albuterol/salbutamol inhaler) used in each of the previous 12-hour time 
periods. This information will be collected by sites at each visit and entered into source 
documents to be kept at the site.   
6.2.5 Peak Expiratory Flow Rate Measurements 
Patients will be given a peak flow meter at Visit 1 for use at home to measure PEFR and 
will be instructed how to use it. Data from the 
 device will synchronize directly 
with the eDiary via Bluetooth. Three PEFR maneuvers should be performed in each 
session, twice daily. The highest PEFR of the 3 efforts from any session will be the one 
that will be recorded in the eDiary.  
Morning PEFR should be recorded between 5:00 am and 10:00 am and evening PEFR 
between 5:00 pm and 11:00 pm. All PEFR measurements should be taken before patients 
take their study drug. Patients should not, whenever possible, use SABA reliever 
therapies for 6 hours before performing PEFR. 
Patients will need to bring the peak flow meter to each clinic visit. 
6.3 
Adverse Events 
6.3.1 Definitions of Adverse Events 
An AE is defined as any untoward medical occurrence in a patient who is administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign, 
symptom, abnormal laboratory finding temporarily associated with the use of the 
investigational medicinal product (IMP), whether or not related to the IMP.  
Any AE that occurs after start of screening but before starting first dose of placebo will 
be captured as an AE but will be considered as not treatment-emergent for the purposes 
of data analysis. 
Adverse reaction: Any untoward and unintended sign (including an abnormal laboratory 
finding) in a patient to an IMP which is at least possibly related to any dose administered 
to that patient. 
A SAE is defined as any AE that: 
• Results in death. 
• Is life-threatening (the term ‘life-threatening’ in the definition of ‘serious’ refers to an 
event in which the patient was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more 
severe). 
• Requires patient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Medically important condition. 

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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient or the patient may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Elective procedures requiring hospitalization will not be considered SAEs if they were 
pre­planned prior to signing the consent. However, complications of elective surgery 
and/or any other events that occur during the hospitalization may be considered serious or 
non-serious adverse events and will need to be captured according to the protocol. 
Generally, study patient’s visit to a hospital during study, e.g., related to an AE, not 
requiring overnight admission will not be regarded as hospitalization. Medical judgment 
should be applied on a case-by-case basis for such events, as they may meet other 
seriousness criteria (i.e., medically important). 
A SUSAR is any adverse reaction that is classed in nature as serious, is considered 
associated with the use of the study drug, and which is not consistent with the available 
information on the medicinal product in question. 
Expected versus unexpected adverse reaction: An unexpected adverse reaction is defined 
as a reaction which in nature or severity is not consistent with the reactions listed in the 
IB. 
Investigator judgment should be used in deciding whether to report the signs and 
symptoms of worsening asthma as an AE or SAE in the eCRF. All serious asthma 
exacerbations occurring during the study should be recorded as an AE. Those 
exacerbations requiring emergency room treatment, or resulting in hospitalization or 
death should be recorded as a SAE (Section 6.3.3). 
6.3.2 Recording Adverse Events 
The clinic staff will record all AEs observed, queried, or spontaneously volunteered by 
the patients (regardless of seriousness or relationship to study treatment) in the 
appropriate section of the patient’s case report form or source documents. AEs will be 
collected as of Visit 1 and throughout the study, including at any return clinic visits, until 
the end of the study.  
Patients experiencing AEs (including those withdrawn from the study due to an AE) will 
be followed until an outcome is determined.  
The following details will be recorded for AEs: 
• Description of event/symptom. 
• Onset date and time of event. 
• End date and time of event. 
• Maximum severity/intensity rated as follows: 
­ 
Mild: Discomfort noted, but no disruption to normal daily activities. 
­ 
Moderate: Discomfort sufficient to reduce or affect normal daily activities. 
­ 
Severe: Inability to work or perform normal daily activities. 
• Action taken with study drug noted as follows: 
­ 
None. 

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­ 
Any other action taken (such as concomitant medication, non-drug therapy, both, or 
none). 
• Outcome of AE noted as follows:  
­ 
Recovered/resolved. 
­ 
Recovered/resolved with sequelae. 
­ 
Ongoing. 
­ 
Unknown. 
­ 
Death. 
• Causality noted as follows: 
­ 
Unrelated: An AE which is clearly and incontrovertibly due only to extraneous causes 
and does not meet criteria listed under possible or probable, and is therefore not 
related to the use of the drug. 
­ 
Possibly related: An AE which might be due to the use of the study medication. An 
alternative explanation, e.g., concomitant drug(s), concomitant disease(s) is 
inconclusive. The relationship in time is reasonable; therefore the casual relationship 
cannot be excluded. 
­ 
Probably related: An AE which might be due to the use of the medication. The 
relationship in time is suggestive (e.g., confirmed by de-challenge). An alternative 
explanation is less likely, e.g., concomitant drug(s), concomitant disease(s). 
­ 
Related: An AE which is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation, e.g., concomitant drug(s), and 
concomitant disease(s). The relationship in time is very suggestive (e.g., it is 
confirmed by de-challenge and re-challenge). 
6.3.3 Follow-up of Adverse Events 
All AEs will be followed up until resolution or until 30 days from the last dose, or until 
the Investigator is of the opinion that follow-up is no longer required. 
Adverse laboratory parameters will be followed up till the values return to baseline, 
acceptable levels, show a tendency towards resolution, or until 30 days from the last 
dose, or until the Investigator is of the opinion that follow-up is no longer required. 
Clinically abnormal vital signs will be followed up until the values return to baseline or 
until 30 days from the last dose, or until the Investigator is of the opinion that follow-up 
is no longer required. 
6.3.4 Reporting Serious Adverse Events 
Any SAE or pregnancy, whether deemed drug-related or not, must be reported by the 
Principal Investigator or the Principal Investigator’s designee simultaneously to the 
Sponsor’s SAE contact, 
 Medical Monitor and Clinical Trials Safety Center, 
Actavis Global Pharmacovigilance, and Actavis Clinical R&D, as specified in Table 3, 
within 24 hours after the Principal Investigator or member of the study team becomes 
aware of its occurrence. 
The Principal Investigator or the Principal Investigator’s designee must complete an SAE 
form (along with the study specific fax coversheet, if needed) within that 24 hour time 

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• Principal Investigator name and site number (if applicable).  
• Patient ID number. 
• Patient initials and date of birth. 
• Patient demographics. 
• Clinical event: 
­ 
Description. 
­ 
Date of onset. 
­ 
Intensity. 
­ 
Treatment (including hospitalization). 
­ 
Relationship to study drug. 
­ 
Action taken regarding study drug. 
If the AE was fatal, the report should include: 
• Cause of death (whether or not the death was related to study drug). 
• Autopsy findings (if available). 
• Death certificate. 
The Principal Investigator or the Principal Investigator’s designee will provide follow-up 
information as it becomes available. The follow-up report will contain a full description 
of the event and any sequelae. Patients who have had an SAE must be followed clinically 
until all parameters (including laboratory) have either returned to normal or are 
stabilized. Once follow-up information becomes available, it must be reported to the 
contacts specified in Table 3, as necessary, within 24 hours of receipt. 
Further details regarding the SAE reporting process will be documented in the Safety 
Management Plan. 
6.3.5 Removal of Patients from Study Due to Adverse Events 
Patients will be advised they are free to withdraw from the study at any time. Over the 
course of the study, the Investigator(s) and/or the Sponsor may discontinue participation 
of any patient from the study in the case of unnecessary risk, adverse drug events, or 
noncompliance. When a patient withdraws from the study, all safety data normally 
required at the end of the study will be obtained, if possible. 
6.3.6 Termination of Study Due to Adverse Events 
If, in the opinion of the Investigators, Sponsor, or the IRB/IEC, the incidence and severity 
of AEs outweighs the benefit of continuing the study, the study may be terminated. In the 
event this course of action is to be pursued, the Investigators will make every attempt to 
communicate with the Sponsor prior to the decision to develop a complete plan of action 
and to assess outcomes. 
6.3.7 Suspected Unexpected Serious Adverse Reactions  
Any SUSAR has additional reporting requirements, as described below.  
• If the SUSAR is fatal or life-threatening, associated with the use of the study drug, 
and unexpected, Regulatory Authorities and IECs will be notified within 7 calendar 

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days after 
 learns of the event. Additional follow-up (cause of death, 
autopsy report, and hospital report) information should be reported within an 
additional 8 days (15 days total).  
• If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with 
the use of the study drug, and unexpected, Regulatory Authorities and IECs will be 
notified within 15 calendar days after
 learns of the event.  
The Sponsor will notify the Investigators in a timely fashion of relevant information 
about SUSARs that could adversely affect the safety of patients. Follow-up information 
may be submitted if necessary.  
The Sponsor will also provide annual safety updates to the Regulatory Authorities and 
IECs responsible for the study. These updates will include information on SUSARs and 
other relevant safety findings. 
6.3.8 Pregnancy 
The Sponsor has a responsibility to monitor the outcome of pregnancies where there has 
been maternal exposure to the study drug.  
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug 
may have interfered with the effectiveness of a contraceptive medication. 
Elective abortions without complications should not be handled as AEs, unless they were 
therapeutic abortions (see below). Hospitalization for normal delivery of a healthy 
newborn should not be considered a SAE. 
Pregnant patients (confirmed positive pregnancy test result at any time from the time of 
study drug administration until the end of the study) must be withdrawn from the study 
(Section 4.4). 
All pregnancies must be reported to 
/Sponsor on the initial pregnancy report 
form within 24 hours after discovery by the Investigator or clinical staff, as described in 
Section 6.3.4.  
The Investigator must follow-up and document the course and the outcome of all 
pregnancies even if the patient was discontinued from the study or if the study has 
finished. 
All outcomes of pregnancy (including voluntary or spontaneous termination, details of 
birth, presence or absence of congenital abnormalities, birth defects, maternal and 
neonatal complications, and possible relationship to study drug) must be reported by the 
Investigator to 
/Sponsor on the pregnancy outcome report form within 30 days 
after he or she has gained knowledge of the normal delivery or elective abortion. 
Any SAE that occurs during pregnancy (including SAEs occurring after last 
administration of study drug) must be recorded on the SAE report form (e.g., maternal 
serious complications, spontaneous or therapeutic abortion, ectopic pregnancy, stillbirth, 
neonatal death, congenital anomaly, or birth defect) and reported within 24 hours in 
accordance with the procedure for reporting SAEs. 
If a female partner of a male study patient who has been exposed to the study drug 
becomes pregnant, the pregnancy and outcome of pregnancy should be monitored. 
The IEC/IRB and Regulatory Authorities will be informed of the pregnancy in 
accordance with local laws and regulations. 

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6.4 
Laboratory Variables 
Blood and urine samples will be collected at the visits presented in the Schedule of 
Procedures (Table 1).  
A central laboratory will perform the routine analysis of blood and urine specimens, as 
identified in the List of Study Personnel. Detailed instructions pertaining to sample 
collection, processing, storage, labeling, and shipping are provided in the laboratory 
manual for this study.  
Laboratory results will not be entered into the eCRF. However, the date and time of 
sampling will be recorded. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date and time of sample collection will be recorded on the eCRF. 
Abnormalities of safety laboratory parameters should be reported as an AE if they are 
considered to be clinically significant. If an abnormal safety laboratory value is 
associated with clinical signs and symptoms, the sign/symptom should be reported as an 
AE and the associated abnormal laboratory result should be considered additional 
information. The reporting of safety laboratory abnormalities as both laboratory findings 
and AEs should be avoided. Abnormalities of safety laboratory parameters that are part of 
the disease profile prior to study treatment do not need to be reported as an AE. 
Approximately 32 mL of blood will be collected during the study (excluding any 
unscheduled/repeat samples).  
The following laboratory variables will be determined (Table 4). 

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Table 4: Laboratory Assessments 
Test Group 
Analyte/Component 
Hematology: 
red blood cell count  
red cell distribution width  
hemoglobin  
hematocrit 
mean cell volume  
mean cell hemoglobin 
platelet count  
 
mean cell hemoglobin concentration 
white blood cell count and differential  
Urinalysis: 
protein 
glucose 
specific gravity 
ketone 
bilirubin 
pH 
blood 
Clinical chemistry: 
protein  
albumin  
total bilirubin  
alanine transaminase  
aspartate transaminase  
glucose  
sodium  
potassium  
calcium  
bicarbonate  
blood urea nitrogen/urea  
creatinine  
alkaline phosphatase  
Serum pregnancy test (β-HCG): In females of childbearing potential only. 
Urine pregnancy test:  
In females of childbearing potential only.  
Urine alcohol/drug/cotinine test: Amphetamines (stimulants), MDMA (ecstasy), barbiturates, 
benzodiazepines, cannabinoids/tetrahydrocannabinol (THC)/marijuana, 
cocaine, opiates, alcohol, and cotinine. 
6.5 
Vital Signs 
Vital signs (blood pressure, pulse, respiratory rate, and body temperature) will be 
measured in accordance with the Schedule of Procedures (Table 1). Vital signs will be 
measured after at least 10 minutes rest in supine position. On Visits 2, 3, and 4, 
measurements will be done in the morning prior to inhalation, and a patient will not be 
administered if his/her blood pressure or pulse is deemed as clinically significant 
abnormal by the Investigator. 
Vital signs need only be taken once during each visit. 
6.6 
Electrocardiograms 
Standard 12-lead ECGs will be performed in accordance with the Schedule of Procedures 
(Table 1). 
12-lead ECG to be measured after at least 10 minutes rest in supine position and the 
patient should be motionless during the recording.  
The ECG may be taken before any blood sampling, or 15 minutes after. Where possible, 
the patient should be examined using the same ECG machine throughout the study. ECGs 
will be recorded digitally and read by the Investigator or the qualified ECG technician for 
recording in the eCRF. A duplicate copy of the ECG reading will be anonymized and 
maintained with the source documents. Care should be taken to assure proper lead 
placement and quality ECG recordings. 

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Any clinically significant finding observed on the ECG (e.g., QTc [Bazett’s] >500 ms) at 
Visit 4, will be record as an AE by the Investigator. 
6.7 
Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Procedures 
(Table 1).  
The examination will include an assessment of the patient’s general appearance 
(including evaluation of extremities, eyes, nose, mouth/throat/neck, and thyroid), 
measurement of height and weight (without shoes), and a review of body systems 
(dermatologic, lymphatic, respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
neurologic, and psychiatric).  

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7 
STUDY CONDUCT 
The schedule, as outlined in Table 1, consists of a Run-in Period and Treatment Period. A 
brief summary of the overall conduct is presented below. 
7.1 
Procedures by Visit 
All times should be recorded using the 24-hour clock (e.g., 23:20, not 11:20 pm). 
All visits must be initiated before 11:00 am, but must be scheduled to allow completion 
of the relevant assessments prior to taking study drug at the patient’s regular morning 
time. 
7.1.1 Informed Consent 
Informed consent/assent may be signed up to 14 days prior to Visit 1. Written informed 
consent/assent must be obtained prior to any study-related procedure which includes 
medication washout and restrictions. 
7.1.2 Screening (Visit 1) 
A summary of the procedures during Visit 1 is below: 
• Check written informed consent/assent has been obtained. 
• Verify conformance with entry criteria. 
• Record medical history (any previous and concomitant diseases occurring before 
screening).  
• Record asthma history (include the confirmation of asthma diagnosis and date of 
diagnosis in addition to documentation of current asthma medication). 
• Record demographic information (age, sex, ethnic origin, race, height, weight, BMI). 
• Record baseline characteristics (general medical history, smoking history). 
• Drug/alcohol/cotinine screen. 
• Record concomitant medication use, including current asthma therapies (previous and 
concomitant medication will be documented as described in Section 5.9). 
• Perform physical examination. 
• Obtain vital signs. 
• Perform 12-lead ECG. 
• Obtain blood and urine samples for clinical laboratory tests. 
• Serum pregnancy test (for females of childbearing potential).  
• Patient training with the 
. 
• Perform spirometry and reversibility measurements (refer to Section 6.1). 
• Review use of eDiary and daily compliance requirements and dispense eDiary and 
PEFR device. 
• Instruct patient on administration of Run-in study drug (refer to Section 5.3). 
• Study staff dispenses study drug (i.e., placebo inhaler) and rescue medication 
(albuterol/salbutamol) for use throughout the study. 

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• AE recording. 
• If a patient is deemed to be suitable to enter the Run-in Period, the first dose of 
placebo medication will be inhaled at the study site at Visit 1, and the correct 
inhalation technique will be reinforced. 
7.1.3 Open Placebo Run-in Period 
Following screening, eligible patients will begin a placebo Run-in Period of at least 
14 days in duration, but not longer than 21 days to wash out any pre-study corticosteroids 
or long-acting bronchodilators, and to establish FEV1 baseline values. Open-label placebo 
medication will be inhaled during the Run-in Period.  
During the Run-in Period patients will be asked to complete the eDiary daily, as 
instructed (Section 6.2). Patients will perform PEFR measurements and inhale placebo 
medication at approximately 12 hour intervals.  
7.1.4 Treatment Period  
Patients will take test, reference, or placebo at approximately 12-hour intervals. At the 
beginning of each visit, the Investigator will thoroughly review the patient’s eDiary 
entries and discuss the results with the patient. The patients will be asked about their 
medication washouts and whether they have experienced any unusual symptoms or 
medical problems since the last visit. Patients will be reminded that they must inhale the 
study drug as instructed. Patients will be instructed to withhold the study drug and not 
perform morning PEFR measurements until they arrive at the clinic on the morning of 
each visit. 
During the 6-week Treatment Period patients will be asked to complete the eDiary daily, 
as instructed (Section 6.2). Patients will perform PEFR measurements and inhale study 
drug at approximately 12 hour intervals. 
7.1.4.1 Visit 2 (Randomization) 
Randomized treatment should begin within 14 days (maximum 21 days) of starting the 
placebo Run-in Period. Patients who remain eligible will be randomized into either the 
test, reference, or placebo treatment group.  
The following will be performed during Visit 2: 
• Collect used and unused study drug. 
• Review eDiary from Run-in Period, and check compliance. 
• Recheck conformance with inclusion/exclusion criteria. 
• Concomitant medications. 
• Contact IWRS for randomization. 
• Vital signs. 
• Asthma symptom score. 
• Spirometry (60, 30, and 5 minutes pre-dose). FEV1 must be in the range of ≥45% and 
≤85% of the predicted value. 
• Inhalation of first dose of study drug under supervision. 

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• Spirometry (0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours post-dose). 
• Dispense study drug and eDiary. 
• Dispense additional rescue medication, if necessary. 
• Provide additional inhalation and/or eDiary training, as relevant. 
• AE recording. 
• Urine pregnancy test (for females of childbearing potential). 
7.1.4.2 Visit 3 
Visit 3 will occur at the end of the third treatment week (treatment day 21 ± 7 days)  
The following will be performed during Visit 3: 
• Collect used and unused study drug. 
• Review eDiary and check compliance.  
• Concomitant medications. 
• Vital signs. 
• Asthma symptom score. 
• Spirometry (60, 30, and 5 minutes pre-dose). 
• Inhalation of study drug under supervision. 
• Dispense study drug and eDiary. 
• Dispense additional rescue medication, if necessary. 
• AE recording. 
• Urine pregnancy test (for females of childbearing potential). 
Note: The same eDiary devices used in placebo run-in and Visit 2 will be returned to the 
patient. 
7.1.4.3 Visit 4 
Visit 4 will occur at the end of the sixth treatment week (treatment day 42 + a time 
window of +7 days).  
The following will be performed during Visit 4: 
• Collect used and unused study drug. 
• Review eDiary and check compliance. 
• Concomitant medications. 
• Physical examination. 
• Vital signs. 
• Asthma symptom score. 
• 12-lead ECG. 
• Samples for clinical laboratory investigations. 
• Serum pregnancy test (for females of childbearing potential).  
• Spirometry (60, 30, and 5 minutes pre-dose).  

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• The last dose of study drug will be inhaled.  
• Inhaler and eDiary will be collected. 
• AE recording. 
The patient will be reminded to report any adverse experiences that occur within 30 days 
after the last visit. 
7.1.5 Early Termination Visit 
If a patient discontinues the study prematurely, he/she will be invited to undergo an early 
termination visit with the same procedures as on Visit 4, except there is no inhalation of 
the study drug. More specifically, a series of at least 3 spirometric measurements will be 
obtained in the morning with an interval of approximately 20 minutes in between. A 
medical follow-up examination including physical examination, blood pressure, pulse, 
ECG, and clinical laboratory investigation will be done. 
The patient will be reminded to report any adverse experiences that occur within 30 days 
after the last visit. 

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8 
STATISTICAL METHODS 
Before database lock, a separate statistical analysis plan (SAP) will be finalized, 
providing detailed methods for the analyses as outlined in the following subsections.  
Any deviations from the planned analyses will be described and justified in the final 
clinical study report. 
8.1 
Study Patients 
8.1.1 Disposition of Patients 
The assignment of patients to analysis populations will be listed and summarized by 
treatment. The tabulation will include the following information:  
• Number (n) of patients receiving at least 1 dose of randomized study drug. 
• Number and percentage of patients completing the study. 
• Number and percentage of patients who were withdrawn (including reasons for 
withdrawal). 
• Number and percentage of patients in each of the analysis sets. 
In addition, the number of patients enrolled, randomized, and completed will be 
presented by treatment and overall and by study site, and will include the number of 
patients withdrawn and the reasons for withdrawal.  
A listing of withdrawals from the study will be presented, including date of 
discontinuation and primary reason. 
8.1.2 Protocol Deviations 
Deviations from the protocol will be assessed as “minor” or “major” in conjunction with 
the Sponsor during a Blinded Data Review Meeting (BDRM). Major deviations from the 
protocol will lead to the exclusion of patients from the PPS. Deviations will be defined 
before database hard lock and unblinding. Major deviations will include the following: 
• Violation of inclusion and/or exclusion criteria. 
• Non-compliance with the dosing schedule (i.e., patients for whom compliance during 
the Treatment Period was not between 75% and 125%). 
• Missing data for the primary endpoints. 
• Administration of prohibited concomitant medications that are expected to influence 
the measurement of the primary endpoints. 
• The treatment blind is broken for a patient. (Note: patients will not be withdrawn from 
the study). 
Further details will be described in the SAP.  

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8.1.3 Analysis Sets 
Analysis Sets 
Definition 
Enrolled Set (ENS): 
All patients who provided informed consent/assent. 
Run-in Set (RiN): 
All patients who enter the Run-in Period. 
Modified Intent-To-Treat 
(mITT) set 
All randomized patients who receive treatment will be 
included. Patients will be included in the analysis as 
randomized. 
Per-Protocol Set (PPS): 
All patients included in the mITT set who have between 
75% and 125% compliance with the dosing schedule in 
the Treatment Period, and had no major protocol 
deviations that are considered to have an impact on the 
analysis of the primary endpoints.  
The PPS will be defined before database lock and 
unblinding during the BDRM. 
Safety Analysis Set (SAF): 
The SAF includes all randomized patients who receive 
treatment, classified by actual treatment received.  
The analysis of the primary endpoints for the assessment of bioequivalence will be based 
on the PPS. The assessment of assay sensitivity will be based on the mITT set. All safety 
analyses will be based on the SAF. 
8.2 
General Considerations 
Data will be summarized by study period, treatment and time point, as applicable. For 
continuous variables, summary statistics will include number of patients, mean, median, 
standard deviation (SD), minimum, and maximum. Categorical variables will be 
summarized using number of patients, frequency, and percentages. Patient listings will 
include all study data. All statistical tests will be 2-sided and will be performed at the 5% 
level of significance, unless otherwise specified. 
Statistical analyses will be performed using SAS (SAS Institute Inc., Cary, NC, US) 
Version 9.1.3 or higher unless otherwise specified. 
8.2.1 Missing Data and Data Conventions: 
Conventions for data analysis and missing data will be provided in the SAP. 
8.3 
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications 
Demographic data characteristics (height, weight, age, sex, race, BMI, and ethnic origin) 
will be listed by patient and summarized by treatment and for the overall study 
population.  
Medical history data will be listed by patient and summarized by treatment. All medical 
history will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 

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8.7.1 Analysis of Bioequivalence 
The co-primary endpoints are: 
• Baseline-adjusted FEV1 AUC0-12 on the first day of the Treatment Period (Visit 2, 
Day 1). 
• Baseline-adjusted pre-dose FEV1, calculated as the mean of the 4 values measured in 
the morning before dosing on the last day of the Treatment Period (Visit 4, Day 42). 
The FEV1 baseline is defined as the average of 4 (at least 2) pre-dose FEV1 values 
obtained at Visit 2.  
The results of the serial FEV1 measurements on Day 1 (absolute values and 
baseline-corrected values) will be listed by patient and summarized by treatment. Figures 
will be presented showing the mean absolute and baseline-corrected measurements versus 
time, by treatment.  
Details regarding the calculations and handling of missing data will be described in the 
SAP. 
The average FEV1 on the last day of randomized treatment (Day 42) will be listed by 
patient and summarized by treatment for both absolute values and changes from baseline 
values.  
The analysis of bioequivalence will be performed as described in Section 8.7. 
In order to demonstrate bioequivalence, the 90% CI for the ratio of means (test versus 
reference) for both primary endpoints must fall between 80.00% and 125.00%.  
Primary analyses will be done for the PPS. Actual values without the logarithms will be 
used in the models. 
8.7.2 Analysis of Assay Sensitivity 
To ensure adequate study sensitivity, the test and reference products should both be 
statistically superior in terms of differences to placebo (p<0.05, 2-sided) with regard to 
the study primary endpoints. Superiority will be assessed using a similar ANCOVA 
model as described above, for both pairs of compared treatments. If adequate sensitivity 
cannot be demonstrated, bioequivalence of test and reference products cannot be 
concluded. 
Any missing data (as a result of patient withdrawal or discontinuation) for 
baseline-adjusted FEV1 at Day 42 will be imputed as described in the SAP. 
8.8 
Safety Analyses 
The safety data will be based on the SAF. A descriptive analysis will be conducted.  
8.8.1 Adverse Events 
All AEs will be coded using MedDRA. 
All AEs will be listed for each patient. Separate listings will be presented for AEs leading 
to discontinuation and SAEs. 
A treatment-emergent AE (TEAE) is defined as an AE occurring at the time of or after 
the first dose of placebo study drug during the Run-in Period. All TEAEs will be assigned 
to one of the following study periods for the purposes of the tabulations: 

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Run-in Period: 
All TEAEs with onset at the time of or after the first dose of placebo 
study drug (Day -14) during the Run-in Period until the time of the 
first dose of randomized study drug (Day 1) 
Treatment Period: 
All TEAEs with onset at the time of or after the first dose of 
randomized study drug (Day 1) during the Treatment Period 
AEs with missing start and/or end dates and/or times (if applicable) will be handled as 
described in the SAP. 
An overview of all TEAEs (N, incidence) will be presented by treatment and study 
period. The overview will include the following: 
• Number and percentage of patients with TEAEs. 
• Number and percentage of patients with drug-related TEAEs. 
• Number and percentage of patients with treatment-emergent SAEs. 
• Number and percentage of patients with TEAEs leading to permanent discontinuation 
of study drug. 
• Number and percentage of patients with TEAEs leading to death. 
Summaries of TEAEs (N, incidence) will be presented by treatment, system organ class 
(SOC), and preferred term (PT) for the following: 
• All TEAEs. 
• Serious treatment-emergent AEs. 
• Drug-related TEAEs. 
• TEAEs leading to permanent discontinuation of study drug. 
Additional summaries will be presented by severity and by causality. 
8.8.2 Safety Laboratory Tests, Vital Signs, and ECGs 
Laboratory safety assessment (i.e., clinical chemistry and hematology), vital signs, and 
ECGs will be assessed by Investigators for the presence of any findings that meet the 
description of an AE. Laboratory test results will not be listed or summarized. Vital signs 
and ECGs will be tabulated and listed. Any positive pregnancy test results will be 
documented on pregnancy report forms.  
8.8.3 Physical Examination 
Physical examination results will be listed by patient and body system. 
8.8.4 Daily Diary Questions 
The PEFR entries from the patients’ diaries will be listed for each patient for both 
morning and evening measurements obtained during the Run-in Period and the Treatment 
Period. 
8.9 
Other Analyses 
The symptom scores and other variables will be collected descriptively. 

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9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
9.1 
Data Quality Assurance 
The study site will implement and maintain quality control and quality assurance 
procedures to insure that the study is conducted, and that the data are generated, 
documented, and reported in compliance with the protocol, GCP, and applicable 
regulatory documents. 
The Sponsor may conduct monitoring and/or audit visits to the CRO study site to verify 
adherence to the study protocol, the protection of the rights and well-being of the patients 
and the accuracy and completeness of reported study data recorded on the source 
documentation. 
9.1.1 Database Management and Quality Control 
All data generated by the site personnel will be captured electronically at each study 
center using eCRFs. Data from external sources (such as laboratory data) will be 
imported into the database. Once the eCRF clinical data have been submitted to the 
central server at the independent data center, corrections to the data fields will be 
captured in an audit trail. The reason for change, the name of the person who performed 
the change, together with the time and date will be logged to provide an audit trail.  
If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the electronic data capture application. The appropriate staff at the study site will 
answer queries sent to the Investigator. The name of the staff member responding to the 
query, and time and date stamp will be captured to provide an audit trail. Once all source 
data verification is complete and all queries are closed, the monitor will freeze the eCRF 
page. 
The specific procedures to be used for data entry and query resolution using the eCRF 
will be provided to study sites in a training manual. In addition, site personnel will 
receive training on the eCRF. 
9.2 
Case Report Forms and Source Documentation 
All source documents from which eCRF entries are derived should be placed in the 
patient’s medical records. Measurements for which source documents are usually 
available include laboratory assessments and ECG. Data that will be entered directly into 
the eCRF (i.e., for which there is no prior written or electronic record of data, such as 
Quality of Life assessments) are considered to be source data. 
The original eCRF entries for each patient may be checked against source documents at 
the study site by the 
 site monitor.  
After review by the site monitor, completed eCRF entries will be uploaded and forwarded 
to the CRO. Instances of missing or uninterpretable data will be discussed with the 
Investigator for resolution.  
The specific procedures to be used for data entry and query resolution using the eCRF 
will be provided to study sites in a training manual. In addition, site personnel will 
receive training on the eCRF. 

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9.2.1 Data Collection 
The Investigators (and appropriately authorized staff) will be given access to an online 
web-based eCRF system which is 21 CFR Part 11 compliant. This system is specifically 
designed for the collection of the clinical data in electronic format. Access and right to 
the eCRF system will be carefully controlled and configured according to each 
individual’s role throughout the study. In general, only the Investigator and authorized 
staff will be able to enter data and make corrections in the eCRFs. 
The eCRF should be completed for each patient included in the study and should reflect 
the latest observations on the patients participating in the study. Therefore, the eCRFs are 
to be completed as soon as possible during or immediately after the patient’s visit or 
assessment. The Investigator must verify that all data entries in the eCRF are accurate 
and correct. If some assessments cannot be done, or if certain information is unavailable, 
not applicable or unknown, the Investigator should indicate this in the eCRF.  
Computerized data-check programs and manual checks will identify any clinical data 
discrepancies for resolution. Corresponding queries will be loaded into the system and 
the site will be informed about new issues to be resolved online. All discrepancies will be 
solved online directly by the Investigator or by authorized staff. Off-line edit checks will 
be done to examine relationships over time and across panels to facilitate quality data. 
After completion, the Investigator will be required to electronically sign off the clinical 
data 
Data about all study drug dispensed to the patient and any dosage changes will be tracked 
on the eCRF.  
Spirometry and eDiary data will be transferred directly from the spirometer and eDiary, 
respectively, to the central spirometry laboratory 
) and are not captured in the 
eCRF. 
9.3 
Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare 
eCRF entries and individual patient’s medical records, assess drug accountability, and 
ensure that the study is being conducted according to pertinent regulatory requirements. 
eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. 
Checking of the eCRF entries for completeness and clarity, and cross-checking with 
source documents, will be required to monitor the progress of the study. Moreover, 
Regulatory Authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical 
Quality Assurance Group may wish to carry out such source data checks and/or on-site 
audit inspections. Direct access to source data will be required for these inspections and 
audits; they will be carried out giving due consideration to data protection and medical 
confidentiality. The Investigator assures 
 and the Sponsor of the necessary 
support at all times. 
Sites will be able to download and print copies of the spirometry and eDiary results. 
Access to spirometry and eDiary source data must be provided via the 
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9.4 
Data Processing 
Patient data (except spirometry, eDiary, and central laboratory data) will be entered by 
site personnel into the eCRF (as detailed in Section 9.2.1).  
The data review and data-handling document, to be developed during the initiation phase 
of the study, will include specifications for consistency and plausibility checks on data 
and will also include data-handling rules for obvious data errors. Query/correction sheets 
for unresolved queries will be sent to the study monitors for resolution with the 
Investigator. The database will be updated on the basis of signed corrections.  
External electronic data (e.g., spirometry data, eDiary data, laboratory data) will be 
transferred from the vendor and loaded into a validated electronic database. Details of 
data transfer will be provided in the spirometry and laboratory manuals. Computerized 
data cleaning checks will be used in addition to manual review to check for discrepancies 
and to ensure consistency of the data. 
Previous and concomitant medications will be coded using the WHO-DRL), which 
employs the ATC classification system. Medical history/current medical conditions and 
AEs will be coded using the MedDRA terminology. 
Previous and concomitant diseases as well as AEs will be coded with MedDRA. 
The versions of the coding dictionaries will be provided in the clinical study report. 
9.5 
Archiving Study Records 
According to ICH guidelines, essential documents should be retained for a minimum of 
2 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 
2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. However, these documents should be retained for a longer period 
if required by the applicable legal requirements. 
9.6 
Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Investigator abide by the principles of the GCP guidelines of the ICH, the Code of 
Federal Regulations, and of the Declaration of Helsinki and all amendments. The study 
also will be carried out in keeping with local legal requirements.  
9.7 
Informed Consent 
A copy of the study specific consent document to be used (prepared in compliance with 
FDA and European regulations and guidelines and in accordance with ICH GCP E6) will 
be reviewed by the IRB/IEC and written approval obtained prior to the start of the study.  
Before each patient is admitted to the study, written informed consent will be obtained 
from the patient (or his/her legally authorized representative) according to the regulatory 
and legal requirements of the participating country. The consent form must be dated and 
retained by the Investigator as part of the study records. The Investigator will not 
undertake any investigation specifically required only for the clinical study until valid 

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consent has been obtained. The terms of the consent and when it was obtained must also 
be documented in the eCRF system. 
For patients who are below the legal age to provide informed consent (per specific 
country requirements), their legal guardian will complete the informed consent form, and 
the patient will complete an assent form. 
For centers in Germany, if applicable: According to the German Medicines Act, under-
age patients must personally provide informed consent (in addition to their legal 
representatives) provided they are able to understand the information given to him/her in 
this study. 
For centers in EU, if applicable: The explicit wish of a minor, or mentally incapacitated 
adult, who is capable of forming an opinion and assessing the study information, to refuse 
participation in or to be withdrawn from the study at any time will be respected by the 
Investigator. 
If a protocol amendment is required, the informed consent form may need to be revised to 
reflect the changes to the protocol. If the consent form is revised, it must be reviewed and 
approved by the appropriate IEC/IRB, and signed by all patients subsequently enrolled in 
the study as well as those currently enrolled in the study. 
9.8 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IEC/IRB/Competent Authorities, in accordance with local legal 
requirements. The Sponsor must ensure that all ethical and legal requirements have been 
met before the first patient is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be 
written, receive approval from the appropriate personnel, and receive IRB/IEC/ 
Competent Authority approval prior to implementation (if appropriate). In the US, 
following approval, the protocol amendment(s) will be submitted to the IND under which 
the study is being conducted.  
Administrative changes (not affecting the patient benefit/risk ratio) may be made without 
the need for a formal amendment. All amendments will be distributed to all protocol 
recipients, with appropriate instructions. 
9.9 
Duration of the Study 
For an individual patient, the planned duration of the study will be up to 8 weeks 
(including 14 days [2 weeks] of placebo Run-in and 42 days [6 weeks] of randomized 
treatment).  
The study will close when all patients have completed Visit 4 (or Early Termination Visit 
in case of early withdrawal). 
9.10 Premature Termination of the Study 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or 
events that suggest a possible hazard to patients if the study continues, the study may be 

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terminated after appropriate consultation between the relevant parties. The study may 
also be terminated early at the Sponsor’s discretion in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study. 
• Failure to enroll patients at an acceptable rate. 
• A decision on the part of the Sponsor to suspend or discontinue development of the 
drug. 
9.11 Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior 
written approval from the Sponsor. 
The anonymity of participating patients must be maintained. Patients will be identified on 
eCRFs and other documents submitted to 
 by their patient number, initials 
and/or birth date, not by name. Documents not to be submitted to 
 that identify 
the patient (e.g., the signed informed consent) must be maintained in confidence by the 
Investigator. An appropriate data privacy statement should be included in the informed 
consent document. 
9.12 Other Ethical and Regulatory Issues 
If a significant safety issue is identified, either from an individual case report or review of 
aggregate data, then the Sponsor will issue prompt notification to all parties– Regulatory 
Authorities, Investigators, and IRB/IECs. 
A significant safety issue is one that has a significant impact on the course of the clinical 
study or program (including the potential for suspension of the development program or 
amendments to protocols) or warrants immediate update of informed consent. 
9.12.1 Institutional Review Board/Independent Ethics Committee 
The Investigator(s) agree to provide the IRB/IEC with all appropriate material, including 
a copy of the protocol, consent document, and advertising text (if study specific 
advertising is used). The study will not be initiated without written IRB/IEC approval of 
the research plan and consent document. Copies of the IRB/IEC approval will be 
forwarded to the Sponsor. The Investigator(s) will provide appropriate reports on the 
progress of this study to the IRB/IEC and Sponsor in accordance with applicable 
government and/or Institute regulations and in agreement with Sponsor policy. The 
IRB/IEC will be informed of any modifications of the protocol or consent document.  
9.12.2 Investigator’s Statement 
The Investigator must agree to conduct the trial as outlined in the approved protocol and 
in accordance with the Sponsor's guidelines and all applicable federal government codes, 
acts and regulations, and ICH GCP (E6).  

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9.13 Publication Policy 
By signing the clinical study protocol, the Investigator agrees with the use of results of 
the clinical study for the purposes of national and international registration, publication 
and information for medical and pharmaceutical professionals. If necessary, the 
competent authorities will be notified of the Investigator’s name, address, qualifications 
and extent of involvement. 
After study completion, a final integrated report covering clinical and statistical aspects of 
the study will be prepared (according to the ICH E3 guideline). As required by the 
applicable regulatory requirements, the clinical study report will be signed by the 
Sponsor’s responsible medical officer as well as the coordinating Investigator (if 
applicable). 
An Investigator or the CRO shall not publish, or present for publication any articles or 
papers or make any presentations, nor assist any other person in publishing any articles or 
papers or making any presentations, or making any public declaration relating or 
referring to the clinical study, the results of the clinical study, in whole or in part, without 
the prior written consent of the Sponsor. 

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11.2 Guide to Lower Limits of BMI in Adolescents 
Age 
5th Percentile BMI (approximate) 
12 
15 
13 
15.5 
14 
16 
15 
16.5 
16 
17 
17 
17.5 
18 
18.25