Clinical trial NCT03756883
Conditions: Asthma
Sponsor: Actavis Inc.
Start date: 2018-12-03; Completion date: 2019-11-10
Enrollment: 999 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized, multiple-dose, blinded, placebo-controlled, parallel-group, multiple-center bioequivalence study with pharmacodynamic endpoints

Detailed description:

Arms: arm 1: Fluticasone Propionate and Salmeterol Inhalation Powder, 100 mcg/50 mcg arm 2: ADVAIR DISKUS® 100/50 (fluticasone propionate and salmeterol) Inhalation Powder arm 3: Placebo
Interventions: intervention 1: Fluticasone Propionate and Salmeterol Inhalation Powder intervention 2: Fluticasone Propionate and Salmeterol Inhalation Powder intervention 3: Placebo Inhalation Powder
Intervention descriptions: intervention 1: 100/50 mcg per actuation intervention 2: 100/50 mcg per actuation intervention 3: No active content

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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1.0 TITLE PAGE 
Drug Product 
Fluticasone Propionate and Salmeterol Inhalation Powder, 
100 mcg/50 mcg 
Population 
Males and non-pregnant females, ≥ 12 years and ≤ 75 years of age, with 
asthma. 
Study Design 
A randomized, multiple-dose, blinded, placebo-controlled, parallel-group, 
multiple-center bioequivalence study with pharmacodynamic endpoints 
Sponsor 
Teva Pharmaceuticals 
Protocol Number 
71736001 
 
71736001 
Protocol Date 
03Jan2019 Final Version 1 
 
 
 
 
 
 
 
 
 
 
This document is a confidential communication of
 and Teva 
Pharmaceuticals. Receipt of this document constitutes an agreement by the recipient that no unpublished 
information contained herein will be disclosed without written approval from 
 and Teva. 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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2.0 KEY STUDY PERSONNEL AND FACILITIES 
Sponsor: 
Teva Pharmaceuticals 
400 Interpace Parkway 
Parsippany NJ, 07054, US 
CRO: 
 
 
 
Sponsor’s Representative: 
  
 
 
 
 
 
 
 
CRO Representative: 
 
 
 
 
 
 
Medical Monitor: 
 
 
 
 
 
 
 
Biostatistician: 
 
 
 
 
 




CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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PRINCIPAL INVESTIGATOR’S SIGNATURE 
 
 
 
I _______________________________________, agree to conduct protocol 71736001 in accordance 
with FDA regulations, ICH guidelines, and Good Clinical Practice. I understand that no deviations from 
the protocol may be made without the prior permission of the Sponsor (Teva Pharmaceuticals) or 
 
, the company managing the study. 
 
 
 
 
 
___________________________________ 
 
 
 
_________________ 
Principal Investigator 
 
 
 
 
 
 
Date 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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4.0 TABLE OF CONTENTS 
 
1.0 TITLE PAGE .......................................................................................................................................... 1 
2.0 KEY STUDY PERSONNEL AND FACILITIES .................................................................................. 2 
3.0 SIGNATURE PAGE .............................................................................................................................. 3 
4.0 TABLE OF CONTENTS ........................................................................................................................ 5 
5.0 SYNOPSIS .............................................................................................................................................. 9 
6.0 STUDY SCHEMATIC ......................................................................................................................... 20 
7.0 LIST OF ABBREVIATIONS AND TERMS ....................................................................................... 22 
8.0 INTRODUCTION ................................................................................................................................ 24 
8.1 Disease Being Treated ...................................................................................................................... 24 
8.2 Availability and Efficacy of Already Approved Therapies .............................................................. 24 
8.3 Scientific and Statistical Considerations ........................................................................................... 25 
8.4 Justification for Use of Placebo ........................................................................................................ 25 
8.5 Risks and Benefits ............................................................................................................................. 25 
9.0 STUDY OBJECTIVES ......................................................................................................................... 26 
10.0 INVESTIGATIONAL PLAN ............................................................................................................. 26 
Study Design and Plan Description ........................................................................................................ 26 
10.1 Selection of Study Design ............................................................................................................... 28 
10.2 Selection of Study Population ......................................................................................................... 28 
10.2.1 Inclusion Criteria...................................................................................................................... 28 
10.2.2 Exclusion Criteria .................................................................................................................... 30 
10.2.3 Randomization Inclusion/Exclusion ........................................................................................ 32 
10.2.4 Restrictions During the Study .................................................................................................. 34 
10.2.5 Removal of Subjects from the Study ....................................................................................... 37 
10.2.6 Exacerbation of Asthma ........................................................................................................... 38 
10.3 Treatments....................................................................................................................................... 38 
10.3.1 Treatment Administration ........................................................................................................ 38 
10.3.2 Study Product Shipment, Storage, and Retention .................................................................... 39 
10.3.3 Method of Assigning Subjects to Treatment Groups ............................................................... 40 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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10.3.4 Study Blind .............................................................................................................................. 40 
10.3.5 Compliance .............................................................................................................................. 42 
10.4 Study Conduct ................................................................................................................................. 42 
10.4.1 Screening Visit ......................................................................................................................... 42 
10.4.2 Visit 1a: General Screening ..................................................................................................... 42 
10.4.3 Visit 1b: Screening (Day -21 to Day -14) ................................................................................ 43 
10.4.4 Screening Repeat (Within 7 days from Visit 1b) ..................................................................... 45 
10.4.5 Visit 2: Randomization (Day 1) ............................................................................................... 46 
10.4.6 Visit 3: End of Study (Day 29 ± 2)/Early Termination ............................................................ 47 
10.5 Study Procedures ............................................................................................................................ 48 
10.5.1 Informed Consent ..................................................................................................................... 48 
10.5.2 Medical History and Baseline Demographics .......................................................................... 48 
10.5.3 Vital Signs ................................................................................................................................ 48 
10.5.4 Height and Weight ................................................................................................................... 48 
10.5.5 Physical Exam .......................................................................................................................... 48 
10.5.6 Clinical Laboratory Testing ..................................................................................................... 48 
10.5.7 Pregnancy Testing .................................................................................................................... 48 
10.5.8 12-Lead ECG ........................................................................................................................... 49 
10.5.9 Concomitant Medication Use ................................................................................................... 49 
10.5.10 Adverse Events ...................................................................................................................... 49 
10.5.11 Spirometry Testing ................................................................................................................. 49 
10.5.12 Reversibility Assessment ....................................................................................................... 50 
10.5.13 Pulse Oximetry ....................................................................................................................... 50 
10.5.14 Peak Flow Measurements ...................................................................................................... 50 
10.5.15 Inclusion/Exclusion Criteria Review ..................................................................................... 50 
10.5.16 Dispense Rescue Medication, Placebo Product, and Instructions .......................................... 50 
10.5.17 Dispense Study Product and Instructions ............................................................................... 50 
10.5.18 Dosing .................................................................................................................................... 51 
10.5.19 Collect Study Product/Rescue Medications ........................................................................... 51 
10.5.20 Provide, Review, and Collect Diary ....................................................................................... 51 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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10.6 Adverse Events ............................................................................................................................... 51 
10.6.1 Adverse Event Definition ......................................................................................................... 51 
10.6.2 Serious Adverse Events ........................................................................................................... 52 
10.6.3 Other Significant Adverse Events ............................................................................................ 53 
10.6.4 Severity .................................................................................................................................... 53 
10.6.5 Relationship of an Adverse Event to the Study Drug .............................................................. 53 
10.6.6 Expectedness ............................................................................................................................ 54 
10.6.7 Recording and Reporting of Adverse Events ........................................................................... 54 
10.6.8 Reporting of Serious Adverse Events ...................................................................................... 55 
10.6.9 Submission of SAEs................................................................................................................. 58 
11.0 STATISTICAL METHODS ............................................................................................................... 58 
11.1 Statistical Plan ................................................................................................................................. 58 
11.2 Determination of Sample Size ........................................................................................................ 58 
11.3 Study Populations ........................................................................................................................... 59 
11.3.1 PP Population ........................................................................................................................... 59 
11.3.2 mITT Population ...................................................................................................................... 59 
11.3.3 Safety Populations.................................................................................................................... 59 
11.4 Baseline Comparability ................................................................................................................... 60 
11.5 Efficacy Endpoints .......................................................................................................................... 60 
11.6 Primary Endpoint Analyses ............................................................................................................ 60 
11.7 Safety Analysis ............................................................................................................................... 61 
12.0 REGULATORY OBLIGATIONS ...................................................................................................... 61 
12.1 Institutional Review Board ............................................................................................................. 61 
12.2 Study Documentation ...................................................................................................................... 62 
12.2.1 Protocol .................................................................................................................................... 62 
12.2.2 Informed Consent ..................................................................................................................... 62 
12.2.3 Protocol and Informed Consent Changes ................................................................................. 62 
12.2.4 Source Documents and Case Report Forms ............................................................................. 63 
12.2.5 Drug Accountability ................................................................................................................. 63 
12.2.6 Drug Storage ............................................................................................................................ 63 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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12.2.7 Retention of Reserve Samples ................................................................................................. 63 
12.2.8 Pregnancies .............................................................................................................................. 64 
12.2.9 Reporting Safety Information to the IRB ................................................................................. 64 
12.2.10 Record Retention.................................................................................................................... 64 
12.2.11 Study Monitoring and Auditing ............................................................................................. 65 
12.2.12 End of the Trial ...................................................................................................................... 65 
12.2.13 Clinical Study Report ............................................................................................................. 65 
12.2.14 Termination of the Study ....................................................................................................... 65 
13.0 REFERENCES ................................................................................................................................... 66 
14.0 APPENDICES .................................................................................................................................... 68 
14.1 APPENDIX A - NAEPP Guidelines for Asthma Severity Classification. National Asthma 
Education and Prevention Program Expert Panel Report 3 .................................................................... 68 
14.2 APPENDIX B - ADVAIR DISKUS® 100/50 (fluticasone propionate/salmeterol) Inhalation 
Powder Package Insert ............................................................................................................................ 69 
14.3 APPENDIX C – Clinical Laboratory Testing ................................................................................. 70 
14.4 APPENDIX D- Amendments to the Protocol ................................................................................. 72 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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5.0 SYNOPSIS 
Protocol Number 
71736001 
Title 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-
Design, Multiple-Center, Clinical Study to Evaluate the Therapeutic 
Equivalence of Fluticasone Propionate and Salmeterol Inhalation Powder, 
100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR 
DISKUS® 100/50 (fluticasone propionate and salmeterol) Inhalation 
Powder, (GlaxoSmithKline) in Subjects With Asthma. 
Objectives 
The objectives of this study are to: 
1. Evaluate the therapeutic equivalence of a generic Fluticasone 
Propionate and Salmeterol Inhalation Powder, 100 mcg/50 mcg 
(Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 
100/50 (fluticasone propionate and salmeterol) Inhalation Powder, 
(GlaxoSmithKline) in subjects with asthma. 
2. Demonstrate the superiority of the Test and Reference (active) 
treatments over Placebo treatment in subjects with asthma. 
Sponsor 
Teva Pharmaceuticals 
Study Products 
1. Test: Fluticasone Propionate and Salmeterol Inhalation Powder, 
100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) 
2. Reference: ADVAIR DISKUS® 100/50 (fluticasone propionate and 
salmeterol) Inhalation Powder, (GlaxoSmithKline) 
3. Placebo: Fluticasone Propionate and Salmeterol Inhalation Powder 
Placebo (FS DPI Placebo; Supplied by Teva Pharmaceuticals Ireland) 
Dosage Regimen 
Subjects will be instructed to administer one inhalation of the study product 
twice daily for 28 ± 2 days. Subjects will administer the first inhalation on 
the morning of Visit 2 (Day 1). The last dose should be administered on the 
evening before Visit 3. Each subject is expected to receive up to 60 doses 
of the study product. 
Study Design 
A randomized, multiple-dose, blinded, placebo-controlled, parallel-group, 
multiple-center bioequivalence study with pharmacodynamic endpoints 
Study Population 
Approximately 
 males and non-pregnant females, ≥ 12 years and ≤ 75 
years of age, diagnosed with asthma (as defined by the National Asthma 
Education and Prevention Program) will be enrolled in the placebo run-in 
period to allow for approximately
 subjects to be randomized to study 
products to obtain 
 subjects in the per-protocol (PP) population. 
Confinement 
Subjects will remain confined to clinic for approximately 13 hours during 
Visit 2 (Day 1). 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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Study Conduct 
Eligible subjects will complete the clinic visits as follows: 
• 
Visit 1: Screening 
o Visit 1a: General Screening (
 
 
o Visit 1b: Screening (Day -21 to -14).  
 
 
 
   
Following completion of Screening procedures, qualified subjects 
will enter into Placebo Run-in: (14-21 days prior to Day 1). 
 
 
• 
Visit 2: Randomization (Day 1) 
• 
Visit 3: End of Study (Day 29 ± 2)/Early Termination 
Screening 
Screening evaluations will be performed in accordance with the study 
schematic. Safety assessments will include: vital sign measurement, height, 
weight, physical examination, serum pregnancy test (for all women of 
childbearing potential), drug, alcohol, and cotinine testing, 12-lead 
electrocardiogram (ECG), and clinical laboratory evaluations. Clinical 
assessments will include Forced Expiratory Volume in 1 second (FEV1) 
taken at each visit. 
 
 
. Forced Volume 
Vital Capacity (FVC) and FEV1/FVC ratio [(FEV1/FVC) x 100] will be 
recorded with FEV1 measurements at each visit. Pre-bronchodilator FEV1 at 
Screening must be 40%-85% (including these values) of predicted value. 
Once a qualifying FEV1 is obtained, 
 puffs 
 
) of albuterol inhalation will be 
administered (at each inhalation, the breath is held for 5-10 second before 
the subject exhales; four separate doses are delivered at approximate 
30 seconds 
intervals) 
and 
spirometry 
will 
be 
repeated 
starting 
approximately 15 minutes from the last inhalation. The subject must 
demonstrate at least 15% reversibility of FEV1 within 30 minutes after 
albuterol administration to qualify for inclusion in the study. Post-


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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bronchodilator vital signs will be obtained. 
 
 
 
 
 
 
 
   
Following completion of Screening procedures, qualified subjects will enter 
into Placebo Run-in: (14-21 days prior to Day 1).  
Enrollment 
Eligible subjects will be enrolled in a placebo run-in period for 14-21 days 
to establish baseline FEV1 values. 
 
 
. Subjects will be dispensed 
an inhaler containing Placebo product to be administered twice daily. 
Subjects must administer at least 
 of the required doses during the run-
in period to be eligible for randomization. Eligible subjects will also receive 
an albuterol inhaler to be used as a rescue medication throughout the study. 
Randomization 
Subjects who meet all inclusion/exclusion and randomization criteria at 
Visit 2 will be randomized to study product in a 
 ratio (Test: 
Reference: Placebo). Serial pulmonary function tests will be performed over 
12 hours at Visit 2. FEV1 should be measured at approximately 
 
 before the first 
dose of study product and approximately 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 
12 hours post-dose. The second dose of study product will be administered 
after the 12-hour FEV1 is collected.
 
  The 
average of the acceptable FEV1 measurements will be used to determine the 
baseline FEV1, which must be ≥ 40% and ≤ 85% of predicted normal value 
and may not vary by more than
 from the qualifying Screening visit 
FEV1 value at Visit 2 for the subject to be eligible for inclusion in the study. 
Placebo compliance during the Run-in Period should be at least 
%.   
Subjects will measure twice-daily (morning and evening) peak expiratory 
flow (PEF; air flow in and out of the lungs) at home using a hand held 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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spirometry device. 
End of Study 
The final three pre-dose FEV1 measurements will be collected at Visit 3. 
The first FEV1 should take place at the same time of day as the 
 
pre-dose measurement, respectively, collected at Visit 2 (± 2 hours). The 
remaining FEV1 measurements should be collected at 
 
 following the preceding measurement.
 
.  
Subjects will be instructed not to dose within 6 hours before FEV1 
measurements at Visit 3. The last dose of study product should be 
administered on the evening before Visit 3.  Subjects should not administer 
the rescue medication within 6 hours before any study visit. 
Inclusion Criteria 
1. Male or non-pregnant, non-lactating female, ≥ 12 years and ≤ 75 years 
of age. 
2. Signed informed consent form that meets all criteria of current Food 
and Drug Administration (FDA) regulations. For subjects who are 
considered minors in the state the study is being conducted (< 18 years 
in most states), the parent or legal guardian should sign the consent 
form and the child will be required to sign a subject “assent” form. 
3. Body mass index (BMI) between 18 kg/m2 and 39 kg/m2, inclusive, for 
subjects > 18 years old. For subjects 12 to 18 years old, BMI between 
15 kg/m2 and 35 kg/m2, inclusive. 
4. Female subjects who are of non-childbearing potential must meet one of 
the following criteria: 
• 
surgically sterile (e.g., bilateral oophorectomy, tubal ligation, 
hysterectomy or permanent sterilization procedures), with the 
procedure performed at least 3 months before initial dosing 
• 
naturally postmenopausal (no menses) for at least 1 year before 
initial dosing and/or has a documented FSH level ≥ 40 mIU/mL at 
screening 
• 
pre-menarchal 
5. Females of childbearing potential must not be pregnant or lactating at 
Screening or Randomization as confirmed by a negative serum 
pregnancy test with a sensitivity of 25 mIU/mL of human chorionic 
gonadotropin at Screening, and a negative urine pregnancy test with a 
sensitivity of less than 50 mIU/mL at all other visits. 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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.  
Women of childbearing potential must agree to the use of a reliable 
method of contraception (e.g., total abstinence, intrauterine device, a 
double-barrier method, oral, transdermal, injected or implanted non- or 
hormonal contraceptive), throughout the study. A sterile sexual partner 
is not considered an adequate form of birth control. Subjects on 
hormonal contraceptives must have been on the same hormonal 
contraceptive for at least one month before the Screening and continue 
throughout the duration of the study. 
6. Diagnosis of asthma (based on National Asthma Education and 
Prevention Program [NAEPP] guidelines) at least 12 weeks before 
Screening. 
7. Pre-bronchodilator FEV1 ≥ 40% and ≤ 85% of predicted at Screening 
and Randomization. 
8. Airway reversibility ≥ 15% of FEV1 within 30 minutes after receiving  
puffs of albuterol inhalation 
, pressurized metered-dose 
inhaler) at Screening. 
9. Able to discontinue use of their asthma medications during the run-in 
period and for the remainder of the study. 
10. Able to replace current short-acting beta-agonists [SABAs] with the 
study supplied salbutamol/albuterol rescue inhaler for use as needed for 
the duration of the study. Subjects must be able to withhold all SABAs 
for at least 6 hours before lung function assessments on study visits. 
11. Able to continue on stable regimen of theophylline for the duration of 
the study and able to withhold theophylline as judged by the 
Investigator for the required time intervals before study visits. See 
Section 10.2.4 for required washouts. 
12. Able to discontinue oral corticosteroids, parenteral corticosteroids and 
oral SABAs for the time intervals before study visits as specified in 
Section 10.2.4. 
13. Able to perform valid and reproducible pulmonary function tests as per 
ATS American Thoracic Society including no evidence of spirometry 
effort-induced bronchoconstriction. 
14. Currently non-smoking (including vapor cigarettes), no use of any 
tobacco products within 1 year prior to Screening and has ≤ 10 pack-
years smoking of historical use (i.e., one pack per day for 10 years). 
15. Ability to use the inhalation products correctly. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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Exclusion Criteria 
1. Life-threatening asthma, defined as a history of asthma episode(s) 
requiring intubation, and/or associated with hypercapnoea; respiratory 
arrest or hypoxic seizures, asthma related syncopal episode(s), or 
asthma-related hospitalizations within one year before Screening or 
during the run-in period. 
2. Allergy or significant history of hypersensitivity, idiosyncratic 
reactions, or intolerance to any sympathomimetic drug (e.g., salmeterol 
or albuterol), or any inhaled, intranasal, or systemic corticosteroid 
therapy, or milk proteins. 
3. History of cystic fibrosis, bronchiectasis, or co-morbid respiratory or 
sinus diseases, including chronic obstructive pulmonary disease, 
chronic bronchitis, emphysema, tuberculosis, pulmonary carcinoma, 
pulmonary fibrosis, pulmonary hypertension that, in the opinion of the 
Investigator, would compromise subject safety or interfere with the 
evaluations. 
4. Evidence of viral or bacterial upper or lower respiratory tract infections 
(e.g., pneumonia, viral bronchitis, sinobronchitis, etc.), sinus infection, 
or middle ear infection within four weeks before Screening or during 
the run-in period. 
5. Current evidence or history of cardiovascular disorders, including 
uncontrolled hypertension, uncontrolled coronary artery disease, known 
aortic or cerebral aneurysm, myocardial infarction or stroke, and/or 
current coronary insufficiency that, in the opinion of the Investigator, 
would compromise subject safety or interfere with the evaluations. 
6. Cardiac arrhythmia or 12-lead ECG abnormalities that, in the opinion of 
the Investigator, would compromise subject safety or interfere with the 
evaluations; or a 
 for females 
using Fredericia formula. 
7. Subjects receiving or who may require during the study non-potassium 
sparing diuretics or medications with the potential to affect the course 
of asthma or to interact with sympathomimetic amines within 30 days 
before Screening. Examples include but not limited to beta blockers, 
oral 
decongestants, 
benzodiazepines, 
digitalis, 
phenothiazines, 
polycyclic antidepressants, monoamine oxidase inhibitors.  
8. History of posterior subcapsular cataracts or glaucoma that, in the 
opinion of the Investigator, would compromise subject safety. 
9. Any clinically significant finding on physical exam or clinical labs that, 
in the opinion of the Investigator, would compromise subject’s safety or 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001 03Jan2019  
  Page 15 of 72 
 
 
data integrity. 
10. History or current evidence of significant renal, hepatic, cardiovascular 
(including ECG with evidence of ischemic heart disease, congestive 
heart failure, and cardiac dysrhythmia), neurologic, hematologic, 
endocrine, psychiatric dysfunction, or any other significant medical 
illness or disorder in the opinion of the Investigator, would compromise 
subject safety or interfere with the evaluations. 
11. History of convulsive disorders.  
12. History within the past 6 months or current evidence of 
hyperthyroidism. 
13. History within the past 6 months or current evidence of uncontrolled 
diabetes. 
14. History of paradoxical bronchospasm. 
15. Use of inhaled SABAs within 6 hours before Screening or use of rescue 
medication within 6 hours before Randomization. 
16. Use of oral SABAs within 
 before Screening. 
17. Use of oral or parenteral corticosteroids within 
 before 
Screening. 
18. Use of muscarinic beta2-agonists (MABAs), ipratropium bromide, or 
ipratropium bromide with albuterol within 
 before Screening. 
19. Use of cromolyn sodium within
 before Screening. 
20. Use of antihistamines (other than cetirizine, desloratadine, or 
diphenhydramine), including fexofenadine and loratadine, 
 
 before Screening or Randomization. 
21. Use of cetirizine within 
 before Screening or Randomization. 
22. Use of desloratadine 
 
 
 before Screening or 
Randomization. 
23. Use of diphenhydramine 
 before Screening or 
Randomization. 
24. Use of inhaled long-acting beta2-agonists (LABAs) (e.g., salmeterol, 
formoterol) or combination products containing bronchodilators (e.g., 
Symbicort) 
 before Screening. 
25. Use of tiotropium within 
 before Screening. 
26. Exercise within 
 before Screening. 
27. Use of leukotriene modifiers within 
 before Screening. 
28. Any surgery within 6 months before Screening that, in the opinion of 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001 03Jan2019 
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the Investigator, would compromise subject safety or integrity of the 
study data. 
29. Biological treatment for asthma, approved or investigational 
 
before Screening and throughout the study. 
30. Receipt of any drug as part of a research study within 30 days before 
Screening. 
31. Positive test results for drugs of abuse, alcohol or cotinine at Screening. 
 
 
. 
32. Employees of the Investigator or research center or their immediate 
family members. 
33. Previous participation in this study. 
34. Inability to understand the requirements of the study and the relative 
information and are unable or not willing to comply with the study 
protocol. 
Randomization 
Inclusion/Exclusion 
At the end of the Run-in period subjects will be randomized to treatment if 
they continue to meet all of the general inclusions criteria and do not meet 
any of the general exclusion criteria.  In addition, they must also meet all 
following inclusion criteria and do not meet any of the following exclusion 
criteria. 
Randomization inclusion criteria: 
1. Compliance with the Run-in placebo treatment dosing 
 as 
evaluated via the diary entries. 
2. Minimum of 2 acceptable, as determined by ERT spirometry as meeting 
all ATS criteria, pre-dose FEV1 measurements needed to establish 
baseline.  
3.  Calculated baseline FEV1 must be ≥ 40% and ≤ 85% of predicted 
normal value. The baseline FEV1 will be calculated by the Principal 
Investigator (or designee) at the respective clinical site. 
Randomization exclusion criteria: 
1. Occurrence of clinically significant asthma exacerbations according to 
the pre-defined criteria (see Section 10.2.6).  
2. Viral or bacterial, U/LRTI or sinus or middle ear infection during the 
Run in Period, or on the first day of treatment. 
3. Use of prohibited medications during the placebo run in period (see 
Washout Table in Section 10.2.4). 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001 03Jan2019  
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4. Change of 
 FEV1 value from baseline 
compared to qualifying Screening FEV1. 
 
 
 
5. Coexisting of all occurrences liver injury that meets Hy’s law criteria, 
defined 
as: 
alanine 
aminotransferase 
(ALT) 
or 
aspartate 
aminotransferase (AST) elevation of > 3x the upper limit of normal 
(ULN), total bilirubin elevation of > 2x ULN, and the absence of initial 
findings of cholestasis (i.e. no substantial increase of alkaline 
phosphatase [ALP]).  
Route of 
Administration 
Oral inhalation 
Efficacy Endpoints 
The two co-primary efficacy endpoints are (1) the baseline-adjusted area 
under the serial FEV1-time curve calculated from time zero to 12 hours 
(AUC0-12h) on Day 1 of treatment (Visit 2), and (2) the baseline-adjusted 
pre-dose FEV1 measured in the morning of Day 29 ± 2 (Visit 3), after the 
last dose in the prior evening. 
Baseline FEV1 is defined as the average of at least two acceptable pre-dose 
FEV1 values on Day 1. 
 
 
 
Statistical Analysis 
The Baseline FEV1 will be subtracted from post-dose FEV1 values to obtain 
the baseline-corrected values on Day 1. Baseline-adjusted area under the 
serial FEV1-time curve from time zero to 12 hours (AUC0-12h) will be 
calculated by the linear trapezoidal method. The statistical analyses will 
involve Analysis of Covariance (ANCOVA) with terms for 
 
as fixed effects and using 
as a covariate in the model. 
Therapeutic Equivalence 
Therapeutic equivalence will be evaluated for the primary endpoint in the 
PP population. 
, the 
adjusted 90% confidence interval will be calculated for the Test/Reference 
ratio of the mean baseline-adjusted AUC0-12h on Day 1 and for the 
Test/Reference ratio of the mean baseline-adjusted morning pre-dose FEV1 
on Day 29 ± 2 using an iterative procedure similar to Fieller’s method. The 
mean baseline value for use in the iterative procedure will be determined 
from the Baseline FEV1 of all subjects receiving active treatment in the PP 
population, without regard to the treatment received. If the adjusted 90% 
confidence intervals for the least-squares mean Test/Reference ratios are 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001 03Jan2019  
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within 80.00-125.00% for both co-primary endpoints, then therapeutic 
equivalence of the Test to Reference product will be considered to have 
been demonstrated. 
Superiority to Placebo 
The superiority of the Test and Reference products over Placebo is 
concluded if the values for mean baseline-adjusted AUC0-12h and mean 
baseline-adjusted morning pre-dose FEV1 on Day 29 ± 2 for the active 
treatments are statistically superior to those respective values of the Placebo 
at the 5% significance level (p < 0.05, two-sided). The superiority of Test 
and Reference treatments over the Placebo will be evaluated in the same 
ANCOVA model for Test vs. Placebo and Reference vs. Placebo. 
 
 
Safety Analysis 
There will be two Safety populations: 
• 
 
 
 
 
 
 
 
All study subjects who were randomized and used the study product on at 
least one occasion will be included in the comparative safety analysis. 
Adverse events (AEs) will be classified using standard Medical Dictionary 
for Regulatory Activities (MedDRA) terminology Version 21.1 or higher 
and presented by treatment group. Summary tables listing the type, date of 
onset, date of resolution, incidence, severity, outcome, action taken, and 
Investigator’s opinion of relationship to the study product will be presented 
by treatment group for AEs reported after randomization. 
Signs and symptoms of asthma will not be considered AEs, unless in the 
Investigator’s opinion, they have increased in frequency and/or severity to 
such an extent that the Investigator/subject considers that it is in the 
subject’s best interest to be dropped from continued participation in the 
study and given alternative therapy for their condition.  
Concomitant medication used during the study will be tabulated by 
treatment by subject. 
Sample Size 
Determination 
 
 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001 03Jan2019  
  Page 19 of 72 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical Study to Evaluate the Therapeutic 
Equivalence of Fluticasone Propionate and Salmeterol Inhalation Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to 
ADVAIR DISKUS® 100/50 (fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
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6.0 STUDY SCHEMATIC 
Procedures 
p
Informed Consent 
Medical History and Baseline Demographics 
Vital Signs 
Height and Weight 
Physical Exam 
Drug, Cotinine, and Alcohol Testing 
Serum Pregnancy Test** 
Urine Pregnancy Test** 
12-Lead ECG 
Clinical Laboratory Testing  
Concomitant Medication 
Spirometry (FEV1 and FVC) § 
Reversibility Test§ 
Pulse Oximetry 
Inclusion/Exclusion Criteria Review 
Dispense Randomized Study Product and Instructions 
Dispense Run-In Product and Instructions 
Dispense Rescue Medication (as applicable) 
Dosing¶ 
Adverse Events 
Provide Diaries  
Collect/Review Diaries 
Collect Placebo from Run-in Period 
Collect Rescue Medication 




CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
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7.0 LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Term 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATS 
American Thoracic Society 
BE 
Bioequivalence 
BP 
Blood Pressure 
C 
Celsius 
CDISC 
Clinical Data Standards Interchange Consortium 
CHF 
Congestive Heart Failure 
COPD 
Chronic obstructive pulmonary disease 
CRO 
Clinical Research Organization 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eCTD 
Electronic Common Technical Document 
EIB 
Exercise-Induced Bronchospasm 
°F 
Fahrenheit 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume (flow rate) in 1 second 
FVC 
Forced Volume Vital Capacity 
HFA 
Hydrofluoroalkane 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LABA 
Long-acting Beta2-Agonist 
MABA 
Muscarinic-Acting Beta2-Agonist 
mcg 
Microgram 
MDMA 
Ecstasy 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat  
mL 
Milliliter 
NAEPP 
National Asthma Education and Prevention Program 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per-Protocol  
RR 
Respiratory Rate 
SABA 
Short-Acting Beta2-Agonist 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
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SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SPE 
Safety Population Enrolled 
SPR 
Safety Population Randomized 
THC 
Tetrahydrocannabinol 
US 
United States 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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8.0 INTRODUCTION 
8.1 Disease Being Treated 
Asthma is a common lung disease that affects an estimated 25 million Americans including more than 
6 million children.1-3 The prevalence of this disease makes it one of the most costly diseases in the 
United States, costing approximately $56 billion per year. The financial burden of the disease extends 
from medical costs to missed work days and lost productivity. Subjects with uncontrolled asthma 
have health care costs that are two times higher than those with controlled asthma.1,3,4 
Asthma is a serious and potentially life-threatening condition characterized by varying symptoms 
including obstructed airflow, bronchial hyper-responsiveness, and underlying inflammation, which 
can result in difficulty breathing, coughing, chest tightness, pain, chest pressure, or wheezing.5-7 
Exacerbation of symptoms may be triggered by a variety of factors including infections, allergens, 
exercise, inhaled irritants, or emotional episodes.1,8 
Asthma diagnosis and severity ranking are carried out on the basis of pulmonary function testing 
using a spirometer, a device that measures Forced Expiratory Volume in 1 second (FEV1), the volume 
of air that can forcibly be blown out in one second, after full inspiration. Lung function is typically 
compromised in asthma subjects (FEV1 predicted value < 85%). Reversibility (full or partial) of 
airway obstruction is an essential component of asthma diagnosis to rule out differential diagnoses 
including chronic obstructive pulmonary disease (COPD), Congestive Heart Failure (CHF) or 
pulmonary embolism. This is determined by an increase in predicted FEV1 > 200 mL or > 12% from 
baseline measure after inhalation of short-acting beta2-agonist (SABA).6 
The severity of asthma is rated on a scale of intermittent, mild persistent, moderate persistent, or 
severely persistent. The rating depends on various factors including degree of impairment in lung 
function, the frequency and intensity of symptoms, susceptibility to future asthma attacks or 
medication side effects. Asthma management focuses on reducing both impairment and risk for the 
subject.9,10 
8.2 Availability and Efficacy of Already Approved Therapies 
There are two types of therapies currently available for the treatment of asthma: quick relief 
medications and long-term control medications.11,12 Quick relief medications or SABAs, for example, 
albuterol sulfate (PROAIR® HFA, PROVENTIL® HFA) and levalbuterol tartrate (XOPENEX HFA®) 
are used to relax airway smooth muscle to promote bronchodilation within minutes of administration. 
These medications typically provide relief for up to 6 hours. SABAs activate the beta adrenergic 
receptors on bronchial smooth muscle to rapidly dilate airway passages and provide relief from 
bronchospasm. SABAs are typically the preferred treatment to prevent exercise-induced 
bronchospasm (EIB) and for the treatment of acute exacerbations of asthma. The medications are 
typically provided as metered-dose inhalers or dry powder inhalers (oral inhalation). Additionally, 
anti-cholinergic medications (i.e., ipratropium) and systemic, intravenous, or oral corticosteroids are 
used to treat acute asthma exacerbations. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
  Page 25 of 72 
 
 
Inhaled corticosteroids have been shown to be the most effective long-term treatment of persistent 
asthma.13 Long-acting beta2-agonists (LABAs) are taken daily to relax the muscles lining the airways 
that carry air to the lungs. This allows the tubes to remain open, making breathing easier. Current 
recommendations are for LABAs to be used only with inhaled corticosteroids. Combination 
medications include fluticasone and salmeterol (ADVAIR DISKUS®, ADVAIR HFA®), budesonide 
and formoterol (Symbicort®), and mometasone and formoterol (Dulera®).14 
8.3 Scientific and Statistical Considerations 
The overall bioequivalence (BE) recommendations for this product are in vitro and in vivo 
(pharmacokinetic [PK] and pharmacodynamic [PD]) studies. Bioequivalence assessment of dry 
powder inhalers is complicated because delivery to the sites of action in the lung does not occur 
primarily after systemic absorption. As such, this locally-acting product is intended to produce its 
effect upon delivery to sites in the lung without relying on systemic absorption, though systemic 
absorption may contribute to its clinical effect. For these reasons, in vitro studies coupled with a PK 
and PD study are required to determine the delivery of drug substance to sites of action in the lung. 
This study satisfies the PD regulatory requirements of the clinical studies. 
8.4 Justification for Use of Placebo 
The FDA Draft Guidance on fluticasone propionate; salmeterol xinafoate powder/inhalation product 
recommends that all subjects participate in a placebo run-in period to wash out any pre-study 
corticosteroids/LABAs and establish baseline FEV1 values.15 
A Placebo group is included in the active treatment period of the study to confirm the sensitivity of 
the study and minimize the possibility of a false positive result of therapeutic equivalence. Therefore, 
in addition to demonstrating therapeutic equivalence between Test and Reference products, both 
active products must show statistical superiority to the Placebo.16,17 Eligible subjects will have an 
 chance of being randomized to Placebo (
 randomization scheme of Test: Reference: 
Placebo). 
All subjects will be dispensed a rescue inhaler to treat sudden asthma symptoms during the placebo 
run-in and active treatment periods of the study. 
8.5 Risks and Benefits 
The risks and benefits to subjects enrolled in clinical research studies that include a Placebo treatment 
group must be carefully considered based on three main criteria, namely: the disease being treated, 
the availability, efficacy and safety of already approved therapies and the scientific and statistical 
requirements of the desired outcome of the research study. The Office of Human Rights Protection, a 
Division of the US Federal Government’s Department of Health and Human Services, has issued a 
detailed guidebook to Institutional Review Boards (IRBs) that includes discussion on the use of 
Placebos in clinical studies.18 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
  Page 26 of 72 
 
 
All subjects enrolled in this study will receive the benefit of free specialized medical care beyond 
standard medical treatment that would be expected through most health insurance plans. In addition, 
the subject will receive a stipend for participation to cover costs and expenses associated with trips to 
the medical facility. 
9.0 STUDY OBJECTIVES 
The objectives of this study are to: 
1. Evaluate the therapeutic equivalence of a generic Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 
100/50 (fluticasone propionate and salmeterol) Inhalation Powder, (GlaxoSmithKline) in subjects 
with asthma. 
2. Demonstrate the superiority of the Test and Reference (active) treatments over Placebo treatment in 
subjects with asthma. 
10.0 INVESTIGATIONAL PLAN 
Study Design and Plan Description 
This randomized, multiple-dose, blinded, placebo-controlled, parallel-design, multiple-center, clinical 
endpoint study has been designed to evaluate the clinical (therapeutic) effect of generic Fluticasone 
Propionate and Salmeterol Inhalation Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals 
Ireland) to ADVAIR DISKUS® 100/50 (fluticasone propionate and salmeterol) Inhalation Powder, 
(GlaxoSmithKline) in subjects with asthma. 
Following a 14-21 day placebo run-in period, subjects who continue to meet inclusion/exclusion criteria 
will be randomized in a 
 ratio (Test: Reference: Placebo) for 28 ± 2 days of treatment. 
Approximately 
 subjects will enter the run-in period to randomize approximately
 subjects to the 
active treatment period of the study. To qualify for inclusion in the study, subjects must be ≥ 12 years 
and ≤ 75 years of age, with a diagnosis of asthma as defined by the National Asthma Education and 
Prevention Program (NAEPP) guidelines at least 12 weeks before Screening.19 
Before any study-specific procedures are performed, all subjects will read and sign the IRB-approved 
informed consent form (ICF) or assent, as applicable. 
Eligible subjects will complete the clinic visits as follows: 
• 
Visit 1: Screening 
o Visit 1a: General Screening
 
 
o Visit 1b: Screening (Day -21 to -14).  
 
 
.   


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
  Page 27 of 72 
 
 
Following completion of Screening procedures, qualified subjects will enter into Placebo Run-in: 
(14-21 days prior to Day 1). 
 
. 
• 
Visit 2: Randomization (Day 1) 
• 
Visit 3: End of Study (Day 29 ± 2)/Early Termination  
Screening 
Screening evaluations will be performed in accordance with the study schematic. Safety assessments will 
include: vital sign measurement, height, weight, physical examination, serum pregnancy test (for all 
women of childbearing potential), drug, alcohol, and cotinine testing, 12-lead electrocardiogram (ECG), 
and clinical laboratory evaluations. Clinical assessments will include FEV1 taken at each visit.
 
 
orced Volume Vital 
Capacity (FVC) and FEV1/FVC ratio [(FEV1/FVC) x 100] will be recorded with FEV1 measurements at 
each visit. Pre-bronchodilator FEV1 at Screening must be 40%-85% (including these values) of predicted 
value. Once a qualifying FEV1 is obtained, 
 puffs 
; 90 mcg per puff, pressurized metered-
dose inhaler) of albuterol inhalation will be administered (at each inhalation, the breath is held for 5-10 
second before the subject exhales; four separate doses are delivered at approximate 30 seconds intervals) 
and spirometry will be repeated starting approximately 15 minutes from the last inhalation. The subject 
must demonstrate at least 15% reversibility of FEV1 within 30 minutes after albuterol administration to 
qualify for inclusion in the study. Post bronchodilator vital signs will be obtained. 
 
 
 
 
   
Following completion of Screening procedures, qualified subjects will enter into Placebo Run-in: (14-21 
days prior to Day 1). 
 
. 
Enrollment 
Eligible subjects will be enrolled in a placebo run-in period for 14-21 days to establish baseline FEV1 
values. Subjects will be dispensed an inhaler containing Placebo product to be administered twice daily. 
Subjects must administer at least 
 of the required doses during the run-in period to be eligible for 
randomization. Subjects will also receive an albuterol inhaler to be used as a rescue medication 
throughout the study. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
  Page 28 of 72 
 
 
Randomization 
Subjects who meet all inclusion/exclusion and randomization criteria at Visit 2 will be randomized to 
study product in a 
 ratio (Test: Reference: Placebo). Serial pulmonary function tests will be 
performed over 12 hours at Visit 2. FEV1 should be measured at approximately 
 
) before the first dose of study product and approximately 
30 minutes, 1, 2, 3, 4, 6, 8, 10, and 12 hours post-dose. The second dose of study product will be 
administered after the 12-hour FEV1 is collected. At least two of the pre-dose FEV1 measurements must 
meet ATS criteria for quality to be acceptable.  The average of the acceptable FEV1 measurements will be 
used to determine the baseline FEV1, which must be ≥ 40% and ≤ 85% of predicted normal value and 
may not vary by more 
 from the qualifying Screening visit FEV1 value at Visit 2 for the 
subject to be eligible for inclusion in the study. 
End of Study 
The final three FEV1 measurements will be collected at Visit 3. The first FEV1 should take place at the 
same time of day as the 
 pre-dose measurement, respectively, collected at Visit 2 (± 2 hours). 
The remaining FEV1 measurements should be collected within 
) following the 
preceding measurement. 
 pre-dose FEV1 measurements must meet ATS criteria for 
quality to be acceptable.  The last dose of study product should be administered on the evening before 
Visit 3.   
 
Subjects should not administer the rescue medication, or study product within 6 hours before any study 
visit. 
10.1 Selection of Study Design 
The study was designed based on the FDA Draft Guidance on fluticasone propionate; salmeterol 
xinafoate powder/inhalation product, and generally accepted standards for the conduct of 
bioavailability and bioequivalence studies.15 
10.2 Selection of Study Population 
10.2.1 Inclusion Criteria 
1. Male or non-pregnant, non-lactating female, ≥ 12 years and ≤ 75 years of age. 
2. Signed informed consent form that meets all criteria of current Food and Drug Administration 
(FDA) regulations. For subjects who are considered minors in the state the study is being 
conducted (< 18 years in most states), the parent or legal guardian should sign the consent 
form and the child will be required to sign a subject “assent” form. 
3. Body mass index (BMI) between 18 kg/m2 and 39 kg/m2, inclusive, for subjects > 18 years 
old. For subjects 12 to 18 years old, BMI between 15 kg/m2 and 35 kg/m2, inclusive. 
4. Female subjects who are of non-childbearing potential must meet one of the following 
criteria: 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019 
  Page 29 of 72 
 
 
• 
surgically sterile (e.g., bilateral oophorectomy, tubal ligation, hysterectomy or permanent 
sterilization procedures), with the procedure performed at least 3 months before initial 
dosing 
• 
naturally postmenopausal (no menses) for at least 1 year before initial dosing and/or has a 
documented FSH level ≥ 40 mIU/mL at screening 
• 
pre-menarchal 
5. Females of childbearing potential must not be pregnant or lactating at Screening or 
Randomization as confirmed by a negative serum pregnancy test with a sensitivity of 25 
mIU/mL of human chorionic gonadotropin at Screening and a negative urine pregnancy test 
with a sensitivity of less than 50 mIU/mL at all other visits. 
 
 
 
Women of childbearing potential must agree to the use of a reliable method of contraception 
(e.g., total abstinence, intrauterine device, a double-barrier method, oral, transdermal, injected 
or implanted non- or hormonal contraceptive), throughout the study. A sterile sexual partner 
is not considered an adequate form of birth control. Subjects on hormonal contraceptives 
must have been on the same hormonal contraceptive for at least one month before the 
Screening and continue throughout the duration of the study. 
6. Diagnosis of asthma (based on National Asthma Education and Prevention Program 
[NAEPP] guidelines) at least 12 weeks before Screening. 
7. Pre-bronchodilator FEV1 ≥ 40% and ≤ 85% of predicted at Screening and Randomization. 
8. Airway reversibility ≥ 15% of FEV1 within 30 minutes after receiving  puffs of albuterol 
inhalation (
, pressurized metered-dose inhaler) at Screening. 
9. Able to discontinue use of their asthma medications during the run-in period and for the 
remainder of the study. 
10. Able to replace current short-acting beta-agonists [SABAs] with the study supplied 
salbutamol/albuterol rescue inhaler for use as needed for the duration of the study. Subjects 
must be able to withhold all SABAs for at least 6 hours before lung function assessments on 
study visits. 
11. Able to continue on stable regimen of theophylline for the duration of the study and able to 
withhold theophylline as judged by the Investigator for the required time intervals before 
study visits. See Section 10.2.4 for required washouts. 
12. Able to discontinue oral corticosteroids, parenteral corticosteroids and oral SABAs for the 
time intervals before study visits as specified in Section 10.2.4. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
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13. Able to perform valid and reproducible pulmonary function tests as per ATS (American 
Thoracic Society) including no evidence of spirometry effort-induced bronchoconstriction. 
14. Currently non-smoking (including vapor cigarettes), no use of any tobacco products within 1 
year prior Screening and has ≤ 10 pack-years smoking of historical use (i.e., one pack per day 
for 10 years). 
15. Ability to use the inhalation products correctly. 
10.2.2 Exclusion Criteria 
1. Life-threatening asthma, defined as a history of asthma episode(s) requiring intubation, 
and/or associated with hypercapnoea; respiratory arrest or hypoxic seizures, asthma related 
syncopal episode(s), or asthma-related hospitalizations within one year before Screening or 
during the run-in period. 
2. Allergy or significant history of hypersensitivity, idiosyncratic reactions, or intolerance to any 
sympathomimetic drug (e.g., salmeterol or albuterol), or any inhaled, intranasal, or systemic 
corticosteroid therapy, or milk proteins. 
3. History of cystic fibrosis, bronchiectasis, or co-morbid respiratory or sinus diseases, 
including chronic obstructive pulmonary disease, chronic bronchitis, emphysema, 
tuberculosis, pulmonary carcinoma, pulmonary fibrosis, pulmonary hypertension that, in the 
opinion of the Investigator, would compromise subject safety or interfere with the 
evaluations. 
4. Evidence of viral or bacterial upper or lower respiratory tract infections (e.g., pneumonia, 
viral bronchitis, sinobronchitis, etc.), sinus infection, or middle ear infection within four 
weeks before Screening or during the run-in period. 
5. Current evidence or history of cardiovascular disorders, including uncontrolled hypertension, 
uncontrolled coronary artery disease, known aortic or cerebral aneurysm, myocardial 
infarction or stroke, and/or current coronary insufficiency that, in the opinion of the 
Investigator, would compromise subject safety or interfere with the evaluations. 
6. Cardiac arrhythmia or 12-lead ECG abnormalities that, in the opinion of the Investigator, 
would compromise subject safety or interfere with the evaluations; or a 
 
 
7. Subjects receiving or who may require during the study non-potassium sparing diuretics or 
medications with the potential to affect the course of asthma or to interact with 
sympathomimetic amines within 30 days before Screening. Examples include but not limited 
to beta blockers, oral decongestants, benzodiazepines, digitalis, phenothiazines, polycyclic 
antidepressants, monoamine oxidase inhibitors.  
8. History of posterior subcapsular cataracts or glaucoma that, in the opinion of the Investigator, 
would compromise subject safety. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
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9. Any clinically significant finding on physical exam or clinical labs that, in the opinion of the 
Investigator, would compromise subject’s safety or data integrity. 
10. History or current evidence of significant renal, hepatic, cardiovascular (including ECG with 
evidence of ischemic heart disease, congestive heart failure, and cardiac dysrhythmia), 
neurologic, hematologic, endocrine, psychiatric dysfunction, or any other significant medical 
illness or disorder in the opinion of the Investigator, would compromise subject safety or 
interfere with the evaluations. 
11. History of convulsive disorders.  
12. History within the past 6 months, or current evidence of hyperthyroidism. 
13. History within the past 6 months, or current evidence of uncontrolled diabetes. 
14. History of paradoxical bronchospasm. 
15. Use of inhaled SABAs within 6 hours before Screening or use of rescue medication within 6 
hours before Randomization. 
16. Use of oral SABAs within 
 before Screening. 
17. Use of oral or parenteral corticosteroids within
 before Screening. 
18. Use of muscarinic beta2-agonists (MABAs), ipratropium bromide, or ipratropium bromide 
with albuterol within 
 before Screening. 
19. Use of cromolyn sodium within
 before Screening. 
20. Use of antihistamines (other than cetirizine, desloratadine, or diphenhydramine), including 
fexofenadine and loratadine, within 
 before Screening or Randomization. 
21. Use of cetirizine within 
 before Screening or Randomization. 
22. Use of desloratadine within 
 before Screening or Randomization. 
23. Use of diphenhydramine within 
 before Screening or Randomization. 
24. Use of inhaled long-acting beta2-agonists (LABAs) (e.g., salmeterol, formoterol) or 
combination products containing bronchodilators (e.g., Symbicort) within 
 before 
Screening. 
25. Use of tiotropium within 
 before Screening. 
26. Exercise within 
 before Screening. 
27. Use of leukotriene modifiers within 
 before Screening. 
28. Any surgery within 6 months before Screening that, in the opinion of the Investigator, would 
compromise subject safety or integrity of the study data. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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29. Biological treatment for asthma, approved or investigational 
 before Screening and 
throughout the study. 
30. Receipt of any drug as part of a research study within 30 days before Screening. 
31. Positive test results for drugs of abuse, alcohol or cotinine at screening. 
 
 
 
32. Employees of the Investigator or research center or their immediate family members. 
33. Previous participation in this study. 
34. Inability to understand the requirements of the study and the relative information and are 
unable or not willing to comply with the study protocol. 
10.2.3 Randomization Inclusion/Exclusion 
At the end of the Run-in period subjects will be randomized to treatment if they continue to meet 
all of the general inclusions criteria and do not meet any of the general exclusion criteria.  In 
addition, they must also meet all following inclusion criteria and do not meet any of the following 
exclusion criteria. 
Randomization inclusion criteria: 
1. Compliance with the Run-in placebo treatment dosing
 as evaluated via the diary 
entries. 
2. Minimum of 2 acceptable, as determined by ERT spirometry as meeting all ATS criteria, pre-
dose FEV1 measurements needed to establish baseline.  
3. Calculated baseline FEV1 must be ≥ 40% and ≤ 85% of predicted normal value. 
 
 
. 
Randomization exclusion criteria: 
1. Occurrence of clinically significant asthma exacerbations according to the pre-defined criteria 
(see Section 10.2.6).  
2. Viral or bacterial, U/LRTI or sinus or middle ear infection during the Run in Period, or on the 
first day of treatment. 
3. Use of prohibited medications during the placebo run-in period (see Washout Table in 
Section 10.2.4). 
4. Change of 
 in calculated average FEV1 value from baseline compared to Screening 
qualifying FEV1. 
 
. 
5. Coexisting of all occurrences liver injury that meets Hy’s law criteria, defined as: alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) elevation of > 3x the upper 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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limit of normal (ULN), total bilirubin elevation of > 2x ULN, and the absence of initial 
findings of cholestasis (i.e. no substantial increase of alkaline phosphatase [ALP]).  


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical Study to Evaluate the Therapeutic 
Equivalence of Fluticasone Propionate and Salmeterol Inhalation Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to 
ADVAIR DISKUS® 100/50 (fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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10.2.4 Restrictions During the Study 
The following medications will not be allowed prior to Screening for the respective time intervals through the run-in period and for the duration of 
the study (see details and exceptions where applicable): 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical Study to Evaluate the Therapeutic 
Equivalence of Fluticasone Propionate and Salmeterol Inhalation Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to 
ADVAIR DISKUS® 100/50 (fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
71736001  03Jan2019 
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CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical Study to Evaluate the Therapeutic 
Equivalence of Fluticasone Propionate and Salmeterol Inhalation Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to 
ADVAIR DISKUS® 100/50 (fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
71736001  03Jan2019  
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CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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Subjects should not exercise within 
 of any study visit.  
Subjects will be requested to refrain from consuming caffeine containing products such as coffee, 
tea, cola drinks, energy drinks, or chocolate within 
 of any study visit, if possible. On Visit 
2, subjects will also be requested to refrain from consuming caffeine-containing products until the 
last point of the spirometry at Visit 2, if possible. 
 
 
 
 
 
 
10.2.5 Removal of Subjects from the Study 
Subjects will be advised that they are free to withdraw from the study at any time for any reason 
or, if necessary, the Investigator may withdraw a subject from the study to protect the health of 
that subject. A subject may also be withdrawn for not complying with study procedures. The 
clinical report will include all reasons for early withdrawals. 
If a randomized subject terminates from the study early, all efforts will be made to complete their 
next scheduled visit to perform all required End of Study/ Early termination visit activities except  
spirometry that does not need to be performed. In case of early termination the Investigator will 
fully document the reason for early termination. Reasons for early termination may include the 
following: 
• 
Subject withdrew consent. 
• 
Significant AE that led the Investigator or subject to withdraw for safety reasons. 
• 
Serious AE, regardless of relationship to study medication. 
• 
Non-compliance with protocol requirements (e.g., use of restricted medication, not 
following dosing procedures, failure to make scheduled study visits in a timely fashion). 
• 
Pregnancy 
• 
Significant worsening of asthma, defined as a clinically significant exacerbation (see 
Section 10.2.6) that requires emergency intervention, treatment with restricted 
medications or hospitalization. Withdrawal of the subject from the study is based on 
Investigator judgment if he or she believes it is in the best interest of the subject to 
withdraw from the study and provided alternative treatment. 
• 
Excessive use of rescue albuterol during the study. See Section 10.2.6. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
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• 
Subject requires the use of rescue medication during serial spirometry at Visit 2. 
• 
Participant enrolls in another clinical trial, or is found to have previously enrolled in this 
clinical trial. 
10.2.6 Exacerbation of Asthma 
The definition of a clinically significant asthma exacerbation for this clinical trial is based on the 
official statement from ATS/ERS Task Force on Asthma Control and Exacerbations.20 
An asthma exacerbation will include at least one of the following: 
 
 
 
. 
Asthma exacerbations meeting the pre-defined criteria above must be recorded as AEs. If they 
meet the definition of an SAE, they should be recorded as such. Any subject who reports the 
occurrence of an asthma exacerbation meeting the definition above during the Run-in period will 
be excluded from randomization. 
 
 
Subjects may also be withdrawn from the study in case of clinically significant worsening of the 
condition and/or at PI discretion. Clinically meaningful worsening of asthma may be indicated by 
a significant decrease of FEV1 and/or PEF at scheduled or unscheduled study visits or during 
study monitoring; excessive use of rescue medication (i.e., 
 
; emergency 
hospitalization or emergency medical attention related to asthma aggravation/exacerbation; 
necessary use of additional, excluded medication for the control of asthma exacerbation or its 
further prevention. 
10.3 Treatments 
10.3.1 Treatment Administration 
During the placebo run-in period, subjects will be instructed to administer one inhalation of the 
Placebo run-in product twice daily (approximately 12 hours apart) for 14-21 days. 
 
 
 Subjects will be instructed on proper oral 
inhalation technique and self-administer the first dose of Placebo under the supervision of the 
Independent Dispenser at Visit 1. The last dose should be administered on the evening before 
Visit 2. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
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Prior to entering in the Placebo run-in period, rescue medication will be dispensed to subjects at 
Visit 1. Subjects will be instructed on proper dosing technique and to use rescue medication if 
asthma symptoms arise during the study.  
During the active treatment period of the study, subjects will be instructed to administer one 
inhalation of the study product with proper technique twice daily (approximately 12 hours apart) 
for 28 ± 2 days. After each inhalation, subjects should rinse his/her mouth with water without 
swallowing to reduce the risk of oropharyngeal candidiasis. Subjects will self-administer the 
morning dose of study product under supervision of the Independent Dispenser at Visit 2. 
Subjects should administer the last dose on the evening before their final visit. Subjects will be 
instructed not to dose within approximately 
 before any study visit.   
Identity of Investigational Product 
The following products will be used in the study: 
• 
Test: Fluticasone Propionate and Salmeterol Inhalation Powder, 100 mcg/50 mcg (Supplied 
by Teva Pharmaceuticals Ireland) 
• 
Reference: ADVAIR DISKUS® 100/50 (fluticasone propionate and salmeterol) Inhalation 
Powder (GlaxoSmithKline) 
• 
Placebo: Fluticasone Propionate and Salmeterol Inhalation Powder Placebo (FS DPI 
Placebo; Supplied by Teva Pharmaceuticals Ireland) 
10.3.2 Study Product Shipment, Storage, and Retention 
The study product will be shipped to each Investigator’s site from the Drug Depot. One individual 
study product inhaler (i.e., Test, Reference or Placebo) will be packaged, as a subject kit. For 
Placebo Run-In, each subject will be assigned to one subject kit.
 
. Each kit will have a 
unique six-digit randomization number. The study product will be blinded, packaged and 
delivered to the site in bulk. The Principal Investigator at each site is responsible for ensuring that 
all study products are stored in a locked, secure location, with access limited to the Investigator 
and his/her designee(s). An accurate inventory of the study medication will be maintained in 
accordance with federal regulations.  
For every study product shipment received at the investigative site, the Investigator (or designee) 
will randomly select study product kits for retention. The selection process will ensure a 
sufficient amount of retention samples are retained as per Sponsor requirement. These kits will be 
affixed with a label by independent dispenser/investigator to be clearly marked as retention 
samples and are not to be used for dispensing to study subjects. The selected retention samples 
will be retained at a third party storage facility 
 under FDA 
regulations as study retention samples.21 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
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At the investigative site all study product will be stored at controlled room temperature between 
20° and 25°C (68° and 77°F) with excursions permitted from 15° to 30°C (59° and 86°F), away 
from direct heat or sunlight in a secure, dry place with access by authorized individuals only. Any 
excursions from the permitted range of 15–30ºC (59º–86ºF) will require prompt notification to 
, and thereafter 
 will notify the Sponsor Designee. The Investigator will be 
responsible for maintaining accurate records of drug receipt, dispensing, and return. At the end of 
the study, all partially used and unused study products will be returned to the Sponsor. 
Once the site has been notified that they may do so, all unused study product and empty or 
partially used study product, other than that randomly selected for retention samples will be 
returned to the Sponsor or designee. It is important that retention samples not be returned to 
, the Sponsor, or the packaging company during or at the end of the study. Sufficient study 
product must be retained for all the sites participating in the study, at the designated third party 
storage facility, to meet the sample retention requirements as outlined by the FDA.21 
An Investigational Product Plan will be provided to clarify study product details and will take 
precedence over what is outlined in the protocol, if differences are noted. 
10.3.3 Method of Assigning Subjects to Treatment Groups 
Enrollment 
At Visit 1, using 
 (IWRS), all subjects 
who have read and signed the ICF will be assigned a Subject number. Eligible subjects will be 
dispensed a blinded Placebo inhaler for the placebo run-in period from the bulk supply provided 
to each site. Subject numbers will consist of a three-digit site number and a three-digit individual 
subject number. The three-digit subject numbers will be assigned automatically in ascending 
order beginning with 101 at each study site. 
Randomization 
The study product will be packaged and blinded by the Drug Depot. Randomization will be pre-
planned according to a computer-generated randomization schedule using 
 
 The system will also assign study product kit 
numbers (based on the randomization schedule created by an independent biostatistician). The 
study product kit number is the identifying number listed on the study product dispensed to 
eligible patients. The study product kit number is a 
.  
At the end of the study, after all the clinical data have been entered and the study database has 
been locked, a copy of the randomization schedule will be sent to the statistician. 
10.3.4 Study Blind 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019 
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1. Informed Consent: Subjects who are willing to comply with study procedures will read, 
understand, and sign an IRB-approved ICF. Subjects who are considered minors in the state 
in which the study is being conducted will read and sign the assent to participate form, and 
their parent or legal guardian must sign the ICF. 
2. Medical History and Baseline Demographics: Collect the subject’s medical history and 
demographic information. 
3. Concomitant Medications: Review the subject’s use of concomitant medication within the 
last
 (confirming washouts). 
4. Dispense Rescue Medication: An inhaler (to be later used at Visit 1b for the reversibility 
assessment, if applicable) will be dispensed to be used as rescue medication during the wash-
out period.  
10.4.3 Visit 1b: Screening (Day -21 to Day -14) 
The following tests, evaluations, and procedures will be performed and documented for each 
subject: 
1. Concomitant Medications: Review the subject’s use of concomitant medication within the 
last 
 (confirming washouts). 
2. Physical Exam: Perform an examination that includes at a minimum general appearance, 
head, ear, eyes, nose, and throat (HEENT), cardiovascular, lungs and thorax, neurological, 
and musculoskeletal. 
3. Height and Weight: Height and weight will be collected. 
4. Pregnancy Test: All females of childbearing potential will have a serum pregnancy test 
performed. The test must be negative for the subject to be eligible for randomization in the 
study. Inconclusive pregnancy tests should be repeated and confirmed negative before 
continued study participation. 
 
 
.   
5. Saliva alcohol test and urine drug/cotinine test: All subjects will have a saliva alcohol test 
and 
a 
urine 
drug 
(amphetamines 
[stimulants], 
MDMA 
[ecstasy], 
barbiturates, 
benzodiazepines, cannabinoids/tetrahydrocannabinol (THC)/marijuana, cocaine, opiates) and 
cotinine test performed. All tests must be negative for the subject to be eligible for enrollment 
in the study. 
 
 
 
6. Clinical Laboratory Testing: All subjects will have a blood sample taken for hematology 
and clinical chemistry testing and a urine sample for urinalysis.
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
  Page 44 of 72 
 
 
 
. 
7. 12-Lead ECG: Subjects will undergo a 12-lead ECG to screen for significant abnormal 
cardiothoracic findings. 
8. Spirometry: FEV1, FVC and FEV1/FVC ratio [(FEV1/FVC) x 100] will be recorded. A pre-
treatment evaluation will be done. Pre-bronchodilator FEV1 at Screening must be 40%-85% 
of predicted value. Another spirometry assessment will be performed within 30 minutes after 
albuterol administration. 
 
 
 
9. Vital Signs: Blood pressure (BP), heart rate (HR), respiratory rate (RR) and temperature will 
be collected before and after reversibility assessment. 
10. Reversibility Assessment: After qualifying FEV1 (40%-85% of predicted value) is obtained; 
puffs 
 mcg; 90 mcg per puff) of albuterol will be administered to the subject through 
an inhaler. The subject must demonstrate at least 15% reversibility of FEV1 within 
30 minutes after albuterol administration to qualify for inclusion in the study. 
 
 
 
 
11. Pulse Oximetry: Pulse oximetry will be measured during the spirometry testing. 
12. Inclusion/Exclusion Criteria Review: Review and confirm that subject fulfills all 
inclusion/exclusion criteria for study eligibility. 
13. Dispense Rescue Medication, Placebo Product, and Instructions 
 
 The inhaler used for the reversibility assessment will be re-dispensed to eligible 
subjects to be used as rescue medication. A new inhaler may be dispensed if needed. Subjects 
will also receive one inhaler of Placebo product with instructions for dose administration. 
14. Dosing (
 After pre-dose spirometry assessments are complete, 
subjects will self-administer study treatment (one puff from the inhaler) with the Independent 
Dispenser observing. The time of actuation will be recorded, as well as the adequacy of 
inhaler technique. 
15. Adverse Events: Subjects will be questioned about any AEs that occurred during the visit. 
16. Provide Diary (if repeat visit is not needed): Subjects will receive a diary to record dosing 
dates and times, AEs, concomitant medications, and rescue medication use. 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
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CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
 Page 46 of 72 
 
 
10.4.5 Visit 2: Randomization (Day 1) 
Subjects, who at Visit 2 no longer meet the inclusion/exclusion or randomization 
inclusion/exclusion criteria, or who in the Investigator’s opinion are not suitable for continued 
participation will not be randomized and will be discontinued from the study after completion of 
appropriate Visit 2 procedures.  
1. Collect Study Product: Placebo product inhalers will be collected. 
2. Vital Signs: BP, HR, RR, and temperature will be collected. 
3. Urine Pregnancy Test: All females of childbearing potential will have a urine pregnancy test 
performed. The test must be negative for the subject to be eligible for randomization in the 
study. 
4. 12-Lead ECG: Subjects may undergo a 12-lead ECG to screen for significant abnormal 
cardiothoracic findings at the discretion of the Investigator. 
5. Collect and Review Diary: Diaries will be collected and reviewed for compliance with 
protocol requirements. 
6. Concomitant Medications: Subjects will be questioned about any changes in concomitant 
medication use since the last visit. The subjects will also be questioned regarding washout of 
drugs prior to lung function testing. 
7. Adverse Events: Subjects will be questioned about AEs since the last visit. 
8. Spirometry: Serial spirometry will be performed over 12 hours. FEV1 should be measured 
approximately 
 before 
the first dose of study product and approximately 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 12 hours 
post-dose. At least two of the pre-dose FEV1 measurements must meet ATS criteria for 
quality to be acceptable. The average of the acceptable FEV1 measurements will be used to 
determine the baseline FEV1, which must be ≥ 40% and ≤ 85% of predicted normal value and 
may not vary by more than
 from the qualifying Screening visit FEV1 value. 
9. Placebo Compliance: During the Run-in Period, should be at leas
 
10. Pulse Oximetry: Pulse oximetry will be measured during the spirometry testing. 
11. Inclusion/Exclusion Criteria Review: Review and confirm that subject continues to fulfill 
all inclusion/exclusion criteria for study eligibility. 
12. Randomization Inclusion/Exclusion Criteria Review: Review and confirm that subject 
fulfills all randomization inclusion/exclusion criteria for study eligibility. 
13. Dispense Study Product and Instructions: 
 
. A review of 
inhaler dosing technique will be performed. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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14. Dispense Rescue Medication: The inhaler used for the reversibility assessment will be 
dispensed to eligible patients to be used as rescue medication, if needed. 
15. Dosing: After pre-dose spirometry assessments are complete, subjects will self-administer 
study treatment (one puff from the inhaler) with the 
 
 The 
time of actuation will be recorded, as well as the adequacy of inhaler technique.  
16. Provide Diary: Subjects will receive a diary to record dosing dates and times, AEs, 
concomitant medications, and rescue medication use. 
17. Schedule Visit 3.  Remind the subjects of the requirements to follow before coming to Visit 
3. 
10.4.6 Visit 3: End of Study (Day 29 ± 2)/Early Termination  
1. Vital Signs: BP, HR, RR, and temperature will be collected. 
2. Physical Exam: Perform an examination of head, ear, eyes, nose, throat, and lungs. 
3. Urine Pregnancy Test: All females of childbearing potential will have a urine pregnancy test 
performed. 
4. Clinical Laboratory Testing: All subjects will have a blood sample taken for hematology 
and clinical chemistry testing and a urine sample for urinalysis. 
5. 12-Lead ECG: Subjects will undergo a 12-lead ECG to screen for significant changes in 
cardiothoracic findings. 
6. Collect and Review Diary: Diaries will be collected and reviewed for compliance with 
protocol requirements. 
7. Concomitant Medications: Subjects will be questioned about any changes in concomitant 
medication use since the last visit. The subjects will also be questioned regarding washout of 
drugs prior to lung function testing. 
8. Adverse Events: Subjects will be questioned about AEs since the last visit. 
9. Spirometry: The final 
 FEV1 measurements will be collected. The first FEV1 should 
occur at the same time of day as the 
pre-dose measurement, respectively, collected 
at Visit 2 (± 2 hours). The remaining FEV1 measurements should be collected at 
 
 following the preceding measurement. 
 
   
10. Pulse Oximetry: Pulse oximetry will be measured during the spirometry testing. 
11. Collect Study Product/Rescue Medication: All study product and rescue medication 
inhalers will be collected. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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10.5 Study Procedures 
10.5.1 Informed Consent 
At Visit 1, before performing any study-related procedures all subjects will read and sign an IRB-
approved ICF. In addition, subjects who are considered minors in the state the study is being 
conducted (< 18 years of age in most states) must have a signed parental/guardian ICF, indicating 
approval to participate, as well as a signed assent to participate form. No subject will be entered 
into the study without reading, understanding and signing an ICF/assent. A copy of the ICF will 
be provided to the subject. If the ICF/assent is required in any language besides English, 
translation will be performed by a certified translator and then approved by the IRB. 
10.5.2 Medical History and Baseline Demographics 
At Visit 1, subjects will be questioned about medical history, including smoking history, acute 
and chronic medical history, and medical history relevant to their asthma. 
Each subject will also be required to provide basic demographic information (i.e., date of birth, 
sex, ethnicity, and race). 
10.5.3 Vital Signs 
The subject’s vital signs will be recorded (BP, HR, RR, and temperature) at each clinic visit. 
10.5.4 Height and Weight 
Height and weight will be collected at Visit 1. 
10.5.5 Physical Exam 
At Visits 1 and 3, the Investigator will perform a general physical exam for each qualified subject 
and any significant findings will be noted. The physical exam at a minimum must include a head, 
ear, eyes, nose, lungs, and throat examination. 
10.5.6 Clinical Laboratory Testing  
As part of the Screening procedures (Visit 1) and at Visit 3 (or early termination for randomized 
subjects only), subjects will have a blood sample taken for hematology and clinical chemistry 
testing and a urine sample for urinalysis. Any clinically significant findings will be noted. 
 
 
 
 
10.5.7 Pregnancy Testing 
A serum pregnancy test on women of childbearing potential will be performed at Screening (Visit 
1). Urine pregnancy tests on women of childbearing potential will be performed the repeat 
screening visit, if applicable, and at Visits 2 and 3. The test(s) must be negative for the subject to 
be eligible for inclusion in the study. 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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 Inconclusive tests must be repeated and confirmed negative prior to 
continuation in the study. If the subject is of non-childbearing potential, the source document 
must list the reason why she is of non-childbearing potential. 
Any subject who becomes pregnant during the study must be discontinued and End of Study 
procedures completed. The outcome of the pregnancy will be followed by the Investigator to birth 
or early termination as appropriate. The pregnancy will be reported as an AE (see Section 12.2.8). 
10.5.8 12-Lead ECG 
Subjects will undergo a 12-lead ECG at Screening and End of Study. An ECG may be performed 
at Visit 2 at the discretion of the Investigator. Any clinically significant findings will be noted. 
10.5.9 Concomitant Medication Use 
At Visit 1, subjects will be questioned about current and concomitant medication use over the 
previous 
. At all subsequent visits, subjects will be questioned about ongoing or new 
concomitant medication use. 
10.5.10 Adverse Events 
At the end of Visit 1, subjects will be questioned about any AEs that occurred during the visit. At 
Visits 2 and 3subjects will be questioned regarding any changes in their medical status since their 
previous visit. Any significant changes observed after ICF/assent signing will be reported as AEs. 
10.5.11 Spirometry Testing 
 
FVC 
and FEV1/FVC ratio [(FEV1/FVC) x 100] will also be recorded along with FEV1 measurements at 
each visit. Pre-bronchodilator FEV1 at Screening must be 40%-85% of predicted value. 
 
. Once qualifying 
FEV1 is obtained, albuterol inhalation 
, pressurized metered-dose inhaler) will be 
administered and another spirometry assessment will be performed. 
Serial pulmonary function tests will be performed over 12 hours at Visit 2. FEV1 should be 
measured approximately
 
before the first dose of study product  and approximately 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 12 
hours post-dose. At least two of the pre-dose FEV1 measurements must meet ATS criteria for 
quality to be acceptable.  The average of the acceptable FEV1 measurements will be used to 
determine the baseline FEV1, which must be ≥ 40% and ≤ 85% of predicted normal value at Visit 
2 for the subject to be eligible for inclusion in the study. 
The final
 FEV1 measurements will be collected at Visit 3. The first FEV1 should occur at 
the same time of day as the 
 pre-dose measurements, respectively, collected at Visit 2 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
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(± 2 hours). The remaining FEV1 measurements should be collected at 
 
following the preceding measurement. 
 
   
10.5.12 Reversibility Assessment 
Once qualifying FEV1 is obtained at Screening, 
 puffs (
 mcg; 90 mcg per puff, pressurized 
metered-dose inhaler) of albuterol inhalation will be administered and spirometry will be 
performed. The subject must demonstrate at least 15% reversibility of FEV1 within 30 minutes 
after albuterol administration to qualify for inclusion in the study. 
 
 
 
 
 
 
10.5.13 Pulse Oximetry 
Pulse oximetry will be measured during spirometry assessments. 
10.5.14 Peak Flow Measurements 
Subjects will measure twice-daily (morning and evening) peak expiratory flow (PEF; air flow in 
and out of the lungs) using a home spirometer/eDiary device. The subject will be dispensed the 
device upon entrance into the placebo run-in period.  The same device will be used for the subject 
throughout their participation in the study.  Subjects will be trained on the use of the device and 
PEF procedures at the Screening visit.  At home PEF measurements are collected for interim 
safety monitoring only, and will not be included in statistical analyses. 
10.5.15 Inclusion/Exclusion Criteria Review 
At Visits 1 and 2, inclusion/exclusion criteria will be reviewed to ensure subjects’ eligibility for 
participation in the study. 
10.5.16 Dispense Rescue Medication, Placebo Product, and Instructions 
At Visit 1 and Visit 2 (if needed), eligible subjects will be dispensed albuterol to be used as a 
rescue medication during the study. Subjects will be dispensed the same albuterol inhaler used for 
the reversibility assessment. Prior to use for reversibility assessments, the rescue medication 
inhaler should be re-primed as appropriate, in an area away from subjects.  At Visit 1, subjects 
will also receive one inhaler of Placebo product with instructions for dose administration. 
Subjects must administer at least 
of the required doses to be eligible for randomization. 
10.5.17 Dispense Study Product and Instructions 
 will dispense randomized study product to eligible subjects at Visit 2, 
along with a set of dosing instructions. A review of inhaler dosing technique will be performed. 
The subjects will be reminded about the blinding requirements of this study. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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10.5.18 Dosing 
Subjects will dose at the clinical site at Visits 1, and 2. The first dose of Placebo product will be 
administered at Visit 1 after completion of spirometry and reversibility assessments. The first 
dose of randomized study product will be administered at Visit 2 after completion of pre-dose 
spirometry assessments.   
10.5.19 Collect Study Product/Rescue Medications 
Placebo product inhalers will be collected at Visit 2. Study product inhalers will be collected at 
Visit 3. Rescue medications will be collected at Visit 3 or any other visit where an additional 
inhaler was dispensed. 
10.5.20 Provide, Review, and Collect Diary 
Subjects will be provided with diaries and trained on their use (eDiary 
 
) including instructions to record dosing dates and times, AEs, concomitant medications, 
and rescue medication use throughout the study. The diaries will be reviewed at each visit by the 
study staff and completed diaries will be collected at the end of the study.  
 
   
10.6 Adverse Events 
Subjects will be encouraged to report signs, symptoms, and any changes in health to the clinic staff. 
Severity of each AE will be determined based on observation and questioning of the subject. The 
Investigator will judge the severity and relationship of the event to the study products. 
10.6.1 Adverse Event Definition 
An AE is any untoward medical occurrence in a subject, regardless of whether it has a causal 
relationship with this treatment. 
In this study, any AE occurring after the subject has signed the ICF/assent until the end of follow-
up period should be recorded and reported as an AE. 
An AE can, therefore, be any unfavorable and unintended physical sign, symptom, or laboratory 
parameter that develops or worsens in severity during the course of this study, or significant 
worsening of the disease under study or of any concurrent disease, whether or not considered 
related to the study product. A new condition or the worsening of a pre-existing condition will be 
considered an AE. Stable chronic conditions (such as arthritis) that are present before study entry 
and do not worsen during this study will not be considered AEs. 
Accordingly, an AE can include any of the following: 
• 
intercurrent illnesses 
• 
physical injuries 
• 
events possibly related to concomitant medication 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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• 
significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions drug interactions 
• 
events occurring during diagnostic procedures or during any washout phase of this study 
• 
laboratory or diagnostic test abnormalities that result in the withdrawal of the subject 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event (SAE), or require medical treatment or further diagnostic work up, or are 
considered by the Investigator to be clinically significant 
 
 
 
• 
A treatment-emergent AE is any AE that occurs after initiation of study product, or any 
event already present that worsens in either intensity or frequency following exposure to 
study product. 
10.6.2 Serious Adverse Events 
An SAE is an AE, regardless of the relationship to study product, and at any dose, that results in 
any of the following outcomes or actions: 
• 
Death 
• 
A life-threatening AE (i.e., the subject was at immediate risk of death from the event as it 
occurred; does not include an event that, had it occurred in a more severe form, might 
have caused death) 
• 
Inpatient hospitalization or prolongation of existing hospitalization means that hospital 
inpatient admission and/or prolongation of hospital stay were required for treatment of an 
AE, or that they occurred as a consequence of the event. Hospitalizations scheduled prior 
to study entry will not be considered SAEs, unless there was worsening of the pre-
existing condition during the subject’s participation in this study 
• 
Persistent or significant disability or incapacity (refers to a substantial disruption of one’s 
ability to conduct normal life functions) 
• 
A congenital anomaly/birth defect 
• 
An important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the subject and may require medical intervention to 
prevent one of the outcomes listed in this definition. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or the development of drug 
dependency or drug abuse. Note: Any suspected transmission of an infectious agent via a 
medicinal product is considered an important medical event. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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An AE that does not meet any of the criteria for seriousness listed above will be regarded as a 
non-serious AE. 
All occurrences of possible drug induced liver injury that meets Hy’s law criteria, defined as all 
of the below, must be reported by the investigator to the sponsor as a serious adverse event: 
• 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation of > 3x 
the upper limit of normal (ULN) 
• 
total bilirubin elevation of > 2x ULN 
• 
absence of initial findings of cholestasis (i.e., no substantial increase of alkaline 
phosphatase [ALP]) 
10.6.3 Other Significant Adverse Events 
When tested, marked haematological and other laboratory abnormalities (other than those 
meeting the definition of serious) and any events that led to an intervention, including withdrawal 
of test drug/investigational product treatment, dose reduction, or significant additional 
concomitant therapy, other than those reported as SAEs should be collected in the electronic case 
report form (eCRF) and summarized in the clinical study report. 
10.6.4 Severity 
The severity of each AE must be recorded as one of the choices on the following scales: 
• 
Mild: No limitation of usual activities 
• 
Moderate: Some limitation of usual activities 
• 
Severe: Inability to carry out usual activities 
10.6.5 Relationship of an Adverse Event to the Study Drug 
Adverse events will be assessed for the relationship to the study product (causality) according to 
the following scale: 
TERM 
DEFINITION 
CLARIFICATION 
No Reasonable 
Possibility (not 
related) 
This category applies to those AEs 
which, after careful consideration, 
are clearly due to extraneous 
causes (disease, environment, etc.) 
or to those AEs, which after 
careful medical consideration at 
the time they are evaluated, are 
judged to be unrelated to the test 
drug. 
An adverse experience may be considered 
No Reasonable Possibility if it is clearly due to 
extraneous causes or when (must have two): 
It does not follow a reasonable temporal sequence 
from the administration of the test drug. 
It could readily have been produced by the subject's 
clinical state, environmental or toxic factors, or 
other modes of therapy administered to the subject. 
It does not follow a known pattern of response to 
the test drug. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019 
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TERM 
DEFINITION 
CLARIFICATION 
It does not reappear or worsen when the drug is re-
administered.  
Reasonable 
Possibility 
(related) 
This category applies to those AE 
for which, after careful medical 
consideration at the time they are 
evaluated, a connection with the 
test drug administration cannot be 
ruled out with certainty or felt 
with a high degree of certainty to 
be related to the test drug. 
An adverse experience may be considered 
Reasonable Possibility related if or when (at least 
two of the following): 
It follows a reasonable temporal sequence from 
administration of the drug. 
It could not be reasonably explained by the known 
characteristics of the subject's clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the subject. 
It disappears or decreases on cessation or reduction 
in dose. There are important exceptions when an 
AE does not disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists. 
It follows a known pattern of response to the test 
drug. 
10.6.6 Expectedness 
An AE that is not included in the AE section of the relevant Safety Information Reference by its 
specificity, severity, outcome, or frequency is considered an unexpected AE. 
The Reference safety information for this study, ADVAIR DISKUS® (fluticasone propionate and 
salmeterol inhalation powder) Product Insert, to be used as reference for safety information can 
be found in Appendix B. 
The Sponsor’s Pharmacovigilance Department will determine the expectedness for all SAEs. 
Neither the contract research organization (CRO) nor the Investigators will determine the 
expectedness. 
10.6.7 Recording and Reporting of Adverse Events 
In this study, safety will be assessed by qualified study personnel by evaluating reported AEs, 
ECGs, physical examination, pulse oximetry, vital signs measurements, and use of concomitant 
medication. 
For AE recording, the study period is defined for each subject as that time period from signature 
of the ICF through the end of the study (including any follow-up period) (see Sections 10.4.1 and 
12.2.12). 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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All AEs that occur during the defined study period must be recorded on the source 
documentation, regardless of the severity of the event or judged relationship to the study product. 
For SAEs, the SAE form must also be completed and the SAE must be reported immediately (see 
Section 10.6.8). The Investigator does not need to actively monitor subjects for AEs once the 
study has ended. However, SAEs occurring in a subject after the treatment of that subject has 
ended should be reported to the Sponsor if the Investigator becomes aware of them. 
At each contact with the subject, the Investigator or designee must question the subject about AEs 
by asking an open ended question such as, “Have you had any unusual symptoms or medical 
problems since the last visit? If yes, please describe.” All reported or observed signs and 
symptoms will be recorded individually, except when considered manifestations of a medical 
condition or disease state. A precise diagnosis will be recorded whenever possible. When such a 
diagnosis is made, all related signs, symptoms, and any test findings may be recorded collectively 
as a single diagnosis on the eCRF and, if it is an SAE, on the SAE form. 
The onset and end dates and times, action taken regarding study product, treatment administered, 
and outcome for each AE must be recorded on the source documentation. 
The relationship of each AE to study product treatment and study procedures, and the severity 
and seriousness of each AE, as judged by the Investigator, must be recorded as described above. 
The clinical course of each AE will be monitored at suitable intervals until resolved or stabilized 
or returned to baseline, until the subject is referred for continued care to a health care professional 
or until a determination of a cause unrelated to the study product or study procedure is made. 
Adverse events will be coded according to Medical Dictionary for Regulatory Activities 
(MedDRA) Version 21.1 or higher and reported with respect to severity, duration, relationship to 
study medication(s), seriousness, and action taken. 
10.6.8 Reporting of Serious Adverse Events 
To satisfy regulatory requirements, all SAEs (as described in Section 10.6.2) that occur during the 
study period (including any protocol-defined follow-up period), regardless of judged relationship 
to treatment with the study product, must be reported to the CRO by the Investigator. The event 
must be reported within 24 hours of when the Investigator learns about it. Completing the SAE 
form and reporting the event must not be delayed, even if not all the information is available. 
A Safety Plan will be provided to clarify details of collecting, recording and reporting of adverse 
events and other safety assessments, as deemed necessary, and will take precedence over what is 
outlined in the protocol, if differences are noted. 
PLEASE NOTE THAT EMAIL IS THE PREFERRED MEANS OF COMMUNICATION. 
The CRO should inform the Sponsor's Pharmacovigilance Department if the whole study is 
discontinued early because of safety reasons. 




CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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Email: 
 
These SAE reports must contain the following information, preferably using the template 
provided by the Sponsor: 
A. Study name/number 
B. Study Product 
C. Investigator details (name, site information, phone) 
D. Subject Number 
E. Subject Initials when appropriate 
F. Subject Demographics 
G. Relevant Medical History and Concomitant Disease 
H. Suspect Medication Information 
I. Clinical Event (i.e., Drug-Event Information and Case Narrative) 
1) Description (Seriousness Criteria, Intensity/Severity, Outcome) 
2) Date of onset and end date (if available) 
3) Treatment (drug, dose, dosage form, dechallenge/rechallenge) 
4) AE Relationship to study product 
5) Action taken regarding study product in direct relationship to the AE 
J. If the AE was Fatal: 
1) Date and cause of death (whether or not the death was related to study drug) 
2) Autopsy findings (if available) 
K. Concomitant Medication Information 
L. Relevant Laboratory/Diagnostic Information 
The SAE form and supportive documents should be filled/written in English. The SAE form 
completion and reporting must not be delayed even if all of the information is not available at the 
time of the initial contact. Additional information (follow-up) about any SAE unavailable at the 
initial reporting should be forwarded within 24 hours of the information becoming available to 
the same address as the initial report. Subjects who have had an SAE during the treatment period 
must be followed clinically until all parameters (including laboratory) have either returned to 
normal or have stabilized or are otherwise explained. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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Each report of an SAE will be reviewed and evaluated by the Investigator and the Sponsor's 
Pharmacovigilance Department to assess the nature of the event and the relationship of the event 
to the study product, study procedures, and to underlying disease. 
10.6.9 Submission of SAEs 
Any SAE will be reported to competent authority and ethics committee according to the country 
specific requirements and the responsibilities defined in Section 10.6.8. All AEs will be reported 
in the clinical study report with the complete information named above according to the 
requirements of the Note for Guidance on Structure and Content of Clinical Study Reports 
(CPMP/ICH/137/95). 
11.0 STATISTICAL METHODS 
11.1 Statistical Plan 
A statistical analysis plan (SAP), detailing the study populations, intended statistical analysis, and 
reporting of the study data, will be prepared as a separate document and finalized before database 
lock. Any deviation from the original statistical plan will be described and justified in the final report, 
as appropriate. The procedure for accounting for missing, unused and spurious data will be included 
in the SAP. The SAP will take precedence over what is outlined in the protocol, if differences are 
noted. 
All statistical analysis will be conducted using SAS®, Version 9.4 or higher. Datasets will be prepared 
using headings from Clinical Data Standards Interchange Consortium (CDISC) Study Data 
Tabulation Model implementation for human clinical trials and Analysis Dataset Model. 
11.2 Determination of Sample Size 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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11.3 Study Populations 
11.3.1 PP Population 
11.3.2 mITT Population 
11.3.3 Safety Populations 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
71736001  03Jan2019  
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11.4 Baseline Comparability 
The following subject demographic characteristics will be summarized separately in the PP, mITT, 
and SPR populations. 
• 
Age (years) 
• 
Sex (Male/Female) 
• 
Ethnicity (Hispanic/non-Hispanic) 
• 
Race (White, Black/African American, Native Hawaiian or Other Pacific Islander, Asian, 
American Indian or Alaska Native) 
• 
Number of years subject has suffered from symptoms caused by asthma 
• 
Baseline FEV1 
Summary tables by treatment group will be presented. Continuous variables will be summarized 
using descriptive statistics (number of observations, median, minimum, maximum, mean, and SD). 
Categorical variables will be summarized using frequencies and percentage. Baseline treatment 
comparisons will be presented using Chi-Square or Cochran-Mantel-Haenszel tests for the categorical 
variables, and Analysis of Variance (ANOVA) for the continuous variables. 
All data will be listed by treatment and subject. 
11.5 Efficacy Endpoints 
The two co-primary efficacy endpoints are (1) the baseline-adjusted area under the serial FEV1-time 
curve calculated from time zero to 12 hours (AUC0-12h) on Day 1 of treatment (Visit 2), and (2) the 
baseline-adjusted pre-dose FEV1 measured in the morning of Day 29 ± 2 (Visit 3), after the last dose 
in the prior evening. 
 
 
  
11.6 Primary Endpoint Analyses 
The Baseline FEV1 will be subtracted from post-dose FEV1 values to obtain the baseline-corrected 
values. Baseline-adjusted area under the serial FEV1-time curve from time zero to 12 hours (AUC0-
12h) will be calculated by the linear trapezoidal method.. The statistical analyses will involve Analysis 
of Covariance (ANCOVA) with terms for 
 as fixed effects and using 
 
as a covariate in the model. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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Therapeutic Equivalence 
Therapeutic equivalence will be evaluated for the primary endpoint in each PP population. Under the 
assumptions of normally distributed data, the adjusted 90% confidence interval will be calculated for 
the Test/Reference ratio of the mean baseline-adjusted AUC0-12h on Day 1 
 and 
for the Test/Reference ratio of the mean baseline-adjusted morning pre-dose FEV1 on Day 29 ± 2 
 using an iterative procedure similar to Fieller’s method. The mean baseline 
value for use in the iterative procedure will be determined from the Baseline FEV1 of all subjects 
receiving active treatment in the PP population, without regard to the treatment received. If the 
adjusted 90% confidence intervals for the least-squares mean Test/Reference ratios are within 80.00-
125.00% for both co-primary endpoints, then therapeutic equivalence of the Test to Reference 
product will be considered to have been demonstrated. 
Superiority to Placebo 
The superiority of the Test and Reference products over Placebo is concluded if the values for mean 
baseline-adjusted AUC0-12h and the mean baseline-adjusted morning pre-dose FEV1 on Day 29 ± 2 for 
the active treatments are statistically superior to those respective values of the Placebo at the 5% 
significance level (p < 0.05, two-sided). The superiority of Test and Reference treatments over the 
Placebo will be evaluated in the same ANCOVA model for Test vs. Placebo and Reference vs. 
Placebo. 
. 
11.7 Safety Analysis 
All study subjects who were randomized and used the study product on at least one occasion will be 
included in the comparative safety analysis. Adverse events will be classified using standard Medical 
Dictionary for Regulatory Activities (MedDRA) terminology Version 21.1 or higher and presented by 
treatment group. Summary tables listing the type, date of onset, date of resolution, incidence, severity, 
outcome, action taken, and Investigator’s opinion of relationship to the study product will be 
presented by treatment group for AEs reported after randomization. 
Signs and symptoms of asthma will not be considered AEs, unless in the Investigator’s opinion, they 
have increased in frequency and/or severity to such an extent that the Investigator/subject considers 
that it is in the subject’s best interest to be dropped from continued participation in the study and 
given alternative therapy for their condition.  
Concomitant medication used during the study will be tabulated by treatment by subject. 
12.0 REGULATORY OBLIGATIONS 
12.1 Institutional Review Board 
The study protocol, ICF, product label (as applicable) and any specific advertising will be submitted 
to, and approved by, an IRB before the start of the study. A form must be signed by the chairman or 
designee of the IRB noting the approvals. This notification of the board's approval along with a 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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description by profession and gender of the board's composition will be provided to the Sponsor 
and/or Sponsor Representative. 
12.2 Study Documentation 
This study will be conducted in compliance with the protocol; Good Clinical Practices and all 
applicable regulations, including the Federal Food, Drug, and Cosmetics Act, United States (US) 
applicable Code of Federal Regulations (title 21), parts 50, 56, 312, 320, and any IRB requirements 
relative to clinical studies; and the Declaration of Helsinki, June 1964, as modified by the 64th World 
Medical Association General Assembly, October 2013.23-26 The Investigator will permit trial-related 
monitoring, audits, IRB review and regulatory inspections providing direct access to source 
data/documents. 
12.2.1 Protocol 
The Investigator indicated on FDA Form 1572 will act as the Principal Investigator at each study 
site. Protocols will be noted as approved by placement of the 
 Representative’s signature 
on the cover page. The Sponsor of the study will also approve the protocol by having a study-
responsible individual sign the protocol cover page. 
12.2.2 Informed Consent 
An ICF that includes all of the relevant elements currently required by FDA and local state 
regulations will be provided to each prospective study subject at Screening, before enrollment 
into the study. In addition, subjects who are considered minors in the state the study is being 
conducted (< 18 years of age in most states) must have a signed parental/guardian ICF, indicating 
approval to participate, as well as a signed assent to participate form. The type and method of 
study, tests to be administered, any potential or possible hazards, and the subject’s right to 
withdraw from the study at any time will be explained to the subjects by the Investigator or 
designee. Once the Investigator or designee is assured that an individual candidate understands 
the implications of participating in this study, the subject will be asked to give consent by signing 
and dating in the appropriate areas of the ICF or assent, as appropriate. The Investigator or 
designee will also sign and date the form, along with a staff member who will sign the ICF as a 
witness to verify that the subject has indeed received information. If any other language is 
required, translation will be performed by a certified translator. A copy of the ICF and/or assent 
will be provided to the subject. 
12.2.3 Protocol and Informed Consent Changes 
Sponsor approved changes to the protocol or the ICFs will be implemented as revisions to the 
original documents and will require additional review and approval by the IRB. Revisions to the 
original protocol will be documented in amendments, incorporated as a preface to the new 
version. Any revision that substantially alters the study design or increases potential risk to the 
subject requires the subject’s consent to continue in the study. The approvals will be processed in 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
71736001  03Jan2019  
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accordance with the established IRB procedures. Copies of all protocol and ICF 
amendments/revisions, along with letters noting IRB approval, will be submitted to the Sponsor. 
12.2.4 Source Documents and Case Report Forms 
All subjects will be identified by initials, date of birth, and a unique subject number. Source 
documents will be used to record all study-related data. Source document entries will be used to 
complete eCRFs. All data and eCRFs will be reviewed, evaluated, and signed by the Investigator, 
as required. 
The original source documents and a copy of the corresponding eCRFs will be retained by the 
Investigator. Subjects who terminate early from the study will have the Visit 3 (end of study) 
source/eCRF completed. 
12.2.5 Drug Accountability 
All study product receipt, inventory, dispensing, dosing, and reconciliation records will be 
maintained in compliance with federal regulations. The study product will be dispensed to 
qualified study subjects according to established procedures. At the end of the study (i.e., at the 
site’s close-out visit) all used and unused study product will be returned to Sponsor or designee. 
12.2.6 Drug Storage 
All study product will be stored at controlled room temperature between 20° and 25°C (68° and 
77°F) with excursions permitted from 15° to 30°C (59° and 86°F), away from direct heat or 
sunlight in a secure, dry place with access by authorized individuals only. Any excursions from 
the permitted range of 15–30ºC (59º–86ºF) will require prompt notification to 
, and 
thereafter 
 will notify the Sponsor Designee. The Investigator will be responsible for 
maintaining accurate records of drug receipt, dispensing, and return. At the end of the study, all 
partially used and unused study products will be returned to Sponsor or designee. 
12.2.7 Retention of Reserve Samples 
For every study product shipment received at the Investigator’s site, the Investigator (or designee) 
will randomly select study product kits for retention. The selection process will ensure a 
sufficient amount of retention samples are retained as per Sponsor requirement. The number of 
each subject kit kept for retention will be noted on the drug accountability form as a retention 
sample, in addition to the retention sample log. These retention samples should be stored under 
the appropriate storage conditions for a minimum of 5 years following the application approval 
or, if not approved, at least 5 years after the completion of the study. Retention samples should 
not be returned to Sponsor/CRO/packaging group at any time. The retention samples will be 
shipped to a third party storage facility: 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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12.2.8 Pregnancies 
If following initiation of study treatment, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study product exposure; the study product will 
be permanently discontinued. The Principal Investigator or designee must immediately notify the 
Medical Monitor of this event. Reporting timelines and 
 contact will be 
consistent with SAE reporting guidelines (see Section 10.6.8 of the protocol), i.e., pregnancies 
will be reported to the 
 within 24 hours to the contacts listed in Section 10.6.8. 
All subjects who become pregnant will be monitored for the outcome of the pregnancy (including 
spontaneous or voluntary termination). If the pregnancy continues to term, the outcome (health of 
the infant up to 8 weeks of age), including details of birth and presence or absence of any birth 
defect, congenital abnormalities, or maternal and newborn complications, will be reported to the 
sponsor. Any complication of pregnancy during the study and any complication of pregnancy that 
the investigator becomes aware of after termination from the study will be reported as an adverse 
event or serious adverse event, as appropriate. 
If the pregnancy does not continue to term, one of the following actions will be taken: 
• 
For a spontaneous abortion, report as a serious adverse event.  
• 
For an elective abortion due to developmental anomalies, report as a serious adverse 
event. 
• 
For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event. 
12.2.9 Reporting Safety Information to the IRB 
The Investigator must promptly report to the Investigator’s IRB all unanticipated problems 
involving risks to subjects. This includes death from any cause and all SAEs occurring during the 
study, regardless of the assessed causality.27 
12.2.10 Record Retention 
All drug accountability records, eCRFs, source data, and related regulatory documents must be 
retained according to 21 CFR 312.62(c) for a period of 2 years following the date the marketing 
application is approved for the drug for the indication for which it is being investigated; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and FDA is notified. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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12.2.11 Study Monitoring and Auditing 
 will be responsible for monitoring the study according to Good Clinical Practice and 
applicable regulations. Monitoring visits are for the purpose of confirming adherence to the 
protocol and to verify complete and accurate data collection. The clinical site will make all 
records associated with the study available to 
 representative during such visits and 
audits. 
Medical advisors and clinical research associates or assistants may request to witness subject 
evaluations occurring as part of this protocol. The study may be subject to audit by the Sponsor, 
Sponsor Representative, or by regulatory authorities. If such an audit occurs, the Investigator 
must agree to allow access to required subject records. By signing this protocol, the Investigator 
grants permission to personnel from the Sponsor, its representatives, and appropriate regulatory 
authorities for on-site monitoring of all appropriate study documentation. 
12.2.12 End of the Trial 
The end of the trial is defined as the time at which the last subject has completed their last visit in 
the study. Upon completion of the study, the study product will no longer be available to the 
subject but the Investigator can, at their discretion, discuss alternative treatments with the subject. 
12.2.13 Clinical Study Report 
At the end of the study a full report per requirements of Sponsor and regulatory authorities will be 
prepared which will include a narrative of the clinical conduct and results of the study, a 
statistical report including a description of the analysis performed, and other documentation as 
may be appropriate. The report will be in electronic format according to the electronic Common 
Technical Document (eCTD) and International Conference on Harmonisation (ICH) formatting 
standards and guidelines.28 Abbreviated New Drug Application summary tables will also be 
generated. Data sets will be provided in SAS® transport (.xpt) format with appropriate description 
(Read Me) files as required by FDA. 
12.2.14 Termination of the Study 
The Sponsor reserves the right to terminate the study at any time for administrative reasons. The 
study may also be terminated by regulatory authorities. An investigator has the right to 
discontinue his/her site’s participation at any time following consultation with the Sponsor. 
Following a decision to discontinue the trial, the investigator will immediately inform both the 
study subjects and the IEC responsible for this trial within 10 working days, stating the reasons 
for discontinuation of the study and, furthermore, advise them in writing of any potential risks to 
the health of study subjects or other persons. It is Sponsor’s responsibility to report the premature 
termination of the study to the regulatory agencies within 15 days providing them with the 
reasons for the trial discontinuation and advising them in writing of any potential risks to the 
health of study subjects or other persons. The CRO may notify the regulatory agency on behalf of 
the Sponsor. 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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13.0 REFERENCES 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
71736001  03Jan2019  
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CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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14.0 APPENDICES 
14.1 APPENDIX A - NAEPP Guidelines for Asthma Severity Classification. National Asthma 
Education and Prevention Program Expert Panel Report 3 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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14.2 APPENDIX B - ADVAIR DISKUS® 100/50 (fluticasone propionate/salmeterol) Inhalation 
Powder Package Insert 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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14.3 APPENDIX C – Clinical Laboratory Testing 
As part of the Screening procedures and at Visit 3 (or early termination for randomized subjects 
only), subjects will have a blood sample taken for hematology and clinical chemistry testing and a 
urine sample for urinalysis. The testing panel should include as a minimum the following tests: 
Hematology 
• 
Hematocrit 
• 
White blood cell count 
• 
Platelets 
• 
Hemoglobin 
• 
Red blood cell count 
• 
Red cell distribution width 
• 
Differential white cell count 
• 
Mean cell volume 
• 
Mean cell hemoglobin 
• 
Mean cell hemoglobin concentration 
Chemistry 
• 
Alkaline phosphatase 
• 
Total bilirubin 
• 
Alanine transaminase 
• 
Creatinine 
• 
Aspartate transaminase 
• 
Glucose 
• 
Blood urea nitrogen 
• 
Bicarbonate 
• 
Calcium  
• 
Potassium 
• 
Sodium 
• 
Total Protein 
• 
Albumin 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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Urinalysis 
• 
Protein 
• 
Glucose 
• 
Specific gravity 
• 
Ketone 
• 
Bilirubin 
• 
pH 
• 
blood 
Clinical Laboratory Testing will be performed at a central laboratory. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Multiple-Dose, Blinded, Placebo-Controlled, Parallel-Design, Multiple-Center, Clinical 
Study to Evaluate the Therapeutic Equivalence of Fluticasone Propionate and Salmeterol Inhalation 
Powder, 100 mcg/50 mcg (Supplied by Teva Pharmaceuticals Ireland) to ADVAIR DISKUS® 100/50 
(fluticasone propionate/salmeterol) Inhalation Powder, (GlaxoSmithKline) in Subjects With Asthma
 
 
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14.4 APPENDIX D- Amendments to the Protocol 
 
Amendment 
Date 
 
1 
12/20/2018 
 
The following revisions were made to the protocol dated 11/13/2018: 
 
   
 
 
 
 
  
 
. 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
STATISTICAL ANALYSIS PLAN                  
Sponsor:
Contract Research Organization:


STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
SAP Final Version Approvals 




STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
List of Abbreviations and Definition of Terms 


STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
TABLE OF CONTENTS


STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001


STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001


STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
1. INTRODUCTION
2. OBJECTIVES
3. OVERALL STUDY DESIGN








STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
Figure 1 Study Schematic




STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
6. STUDY ENDPOINTS
7. STUDY POPULATIONS
Per-Protocol (PP) Populations




STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
Modified Intent-to-Treat (mITT) Population
Safety Populations
8. STATISTICAL ANALYSIS METHODS
p


STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
8.1 Baseline Characteristics
8.1.1 Subject Disposition
8.1.2 Demographic and Other Baseline Characteristics




STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
FEV1 Baseline.
Calculation of FEV1 AUC0-12.
Calculation of Baseline-adjusted Pre-dose FEV1 at End of Treatment.








STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
8.3.2 Vital Signs
8.3.3 Pregnancy Test
8.3.4 Clinical Laboratory Testing 
8.3.5 12-Lead ECG


STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
8.3.6 Physical Exam 
8.4 Multiple Comparisons
8.5 Methods for Handling Missing Data 
8.6 Interim Analyses 
8.7 Changes to the Protocol Defined Statistical Analysis Plan 


STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001


STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
9. TABLE, LISTING AND FIGURE SHELLS
®


STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
Appendix A: Outline of Statistical Analysis Method using SAS PROC GLM


STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001


STATISTICAL ANALYSIS PLAN
Fluticasone Propionate and Salmeterol Inhalation Powder                 Protocol No.  71736001
Appendix B: TABLE AND  LISTING SHELLS