Clinical trial NCT03528577
Conditions: Asthma
Sponsor: Sun Pharmaceutical Industries Limited
Start date: 2018-09-22; Completion date: 2019-08-03
Enrollment: 128 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma

Detailed description:

Arms: arm 1: Albuterol Sulfate Inhalation Aerosol, eq 90 mcg arm 2: PROAIR® HFA (albuterol sulfate) Inhalation Aerosol, eq 90 mcg arm 3: Placebo for Albuterol Sulfate Inhalation Aerosol arm 4: Placebo for Albuterol Sulfate Inhalation Aerosol
Interventions: intervention 1: Zero-dose intervention 2: 90 mcg of PROAIR® HFA intervention 3: 180 mcg of 90 mcg of PROAIR® HFA intervention 4: 90 mcg of albuterol sulfate inhalation aerosol
Intervention descriptions: intervention 1: Treatment A intervention 2: Treatment B intervention 3: Treatment C intervention 4: Treatment D

Protocol documents:
Prot_002.pdf: 
CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 1 of 59 
 
 
1.0 TITLE PAGE 
Drug Product 
Albuterol Sulfate Inhalation Aerosol, eq 90 mcg base 
Population 
Approximately 123 males and non-pregnant females, 18-65 years of age 
inclusive, with stable mild asthma 
Study Design 
A randomized, single-dose, double-blind, double-dummy, four-period, 
four-sequence, four-treatment, placebo and active controlled, comparative, 
multiple-center, crossover-design, bronchoprovocation bioequivalence 
study with pharmacodynamic endpoints  
Sponsor 
Sun Pharmaceuticals Industries Limited 
Protocol Number 
CLR_17_08 
 
 
Protocol Date 
04/05/2018 
 
 
 
 
 
 
 
 
 
 
 
This document is a confidential communication of 
Receipt of 
this document constitutes an agreement by the recipient that no unpublished information contained herein 
will be disclosed without 
 written approval. 
NIIRB 
April 17, 2018 
APPROVED 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
 Page 2 of 59 
 
 
2.0 KEY STUDY PERSONNEL AND FACILITIES 
Sponsor: 
 
Sun Pharmaceuticals Industries Limited 
Formulation Development Department  
Tandalja, Baroda 
Gujarat, 390020, India 
 
CRO: 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRO Representative: 
 
 
 
 
 
 
 
 
Medical Monitor: 
 
 
 
 
 
 
 
 
Biostatistician: 
 
 
 
 
 
 
 




CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 4 of 59 
 
 
PRINCIPAL INVESTIGATOR’S SIGNATURE 
 
 
 
I _______________________________________, agree to conduct protocol CLR_17_08 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 (Sun Pharmaceuticals Industries 
Limited) or 
the company managing the study. 
 
 
 
 
 
___________________________________ 
 
 
 __________ 
Principal Investigator 
 
 
 
 
 
 
Date 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 5 of 59 
 
 
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 ......................................................................................................................... 18 
7.0 LIST OF ABBREVIATIONS AND TERMS ....................................................................................... 19 
8.0 INTRODUCTION ................................................................................................................................ 20 
8.1 Disease Being Treated ...................................................................................................................... 20 
8.2 Availability and Efficacy of Already Approved Therapies .............................................................. 20 
8.3 Scientific and Statistical Considerations ........................................................................................... 21 
8.4 Justification for Use of Placebo ........................................................................................................ 21 
8.5 Risks and Benefits ............................................................................................................................. 22 
9.0 STUDY OBJECTIVES ......................................................................................................................... 22 
10.0 INVESTIGATIONAL PLAN ............................................................................................................. 22 
10.1 Study Design and Plan Description ................................................................................................ 22 
10.2 Selection of Study Design ............................................................................................................... 24 
10.3 Selection of Study Population ......................................................................................................... 24 
10.3.1 Inclusion Criteria...................................................................................................................... 24 
10.3.2 Exclusion Criteria .................................................................................................................... 25 
10.3.3 Restrictions During the Study .................................................................................................. 27 
10.3.4 Removal of Subjects from the Study ....................................................................................... 28 
10.4 Treatments....................................................................................................................................... 29 
10.4.1 Treatments Administration ...................................................................................................... 29 
10.4.2 Identity of Investigational Product ........................................................................................... 29 
10.4.3 Study Product Shipment, Storage and Retention ..................................................................... 30 
10.4.4 Method of Assigning Subjects to Treatment Groups ............................................................... 30 
10.4.5 Study Blind .............................................................................................................................. 31 
10.4.6 Compliance .............................................................................................................................. 32 
10.5 Study Conduct ................................................................................................................................. 32 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 6 of 59 
 
 
10.5.1 Visit 1 (Day -14 to Day -1): Screening .................................................................................... 32 
10.5.2 Visit 2: Period 1 Dosing and Clinical Assessment ................................................................... 33 
10.5.3 Visit 3: Period 2 Dosing and Clinical Assessment ................................................................... 34 
10.5.4 Visit 4: Period 3 Dosing and Clinical Assessment ................................................................... 36 
10.5.5 Visit 5: Period 4 Dosing and Clinical Assessment, End of Study............................................ 37 
10.6 Study Procedures ............................................................................................................................ 38 
10.6.1 Informed Consent ..................................................................................................................... 38 
10.6.2 Baseline Demographics ............................................................................................................ 39 
10.6.3 Medical History........................................................................................................................ 39 
10.6.4 Vital Signs ................................................................................................................................ 39 
10.6.5 Height and Weight ................................................................................................................... 39 
10.6.6 Physical Exam .......................................................................................................................... 39 
10.6.7 Urine Pregnancy Test ............................................................................................................... 39 
10.6.8 12-Lead ECG ........................................................................................................................... 39 
10.6.9 Chest X-Ray ............................................................................................................................. 39 
10.6.10 Concomitant Medication Use ................................................................................................. 39 
10.6.11 Adverse Events ...................................................................................................................... 40 
10.6.12 Spirometry Testing ................................................................................................................. 40 
10.6.13 Saline Control Administration ............................................................................................... 40 
10.6.14 Methacholine Challenge ........................................................................................................ 41 
10.6.15 Pulse Oximetry ....................................................................................................................... 41 
10.6.16 Prime and Dispense Study Product and Instructions ............................................................. 41 
10.6.17 Collecting Study Product ....................................................................................................... 42 
10.6.18 Provide, Collect, and Review Diary ....................................................................................... 42 
10.7 Adverse Events ............................................................................................................................... 42 
10.7.1 Definitions ................................................................................................................................ 42 
10.7.2 Events Not to Be Considered Adverse Events ......................................................................... 43 
10.7.3 Severity of Adverse Events ...................................................................................................... 43 
10.7.4 Relationship of Adverse Events ............................................................................................... 43 
10.7.5 Expectedness Assessment ........................................................................................................ 44 
10.8 Serious Adverse Events .................................................................................................................. 45 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 7 of 59 
 
 
10.8.1 Definition of a Serious Adverse Event..................................................................................... 45 
10.8.2 Events That Do Not Meet the Definition of a Serious Adverse Event..................................... 45 
10.8.3 Serious Adverse Event Reporting ............................................................................................ 45 
10.9 Definition of the Adverse Event Reporting Period: ........................................................................ 47 
10.10 Monitoring of Subjects with Adverse Events ............................................................................... 47 
10.11 Pregnancy ...................................................................................................................................... 47 
11.0 STATISTICAL METHODS ............................................................................................................... 47 
11.1 Statistical Plan ................................................................................................................................. 47 
11.2 Determination of Sample Size ........................................................................................................ 48 
11.3 Study Populations ........................................................................................................................... 48 
11.3.1 Per-Protocol (PP) Population ................................................................................................... 48 
11.3.2 Pharmacodynamic (PD) Population ......................................................................................... 48 
11.3.3 Safety Populations.................................................................................................................... 48 
11.4 Subject Characteristics .................................................................................................................... 49 
11.5 Primary Pharmacodynamic Endpoint ............................................................................................. 49 
11.6 Pharmacodynamic Equivalence ...................................................................................................... 49 
11.6 Safety Analysis ............................................................................................................................... 50 
12.0 REGULATORY OBLIGATIONS ...................................................................................................... 50 
12.1 Institutional Review Board ............................................................................................................. 50 
12.2 Study Documentation ...................................................................................................................... 50 
12.2.1 Protocol .................................................................................................................................... 51 
12.2.2 Informed Consent ..................................................................................................................... 51 
12.2.3 Protocol and Informed Consent Changes ................................................................................. 51 
12.2.4 Source Documents and Electronic Case Report Forms ........................................................... 51 
12.2.5 Drug Accountability ................................................................................................................. 51 
12.2.6 Drug Storage ............................................................................................................................ 52 
12.2.7 Reporting Safety Information to the IRB ................................................................................. 52 
12.2.8 Record Retention...................................................................................................................... 52 
12.2.9 Study Monitoring and Auditing ............................................................................................... 52 
12.2.10 End of the Trial ...................................................................................................................... 52 
12.2.11 Clinical Study Report ............................................................................................................. 52 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 8 of 59 
 
 
13.0 REFERENCES ................................................................................................................................... 54 
14.0 APPENDICES .................................................................................................................................... 55 
14.1 APPENDIX A – NAEPP Guidelines for Asthma Severity Classification ...................................... 55 
14.2 APPENDIX B – PROAIR® HFA (albuterol sulfate) Inhalation Aerosol Package Insert ............... 56 
14.3 APPENDIX C – Albuterol Sulfate Inhalation Aerosol Investigator’s Brochure ............................ 57 
14.4 APPENDIX D – Amendments to the Protocol ............................................................................... 58 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 9 of 59 
 
 
5.0 SYNOPSIS 
Protocol Number 
 
Title 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-
Period, Four-Sequence, Four-Treatment, Placebo and Active Controlled, 
Comparative, Multiple-Center, Crossover-Design, Bronchoprovocation 
Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate 
Inhalation Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries 
Limited) to PROAIR® HFA (albuterol sulfate) Inhalation Aerosol, eq 90 
mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma 
Objectives 
1. Demonstrate the pharmacodynamic equivalence of the Test 
formulation of albuterol sulfate inhalation aerosol, eq 90 mcg base 
(Sun Pharmaceuticals Industries Limited) to the marketed product 
PROAIR® HFA (albuterol sulfate) Inhalation Aerosol, eq 90 mcg base 
(Teva Respiratory, LLC) using methacholine bronchoprovocation in 
subjects with stable, mild asthma based on National Asthma Education 
and Prevention Program (NAEPP) guidelines. 
2. Compare the safety of Test, low-dose Reference, high-dose Reference, 
and Placebo treatments in subjects with stable, mild asthma based on 
NAEPP guidelines. 
Sponsor 
Sun Pharmaceuticals Industries Limited 
Study Products 
• 
Test (T active): Albuterol Sulfate Inhalation Aerosol, eq 90 mcg base 
per inhalation (Sun Pharmaceuticals Industries Limited) 
• 
Reference (R active): PROAIR® HFA (albuterol sulfate) Inhalation 
Aerosol, eq 90 mcg base per inhalation (Teva Respiratory, LLC) 
• 
Test Placebo (T Placebo): Placebo for Albuterol Sulfate Inhalation 
Aerosol (i.e., vehicle canister with T active actuator [Sun 
Pharmaceuticals Industries Limited]) 
• 
Reference Placebo (R Placebo): Placebo for Albuterol Sulfate 
Inhalation Aerosol (i.e., vehicle canister with R active actuator [Sun 
Pharmaceuticals Industries Limited]) 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 10 of 59 
 
 
Treatments  
During each period, subjects will receive four puffs of study product from 
four different inhalers (each dose from a separate inhaler). Treatments will 
be as follows: 
Treatment A: Zero-dose 
Two different Reference Placebo inhalers 
and two different Test Placebo inhalers 
1 puff Inhaler 1 
1 puff Inhaler 2 
1 puff Inhaler 3 
1 puff Inhaler 4 
 
Treatment B: 90 mcg of Reference 
One Reference inhaler, one Reference 
Placebo inhaler, and two different Test 
Placebo inhalers 
1 puff Inhaler 1 
1 puff Inhaler 2 
1 puff Inhaler 3 
1 puff Inhaler 4 
 
Treatment C: 180 mcg of Reference 
Two different Reference inhalers and two 
different Test Placebo inhalers 
1 puff Inhaler 1 
1 puff Inhaler 2 
1 puff Inhaler 3 
1 puff Inhaler 4 
 
Treatment D: 90 mcg of Test 
One Test inhaler, one Test Placebo inhaler, 
and two different Reference Placebo 
inhalers 
1 puff Inhaler 1 
1 puff Inhaler 2 
1 puff Inhaler 3 
1 puff Inhaler 4 
 
Study Design 
A randomized, single-dose, double-blind, double-dummy, four-period, 
four-sequence, four-treatment, placebo and active controlled, comparative, 
multiple-center, crossover-design, bronchoprovocation bioequivalence 
study with pharmacodynamic endpoints 
Study Population 
Approximately 123 males and non-pregnant females, 18-65 years of age 
inclusive, with stable, mild asthma 
Confinement 
Subjects will remain confined to clinic for approximately 3-9 hours during 
each dosing and clinical assessment period (Visits 2-5). 
Study Conduct 
Eligible subjects will complete 5 clinic visits as follows: 
• 
Visit 1: Screening (Day -14 to -1) 
• 
Visit 2: Period 1 
• 
Visit 3: Period 2 
• 
Visit 4: Period 3 
• 
Visit 5: Period 4 
Clinical assessments will include Forced Expiratory Volume in 1 second 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 11 of 59 
 
 
(FEV1) taken at each visit. If reattempts are necessary, an acceptable FEV1 
is defined as the highest of three to four acceptable curves obtained at each 
time point. Forced Volume Vital Capacity (FVC) and FEV1/FVC ratio 
[(FEV1/FVC) x 100] will also be recorded along with FEV1 measurements 
at each visit. 
Screening 
Screening evaluations will be performed in accordance with the study 
schematic. Clinical assessments will include: vital sign measurement, 
height, weight, physical examination, urine pregnancy test (for all women 
of childbearing potential), 12-lead electrocardiogram (ECG), and pulse 
oximetry (during methacholine bronchoprovocation challenges). Chest x-
ray may be performed at discretion of the Investigator. Qualifying FEV1 at 
Screening must be ≥ 80% of predicted value. Once Qualifying FEV1 is 
obtained, a normal sterile saline control will be administered to the subject 
through a nebulizer. Spirometry will be performed following the saline 
administration. Post-saline FEV1 should not drop more than 10% from pre-
saline (Qualifying) FEV1 and should be ≥ 70% of predicted value. If the 
subject fails to meet any of these requirements, the procedures must be 
stopped, rescue albuterol administered, and the visit should be 
rescheduled. All clinical assessments except height and weight will be 
performed at each rescheduled visit. Subjects who fail three consecutive 
visits will not be eligible to participate in the study. Subjects meeting post-
saline FEV1 criteria will undergo methacholine bronchoprovocation 
challenge with progressively increasing concentrations to determine the 
subject’s baseline provocation concentration of inhaled methacholine 
required to reduce FEV1 by 20% (PC20) relative to the post-saline value. 
The maximum concentration of methacholine to be administered in this 
step will be 8 mg/mL. Subjects who do not respond to methacholine doses 
at or below 8 mg/mL will not be eligible for enrollment in the study. 
Once the procedures have been completed, two puffs (180 mcg; 90 mcg 
per puff) of rescue albuterol will be administered and spirometry will be 
performed approximately 15 minutes later until the subject’s FEV1 returns 
to within 90% of the best post-saline FEV1 or until the Principal 
Investigator determines that the FEV1 has stabilized and it is safe to allow 
the subject to leave the site. Vital signs will also be repeated. 
Dosing Visits 
Eligible subjects will return for four treatment visits. The first dosing visit 
will occur no more than 14 days after Screening procedures and the 
interval (washout period) between dosing visits should be at least 48 
hours. At each treatment visit, the following will be performed before 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 12 of 59 
 
 
dosing: 
• 
Vital sign measurement 
• 
12-lead ECG 
• 
Pulse 
oximetry 
(during 
methacholine 
bronchoprovocation 
challenges) 
• 
Concomitant medication update (confirming washouts) 
• 
Adverse event (AE) review 
• 
Urine pregnancy test for all women of childbearing potential 
A pre-treatment evaluation will be performed. This will confirm that pre-
challenge FEV1 is ≥ 80% of predicted and within 88 and 112% of 
qualifying spirometry value at Screening visit. After the first inhalation of 
saline control is administered, the FEV1 should not drop more than 10% 
compared to pre-challenge FEV1 value and should be ≥ 70% of the 
predicted value. If the subject fails to meet any of these requirements, the 
procedures must be stopped, rescue albuterol administered, and the visit 
should be rescheduled. A minimum washout of 48 hours is required 
between visits. Subjects who fail three consecutive visits should be 
dropped from the study. Subsequently, review of inhaler dosing technique, 
priming and preparation of inhalers will be performed. The subject will 
receive one of the four randomized study treatments. The time of last 
actuation will be recorded, as well as the adequacy of inhaler technique. 
Approximately 15 minutes after the last inhalation of study treatment, a 
methacholine 
bronchoprovocation 
challenge 
will 
be 
given 
with 
progressive concentrations to determine the PC20. The 20% reduction in 
FEV1 will be determined relative to the post-saline FEV1 measured before 
the administration of study product. 
After the procedures have been completed, two puffs (180 mcg; 90 mcg 
per puff) of rescue albuterol will be administered to reverse airway 
obstruction and subjects will be followed until FEV1 returns to within 90% 
of the best post-saline FEV1 captured on that study day or until the 
Principal Investigator determines that the FEV1 has stabilized and it is safe 
to allow the subject to leave the site. Vital signs will also be repeated. 
Subjects who withdraw prematurely will be evaluated at a final visit, but 
spirometry, chest x-rays, and methacholine administration do not need to 
be performed. 
The spirometry procedures and the methacholine bronchoprovocation 
challenges in this study are to be performed in accordance with the 
American Thoracic Society (ATS) Guidelines for Methacholine and 
Exercise 
Challenge 
Testing. 
The 
maximum 
methacholine 
dose 
administered will be 8 mg/mL at Screening and 128 mg/mL for treatment 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 13 of 59 
 
 
visits. 
Inclusion Criteria 
1. Men or non-pregnant women 18 to 65 years of age. 
2. Signed informed consent form that meets all criteria of current Food 
and Drug Administration (FDA) regulations. 
3. Females of childbearing potential must not be pregnant or lactating (as 
confirmed by a negative urine pregnancy test with a sensitivity of less 
than 50 mIU/mL or equivalent units of human chorionic 
gonadotropin). 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. 
4. Male subjects who are considered potent must be willing to avoid 
passage of semen to their partner and use an acceptable barrier method 
of contraception throughout the duration of the study. Each man will 
be considered potent unless surgically sterilized (with appropriate 
post-vasectomy documentation of the absence of sperm in the 
ejaculate). 
5. Subjects with a diagnosis of stable, mild asthma (based on NAEPP 
guidelines), confirmed by prior medical records, for at least 6 months 
before Screening. 
The subjects should fulfill the following NAEPP criteria: 
a. Symptoms: > 2 days per week but not daily 
b. Nighttime awakenings: 3-4 times per month 
c. Short-acting beta2-agonist (SABA) use for symptom 
control (other than for exercise-induced bronchospasm): 
> 2 days per week but not daily AND no more than one time 
on any day. 
d. Interference with Normal Activity: Minor limitation 
6. FEV1 ≥ 80% of predicted at Screening day and no more than 10% drop 
in FEV1 and no less than 70% of predicted post-saline control. 
7. Airway responsiveness to methacholine demonstrated by a pre-
albuterol dose PC20 ≤ 8 mg/mL at Screening. 
8. Able to perform valid and reproducible pulmonary function tests 
including 
no 
evidence 
of 
spirometry 
effort-induced 
bronchoconstriction. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 14 of 59 
 
 
9. Non-smoker for at least 6 months before Screening and a maximum 
smoking history of five pack-years (i.e., one pack per day for five 
years). 
10. Ability to use inhalation aerosol correctly. 
Exclusion Criteria 
1. Allergy or significant history of hypersensitivity or idiosyncratic 
reactions or intolerance to albuterol sulfate, beta2 receptor-agonist 
drug, HFA and/or any related compounds. 
2. Need for daily oral corticosteroids in the past three months. 
3. History of seasonal asthma exacerbations, in which case the subject 
should be studied outside of the relevant allergen season. 
4. History of cystic fibrosis, bronchiectasis, or co-morbid respiratory or 
sinus diseases, including chronic obstructive pulmonary disease 
(COPD), 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. 
5. Evidence of conditions that could alter airway reactivity to 
methacholine, including upper or lower respiratory tract infections 
(e.g., pneumonia, viral bronchitis, allergic rhinitis, sinobronchitis, etc.) 
within 6 weeks before Screening. 
6. Treatment in emergency room or hospitalization for acute asthmatic 
symptoms within 3 months before Screening. 
7. Current cardiovascular disorders, including uncontrolled hypertension, 
known aortic or cerebral aneurysm, myocardial infarction or stroke in 
the last 6 months, and/or current coronary insufficiency that, in the 
opinion of the Investigator, would compromise subject safety or 
interfere with the evaluations. 
8. Cardiac 
arrhythmia 
or 
12-lead 
electrocardiogram 
(ECG) 
abnormalities, that in the opinion of the Investigator would 
compromise subject safety or interfere with the evaluations, or a 
QTc > 440 ms for males and > 460 ms for females using Fredericia 
formula. 
9. Subjects receiving beta blocker via any route or who may require beta 
blockers during the study. 
10. History of narrow angle glaucoma. 
11. Any clinically significant finding on physical exam, ECG, or chest x-
ray (to be performed at Investigator’s discretion) that, in the opinion of 
the Investigator, would compromise subject’s safety or data integrity. 
12. History of significant renal, hepatic, cardiovascular (including ECG 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 15 of 59 
 
 
with evidence of ischemic heart disease, congestive heart failure), 
neurologic, endocrine dysfunction, or any other significant medical 
illness or disorder in the opinion of the Investigator, would 
compromise subject safety or interfere with the evaluations. 
13. History of convulsive disorders or hyperthyroidism. 
14. History of uncontrolled diabetes. 
15. History of paradoxical bronchospasm. 
16. SABAs use within 8 hours before Screening. 
17. Use of muscarinic beta2-agonists (MABAs), ipratropium bromide, or 
ipratropium bromide with albuterol within 24 hours before Screening. 
18. Use of cromolyn sodium within 8 hours before Screening. 
19. Use of nedocromil within 48 hours before Screening 
20. Use of antihistamines (hydroxyzine, cetirizine, etc.) within 24 hours 
before Screening. 
21. Use of long-acting beta2-agonists (LABAs) (e.g., salmeterol, 
formoterol) or combination products containing bronchodilators (e.g., 
Symbicort) within 48 hours before Screening. 
22. Use of tiotropium within one week before Screening. 
23. Inhalation corticosteroids must have remained at a constant dosage for 
the previous 4 weeks; their withholding is at discretion of the 
Investigator. 
24. Use of theophylline medications within 24 hours before Screening. 
25. Consumption of caffeine containing products such as coffee, tea, cola 
drinks, energy drinks or chocolate on the day of Screening. 
26. Exercise within 6 hours before Screening. 
27. Use of beta blockers, non-potassium sparing diuretics, digoxin, 
monoamine oxidase inhibitors, cholinesterase inhibitors or tri-cyclic 
anti-depressants within 30 days before Screening. 
28. Use of leukotriene modifiers within 24 hours before Screening. 
29. Any surgery within 6 months before Screening that, in the opinion of 
the Investigator, would compromise subject safety or integrity of the 
study data. 
30. Receipt of any drug as part of a research study within 30 days before 
Screening. 
31. Employees of the Investigator or research center or their immediate 
family members. 
32. Previous participation in this study. 
33. Inability to understand the requirements of the study and the relative 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 16 of 59 
 
 
information and are unable or not willing to comply with the study 
protocol. 
Route of 
Administration 
Oral inhalation 
Primary 
Pharmacodynamic 
Endpoint 
The primary pharmacodynamic endpoint will be the post-dose PC20, which 
is the provocative concentration of the methacholine challenge agent 
required to reduce the FEV1 by 20% following administration of differing 
doses of albuterol (or placebo) by inhalation. The 20% reduction in FEV1 
will be determined relative to the post-saline FEV1 measure before the 
placebo or albuterol administration.  
Statistical Analysis 
The primary bioequivalence analysis will use the Pharmacodynamic (PD) 
population. A secondary analysis will test the primary pharmacodynamic 
endpoint using the Per-Protocol (PP) population. 
Pharmacodynamic equivalence will be based on the Dose-Scale method of 
analysis of the post-dose PC20FEV1 (mg/mL) data using non-linear Emax 
modeling, as outlined in the FDA Draft Guidance on Orlistat capsule.1 The 
methacholine PC20FEV1 will be calculated by linear interpolation from the 
observed data relating the % decrease in FEV1 from the post-saline FEV1 
to the concentration of methacholine that provokes at least a 20% decrease 
in FEV1. The PC20FEV1 data will be log-transformed if they are log-
normally distributed. 
If the 90% confidence interval for the relative bioavailability (F) falls 
within 67.00-150.00% then pharmacodynamic equivalence will be 
considered to have been demonstrated. F is the potency ratio of the doses 
of Test and Reference formulations that produce an equivalent 
pharmacodynamic response at the ED50 of the Reference dose-response 
Emax curve. The 90% confidence interval for F will be estimated by a 
bootstrap procedure using Efron’s bias-corrected and accelerated (BCA) 
method.  
Safety Analysis 
All study subjects who receive at least one actuation of any of the study 
products will be included in the comparative safety analysis. Adverse 
events will be classified using standard Medical Dictionary for Regulatory 
Activities (MedDRA) terminology Version 21.0 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 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 17 of 59 
 
 
subject’s best interest to be dropped from continued participation in the 
study and given alternative therapy for their condition. If sufficient data 
exist, then AEs frequencies will be compared among treatments using 
Fisher’s exact test. 
Concomitant medication used during the study will be tabulated by 
treatment by subject. 
Sample Size 
Determination 
The sample size estimation for this study was based on data from the study 
by Newhouse et al. that reported the bronchoprotective effect of inhaled 
salbutamol (albuterol) on methacholine PC20FEV1.2 
The highest within-subject coefficient of variability (COV) value for ln-
transformed PC20 was estimated as 0.846 from the mean ratio and SD 
values for the PC20 at the 200 and 100 mcg doses (Table 1 in reference 2). 
Based on this COV, 98 evaluable subjects would be required in the PD 
population to demonstrate pharmacodynamic equivalence (i.e., 90% 
confidence interval on F is within the bioequivalence limits of 0.67 to 
1.50) with 90% power for a crossover study, assuming a true ratio of F = 
1.1. To allow for approximately 20% of subjects that may discontinue 
from the study or have major protocol violations, and therefore not qualify 
for the PD population, up to 123 subjects will be randomized in the study. 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 18 of 59 
 
 
6.0 STUDY SCHEMATIC 
Procedures 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Screening 
Period 1 
Period 2 
Period 3 
Period 4 
End of Study 
Informed Consent 
X 
Baseline Demographics 
X 
Medical History 
X 
 
 
 
 
Vital Signs* 
X 
X 
X 
X 
X 
Height and Weight 
X 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
Urine Pregnancy Test** 
X 
X 
X 
X 
X 
12-Lead ECG  
X 
X† 
X† 
X† 
X† 
Chest X-Ray‡ 
X 
 
Concomitant Medication 
X 
X 
X 
X 
X 
Spirometry (FEV1 and FVC)§ 
X 
X 
X 
X 
X 
Saline Control Administration 
X 
X 
X 
X 
X 
Methacholine Challenge 
X 
X 
X 
X 
X 
Pulse Oximetry 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
Review 
X 
 
 
 
 
Prime, dispense study product and 
instructions 
 
X 
X 
X 
X 
Dosingǁ 
X 
X 
X 
X 
Assessment of Compliance 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Provide Diary 
X 
X 
X 
X 
Collect /Review Diary 
 
X 
X 
X 
X 
Schedule next visit 
X 
X 
X 
X 
* Vital signs will be measured before and after methacholine bronchoprovocation challenges at all visits. 
** Female subjects of childbearing potential. 
† 12-lead ECG to be performed at Screening may be repeated before methacholine bronchoprovocation challenges 
at discretion of Investigator. 
‡ Chest X-ray is to be performed at discretion of Investigator. 
§ FEV1 and FVC measurements will be performed before saline control, after saline control, and after methacholine 
administration. If reattempts are necessary, an acceptable FEV1 is defined as the highest of three to four acceptable 
curves obtained at each time point. 
ǁ Subjects will receive four puffs of study product from four different inhalers (each dose from a separate inhaler). 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 19 of 59 
 
 
7.0 LIST OF ABBREVIATIONS AND TERMS 
Abbreviation Term 
Abbreviation 
Term 
µg 
microgram 
PC20 
Concentration (mg/mL) of methacholine 
required to reduce FEV1 by 20% 
ADaM 
Analysis Dataset Model 
PD 
Pharmacodynamic 
AE 
Adverse Event 
PE 
Pulmonary Embolism 
ANDA 
Abbreviated New Drug Application 
PFT 
Pulmonary Function Tests 
ATS 
American Thoracic Society 
PP 
Per-Protocol  
BCA 
Bias-corrected and accelerated 
RR 
Respiratory Rate 
BP 
Blood Pressure 
SABA 
Short-Acting Beta2-Agonist 
C 
Celsius 
SAE 
Serious Adverse Event 
CDISC 
Clinical Data Standards Interchange Consortium 
SAS 
Statistical Analysis Software 
CHF 
Congestive Heart Failure 
SDTM 
Study Data Tabulation Model 
COPD 
Chronic Obstructive Pulmonary Disease 
SUSAR 
Suspected Unsuspected Serious Adverse 
Reaction 
CRO 
Clinical Research Organization 
US 
United States 
ECG 
Electrocardiogram 
USP 
United States Pharmacopeia 
eCRF 
electronic Case Report Form 
 
 
eCTD 
Electronic Common Technical Document 
 
 
EIB 
Exercise-Induced Bronchospasm 
 
 
°F 
Fahrenheit 
 
 
F 
Relative bioavailability 
 
 
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 of 
Technical Requirements for Pharmaceuticals for 
Human Use 
 
 
ICS 
Inhaled Corticosteroid 
 
 
IRB 
Institutional Review Board 
 
 
kg 
Kilograms 
 
 
LABA 
Long-Acting Beta2-Agonist 
 
 
MABA 
Muscarinic-Acting Beta2-Agonist 
 
 
MDI 
Metered Dose Inhaler 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
mITT 
modified Intent-to-Treat  
 
 
mL 
Milliliter 
 
 
NAEPP 
National Asthma Education and Prevention 
Program 
 
 
OGD 
Office of Generic Drugs 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 20 of 59 
 
 
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.3-5 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.3,5,6 
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.7-9 
Exacerbation of symptoms may be triggered by a variety of factors including infections, allergens, 
exercise, inhaled irritants, or emotional episodes.3,10 
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 (PE). This is determined by an increase in predicted FEV1 > 200 mL or > 12% 
from baseline measure after inhalation of short-acting beta2-agonist (SABA).8 
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.11,12 
8.2 Availability and Efficacy of Already Approved Therapies 
There are two types of therapies currently available for the treatment of asthma, long-term control 
medications and quick relief medications.13,14 Inhaled corticosteroids (ICSs) have been shown to be 
the most effective long-term treatment of persistent asthma.15 Quick relief medications or short-acting 
beta-agonists (SABAs), for e.g., 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 (MDIs) 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, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 21 of 59 
 
 
8.3 Scientific and Statistical Considerations 
The methacholine PC20FEV1 (mg/mL) will be calculated by linear interpolation from the observed 
data relating the % decrease in FEV1 from the post-saline FEV1 to the concentration of methacholine 
that provokes at least a 20% decrease in FEV1. In the event that subjects receiving the maximum 
concentration of methacholine (128 mg/mL) at any treatment visit (Visits 2-5) do not achieve at least 
a 20% fall in FEV1, then they will have their PC20FEV1 data interpolated as though they had achieved 
positivity at 128 mg/mL (i.e., PC20FEV1 will be imputed as 128 mg/mL) and will be included in the 
Per-Protocol (PP) population. The PC20FEV1 data will be log-transformed if they are log-normally 
distributed. 
PD20FEV1 (mg) may also be evaluated to correct for the dose of methacholine delivered if different 
volumes of methacholine are administered as result of different nebulizer flow rate, number of 
breaths, or nebulizer time. The maximum methacholine dose administered will be 8 mg/mL at 
Screening and 128 mg/mL (i.e., PC20FEV1 will be imputed as 128 mg/mL) for treatment visits. The 
use of 128 mg/mL of methacholine is necessary to allow for a minimum 4-fold decrease in 
sensitivity; however, this dose is higher than the 25 mg/mL dose approved for administration of 
methacholine chloride in the United States. Therefore, a Bio-IND application is being filed with the 
United States (US) Food and Drug Administration (FDA) Office of Generic Drugs (OGD) for use of 
Provocholine® (methacholine chloride USP) concentrations that may exceed the labeled 25.0 mg/mL 
concentration. 
8.4 Justification for Use of Placebo 
A Placebo treatment arm is required for application of the Dose-Scale method for a 
bronchoprovocation study. The Placebo treatment will provide the baseline response in the absence of 
the drug for fitting of the Emax model to the dose-response PC20FEV1 data of the Reference product. 
All subjects will undergo one zero-dose treatment (four inhalations of placebo) across the four 
periods of the study. The lack of a bronchoprotective effect provided by either the Reference or the 
Test product at higher doses of methacholine implies that the bronchoprovocation challenge test 
delivered during the zero-dose does not differ from a regular methacholine bronchoprovocation test 
and does not compromise subject’s safety. Bronchoprovocation challenge tests represent a valuable 
and well validated tool for the diagnosis of respiratory conditions. All methacholine 
bronchoprovocation challenges are performed in accordance with the American Thoracic Society 
(ATS) Guidelines for Methacholine and Exercise Challenge Testing in order to ensure subjects’ 
safety and good quality testing. Mainly, the challenge test is initiated exclusively if the subject shows 
an acceptable functional pulmonary profile (a baseline FEV1 above 70% of predicted) and it is 
interrupted if a safety threshold is met (drop in FEV1 ≥ 20%). At the end of each challenge, each 
subject will be administered a rescue medication (albuterol) in order to ensure proper reversion of the 
bronchoconstriction, if present; under the Principal Investigator’s supervision, the subject will be 
leaving the investigative site only when an acceptable FEV1 is reached. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 22 of 59 
 
 
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 USA 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.16 
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 
1. Demonstrate the pharmacodynamic equivalence of the Test formulation albuterol sulfate HFA 
inhalation aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to the marketed product 
PROAIR® HFA (albuterol sulfate) Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in 
subjects with stable, mild asthma based on National Asthma Education and Prevention Program 
(NAEPP) guidelines. 
2. Compare the safety of Test, low-dose Reference, high-dose Reference, and Placebo treatments in 
subjects with stable, mild asthma based on NAEPP guidelines. 
10.0 INVESTIGATIONAL PLAN 
10.1 Study Design and Plan Description 
This randomized, single-dose, double-blind, double-dummy, four-period, four-sequence, four-
treatment, Placebo and active controlled, comparative, multiple-center, crossover-design 
bronchoprovocation study has been designed to evaluate the pharmacodynamic equivalence of 
albuterol sulfate HFA inhalation aerosol, eq 90 mcg base per inhalation (Sun Pharmaceuticals 
Industries Limited) to PROAIR® HFA (albuterol sulfate) Inhalation Aerosol, eq 90 mcg base per 
inhalation (Teva Respiratory, LLC) in subjects with stable, mild asthma. 
Approximately 123 subjects with persistent bronchial asthma will be randomized. To qualify for 
inclusion in the study, subjects must be at least 18 years of age, with a documented diagnosis of mild 
asthma as defined by the NAEPP guidelines at least 6 months before Screening. 
Randomized subjects who withdraw from the study will not be replaced. 
Before any study-specific procedures are performed, all subjects will read and sign the IRB-approved 
informed consent form. 
Eligible subjects will complete 5 clinic visits as follows: 
• 
Visit 1: Screening (Day -14 to -1) 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 23 of 59 
 
 
• 
Visit 2: Period 1 
• 
Visit 3: Period 2 
• 
Visit 4: Period 3 
• 
Visit 5: Period 4 
Clinical assessments will include FEV1 taken at each visit. If reattempts are necessary, an acceptable 
FEV1 is defined as the highest of three to four acceptable curves obtained at each time point. FVC and 
FEV1/FVC ratio [(FEV1/FVC) x 100] will also be recorded along with FEV1 measurements at each 
visit. 
Screening 
Screening evaluations will be performed in accordance with the study calendar. Clinical assessments 
will include: vital sign measurement, height, weight, physical examination, urine pregnancy test (for 
all women of childbearing potential), 12-lead electrocardiogram (ECG), and pulse oximetry (during 
methacholine bronchoprovocation challenges). Chest x-ray may be performed at discretion of the 
Investigator. Qualifying FEV1 at Screening must be ≥ 80% of predicted value. Once Qualifying FEV1 
is obtained, a sterile, saline control will be administered to the subject through a nebulizer. 
Spirometry will be performed following the saline administration. Post-saline FEV1 should not drop 
more than 10% from pre-saline FEV1 and should be ≥ 70% of predicted value. If the subject fails to 
meet any of these requirements, the procedures must be stopped, rescue albuterol administered, and 
the visit should be rescheduled. All clinical assessments except height and weight will be performed 
at each rescheduled visit. Subjects who fail three consecutive visits will not be eligible to participate 
in the study. Subjects meeting post-saline FEV1 criteria will undergo methacholine 
bronchoprovocation challenge with progressively increasing concentrations to determine the subject’s 
baseline provocation concentration of inhaled methacholine required to reduce FEV1 by 20% (PC20) 
relative to the post-saline value. The maximum concentration of methacholine to be administered in 
this step will be 8 mg/mL. Subjects who do not respond to methacholine doses at or below 8 mg/mL 
will not be eligible for enrollment in the study. 
Once the methacholine challenge test is completed, rescue albuterol will be administered and 
spirometry will be performed approximately 15 minutes later until the subject’s FEV1 returns to 
within 90% of the best post-saline FEV1 or until the Principal Investigator determines that the FEV1 
has stabilized and it is safe to allow the subject to leave the site. Vital signs will also be repeated. 
Dosing Visits 
Eligible subjects will return for four treatment visits. The first dosing visit will occur no more than 14 
days after Screening procedures and the interval (washout period) between dosing visits should be at 
least 24 hours. At each treatment visit, the following will be performed before dosing: 
• 
Vital sign measurement 
• 
12-lead electrocardiogram (ECG) as the discretion of the Investigator after the initial 
Screening visit 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 24 of 59 
 
 
• 
Pulse oximetry (during methacholine bronchoprovocation challenges) 
• 
Concomitant medication update (confirming washouts) 
• 
Adverse Events (AE) review 
• 
Urine pregnancy test for all women of childbearing potential 
A pre-treatment evaluation will be performed. This will confirm that pre-challenge FEV1 is ≥ 80% of 
predicted and within 88 and 112% of qualifying spirometry value at Screening visit. After the first 
inhalation of saline control is administered, the FEV1 should not drop more than 10% compared to 
pre-challenge value and should be ≥ 70% of the predicted value. If the subject fails to meet any of 
these requirements, the procedures must be stopped, albuterol administered, and the visit should be 
rescheduled. Subjects who fail three consecutive visits should be dropped from the study. 
Subsequently, review of inhaler dosing technique, priming and preparation of inhalers will be 
performed. The subject will receive one of the four randomized study treatments. The time of last 
actuation will be recorded, as well as the adequacy of inhaler technique. Approximately 15 minutes 
after the last inhalation of study treatment, a methacholine bronchoprovocation challenge will be 
given with progressive concentrations to determine the PC20. The 20% reduction in FEV1 will be 
determined relative to the post-saline FEV1. After the procedures have been completed, albuterol will 
be administered to reverse airway obstruction and subjects will be followed until FEV1 returns to 
within 90% of the best FEV1 captured during the saline stage on that study day or until the Principal 
Investigator determines that the FEV1 has stabilized and it is safe to allow the subject to leave the site. 
Subjects who withdraw prematurely will be evaluated at a final visit, but spirometry, chest x-rays, and 
methacholine administration do not need to be performed. 
The spirometry procedures and the methacholine bronchoprovocation challenges in this study are to 
be performed in accordance with the ATS Guidelines for Methacholine and Exercise Challenge 
Testing.17 The maximum methacholine dose administered will be 8 mg/mL at Screening and 
128 mg/mL for treatment visits. 
10.2 Selection of Study Design 
The study was designed based on the FDA Draft Guidance on albuterol sulfate metered/inhalation 
products, and generally accepted standards for the conduct of bioavailability and bioequivalence 
studies.18 
To minimize any possibility of a carry-over effect, a washout period of at least 48 hours was selected 
for this study based on the FDA guidance. 
10.3 Selection of Study Population 
10.3.1 Inclusion Criteria 
1. Men or non-pregnant women 18 to 65 years of age. 
2. Signed informed consent form that meets all criteria of current FDA regulations. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 25 of 59 
 
 
3. Females of childbearing potential must not be pregnant or lactating (as confirmed by a 
negative urine pregnancy test with a sensitivity of less than 50 mIU/mL or equivalent units of 
human chorionic gonadotropin). 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. 
4. Male subjects who are considered potent must be willing to avoid passage of semen to their 
partner and use an acceptable barrier method of contraception throughout the duration of the 
study. Each man will be considered potent unless surgically sterilized (with appropriate post-
vasectomy documentation of the absence of sperm in the ejaculate). 
5. Subjects with diagnosis of stable, mild asthma (based on NAEPP guidelines), confirmed by 
prior medical records, for at least 6 months before Screening. 
The subjects should fulfill the following NAEPP criteria: 
a. Symptoms: > 2 days per week but not daily 
b. Nighttime awakenings: 3-4 times per month 
c. Short-acting beta2-agonist (SABA) use for symptom control (other than for 
EIB): > 2 days per week but not daily AND no more than one time on any day. 
d. Interference with Normal Activity: Minor limitation 
6. FEV1 ≥ 80% of predicted at Screening day and no more than 10% drop in FEV1 and no less 
than 70% of predicted post-saline control. 
7. Airway responsiveness to methacholine demonstrated by a pre-albuterol dose PC20 ≤ 8 
mg/mL at Screening. 
8. Able to perform valid and reproducible pulmonary function tests including no evidence of 
spirometry effort-induced bronchoconstriction. 
9. Non-smoker for at least 6 months before Screening and a maximum smoking history of five 
pack-years (i.e., one pack per day for five years). 
10. Ability to use inhalation aerosol correctly. 
10.3.2 Exclusion Criteria 
1. Allergy or significant history of hypersensitivity or idiosyncratic reactions or intolerance to 
albuterol sulfate, beta2 receptor-agonist drug, HFA and/or any related compounds. 
2. Need for daily oral corticosteroids in the past three months. 
3. History of seasonal asthma exacerbations, in which case the subject should be studied outside 
of the relevant allergen season. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 26 of 59 
 
 
4. History of cystic fibrosis, bronchiectasis, or co-morbid respiratory or sinus diseases, 
including COPD, 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. 
5. Evidence of conditions that could alter airway reactivity to methacholine, including upper or 
lower respiratory tract infections (e.g., pneumonia, viral bronchitis, allergic rhinitis, 
sinobronchitis, etc.) within 6 weeks before Screening. 
6. Treatment in emergency room or hospitalization for acute asthmatic symptoms within 3 
months before Screening. 
7. Current cardiovascular disorders, including uncontrolled hypertension, known aortic or 
cerebral aneurysm, myocardial infarction or stroke in the last 6 months, and/or current 
coronary insufficiency that, in the opinion of the Investigator, would compromise subject 
safety or interfere with the evaluations. 
8. Cardiac arrhythmia or 12-lead electrocardiogram (ECG) abnormalities, that in the opinion of 
the Investigator would compromise subject safety or interfere with the evaluations, or a 
QTc > 440 ms for males and > 460 ms for females using Fredericia formula. 
9. Subjects receiving beta blocker via any route or who may require beta blockers during the 
study. 
10. History of narrow angle glaucoma. 
11. Any clinically significant finding on physical exam, ECG, or chest x-ray (to be performed at 
Investigator’s discretion) that, in the opinion of the Investigator, would compromise subject’s 
safety or data integrity. 
12. History of significant renal, hepatic, cardiovascular (including ECG with evidence of 
ischemic heart disease, congestive heart failure), neurologic, endocrine dysfunction, or any 
other significant medical illness or disorder in the opinion of the Investigator, would 
compromise subject safety or interfere with the evaluations. 
13. History of convulsive disorders or hyperthyroidism. 
14. History of uncontrolled diabetes. 
15. History of paradoxical bronchospasm. 
16. SABAs use within 8 hours before Screening. 
17. Use of muscarinic beta2-agonists (MABAs), ipratropium bromide, or ipratropium bromide 
with albuterol within 24 hours before Screening. 
18. Use of cromolyn sodium within 8 hours before Screening. 
19. Use of nedocromil within 48 hours before Screening 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 27 of 59 
 
 
20. Use of antihistamines (hydroxyzine, cetirizine, etc.) within 24 hours before Screening. 
21. Use of long-acting beta2-agonists (LABAs) (e.g., salmeterol, formoterol) or combination 
products containing bronchodilators (e.g., Symbicort) within 48 hours before Screening. 
22. Use of tiotropium within one week before Screening. 
23. Inhalation corticosteroids must have remained at a constant dosage for the previous 4 weeks; 
their withholding is at discretion of the Investigator. 
24. Use of theophylline medications within 24 hours before Screening. 
25. Consumption of caffeine containing products such as coffee, tea, cola drinks, energy drinks 
or chocolate on the day of Screening. 
26. Exercise within 6 hours before Screening. 
27. Use of beta blockers, non-potassium sparing diuretics, digoxin, monoamine oxidase 
inhibitors, cholinesterase inhibitors or tri-cyclic anti-depressants within 30 days before 
Screening. 
28. Use of leukotriene modifiers within 24 hours before Screening. 
29. Any surgery within 6 months before Screening that, in the opinion of the Investigator, would 
compromise subject safety or integrity of the study data. 
30. Receipt of any drug as part of a research study within 30 days before Screening. 
31. Employees of the Investigator or research center or their immediate family members. 
32. Previous participation in this study. 
33. Inability to understand the requirements of the study and the relative information and are 
unable or not willing to comply with the study protocol. 
10.3.3 Restrictions During the Study 
The following medications will not be allowed when subjects are enrolled in the study: 
• 
Beta blockers 
• 
Non-potassium sparing diuretics 
• 
Digoxin 
• 
Monoamine oxidase inhibitors 
• 
Cholinesterase inhibitors 
• 
Tri-cyclic anti-depressants 
• 
MABAs within 24 hours before any study visit. 
• 
SABAs within 8 hours before any study visit. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 28 of 59 
 
 
• 
Ipratropium bromide or ipratropium bromide with albuterol within 24 hours before any 
study visit. 
• 
Cromolyn sodium within 8 hours before any study visit. 
• 
LABAs (e.g., salmeterol, formoterol) or combination products containing bronchodilators 
(e.g., Symbicort) within 48 hours before any study visit. 
• 
Tiotropium within one week before any study visit. 
• 
Theophylline medications within 24 hours before any study visit. 
• 
Leukotriene modifiers within 24 hours before any study visit. 
• 
Nedocromil within 48 hours before any study visit. 
• 
Antihistamines within 24 hours before any study visit. 
Inhalation corticosteroids must have remained at a constant dosage for the previous 4 weeks; their 
withholding is at discretion of the Investigator. Subjects should not consume caffeine containing 
products such as coffee, tea, cola drinks, energy drinks or chocolate on the day of any study visit. 
Subjects should not exercise within 6 hours of any study visit. 
10.3.4 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. 
All subjects who receive randomized treatment will be included in the safety analysis. If a subject 
terminates from the study early, all efforts will be made to complete their next visit study 
procedures, but spirometry chest x-rays, and methacholine administration do 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. 
• 
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 such that the Investigator and/or subject believes it is in 
the best interest of the subject to withdraw from the study and be provided alternative 
treatment. 
• 
Participant enrolls in another clinical trial, or is found to have previously enrolled in this 
clinical trial. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 29 of 59 
 
 
10.4 Treatments 
10.4.1 Treatments Administration 
The Independent Dispenser will prime each inhaler of study product before using for the first 
time by shaking well for 5 seconds, then releasing 3 test sprays into the air, away from the face, 
until a uniform spray is obtained. The Independent Dispenser will dispense 4 study inhalers 
containing randomized study product, according to treatments listed in table above, to each 
eligible subject, along with a set of dosing instructions. Subjects will administer one puff (oral 
inhalation) from each of the provided inhalers with a spacer at 1 minute intervals, in accordance 
with dosing instructions, with the Independent Dispenser observing. The date and time of dose 
will be recorded. Treatments will be as follows: 
Treatment A: Zero-dose 
Two different Reference Placebo inhalers and two different 
Test Placebo inhalers 
1 puff Inhaler 1 
1 puff Inhaler 2 
1 puff Inhaler 3 
1 puff Inhaler 4 
Treatment B: 90 mcg of Reference 
One Reference inhaler, one Reference Placebo inhaler, and two 
different Test Placebo inhalers 
1 puff Inhaler 1 
1 puff Inhaler 2 
1 puff Inhaler 3 
1 puff Inhaler 4 
Treatment C: 180 mcg of Reference 
Two different Reference inhalers and two different Test 
Placebo inhalers 
1 puff Inhaler 1 
1 puff Inhaler 2 
1 puff Inhaler 3 
1 puff Inhaler 4 
Treatment D: 90 mcg of Test 
One Test inhaler, one Test Placebo inhaler, and two different 
Reference Placebo inhalers 
1 puff Inhaler 1 
1 puff Inhaler 2 
1 puff Inhaler 3 
1 puff Inhaler 4 
10.4.2 Identity of Investigational Product 
The following products will be used in the study: 
• 
Test (T active): Albuterol Sulfate Inhalation Aerosol, eq 90 mcg base per inhalation (Sun 
Pharmaceuticals Industries Limited) 
• 
Reference (R active): PROAIR® HFA (albuterol sulfate) Inhalation Aerosol, eq 90 mcg 
base per inhalation (Teva Respiratory, LLC) 
• 
Test Placebo (T Placebo): Placebo for Albuterol Sulfate Inhalation Aerosol (i.e., vehicle 
canister with T active actuator [Sun Pharmaceuticals Industries Limited]) 
• 
Reference Placebo (R Placebo): Placebo for Albuterol Sulfate Inhalation Aerosol (i.e., 
vehicle canister with R active actuator [Sun Pharmaceuticals Industries Limited]) 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 30 of 59 
 
 
The Reference product, PROAIR ® HFA (albuterol sulfate) inhalation aerosol, is supplied as an 
8.5 g pressurized aluminum canister in a box. Each canister contains 200 metered actuations and 
is supplied with a red plastic actuator (or mouthpiece) and a white mouthpiece cap. Each 
actuation delivers 120 mcg of albuterol sulfate from the canister valve and 108 mcg of albuterol 
sulfate from the actuator mouthpiece (equivalent to 90 mcg of albuterol base). 
10.4.3 Study Product Shipment, Storage and Retention 
The study product will be shipped to each Investigator’s site from a centralized pharmacy. 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 product will be maintained in accordance with federal regulations. 
Randomization of treatments will be generated in blocks. Four patient kits, each containing the 
four treatments (A, B, C and D), will constitute a block. Retention samples will be kept aside by 
study site to comply the applicable regulatory requirement. For any re-supply shipments of 
randomized study product retention samples will be kept aside by the study site. These samples 
should not be used for dispensing to study subjects and will be retained at the site under FDA 
regulations as study retention samples.17 
All study product will be stored at controlled room temperature between 15° and 25°C (59° and 
77°F), away from direct sunlight (or freezing temperatures) in a secure place with access by 
authorized individuals only. Any excursions from the permitted range of 15–25ºC (59º–77ºF) will 
require prompt notification to 
 and thereafter 
 will notify the Sponsor Designee. 
The inhalers are to be stored with actuators ‘down’. 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
 
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 may be 
returned to 
 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 medication must be retained among the sites participating in the study to meet 
the sample retention requirements in accordance with FDA regulations (21 CFR 320.38 and 21 
CFR 320.63.). 
10.4.4 Method of Assigning Subjects to Treatment Groups 
At Visit 1 eligible subjects will be enrolled in the study, and scheduled for Visit 2. At Visit 2, 
eligible subjects will be randomized to one of the four sequences as shown below. Treatments 
will be administered according to a four-treatment, four-period, four-sequence design. The 
randomization will be generated in blocks of four with each sequence occurring once in each 
block. 
Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
1 
A 
B 
C 
D 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 31 of 59 
 
 
2 
D 
C 
B 
A 
3 
C 
A 
D 
B 
4 
B 
D 
A 
C 
Each subject will receive a ‘Treatment Box’ containing four inhalers (contained in small boxes) 
of study product, corresponding to one of the four treatments (A, B, C or D) assigned to the study 
period as demonstrated in the table above. 
Subjects will be randomized to a treatment regimen in a blinded fashion by assigning 
randomization numbers in ascending sequential order starting with the lowest available 
randomization number at each site. All subjects randomized will be identified by initials, date of 
birth, and a unique seven-digit subject number. The first two-digits will identify the Investigator 
site where the subject was enrolled and the last five will correspond with the randomization 
number of study product ‘Treatment Box’ assigned to the subject. A perforated or two-part label 
will be attached to each of the small boxes containing individual inhalers. Both pieces of the label 
should include the following information: Protocol number, randomization number, space for 
subject’s initials, statement that the study product is for Investigational Use only, space for 
dispensing date and the Sponsor’s name. In addition all subjects will be provided with written 
instructions on how to use the study medication. One part of the label will remain attached to the 
box. The other part will be removed before dispensing and attached to the study product log. 
10.4.5 Study Blind 
The Investigator, staff at the study site, study monitors, and data analysis/management personnel 
will be blinded to the subject assignment. The subject will be requested not to discuss the 
appearance of the study product canister with the Investigator or study staff outside of the 
Independent Dispenser. 
Each study site will have at least one Independent Dispenser. The role of the Independent 
Dispenser is to dispense and collect all study product inhalers from the subjects, observe subject 
dosing in the office and to ensure the study product logs are reported correctly. They should not 
be involved in collecting any efficacy or safety data in the study thus ensuring the integrity of the 
study blind. This will allow the study to be conducted under double-dummy conditions. 
To ensure that information that could potentially bias handling of data is not disclosed, the 
clinical packaging company will hold the randomization scheme until database lock. For each 
subject an unblinding card contained within a sealed envelope will be provided, to be opened in 
case of medical emergency only. The unblinding cards should be stored in a secure location at all 
times. 
The treatment code may be revealed on an individual basis in the case of a serious adverse event 
(SAE) for which the Investigator must know the identity of the study product to initiate 
appropriate treatment. 
All SAEs will be evaluated for expectedness and causality by the Investigator or designee. 
Unblinding of sponsor’s designated Pharmacovigilance personnel  will be done for subjects 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 32 of 59 
 
 
experiencing an  SAE if it is required by FDA for regulatory reporting purposes. This unblinding 
is only for reporting purposes and all other study personnel from the Sponsor, 
 and the 
study site will continue to be blinded to the treatment allocation. 
Where possible, the Sponsor and 
 Medical Monitor should be contacted before breaking 
the blind for any subject. In the event the blind is broken for any reason Sponsor and
 will 
be notified as soon as possible in writing of the details of the occurrence. 
All randomized bottles will be checked for any evidence of tampering. Any subject who has the 
blind broken during the study, or whose randomized bottle shows any evidence of tampering will 
only be eligible for inclusion in the safety analysis. 
At the conclusion of the study, after the database has been locked, each site will be sent a sealed 
envelope containing the full study randomization scheme that should be retained with the study 
documents in the event of an FDA Inspection. 
All study products are similar in size, shape and color. A standard label overlay will be used and 
there is no difference in odor of the products. Therefore, all three products are indistinguishable. 
This will allow the study to be conducted under double-blind conditions, such that neither the 
subject nor the Investigator or study staff members will know the identity of each subject’s 
treatment. 
10.4.6 Compliance 
Subjects will self-administer study treatments in the clinic during each of the Visits 2-5, as per 
dosing instructions provided, and with the Independent Dispenser observing. Subjects who fail to 
administer study product per instructions, or attempt to tamper blinding labels will be considered 
non-compliant. 
10.5 Study Conduct 
10.5.1 Visit 1 (Day -14 to Day -1): Screening 
1. Informed Consent: Subjects who are willing to comply with study procedures will read, 
understand and sign an informed consent. 
2. Baseline Demographics: Collect the subject’s demographic information. 
3. Medical History: Collect the subject’s medical history. Subject must have a documented 
diagnosis of stable, mild asthma as confirmed by prior medical records. 
4. Vital Signs: Blood pressure (BP), heart rate (HR), respiratory rate (RR) and temperature will 
be collected before and after methacholine procedures. 
5. Height and Weight: Height and weight will be collected. 
6. Physical Exam: Perform an examination of head, ear, eyes, nose, throat and lungs. 
7. 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 inclusion in the study. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 33 of 59 
 
 
8. 12-Lead ECG: Subjects may undergo a 12-lead ECG to screen for significant abnormal 
cardio-thoracic findings. 
9. Chest X-ray: Chest x-ray may be performed at the discretion of the Investigator. 
10. Concomitant Medications: Review the subject’s use of concomitant medication within the 
last 6 months. 
11. Spirometry: FEV1, FVC and FEV1/FVC ratio [(FEV1/FVC) x 100] will be recorded before 
and after saline administration. Once the methacholine test is completed, rescue albuterol will 
be administered and spirometry will be performed approximately 15 minutes later until the 
subject’s FEV1 returns to within 90% of the best post-saline FEV1 or until the Investigator 
determines that the FEV1 has stabilized and it is safe to allow the subject to leave the site. 
12. Saline Control Administration: Once Qualifying FEV1 is obtained, a saline control will be 
administered to the subject through a nebulizer. 
13. Methacholine Challenge: Subjects meeting post-saline FEV1 criteria will undergo 
methacholine bronchoprovocation challenge with progressively increasing concentrations to 
determine the subject’s baseline provocation concentration of inhaled methacholine required 
to reduce FEV1 by 20% (PC20) relative to the post-saline value. The maximum concentration 
of methacholine be administered in this step will be 8 mg/mL. Methacholine should be 
diluted per the ATS recommendations and recorded when PC20 is reached. 
14. Pulse Oximetry: Pulse oximetry will be measured during the methacholine challenge. 
15. Inclusion/Exclusion Criteria Review: Review and confirm that subject fulfills all 
inclusion/exclusion criteria for study eligibility. 
16. Provide Diary: Subjects will receive a diary to record AEs or concomitant medications. 
17. Adverse Events: Patients will be questioned about any AEs that occurred during the visit. 
18. Schedule Visit 2 
10.5.2 Visit 2: Period 1 Dosing and Clinical Assessment 
1. Vital Signs: BP, HR, RR and temperature will be collected before and after methacholine 
procedures. 
2. Urine Pregnancy Test: All females of childbearing potential will have a urine pregnancy test 
performed before dosing. The test must be negative for the subject to be eligible for 
continuation in the study. 
3. 12-Lead ECG: Subjects may undergo a 12-lead ECG to screen for significant abnormal 
cardio-thoracic findings at the discretion of the Investigator. 
4. Concomitant Medications: Subjects will be questioned about any changes in concomitant 
medication use since the last visit. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 34 of 59 
 
 
5. Spirometry: FEV1, FVC and FEV1/FVC ratio [(FEV1/FVC) x 100] will be recorded before 
and after saline administration. A pre-treatment evaluation will confirm that pre-challenge 
FEV1 is ≥ 80% of predicted and within 88 and 112% of qualifying spirometry value at 
Screening visit. Spirometry will be performed following the saline administration. Post-saline 
FEV1 should not drop more than 10% from pre-saline (Qualifying) FEV1 and should 
be ≥ 70% of predicted value. Spirometry procedures will be performed after the 
administration of methacholine and will be repeated until PC20 is found. Once the 
methacholine test is completed, rescue albuterol will be administered and spirometry will be 
performed approximately 15 minutes later until the subject’s FEV1 returns to within 90% of 
the best post-saline FEV1 or until the Investigator determines that the FEV1 has stabilized and 
it is safe to allow the subject to leave the site. 
6. Saline Control Administration: Once Qualifying FEV1 is obtained, a saline control will be 
administered to the subject through a nebulizer. 
7. Prime and Dispense Study Product and Instructions: An Independent Dispenser will 
prime and dispense randomized treatment (a set of four inhalers) to subject, along with a set 
of dosing instructions. Subjects will be assigned a randomization number. A review of inhaler 
dosing technique, priming and preparation of inhalers will be performed. 
8. Dosing: Before the methacholine challenge, subjects will self-administer study treatment (one 
puff from each of the four inhalers) with the Independent Dispenser observing. The time of 
last actuation will be recorded, as well as the adequacy of inhaler technique. 
9. Methacholine Challenge: Approximately 15 minutes after the last inhalation of study 
product, subjects will undergo methacholine bronchoprovocation challenge with progressive 
concentrations to determine the subject’s PC20. The 20% reduction in FEV1 will be 
determined relative to the post-saline FEV1. Methacholine should be diluted per the ATS 
recommendations. 
10. Pulse Oximetry: Pulse oximetry will be measured during the methacholine challenge and 
recorded when PC20 is reached. 
11. Assessment of Compliance: The site staff/Independent Dispenser will record any non-
compliance to dosing instructions. 
12. Provide Diary: Subjects will receive a diary to record AEs or concomitant medications. 
13. Collect/Review Diary: Diaries will be collected and reviewed for compliance with the 
protocol. 
14. Adverse Events: Subjects will be questioned about AEs since the last visit. 
15. Schedule next visit. 
10.5.3 Visit 3: Period 2 Dosing and Clinical Assessment 
The interval between Visit 2 dosing and Visit 3 dosing should be at least 48 hours 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 35 of 59 
 
 
1. Vital Signs: BP, HR, RR and temperature will be collected before and after methacholine 
procedures. 
2. Urine Pregnancy Test: All females of childbearing potential will have a urine pregnancy test 
performed before dosing. The test must be negative for the subject to be eligible for 
continuation in the study. 
3. 12-Lead ECG: Subjects may undergo a 12-lead ECG to screen for significant abnormal 
cardio-thoracic findings at the discretion of the Investigator. 
4. Concomitant Medications: Subjects will be questioned about any changes in concomitant 
medication use since the last visit. 
5. Spirometry: FEV1, FVC and FEV1/FVC ratio [(FEV1/FVC) x 100] will be recorded before 
and after saline administration. A pre-treatment evaluation will confirm that pre-challenge 
FEV1 is ≥ 80% of predicted and within 88 and 112% of qualifying spirometry value at 
Screening visit. Spirometry will be performed following the saline administration. Post-saline 
FEV1 should not drop more than 10% from pre-saline (Qualifying) FEV1 and should 
be ≥ 70% of predicted value. Spirometry procedures will be performed after the 
administration of methacholine and will be repeated until PC20 is found. Once the 
methacholine test is completed, albuterol will be administered and spirometry will be 
performed approximately 15 minutes later until the subject’s FEV1 returns to within 90% of 
the best post-saline FEV1 or until the Investigator determines that the FEV1 has stabilized and 
it is safe to allow the subject to leave the site. 
6. Saline Control Administration: Once Qualifying FEV1 is obtained, a saline control will be 
administered to the subject through a nebulizer. 
7. Prime and Dispense Study Product and Instructions: An Independent Dispenser will 
prime and dispense randomized treatment (a set of four inhalers) to subject, along with a set 
of dosing instructions. A review of inhaler dosing technique, priming and preparation of 
inhalers will be performed. 
8. Dosing: Before the methacholine challenge, subjects will self-administer study treatment (one 
puff from each of the four inhalers) with the Independent Dispenser observing. The time of 
last actuation will be recorded, as well as the adequacy of inhaler technique. 
9. Methacholine Challenge: Approximately 15 minutes after the last inhalation of study 
product, subjects will undergo methacholine bronchoprovocation challenge with progressive 
concentrations to determine the subject’s PC20. The 20% reduction in FEV1 will be 
determined relative to the post-saline FEV1. Methacholine should be diluted per the ATS 
recommendations. 
10. Pulse Oximetry: Pulse oximetry will be measured during the methacholine challenge and 
recorded when PC20 is reached. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 36 of 59 
 
 
11. Assessment of Compliance: The site staff/Independent Dispenser will record any non-
compliance to dosing instructions. 
12. Provide Diary: Subjects will receive a diary to record AEs or concomitant medications. 
13. Collect/Review Diary: Diaries will be collected and reviewed for compliance with the 
protocol. 
14. Adverse Events: Subjects will be questioned about AEs since the last visit. 
15. Schedule next visit 
10.5.4 Visit 4: Period 3 Dosing and Clinical Assessment 
The interval between Visit 3 dosing and Visit 4 dosing should be at least 48 hours 
1. Vital Signs: BP, HR, RR and temperature will be collected before and after methacholine 
procedures. 
2. Urine Pregnancy Test: All females of childbearing potential will have a urine pregnancy test 
performed before dosing. The test must be negative for the subject to be eligible for 
continuation in the study. 
3. 12-Lead ECG: Subjects may undergo a 12-lead ECG to screen for significant abnormal 
cardio-thoracic findings at the discretion of the Investigator. 
4. Concomitant Medications: Subjects will be questioned about any changes in concomitant 
medication use since the last visit. 
5. Spirometry: FEV1, FVC and FEV1/FVC ratio [(FEV1/FVC) x 100] will be recorded before 
and after saline administration. A pre-treatment evaluation will confirm that pre-challenge 
FEV1 is ≥ 80% of predicted and within 88 and 112% of qualifying spirometry value at 
Screening visit. Spirometry will be performed following the saline administration. Post-saline 
FEV1 should not drop more than 10% from pre-saline (Qualifying) FEV1 and should 
be ≥ 70% of predicted value. Spirometry procedures will be performed after the 
administration of methacholine and will be repeated until PC20 is found. Once the 
methacholine test is completed, albuterol will be administered and spirometry will be 
performed approximately 15 minutes later until the subject’s FEV1 returns to within 90% of 
the best post-saline FEV1 or until the Investigator determines that the FEV1 has stabilized and 
it is safe to allow the subject to leave the site. 
6. Saline Control Administration: Once Qualifying FEV1 is obtained, a saline control will be 
administered to the subject through a nebulizer. 
7. Prime and Dispense Study Product and Instructions: An Independent Dispenser will 
prime and dispense randomized treatment (a set of four inhalers) to subject, along with a set 
of dosing instructions. A review of inhaler dosing technique, priming and preparation of 
inhalers will be performed. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 37 of 59 
 
 
8. Dosing: Subjects will self-administer study treatment (one puff from each of the four 
inhalers) with the Independent Dispenser observing. The time of last actuation will be 
recorded, as well as the adequacy of inhaler technique. 
9. Methacholine Challenge: Approximately 15 minutes after the last inhalation of study 
product, subjects will undergo methacholine bronchoprovocation challenge with progressive 
concentrations to determine the subject’s PC20. The 20% reduction in FEV1 will be 
determined relative to the post-saline FEV1. Methacholine should be diluted per the ATS 
recommendations. 
10. Pulse Oximetry: Pulse oximetry will be measured during the methacholine challenge and 
recorded when PC20 is reached. 
11. Assessment of Compliance: The site staff/Independent Dispenser will record any non-
compliance to dosing instructions. 
12. Provide Diary: Subjects will receive a diary to record AEs or concomitant medications 
throughout the study. 
13. Adverse Events: Subjects will be questioned about AEs since the last visit. 
14. Collect/Review Diary: Diaries will be collected and reviewed for compliance with the 
protocol. 
15. Schedule next visit 
10.5.5 Visit 5: Period 4 Dosing and Clinical Assessment, End of Study 
The interval between Visit 4 dosing and Visit 5 dosing should be at least 48 hours 
1. Vital Signs: BP, HR, RR and temperature will be collected before and after methacholine 
procedures. 
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 before dosing. The test must be negative for the subject to be eligible for 
continuation in the study. 
4. 12-Lead ECG: Subjects will undergo a 12-lead ECG to screen for significant abnormal 
cardio-thoracic findings at the discretion of the Investigator. 
5. Concomitant Medications: Subjects will be questioned about any changes in concomitant 
medication use since the last visit. 
6. Spirometry: FEV1, FVC and FEV1/FVC ratio [(FEV1/FVC) x 100] will be recorded before 
and after saline administration. A pre-treatment evaluation will confirm that pre-challenge 
FEV1 is ≥ 80% of predicted and within 88 and 112% of qualifying spirometry value at 
Screening visit. Spirometry will be performed following the saline administration. Post-saline 
FEV1 should not drop more than 10% from pre-saline (Qualifying) FEV1 and should be ≥ 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 38 of 59 
 
 
70% of predicted value. Spirometry procedures will be performed after the administration of 
methacholine and will be repeated until PC20 is found. Once the methacholine test is 
completed, albuterol will be administered and spirometry will be performed approximately 15 
minutes later until the subject’s FEV1 returns to within 90% of the best post-saline FEV1 or 
until the Investigator determines that the FEV1 has stabilized and it is safe to allow the 
subject to leave the site. 
7. Saline Control Administration: Once Qualifying FEV1 is obtained, a saline control will be 
administered to the subject through a nebulizer. 
8. Prime and Dispense Study Product and Instructions: An Independent Dispenser will 
prime and dispense randomized treatment (a set of four inhalers) to subject, along with a set 
of dosing instructions. A review of inhaler dosing technique, priming and preparation of 
inhalers will be performed. 
9. Dosing: Before the methacholine challenge, subjects will self-administer study treatment (one 
puff from each of the four inhalers) with the Independent Dispenser observing. The time of 
last actuation will be recorded, as well as the adequacy of inhaler technique. 
10. Methacholine Challenge: Approximately 15 minutes after the last inhalation of study 
product, subjects will undergo methacholine bronchoprovocation challenge with progressive 
concentrations to determine the subject’s PC20. The 20% reduction in FEV1 will be 
determined relative to the post-saline FEV1. Methacholine should be diluted per the ATS 
recommendations. 
11. Pulse Oximetry: Pulse oximetry will be measured during the methacholine challenge and 
recorded when PC20 is reached. 
12. Assessment of Compliance: The site staff/Independent Dispenser will record any non-
compliance to dosing instructions. 
13. Adverse Events: Subjects will be questioned about AEs since the last visit. 
14. Collect/Review Diary: Completed diaries will be collected and reviewed for compliance 
with the protocol. 
15. Exit patient from the study 
10.6 Study Procedures 
10.6.1 Informed Consent 
At Visit 1, before performing any study-related procedures the study subject must sign the IRB-
approved ICF. The ICF will be reviewed and approved by an IRB before study commencement. 
No subject will be entered into the study without reading, understanding and signing an ICF. If 
the ICF is required in any language besides English, translation will be performed by a certified 
translator and then approved by the IRB. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 39 of 59 
 
 
10.6.2 Baseline Demographics 
At Visit 1, each subject will be required to provide basic demographic information (i.e., date of 
birth, sex, ethnicity, and race and tobacco use/smoking history). 
10.6.3 Medical History 
At Visit 1, subjects will be questioned about medical history, including acute and chronic medical 
history and medical history relevant to their asthma. Subject must have a documented diagnosis 
of stable, mild asthma as confirmed by prior medical records. 
10.6.4 Vital Signs 
The subject’s vital signs will be recorded (pulse, BP, temperature and respiration rate) before and 
after methacholine procedures at each clinic visit. 
10.6.5 Height and Weight 
Height and weight will be collected at Visit 1. 
10.6.6 Physical Exam 
At Visits 1 and 5, 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. 
10.6.7 Urine Pregnancy Test 
Urine pregnancy tests on women of childbearing potential will be performed at each clinic visit. 
The test must be negative for the subject to be eligible for inclusion 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. 
Subjects with a positive pregnancy test during Screening will not be enrolled in the study. 
Subjects who report they have become pregnant or who have a positive pregnancy test at the end 
of study visit will be followed to completion of the pregnancy. The pregnancy will be reported as 
an AE. 
10.6.8 12-Lead ECG 
Subjects will undergo a 12-lead ECG at Screening. An ECG may be performed at subsequent 
visits at the discretion of the Investigator. Any clinically significant findings will be noted. 
10.6.9 Chest X-Ray 
A chest x-ray may be performed at Visit 1 at the discretion of the Investigator. 
10.6.10 Concomitant Medication Use 
At Visit 1, subjects will be questioned about current and concomitant medication use over the 
previous 6 months. At all subsequent visits, subjects will be questioned about ongoing or new 
concomitant medication use. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 40 of 59 
 
 
10.6.11 Adverse Events 
At the end of Visit 1, patients will be questioned about any AEs that occurred during the visit. At 
Visits 2, 3, 4, and 5 patients will be questioned regarding any changes in their medical status 
since their previous visit. Any significant changes observed after ICF signing will be reported as 
AEs. 
10.6.12 Spirometry Testing 
FEV1 and FVC measurements will be performed using the KoKo® Pulmonary Function Testing 
Spirometer with built-in dosimeter (Koko® Digidoser, Item# 323205) or the KoKo Dosimeter 
(Item # 414400-A) in accordance with the ATS Guidelines for Methacholine and Exercise 
Challenge Testing.17 Instructions and demonstration of use will be provided to subjects at the time 
of receipt of randomized treatment. 
FEV1 measurement is reported in liters, and data are digitally displayed on the KoKo Dosimeter 
device monitor for recording. Normal values for FEV1 vary according to age, sex, height, mass 
and ethnicity. To account for such variations, FEV1 % predicted will be calculated. FEV1 % 
predicted is defined as subject’s FEV1 value expressed as a percentage of the reference average 
FEV1 for a person of similar age, sex and body composition. 
FEV1, FVC and FEV1/FVC ratio [(FEV1/FVC) x 100] will be recorded before and after saline 
administration at each visit. Qualifying FEV1 at Screening must be ≥ 80% of predicted value. 
Spirometry will be performed before and after the saline administration. Post-saline FEV1 should 
not drop more than 10% from pre-saline (Qualifying) FEV1 and should be ≥ 70% of predicted 
value. If the subject fails to meet either requirement, the challenge must be stopped, rescue 
albuterol administered and the visit should be rescheduled. Subjects who fail three consecutive 
visits should be dropped from the study. 
Pre-treatment evaluations will be completed at each dosing visit. This evaluation will confirm that 
pre-challenge FEV1 is ≥ 80% of predicted and within 88 and 112% of qualifying spirometry value 
at Screening visit. After the first inhalation of saline control is administered, the FEV1 should not 
drop more than 10% compared to pre-challenge value. If the subject fails to meet either 
requirement, the challenge must be stopped, albuterol administered and the visit should be 
rescheduled. Subjects who fail three consecutive visits should be dropped from the study. 
Spirometry procedures will be performed after the administration of methacholine and will be 
repeated until PC20 is found. After the procedures have been completed, albuterol will be 
administered to reverse airway obstruction and subjects will be followed until FEV1 returns to 
within 90% of the best FEV1 captured during the saline stage on that day or until the Principal 
Investigator determines that the FEV1 has stabilized and it is safe to allow the subject to leave the 
site. 
10.6.13 Saline Control Administration 
Once Qualifying FEV1 is obtained, a saline control will be administered to the subject through a 
nebulizer. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 41 of 59 
 
 
10.6.14 Methacholine Challenge 
The spirometry procedures and the methacholine bronchoprovocation challenges in this study are 
to be performed in accordance with the ATS Guidelines for Methacholine and Exercise Challenge 
Testing. 
Screening 
Subjects meeting FEV1 criteria will undergo methacholine bronchoprovocation challenge with 
progressively increasing concentrations to determine the subject’s baseline provocation 
concentration of inhaled methacholine required to reduce FEV1 by 20% (PC20) relative to the 
post-saline value.  
Methacholine should be prepared in doubling concentrations as recommended by the ATS for the 
two-minute tidal breathing dosing protocol.17 
Saline (0.0 mg/mL), 0.03 mg/mL, 0.06 mg/mL, 0.125 mg/mL, 0.25 mg/mL, 0.50 mg/mL, 1 
mg/mL, 2 mg/mL, 4 mg/mL, 8 mg/mL 
The maximum concentration of methacholine be administered in this step will be 8 mg/mL. 
Subjects who do not respond to methacholine doses at or below 8 mg/mL will not be eligible for 
enrollment in the study. 
Dosing Visit 
Approximately 15 minutes after the last inhalation of study product, a methacholine 
bronchoprovocation challenge will be given with progressive concentrations in order to determine 
the PC20. The 20% reduction in FEV1 will be determined relative to the post-saline FEV1.  
Methacholine should be prepared in the following concentrations: 
Saline (0.0 mg/mL), 0.03 mg/mL, 0.06 mg/mL, 0.125 mg/mL, 0.25 mg/mL, 0.50 mg/mL, 1 
mg/mL, 2 mg/mL, 4 mg/mL, 8 mg/mL, 16 mg/mL, 32 mg/mL, 64 mg/mL, 128 mg/mL 
The maximum methacholine dose at each dosing visit will be 128 mg/mL. 
10.6.15 Pulse Oximetry 
Pulse oximetry will be monitored during the methacholine challenge and recorded when PC20 is 
reached. 
10.6.16 Prime and Dispense Study Product and Instructions 
Before dispensing the study product, the Independent Dispenser will prime the inhaler of study 
product immediately before using for the first time by releasing 3 test sprays into the air, shaking 
well for 5 seconds before each spray, until a uniform spray is obtained. Priming of randomized 
study product should occur in a separate area, away from subjects. The Independent Dispenser 
will dispense 4 inhalers of randomized study product to each eligible subject, along with a set of 
dosing instructions. Subjects will be asked to dose in clinic with Independent Dispenser 
observing. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 42 of 59 
 
 
10.6.17 Collecting Study Product 
Study product inhalers will be collected at each visit following dosing. 
10.6.18 Provide, Collect, and Review Diary 
Subjects will be provided dosing instructions to facilitate consistent dosing before 
pharmacodynamic (PD) recordings at each clinic visit. 
Subjects will be provided with a diary, with instructions, to record AEs and concomitant 
medications throughout the study. The diary will be collected and reviewed for compliance with 
the protocol at Visits 2-5 by the study staff. 
10.7 Adverse Events 
The subjects will be monitored throughout the study for any AEs. Adverse events will be collected 
through both solicited and unsolicited means and subsequently coded in tabular form using the 
MedDRA (Version 21.0 or higher) Adverse Event Dictionary. The subjects will be encouraged to 
report signs, symptoms, and any changes in health to the clinic staff. Severity of each AE will be 
determined by the clinic staff based on observation and questioning of the subjects. The Investigator 
will judge the relationship of the event to the study product. Adverse events should be followed up until 
end of study visit or last dose of study product administration.. 
10.7.1 Definitions 
Adverse Event 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with treatment. An AE can therefore be any unfavorable and unintended sign, 
symptom or disease, temporally associated with the use of a medicinal (investigational) product, 
whether or not related to this product. This includes events not seen at baseline, or worsened even 
if present at baseline. 
Action taken with study product: 
• 
Drug Withdrawn 
• 
Dose not changed 
• 
Not Applicable 
Outcome: 
• 
Recovered/ Resolved 
• 
Recovering/ Resolving 
• 
Recovered/ resolved with sequelae 
• 
Not Recovered/ Not Resolved 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 43 of 59 
 
 
• 
Fatal 
• 
Unknown 
10.7.2 Events Not to Be Considered Adverse Events 
Medical baseline or pre-dosing conditions present at the initial study visit that do not worsen in 
severity or frequency during the study are defined as Baseline Medical Conditions and are not to 
be considered AEs. 
10.7.3 Severity of Adverse Events 
Severity of AE 
The severity of the AE will be graded by the Investigator using the following criteria as 
guidelines: 
• 
MILD: Awareness of symptom but does not interfere with routine activities. 
• 
MODERATE: Discomfort sufficient to interfere with routine activities. 
• 
SEVERE: Impossible to perform routine activities. 
10.7.4 Relationship of Adverse Events 
Relationship to the Study Product 
TERM 
DEFINITION 
CLARIFICATION 
Unrelated 
Those AEs which, after careful consideration, are clearly due to extraneous causes (medical history, 
demography details, disease, environment, etc.) 
Unlikely 
A clinical event, including laboratory test 
abnormality, with a temporal relationship to 
drug administration which makes a causal 
relationship improbable, and in which other 
drugs, chemicals or underlying disease 
provide plausible explanations. 
1. It does not follow a reasonable temporal sequence 
(Improbable 
temporal 
relationship) 
from 
administration of the drug. 
2. It could also be explained by patient's concurrent 
disease, environmental factors, medical history and 
other concomitant drugs or chemicals including food-
drug interactions 
Possibly 
A clinical event, including laboratory test 
abnormality, 
with 
a 
reasonable 
time 
sequence to administration of the drug, but 
which 
could 
also 
be 
explained 
by 
concurrent disease or other drugs or 
chemicals. Information on drug withdrawal 
may be lacking or unclear. 
1. It follows a reasonable temporal sequence from 
administration of the drug. 
2. It could also be explained by patient's concurrent 
disease, environmental factors, medical history and 
other concomitant drugs or chemicals (including food-
drug interactions). 
3. There is no information or uncertainty with regard to 
what has happened after stopping the drug. 
Probably 
A clinical event, including laboratory test 
abnormality, 
with 
a 
reasonable 
time 
sequence to administration of the drug, 
1. It follows a reasonable temporal sequence from 
administration of the drug. 
2. It could not be readily explained (unlikely) by the 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 44 of 59 
 
 
TERM 
DEFINITION 
CLARIFICATION 
unlikely to be attributed to concurrent 
disease or other drugs or chemicals, and 
which follows a clinically reasonable 
response on withdrawal (de-challenge). Re-
challenge information is not required to 
fulfill this definition. 
patient’s concurrent disease, environmental factors, 
medical history and other concomitant drugs or 
chemicals including food-drug interactions. 
3. It disappears or decreases in severity on cessation or 
reduction in dose or on administration of a specific 
antagonist wherever possible. There are important 
exceptions when an adverse event does not disappear 
upon discontinuation of the drug, yet drug relatedness 
clearly exists. 
4. No re-challenge information is available or possible. 
Certainly 
A clinical event, including laboratory test 
abnormality, occurring in a plausible time 
relationship to drug administration, and 
which cannot be explained by concurrent 
disease or other drugs or chemicals. The 
response to withdrawal of the drug (de-
challenge) should be clinically plausible. 
The 
event 
must 
be 
definitive 
pharmacologically or phenomenologically, 
using a satisfactory re-challenge procedure 
if necessary. 
1. It follows a plausible time sequence to drug intake, 
this means that there is a positive argument in 
sufficient detail to support the view that the drug is 
causally involved, pharmacologically or pathologically 
e.g., pharmacokinetics and type of reaction.  
2. It could not be explained by patient's concurrent 
disease, environmental factors, medical history and 
other concomitant drugs or chemicals including food-
drug interactions (i.e., no alternative causes). 
3. It disappears or decreases in severity on cessation or 
reduction in dose or on administration of a specific 
antagonist wherever possible. 
4. It is an objective and specific medical disorder or a 
recognized pharmacological phenomenon for instance 
‘grey baby syndrome’ and chloramphenicol or 
anaphylaxis immediately after the administration of a 
drug that had been given previously. This means that 
any other event is automatically excluded and can 
never qualify for ‘Certain’ (even in the case of a 
positive re-challenge observation).  
5. It reappears on re-administration of the drug (only if 
ethically correct i.e., in case of non-serious, and easily 
treatable AEs).  
10.7.5 Expectedness Assessment 
The sponsor’s designated Pharmacovigilance personnel will be responsible for determining 
expectedness. 
The most recent version of the albuterol sulfate Investigator’s Brochure will serve as Reference 
Safety Information for determination of expectedness. 
The package insert of PROAIR® HFA (albuterol sulfate) Inhalation Aerosol will be used for 
assessment of expectedness of SAEs occurring in patients treated with PROAIR® HFA. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
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10.8 Serious Adverse Events 
10.8.1 Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose : 
• 
Results in death: includes all deaths, even those that appear to be completely unrelated to 
study treatment (e.g., car accident where subject is a passenger). 
• 
Is life-threatening: in the view of the Investigator, the subject is at immediate risk of 
death at the time of the event. 
• 
Results in persistent or significant disability or incapacity (substantial disruption of one’s 
ability to conduct normal life). 
• 
Requires insubject hospitalization or prolongation of existing hospitalization. 
• 
Causes congenital anomaly or birth defect.an important medical event that may not be 
immediately life-threatening or result in death or hospitalization, but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the serious 
outcomes listed above (e.g., intensive treatment in an emergency room, convulsions that 
do not result in hospitalizations). Emergency Room visits that require medical or surgical 
intervention to prevent one of the other serious outcomes listed above are considered an 
SAE. 
10.8.2 Events That Do Not Meet the Definition of a Serious Adverse Event 
Elective hospitalizations to administer, or to simplify study treatment or study procedures (e.g., 
an overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (e.g., undesirable effects of any administered 
treatment) must be documented and reported as SAEs). 
10.8.3 Serious Adverse Event Reporting 
Any SAE, whether deemed drug-related or not, must be reported by the Investigator to 
 
and sponsor’s designated Pharmacovigilance personnel by email/fax within 24 hours after the 
Principal Investigator or Study Coordinator becomes aware of its occurrence. The Principal 
Investigator or the Principal Investigator’s designee must complete an SAE Form and email/fax it 
to 
 and 
 within 24 hours of notification 
of the event. 
Any SAEs should be reported to 
 and 
 
within 24 hours. Following is the contact information: 
 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
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The US FDA shall be initially notified by an expedited safety report of any SAE by the Sponsor, 
no later than 15 calendar days from the “date learned” of the event. The US FDA will be initially 
notified within 7 calendar days of any fatal or life-threatening SAEIf the safety report submitted 
within 7 calendar days is complete, an additional submission within 15 days from ”day 0” is not 
required.  
Sponsor’s designeewill inform other investigators involved in the study within 15 days of 
becoming aware of the occurrence of the SAE or as per regulation. 
All AEs encountered during the study will be reported on the appropriate form and summarized 
in the final report. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
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10.9 Definition of the Adverse Event Reporting Period: 
The AE/SAE reporting period for safety surveillance begins after the patient has signed ICF and 
continues until end of study visit or early termination visit. 
10.10 Monitoring of Subjects with Adverse Events 
Adverse events will be recorded and assessed continuously throughout the study and will be assessed 
for final outcome at the End of Study visit. All AE/SAEs ongoing at the End of Study visit must be 
monitored and followed up by the Investigator until stabilization/resolution or until the outcome is 
known as per medical judgment of Investigator, unless the subject is documented as “lost to follow-
up”. Reasonable attempts to obtain this information must be made and documented. It is also the 
responsibility of the Investigator to ensure that any necessary additional therapeutic measures and 
follow-up procedures are performed.  
Any AE/SAE that occurs after the End of Study visit or early termination visit will be reported if it is 
considered related to study product by Investigator. 
10.11 Pregnancy  
A pregnancy test will be performed at Screening and at all visits specified in the protocol. Subjects 
with a positive test at Screening will be excluded from study. If a subject becomes pregnant during 
the study, the pregnancy will be recorded as a significant medical event and reported per SAE 
reporting procedure and the subject will be withdrawn from the study immediately. Women of 
childbearing potential will be instructed to practice an acceptable method of birth control for the 
duration of the study. Similarly, male subjects enrolled to the study will be instructed not to father a 
child and avoid passage of semen to their partner by using an acceptable contraceptive method 
discussed by the Investigator during their enrollment into the study. If a female partner of the male 
subject becomes pregnant during the study, the pregnancy will be recorded appropriately. The 
pregnancy reporting form will be completed and submitted to sponsor’s designated 
Pharmacovigilance personnel within timelines defined in protocol for SAE reporting. All pregnancies 
(female subject and female partner of male subject) shall be followed every three months until its 
outcome and one month post-delivery. If there are abnormalities present at delivery, the newborn will 
be followed for an appropriate period, up to three months, to assess the functional and health status. If 
there is an SAE in association with pregnancy or delivery, the SAE will be followed until resolution 
or stabilization. 
11.0 STATISTICAL METHODS 
11.1 Statistical Plan 
A statistical analysis plan, detailing the intended statistical analysis 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 statistical analysis plan. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
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All statistical analysis will be conducted using SAS®, Version 9.4. A dose-scale pharmacodynamic 
(PD) analysis will be conducted using NONMEM®. Datasets will be prepared using headings from 
Clinical Data Standards Interchange Consortium (CDISC) Study Data Tabulation Model (SDTM) 
implementation for human clinical trials and Analysis Dataset Model (ADaM). 
11.2 Determination of Sample Size 
The sample size estimation for this study was based on data from the study by Newhouse et al. that 
reported the bronchoprotective effect of inhaled salbutamol (albuterol) on methacholine PC20FEV1.2  
The highest within-subject coefficient of variability (COV) value for ln-transformed PC20 was 
estimated as 0.846 from the mean ratio and SD values for the PC20 at the 200 and 100 mcg doses 
(Table 1 in reference 2). Based on this COV, 98 evaluable subjects would be required in the PD 
population to demonstrate pharmacodynamic equivalence (i.e., 90% confidence interval on relative 
bioavailability [F] is within the bioequivalence limits of 0.67 to 1.50) with 90% power for a crossover 
study, assuming a true ratio of F = 1.1. To allow for approximately 20% of subjects that may 
discontinue from the study or have major protocol violations, and therefore not qualify for the PD 
population, up to 123 subjects will be randomized in the study.  
11.3 Study Populations 
11.3.1 Per-Protocol (PP) Population 
The PP population will include all subjects who: 
• 
Completed all four randomized treatment periods. 
• 
Were compliant with study treatment dosing procedures. 
• 
Did not use any restricted concomitant medications. 
• 
Did not have any other significant protocol deviations. 
11.3.2 Pharmacodynamic (PD) Population 
The PD population used in the dose-scale analyses will include patients who: 
• 
Completed at least one of the four randomized treatment periods. 
• 
Were compliant with study treatment dosing procedures. 
• 
Did not use any restricted concomitant medications. 
• 
Did not have any other significant protocol deviations. 
11.3.3 Safety Populations 
The Safety population will include all subjects who administered at least one actuation of any of 
the study products. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
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11.4 Subject Characteristics 
The following subject demographic characteristics will be summarized separately in the PP, PD and 
Safety 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) 
• 
Tobacco use (yes/no) 
• 
Number of years subject has suffered from symptoms caused by asthma 
• 
Qualifying spirometry 
• 
PC20FEV1 
11.5 Primary Pharmacodynamic Endpoint 
The primary pharmacodynamic endpoint will be the post-dose PC20, which is the provocative 
concentration of the methacholine challenge agent required to reduce the FEV1 by 20% following 
administration of differing doses of albuterol (or placebo) by inhalation. The 20% reduction in FEV1 
will be determined relative to the post-saline FEV1 measure before the placebo or albuterol 
administration. 
11.6 Pharmacodynamic Equivalence 
The primary bioequivalence evaluation using the dose-scale analysis will be performed using the PD 
population; NONMEM allows for the use of all available data, without biasing the F estimation. This 
bioequivalence test will be conducted at the 0.05 significance level. If bioequivalence is achieved for 
the PD population, the same test will also be conducted on the PP population at the same significance 
level. If bioequivalence is not achieved for the PD population then no test will be conducted on the 
PP. As a result of this step-down approach, no adjustment is necessary on the significance levels for 
either test. 
Pharmacodynamic equivalence between Test and Reference products will be based on the Dose-Scale 
method of analysis of the post-dose PC20FEV1 (mg/mL) data using non-linear Emax modeling, as 
outlined in the FDA Draft Guidance on Orlistat capsule.1 Alternative models may be tested if 
warranted by the data, and these models as well as the specific criteria related to their use, will be 
described in the statistical analysis plan. The methacholine PC20FEV1 will be calculated by linear 
interpolation from the observed data relating the % decrease in FEV1 from the post-saline FEV1 to the 
concentration of methacholine that provokes at least a 20% decrease in FEV1. This interpolation will 
be based on log transformed methacholine concentrations. In the event that subjects receiving the 
maximum concentration of methacholine (128 mg/mL) at any treatment visit (Visits 2-5) do not 
achieve at least a 20% fall in FEV1, then they will have their PC20FEV1 data interpolated as though 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 50 of 59 
 
 
they had achieved positivity at 128 mg/mL (i.e., PC20FEV1 will be imputed as 128 mg/mL) and will 
be included in the PP population. The PC20FEV1 data will be log-transformed if they are log-normally 
distributed. 
If the 90% confidence interval for F falls within 67.00-150.00% then pharmacodynamic equivalence 
will be considered to have been demonstrated. F is the potency ratio of the doses of Test and 
Reference formulations that produce an equivalent pharmacodynamic response at the ED50 of the 
Reference dose-response Emax curve. The 90% confidence interval for F will be estimated by a 
bootstrap procedure using Efron’s bias-corrected and accelerated (BCA) method. 
11.6 Safety Analysis 
All study subjects who receive at least one actuation of any of the study products will be included in 
the comparative safety analysis. Adverse events will be classified using standard Medical Dictionary 
for Regulatory Activities (MedDRA) terminology Version 21.0 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. If sufficient data exist, then AEs frequencies will be 
compared among treatments using Fisher’s exact test. 
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 
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, 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 2013.19-22The Investigator will permit trial-related 
monitoring, audits, IRB review and regulatory inspections providing direct access to source 
data/documents. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
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12.2.1 Protocol 
The Investigator indicated on Form FDA 1572 will act as the Principal Investigator at each study 
site. Protocols will be noted as approved by placement of the 
 
signature 
on the signature page. The Sponsor of the study will also approve the protocol by having a study-
responsible individuals sign the protocol signature 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. 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. The person 
obtaining consent will also sign and date the form, along with the Investigator who will sign the 
ICF to verify that the subject has indeed received information. A copy of the ICF will be provided 
to the subject. 
12.2.3 Protocol and Informed Consent Changes 
Revisions to the original protocol will be documented in amendments, incorporated as a preface 
to the new version and approved by the IRB. 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. Revisions to the original ICF will also be approved by the IRB. The approvals will be 
processed in 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 Electronic Case Report Forms 
All subjects will be identified by initials, and a unique subject number. Source documents will be 
used to record all study-related data. Source document entries will be used to complete electronic 
case report forms (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 4 (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 (after the 
database has been locked) all used and unused study product, other than that which has been 
randomly selected for retention samples, will be returned to Sponsor or designee. 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
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12.2.6 Drug Storage 
All study product will be stored at controlled room temperature between 15° and 25°C (59° and 
77°F), away from direct sunlight (or freezing temperatures) in a secure place with access by 
authorized individuals only. Any excursions from the permitted range of 15–25ºC (59º–77ºF) will 
require prompt notification to 
 and thereafter 
 will notify the Sponsor. The 
inhalers are to be stored with actuators ‘down’. 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 product will be returned to
 
12.2.7 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.23 
12.2.8 Record Retention 
All drug accountability records, CRFs, source data and related regulatory documents must be 
retained for at least two years following completion of the study or for two years after the Test 
product has been approved for marketing by the FDA, if applicable. 
12.2.9 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. 
12.2.10 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. 
12.2.11 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 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 53 of 59 
 
 
Technical Document (eCTD) and International Conference on Harmonisation (ICH) formatting 
standards and guidelines.24 Abbreviated New Drug application (ANDA) 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. 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
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  Page 54 of 59 
 
 
13.0 REFERENCES 
1 
FDA. Draft Guidance on Orlistat.  (2010). 
2 
Newhouse, M. T., Patel, P. & Parry-Billings, M. Protection against methacholine-induced 
bronchospasm: salbutamol pMDI versus Clickhaler DPI. Eur Respir J 21, 816-820 (2003). 
3 
Matthew C. Miles, S. P. P. Asthma, <http://www.merckmanuals.com/professional/pulmonary-
disorders/asthma-and-related-disorders/asthma> (2013). 
4 
Akinbami, L. J. et al. Trends in asthma prevalence, health care use, and mortality in the United 
States, 2001-2010. NCHS Data Brief, 1-8 (2012). 
5 
CDC. Asthma in the US. CDC Vital Signs (2011). 
6 
Beam, D. S. Value of inhaled corticosteroid therapy in long-term asthma management. P T 35, 
377-416 (2010). 
7 
Martin, R. J. Therapeutic significance of distal airway inflammation in asthma. J Allergy Clin 
Immunol 109, S447-460 (2002). 
8 
NAEPP. Guidelines for the Diagnosis and Management of Asthma. (2007). 
9 
Meurs, H., Gosens, R. & Zaagsma, J. Airway hyperresponsiveness in asthma: lessons from in 
vitro model systems and animal models. Eur Respir J 32, 487-502, 
doi:10.1183/09031936.00023608 (2008). 
10 
CDC.    (ed CDC) (2006). 
11 
NIH.  Vol. 12-5075  (ed Lung U.S. Department of Health and Human Services; National 
Institutes of Health; National Heart, and Blood Institute) (2012). 
12 
Wood, P. R. & Hill, V. L. Practical management of asthma. Pediatr Rev 30, 375-385; quiz 385, 
doi:10.1542/pir.30-10-375 (2009). 
13 
Yawn, B. P. Factors accounting for asthma variability: achieving optimal symptom control for 
individual patients. Prim Care Respir J 17, 138-147, doi:10.3132/pcrj.2008.00004 (2008). 
14 
NIH. How Is Asthma Treated and Controlled?, <http://www.nhlbi.nih.gov/health/health-
topics/topics/asthma/treatment> (2014). 
15 
Adams, N. P. & Jones, P. W. The dose-response characteristics of inhaled corticosteroids when 
used to treat asthma: an overview of Cochrane systematic reviews. Respir Med 100, 1297-1306, 
doi:10.1016/j.rmed.2006.04.015 (2006). 
16 
Penslar. IRB Guidebook, Office for Human Rights Protection. US Department of Health and 
Human Services (1993). 
17 
American Thoracic Society - Guidelines for Methacholine and Exercise Challenge Testing. 
American journal of respiratory and critical care medicine 161, 309-329 (1999). 
18 
FDA. Draft Guidance on Albuterol Sulfate.  (2013). 
19 
FDA. 21CFR 320 Procedures for Determining the Bioavailability or Bioequivalence of Drug 
Products. Department of Health and Human Services, Subchapter D-Drugs for Human Use 5 
(2014). 
20 
FDA. 21CFR Part 50 Protection of Human Subjects. Department of Health and Human Services, 
Subchapter A-General 1 (2014). 
21 
FDA. 21CFR Part 56 Institutional Review Boards. Department of Health and Human Services, 
Subchapter A-General 1 (2014). 
22 
World Medical Association Declaration of Helsinki: ethical principles for medical research 
involving human subjects. Jama 310, 2191-2194, doi:10.1001/jama.2013.281053 (2013). 
23 
FDA. 21CFR 312.32: IND Safety Reporting.  (2010). 
24 
ICH. Structure and Content of Clinical Study Reports E3.  Step 4 version (1996). 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 55 of 59 
 
 
14.0 APPENDICES 
14.1 APPENDIX A – NAEPP Guidelines for Asthma Severity Classification 
 
 
 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 56 of 59 
 
 
14.2 APPENDIX B – PROAIR® HFA (albuterol sulfate) Inhalation Aerosol Package Insert 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 57 of 59 
 
 
14.3 APPENDIX C – Albuterol Sulfate Inhalation Aerosol Investigator’s Brochure 
 
 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 58 of 59 
 
 
14.4 APPENDIX D – Amendments to the Protocol 
Amendment 
Date 
 
1 
09/06/2017 
 
The following revisions were made to the protocol dated 06/01/2017. 
• 
Revision Date: Title page and Footer 
• 
Added to Screening Section-All clinical assessments except height and weight will be 
performed at each rescheduled visit. Pg 9 and 22 
• 
Inclusion Criteria  Deleted from # 3 - such as condom plus diaphragm with spermicide 
• 
Study schematic updated 
• 
Added: Scientific and statistical considerations corrected to read interpolated not 
extrapolated; clarification on FEV1 imputation was added. Pg 20 and pg 45 
• 
Added: Screening updated to match synopsis (“rescue” added to albuterol administration and 
added repeated vital signs). Page 22 
• 
Added AE assessment to procedures in 10.5.1. Page 32: 
• 
Added to Methacholine Challenge throughout all visits  
o meeting post-saline FEV1 criteria  
o Methacholine should be diluted per the ATS recommendations and recorded when PC20 is 
reached. 
• 
Added to Urine Pregnancy Test throughout all visits 
o before dosing. 
• 
Added to Pulse Oximetry throughout all visits 
o and recorded when PC20 is reached. 
• 
Added collect/review diary to visits 2-5 
• 
Corrected for consistency to say “through a nebulizer”. Section 10.5.3 point # 6 
• 
Changed through out to comply with the guidance 
o Gender to Sex 
• 
Corrected Section 10.6.8 
• 
Added to Section 10.6.11, Adverse Events:  
o At the end of Visit 1, patients will be questioned about any AEs that occurred during the 
visit. At Visits 2, 3, 4, and 5 patients will be questioned regarding any changes in their 
medical status since their previous visit. Any significant changes observed after ICF 
signing will be reported as AEs 
• 
Added to Section 10.6.12:  
o If the subject fails to meet either requirement, the challenge must be stopped, rescue 
albuterol administered and the visit should be rescheduled. Subjects who fail three 


CONFIDENTIAL PROTOCOL 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, Four-
Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-Design, 
Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation 
Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, Mild Asthma
 
  04/05/2018  Rev. 3  
  Page 59 of 59 
 
 
consecutive visits should be dropped from the study. 
• 
Added to Section 10.6.14: 
o Methacholine should be prepared in doubling concentrations as recommended by the ATS 
for the two-minute tidal breathing dosing protocol.17 
Saline (0.0 mg/mL), 0.03 mg/mL, 0.06 mg/mL, 0.125 mg/mL, 0.25 mg/mL, 0.50 mg/mL, 1 
mg/mL, 2 mg/mL, 4 mg/mL, 8 mg/mL 
o Methacholine should be prepared in the following concentrations: 
Saline (0.0 mg/mL), 0.03 mg/mL, 0.06 mg/mL, 0.125 mg/mL, 0.25 mg/mL, 0.50 mg/mL, 1 
mg/mL, 2 mg/mL, 4 mg/mL, 8 mg/mL, 16 mg/mL, 32 mg/mL, 64 mg/mL, 128 mg/mL 
• 
Corrected Section 10.6.15: Pulse oximetry will be monitored during the methacholine 
challenge and recorded when PC20 is reached. 
• 
Corrected title of 10.6.18 (previously 10.6.16) and corrected the text to match the procedures 
described in 10.5. 
 
 
Amendment 
Date 
 
2 
10/06/2017 
 
• 
Updated AE, SAE, and pregnancy collection and reporting information. 
• 
Added procedures for breaking the blind in the event of an SAE/SUSAR. 
 
 
Amendment 
Date 
 
3 
04/05/2018 
 
The following revisions were made to the protocol dated 10/06/2017: 
• 
Updated Inclusion/Exclusion criteria. 
• 
Revised procedures for selection of retention samples. 
• 
Removed mITT population and replaced with PD population. 
• 
Revised PD analysis text throughout. 
• 
Removed “Other” from the list of Race options. 
• 
Updated MedDRA version. 
• 
Revised AE/SAE reporting procedures. 
• 
Added expectedness assessment. 
• 
Added Investigator’s Brochure and Product Insert to protocol appendices. 
 

SAP_001.pdf: 
Table of Contents
STATISTICAL ANALYSIS PLAN
1
1. INTRODUCTION
9
2. OBJECTIVES
9
3. OVERALL STUDY DESIGN
9
4. IDENTITY O F INVESTIGATIONAL PRODUCT
14
5. RANDOMIZATION AND BLINDING
14
6. SAMPLE SIZE
15
7. STUDY POPULATIONS
16
Per-Protocol (PP) Population
16
Pharmacodynamic (PD) Population
16
Safety Populations
16
8. STATISTICAL ANALYSIS METHODS
17
8.1 Baseline Characteristics
17
8.1.1 Patient Disposition
17
8.1.2 Demographic and Other Baseline Characteristics
17
8.1.3 Medical History
18
8.1.4 Concomitant Medications
18
8.2 Pharmacodynamic Equivalence Analyses
18
8.2.1 Primary Pharmacodynamic Endpoint
18
8.2.2 Population
19
8.2.3 PC20 Log Transformation
19
8.2.4 NONMEM® Dataset Preparation
19
8.2.5 Dose-Scale Approach
19
8.2.6 Dose Response Emax Model
20
8.2.7 Alternative Approach to the Dose Response Emax Model
20
8.2.8 Bootstrap
25
8.2.9 Calculation of Confidence Intervals for Frel
25
8.2.10 Calculation of Confidence Intervals for Frel
26
8.3 Safety Analysis
26
8.3.1 Adverse Events
26
8.3.2 Vital Signs
27
8.3.3 Physical Exam
27
8.3.4 12-lead ECG
27
8.3.5 Pregnancy Test
28
8.3.6 Concentration of Methacholine Required to Reduce FEV1 by 20% (PC20)
28
8.3.7 Forced Expiratory Volume (flow rate) in 1 second (FEV1)
28
clr_17_08-statistical-methods
TOC 1


8.3.8 Protocol Deviations
28
8.4 Multiple Comparisons
28
8.5 Methods for Handling Missing Data
28
8.6 Interim Analyses
28
9. TABLE, LISTING AND FIGURE SHELLS
28
T16.1.9.1 Summary of Patient Disposition
30
T16.1.9.2 Summary of Protocol Deviations
31
T16.1.9.3 Summary of Patient’s Treatments Included in the Pharmacodynamic Analysis
32
T16.1.9.4 Summary of Demographic Data and Baseline Characteristics
33
T16.1.9.5 Summary of Demographic Data and Baseline Characteristics
35
T16.1.9.6 Summary of Demographic Data and Baseline Characteristics
35
T16.1.9.7 Summary of Concentration (mg/mL) of Methacholine Required to Reduce 
FEV1 by 20% (PC20)
36
T16.1.9.8 Summary of Concentration (mg/mL) of Methacholine Required to Reduce 
FEV1 by 20% (PC20)
36
T16.1.9.9 Summary of Concentration (mg/mL) of Methacholine Required to Reduce 
FEV1 by 20% (PC20)
36
T16.1.9.10 Summary of Pre-challenge Forced Expiratory Volume (flow rate) in 1 
second (FEV1)
37
T16.1.9.11 Summary of Pre-challenge Forced Expiratory Volume (flow rate) in 1 
second (FEV1)
38
T16.1.9.12 Summary of Pre-challenge Forced Expiratory Volume (flow rate) in 1 
second (FEV1)
38
T16.1.9.13 Overall Summary of Adverse Events
39
T16.1.9.14.1 Summary of Frequency of All Adverse Events by System Organ Class
40
T16.1.9.14.2 Summary of Frequency of Serious Adverse Events by System Organ Class
41
T16.1.9.15.1 Summary of Frequency of All Adverse Events by Relationship to Study 
Drug
42
T16.1.9.15.2 Summary of Frequency of Serious Adverse Events by Relationship to 
Study Drug
43
T16.1.9.16.1 Summary of Frequency of All Adverse Events by Severity
44
T16.1.9.16.2 Summary of Frequency of Serious Adverse Events by Severity
45
T16.1.9.17 Summary of Vital Signs
46
L16.2.1 Listing of Discontinued Subjects
47
L16.2.2 Listing of Protocol Deviations
48
clr_17_08-statistical-methods
TOC 2


L16.2.3.1 Listing of Subjects Excluded from the Per-Protocol Population
49
L16.2.3.2 Listing of Subjects Excluded from the Pharmacodynamic Population
50
L16.2.4.1 Listing of Demographic Data
51
L16.2.4.2 Listing of Medical History
52
L16.2.4.3 Listing of Concomitant Medication
53
L16.2.5 Listing of Dosing
54
L16.2.6.1 Listing of Methacholine Challenge and Pulse Oximetry
55
L16.2.6.2 Listing of Methacholine Challenge Stages
56
L16.2.6.3 Listing of Spirometry Test
58
L16.2.7.1 Listing of Adverse Events (Safety Population Randomization Period)
59
L16.2.7.2 Listing of Adverse Events (Safety Population Screening Period)
60
L16.2.7.3 Listing of Positive Pregnancy Test Results
61
L16.2.7.4 Listing of Abnormal Physical Examinations
62
L16.2.8.1 Listing of Vital Signs
63
L16.2.8.2 Listing of 12-Lead ECG
64
NTF- Tables and Listings Numberings Change
66
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STATISTICAL ANALYSIS PLAN 
 
Albuterol Sulfate Inhalation Aerosol                 Protocol / Study No.  CLR_17_08/ 
 
 
12/21/2018 
                 Sun Pharmaceuticals Industries Limited  
            Page 1 of 64 
           
STATISTICAL ANALYSIS PLAN                     
 
 
A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-Period, Four-Sequence, 
Four-Treatment, Placebo and Active Controlled, Comparative, Multiple-Center, Crossover-
Design, Bronchoprovocation Study to Evaluate the Pharmacodynamic Equivalence of Albuterol 
Sulfate Inhalation Aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to 
PROAIR® HFA (albuterol sulfate) Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) 
in Subjects With Stable, Mild Asthma 
 
 
Protocol Number: CLR_17_08 
 
 
Sponsor: 
Sun Pharmaceuticals Industries Limited 
Formulation Development Department  
Tandalja, Baroda 
Gujarat, 390020, India 
 
 
 
 
 
 
 
 
 
December 21, 2018 
Final Version 1.0 
 
 
clr_17_08-statistical-methods
Page 1


clr_17_08-statistical-methods
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STATISTICAL ANALYSIS PLAN 
 
Albuterol Sulfate Inhalation Aerosol                 Protocol / Study No.  CLR_17_08/
 
 
12/21/2018 
                 Sun Pharmaceuticals Industries Limited  
            Page 3 of 64 
Revision History 
VERSION 
DATE 
DESCRIPTION OF REVISIONS 
REVISED 
BY 
Draft 1.0 
September 24, 2018 
New Document 
 
Final 1.0 
December 21, 2018 
Incorporate client’s comments and finalize 
SAP 
 
 
 
 
 
 
 
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STATISTICAL ANALYSIS PLAN 
 
Albuterol Sulfate Inhalation Aerosol                 Protocol / Study No.  CLR_17_08/
 
 
12/21/2018 
                 Sun Pharmaceuticals Industries Limited  
            Page 4 of 64 
List of Abbreviations and Terms 
Abbreviation 
Term 
AE 
Adverse Event 
ADaM 
Analysis Data Model 
ANDA 
Abbreviated New Drug Application 
ATS 
American Thoracic Society 
C 
Celsius 
CDISC 
Clinical Data Standards Interchange Consortium 
CRO 
Clinical Research Organization 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
eCTD 
Electronic Common Technical Document 
°F 
Fahrenheit 
F 
Relative bioavailability 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume (flow rate) in 1 second 
FVC 
Forced Volume Vital Capacity 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
kg 
Kilograms 
mcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-to-Treat  
mL 
Milliliter 
NAEPP 
National Asthma Education and Prevention Program 
OGD 
Office of Generic Drugs 
PC20 
Concentration (mg/mL) of methacholine required to reduce FEV1 by 20% 
PD 
Pharmacodynamic 
PP 
Per-Protocol  
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SDTM 
Study Data Tabulation Model 
 
 
 
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STATISTICAL ANALYSIS PLAN 
 
Albuterol Sulfate Inhalation Aerosol                 Protocol / Study No.  CLR_17_08/
 
 
12/21/2018 
                 Sun Pharmaceuticals Industries Limited  
            Page 5 of 64 
TABLE OF CONTENTS 
 
_Toc533144464 
1. INTRODUCTION .......................................................................................................................8 
2. OBJECTIVES ..............................................................................................................................8 
3. OVERALL STUDY DESIGN .....................................................................................................8 
4. IDENTITY O F INVESTIGATIONAL PRODUCT .................................................................13 
5. RANDOMIZATION AND BLINDING....................................................................................13 
6. SAMPLE SIZE ..........................................................................................................................14 
7. STUDY POPULATIONS ..........................................................................................................15 
8. STATISTICAL ANALYSIS METHODS .................................................................................16 
8.1 Baseline Characteristics ......................................................................................................16 
8.1.1 Patient Disposition ......................................................................................................16 
8.1.2 Demographic and Other Baseline Characteristics .......................................................16 
8.1.3 Medical History ...........................................................................................................17 
8.1.4 Concomitant Medications ...........................................................................................17 
8.2 Pharmacodynamic Equivalence Analyses...........................................................................17 
8.2.1 Primary Pharmacodynamic Endpoint ..........................................................................17 
8.2.2 Population ....................................................................................................................18 
8.2.3 PC20 Log Transformation ............................................................................................18 
8.2.4 NONMEM® Dataset Preparation ................................................................................18 
8.2.5 Dose-Scale Approach ..................................................................................................18 
8.2.6 Dose Response Emax Model .......................................................................................19 
8.2.7 Alternative Approach to the Dose Response Emax Model .........................................19 
8.2.8 Bootstrap .....................................................................................................................24 
8.2.9 Calculation of Confidence Intervals for Frel ...............................................................24 
8.2.10 Calculation of Confidence Intervals for Frel ..............................................................25 
8.3 Safety Analysis ...................................................................................................................25 
8.3.1 Adverse Events ............................................................................................................25 
8.3.2 Vital Signs ...................................................................................................................26 
8.3.3 Physical Exam .............................................................................................................26 
8.3.4 12-lead ECG ................................................................................................................26 
8.3.5 Pregnancy Test ............................................................................................................27 
8.3.6 Concentration of Methacholine Required to Reduce FEV1 by 20% (PC20) ...............27 
8.3.7 Forced Expiratory Volume (flow rate) in 1 second (FEV1) ........................................27 
8.3.8 Protocol Deviations .....................................................................................................27 
8.4 Multiple Comparisons .........................................................................................................27 
8.5 Methods for Handling Missing Data ...................................................................................27 
8.6 Interim Analyses .................................................................................................................27 
9. TABLE, LISTING AND FIGURE SHELLS ............................................................................27 
T16.1.9.1 Summary of Patient Disposition ...............................................................................29 
T16.1.9.2 Summary of Protocol Deviations..............................................................................30 
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T16.1.9.3 Summary of Patient’s Treatments Included in the Pharmacodynamic 
Analysis..............................................................................................................................31 
T16.1.9.4 Summary of Demographic Data and Baseline Characteristics .................................32 
T16.1.9.5 Summary of Demographic Data and Baseline Characteristics .................................34 
T16.1.9.6 Summary of Demographic Data and Baseline Characteristics .................................34 
T16.1.9.7 Summary of Concentration (mg/mL) of Methacholine Required to Reduce 
FEV1 by 20% (PC20) .........................................................................................................35 
T16.1.9.8 Summary of Concentration (mg/mL) of Methacholine Required to Reduce 
FEV1 by 20% (PC20) .........................................................................................................35 
T16.1.9.9 Summary of Concentration (mg/mL) of Methacholine Required to Reduce 
FEV1 by 20% (PC20) .........................................................................................................35 
T16.1.9.10 Summary of Pre-challenge Forced Expiratory Volume (flow rate) in 1 
second (FEV1) ...................................................................................................................36 
T16.1.9.11 Summary of Pre-challenge Forced Expiratory Volume (flow rate) in 1 
second (FEV1) ...................................................................................................................37 
T16.1.9.12 Summary of Pre-challenge Forced Expiratory Volume (flow rate) in 1 
second (FEV1) ...................................................................................................................37 
T16.1.9.13 Overall Summary of Adverse Events .....................................................................38 
T16.1.9.14.1 Summary of Frequency of All Adverse Events by System Organ Class ............39 
T16.1.9.14.2 Summary of Frequency of Serious Adverse Events by System Organ 
Class ...................................................................................................................................40 
T16.1.9.15.1 Summary of Frequency of All Adverse Events by Relationship to Study 
Drug ...................................................................................................................................41 
T16.1.9.15.2 Summary of Frequency of Serious Adverse Events by Relationship to 
Study Drug .........................................................................................................................42 
T16.1.9.16.1 Summary of Frequency of All Adverse Events by Severity................................43 
T16.1.9.16.2 Summary of Frequency of Serious Adverse Events by Severity .........................44 
T16.1.9.17 Summary of Vital Signs..........................................................................................45 
L16.2.1 Listing of Discontinued Subjects .................................................................................46 
L16.2.2 Listing of Protocol Deviations .....................................................................................47 
L16.2.3.1 Listing of Subjects Excluded from the Per-Protocol Population ..............................48 
L16.2.3.2 Listing of Subjects Excluded from the Pharmacodynamic Population ....................49 
L16.2.4.1 Listing of Demographic Data ...................................................................................50 
L16.2.4.2 Listing of Medical History........................................................................................51 
L16.2.4.3 Listing of Concomitant Medication ..........................................................................52 
L16.2.5 Listing of Dosing .........................................................................................................53 
L16.2.6.1 Listing of Methacholine Challenge and Pulse Oximetry ..........................................54 
L16.2.6.2 Listing of Methacholine Challenge Stages ...............................................................55 
L16.2.6.3 Listing of Spirometry Test ........................................................................................57 
L16.2.7.1 Listing of Adverse Events (Safety Population Randomization Period) ...................58 
L16.2.7.2 Listing of Adverse Events (Safety Population Screening Period) ............................59 
L16.2.7.3 Listing of Positive Pregnancy Test Results ..............................................................60 
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L16.2.7.4 Listing of Abnormal Physical Examinations ............................................................61 
L16.2.8.1 Listing of Vital Signs ................................................................................................62 
L16.2.8.2 Listing of 12-Lead ECG ...........................................................................................63 
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Albuterol Sulfate Inhalation Aerosol                 Protocol / Study No.  CLR_17_08/
 
 
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            Page 8 of 64 
1. INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the final Clinical Study Protocol CLR_17_08 
 Study No. 
 Rev 5.0 dated 08/28/2018. The SAP provides details on the 
planned statistical methodology for the analysis of the study data. The SAP also outlines the 
statistical programming specifications for the tables, listings and figures. 
This SAP describes the study endpoints, derived variables, anticipated data transformations and 
manipulations, and other details of the analyses not provided in the study protocol. This SAP 
therefore outlines in detail all other aspects pertaining to the planned analyses and 
presentations for this study. 
The following documents were reviewed in preparation of this SAP: 
• Final Clinical Study Protocol CLR_17_08 (
 Study No. 
 Rev 5.0 dated 
08/28/2018 
• The final Electronic Case Report Form (eCRF) specification for 
 Study No. 
 
The reader of this SAP is encouraged to also read the clinical protocol for details on the 
conduct of this study, and the operational aspects of clinical assessments and timing for 
completing a patient in this study. 
2. OBJECTIVES 
The objectives of this study are to: 
1. Demonstrate the pharmacodynamic equivalence of the Test formulation of albuterol sulfate 
inhalation aerosol, eq 90 mcg base (Sun Pharmaceuticals Industries Limited) to the marketed 
product PROAIR® HFA (albuterol sulfate) Inhalation Aerosol, eq 90 mcg base (Teva 
Respiratory, LLC) using methacholine bronchoprovocation in subjects with stable, mild 
asthma based on National Asthma Education and Prevention Program (NAEPP) guidelines. 
2. Compare the safety of Test, low-dose Reference, high-dose Reference, and Placebo 
treatments in subjects with stable, mild asthma based on NAEPP guidelines. 
3. OVERALL STUDY DESIGN 
This randomized, single-dose, double-blind, double-dummy, four-period, four-sequence, four-
treatment, Placebo and active controlled, comparative, multiple-center, crossover-design 
bronchoprovocation study has been designed to evaluate the pharmacodynamic equivalence of 
albuterol sulfate HFA inhalation aerosol, eq 90 mcg base per inhalation (Sun Pharmaceuticals 
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            Page 9 of 64 
Industries Limited) to PROAIR® HFA (albuterol sulfate) Inhalation Aerosol, eq 90 mcg base per 
inhalation (Teva Respiratory, LLC) in subjects with stable, mild asthma. 
Approximately 123 subjects with persistent bronchial asthma will be randomized. To qualify for 
inclusion in the study, subjects must be at least 18 years of age, with a documented diagnosis of 
mild asthma as defined by the NAEPP guidelines at least 6 months before Screening. 
Randomized subjects who withdraw from the study will not be replaced. 
Before any study-specific procedures are performed, all subjects will read and sign the IRB-
approved informed consent form. 
Eligible subjects will complete 5 clinic visits as follows: 
• Visit 1: Screening (Day -14 to -1) 
• Visit 2: Period 1 
• Visit 3: Period 2 
• Visit 4: Period 3 
• Visit 5: Period 4 
Clinical assessments will include FEV1 taken at each visit. If reattempts are necessary, an 
acceptable FEV1 is defined as the highest of three to four acceptable curves obtained at each 
time point. FVC and FEV1/FVC ratio [(FEV1/FVC) x 100] will also be recorded along with 
FEV1 measurements at each visit. 
Screening 
Screening evaluations will be performed in accordance with the study calendar. Clinical 
assessments will include: vital sign measurement, height, weight, physical examination, urine 
pregnancy test (for all women of childbearing potential), 12-lead electrocardiogram (ECG), and 
pulse oximetry (during methacholine bronchoprovocation challenges). Chest x-ray may be 
performed at discretion of the Investigator. Qualifying FEV1 at Screening must be ≥ 80% of 
predicted value. Once Qualifying FEV1 is obtained, a sterile, saline control will be administered 
to the subject through a nebulizer. Spirometry will be performed following the saline 
administration. Post-saline FEV1 should not drop more than 10% from pre-saline FEV1 and 
should be ≥ 70% of predicted value. If the subject fails to meet any of these requirements, the 
procedures must be stopped, rescue albuterol administered, and the visit should be rescheduled. 
All clinical assessments except height and weight will be performed at each rescheduled visit. 
Subjects who fail three consecutive visits will not be eligible to participate in the study. Subjects 
meeting post-saline FEV1 criteria will undergo methacholine bronchoprovocation challenge with 
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progressively increasing concentrations to determine the subject’s baseline provocation 
concentration of inhaled methacholine required to reduce FEV1 by 20% (PC20) relative to the 
post-saline value. The maximum concentration of methacholine to be administered in this step 
will be 8 mg/mL. Subjects who do not respond to methacholine doses at or below 8 mg/mL will 
not be eligible for enrollment in the study. 
Once the methacholine challenge test is completed, rescue albuterol will be administered and 
spirometry will be performed approximately 15 minutes later until the subject’s FEV1 returns to 
within 90% of the best post-saline FEV1 or until the Principal Investigator determines that the 
FEV1 has stabilized and it is safe to allow the subject to leave the site. Vital signs will also be 
repeated. 
Dosing Visits 
Eligible subjects will return for four treatment visits. The first dosing visit will occur no earlier 
than 24 hours and no more than 14 days after Screening procedures and the interval (washout 
period) between dosing visits should be at least 48 hours. At each treatment visit, the following 
will be performed before dosing: 
• Vital sign measurement 
• 12-lead electrocardiogram (ECG) as the discretion of the Investigator after the initial 
Screening visit 
• Pulse oximetry (during methacholine bronchoprovocation challenges) 
• Concomitant medication update (confirming washouts) 
• Adverse Events (AE) review 
• Urine pregnancy test for all women of childbearing potential 
A pre-treatment evaluation will be performed. This will confirm that pre-challenge FEV1 is ≥ 
80% of predicted and within 88 and 112% of qualifying spirometry value at Screening visit. 
After the first inhalation of saline control is administered, the FEV1 should not drop more than 
10% compared to pre-challenge value and should be ≥ 70% of the predicted value. If the subject 
fails to meet any of these requirements, the procedures must be stopped, albuterol administered, 
and the visit should be rescheduled. Subjects who fail three consecutive visits should be dropped 
from the study. 
Subsequently, review of inhaler dosing technique, priming and preparation of inhalers will be 
performed. The subject will receive one of the four randomized study treatments. The time of 
last actuation will be recorded, as well as the adequacy of inhaler technique. Approximately 15 
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minutes after the last inhalation of study treatment, a methacholine bronchoprovocation 
challenge will be given with progressive concentrations to determine the PC20. The 20% 
reduction in FEV1 will be determined relative to the post-saline FEV1. After the procedures have 
been completed, albuterol will be administered to reverse airway obstruction and subjects will be 
followed until FEV1 returns to within 90% of the best FEV1 captured during the saline stage on 
that study day or until the Principal Investigator determines that the FEV1 has stabilized and it is 
safe to allow the subject to leave the site. 
Subjects who withdraw prematurely will be evaluated at a final visit, but spirometry, chest x-
rays, and methacholine administration do not need to be performed. 
The spirometry procedures and the methacholine bronchoprovocation challenges in this study are 
to be performed in accordance with the ATS Guidelines for Methacholine and Exercise 
Challenge Testing. The maximum methacholine dose administered will be 8 mg/mL at Screening 
and 128 mg/mL for treatment visits. 
 
 
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Figure 1: Study Schematic 
Procedures 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Screening 
Period 1 
Period 2 
Period 3 
Period 4 
End of Study 
Informed Consent 
X 
Baseline Demographics 
X 
Medical History 
X 
Vital Signs* 
X 
X 
X 
X 
X 
Height and Weight 
X 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
Urine Pregnancy Test** 
X 
X 
X 
X 
X 
12-Lead ECG  
X 
X† 
X† 
X† 
X† 
Chest X-Ray‡ 
X 
 
Concomitant Medication 
X 
X 
X 
X 
X 
Spirometry (FEV1 and FVC)§ 
X 
X 
X 
X 
X 
Saline Control Administration 
X 
X 
X 
X 
X 
Methacholine Challenge 
X 
X 
X 
X 
X 
Pulse Oximetry 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
Review 
X 
 
 
 
 
Prime, dispense study product and 
instructions 
 
X 
X 
X 
X 
Dosingǁ 
X 
X 
X 
X 
Assessment of Compliance 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Provide Diary 
X 
X 
X 
X 
 
Collect /Review Diary 
 
X 
X 
X 
X 
Schedule next visit 
X 
X 
X 
X 
 
* Vital signs will be measured before and after methacholine bronchoprovocation challenges at all visits. 
** Female subjects of childbearing potential. 
† 12-lead ECG to be performed at Screening may be repeated before methacholine bronchoprovocation challenges 
at discretion of Investigator. 
‡ Chest X-ray is to be performed at discretion of Investigator. 
§ FEV1 and FVC measurements will be performed before saline control, after saline control, and after methacholine 
administration. If reattempts are necessary, an acceptable FEV1 is defined as the highest of three to four acceptable 
curves obtained at each time point. 
ǁ Subjects will receive four puffs of study product from four different inhalers (each dose from a separate inhaler). 
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4. IDENTITY O F INVESTIGATIONAL PRODUCT 
The following products will be used in the study: 
Test (T active): Albuterol Sulfate Inhalation Aerosol, eq 90 mcg base per inhalation (Sun 
Pharmaceuticals Industries Limited) 
Reference (R active): PROAIR® HFA (albuterol sulfate) Inhalation Aerosol, eq 90 mcg base per 
inhalation (Teva Respiratory, LLC) 
Test Placebo (T Placebo): Placebo for Albuterol Sulfate Inhalation Aerosol (i.e., vehicle 
canister with T active actuator [Sun Pharmaceuticals Industries Limited]) 
Reference Placebo (R Placebo): Placebo for Albuterol Sulfate Inhalation Aerosol (i.e., vehicle 
canister with R active actuator [Sun Pharmaceuticals Industries Limited]) 
 
Treatments will be as follows: 
Treatment A: Zero-dose 
Two different Reference Placebo inhalers and two 
different Test Placebo inhalers 
1 puff Inhaler 1 
1 puff Inhaler 2 
1 puff Inhaler 3 
1 puff Inhaler 4 
Treatment B: 90 mcg of Reference 
One Reference inhaler, one Reference Placebo inhaler, 
and two different Test Placebo inhalers 
1 puff Inhaler 1 
1 puff Inhaler 2 
1 puff Inhaler 3 
1 puff Inhaler 4 
Treatment C: 180 mcg of Reference 
Two different Reference inhalers and two different Test 
Placebo inhalers 
1 puff Inhaler 1 
1 puff Inhaler 2 
1 puff Inhaler 3 
1 puff Inhaler 4 
Treatment D: 90 mcg of Test 
One Test inhaler, one Test Placebo inhaler, and two 
different Reference Placebo inhalers 
1 puff Inhaler 1 
1 puff Inhaler 2 
1 puff Inhaler 3 
1 puff Inhaler 4 
 
5. RANDOMIZATION AND BLINDING 
At Visit 1 eligible subjects will be enrolled in the study, and scheduled for Visit 2. At Visit 2, 
eligible subjects will be randomized to one of the four sequences as shown below. Treatments 
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will be administered according to a four-treatment, four-period, four-sequence design. The 
randomization will be generated in blocks of four with each sequence occurring once in each 
block. 
Sequence Period 1 
Period 2 
Period 3 
Period 4 
1 
A 
B 
C 
D 
2 
D 
C 
B 
A 
3 
C 
A 
D 
B 
4 
B 
D 
A 
C 
 
 
 
. 
Subjects will be randomized to a treatment regimen in a blinded fashion by assigning 
randomization numbers in ascending sequential order starting with the lowest available 
randomization number at each site. All subjects randomized will be identified by initials, date of 
birth, and a unique seven-digit subject number. The first two-digits will identify the Investigator 
site where the subject was enrolled and the last five will correspond with the randomization 
number of study product ‘Treatment Box’ assigned to the subject. A perforated or two-part label 
will be attached to each of the small boxes containing individual inhalers. Both pieces of the 
label should include the following information: Protocol number, randomization number, space 
for subject’s initials, statement that the study product is for Investigational Use only, space for 
dispensing date and the Sponsor’s name. In addition all subjects will be provided with written 
instructions on how to use the study medication. One part of the label will remain attached to the 
box. The other part will be removed before dispensing and attached to the study product log. 
The Investigator, staff at the study site, study monitors, and data analysis/management personnel 
will be blinded to the patient assignment. 
6. SAMPLE SIZE 
The sample size estimation for this study was based on data from the study by Newhouse et al. 
that reported the bronchoprotective effect of inhaled salbutamol (albuterol) on methacholine 
PC20FEV1.  
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The highest within-subject coefficient of variability (COV) value for ln-transformed PC20 was 
estimated as 0.846 from the mean ratio and SD values for the PC20 at the 200 and 100 mcg doses 
(Table 1 in reference 2). Based on this COV, 98 evaluable subjects would be required in the PD 
population to demonstrate pharmacodynamic equivalence (i.e., 90% confidence interval on 
relative bioavailability [F] is within the bioequivalence limits of 0.67 to 1.50) with 90% power 
for a crossover study, assuming a true ratio of F = 1.1. To allow for approximately 20% of 
subjects that may discontinue from the study or have major protocol violations, and therefore not 
qualify for the PD population, up to 123 subjects will be randomized in the study.  
7. STUDY POPULATIONS 
Per-Protocol (PP) Population 
The PP population will include all subjects who: 
• Completed all four randomized treatment periods with an evaluable PC20FEV1 in each 
period. 
• Were compliant with study treatment dosing procedures. 
• Did not use any restricted concomitant medications. 
• Did not have any other significant protocol deviations. 
Pharmacodynamic (PD) Population 
The PD population used in the dose-scale analyses will include subjects who: 
• Completed at least one of the four randomized treatment periods with an evaluable 
PC20FEV1. 
• Were compliant with study treatment dosing procedures. 
• Did not use any restricted concomitant medications.  
• Did not have any other significant protocol deviations. 
Safety Populations 
The Safety population will include all subjects who administered at least one actuation of any of 
the four investigational products (Test, Reference, Test Placebo, Reference Placebo) in any of 
the four randomized treatment periods. 
PP and PD populations will be shortlisted upon a blinded review of the data by CRO and sponsor 
before database lock. 
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8. STATISTICAL ANALYSIS METHODS 
According to standard statistical practice, the significance threshold is set to p < 0.05 (two-
tailed). Data will be summarized with respect to demographic and baseline characteristics and 
safety variables. 
For categorical variables and non-missing data, the number and percent of each category within 
a parameter will be calculated. For continuous variables, statistics will include n, mean, standard 
deviation, median, minimum and maximum values. 
All statistical analyses will be conducted using Statistical Analysis System (SAS®, version 9.4 or 
higher). 
 
 
 
 
8.1 Baseline Characteristics 
8.1.1 Patient Disposition 
The patient disposition information will be summarized overall. The number of subjects 
randomized will be tabulated overall. In addition, completion status and primary reason for 
withdrawal will be summarized overall. 
8.1.2 Demographic and Other Baseline Characteristics 
The following subject demographic characteristics will be summarized separately in the PP, PD 
and Safety 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) 
• Tobacco use (yes/no) 
• Number of years patient suffered from symptoms caused by asthma 
• Qualifying spirometry (Visit 1, Pre- and Post-saline) 
• PC20 FEV1 at Visit 1 
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Continuous variables will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, maximum); categorical variables will be described in frequencies 
and percentages. Summary tables will be included. 
All data will be listed by patient. 
8.1.3 Medical History 
At Visit 1, subjects will be questioned about medical history, including acute and chronic 
medical history and medical history relevant to their asthma.  
Medical history data will be listed by patient. 
8.1.4 Concomitant Medications 
On Visit 1, subjects will be asked to list their current and recent (≤ 6 months) medication use. 
During all subsequent visits, subjects will be asked about ongoing and new concomitant 
medications.  
All prior and concomitant medications will be listed by patient. 
8.2 Pharmacodynamic Equivalence Analyses 
Pharmacodynamic (PD) equivalence between Test and Reference will be based on the dose-scale 
method of analysis of the post-dose PC20 (mg/mL) data using non-linear Emax modeling, as 
outlined in the FDA Draft Guidance on Orlistat capsule (3). Alternative models may be tested if 
warranted by the data, and these models as well as the specific criteria related to their use, are 
described in more detail in Section 8.2.7. 
8.2.1 Primary Pharmacodynamic Endpoint 
The primary pharmacodynamic endpoint is the post-dose PC20, which is the provocative 
concentration of methacholine challenge agent required to reduce the forced expiry volume in 
one second (FEV1) by 20%, following the administration of different doses of albuterol (or 
placebo) by inhalation.  
The 20% reduction in FEV1 will be determined relative to the post-saline FEV1 measure before 
placebo or albuterol administration. The methacholine PC20 will be calculated by linear 
interpolation from the observed data relating the % decrease in FEV1 from the post-saline FEV1 
to the concentration of methacholine that provokes at least a 20% decrease in FEV1. This 
interpolation will be based on log transformed methacholine concentrations. In the event that 
subjects receiving the maximum concentration of methacholine (128 mg/mL) at any dosing visit 
(Visits 2-5) do not achieve at least a 20% fall in FEV1, then they will have their PC20FEV1 data 
recorded as > 128 mg/mL and the data from that visit will be excluded from the statistical 
analysis; the data from the other Visits for these subjects will be eligible for inclusion in the PD 
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population but will be excluded from the PP population. 
8.2.2 Population 
The primary dose-scale analysis will be performed using the PD population as NONMEM 
allows for the use of all available data, without biasing the F estimation. For information 
purposes only, an additional dose-scale analysis will be performed using the PP population.   
  
8.2.3 PC20 Log Transformation 
The FDA product-specific guidance for albuterol sulfate explains that “log transformation of the 
PD data before fitting the Emax model is recommended for dose-scale analysis” (4); however, 
this guidance does not specify which log transformation should be used. Therefore, the PC20 
values will be transformed using the reported Log2 method (5,6), prior to NONMEM® dataset 
construction. 
 
 
The datasets will include individual albuterol dosing information and PC20 data. The actual 
dosing amount per treatment period will be used. Formulation will also be entered in the dataset. 
These will be entered as 0 for the reference product and 1 for the test product. The placebo dose 
will also be considered as the reference formulation. The dose amount for the placebo treatment 
will be set to 0. Data will be excluded from the analysis if insufficient or inaccurate dosing 
information are recorded. 
8.2.5 Dose-Scale Approach 
To assess bioequivalence using PD endpoints, the FDA albuterol-specific guidance (4) 
recommends using the dose-scale approach described in FDA’s orlistat guidance (3). This 
approach involves fitting dose-response data using the following equation: 
Equation 1 
rel
rel
F
Dose
ED
F
Dose
E
E
⋅
+
⋅
⋅
+
=
50
0
max
Response
 
In Equation 1, the response is the measured PC20, E0 is the baseline response, Emax is the 
maximal response, ED50 is the dose associated with half of the maximal response and Frel is the 
relative bioavailability of the test product compared to that of the reference product. This model 
is based on the assumption that E0, ED50 and Emax are the same for the test and reference 
products. 
The FDA orlistat guidance allows for the dose-scale Emax model to be fitted either to the mean 
or to the individual scores of dose response data. The analysis described in this plan will be 
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based on each individual score because this method is generally considered more robust in a 
bioequivalence (BE) crossover trial. 
The PC20 data will be analyzed based on a two-step dose-scale analysis to estimate Frel: 
• Firstly, a dose-response relationship will be mathematically described by fitting the 
relevant Emax model to the individual dose-response data, and an estimate for Frel will be 
obtained. 
• Secondly, a 90% confidence interval for Frel will be estimated by using Efron's (7) bias-
corrected and accelerated (BCa) method. 
8.2.6 Dose Response Emax Model 
The analysis will use the FDA recommended Emax model using NONMEM®. The model will 
include the following: 
• Etas will be included on PD parameters E0, Emax and ED50, coded as Theta(x)+Eta(x) 
for E0 and Emax and as Theta(x)*exp(Eta(x)) for ED50. 
• The possibility of adding an eta on the Frel parameter will be tested.. 
• A combination of proportional and additive residual error (Epsilons). 
Additionally, the model may be simplified by removing certain parameters (Etas or Epsilons) if 
they are estimated to be close to the boundary (e.g., 0). 
Quality of fit and selection of an alternate model will be determined using the objective function. 
A lower objective function is preferred if a model has the same number of parameters. 
Otherwise, the model will be chosen according to the difference in the MOF based on a Chi-
square distribution (p < 0.01 will be considered significant), taking the difference in the numbers 
of fitted parameters into account. Throughout the modeling process, the first-order conditional 
estimate (FOCE) option in NONMEM will be used. 
8.2.7 Alternative Approach to the Dose Response Emax Model 
The Emax model (as described in Sections 8.2.5 and 8.2.6) is the model described by the FDA in 
the Orlistat guidance (3) and is the preferred one.  However, based on the results of this Emax 
model, further analysis may be required. More specifically, an alternate approach will be used to 
re-analyze the data if the following 2 criteria are met: 
• If the predicted response of the low-dose and high-dose of albuterol fall within 20-80% of 
the maximum response. 
• If the predicted response for the low-dose of albuterol is ≥ 75% of the predicted response 
for the high-dose albuterol. 
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Therefore, if the Emax model previously described in this section is appropriate at describing the 
PC20 data, it will be used and will be considered final. However, if this Emax model is 
considered inappropriate (based on criteria listed above), the alternative modeling approach will 
be used as described below. 
The relationship between dose and response can often be described by a hyperbolic curve that is 
defined by the following equation, often called the “Emax model”: 
Equation 2 
𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒= 𝐸𝑚𝑎𝑥∙𝐷𝑜𝑠𝑒
𝐷𝑜𝑠𝑒+ 𝐷50
 
 
This relationship is depicted below, in Figure 1. 
Figure 1. Example of Emax Dose-Response Relationship  
 
In theory, a minimum of two observations are required to estimate the two model parameters 
(Emax and D50). Ideally, these two data points should be as far apart as possible, and lie close to 
the inflection points on the curve, to properly characterize Emax and D50. This ideal scenario is 
depicted in Figure 2; with the predicted Emax curve in black, observed data represented by red 
circles, and their associated error shown by vertical lines passing through the circle’s center. 
 
 
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Figure 2. Example of Emax Relationship with Data Points that are Spread Out 
 
Figure 2 depicts the ideal scenario; however, in practice the data points may not always lie this 
far apart.  If these two data points are too close to one and other, Emax and ED50 estimations can 
be more difficult and less certain. 
In other words, different Emax relationships, or combinations of parameter estimates (Emax and 
ED50), could explain the same data points; therefore, it becomes more difficult to know with 
certainty which relationship reflects reality.  This problem is illustrated in Figure 3, where very 
different Emax curves (denoted by the black, blue and yellow lines) all pass through the same 
two observed data points (red points with vertical error bars). 
 
 
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Figure 3. Example of Possible Emax Curves for the Same Data Points 
 
If the response data associated with the two doses (90 mg and 180 mg) are close to one and 
other, which is analogous to the scenario depicted in Figure 3, this proximity of the data will 
make it difficult to properly estimate the parameters Emax and ED50. 
In such cases, log-transformation of the independent variable (dose) can be beneficial.  The log10 
transformation of dose is used in such analyses. Despite the hyperbolic nature of the Emax curve, 
it is recognized that when the data on the X-axis are log-transformed, the relationship becomes 
more linear, especially between doses that are associated with 20% and 80% of Emax. (8); this is 
illustrated in Figure 4. 
 
 
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Figure 4. Depiction of Log-Linear Dose-Response Relationship 
 
When using a log-linear model, the relationship between log(dose) and response can be 
described by a straight-line between 20% and 80% of the maximum effect. Consequently, it is no 
longer necessary to estimate Emax and ED50 parameters, thereby removing the uncertainty 
associated with these parameter estimates.  Instead, the relationship between log(dose) and 
response can be described by a simple slope and intercept. 
It can also be appreciated from Figure 4 that when using the log-linear model, the intercept (the 
hypothetical response at dose zero based on a linear relationship) is not equivalent to the E0 that 
is associated with the Emax model.  Therefore, response data associated with the placebo should 
not be fitted by the log-linear model for two reasons: 
1) Linearity only applies to doses that are associated with responses that are between 20% 
and 80% of the maximal response.  By definition, this excludes a dose of zero that is not 
associated with a response.  
2) Inclusion of placebo data would falsely bias the estimation of the intercept parameter, and 
the slope that would be fitted by the model would not reflect the true slope.  Other 
parameter estimates (such as Frel) will also be unreliable.   
For the reasons above, the placebo data should not be fitted in the log-linear model.  In such an 
analysis, only response data associated with the 90 mg and 180 mg should be fitted by this type 
of model. An additional analysis may be done for which the response data associated with the 90 
mg and 180 mg may be placebo-corrected to account for the placebo effect. 
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Therefore, in this alternate model, PC20 would be fitted according to the following equation: 
Equation 3 
𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒= 𝐼𝑛𝑡𝑒𝑟𝑐𝑒𝑝𝑡+ 𝑆𝑙𝑜𝑝𝑒∗𝐷𝑜𝑠𝑒∗𝐹𝑟𝑒𝑙 
In this relationship, both response and dose are log-transformed. 
The analysis using the Emax model detailed in the previous section will be presented for 
information purposes only even if this alternative approach is used. 
8.2.8 Bootstrap 
In the FDA orlistat guidance (3), 90% CI are constructed using a nonparametric bootstrap 
technique. Essentially, subjects are repeatedly sampled at random with replacement, creating 
new datasets of the same size as the original dataset and new PD parameters are estimated using 
the same final model.  Ten thousand (10 000) of these bootstrap samples will be constructed and 
NONMEM® analyses will be performed on all.  A matrix of bootstrap mean population estimates 
(Frel) will thus be obtained (9). Only the bootstrap for successful NONMEM® analyses will be 
used to build the 90% CI. 
Bootstrapping analyses will be conducted using Wings for NONMEM® version WFN7. 
8.2.9 Calculation of Confidence Intervals for Frel 
The bias-corrected and accelerated (BCa) method for constructing the 90% CI for Frel will be 
employed as described in the FDA guidance for orlistat (3), using the formulae described by 
Efron & Tibshirani (7). 
The BCa interval of intended coverage 1-2α is given by Equation 4, where
(
)
1
ˆ
α
θ ∗
and 
(
)
2
ˆ
α
θ ∗
are the 
100·α1
th and 100·α2
th percentiles of the B bootstrap replications, respectively.  The variables α1 
and α2 are defined in Equations 5a and 5b. 
Equation 4 
(
)
(
)
(
)
2
1
ˆ
,
ˆ
:
α
α
θ
θ
∗
∗
a
BC
 
Equations 5a 
( )
( )
(
)





+
⋅
−
+
+
Φ
=
α
α
α
z
z
a
z
z
z
0
0
0
1
ˆ
ˆ
1
ˆ
ˆ
 
Equation 5b 
(
)
(
)
(
)





+
⋅
−
+
+
Φ
=
−
−
α
α
α
1
0
1
0
0
2
ˆ
ˆ
1
ˆ
ˆ
z
z
a
z
z
z
 
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In Equations 5a and 5b, Φ(·) represents the standard normal cumulative distribution function and 
z(α) is the 100·αth percentile point of a standard normal distribution. The variables aˆ and 
0ˆz  
represent acceleration and bias-correction, respectively.  They are computed as described by 
Equations 6 and 7. 
 
Equation 6 
( )
{
}






<
Φ
=
∗
−
B
b
z
θ
θ
ˆ
ˆ
#
ˆ
1
0
 
Equation 7 
( )
( )
(
)
( )
( )
(
)
{
}
2
3
1
2
1
3
ˆ
ˆ
6
ˆ
ˆ
ˆ
∑
∑
=
⋅
=
⋅
−
−
=
n
i
i
n
i
i
a
θ
θ
θ
θ
 
In Equation 6, Φ-1(·) indicates the inverse function of a standard normal cumulative distribution 
function.  The numerator represents the number of bootstrap values 
( )
b
∗
θˆ
 that are less than the 
original estimate of θˆ.  B is the number of bootstrap replicates. 
Equation 7 uses 
( )⋅
θˆ  and 
( )i
θˆ , which are the average values of all jackknife replications and the ith 
jackknife replication of θˆ, respectively. 
The calculation of the BCa interval will be performed with the code provided by Efron & 
Tibshirani (10), using S-Plus for Windows®. 
8.2.10 Calculation of Confidence Intervals for Frel 
The test formulation will be declared bioequivalent to the reference formulation if the estimated 
Frel and the 90% CI are completely contained within the range of 67.00 to 150.00%.   
8.3 Safety Analysis 
All study subjects who administered at least one actuation of any of the study products (Safety 
Population) will be included in the comparative safety analysis. 
8.3.1 Adverse Events 
All the adverse events (AEs) reported throughout the study will be coded and classified 
according to the MedDRA (Medical Dictionary for Regulatory Activities) coding dictionary 
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(Version 20.0 or higher). Each adverse event is to be evaluated for date of start and end, 
seriousness, severity, causal relationship with the study drugs, action taken and outcome. 
A summary table of the number and percent of subjects with AEs by system organ class, 
preferred term, will be presented. Each patient will be counted only once within each preferred 
term. Other summaries may be added based on the data obtained. 
A frequency summary table of the number of AEs by system organ class, preferred term, and 
severity will be presented. Severity will be classified as “Mild”, “Moderate” or “Severe”. 
Similarly, a frequency summary table of the number of AEs by system organ class, preferred 
term, and relationship to a study drug will be presented. Relationship to a study drug will be 
classified as “Not Related” or “Related” where causality “Certain, Probable and Possible” will be 
assessed as “Related” while “Unlikely and Unrelated” will be assessed as “Not Related”. 
A frequency summary table of the number of SAEs by system organ class, preferred term will 
also be presented by treatment group. 
If sufficient data exist, AEs frequencies will be compared among treatments using Fisher’s exact 
test. If the overall Fisher’s exact test is significant for comparisons across the 4 treatments, pair-
wise testing between treatments will be conducted to determine which contrasts are significant. 
All AEs will be listed by patient for the Safety Population.  
8.3.2 Vital Signs 
At each clinic visit, subjects’ vital signs (pulse, BP, temperature, and respiration rate) will be 
recorded before and after methacholine procedures. 
Descriptive summaries (number of observations, mean, standard deviation, minimum, median 
and maximum) will be provided by treatment and time point. 
All data will be listed by patient. 
8.3.3 Physical Exam 
At Visits 1 and 5, the Investigator will perform a general physical exam for each qualified 
patient; any significant findings will be noted. At minimum, the physical exam must include a 
head, ear, eyes, nose, lungs and throat examination. 
Any abnormal physical exam results will be listed by patient and visit. 
8.3.4 12-lead ECG 
Subjects will undergo a 12-lead ECG at Screening. An ECG may be performed at subsequent 
visits at the Investigator`s discretion. Any clinically significant findings will be noted. 
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12-lead ECG results will be listed by patient and visit. 
8.3.5 Pregnancy Test 
Urine pregnancy tests on women of childbearing potential will be performed at each clinic visit, 
including rescheduled visits. 
Positive urine pregnancy test results will be listed by patient and visit. 
8.3.6 Concentration of Methacholine Required to Reduce FEV1 by 20% (PC20) 
Descriptive summaries (number of observations, mean, standard deviation, minimum, median 
and maximum) will be provided separately for PC20 by treatment for the PP, PD and Safety 
Population. 
8.3.7 Forced Expiratory Volume (flow rate) in 1 second (FEV1) 
Descriptive summaries (number of observations, mean, standard deviation, minimum, median 
and maximum) will be provided separately for pre-challenge FEV1 by visit for the PP, PD and 
Safety Population. 
8.3.8 Protocol Deviations 
The total number of subjects with protocol deviation, the total number of protocol deviations as 
well as protocol deviation categories will be summarized. 
Protocol deviations will be listed by patient.  
8.4 Multiple Comparisons 
No multiple comparison adjustment will be made in this study. 
8.5 Methods for Handling Missing Data 
Each demographic and baseline characteristic variable will be analyzed using all available data. 
Thus, subjects with missing data will only be excluded from analyses for which data are not 
available. 
8.6 Interim Analyses 
No interim analyses are planned for this study. 
9. TABLE, LISTING AND FIGURE SHELLS 
The following shells are included to provide a framework for displaying data in the final clinical 
study report. These shells are meant to provide a general layout for final Tables, Listings and 
Figures; therefore, they may not reflect every aspect of the current study. 
Tables, Listings and Figures are numbered in accordance with the ICH structure. Following data 
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analyses, table headers, variables names and footnotes will be modified as needed.  
Descriptive and inferential statistical (including bootstrap) analyses will be performed using 
SAS® statistical software version 9.4 or higher and NONMEM®, unless otherwise noted. 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
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T16.1.9.1 Summary of Patient Disposition 
Subjects 
 
Overall 
(n (%)) 
Subjects Screened 
xx 
Subjects Randomized 
xx 
Safety Population 
xx 
Completed Study 
xx (xx.x) 
Terminated Early 
xx (xx.x) 
    Adverse Event 
xx (xx.x) 
    Lack of Efficacy 
xx (xx.x) 
    Lost to follow-up 
xx (xx.x) 
    etc. 
xx (xx.x) 
 
xx (xx.x) 
     Other 
xx (xx.x) 
 
                                                                   % is based on total number of subjects in the safety population. 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 30 of 64 
T16.1.9.2 Summary of Protocol Deviations 
(Safety Population) 
 
 
Total 
N = xx 
Total Subjects with Protocol Deviations 
xx 
Total Deviations 
xx 
    Assessment conducted out of window 
xx 
    Lost to Follow-up 
xx 
    Missed Visit 
xx 
    Non-compliance with study drug 
xx 
    Non-compliance with study procedures 
xx 
    Restricted Medication 
xx 
    etc. 
xx 
     
xx 
    Other 
xx 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 31 of 64 
T16.1.9.3 Summary of Patient’s Treatments Included in the Pharmacodynamic Analysis  
 
 
Patient 
Screen  
Number 
Patient 
Randomization   
Number 
Sequence 
 
Treatment A 
Treatment B 
 
Treatment C 
 
Treatment D 
xx-xxxx 
 
xx-xxxxx 
 
1 
 
Yes 
Yes 
 
Yes 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 32 of 64 
T16.1.9.4 Summary of Demographic Data and Baseline Characteristics 
(Safety Population) 
 
 
Total 
N = xx 
Age (years) 
n 
xx 
 
Mean ± SD 
xx.x ± x.x 
 
Median 
xx.x 
 
Range 
xx-xx 
Race (n (%)) 
American Indian or Alaska Native 
xx (xx.x) 
 
Asian 
xx (xx.x) 
 
Black/African American 
xx (xx.x) 
 
Native Hawaiian or other Pacific Islander 
xx (xx.x) 
 
White 
xx (xx.x) 
 
Other 
xx (xx.x) 
Ethnicity (n (%)) 
Hispanic or Latino 
xx (xx.x) 
 
Not Hispanic or Latino 
xx (xx.x) 
Gender (n (%)) 
Female 
xx (xx.x) 
 
Male 
xx (xx.x) 
Tobacco use (n (%)) 
Yes 
xx (xx.x) 
 
No 
xx (xx.x) 
Number of years patient has suffered 
from symptoms caused by asthma 
 
n 
xx 
 
Mean ± SD 
xx.x ± x.x 
 
Median 
xx.x 
 
Range 
xx-xx 
                   
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 33 of 64 
 
 
Total 
N = xx 
 
 
 
FEV1 (L) (Pre-saline) 
n 
xx 
 
Mean ± SD 
xx.x ± x.x 
 
Median 
xx.x 
 
Range 
xx-xx 
FEV1 (L) (Post-saline) 
n 
xx 
 
Mean ± SD 
xx.x ± x.x 
 
Median 
xx.x 
 
Range 
xx-xx 
PC20 FEV1 (mg/mL) 
n 
xx 
 
Mean ± SD 
xx.x ± x.x 
 
Median 
xx.x 
 
Range 
xx-xx 
 
 
 
        
  N= number of subjects in the safety population; n= number of subjects with data available; % is based on N 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
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Similar table will be created for: 
T16.1.9.5 Summary of Demographic Data and Baseline Characteristics 
(Pharmacodynamic Population) 
 
T16.1.9.6 Summary of Demographic Data and Baseline Characteristics 
(Per-Protocol Population) 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 35 of 64 
 
T16.1.9.7 Summary of Concentration (mg/mL) of Methacholine Required to Reduce FEV1 by 20% (PC20) 
(Safety Population) 
Statistic 
Treatment A 
N = xx 
Treatment B 
N = xx 
Treatment C 
N = xx 
Treatment D 
N = xx 
n 
xx 
xx 
xx 
xx 
Mean ± SD 
xxx.x ± xx.x 
xxx.x ± xx.x 
xxx.x ± xx.x 
xxx.x ± xx.x 
Median 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
Range 
xxx.x – xxx.x 
xxx.x – xxx.x 
xxx.x – xxx.x 
xxx.x – xxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
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T16.1.9.8 Summary of Concentration (mg/mL) of Methacholine Required to Reduce FEV1 by 20% (PC20) 
(Pharmacodynamic Population) 
T16.1.9.9 Summary of Concentration (mg/mL) of Methacholine Required to Reduce FEV1 by 20% (PC20) 
(Per-Protocol Population) 
 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
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T16.1.9.10 Summary of Pre-challenge Forced Expiratory Volume (flow rate) in 1 second (FEV1) 
(Safety Population) 
Visit 
Statistic 
Overall 
Visit 1 (Pre-saline) 
N 
xx 
 
Mean ± SD 
xxx.x ± xx.x 
 
Median 
xxx.x 
 
Range 
xxx.x – xxx.x 
Visit 1 (Post-saline) 
N 
xx 
 
Mean ± SD 
xxx.x ± xx.x 
 
Median 
xxx.x 
 
Range 
xxx.x – xxx.x 
 
 
 
Visit 2 (Pre-saline) 
N 
xx 
 
Mean ± SD 
xxx.x ± xx.x 
 
Median 
xxx.x 
 
Range 
xxx.x – xxx.x 
 
 
 
Visit 2 (Post-saline) 
N 
xx 
 
Mean ± SD 
xxx.x ± xx.x 
 
Median 
xxx.x 
 
Range 
xxx.x – xxx.x 
Visit 3 (Pre-saline) 
 
 
Visit 3 (Post-saline) 
 
 
Visit 4 (Pre-saline) 
 
 
Visit 4 (Post-saline) 
 
 
Visit 5 (Pre-saline) 
 
 
Visit 5 (Post-saline) 
 
 
 
 
 
 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 37 of 64 
 
 
T16.1.9.11 Summary of Pre-challenge Forced Expiratory Volume (flow rate) in 1 second (FEV1) 
(Pharmacodynamic Population) 
T16.1.9.12 Summary of Pre-challenge Forced Expiratory Volume (flow rate) in 1 second (FEV1) 
(Per-Protocol Population) 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
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T16.1.9.13 Overall Summary of Adverse Events  
(Safety Population) 
Description 
Treatment A 
N = xx 
n (%) 
Treatment B 
N = xx 
n (%) 
Treatment C 
N = xx 
n (%) 
Treatment D 
N = xx 
n (%) 
Total 
N = xx 
n (%) 
Subjects in Safety Analysis Population 
xx 
xx 
xx 
xx 
xx 
  Subjects with at least one AE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Discontinued study drug due to above AEs  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
AEs reported 
xx 
xx 
xx 
xx 
xx 
  Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Not Related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Death 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Serious AE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      “Certain, Probable and Possible” were assessed as “Related” while “Unlikely and Unrelated” were assessed as “Not Related”. 
 
 
            
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
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T16.1.9.14.1 Summary of Frequency of All Adverse Events by System Organ Class 
(Safety Population) 
Body System/ 
MedDRA Term 
Treatment A 
N = xx 
 
Treatment B  
N = xx 
 
Treatment C 
N = xx 
   
Treatment D 
N = xx 
 
Fisher’s 
P-value 
Events 
Subjects 
n (%) 
 
Events 
Subjects 
n (%) 
Events 
Subjects 
n (%) 
Events 
Subjects 
n (%) 
Patient with at least 
one AE 
xx 
xx (xx.x)  
 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
x.xxxx 
Ear and labyrinth 
disorders/ Ear pain 
xx 
xx (xx.x)  
 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  N= number of subjects in the safety population in that particular group; n= number of subjects with data available for that particular group;  
% is based on N 
 
 Programming Note: Note that if the overall Fisher’s exact test is significant for comparisons across the 4 treatments then pair-wise testing between treatments 
will be conducted to determine which contrasts are significant.  
                                    
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
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T16.1.9.14.2 Summary of Frequency of Serious Adverse Events by System Organ Class 
(Safety Population) 
Body System/ 
MedDRA Term 
Treatment A 
N = xx 
 
Treatment B  
N = xx 
 
Treatment C 
N = xx 
   
Treatment D 
N = xx 
 
Fisher’s 
P-value 
Events 
Subjects 
n (%) 
 
Events 
Subjects 
n (%) 
Events 
Subjects 
n (%) 
Events 
Subjects 
n (%) 
Patient with at least 
one AE 
xx 
xx (xx.x)  
 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
x.xxxx 
Ear and labyrinth 
disorders/ Ear pain 
xx 
xx (xx.x)  
 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  N= number of subjects in the safety population in that particular group; n= number of subjects with data available for that particular group;  
% is based on N 
 
 Programming Note: Note that if the overall Fisher’s exact test is significant for comparisons across the 4 treatments then pair-wise testing between treatments 
will be conducted to determine which contrasts are significant.  
                                    
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
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T16.1.9.15.1 Summary of Frequency of All Adverse Events by Relationship to Study Drug  
(Safety Population) 
Body System/ 
MedDRA Term 
Treatment A 
N = xx 
 
Treatment B  
N = xx 
 
Treatment C 
N = xx 
   
Treatment D 
N = xx 
 
Related 
n (%) 
Not 
Related 
n (%) 
 
Related 
n (%) 
Not 
Related 
n (%) 
Related 
n (%) 
Not Related 
n (%) 
Related 
n (%) 
Not Related 
n (%) 
Patient with at least 
one AE 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Ear and labyrinth 
disorders/ Ear pain 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                    N= number of subjects in the safety population in that particular group; n= number of subjects with data available for that particular group;  
                    % is based on N 
                “Certain, Probable and Possible” were assessed as “Related” while “Unlikely and Unrelated” were assessed as “Not Related”. 
 
 
                              
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
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T16.1.9.15.2 Summary of Frequency of Serious Adverse Events by Relationship to Study Drug  
(Safety Population) 
Body System/ 
MedDRA Term 
Treatment A 
N = xx 
 
Treatment B  
N = xx 
 
Treatment C 
N = xx 
   
Treatment D 
N = xx 
 
Related 
n (%) 
Not 
Related 
n (%) 
 
Related 
n (%) 
Not 
Related 
n (%) 
Related 
n (%) 
Not Related 
n (%) 
Related 
n (%) 
Not Related 
n (%) 
Patient with at least 
one AE 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Ear and labyrinth 
disorders/ Ear pain 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                    N= number of subjects in the safety population in that particular group; n= number of subjects with data available for that particular group;  
                    % is based on N 
                “Certain, Probable and Possible” were assessed as “Related” while “Unlikely and Unrelated” were assessed as “Not Related”. 
 
 
                              
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
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T16.1.9.16.1 Summary of Frequency of All Adverse Events by Severity  
                       (Safety Population) 
 
Treatment A 
N = xx 
 
 
Treatment B  
N = xx 
 
Treatment C 
N = xx 
 
Treatment D  
N = xx 
Body System/ 
MedDRA Term 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%)  
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
Patient with at least 
one AE 
xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)   
xx (xx.x)  xx (xx.x)  xx (xx.x) 
Ear and labyrinth 
disorders/ Ear pain 
xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)   
xx (xx.x)  xx (xx.x)  xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  N= number of subjects in the safety population in that particular group; n= number of subjects with data available for that particular group;  
% is based on N 
 
                                     
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
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T16.1.9.16.2 Summary of Frequency of Serious Adverse Events by Severity  
                       (Safety Population) 
 
Treatment A 
N = xx 
 
 
Treatment B  
N = xx 
 
Treatment C 
N = xx 
 
Treatment D  
N = xx 
Body System/ 
MedDRA Term 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%)  
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
Patient with at least 
one AE 
xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)   
xx (xx.x)  xx (xx.x)  xx (xx.x) 
Ear and labyrinth 
disorders/ Ear pain 
xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)  xx (xx.x)   
xx (xx.x)  xx (xx.x)  xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  N= number of subjects in the safety population in that particular group; n= number of subjects with data available for that particular group;  
% is based on N 
 
                                     
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 45 of 64 
T16.1.9.17 Summary of Vital Signs  
(Safety Population) 
Vital Signs 
 
Time 
Point 
Statistic 
Treatment A 
N = xx 
Treatment B 
N = xx 
Treatment C 
N = xx 
Treatment D 
N = xx 
Systolic Blood Pressure (mmHg) 
Pre-Challenge 
n 
Xx 
xx 
xx 
xx 
 
Mean ± SD 
xxx.x ± xx.x 
xxx.x ± xx.x 
xxx.x ± xx.x 
xxx.x ± xx.x 
 
 
Median 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
 
 
Range 
xxx.x – xxx.x 
xxx.x – xxx.x 
xxx.x – xxx.x 
xxx.x – xxx.x 
 
Post-Challenge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diastolic Blood Pressure (mmHg) 
 
 
 
 
 
 
Pulse Rate (beats/min) 
 
 
 
 
 
 
Respiration Rate (breaths/min) 
 
 
 
 
 
 
Temperature (F) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 46 of 64 
L16.2.1 Listing of Discontinued Subjects 
Patient 
Screen 
Number 
Patient 
Randomization   
Number 
Sequence 
 
Date of  
Early Termination 
Early Termination  
Reason 
xx-xxxx 
 
xx-xxxxx 
 
1 
 
yyyy-mm-dd 
Lost to Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 47 of 64 
L16.2.2 Listing of Protocol Deviations 
Patient 
Screen 
Number 
Patient 
Randomization   
Number 
Sequence 
Event Description 
xx-xxxx 
 
xx-xxxxx 
 
1 
 
Outside Visit Window (Visit 3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 48 of 64 
L16.2.3.1 Listing of Subjects Excluded from the Per-Protocol Population 
Patient 
Screen 
Number 
Patient 
Randomization   
Number 
Sequence 
Exclusion Reason 
xx-xxxx 
 
xx-xxxxx 
 
1 
 
Patient did not meet IE criterion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 49 of 64 
L16.2.3.2 Listing of Subjects Excluded from the Pharmacodynamic Population  
Patient 
Screen 
Number 
Patient 
Randomization   
Number 
Sequence 
Exclusion Reason 
xx-xxxx 
 
xx-xxxxx 
1 
 
Patient did not meet IE criterion 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 50 of 64 
L16.2.4.1 Listing of Demographic Data 
Patient 
Screen 
Number 
Patient 
Randomization   
Number 
Sequence 
Age 
(yrs) 
Gender 
Ethnicity 
Race 
xx-xxxx 
 
xx-xxxxx 
 
1 
 
21 
 
Female 
 
Not Hispanic or Latino 
 
Black or African American 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 51 of 64 
L16.2.4.2 Listing of Medical History 
Patient  
Screen  
Number 
Patient 
Randomization  
Number 
Sequence 
System 
Diagnosis or 
Surgical 
Procedure 
Start Date 
End Date 
Ongoing 
xx-xxxx 
xx-xxxxx 
 
1 
 
xxxxxxxxxxxxxx 
 
xxxxxxxxxxx 
 
yyyy-mm-dd 
 
yyyy-mm-dd 
 
 
 
xx-xxxx 
 
xx-xxxxx 
2 
xxxxxxxxxxxxxxxx 
 
Xxxxxxxxxxxx 
 
yyyy-mm-dd 
 
 
Ongoing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 52 of 64 
L16.2.4.3 Listing of Concomitant Medication 
Patient  
Screen 
Number 
Patient 
Randomization   
Number 
Sequence Medication 
Dosage 
Frequency* Route 
Start/End 
Date 
Indication 
xx-xxxx 
xx-xxxxx 
 
1 
 
Lisinopril 
20 MG 
QD 
PO 
yyyy-mm-dd / 
yyyy-mm-dd 
Hypertension 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
*PRN - As needed; QD – Daily (once per day); Q4H - Every 4 hours; Q8H - Every 8 hours; Q12H - Every 12 hours; BID - Twice per day; TID - 3 
times per day; QID - 4 times per day; QOD - Every other day; QS - Every week; QM - Every month; Q3M - Every 3 months 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 53 of 64 
L16.2.5 Listing of Dosing 
Patient  
Screen 
Number 
Patient 
Randomi
zation   
Number 
Sequence 
 
Visit 
Is the 
Patient 
Eligible for 
Dosing? 
First 
Actuation 
Time 
Last 
Actuation 
Time 
Was the Study 
Product 
Primed?  
Was the Patient 
Instructed on 
How to Properly 
Dose? 
Dispenser Observe 
the Study  
Product Was 
Administered? 
Was the Patient 
Compliant with the 
Dosing Instruction? 
xx-xxxx xx-xxxxx 
 
1 
 
Visit 2 
Yes 
hh:mm 
hh:mm 
Yes 
Yes 
Yes 
Yes 
 
 
 
Visit 3 
Yes 
hh:mm 
hh:mm 
Yes 
Yes 
Yes 
No (Spray mist was 
seen) 
 
 
 
Visit 4 
Yes 
hh:mm 
hh:mm 
Yes 
Yes 
Yes 
Yes 
 
 
 
Visit 5 
Yes 
hh:mm 
hh:mm 
Yes 
Yes 
Yes 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 54 of 64 
L16.2.6.1 Listing of Methacholine Challenge and Pulse Oximetry 
Patient  
Screen 
Number 
Patient 
Randomi-
zation   
Number 
Sequence 
 
 
Visit 
Methacholine 
Bronchoprovocation 
Challenge 
Administration Time 
Time FEV1 
Reduced  
by ≥ 20% 
Treatment 
Dose (mcg) 
PC20 
(mg/mL)  
Pulse 
Oximetry 
Time 
Pulse 
Oximetry 
 (%) 
FEV1 at Time 
of Discharge 
(L)  
xx-xxxx 
xx-xxxxx 
 
1 
 
Visit 1 
hh:mm 
hh:mm 
NA 
xxx.x 
hh:mm 
xx.x 
xxx.x 
 
 
 
Visit 2 
hh:mm 
hh:mm 
Placebo, 0 
xxx.x 
hh:mm 
xx.x 
xxx.x 
 
 
 
Visit 3 
hh:mm 
hh:mm 
Test, 90 
xxx.x 
hh:mm 
xx.x 
xxx.x 
 
 
 
Visit 4 
hh:mm 
hh:mm 
Reference, 90 
xxx.x 
hh:mm 
xx.x 
xxx.x 
 
 
 
Visit 5 
hh:mm 
hh:mm 
Reference, 180 
xxx.x 
hh:mm 
xx.x 
xxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Methacholine Bronchoprovocation Challenge administration time refers to the time of the start of the first MC bronchoprovocation 
challenge administration. 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 55 of 64 
L16.2.6.2 Listing of Methacholine Challenge Stages 
Patient   
Screen 
Number 
Patient 
Randomi-
zation   
Number 
Sequence 
 
Visit 
StageN 
Stage 
FEV1 
FVC 
 
FEV1/FVC x 100 
xx-xxxx 
 
 
xx-xxxxx 
1 
Visit 1 
Visit 1 
Visit 1 
Visit 1 
Visit 1 
Visit 1 
Visit 1 
Visit 1 
Visit 1 
Visit 1 
Visit 1 
Visit 1 
Visit 2 
Visit 2 
Visit 2 
Visit 2 
Visit 2 
Visit 2 
Visit 2 
Visit 2 
Visit 2 
Visit 2 
Visit 2 
Visit 2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Pre-Saline 
Post-Saline 
0.0312 
0.0625 
0.1250 
0.2500 
0.5000 
1.0000 
2.0000 
4.0000 
8.0000 
Recovery 
Pre-Saline 
Post-Saline 
0.0312 
0.0625 
0.1250 
0.2500 
0.5000 
1.0000 
2.0000 
4.0000 
8.0000 
16.0000 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 56 of 64 
Visit 2 
Visit 2 
Visit 2 
Visit 2 
11 
12 
13 
14 
32.0000 
64.0000 
128.0000 
Recovery 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 3 
 
 
 
 
 
 
 
 
Visit 4 
 
 
 
 
 
 
 
 
Visit 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
                             Visit 3-5 will be the same as Visit 2. 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 57 of 64 
L16.2.6.3 Listing of Spirometry Test 
Patient  
Screen 
Number 
Patient 
Randomization  
Number 
Sequence 
Visit 
Is the Qualifying FEV1 >= 80% 
Predicted Value? / and within 88-
112% of Qualifying FEV1 from 
the Screening Visit? 
Was a 2-Minute Inhalation 
of a Normal Sterile Saline 
Control Administered? 
Was the Post-saline FEV1 
<= a 10% Drop from the 
Qualifying FEV1 and 
>=70% of Predicted Value? 
xx-xxxx 
xx-xxxxx 
1 
Visit 2 
Yes 
Yes 
Yes 
 
 
 
Visit 3 
Yes 
Yes 
Yes 
 
 
 
Visit 4 
Yes 
Yes 
Yes 
 
 
 
Visit 5 
Yes 
Yes 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 58 of 64 
L16.2.7.1 Listing of Adverse Events (Safety Population Randomization Period) 
 
Treatment 
Patient 
Randomi-
zation 
Number 
System Organ Class / 
MedDRA Term / 
AE Term 
Start /End 
 Date 
Severity 
Relationship 
to Study 
Drug 
Outcome 
Action 
Taken 
Other 
Action 
Taken 
SAE? 
Treatment A xx-xxxxx 
Nervous system disorders / 
Headache / 
Headache 
yyyy-mm-dd / 
yyyy-mm-dd 
Mild 
Possible  
Recovered 
Dose Not 
Changed 
None 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment B  
 
 
 
 
 
 
 
 
Treatment C  
 
 
 
 
 
 
 
 
Treatment D  
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 59 of 64 
L16.2.7.2 Listing of Adverse Events (Safety Population Screening Period) 
Patient 
Screen 
Number 
System Organ Class / 
MedDRA Term / 
AE Term 
Start /End 
 Date 
Severity 
Relationship 
to Study 
Drug 
Outcome 
Action 
Taken 
Other 
Action 
Taken 
SAE? 
xx-xxxx 
Nervous system disorders / 
Headache / 
Headache 
yyyy-mm-dd / 
yyyy-mm-dd 
Mild 
Possible 
Recovered 
Dose Not 
Changed 
None 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 60 of 64 
L16.2.7.3 Listing of Positive Pregnancy Test Results 
Patient  
Screen  
Number 
Patient 
Randomization   
Number 
Sequence 
Visit  
Results 
xx-xxxx 
xx-xxxxx 
1 
Visit 3 
Positive 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 61 of 64 
L16.2.7.4 Listing of Abnormal Physical Examinations 
Patient  
Screen  
Number 
Patient 
Randomization   
Number 
Sequence 
Visit  
Body 
System 
 
Result 
xx-xxxx 
xx-xxxxx 
1 
Visit 1 
xxxxxxx 
Abnormal (xxxxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 62 of 64 
L16.2.8.1 Listing of Vital Signs 
Patient  
Screen 
Number 
Patient 
Randomization  
Number 
Sequence Visit 
Time Point 
Systolic BP 
(mmHg) 
Diastolic BP 
(mmHg) 
Pulse Rate 
(beats/min) 
Respiration 
Rate 
(breaths/min) 
Temperature 
(F) 
xx-xxxx 
xx-xxxxx 
1 
Visit 1 
Pre-Challenge 
120 
70 
84 
18 
98.6 
 
 
 
 
Post-Challenge 
140 
80 
74 
18 
97.0 
 
 
 
Visit 2 
Pre-Challenge 
140 
80 
74 
18 
97.0 
 
 
 
 
Post-Challenge 
140 
80 
74 
18 
97.0 
 
 
 
Visit 3 
Pre-Challenge 
140 
80 
74 
18 
97.0 
 
 
 
 
Post-Challenge 
140 
80 
74 
18 
97.0 
 
 
 
Visit 4 
Pre-Challenge 
140 
80 
74 
18 
97.0 
 
 
 
 
Post-Challenge 
140 
80 
74 
18 
97.0 
 
 
 
Visit 5 
Pre-Challenge 
140 
80 
74 
18 
97.0 
 
 
 
 
 
Post-Challenge 
140 
80 
74 
18 
97.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 63 of 64 
L16.2.8.2 Listing of 12-Lead ECG 
Patient  
Screen 
Number 
Patient 
Randomization   
Number 
Sequence 
Visit 
ECG 
Date 
ECG 
Time 
ECG  
Result 
Comments 
xx-xxxx 
xx-xxxxx 
1 
Visit 1 
yyyy-mm-dd 
hh:mm 
Abnormal (Not Clinically 
Significant) 
xxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequence: 1=ABCD, 2=DCBA, 3=CADB, 4=BDAC 
 
 
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Albuterol Sulfate Inhalation Aerosol                                                                         Protocol / Study No.  AI CLR_17_08/
 
 
12/21/2018                                               Sun Pharmaceuticals Industries Limited                                                          Page 64 of 64 
REFERENCES 
 
1. American Thoracic Society - Guidelines for Methacholine and Exercise Challenge Testing. American journal of respiratory and 
critical care medicine 161, 309-329 (1999). 
2. Saluja B, D. R., Kim SH, Lee SL. in Respiratory Drug Delivery.  413-416. 
3. Draft Guidance on Orlistat.  Food and Drug Administration's Office of Generic Drugs. Recommended Feb 2010, Revised Aug 
2010. Retrieved on Jan 15 2018 from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM201268.pdf 
4. Draft Guidance on Albuterol Sulfate.  Food and Drug Administration's Office of Generic Drugs. Recommended Apr 2013, 
Revised Dec 2016. Retrieved on Jan 15 2018 from: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM346985.pdf  
5. Inman MD, Hamilton AL, Kerstjens HAM, Watson RM, O’Byrne PM. The utility of methacholine airway responsiveness 
measurements in evaluating anti-asthma drugs. J Allergy Clin Immunol.  1998;101(3):342-348 
6. Mauger EA, Mauger DT, Fish JE, Chinchili VM, Israel E. Summarizing Methacholine Challenges in Clinical Research. Control 
Clin Trials. 2001;22(6 Suppl):244S-251S 
7. Efron B, Tibshirani RJ.  An Introduction to the Bootstrap.  (Chapman & Hall: New York, NY, 1993) 
8. Gibaldi M, Perrier D. Pharmacokinetics, Second Edition, Revised and Expanded. (Marcel Dekker Inc: New York, NY, 1982) 
9. Bonate PL.  Pharmacokinetic-Pharmacodynamic Modeling and Simulation, Second Edition.  (Springer Science+Business Media, 
Inc: New York, NY, 2011) 
10. StatLib, Department of Statistics, Carnegie Mellon University (http://lib.stat.cmu.edu) 
 
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1 
 
 
 
NOTE TO FILE  
 
 
STUDY TITLE: A Randomized, Single-Dose, Double-Blind, Double-Dummy, Four-
Period, Four-Sequence, Four-Treatment, Placebo and Active Controlled, Comparative, 
Multiple-Center, Crossover-Design, Bronchoprovocation Study to Evaluate the 
Pharmacodynamic Equivalence of Albuterol Sulfate Inhalation Aerosol, eq 90 mcg base 
(Sun Pharmaceuticals Industries Limited) to PROAIR® HFA (albuterol sulfate) 
Inhalation Aerosol, eq 90 mcg base (Teva Respiratory, LLC) in Subjects With Stable, 
Mild Asthma 
PROTOCOL NO.: CLR_17_08 (Revision 6.0) 
 
 
 
This Note to File explains the changing of numbering as per ICH guidance E3 for Tables, 
Listings and Figures that are included in the final SAP dated December 21, 2018.  
 
 
T14.1.1 Summary of Patient Disposition 
T14.1.2 Summary of Protocol Deviations 
T14.1.3 Summary of Patient’s Treatments Included in the Pharmacodynamic Analysis  
T14.1.4 Summary of Demographic Data and Baseline Characteristics 
T14.1.5 Summary of Demographic Data and Baseline Characteristics 
T14.1.6 Summary of Demographic Data and Baseline Characteristics 
T14.2.1.1 Summary of Concentration (mg/mL) of Methacholine Required to Reduce 
FEV1 by 20% (PC20) (Safety Population)  
T14.2.1.2 Summary of Concentration (mg/mL) of Methacholine Required to Reduce 
FEV1 by 20% (PC20) (Pharmacodynamic Population) 
T14.2.1.3 Summary of Concentration (mg/mL) of Methacholine Required to Reduce 
FEV1 by 20% (PC20)  (Per-Protocol Population) 
T14.2.2.1 Summary of Pre-challenge Forced Expiratory Volume (flow rate) in 1 second 
(FEV1) (Safety Population) 
 T14.2.2.2 Summary of Pre-challenge Forced Expiratory Volume (flow rate) in 1 second 
(FEV1) (Pharmacodynamic Population) 
T14.2.2.3 Summary of Pre-challenge Forced Expiratory Volume (flow rate) in 1 second 
(FEV1) (Per-Protocol Population) 
T14.3.1.1 Overall Summary of Adverse Events 
T14.3.1.2 Summary of Frequency of All Adverse Events by System Organ Class 
T14.3.1.3 Summary of Frequency of Serious Adverse Events by System Organ Class 
T14.3.1.4 Summary of Frequency of All Adverse Events by Relationship to Study Drug 
T14.3.1.5 Summary of Frequency of Serious Adverse Events by Relationship to Study 
Drug 
T14.3.1.6 Summary of Frequency of All Adverse Events by Severity 
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