Conditions: Bronchial Asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1550
Healthy volunteers: no

Brief summary:
To compare the therapeutic equivalence of Beclomethasone Dipropionate MDI (Inhalation Aerosol) 0.04 mg/ INH with the marketed QVAR® 40 mcg (Beclomethasone dipropionate hydrofluoroalkane (HFA)) and to demonstrate superiority of both active treatments over placebo.

Detailed description:
This study is to demonstrate the pharmacodynamic bioequivalence of the test product to the reference product in terms of improvement in FEV1 measured before and after 4 weeks of treatment in adult patients with chronic stable asthma.

Arms:
arm 1: One inhalation of Beclomethasone dipropionate HFA, 0.04 mg/ INH (Test) twice daily. arm 2: One inhalation of QVAR® 40 mcg (Beclomethasone dipropionate HFA), Inhalation Aerosol twice daily. arm 3: One inhalation of Placebo Inhalation Aerosol twice daily.

Interventions: intervention 1: Test Product intervention 2: Reference Product intervention 3: Placebo
Intervention descriptions: intervention 1: Beclomethasone Dipropionate Inhalation Aerosol, 40 mcg intervention 2: Beclomethasone Dipropionate Inhalation Aerosol, 40 mcg intervention 3: Placebo Product

Protocol document:
Prot_000.pdf: 
.  
 
 
 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 1 of 81 
 
 
CLINICAL TRIAL PROTOCOL  
Protocol Title:                                
A randomized, multiple-dose, double blind, 
placebo controlled, parallel group, multicentric  
study to evaluate Efficacy and Safety of Beclo-
methasone Dipropionate Metered Dose Inhaler   
(Inhalation Aerosol) (0.04mg/ INH) in male and/
 or female subjects with Asthma [Group I (Test):
 Beclomethasone Dipropionate 0.04 mg/ INH;   
Group II (Reference): QVAR® 40 mcg (Beclo-
methasone dipropionate HFA); and Group III: 
Placebo] 
Protocol Number: 
           CR176-17 
Version & Date of Protocol: 
Version 1.0, Amendment 02 Dated 07.08.2019 
Investigational Product: 
Beclomethasone Dipropionate Metered 
Dose Inhaler (Inhalation Aerosol) (0.04 mg/ 
INH); 
Manufactured by: Aurolife, a subsidiary of 
Aurobindo Pharma, USA, Inc., 2929 Weck Dr., 
Durham, NC 27709. 
Reference Product:                           QVAR® 40 mcg (Beclomethasone dipropionate 
HFA), Inhalation Aerosol; 
Marketed by: Teva Pharmaceuticals LLC Frazer, 
PA 19355. 
NDC code: 59310-202-12 
Study Phase: 
Clinical Pharmacodynamic BE Study 
Sponsor: 
 
 
 
Aurobindo Pharma Research Center-II 
Survey No -71 & 72, Indrakaran Village, 
Kandi Mandal, Sangareddy  
Dt Telangana -502329, India, 
Tel. no: +91-40-8455223700 Ext-1516, 
 
CRO: 
AXIS Clinicals Ltd 
1-121/1, Miyapur 
Hyderabad 500049, India 
Telephone: +91 40 4040 8064 
 
FAX – 91-40-4040 8060 
 
Confidentiality Statement 
This document is property of sponsor (Aurobindo Pharma, India). Information in this document is 
confidential. No part of it may be transmitted, reproduced, published or used by persons other than 
those who are authorized or have written permission from sponsor (Aurobindo Pharma, India) to do so. 
 


.  
 
 
 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 2 of 81 
 
 
       PROTOCOL SYNOPSIS  
Name of Sponsor/ 
Company: 
Aurobindo Pharma, India 
For National 
Authority Use 
Only  
Name of Finished 
Product: 
Beclomethasone Dipropionate MDI 0.04 mg/ 
INH 
Name of Active 
Ingredient: 
Beclomethasone 
Protocol No and version:
CR176-17 and Version 1.0, Amendment 02 
Study centers:  
Approximately 40 centers across India 
Study duration: 52 Days 
Clinical Pharmacodynamic BE Study 
Objectives: 
Primary Objective: 
To compare the therapeutic equivalence of Beclomethasone Dipropionate 
MDI (Inhalation Aerosol) 0.04 mg/ INH with the marketed QVAR® 40 mcg 
(Beclomethasone dipropionate hydrofluoroalkane (HFA)) and to demonstrate 
superiority of both active treatments over placebo. 
Secondary Objective: 
The secondary objective is to assess the safety and tolerability of 
Beclomethasone Dipropionate Metered Dose Inhaler (Inhalation Aerosol) 
(0.04 mg/ INH)  
Study 
Population 
Male and female subjects aged ≥ 18 years and ≤ 65 years diagnosed with 
Asthma for at least 12 months prior to screening. 
Methodology: 
1. This is a randomized, multiple-dose, double blind, placebo-controlled, 
parallel group, multicentric study to evaluate the Efficacy and Safety of 
Beclomethasone Dipropionate (0.04 mg/ INH) Metered Dose Inhaler 
 (Inhalation Aerosol) in male and/ or female subjects with Asthma.  
2. The study is divided into 3 periods: Screening period (7 days), Run-in 
period (up to 14 days) and Treatment period (28 days). 
3. A total of five visits to the Investigator site are scheduled; Screening 
Visit (Day -7 to Day -1), visit 2 on Day 0 for start of run in period, 
Randomization visit (Day 15 + 1), On-treatment visit (Day 21 ± 1) and 
End of Study/ EOS Visit (Day 42 ± 2).  
4. The total duration for a study subject will be approximately 52 Days 
including 7 days of screening, 14 days of run-in period with one day of 
window period, 28 days of treatment period and two days of window 
period.   
5. On Visit 1 (Screening visit), subjects with asthma diagnosed as per 
National Asthma Education and Prevention Program at least 12 months 


.  
 
 
 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 3 of 81 
 
 
Name of Sponsor/ 
Company: 
Aurobindo Pharma, India 
For National 
Authority Use 
Only  
Name of Finished 
Product: 
Beclomethasone Dipropionate MDI 0.04 mg/
INH 
Name of Active 
Ingredient: 
Beclomethasone 
Protocol No and version:
CR176-17 and Version 1.0, Amendment 02
Study centers:  
Approximately 40 centers across India 
Study duration: 52 Days 
Clinical Pharmacodynamic BE Study 
prior will be briefed about the study and Informed Consent Form will be 
obtained from the subjects. After signing of the ICF, an exhaled nitric 
oxide (FeNO) test will be performed. Subjects will not be considered for 
further screening procedures, if FeNO is < 25 ppb. 
6. Subjects will undergo pulmonary function test (PFT) through spirometer 
and those subjects with FEV1 of ≥ 45% and ≤ 85% of predicted value 
will undergo further screening procedures.  
7. On Visit 2 (Day 0), after completion of screening procedures, eligible 
subjects will be advised to start the placebo run-in period of 14 days with 
one day of window period. Subjects will be provided with placebo 
metered dose inhaler and advised to take one inhalation twice daily 
during entire course of run in period.  
8. Subject diary and rescue medication (Salbutamol) will also be dispensed 
to the subjects and detailed instructions will be provided regarding filling 
of subject diary and usage of rescue medication and placebo. FEV1 will 
be measured by Spirometry on this visit. Highest FEV1 will be 
considered from the 3 acceptable readings in this session for inclusion 
into study. 
9. On Visit 3 (Day 15+1), subjects will be instructed to bring subject diaries 
and study medication (placebo and rescue medication) for reconciliation 
by the study team. The subject diary entries will be checked to ensure 
compliance. Usage of the placebo medication will be cross verified 
through the subject diary entries. 
10. An exhaled nitric oxide (FeNO) test will be performed followed by 
Asthma Control Test (ACT) questionnaire evaluation in this visit. 
11. Subjects’ baseline FEV1 readings by performing Spirometry (average of 
pre dose highest FEV1 values at two time points- Patient needs to 
perform one baseline Spirometry session with minimum of 3 acceptable 
readings and then after a gap of minimum 30 minutes, one more baseline 
session will be performed with minimum of 3 acceptable readings. 


.  
 
 
 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 4 of 81 
 
 
Name of Sponsor/ 
Company: 
Aurobindo Pharma, India 
For National 
Authority Use 
Only  
Name of Finished 
Product: 
Beclomethasone Dipropionate MDI 0.04 mg/
INH 
Name of Active 
Ingredient: 
Beclomethasone 
Protocol No and version:
CR176-17 and Version 1.0, Amendment 02
Study centers:  
Approximately 40 centers across India 
Study duration: 52 Days 
Clinical Pharmacodynamic BE Study 
Highest value from both the sessions will be noted. Average of both the 
highest readings will be considered as baseline FEV1 value) will be 
noted. The baseline score for the Investigator’s Global Evaluation will be 
recorded. 
12. Subjects airway reversibility will be checked by performing a 
bronchodilator test wherein the initial baseline lung volume is measured 
by spirometer followed by administration of 360 mcg (90 mcg X 4 puffs 
at intervals approx.10 sec to 15 sec between each puff) of Salbutamol 
inhalation and then a repeat lung volume measurement by spirometer 
within 30 minutes of Inhalation of Salbutamol. 
13. Only subjects with ≥ 15 % and > 0.20 L reversibility of FEV1 at the time 
of first day of treatment visit will be considered for treatment period. 
14. Subjects who meet the applicable Inclusion and Exclusion criteria will be 
randomized to either of the Test/ Reference/ Placebo groups in a 2:2:1 as 
per the pre-specified randomization schedule. Subjects will receive their 
assigned study medication, along with instructions regarding method of 
administration. All subjects are required to take one inhalation of the 
assigned study medication two times daily for 4 weeks.    
15. The first dose of study medication will be administered to the subject at 
the site in the morning and the second dose will be self-administered by 
the subject in the evening at his/ her home and the subject will be advised 
to take one inhalation twice daily during the 4 weeks treatment period. 
Study medication, rescue medication (Salbutamol) and subject diary will 
be dispensed to the subject.  
16. Subjects need to return for Visit 4 (Day 21 ± 1). The predose FEV1 
readings will be taken. Highest FEV1 will be considered from the 3 
acceptable readings in this session.  
17. Also, measurement of vital signs, general and systemic examination and 
AE monitoring will be done. Compliance of subject dairy and 
concomitant medication will be checked.  


.  
 
 
 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 5 of 81 
 
 
Name of Sponsor/ 
Company: 
Aurobindo Pharma, India 
For National 
Authority Use 
Only  
Name of Finished 
Product: 
Beclomethasone Dipropionate MDI 0.04 mg/
INH 
Name of Active 
Ingredient: 
Beclomethasone 
Protocol No and version:
CR176-17 and Version 1.0, Amendment 02
Study centers:  
Approximately 40 centers across India 
Study duration: 52 Days 
Clinical Pharmacodynamic BE Study 
18. Subjects need to return for Visit 5 (Day 42 ± 2: End of Study/EOS). 
FEV1 will be measured in the morning prior to the dosing of inhaled 
medications on this day at the same time (with a window period of ± 30 
min) as that of the baseline reading on Visit 3. Two sessions with at least 
3 acceptable readings each will be performed. Highest value from both 
the sessions will be noted. Average of both the highest readings will be 
considered as EOS FEV1 value. 
19. An exhaled nitric oxide (FeNO) test will be performed. The Asthma 
Control Test (ACT) questionnaire will be evaluated and the 
Investigator’s Global Evaluation will be performed. Also, measurement 
of vital signs, general and systemic examination, concomitant medication 
recording and AE monitoring will be done. Urine Pregnancy Test (for 
females of child bearing potential) will be done. Clinical laboratory tests 
will be repeated to check safety of subjects before they are discharged 
from the study. 
20. The subjects are required to submit their issued study drug container, 
rescue medication and subject diaries for compliance checking.  
Number of 
subjects 
Assuming 5% loss from enrolled population to mITT population, 1550 
subjects will be enrolled in this study. Subjects will be enrolled in 2:2:1 
proportion as 620:620:310 (Test: RLD: Placebo respectively).  
Diagnosis and 
main criteria 
for inclusion 
and Exclusion: 
Inclusion Criteria: 
1. Adult male or female subjects of aged ≥18 to ≤ 65 years inclusive. 
2. Diagnosis of asthma as defined by the National Asthma Education and 
Prevention Program at least 12 months prior to screening.  
3. Pre-bronchodilator FEV1 of ≥ 45% and ≤ 85% of predicted value during 
the screening visit and on the first day of treatment visit.  
4. ≥15% and > 0.20 L reversibility of FEV1 within 30 minutes following 
360 mcg of Salbutamol inhalation (pMDI) on the first day of treatment 
visit. 


.  
 
 
 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 6 of 81 
 
 
Name of Sponsor/ 
Company: 
Aurobindo Pharma, India 
For National 
Authority Use 
Only  
Name of Finished 
Product: 
Beclomethasone Dipropionate MDI 0.04 mg/
INH 
Name of Active 
Ingredient: 
Beclomethasone 
Protocol No and version:
CR176-17 and Version 1.0, Amendment 02
Study centers:  
Approximately 40 centers across India 
Study duration: 52 Days 
Clinical Pharmacodynamic BE Study 
5. Subjects with FeNO > 25 ppb at screening and on the first day of 
treatment visit. 
6. Subjects stable on their chronic asthma treatment regimen for at least 
four weeks prior to enrollment.  
7. Subject should able to replace current SABAs with Salbutamol inhaler 
for use as needed for the duration of the study.   
8. Subject should be able to withhold all inhaled SABAs for at least six 
hours prior to lung function assessments on study visits.  
9. Ability to discontinue their asthma medications (inhaled corticosteroids 
and long-acting β agonists) during the run-in period and for remainder of 
the study. 
10. Asthma patients who are stable on low dose ICS or low dose ICS+LABA 
or who would be stable with low dose ICS as per Investigator’s clinical 
judgement. 
11. Currently non-smoking; had not used tobacco products (i.e., cigarettes, 
cigars, pipe tobacco) within the past year, and having had ≤ 10 pack-
years of historical use.  
12. Willingness to give their written informed consent to participate in the 
study. 
13. Subjects willing to perform all study related procedures including the use 
of study inhalers, Spirometry and willing to complete the Subject diary. 
14. Female of child-bearing potential, agreed to use a reliable method of 
contraception during study (e.g., condom + spermicide, IUD, oral, 
transdermal, injected or implanted hormonal contraceptives). 
 
 
Exclusion Criteria: 
1. Life-threatening asthma, a history of asthma episodes(s) requiring 


.  
 
 
 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 7 of 81 
 
 
Name of Sponsor/ 
Company: 
Aurobindo Pharma, India 
For National 
Authority Use 
Only  
Name of Finished 
Product: 
Beclomethasone Dipropionate MDI 0.04 mg/
INH 
Name of Active 
Ingredient: 
Beclomethasone 
Protocol No and version:
CR176-17 and Version 1.0, Amendment 02
Study centers:  
Approximately 40 centers across India 
Study duration: 52 Days 
Clinical Pharmacodynamic BE Study 
intubation, and/or associated with hypercapnia, respiratory arrest or 
hypoxic seizures, asthma related syncopal episode(s). 
2. Hospitalizations within the past year prior to the screening for the 
conditions mentioned in exclusion criteria No.01 or during the run-in 
period.  
3. Significant respiratory disease other than asthma (COPD, interstitial 
lung disease, etc.)  
4. Evidence or history of clinically significant disease or abnormality 
including congestive heart failure, uncontrolled hypertension  
5.  Evidence or history of clinically significant disease or abnormality 
including uncontrolled coronary artery disease, myocardial infarction, or 
cardiac dysrhythmia.  
6. Historical or current evidence of significant hematologic, hepatic, 
neurologic, psychiatric, renal, or other diseases that, in the opinion of the 
investigator, would put the subject at risk through study participation, or 
would affect the study analyses if the disease exacerbates during the 
study. 
7. Viral or bacterial, upper or lower respiratory tract infection, or sinus, or 
middle ear infection within four weeks prior to the screening, during the 
run-in period, or on the day of treatment.  
8. Hypersensitivity to Beclomethasone or any of the ingredients of the 
formulation and any sympathomimetic drug (e.g., Salbutamol) or any 
inhaled, intranasal, or systemic corticosteroid therapy.  
9. Subjects receiving β2-blockers, anti-arrhythmics, anti-depressants, and 
monoamine oxidase inhibitors within 4 weeks prior to the screening.  
10. Subjects who required systemic corticosteroids (for any reason) within 
the past 2 months. 
11. Clinically significant abnormalities in ECG at screening as per 


.  
 
 
 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 8 of 81 
 
 
Name of Sponsor/ 
Company: 
Aurobindo Pharma, India 
For National 
Authority Use 
Only  
Name of Finished 
Product: 
Beclomethasone Dipropionate MDI 0.04 mg/
INH 
Name of Active 
Ingredient: 
Beclomethasone 
Protocol No and version:
CR176-17 and Version 1.0, Amendment 02
Study centers:  
Approximately 40 centers across India 
Study duration: 52 Days 
Clinical Pharmacodynamic BE Study 
investigators discretion. 
12. Female subjects who are pregnant, nursing or planning a pregnancy 
during the study. 
13. Subjects who have participated in another investigational drug or device 
research study within 30 days of screening. 
14. Subjects who are using any medication or has any disease which in the 
judgment of the Investigator will interfere with the conduct or 
interpretation of the study. 
Investigational 
and Reference 
Product, dose 
and mode of 
administration:
Group-I (Test): Beclomethasone Dipropionate Metered Dose Inhaler (0.04 
mg/ INH)  
Manufactured by: Aurolife, a subsidiary of Aurobindo Pharma, USA, Inc. 
2929 Weck Dr., Durham, NC 27709. 
Group-II (Reference): QVAR® 40 mcg (Beclomethasone dipropionate 
HFA), Inhalation Aerosol 
Marketed by: Teva Pharmaceuticals LLC Frazer, PA 19355. 
NDC code: 59310-202-12 
 
Group-III: Placebo 
Manufactured by: Aurolife, a subsidiary of Aurobindo Pharma, USA, Inc. 
2929 Weck Dr., Durham, NC 27709. 
Subjects will receive one inhalation (0.04 mg/ INH) of Study medication 
(either Test/Reference/Placebo) twice daily. 
Concomitant 
Medication 
No other asthma medication will be allowed in the study, except for the use 
of inhaled short-acting ß2- agonist Salbutamol pMDI as rescue medication 
throughout the study duration. Subjects will be allowed to use Salbutamol, 
maximum of 6 puffs/ day, if required. 
Efficacy 
Endpoints 
Primary Endpoint 
 Mean change in Forced Expiratory volume in 1 second (FEV 1) from 
baseline (visit 3) to end of study visit (visit 5). 


.  
 
 
 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 9 of 81 
 
 
Name of Sponsor/ 
Company: 
Aurobindo Pharma, India 
For National 
Authority Use 
Only  
Name of Finished 
Product: 
Beclomethasone Dipropionate MDI 0.04 mg/
INH 
Name of Active 
Ingredient: 
Beclomethasone 
Protocol No and version:
CR176-17 and Version 1.0, Amendment 02
Study centers:  
Approximately 40 centers across India 
Study duration: 52 Days 
Clinical Pharmacodynamic BE Study 
Note: “Baseline morning FEV1 readings at visit 3 will be the average of pre 
dose highest FEV1 values at two time points (i.e., Patient needs to perform 
one baseline Spirometry session with minimum of 3 acceptable readings and 
then after a gap of minimum 30 minutes, one more baseline session will be 
performed with minimum of 3 acceptable readings. Highest value from both 
the sessions will be noted. Average of both the highest readings will be 
considered as baseline FEV1 value). Sampling need to be taken on the same 
time (with a window period of ± 30 min) of day as used for first day of a 4 
week treatment on the last day of a 4-week treatment. 
Secondary Endpoints 
 Mean change in FeNO value from base line (visit 1 & 3) to end of study 
visit (visit 5) 
 Percentage of subjects with reduction of FeNO from Baseline (Visit 1 & 
3) to End of Study (Visit 5)  
Safety 
Endpoints 
Safety will be assessed on the basis of reported adverse events, serious 
adverse events and laboratory assessments. 
Statistical 
Analysis 
1. Primary endpoint will be analyzed by comparing between Test and 
Reference groups for Equivalence and further comparing between Test 
group versus Placebo and Reference group versus Placebo for 
Superiority.  
2. Test group will be declared equivalent to Reference group, if the 90 % CI 
of the ratio between the Test product and Reference product for the 
primary endpoint is within the limits of 80.00% - 125.00% at the end of 
study (Day 42 ± 2). 
3. At study conclusion, Test and Reference groups will each be evaluated 
for Superiority over Placebo (p < 0.05) at Visit 5/ EOS (Day 42 ± 2). For 
this the mITT analysis population and Last Observation Carried Forward 
(LOCF) will be used. 
 


 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 10 of 81 
 
 
Table – I:  TABLE OF EVENTS 
Procedure  
Screening 
Period 
 
Run-in 
Period 
Treatment Period 
End of 
Study 
-7 days 
 Day 0 
 Day 1 to 
Day 14 
 Day 15 + 1  Day 21±1
 Day 42±2 
Visit  
1 
2 
-- 
3 
4 
5 
Informed consent 
X 
-- 
-- 
-- 
-- 
-- 
Eligibility criteria 
X 
-- 
-- 
X 
-- 
-- 
Demography 
X 
-- 
-- 
-- 
-- 
-- 
Medical and Medication 
History1 
X 
-- 
-- 
-- 
-- 
-- 
General & Systemic 
Examination2 
X 
X 
-- 
X 
X 
X 
Vital signs3 
X 
X 
-- 
X 
X 
X 
Serum Pregnancy Test  (for 
females of child bearing 
potential) 
X 
-- 
-- 
-- 
-- 
-- 
Urine Pregnancy Test (for 
females of child bearing 
potential) 
-- 
-- 
-- 
X 
-- 
X 
Clinical Laboratory Test4 
X 
-- 
-- 
-- 
-- 
X 
12 lead ECG 
X 
-- 
-- 
-- 
-- 
-- 
Chest X-Ray (PA view) 
X 
-- 
-- 
-- 
-- 
-- 
FeNO Estimation 
X 
-- 
-- 
X 
-- 
X 
FEV1 value recording 
(through Spirometry)  
X 
X 
-- 
X 
X 
X 
Bronchodilator/ Reversibility  
test  
-- 
-- 
-- 
X 
-- 
-- 
Placebo Canister Dispensing  
(for Run-in period) 
-- 
X 
-- 
-- 
-- 
-- 
Collection of Placebo Canister 
given in run-in Period 
-- 
-- 
-- 
X 
-- 
-- 
Rescue Medication 
Dispensing 
-- 
X 
-- 
X 
-- 
-- 
Collection of rescue 
medication canister 
-- 
-- 
-- 
X 
-- 
X 
Subject Diary Card 
Dispensing  
-- 
X 
-- 
-- 
-- 
-- 
Placebo Administration 
(in Run-in Period) 
-- 
-- 
One 
inhalation 
-- 
-- 
-- 


 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 11 of 81 
 
 
Procedure  
Screening 
Period 
 
Run-in 
Period 
Treatment Period 
End of 
Study 
-7 days 
 Day 0 
 Day 1 to 
Day 14 
 Day 15 + 1  Day 21±1
 Day 42±2 
Visit  
1 
2 
-- 
3 
4 
5 
two times 
daily from 
Day 1  to 
Day 14 
Subject Diary Card 
Compliance  
-- 
-- 
-- 
X 
X 
X 
Placebo administration 
compliance (Run-in- Period) 
-- 
-- 
-- 
X 
-- 
-- 
Randomization 
-- 
-- 
-- 
X 
-- 
-- 
Study Drug Dispensing  
(for Treatment period) 
-- 
-- 
-- 
X 
-- 
-- 
Study Drug Administration 
-- 
-- 
-- 
One inhalation two times daily from 
Day 15  to Day 42 
Collection of Study Drug 
Canister 
-- 
-- 
-- 
-- 
-- 
X 
Collection of Subject Diary  
-- 
-- 
-- 
-- 
-- 
X 
 
Concomitant  Medication 
Check  
X 
X 
X 
X 
X 
X 
Adverse event recording 
X 
X 
X 
X 
X 
X 
Asthma Control Test 
Questionnaire 
-- 
-- 
-- 
X 
-- 
X 
Investigator’s Global 
Evaluation 
-- 
-- 
-- 
X 
-- 
X 
 
1Medical and medication history will be performed at screening visit only. 
2General and Systemic examination includes head, neck, eye, ear, nose, throat, skin & appendages, renal, 
cardiovascular, pulmonary, reproductive, endocrine, gastrointestinal, nervous system, musculo-skeletal, peripheral 
vascular and psychiatric. 
3Vital signs include: blood pressure (supine), respiration rate, pulse rate and body temperature in 0F/0C. 
4 Haematology panel includes haemoglobin, haematocrit, white blood cell count with differential cell count, red 
blood cell count and platelets. Serum chemistry panel will include blood urea nitrogen, creatinine, albumin, alkaline 
phosphatase, total bilirubin, aspartate aminotransferase, alanine aminotransferase random blood sugar, sodium, 
potassium, and chloride. Serum pregnancy test (for females of child bearing potential) will be done at screening 
only.   
  


 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 12 of 81 
 
 
SIGNATURE PAGE 
The final protocol has been reviewed for completeness, accuracy, and compliance with 
applicable regulatory expectations. 
AUTHORED BY: 
 
 
 
Name: Krishna Kumar P 
Designation: Scientific Writer 
Department: Clinical Research 
 
 
 
 
Signature and Date 
REVIEWED BY: 
 
 
 
Name: Someswara Rao. K 
Designation: Sr. General Manager  
Department: Pharmacokinetics and 
Biostatistics 
 
 
 
 
Signature and Date 
REVIEWED BY: 
 
 
 
Name: Dr. Mohammed Sajid 
Designation: Medical Manager 
Department: Clinical Research 
 
 
 
 
Signature and Date 
APPROVED BY: 
 
 
 
Name: Dr. Subhra Lahiri 
Designation: Associate Vice President 
Department: Clinical Research 
 
 
 
 
Signature and Date 
 
  
 
 


 
 
Protocol No: CR176-17, Version 1.0, Amendment 02 Dated 07.08.2019     Confidential                    Page 13 of 81 
 
 
Table of Contents 
CONFIDENTIALITY STATEMENT ...................................................................................1 
PROTOCOL SYNOPSIS ........................................................................................................2 
SIGNATURE PAGE ..............................................................................................................12 
TABLE OF CONTENTS ......................................................................................................13 
LIST OF ABBREVIATIONS ...............................................................................................16 
1.0 
INTRODUCTION......................................................................................................18 
1.1. 
Study Rationale ..............................................................................................29 
2.0 
STUDY OBJECTIVES ..............................................................................................30 
2.1. 
Primary Objective ..........................................................................................30 
2.2. 
Secondary Objective ......................................................................................30 
3.0 
STUDY DESIGN ........................................................................................................31 
4.0 
STUDY VISITS ..........................................................................................................34 
4.1. 
Visit 1: Screening (Day -7 to Day -1) ............................................................34 
4.2. 
Visit 2: (Day 0) ................................................................................................35 
4.3. 
Placebo Run in period (Day 1 to Day 14) .....................................................36 
4.4. 
Randomization (Day 15 + 1) .........................................................................37 
4.5. 
Visit 4 (Day 21 ± 1) .........................................................................................38 
4.6. 
End of Study (Day 42 ± 2) .............................................................................39 
4.7. 
Withdrawal Visit ............................................................................................40 
5.0 
STUDY POPULATION ............................................................................................41 
5.1. 
Number of subjects ........................................................................................41 
5.2. 
Inclusion criteria ............................................................................................41 
5.3. 
Exclusion criteria ...........................................................................................42 
5.4. 
Subject Withdrawal .......................................................................................43 
6.0 
STUDY ENDPOINTS ................................................................................................44 
6.1. 
Efficacy Endpoints .........................................................................................44 
6.2. 
Safety Endpoints ............................................................................................44 
7.0 
ASSESSMENT OF STUDY ENDPOINTS ..............................................................45 
7.1. 
Assessment of Efficacy Endpoints ................................................................45 
7.2. 
Assessment of Safety Endpoints ...................................................................45 
7.2.1. Clinical Laboratory Evaluations ........................................................45 
7.2.2. Vital Signs 46 
7.2.3. General and Systemic Evaluation.......................................................46 
7.2.4. Adverse events ......................................................................................46 
8.0 
ADVERSE EVENTS .................................................................................................47 
8.1. 
Definitions .......................................................................................................47 
8.2. 
Severity............................................................................................................48 
8.3. 
Relationship ....................................................................................................48 
8.4. 
Reporting of Adverse Events ........................................................................49 
8.5. 
Follow-up of Adverse Events ........................................................................51 
8.6. 
Asthma exacerbations ....................................................................................51 


 
 
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9.0 
STUDY TREATMENTS ...........................................................................................53 
9.1. 
Description of Investigational Product ........................................................53 
9.2. 
Investigational product Administration ......................................................53 
9.3. 
Packaging and Labeling of Study drug ........................................................56 
9.4. 
Randomization ...............................................................................................57 
9.5. 
Masking and Unmasking ...............................................................................58 
9.6. 
Treatment Compliance ..................................................................................58 
9.7. 
Prohibited Medications .................................................................................59 
9.8. 
Study Drug Accountability............................................................................59 
10.0 
STATISTICS AND DATA COLLECTION ............................................................60 
10.1. 
Sample Size Calculation ................................................................................60 
10.2. 
Subject Disposition.........................................................................................61 
10.2.1. Safety Population ...............................................................................61 
10.2.2. mITT Population ................................................................................61 
10.2.3. Per Protocol Population ....................................................................61 
10.3. 
Subject Characteristics ..................................................................................62 
10.4. 
Analysis of Efficacy Data...............................................................................62 
10.4.1. Primary Efficacy Variable ................................................................62 
10.4.2. Primary Analysis ................................................................................62 
10.4.3. Secondary Efficacy Variables ...........................................................63 
10.4.4. Secondary Analysis ............................................................................63 
10.4.5. Imputation for Missing Data.............................................................63 
10.5. 
Safety Analysis ...............................................................................................64 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................65 
11.1. 
Direct Access to Source Documents and Study Monitoring ......................65 
11.2. 
Data Management/ Coding ...........................................................................66 
11.3. 
Quality Assurance Audit ...............................................................................66 
11.4. 
Data Collection ...............................................................................................67 
12.0 
ETHICS ......................................................................................................................68 
12.1. 
Ethics Committee ...........................................................................................68 
12.2. 
Ethical Conduct of the Study ........................................................................68 
12.3. 
Regulatory Approval .....................................................................................68 
12.4. 
Subject Information and Informed Consent ...............................................68 
13.0 
STUDY ADMINISTRATION ..................................................................................70 
13.1. 
Administrative Structure ..............................................................................70 
13.2.                Data Handling and Record Keeping………………………72 
13.3. 
Investigator Information ...............................................................................71 
13.3.1. Investigator Obligations ....................................................................71 
13.3.2. Protocol Deviations and Protocol Waivers ......................................72 
13.3.3. Publication Policy...............................................................................72 
13.3.4. Data Ownership .................................................................................72 
13.4. 
Financing and Insurance ...............................................................................72 


 
 
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14.0 
REFERENCES ...........................................................................................................73 
APPENDIX 1: SPONSOR PROTOCOL AGREEMENT……………………………….74 
APPENDIX 2:  INVESTIGATOR PROTOCOL AGREEMENT ....................................75 
APPENDIX 3: INVESTIGATOR’S GLOBAL EVALUATION (ASSESSED BY 
INVESTIGATORS) ...................................................................................................76 
APPENDIX 4: ASTHMA CONTROL QUESTIONNAIRE TEST ..................................77 
APPENDIX 5: NATIONAL ASTHMA EDUCATION AND PREVENTION PROGRAM-
ASTHMA DIAGNOSIS CRITERIA .......................................................................78 
APPENDIX 6: ESCAPE CRITERIA FOR ASTHMA .......................................................79 
 


 
 
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LIST OF ABBREVIATIONS 
ACT 
American Thoracic Society 
ADR 
Adverse Drug Reaction 
17-BMP 
Beclomethasone-17-monopropionate   
AE 
Adverse Event 
AIDS 
Acquired immunodeficiency syndrome 
ANCOVA 
Analysis of Covariance 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase 
BDP 
Beclomethasone dipropionate 
BMD 
Bone Mineral Density 
BMI  
Basal Metabolic Index 
BOH 
Beclomethasone 
BP  
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CDSCO 
Central Drugs Standard Control Organization  
COPD 
Chronic obstructive pulmonary disease 
CQA 
Clinical Quality Assurance 
CRA  
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization  
DCGI 
Drugs Controller General of India 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EOS  
End of Study 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FeNO 
Exhaled Nitric Oxide 
FEV1 
Forced expiratory volume in 1 second 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HDL  
High-density lipoprotein 
HPA 
Hypothalamic-pituitary-adrenal  
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICMR 
Indian Council for Medical Research 


 
 
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ICSs 
Inhaled corticosteroids 
IG 
Immunoglobulin 
IP 
Investigational Product 
ITT 
Intent-to-Treat  
IWRS 
Interactive Web Response System 
LAR 
Legally Acceptable Representative 
LABA 
Long Acting Beta Agonists 
LDL 
Low-density lipoprotein 
LOCF 
Last Observation Carried Forward  
MDI 
Metered-Dose Inhaler 
MedDRA 
Medical Dictionary for Regulatory Affairs 
mITT 
modified Intent-to-Treat  
Ml 
Milliliter 
NABL 
National Accreditation Board for Testing and Calibration Laboratories 
OTC 
Over-the-counter 
PEF 
Peak expiratory flow 
PFT 
Pulmonary Function Test 
PI 
Principal Investigator 
PP 
Per Protocol 
ppb 
Parts Per Billion 
RBC 
Red blood cell count  
RLD 
reference listed drug  
SAE 
Serious Adverse Event 
SOC 
System Organ Class  
SOP 
Standard Operating Procedure 
US/USA 
United States of America 
UAE 
Unexpected Adverse Events  
VZIG 
Varicella-zoster immune globulin 
WBC 
White blood cell count  
 
 
 


 
 
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1.0 
INTRODUCTION 
Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular 
elements play a role. The chronic inflammation is associated with airway hyperresponsiveness 
that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, 
particularly at night or in the early morning. These episodes are usually associated with 
widespread, but variable, airflow obstruction within the lung that is often reversible either 
spontaneously or with treatment1. The incidence and prevalence of asthma have increased during 
the past 20 years, affecting 5-10% of the global population2. 
The administration of corticosteroids via inhalation is considered the optimal route for 
appropriate drug delivery for treatment of bronchial asthma and could reduce asthma 
hospitalizations by as much as 80%3. The inflammatory process in asthma involves the increased 
expression of a wide variety of pro-inflammatory chemokines, cytokines, growth factors, lipid 
mediators, adhesion molecules, enzymes, and increased numbers of resident and invading 
inflammatory cells4.  
Inhaled corticosteroids (ICSs) are believed to exert their effects after translocation into the 
nucleus of the respiratory epithelial cell and other cells in the airway, via the glucocorticoid 
receptor. The steroid-receptor complex within the nucleus promotes transcription of genes that 
decrease inflammation and inhibit transcription of genes that encode proteins that increase 
inflammation. There is also evidence that ICSs may facilitate the action of β2 adrenergic agonists 
by increasing the concentrations of β2 adrenergic receptors on smooth muscle cells and 
decreasing airway smooth-muscle cell hypo responsiveness to β2 agonist5. 
Regardless of the structure differences of the various ICSs, they all work through the same 
mechanism of action. Differences in the chemical structure of the various ICSs cause differences 
in their pharmacokinetic properties, which can be advantageous for clinical efficacy and safety. 
 
Pharmacokinetic and Pharmacodynamic Features of different Inhaled Corticosteroids6 
 


 
 
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Pathophysiology and pathogenesis of bronchial asthma7 
Airflow limitation in asthma is recurrent and caused by a variety of changes in the airway. These 
include: 
Bronchoconstriction: In bronchial asthma, the main physiological event leading to clinical 
symptoms is airway narrowing. In acute exacerbations of asthma bronchoconstriction occurs 
quickly to constrict the airways as a response to exposure to a different stimuli including 
allergens or irritants. Allergen-induced acute bronchoconstriction results from an IgE-dependent 
release of mediators from mast cells which includes histamine, tryptase, leukotrienes, and 
prostaglandins. Aspirin and other nonsteroidal anti-inflammatory drugs can also cause acute 
airflow obstruction and this non-IgE-dependent response also involves mediator release from 
airway cells. 
Airway edema: This results from persistent and progressive inflammation. 
Airway hyperresponsiveness: It is an exaggerated bronchoconstrictor response to a wide 
variety of stimuli and it is a major, but not necessarily unique, feature of asthma. The cause for 
this hyperresponsiveness is inflammation, dysfunctional neuroregulation, and structural changes; 
inflammation is the major factor in determining the degree of airway hyperresponsiveness. 
Treatment directed toward reducing inflammation can reduce airway hyperresponsiveness and 
improve asthma control. 
Airway remodeling: Airflow limitation may be only partially reversible in few patients. 
Permanent structural changes in the form of progressive loss of lung function can occur and it is 
not prevented by or fully reversible by current therapies. Airway remodeling involves many of 
the structural changes like thickening of the sub-basement membrane, subepithelial fibrosis, 
airway smooth muscle hypertrophy and hyperplasia, blood vessel proliferation and dilation, and 
mucous gland hyperplasia and hypersecretion.  
Diagnosis of asthma7:  
To establish a diagnosis of asthma, the clinician should determine that  
— Episodic symptoms of airflow obstruction or airway hyperresponsiveness are present. 
— Airflow obstruction is at least partially reversible. 
— Alternative diagnoses are excluded. 
Recommended methods to establish the diagnosis are  
— Detailed medical history. 
— Physical exam focusing on the upper respiratory tract, chest, and skin. 


 
 
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— Spirometry to demonstrate obstruction and assess reversibility.  
Reversibility is determined either by an increase in FEV1 of ≥12 percent from baseline or by an 
increase ≥10 percent of predicted FEV1 after inhalation of a short-acting bronchodilator. 
— Alternative diagnoses should be excluded. 
Classification of Asthma Severity7 
 
7National Institutes of Health, author. National Asthma Education and Prevention Program Expert Panel Report 3: 
Guidelines for the Diagnosis and Management of Asthma. 2007.  
 
Treatment of asthma7: 
Asthma drugs are classified as either relievers or controllers or more broadly as either 
bronchodilator or anti-inflammatory drugs.  
Reliever asthma drugs are bronchodilators that act fast usually within the first few minutes. 
Controller medications are the main stay of asthma management because they target the 
underlying inflammatory process. Controller drugs include corticosteroids, Leukotriene 
modifiers and anti- Immunoglobulin E therapy. 


 
 
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Step wise approach for managing asthma in youth’s ≥ 12 years age and adults   
 
7National Institutes of Health, author. National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis 
and Management of Asthma. 2007.  
 
QVAR® 40 mcg (Beclomethasone dipropionate HFA 40 mcg), Inhalation Aerosol 
 
The active component of QVAR 40 mcg Inhalation Aerosol and QVAR 80 mcg Inhalation 
Aerosol is beclomethasone dipropionate, USP, a corticosteroid having the chemical name 9- 
chloro-11ß,17,21-trihydroxy-16ß-methylpregna-1,4-diene-3, 
20-dione 
17, 
21-dipropionate. 
Beclomethasone dipropionate (BDP) is a diester of beclomethasone, a synthetic corticosteroid 
chemically related to dexamethasone9. 
INDICATIONS AND USAGE 
QVAR is indicated in the maintenance treatment of asthma as prophylactic therapy in patients 5 
years of age and older. QVAR is also indicated for asthma patients who require systemic 
corticosteroid administration, where adding QVAR may reduce or eliminate the need for the 
systemic corticosteroids. 
 


 
 
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Important Limitations of Use: 
• Beclomethasone is NOT indicated for the relief of acute bronchospasm. 
 
CONTRAINDICATIONS  
Status Asthmaticus  
QVAR is contraindicated in the primary treatment of status asthmaticus or other acute episodes 
of asthma where intensive measures are required.  
 
Hypersensitivity  
QVAR is contraindicated in patients with known hypersensitivity to beclomethasone 
dipropionate or any of the ingredients in QVAR. 
 
WARNINGS AND PRECAUTIONS  
Local Effects  
Localized infections with Candida albicans have occurred in the mouth and pharynx in some 
patients receiving QVAR. If oropharyngeal candidiasis develops, it should be treated with 
appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with QVAR 
therapy, but at times therapy with QVAR may need to be temporarily interrupted under close 
medical supervision. Rinsing the mouth after inhalation is advised. 
 
Deterioration of Asthma and Acute Episodes  
QVAR is not indicated for the relief of acute symptoms, i.e., as rescue therapy for the treatment 
of acute episodes of bronchospasm. An inhaled, short-acting beta-2 agonist, not QVAR, should 
be used to relieve acute symptoms such as shortness of breath. Instruct patients to contact their 
physician immediately if episodes of asthma that are not responsive to bronchodilators occur 
during the course of treatment with QVAR. During such episodes, patients may require therapy 
with oral corticosteroids. 
 
Transferring Patients from Systemic Corticosteroid Therapy 
Particular care is needed in patients who are transferred from systemically active corticosteroids 
to QVAR because deaths due to adrenal insufficiency have occurred in asthmatic patients during 
and after transfer from systemic corticosteroids to less systemically available inhaled 
corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required 
for recovery of hypothalamic-pituitary-adrenal (HPA) function. 


 
 
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Patients who have been previously maintained on 20 mg or more per day of prednisone (or its 
equivalent) may be most susceptible, particularly when their systemic corticosteroids have been 
almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs 
and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infections 
(particularly gastroenteritis) or other conditions with severe electrolyte loss. Although QVAR 
may provide control of asthmatic symptoms during these episodes, in recommended doses it 
supplies less than normal physiological amounts of glucocorticoid systemically and does NOT 
provide the mineralocorticoid that is necessary for coping with these emergencies. 
 
During periods of stress or a severe asthmatic attack, patients who have been withdrawn from 
systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) 
immediately and to contact their physician for further instruction. These patients should also be 
instructed to carry a warning card indicating that they may need supplementary systemic steroids 
during periods of stress or a severe asthma attack. 
 
Patients requiring oral or other systemic corticosteroids should be weaned slowly from oral or 
other systemic corticosteroid use after transferring to QVAR. Lung function (FEV1 or PEF), 
beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral 
or other systemic corticosteroids. In addition to monitoring asthma signs and symptoms, patients 
should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, 
weakness, nausea and vomiting, and hypotension. 
 
Transfer of patients from systemic corticosteroid therapy to QVAR may unmask allergic 
conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, 
conjunctivitis, eczema, arthritis, and eosinophilic conditions.  
During withdrawal from oral corticosteroids, some patients may experience symptoms of 
systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and 
depression, despite maintenance or even improvement of respiratory function. 
 
Immunosuppression 
Persons who are on drugs which suppress the immune system are more susceptible to infections 
than healthy individuals. Chickenpox and measles, for example, can have a more serious or even 
fatal course in non-immune children or adults on corticosteroids. In such children or adults who 
have not had these diseases or been properly immunized, particular care should be taken to avoid 
exposure. It is not known how the dose, route and duration of corticosteroid administration 
affects the risk of developing a disseminated infection. Nor is the contribution of the underlying 
disease and/or prior corticosteroid treatment known. If exposed to chickenpox, prophylaxis with 
varicella-zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis 


 
 
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with pooled intramuscular immunoglobulin (IG) may be indicated. If chickenpox develops, 
treatment with antiviral agents may be considered.  
Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent 
tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, parasitic or 
viral infections; or ocular herpes simplex. 
 
Paradoxical Bronchospasm  
Inhaled corticosteroids may produce inhalation induced bronchospasm with an immediate 
increase in wheezing after dosing that may be life-threatening. If inhalation induced 
bronchospasm occurs following dosing with QVAR, it should be treated immediately with an 
inhaled, short-acting bronchodilator. Treatment with QVAR should be discontinued and alternate 
therapy instituted. 
 
Immediate Hypersensitivity Reactions  
Hypersensitivity reactions, such as urticaria, angioedema, rash, and bronchospasm, may occur 
after administration of QVAR. Discontinue QVAR if such reactions occur. 
 
Hypercorticism and Adrenal Suppression  
QVAR will often help control asthma symptoms with less suppression of HPA function than 
therapeutically equivalent oral doses of prednisone. Since beclomethasone dipropionate is 
absorbed into the circulation and can be systemically active at higher doses, the beneficial effects 
of QVAR in minimizing HPA dysfunction may be expected only when recommended dosages 
are not exceeded and individual patients are titrated to the lowest effective dose.  
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with 
QVAR should be observed carefully for any evidence of systemic corticosteroid effects. 
Particular care should be taken in observing patients postoperatively or during periods of stress 
for evidence of inadequate adrenal response.  
It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression 
(including adrenal crisis) may appear in a small number of patients, particularly when 
beclomethasone dipropionate is administered at higher than recommended doses over prolonged 
periods of time. If such effects occur, the dosage of QVAR should be reduced slowly, consistent 
with accepted procedures for reducing systemic corticosteroids and for management of asthma 
symptoms. 
 
Effects on Growth  
Orally inhaled corticosteroids, including QVAR, may cause a reduction in growth velocity when 
administered to pediatric patients. Monitor the growth of pediatric patients receiving QVAR 


 
 
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routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled 
corticosteroids, including QVAR, titrate each patient’s dose to the lowest dosage that effectively 
controls his/ her symptom. 
 
Reduction in Bone Mineral Density  
Decreases in bone mineral density (BMD) have been observed with long-term administration of 
products containing inhaled corticosteroids. The clinical significance of small changes in BMD 
with regard to long-term outcomes, such as fracture, is unknown. Patients with major risk factors 
for decreased bone mineral content, such as prolonged immobilization, family history of 
osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and 
corticosteroids) should be monitored and treated with established standards of care. 
 
Eye Disorders  
Glaucoma, increased intraocular pressure, blurred vision and cataracts have been reported 
following the use of long-term administration of inhaled corticosteroids. Therefore, close 
monitoring is warranted in patients with a change in vision or with a history of increased 
intraocular pressure, blurred vision, glaucoma and/or cataracts while using QVAR. 
 
ADVERSE REACTIONS  
Systemic and local corticosteroid use may result in the following:  
 
 Candida albicans infection  
 Immunosuppression  
 Hypercorticism and adrenal suppression  
 Growth effects and Use in Specific Populations  
 Eye Disorders 
Clinical Trials Experience  
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials 
of another drug and may not reflect the rates observed in practice. 
The following reporting rates of common adverse experiences are based upon 4 clinical trials in 
which 1196 patients (671 female and 525 male adults previously treated with as-needed 
bronchodilators and/or inhaled corticosteroids) were treated with QVAR (doses of 40, 80, 160, 
or 320 mcg twice daily) or CFC-BDP (doses of 42, 168, or 336 mcg twice daily) or placebo. 
Below table includes all events reported by patients taking QVAR (whether considered drug 


 
 
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related or not) that occurred at a rate over 3% for QVAR. In considering these data, difference in 
average duration of exposure and clinical trial design should be taken into account. 
Adverse Events Reported by at Least 3% of the Patients for QVAR by Treatment and 
Daily Dose 
Adverse 
Events 
Placebo 
(N=289) 
% 
QVAR 
Total 
(N=624)
% 
80-160 
mcg 
(N=233) 
% 
320 
mcg 
(N=335) 
% 
640 
mcg 
(N=56) 
% 
Headache
9
12
15
8
25
Pharyngitis
4
8
6
5
27
Upper resp tract 
infection 
11 
9 
7 
11 
5 
Rhinitis
9
6
8
3
7
Increased asthma 
symptoms 
18 
3 
2 
4 
0 
Oral symptoms 
inhalation route 
2 
3 
3 
3 
2 
Sinusitis
2
3
3
3
0
Pain
<1
2
1
2
5
Back pain
1
1
2
<1
4
Dysphonia
2
<1
1
0
4
 
Other adverse events that occurred in these clinical trials using QVAR with an incidence of 1% 
to 3% and which occurred at a greater incidence than placebo were nausea, dysmenorrhea, and 
coughing. Oropharyngeal candidiasis occurred in < 1% of patients in both QVAR and placebo 
treatment groups. 
 


 
 
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CLINICAL PHARMACOLOGY  
Mechanism of Action  
Beclomethasone dipropionate is a corticosteroid demonstrating potent anti-inflammatory 
activity. The precise mechanism of corticosteroid action on asthma is not known. Corticosteroids 
have been shown to have multiple anti-inflammatory effects, inhibiting both inflammatory cells 
(e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and release 
of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines). These 
anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.  
 
Beclomethasone dipropionate is a prodrug that is rapidly activated by hydrolysis to the active 
monoester, 17 monopropionate (17-BMP). Beclomethasone 17 monopropionate has been shown 
in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is 
approximately 13 times that of dexamethasone, 6 times that of triamcinolone acetonide, 1.5 
times that of budesonide and 25 times that of beclomethasone dipropionate. The clinical 
significance of these findings is unknown. Studies in patients with asthma have shown a 
favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects 
with recommended doses of QVAR. 
 
Pharmacodynamics  
HPA Axis Effects  
The effects of QVAR on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 40 
corticosteroid-naive patients. QVAR, at doses of 80, 160 or 320 mcg twice daily was compared 
with placebo and 336 mcg twice daily of beclomethasone dipropionate in a CFC propellant 
based formulation (CFC-BDP). Active treatment groups showed an expected dose-related 
reduction in 24-hour urinary-free cortisol (a sensitive marker of adrenal production of cortisol). 
Patients treated with the highest dose recommended of QVAR (320 mcg twice daily) had a 
37.3% reduction in 24-hour urinary-free cortisol compared to a reduction of 47.3% produced by 
treatment with 336 mcg twice daily of CFC-BDP. There was a 12.2% reduction in 24-hour 
urinary-free cortisol seen in the group of patients that received 80 mcg twice daily of QVAR and 
a 24.6% reduction in the group of patients that received 160 mcg twice daily. An open label 
study of 354 asthma patients given QVAR at recommended doses for one year assessed the 
effect of QVAR treatment on the HPA axis (as measured by both morning and stimulated plasma 
cortisol). Less than 1% of patients treated for one year with QVAR had an abnormal response 
(peak less than 18 mcg/dL) to short-cosyntropin test. 
 
 
 


 
 
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Pharmacokinetics  
Beclomethasone dipropionate (BDP) undergoes rapid and extensive conversion to 
beclomethasone-17-monopropionate (17-BMP) during absorption. The pharmacokinetics of 17 
BMP has been studied in asthmatics given single doses.  
 
Absorption: The mean peak plasma concentration (Cmax) of BDP was 88 pg/ml at 0.5 hour 
after inhalation of 320 mcg using QVAR (4 actuations of the 80 mcg/actuation strength). The 
mean peak plasma concentration of the major and most active metabolite, 17-BMP, was 1419 
pg/ml at 0.7 hour after inhalation of 320 mcg of QVAR. When the same nominal dose is 
provided by the two QVAR strengths (40 and 80 mcg/actuation), equivalent systemic 
pharmacokinetics can be expected. The Cmax of 17-BMP increased dose proportionally in the 
dose range of 80 and 320 mcg.  
 
Metabolism: Three major metabolites are formed via cytochrome P450-3A catalyzed 
biotransformation: beclomethasone-17-monopropionate (17-BMP), beclomethasone-21 
monopropionate (21-BMP) and beclomethasone (BOH). Lung slices metabolize BDP rapidly to 
17-BMP and more slowly to BOH. 17-BMP is the most active metabolite.  
 
Distribution: The in vitro protein binding for 17-BMP was reported to be 94-96% over the 
concentration range of 1000 to 5000 pg/mL. Protein binding was constant over the concentration 
range evaluated. There is no evidence of tissue storage of BDP or its metabolites.  
 
Elimination: The major route of elimination of inhaled BDP appears to be via hydrolysis. More 
than 90% of inhaled BDP is found as 17-BMP in the systemic circulation. The mean elimination 
half-life of 17-BMP is 2.8 hours. Irrespective of the route of administration (injection, oral or 
inhalation), BDP and its metabolites are mainly excreted in the feces. Less than 10% of the drug 
and its metabolites are excreted in the urine. 
 
CLINICAL STUDIES  
Blinded, randomized, parallel, placebo-controlled and active-controlled clinical studies were 
conducted in 940 adult asthma patients to assess the efficacy and safety of QVAR in the 
treatment of asthma. Fixed doses ranging from 40 mcg to 160 mcg twice daily were compared to 
placebo, and doses ranging from 40 mcg to 320 mcg twice daily were compared with doses of 42 
mcg to 336 mcg twice daily of an active CFC-BDP comparator. These studies provided 
information about appropriate dosing through a range of asthma severity. A blinded, 
randomized, parallel, placebo-controlled study was conducted in 353 pediatric patients (age 5 to 
12 years) to assess the efficacy and safety of HFA beclomethasone dipropionate in the treatment 
of asthma. Fixed doses of 40 mcg and 80 mcg twice daily were compared with placebo in this 
study. In these adult and pediatric efficacy trials, at the doses studied, measures of pulmonary 


 
 
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function [forced expiratory volume in 1 second (FEV1) and morning peak expiratory flow (AM 
PEF)] and asthma symptoms were significantly improved with QVAR treatment when compared 
to placebo. 
In controlled clinical trials with adult patients not adequately controlled with beta-agonist alone, 
QVAR was effective at improving asthma control at doses as low as 40 mcg twice daily (80 
mcg/day). Comparable asthma control was achieved at lower daily doses of QVAR than with 
CFC-BDP. Treatment with increasing doses of both QVAR and CFC-BDP generally resulted in 
increased improvement in FEV1. In this trial the improvement in FEV1 across doses was greater 
for QVAR than for CFC-BDP, indicating a shift in the dose response curve for QVAR. 
 
Proper Use and Care of the Inhaler  
Priming: Priming is essential to ensure appropriate beclomethasone dipropionate content in each 
actuation. Instruct patients to prime the inhaler before using for the first time and in cases where 
the inhaler has not been used for more than 10 days by releasing two sprays into the air, away 
from the face.  
Cleaning: For normal hygiene, the mouthpiece of the inhaler should be cleaned weekly with a 
clean, dry tissue or cloth. DO NOT WASH OR PUT ANY PART OF THE INHALER IN 
WATER.  
Dose Counter: Inform patients that QVAR has a dose counter attached to the actuator. When the 
patient receives the inhaler, a black dot will appear in the viewing window until it has been 
primed 2 times, at which point the total number of actuations will be displayed. The dose counter 
will count down each time a spray is released. The dose-counter window displays the number of 
sprays left in the inhaler in units of two (e.g., 120, 118, 116, etc). When the counter displays 20, 
the color of the numbers will change to red to remind the patient to contact their pharmacist for a 
refill of medication or consult their physician for a prescription refill. When the dose counter 
reaches 0, the background will change to solid red. Inform patients to discard the QVAR inhaler 
when the dose counter displays 0 or after the expiration date on the product, whichever comes 
first. 
1.1. 
Study Rationale 
Aurobindo Pharma, India, is seeking marketing approval for Beclomethasone Dipropionate 
Metered Dose Inhaler (0.04 mg/INH) in USA, for which demonstration of equivalence in 
efficacy to a reference QVAR® 40 mcg (Beclomethasone dipropionate hydrofluoroalkane) is 
required; therefore an appropriate comparability exercise is required to demonstrate that the 
similar therapeutic benefit with that of reference medicinal products in terms of quality, safety 
and efficacy is achieved and superiority in efficacy to that of placebo. 


 
 
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2.0 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
To compare the therapeutic equivalence of Beclomethasone Dipropionate MDI (Inhalation 
Aerosol) 0.04 mg/ INH with the marketed QVAR® 40 mcg (Beclomethasone dipropionate hydro
fluoroalkane (HFA)) and to demonstrate superiority of both active treatments over placebo. 
2.2. 
Secondary Objective 
The secondary objective is to assess the safety and tolerability of Beclomethasone Dipropionate 
MDI (Inhalation Aerosol) 0.04 mg/ INH. 
 
 


 
 
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3.0 
STUDY DESIGN 
This is a randomized, multiple dose, double blind, placebo controlled, parallel group, multicentr-
ic study to evaluate the Efficacy and Safety of Beclomethasone Dipropionate (0.04 mg/ INH) Me
tered Dose Inhaler in male and/ or female subjects with Asthma [Group I (Test): Beclomethasone
 Dipropionate 0.04 mg/ INH; Group II (Reference): QVAR® 40 mcg (Beclomethasone dipropion
ate HFA), Inhalation Aerosol; and Group III: Placebo]. 
A total of five visits will be scheduled to the investigator site [i.e., Screening Visit (Day -7 to 
Day -1), Run in period (visit 2) on Day 0, Randomization visit (visit 3- Day 15 + 1), On-
treatment visit (visit 4- Day 21 ± 1) and the End of Study visit (visit 5- Day 42 ± 2)].  
All subjects will be reported to the study site for screening.  Subjects with asthma diagnosed as 
per National Asthma Education and Prevention Program at least 12 months prior will be briefed 
about the study and Informed Consent Form will be obtained. An exhaled nitric oxide (FeNO) 
test will be performed. If FeNO is < 25 ppb, those subjects will not be screened further. 
Pulmonary function test (PFT) by spirometer will be performed. After completion of the required 
screening tests and procedures, subjects meeting all the inclusion criteria and none of the 
exclusion criteria will be asked to visit the study site for run-in period. Subjects will be provided 
with placebo metered dose inhaler in the run-in period and will be advised to take one inhalation 
twice daily for two weeks. Subjects will be provided with subject diary and rescue medication 
(Salbutamol) with detail instructions regarding filling of subject diary and usage of rescue 
medication (Salbutamol).   
Subjects will be required to visit on Day 15 + 1 and those subjects who completed the placebo 
run period and met the applicable eligible criteria will be randomized. An exhaled nitric oxide 
(FeNO) test will be performed on day 15 + 1. Pulmonary function test (PFT) by spirometer will 
be performed. Airway reversibility will be checked.  According to the randomization scheme, 
subjects will be supplied with the study medication (either Test or Reference or Placebo in 2:2:1 
ratio as per the randomization schedule) along with diary card with instructions regarding filling 
of subject diary.  
Subjects will be advised to take one inhalation twice daily for 4 weeks in the morning and 
evening, preferably on the same time period during the entire treatment period. Subjects need to 


 
 
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report to the Investigator site on day 21± 1 and 42 ± 2. At these visits (Visit 4 and Visit 5), 
efficacy and safety evaluation will be done. At the EOS visit (Visit 5), subjects will go through 
all the end of study evaluation procedures, as outlined in the Table of Events (Table I). They 
will be clinically evaluated for the assessment of the efficacy parameters and Investigator’s 
Global Evaluation Score.  
At every study visit, all the procedures mentioned in the Table of events (Table I) will be carried 
out. Safety assessments (reporting of adverse events and serious adverse events if any, clinical 
laboratory measures and vital sign parameters) will be performed and any change in concomitant 
medications will be noted at all the scheduled visits.  


 
 
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Note:  After Placebo Run-in Period, subjects will be randomized either to test/ reference/ placebo 
if they fulfill the eligibility criteria.  
 
 
 


 
 
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4.0 
STUDY VISITS 
There will be a total of five visits in this study:   
 Screening (Day -7 to Day -1);  
 Run in period (Visit 2: Day 0);  
 Randomization visit (Visit 3: Day 15 + 1) 
 On-treatment Visit (Visits 4: Day 21 ± 1) and 
 End of study visit (Visit 5: Day 42 ± 2) 
Total expected duration for a subject in the study is 52 days. 
4.1. 
Visit 1: Screening (Day -7 to Day -1) 
All subjects should be screened within 7 days prior to start of Placebo run-in period. Voluntarily 
given informed consent will be obtained from each subject and or/ Legally Acceptable 
Representative (LAR) and or/ Impartial Witness, prior to commencing any study specific 
procedures. Investigator at investigational site will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risk and benefit of the 
study.  
During the informed consent process, subjects shall also be made aware of the associated risks 
and other possible alternate medications for the same indication.  
Subjects must be made aware that they are free to discontinue the study at any point of time 
during the study, and in case of trial related injury/death they will be provided free medical 
management and financial compensation as per the regulatory practice. Subject will be given 
opportunity to ask questions and adequate time will be given to consider the written information 
provided.  Investigator at site must retain the original, signed ICF for the study file.  A copy of 
the signed ICF shall be given to the subject. 
Once informed consent has been obtained, the subject’s eligibility to enter the study will be 
verified in accordance with the inclusion and exclusion criteria.  The procedures that will be 
carried out during this visit are mentioned in Table II. 
During the screening period from Day -7 to Day -1 (Visit 1), screening lab investigations and 
general & systemic examination will be conducted; the subjects’ vital signs, concomitant 
medications as well as detailed medical and medication history will be noted. At the screening 
visit, all medications taken within 14 days prior to screening, including over-the-counter (OTC) 
products will be recorded. An exhaled nitric oxide (FeNO) test will be performed, if FeNO < 25 
ppb, then subject will not be further screened. Spirometry test will be performed to evaluate 


 
 
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FEV1 value. Highest value of 3 acceptable readings in this session will be considered for 
inclusion into study. 
Table II: Procedures on Screening Visit 
Procedure 
Screening Visit 
(Day -7 to Day -1) 
 Informed consent  
X 
Eligibility criteria  
X 
Demography* 
X 
Medical and Medication History 
X 
General & Systemic Examination 
X 
Vital signs 
X 
Laboratory Investigations 
X 
Serum pregnancy test (for females of child 
bearing potential) 
X 
12 Lead ECG 
X 
Chest X-Ray (PA view) 
X 
FeNO estimation 
X 
FEV1 value recording (through Spirometry) 
X 
Concomitant medication check 
X 
Adverse event recording 
X 
 General and Systemic examination includes head, neck, eye, ENT, skin & appendages, renal, cardiovascular, 
pulmonary, reproductive, endocrine, gastrointestinal, nervous system, musculoskeletal, peripheral vascular and 
psychiatric 
 Vital signs include Blood Pressure (Supine), Respiration Rate, Pulse Rate and Body Temperature in0F/ 0C. 
 Haematology panel includes haemoglobin, haematocrit, white blood cell count with differential cell count, red 
blood cell count and platelets. Serum chemistry panel will include blood urea nitrogen, creatinine, albumin, 
alkaline phosphatase, total bilirubin, aspartate aminotransferase, alanine aminotransferase, random blood sugar, 
sodium, potassium, and chloride. Serum pregnancy test (for females of child bearing potential) will be done at 
screening only.  
 *If a valid age certificate of subject is not available, the subject will give written confirmation of the age and 
will be authenticated by Investigator. 
AE monitoring will be done at all stages of the study after signing of the ICF. The PI/ study staff 
shall instruct the subject to inform immediately in case of any emergency or untoward symptoms 
during any point of the study. Once all assessments and laboratory tests have been completed, 
the subject will be asked to visit the site on Day 0.  
4.2. 
Visit 2: (Day 0) 
Subjects fulfilling all inclusion and none of the exclusion criteria will be considered for Run-in 
period. Subjects vital signs, concomitant medication, adverse events, general and systemic 
evaluation will be done. FEV1 values will be recorded using spirometry. Highest value of 3 


 
 
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acceptable readings in this session will be considered. Subjects will be provided with placebo 
and will be advised to inhale the product twice daily for 2 weeks. Subjects will be provided with 
subject diary and rescue medication (Salbutamol) with the instructions to fill the diary and for 
the use of rescue medication (Salbutamol). This Run-in period is required to wash out any pre-
study corticosteroids/long-acting bronchodilators, to establish FEV1 baseline values and to 
evaluate subject disease conditions, need of rescue medication and treatment compliance.  Table 
III shows a list of all procedures to be completed on Visit 2. 
Table III Procedures on Day 0 
Procedure 
 Day 0 
General & Systemic Examination 
X 
Vital signs 
X 
Spirometry 
X 
Dispensing of Placebo product 
(for Run-in period) 
X 
Rescue Medication Dispensing 
X 
Subject Diary Dispensing 
X 
Concomitant medication check 
X 
Adverse event recording 
X 
 General and Systemic examination includes head, neck, eye, ENT, skin & appendages, renal, cardiovascular, 
pulmonary, reproductive, endocrine, gastrointestinal, nervous system, musculoskeletal, peripheral vascular and 
psychiatric 
 Vital signs includes Blood Pressure (Supine), Respiration Rate, Pulse Rate and Body Temperature in 0F/0C. 
 
4.3. 
Placebo Run in period (Day 1 to Day 14) 
During the Run-in period, subjects will administer one inhalation of placebo twice daily for 2 
weeks duration. Subjects will be requested to mention any concomitant medications used during 
this time in their subject diaries. During this period, pre-study corticosteroids/ long-acting 
bronchodilators will be washed out and  FEV1 baseline values will be established.  
Table IV Procedures from Day 1 to Day 14 
Procedure 
Run-in Period 
Day 1 to Day 14 
Placebo administration 
One inhalation two 
times daily from Day 1 
to Day 14  
Concomitant medication check  
X 
Adverse event recording 
X 
 
 


 
 
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4.4. 
Randomization (Day 15 + 1) 
Subjects who have completed Run in period will be advised to visit the Investigator site on day 
15 + 1 for randomization. Subjects’ compliance to the run in period will be assessed with respect 
to the placebo and rescue medication administration as per the details entered in subject diary. 
Subjects who successfully completed the run-in period will undergo exhaled nitric oxide (FeNO) 
test. Airway reversibility will be checked by performing a bronchodilator test wherein the initial 
baseline lung volume is measured by spirometer followed by administration of 360 mcg of 
Salbutamol inhalation and then a repeat lung volume measurement by spirometer within 30 
minutes of Inhalation of Salbutamol. Subject’s baseline FEV1 readings will be noted before the 
morning dose. “Baseline morning FEV1 readings at visit 3 will be the average of pre dose 
highest FEV1 values at two time points (i.e., Patient needs to perform one baseline Spirometry 
session with minimum of 3 acceptable readings and then after a gap of minimum 30 minutes, one 
more baseline session will be performed with minimum of 3 acceptable readings. Highest value 
from both the sessions will be noted. Average of both the highest readings will be considered as 
baseline FEV1 value).   
The subjects who met all the applicable eligible criteria will be randomized to either 
Test/ Reference/ Placebo groups in a 2:2:1 as per the pre-specified randomization schedule. 
Subjects will receive their assigned study medication, along with instructions regarding method 
of administrations. All subjects will be required to take one inhalation twice daily for 4 weeks. 
The Asthma Control Test (ACT) questionnaire will be evaluated in this visit. The baseline score 
for the Investigator’s Global Evaluation will be recorded. 
Study medication, rescue medication (Salbutamol) and subject diary will be dispensed to the 
subject with a detail instruction regarding how study medication and rescue medication need to 
be taken and filling instructions of the subject diary. 
The first dose of study medication will be administered at the site in the morning to the subject 
and the subject will self-administer the second dose in the evening at his/ her home.  
Table V Procedures from Day 15 +1 
Procedure 
 Treatment Period 
 
Day 15 +1 
Placebo administration 
compliance (Run in period) 
X 
Collection of Placebo Canister 
given in run-in period 
X 
Eligibility criteria (applicable) 
X 
General & Systemic Examination
X 


 
 
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Procedure 
 Treatment Period 
Vital signs 
X 
Urine Pregnancy Test (for 
females of child bearing 
potential) 
X 
Collection of rescue medication  
canister 
X 
FeNO estimation 
X 
Reversibility/Bronchodilator test 
X 
FEV1 baseline value recording  
(through Spirometry) 
X 
Randomization 
X 
Study Drug Dispensing  
(for Treatment period) 
X 
Rescue Medication Dispensing 
X 
Study Drug Administration 
One inhalation two times daily 
from Day 15 to Day 42 
Subject Diary Card Compliance 
X 
Concomitant Medication check 
X 
Adverse event recording 
X 
Asthma Control Test 
Questionnaire 
X 
Investigator’s Global Evaluation 
X 
 General and Systemic examination includes head, neck, eye, ENT, skin & appendages, renal, cardiovascular, 
pulmonary, reproductive, endocrine, gastrointestinal, nervous system, musculoskeletal, peripheral vascular and 
psychiatric 
 Vital signs include Blood Pressure (Supine), Respiration Rate, Pulse Rate and Body Temperature in0F/ 0C. 
4.5. 
Visit 4 (Day 21 ± 1) 
Subjects will be asked to visit the site on Day 21 ± 1 (Visit 4). The predose FEV1 readings will 
be taken in the morning. Highest value from three acceptable readings will be considered. 
Measurement of vital signs, general and systemic examination, 
andAE monitoring will also be done. Compliance of subject dairy, study medication and 
concomitant medication will be checked. 
Table VI Procedures from Day 21 ± 1 
Procedure 
 Treatment Period 
 
Day 21 ± 1 
General & Systemic Examination
X 
Vital signs 
X 
Spirometry 
X 
Study Drug Administration 
One inhalation two times daily 


 
 
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from Day 15 to Day 42 
Subject Diary Card Compliance 
X 
Concomitant Medication check 
X 
Adverse event recording 
X 
 General and Systemic examination includes head, neck, eye, ENT, skin & appendages, renal, cardiovascular, 
pulmonary, reproductive, endocrine, gastrointestinal, nervous system, musculoskeletal, peripheral vascular and 
psychiatric 
 Vital signs include Blood Pressure (Supine), Respiration Rate, Pulse Rate and Body Temperature in0F/ 0C. 
 
4.6. 
End of Study (Day 42 ± 2)   
Subjects will be asked to visit the site on Day 42 ± 2, End of Study/EOS (Visit 5). The FEV1 
readings will be taken before morning dosing of inhaled medication corresponding to the time 
(with a window period of ± 30 min) of predose FEV1 taken on the 1st day of the start of the 
treatment. Two spirometry sessions with at least 3 acceptable readings each will be performed. 
Highest value from both the sessions will be noted. Average of both the highest readings will be 
considered as EOS FEV1 value. An exhaled nitric oxide (FeNO) test will be performed. The 
Asthma Control Test (ACT) questionnaire will be evaluated and the Investigator’s Global 
Evaluation will be performed. Measurement of vital signs, general and systemic examination, 
concomitant medication recording and AE monitoring will also be done. Subject diary, study 
medication and rescue medication will be collected from the subjects and efficacy evaluation 
will be done. Clinical laboratory tests will be repeated to check safety of subjects. Urine 
Pregnancy Test will be done for females of child bearing potential.  
Table VII shows a list of all procedures to be completed on End of Study. 
Table VII: End of Study 
Procedure 
End of Study 
Day 42 ± 2 
General & Systemic Examination 
X 
Vital signs 
X 
Urine Pregnancy Test (for females of 
child bearing potential) 
X 
Laboratory Investigations 
X 
FeNO estimation 
X 
Spirometry 
X 
Subject Diary Card Compliance 
X 
Concomitant Medication check 
X 
Adverse event recording 
X 
Asthma Control Test Questionnaire 
X 


 
 
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Procedure 
End of Study 
Day 42 ± 2 
Investigator’s Global Evaluation 
X 
Collection of subject diary, study 
drug and rescue medication canister 
X 
 General and Systemic examination includes head, neck, eye, ENT, skin & appendages, renal, cardiovascular, pulmonary, 
reproductive, endocrine, gastrointestinal, nervous system, musculoskeletal, peripheral vascular and psychiatric 
 Vital signs include Blood Pressure (Supine), Respiration Rate, Pulse Rate and Body Temperature in0F/ 0C. 
 Haematology panel includes haemoglobin, haematocrit, white blood cell count with differential cell count, red blood cell 
count and platelets. Serum chemistry panel will include blood urea nitrogen, creatinine, albumin, alkaline phosphatase, total 
bilirubin, aspartate aminotransferase, alanine aminotransferase, random blood sugar, sodium, potassium, and chloride.  
On Visit 5, subjects will be asked to complete all other end of study procedures. The subjects are 
required to submit their issued study drug and subject diaries for compliance checking. 
4.7. 
Withdrawal Visit 
A subject must be prematurely withdrawn from the study if the subject fulfills any of the 
withdrawal criteria specified in Section 5.4. In addition to the withdrawal procedures including 
General and Systemic Examination, Vital Signs, Urine Pregnancy Test and Clinical Laboratory 
Tests, the details of concomitant therapies will also be recorded. 
 
 


 
 
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5.0 
STUDY POPULATION 
5.1. 
Number of subjects 
Assuming 5% loss from Enrolled population to mITT population, 1550 subjects will be enrolled 
in this study. Subjects will be enrolled in 2:2:1 proportion (Test: RLD: Placebo respectively) as 
620:620:310. 
5.2. 
Inclusion criteria 
1. Adult male or female subjects of aged ≥18 to ≤ 65 years inclusive. 
2. Diagnosis of asthma as defined by the National Asthma Education and Prevention Program 
at least 12 months prior to screening.  
3. Pre-bronchodilator FEV1 of ≥ 45% and ≤ 85% of predicted value during the screening visit 
and on the first day of treatment visit.  
4. ≥15% and > 0.20 L reversibility of FEV1 within 30 minutes following 360 mcg of 
Salbutamol inhalation (pMDI) on the first day of treatment visit. 
5. Subjects with FeNO > 25 ppb at screening and on the first day of treatment visit. 
6. Subjects stable on their chronic asthma treatment regimen for at least four weeks prior to 
enrollment.  
7. Subject should able to replace current SABAs with Salbutamol inhaler for use as needed for 
the duration of the study.   
8. Subject should be able to withhold all inhaled SABAs for at least six hours prior to lung 
function assessments on study visits.  
9. Ability to discontinue their asthma medications (inhaled corticosteroids and long-acting β 
agonists) during the run-in period and for remainder of the study. 
10. Asthma patients who are stable on low dose ICS or low dose ICS+LABA or who would be 
stable with low dose ICS as per Investigator’s clinical judgement. 
11. Currently non-smoking; had not used tobacco products (i.e., cigarettes, cigars, pipe tobacco) 
within the past year, and having had ≤ 10 pack-years of historical use.  
12. Willingness to give their written informed consent to participate in the study. 


 
 
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13. Subjects willing to perform all study related procedures including the use of study inhalers, 
Spirometry and willing to complete the Subject diary. 
14. Female of child-bearing potential, agreed to use a reliable method of contraception during 
study (e.g., condom + spermicide, IUD, oral, transdermal, injected or implanted hormonal 
contraceptives). 
 
5.3. 
Exclusion criteria 
1. Life-threatening asthma, a history of asthma episodes(s) requiring intubation, and/or 
associated with hypercapnia, respiratory arrest or hypoxic seizures, asthma related 
syncopal episode(s). 
2. Hospitalizations within the past year prior to the screening for the conditions mentioned 
in exclusion criteria No.01 or during the run-in period.  
3. Significant respiratory disease other than asthma (COPD, interstitial lung disease, etc.)  
4. Evidence or history of clinically significant disease or abnormality including congestive 
heart failure, uncontrolled hypertension  
5.  Evidence or history of clinically significant disease or abnormality including 
uncontrolled coronary artery disease, myocardial infarction, or cardiac dysrhythmia.  
6. Historical or current evidence of significant hematologic, hepatic, neurologic, psychiatric, 
renal, or other diseases that, in the opinion of the investigator, would put the subject at 
risk through study participation, or would affect the study analyses if the disease 
exacerbates during the study. 
7. Viral or bacterial, upper or lower respiratory tract infection, or sinus, or middle ear 
infection within four weeks prior to the screening, during the run-in period, or on the day 
of treatment.  
8. Hypersensitivity to Beclomethasone or any of the ingredients of the formulation and any 
sympathomimetic drug (e.g., Salbutamol) or any inhaled, intranasal, or systemic 
corticosteroid therapy.  
9. Subjects receiving β2-blockers, anti-arrhythmics, anti-depressants, and monoamine 
oxidase inhibitors within 4 weeks prior to the screening.  
10. Subjects who required systemic corticosteroids (for any reason) within the past 2 months. 
11. Clinically significant abnormalities in ECG at screening as per investigators discretion. 
12. Female subjects who are pregnant, nursing or planning a pregnancy during the study. 


 
 
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13. Subjects who have participated in another investigational drug or device research study 
within 30 days of screening. 
14. Subjects who are using any medication or has any disease which in the judgment of the 
Investigator will interfere with the conduct or interpretation of the study. 
5.4. 
Subject Withdrawal 
All subjects are free to withdraw from participation in the study at any time, for any 
reason, specified or unspecified, and without prejudice to further treatment.  The criteria 
for enrollment are to be followed explicitly.  If a subject who does not meet enrollment 
criteria is inadvertently enrolled, that subject will be withdrawn from the study and the 
Sponsor or AXIS must be contacted.  An exception may be granted in rare circumstances 
where there is a compelling safety reason to allow the subject to continue. In these rare 
cases, the PI must obtain documented approval from the Sponsor or designee to allow the 
subject to continue in the study. Subjects who withdraw themselves or withdrawn by PI 
for lack of efficacy or Adverse events will be provided free available treatment as per the 
clinical practice of the PI. PI/ study team need to educate the subjects for completion of 
study and must make all possible efforts to contact the subject if they do not visit the site 
as per the schedule within window period. 
In addition, study drug will be stopped and subject can be withdrawn from the study in 
the following circumstances: 
 The investigator decides that the subject must be withdrawn 
 Subjects who experience asthma exacerbations that requires treatment with systemic 
corticosteroids, LABA and high dose ICS’s  
 If subject develops a medical condition that requires consistent use of prohibited 
medication  
 Use of rescue medication more than 600 micrograms per day 
 If FEV1 value is < 45 % on Day 21+ 1 
 The subject is unwilling to continue in the study 
 Violation of criteria listed in the Protocol 
 Noncompliance with Protocol 
 Any treated subject who has an adverse reaction to study medication that threatens 
his/her well-being if continued in the study 
 If the Investigator decides to stop the treatment 
 The Investigator or the Sponsor, for any reason, decides to stop the study 
Subjects who withdraw from the study early will have early withdrawal procedures 
performed.  Subjects who withdraw from the study will not be replaced. 
 


 
 
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6.0 
STUDY ENDPOINTS 
6.1. 
Efficacy Endpoints 
Primary Endpoint: 
 Mean change in Forced Expiratory volume in 1 second (FEV 1) from baseline (visit 3) to 
end of study visit (visit 5). 
 
Note: “Baseline morning FEV1 readings at visit 3 will be the average of pre dose highest FEV1 
values at two time points (i.e., Patient needs to perform one baseline Spirometry session with 
minimum of 3 acceptable readings and then after a gap of minimum 30 minutes, one more 
baseline session will be performed with minimum of 3 acceptable readings. Highest value from 
both the sessions will be noted. Average of both the highest readings will be considered as 
baseline FEV1 value). Sampling need to be taken on the same time (with a window period of ± 
30 min) of day as used for first day of a 4 week treatment on the last day of a 4-week treatment. 
 
Secondary Endpoints: 
 Mean change in FeNO value from base line (visit 1 & 3) to end of study visit (visit 5) 
 Percentage of subjects with reduction of FeNO from Baseline (Visit 1 & 3) to End of Study 
(Visit 5)  
6.2. 
Safety Endpoints 
Safety will be assessed based on reported adverse events, serious adverse events and laboratory 
assessments. 
 


 
 
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7.0 
ASSESSMENT OF STUDY ENDPOINTS 
7.1. 
Assessment of Efficacy Endpoints 
The primary efficacy endpoint will be evaluated on mean change in Forced Expiratory 
Volume in 1 second (FEV1) from baseline (Visit 3) to end of study (Visit 5). 
The secondary efficacy endpoints will be evaluated on mean change in FeNO value from 
baseline (visit 1 & 3) to end of study visit (visit 5) and percentage of subjects with 
reduction of FeNO from baseline (visit 1 & 3) to end of study visit (visit 5). 
7.2. 
Assessment of Safety Endpoints 
Safety will be assessed based on following for  
 Clinical Laboratory investigation 
 Vital signs evaluation 
 General and systemic examination  
 Reported Adverse Events and Serious adverse events 
7.2.1. Clinical Laboratory Evaluations 
All laboratory investigations shall be performed at designated laboratory (NABL 
Accredited).  
Approximately 15 mL of venous blood for routine tests will be withdrawn at screening and 
end of study. Additional blood may be withdrawn if deemed necessary.  
1. 
Hematology Panel: Hemoglobin (Hb%), Hematocrit, White blood cell count (WBC), 
Total differential count, Red blood cell count (RBC), Platelet count 
2. 
Renal function tests: BUN, Creatinine 
3. 
Liver function tests: Albumin, Alkaline phosphatase, Total bilirubin, Aspartate 
aminotransferase (AST) and Alanine aminotransferase (ALT) 
4. 
Random blood sugar  
5. 
Serum electrolytes: Sodium, Potassium and Chloride 
6. 
Serum pregnancy test (at screening only for females of child bearing potential)  
Additional laboratory evaluations may be performed, if deemed necessary (for safety reasons), 
but should be informed to the Medical Manager / CRA and shall be notified to the EC. Any 
unscheduled lab test required by the Investigator for safety reasons, site specific local laboratory 
can be approached. 
 
 
 


 
 
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7.2.2. Vital Signs 
Vital signs (Blood Pressure, Pulse Rate, Body temperature and Respiratory rate) will be recorded 
at all the visits and at any time at the discretion of the Investigator. Systolic BP will be measured 
after the subject has rested for at least 5 minutes in supine position. 
7.2.3. General and Systemic Evaluation 
A general and systemic examination will be conducted by a physician at each study visit and 
includes (at a minimum) a thorough examination of Head, Neck, Eye, Ear, Nose, Throat, Skin & 
Appendages, Renal, Cardiovascular, Pulmonary, Reproductive, Endocrine, Gastrointestinal, 
Nervous System, Musculoskeletal, Peripheral Vascular system and Psychiatric. 
7.2.4. Adverse events 
All reported adverse events and serious adverse events will be recorded and reported as per 
section Adverse Events. 
 
 


 
 
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8.0 
ADVERSE EVENTS 
8.1. 
Definitions 
The following International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) AE definitions apply to this study: 
  
Adverse Event: An AE means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  
Serious Adverse Event: An SAE, experience or reaction, is any untoward medical occurrence 
(whether considered to be related to study drug or not) that at any dose:  
 
Results in death.  
 
Is life-threatening (the patient is at a risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more severe).  
 
Requires in patient hospitalization or prolongation of existing hospitalization: Hospital 
admissions and/or surgical operations planned before or during a study are not considered 
AEs if the illness or disease existed before the patient is enrolled in the study, provided that it 
did not deteriorate in an unexpected way during the study.  
 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.  
 
Results in a congenital abnormality/birth defect.  
 
Other: Medically significant events, which do not meet any of the criteria above, but may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other serious outcomes listed in the definition above. Examples of such events are blood 
dyscrasias (e.g., neutropenia or anemia requiring blood transfusion, etc.) or convulsions that 
do not result in hospitalization.  
An adverse drug reaction (ADR) is defined as all noxious and unintended responses to a 
medicinal product related to any dose.  
 
Unexpected adverse event or unexpected suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered ‘‘unexpected’’ if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current application, as amended. For example, 
under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) 
if the investigator brochure listed only cerebral vascular accidents. ‘‘Unexpected,’’ as used in 
this definition, also refers to adverse events or suspected adverse reactions that are mentioned in 


 
 
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the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
Each and every unexpected adverse event observed during study will be medically managed 
Investigator team at site and followed up till resolution or stabilization. All the details of UAE 
will be captured in AE pages of CRF/ eCRF. If UAE qualifies for any of the SAE criteria the 
timelines for recording and reporting the UAE will be as per SAE timelines. 
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug. The action taken and the outcome must also be recorded.  
8.2. 
Severity 
The severity of unsolicited AEs will be characterized as “mild”, “moderate”, or “severe” 
according to the following definitions: 
Table VIII: Severity of adverse reactions 
Mild 
Moderate 
Severe 
Events are usually transient 
and do not interfere with the 
subject’s daily activities. 
Events introduce a low level 
of inconvenience or concern 
to the subject and may 
interfere with daily activities.
Events interrupt the subject’s 
usual daily activity. 
 
8.3. 
Relationship 
The causal relationship between the study drug and the AE has to be characterized as related, 
unrelated, unlikely, possible, probable, or unknown (unable to judge).  
Table IX: Causality Assessment  
Related 
Events can be classified as “related” when there is a direct possibility 
that the study drug cause AE. 
Unrelated 
Events can be classified as “unrelated” if there is not a reasonable 
possibility that the study drug caused the AE. 
Unlikely 
An “unlikely” relationship suggests that only a remote connection 
exists between the study drug and the reported AE.  Other conditions, 
including chronic illness, progression or expression of the disease state 
or reaction to concomitant medication, appear to explain the reported 
AE. 
Possible 
A “possible” relationship suggests that the association of the AE with 


 
 
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the study drug is unknown; however, the AE is not reasonably 
supported by other conditions. 
Probable 
A “probable” relationship suggests that a reasonable temporal sequence 
of the AE with drug administration exists and, in the Investigator’s 
clinical judgment, it is likely that a causal relationship exists between 
the drug administration and the AE, and other conditions (concurrent 
illness, progression or expression of disease state or concomitant 
medication reactions) do not appear to explain the AE. 
Unknown 
All efforts should be made to classify the AE according to the above 
categories.  The category “unknown” (unable to judge) may be used 
only if the causality is not assessable, e.g., because of insufficient 
evidence, conflicting evidence, conflicting data, or poor 
documentation. 
 
8.4. 
Reporting of Adverse Events 
Adverse Events 
All AEs that occur in a subject from the time subject signs the ICF for the study, regardless of 
severity, causality, and whether or not they occurred during the course of the trial are to be 
recorded in the appropriate AE pages (either ‘serious’ or ‘non-serious’) in the CRFs/ eCRFs. 
Investigator shall complete all the details requested including dates of onset, severity, action 
taken, treatment measures, outcome, and relationship to study drug, and any other treatment 
measures undertaken. Each event should be recorded separately.  
 
At the End of study visit, subjects will be queried regarding any AEs that have occurred since the 
Treatment visit. Subjects will be asked to volunteer information with a non-leading question such 
as, “How have you felt since your last visit?” Study center personnel will then record all 
pertinent information in the subject’s CRF/ eCRF.  
 
Serious Adverse Events 
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, Investigator 
must report the event as per Appendix XI to sponsor/AXIS, Licensing authority and ethics 
committee. Sponsor/AXIS with Investigator shall send SAE report after due analysis to 
Licensing authority, ethics committee and head of the institute where trial is being conducted 
within 14 days. Investigator shall ensure that ethics committee shall send SAE report and its 
opinion on financial compensation within 30 days to the licensing authority. Sponsor shall pay 
compensation as per the orders by licensing authority within 30 days of receipt of orders from 
licensing authority. A follow up report shall be sent to sponsor/AXIS, Licensing authority, and 


 
 
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head of the institute where trial is conducted within 14 days of the occurrence of SAE which 
shall include outcome and treatment provided. If, during follow-up, any non-serious AE worsens 
and eventually meets the criteria for an SAE, that AE should be recorded as a new SAE.  
 
The study center must transmit the SAE form to the SAE fax number +91-40-4040 8060 or email 
to safety@axisclinicals.com. SAE form (as per appendix XI compliance) shall be sent to licensing 
authority and Ethics committee which accorded approval at the site. Even if an initial report is 
made aware by the site personnel telephonically to the sponsor or AXIS representative, an SAE 
form completed with all available details must still be faxed within 24 hours of knowledge of the 
event at the study center.  
Supplemental information shall be submitted as soon as available and may include laboratory 
results, radiology reports, progress notes, hospital admission and emergency room notes, 
treatments administered for the events, holding and observation notes, discharge summaries, 
autopsy reports, and death certificates.  
The Investigator is expected to take all therapeutic measures necessary for resolution of the SAE. 
Any medications or procedures necessary for treatment of the SAE must be recorded on the 
appropriate pages of the subject’s CRF/eCRF and SAE form. All SAEs are to be followed up by 
the study staff until resolution or until the SAE is deemed stable. The Sponsor or AXIS may 
contact the study center to solicit additional information or follow up on the event. 
The original CRF/ eCRF pages should be returned immediately to the CRF/eCRF binder.  The 
information must include at least the following: 
 
Name, address, and telephone number of the reporting Investigator. 
 
Study drug and Protocol Number. 
 
Subject identification number, initials, sex, and date of birth. 
 
Description of the SAE, measures taken, and outcome. 
 
Preliminary classification of causal relationship by the Investigator. 
Additional follow-up information should be completed on an SAE follow-up form with a copy 
sent to the Sponsor /AXIS and the original placed in the SAE section of the CRF/ eCRF binder. 
 
 


 
 
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In the case of fatal or life-threatening events please also immediately telephone the Safety 
Surveillance and Reporting Unit: 
Country 
Name/Phone number: 
India  
 
Dr. Subhra Lahiri  
Associate Vice President – Clinical Research 
AXIS Clinicals Limited.  
1-121/1, Miyapur, Hyderabad-500049  
Direct : +91-40-40408064  
Fax : +91-40-40408060  
Mobile : +91-8886221089  
e-mail : subhra.l@axisclinicals.com 
safety@axisclinicals.com 
India  
 
Dr. Mohd. Sajid 
Medical Manager 
AXIS Clinicals Limited 
1-121/1, Miyapur, 
Hyderabad 500049, India. 
Tel: +91 40 4040 8267 
Fax: +91 4040 8003/8060 
Mob: +91 9739812605 
Email: Sajid.m@axisclinicals.com 
In case of an accidental overdose, the study center personnel will take necessary measures to 
bring the subject to a stable state and will report overdose to AXIS Clinicals.  
8.5. 
Follow-up of Adverse Events 
Any AEs observed after signing the ICF till study completion will be followed up to resolution.  
Resolution means that the subject has returned to a baseline state of health or the PI does not 
expect any further deterioration of the condition. 
8.6. 
Asthma exacerbations  
Asthma exacerbations 
Asthma exacerbations are episodes characterized by a progressive increase in symptoms of 
shortness of breath, cough, wheezing or chest tightness and progressive decrease in lung 
function, i.e. they represent a change from the subject’s usual status that is sufficient to require a 
change in treatment. 
 


 
 
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* Exacerbations are identified as events characterized by a change from the subject’s previous 
status. 
 
Severe asthma exacerbations 
Severe asthma exacerbations are defined as events that require urgent action on the part of the 
subject and physician to prevent a serious outcome, such as hospitalization or death from asthma. 
 
Management of asthma exacerbations 
All asthma exacerbations would be managed by stepwise approach as suggested by the Global 
initiative for asthma 2018 strategy for asthma management & prevention. Please see the 
Appendix -6 for more details. 
 
 


 
 
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9.0 
STUDY TREATMENTS 
9.1. 
Description of Investigational Product 
Group-I: Test 
Name: Beclomethasone Dipropionate Metered Dose Inhaler (Inhalation Aerosol) (0.04 mg/ 
INH); 
Manufactured by: Aurolife, a subsidiary of Aurobindo Pharma, USA, Inc., 2929 Weck Dr., 
Durham, NC 27709. 
 
Group-II: Reference  
Name: QVAR® 40 mcg (Beclomethasone dipropionate hydrofluoroalkane), Inhalation Aerosol; 
Manufactured by: Teva Pharmaceuticals LLC Frazer, PA 19355. 
NDC code: 59310-202-12 
Group-III: Placebo 
Manufactured by: Aurolife, a subsidiary of Aurobindo Pharma, USA, Inc., 2929 Weck Dr., 
Durham, NC 27709. 
Subjects will receive one inhalation (0.04 mg/ INH) of Study medication (Test/ Reference/ 
Placebo) twice daily.  
9.2. 
Investigational product Administration 
As per randomization schedule, subjects will be randomized to either the Test or Reference or 
Placebo in 2:2:1 ratio. 
 
Instructions for Use  
There are 2 main parts of your inhaler including the:  
 
 Metal canister that holds the medicine (See Figure A)  
 Plastic actuator that sprays the medicine from the canister (See Figure A) 
 
 
 
 


 
 
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Figure A
 
 The inhaler has a protective dust cap that covers the mouthpiece of the actuator (See 
Figure A). The protective dust cap should be removed before use. 
 The inhaler comes with a dose counter located on the back of the actuator (See Figure B). 
The dose counter window will show you the number of actuations (puffs) of medicine 
remaining in units of 2. The inhaler contains “120” actuations (puffs). 
Figure B  
 
 
 The first time you use inhaler, the dose counter will show “120” actuations remaining 
(See Figure B). Each time you press the metal canister, a puff of medicine is released and 
the dose counter will count down.  
 When the dose counter reaches 0, it will continue to show 0 and you should replace your 
inhaler.  
 The dose counter cannot be reset and is permanently attached to the actuator. Never 
change the numbers for the dose counter or touch the pin inside the actuator 
Do not remove the metal canister from the plastic actuator. 
  
Before using your inhaler:  
Remove the cap from the mouthpiece of the actuator (See Figure C). Check the mouthpiece for 
objects before use. Make sure the metal canister is fully inserted into the actuator. 
 


 
 
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Figure C 
 
Priming your inhaler:  
 
Before you use your inhaler for the first time or if you have not used your Inhaler for more than 
10 days, you will need to prime your Inhaler. 
 Before priming, the inhaler will show a black dot in the dose counter window (See Figure 
D). 
Figure D
 
 
 Hold the Inhaler in the upright position and with the mouthpiece pointing away from you. 
 Press down on the metal canister 2 times and release 2 actuations (puffs) into the air and 
away from your face.  
 After priming 2 times, the dose counter should read “120.” 
Your Inhaler is now ready to use. 
 
Using your inhaler:  
Step 1: Remove the cap from the mouthpiece of the actuator (See Figure C). Check the 
mouthpiece for objects before use. Make sure the metal canister is fully inserted into the 
actuator.  
 


 
 
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Step 2: Breathe out as fully as you comfortably can. Hold the inhaler in the upright position (See 
Figure E). Close your lips around the mouthpiece, keeping your tongue below it. 
Figure E
 
 
Step 3: While breathing in deeply and slowly, press down on the metal canister with your finger 
(See Figure E). When you have finished breathing in, hold your breath as long as you 
comfortably can (5 to 10 seconds). 
 
Step 4: Take your finger off the metal canister and remove the inhaler from your mouth. Breathe 
out gently. 
 
After using your inhaler:  
 Replace the cap over the mouthpiece right away after use.  
 You should rinse your mouth with water after you finish using inhaler. 
 Clean the mouthpiece of your inhaler weekly with a clean, dry tissue or cloth.  
 Do not wash or put any part of your inhaler in water10. 
 
9.3. 
Packaging and Labeling of Study drug 
Packaging and labeling of study medication will be conducted as per applicable regulations by 
the third party. Study medication will be supplied by Aurobindo Pharma Ltd to the third party 
service provider engaged for randomization and drug supply management.  
 
 


 
 
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9.4. 
Randomization 
This will be randomized and double blind study. The actual treatment given to individual subject 
will be determined by a randomization scheme prepared by third party. Randomization will be 
done after completion of placebo run in period. 
An IWRS (Interactive Web Response System) will be used to administer the randomization 
schedule. The programming, validation and monitoring of the randomization process by IWRS 
will be guided by the applicable SOPs of the IWRS vendor. In practice, the investigator or 
designee will use the IWRS system to receive the dosing formulation (test/reference/ placebo) 
for the subject. 
A computerized randomization code will be generated by third party or designate, appropriate to 
the study design. 
A third party or designate will provide password protected study randomization code via a secure 
file transfer procedure prior to the start of the study to the IWRS vendor. Only those individuals 
performing investigational medicinal product dispensing/ reconciliation activities are to have 
access to the randomization code. No further distribution of the randomization code to 
individuals not involved in dispensing the investigational medicinal products is permitted 
without proper documentation and rationale. If the randomization is maintained in paper format 
(i.e. hard copy), it will be retained with limited access under lock and key. Study participants 
will be aware that they will receive different formulations of a same drug without being 
informed which product (Test or Reference or Placebo) is being administered. Furthermore, the 
randomization code will not be available to the physician and nursing staff involved in the 
collection, monitoring, revision, or evaluation of adverse events or to clinical staff who could 
have an impact on the outcome of the study. 
The randomization code must not be broken except in emergency situations for which the 
identification of the study treatment of a subject is required by the Qualified Investigator to 
complete a serious adverse event report or the clinical report. In such situations, the 
randomization information will be accessed through IWRS by the designated individual(s) 
pharmacist, and the date and reason for breaking the blind must be recorded. 
Biostatistics group or designate will release the randomization code to designated study team 
members following the release of the study data. The randomization code will be used for 
subject assignment to treatment and for statistical and reporting purposes. 
Screening number assigned to a study subject will remain the same throughout the study. The 
subjects may participate in the study only once and discontinued subjects must not be re-
enrolled. If subject withdraws consent after randomization allotted or does not receive study 
treatment for any reason, the randomization number will not be re-used. 


 
 
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No member of study site or the study team will have access to randomization code until 
completion of the study statistical analysis.  
Subject Identification Code Numbering System 
Once a subject’s eligibility criteria is satisfied, the subject will be assigned with screening 
number, starting with three digit site number followed by three digit subject number (e.g., 
201001) in chronological order of enrollment in each site. The Investigator will issue the Study 
Drug to the subject as per IWRS method. If subject discontinues the study, the subject number 
will not be reused, and the subject will not be allowed to reenter the study. 
9.5. 
Masking and Unmasking 
This is a Randomized, Multiple-dose, Double-blind, Placebo Controlled, Parallel group and 
Multicentric study. It will be ensured that neither subject nor investigator/research team can 
differentiate between test, reference and placebo. The treatment each subject will receive will not 
be disclosed to the investigators, study center personnel, subject, sponsor, or AXIS staff involved 
in the study conduct, monitoring, data review or analysis.  The treatment codes will be held by 
the independent third party.  
Neither any member of study site nor the study team will have access to randomization code 
until completion of the study and database lock. 
9.6. 
Treatment Compliance 
Compliance will be assessed by subject diary and inhalation records of study medication. This 
will be recorded in the CRF/ eCRF.  
Treatment compliance will be assessed on the basis of diary cards with following formula 
 
(Number of doses administered) x 100 
Number of expected doses 
Compliance will be presented as subjects who have taken approximately 75% to 125% of the 
doses of the assigned study drug and completed the evaluation within the designated visit. 
Example: If subject received 18 doses of study medication and discontinued from study on day 
11. Study medication needs to be taken twice daily for 28 days, hence the expected number of 
doses would be 56.  Treatment Compliance = 18/56 X 100= 32.1%. 
 
 


 
 
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9.7. 
Prohibited Medications 
During the study no other asthma medication will be allowed except investigational product and 
Salbutamol rescue inhalation. Due to the nature of the study and the Test product, certain 
medications which may interfere with the interpretation of the study results are prohibited 04 
weeks before study enrollment as well as during the course of the study. These are outlined 
below: 
1. ß2 Blockers  
2.  Anti-arrhythmitics, anti-depressants, MOA inhibitors  
3. Inhaled or other forms of Corticosteriods, LABA  
4. Anticholinergics, Anti-histamines, Nedocromil, Sodium Cromoglycate, Leukotriene 
antagonists, Xanthine derivatives, Ephedrine. 
9.8. 
Study Drug Accountability 
Study medication will be provided by the Sponsor to the investigators through a third party 
packaging vendor. Study medication shall be kept under controlled access i.e., locked area with 
restricted access at investigator site and will be supplied only to suitable subjects under the 
responsibility of investigator/ study personnel. Study medication shall be stored under specified 
storage conditions as mentioned in the IP label. Investigator/ Study personnel will receive study 
medication and will document the same in applicable documents.  
A record of study medication dispensed to trial subjects and returned shall be appropriately 
documented in IP logs provided by Axis/ third party.  
At the end of study or in between if required investigator will return the used/ unused/ expired/ 
defective/ empty/ partially used study medication to third party and will document the same. 
Study medication can be destructed at site as per applicable regulations in presence of authorized 
study personnel and certificate for destruction shall be obtained and filed in Trial Master File and 
copy in Site Master File. 
Investigator, a member of the investigational staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study drugs using the IP Accountability 
Forms.  These forms must be available for inspection at any time. 
 


 
 
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10.0 
STATISTICS AND DATA COLLECTION 
A general description of the statistical methods to be used to analyze the data is outlined below. 
Specific detailed description of analyses including list of displays will be provided in the 
Statistical Analysis Plan which will be finalized before clinical study data base lock. Data 
management plan will be prepared and finalized before data base designing. 
General Analysis Considerations 
Continuous data will be described using non-missing observations (n), Mean, Standard 
Deviation, Median, Minimum and Maximum values. Categorical data will be described using 
counts and percentages. Analyses will be performed using SAS version 9.2 or above. 
Unless specified otherwise, all statistical testing will be two-sided and will be performed using 
significance (α) level of 0.05. 
 
10.1. Sample Size Calculation 
Computer simulations (100,000 trials/subject number evaluated) were performed using 
Statistics101: Resampling Simulator Version 4.6 (John Grosberg, stats101@statistics101.net) 
assuming that approximately 80% of ITT subjects would also qualify as PP.  The proportion of 
the trials where the 90% confidence interval on the Test-to-Reference ratio was within the 
interval 0.80 to 1.25 in the PP population was considered the power for Bioequivalence for the 
subject number evaluated.  Likewise, the proportion of trials where both the Test and Reference 
means were greater than, and statistically different from (p < 0.05, 2-sided), that of the placebo 
in the mITT population was considered the power for Superiority for the subject number.  The 
proportion of the trials that demonstrated both Bioequivalence in the PP population and 
Superiority in the mITT population was considered the power for study success.  The results of 
these simulations are provided in the following table. Change from baseline in FEV1 for Test, 
Reference and Placebo was considered to be 0.24 L, 0.24 L and 0.05 L respectively. These 
considerations are based upon results of study 1081 mentioned in the Summary Basis of 
Approvals for QVAR®.  Coefficient of Variation for Mean change from baseline in FEV1 value 
was assumed to be 115.5% of the Reference Mean. 
 
mITT Subjects* 
(Test: RLD: Placebo) 
PP Subjects** 
(Test: RLD: Placebo) 
Power  
Bioequivalence 
Power Superiority 
Power 
Study Success 
588:588:294 
(1470) 
470:470:235 
(1175) 
0.80 
>0.99 
0.80 
 
Based upon calculations shown in table above, a sample size of 1470 subjects in mITT 
population (588:588:294 subjects in Test: RLD: Placebo respectively) with 1175 in the PP 
population (470:470:235) will have 80% power to demonstrate both bioequivalence between the 
two active treatments and to show that each of these are superior to placebo.  


 
 
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Assuming 5% loss from Enrolled population to mITT population, 1550 subjects will be enrolled 
in this study. Subjects will be enrolled in 2:2:1 proportion (Test: RLD: Placebo respectively).  
Randomization 
This study will be double blind randomized parallel group study with three arms: Reference 
Formulation, Test Formulation, Placebo formulation. Randomization will be in 2:2:1 proportion. 
The potential total enrolled sample size will be 1550 subjects [(620 (Test): 620 (Reference): 310 
(Placebo)]. The subjects will be assigned to the placebo or active groups as per a predetermined 
randomization schedule. Randomization schedule will be generated using appropriate software 
package.  
 
10.2. Subject Disposition 
Number of subjects screened, entered run-in period, randomized, completed and discontinued 
will be presented along with reasons for screen failure and study discontinuation.  Number of 
subjects assigned to various analysis populations will be presented.  Reasons for exclusions from 
mITT and PP population will be listed by subject. 
 
10.2.1. Safety Population 
The Safety population will include all randomized subjects who received at least one dose of 
investigational study treatment during double blind treatment period. 
 
10.2.2. mITT Population 
The mITT population will include all randomized subjects who meet all inclusion/exclusion 
criteria, receive study treatment, and have at least one post baseline efficacy assessment. If 
subject discontinued due to lack of efficacy and does not have a post baseline value, then subject 
will be included in mITT population with baseline value carried forward. Missing efficacy 
results in the mITT population will be imputed using last observation carried forward (LOCF). 
The mITT population will be used to compare both test and reference products for superiority 
over placebo. 
 
10.2.3. Per Protocol Population 
The PP population will include all randomized subjects who meet all inclusion/exclusion criteria, 
are found to be compliant with the assigned study treatment, who return to the study site for the 
primary endpoint visit at 4 weeks (+/- 2 days) OR discontinue from the study as a treatment 
failure, and do not have any major protocol deviation impacting efficacy outcome. The PP 
population will be used for the bioequivalence evaluation of test vs. reference. Subjects who 


 
 
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used at least 75% and no more than 125% of study treatment doses will be considered to be 
compliant to study medication. Compliance will be assessed based upon diary data for study 
drug administration. Protocol deviations will be classified as major (impacting efficacy 
assessment) or minor, prior to database lock using blinded study data by study personnel who are 
not aware of treatment assignments. Protocol deviation classification and individual subject’s 
assignment to analysis population will be finalized before unblinding of data. Summary of 
subjects with Major vs. Minor Protocol deviations will be provided along with listing. 
Subjects discontinued early for reasons other than lack of efficacy will be excluded from the PP 
population, but included in the mITT population. Subjects discontinued early for lack of efficacy 
will be included in the PP population, using LOCF imputation for missing efficacy results. The 
PP population will be used to compare test and reference products for equivalence. 
 
10.3. Subject Characteristics 
Summary for Demographic and Baseline disease characteristics will be presented. These will 
include age, sex, race, ethnicity, body weight, height, body mass index, duration of asthma, prior 
use of anti-asthmatic treatments and baseline FEV1 values as well as FEV1 as percent of 
predicted. 
Summary statistics of compliance to study treatment and duration of exposure will be presented. 
 
10.4. Analysis of Efficacy Data 
10.4.1. Primary Efficacy Variable 
Mean change in Forced Expiratory volume in 1 second (FEV 1) from baseline (visit 3) to Week 
4 i.e. end of study visit (visit 5), will be analysed as primary end point.  
FEV1 will be recorded at Visit 5 in the morning, prior to the dosing of inhaled medications. 
“Baseline morning FEV1 readings at visit 3 will be the average of pre dose highest FEV1 values 
at two time points (i.e., Patient needs to perform one baseline Spirometry session with minimum 
of 3 acceptable readings and then after a gap of minimum 30 minutes, one more baseline session 
will be performed with minimum of 3 acceptable readings. Highest value from both the sessions 
will be noted. Average of both the highest readings will be considered as baseline FEV1 value). 
Sampling need to be taken on the same time (with a window period of ± 30 min) of day as used 
for first day of a 4 week treatment on the last day of a 4-week treatment. 
 
10.4.2. Primary Analysis 
The primary endpoint is the change from baseline to week 4 for FEV1. The statistical 
evaluations for this endpoint are described below.   


 
 
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Equivalence 
Compound Hypothesis to be tested is  
H0: µT / µR ≤ θ1    or µT / µR ≥ θ2 versus HA:  θ1< µT / µR< θ2 
Where µT = mean of test treatment, and µR = mean of reference treatment 
 
Analysis of covariance (ANCOVA) will be used to evaluate the mean change in FEV1 at 
week 4, for the test and reference treatments using baseline FEV1 as a covariate and 
treatment and clinical site as factors.  The 90% confidence interval will be computed by 
Fieller’s Theorem based on the results from the ANCOVA. The 90 % confidence interval on 
the test-to-reference ratio must contain within the interval 80.00% to 125.00% for the test 
and reference products to be considered equivalent to each other. 
 
       Superiority 
Analysis of Covariance will be used to compare each active treatment with placebo using 
Baseline FEV1 as covariate and clinical site and treatment as factor. If the active treatment 
shows a greater increase in FEV1 from baseline than that for the placebo, and the difference 
between it and the placebo is statistically significant (p<0.05), then the active treatment will 
be considered superior to placebo.  Superiority must be shown for both active treatments over 
placebo for the equivalence evaluation between the test and reference treatments to be 
considered valid. 
10.4.3. Secondary Efficacy Variables 
 Mean change in FeNO value from base line (visit 3) to end of study visit (visit 5) 
 Percentage of subjects with reduction of FeNO from Baseline (Visit 3) to End of Study 
(Visit 5)  
 
10.4.4. Secondary Analysis 
Descriptive Summary statistics will be presented for all secondary endpoints for active treatment 
groups.  
Number and percentage of subjects meeting the criteria for reduction (atleast 20 % for FeNO ≥ 
50 ppb values and atleast 10 % for FeNO < 50 ppb) in FeNO will be presented.  
 
10.4.5. Imputation for Missing Data 
For subjects included in the mITT population, and for those PP subjects who discontinue due to 
lack of treatment efficacy, Last Observation Carried Forward (LOCF) imputation will be used 
to impute missing EOS values for FEV1. If a subject discontinued due to lack of efficacy does 


 
 
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not have a post baseline value, then the baseline value will be carried forward. No imputation 
will be performed for missing safety data. 
 
10.5. Safety Analysis 
Summary of adverse events, Treatment Emergent Adverse Events, Serious adverse event, events 
leading to discontinuation and treatment related adverse events will be presented for each arm. 
Summary of Vital signs and Laboratory parameter values at relevant time-points as well as 
change from baseline will be presented. Summary of use of various concomitant medications 
will be presented. By Subject data listings will be presented for all safety data captured on CRF/ 
eCRF. 
 
 


 
 
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11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
According to the International Conference on Harmonization (ICH) Harmonized Tripartite 
Guideline for Good Clinical Practice (ICH-GCP), AXIS/sponsor is responsible for implementing 
and maintaining quality assurance and quality control systems with written SOPs.  
Quality control will be applied to each stage of data handling.  
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
• 
Site Initiation visit 
• 
Early site visits post-enrollment 
• 
Routine site monitoring 
• 
Ongoing site communication and training  
• 
Data management quality control checks 
• 
Continuous data acquisition and cleaning 
• 
Internal review of data 
• 
Quality control check of the final clinical study report 
In addition, sponsor and/or AXIS Clinical Quality Assurance (CQA) Department may conduct 
periodic audits of the study processes, including, but not limited to study site, site visits, central 
laboratories, vendors, clinical database, and final clinical study report.  When audits are 
conducted, access must be authorized for all study related documents including medical history 
and concomitant medication documentation to authorized sponsor’s representatives and 
regulatory authorities. 
11.1. Direct Access to Source Documents and Study Monitoring  
Investigator will prepare and maintain adequate and accurate source documents to record all 
observations and other pertinent data for each subject entered into the study.   
Investigator will allow the sponsor, AXIS, and authorized regulatory authorities to have direct 
access to all documents pertaining to the study. 
The Sponsor has engaged the services of a Contract Research Organization (CRO), AXIS 
Clinicals, to perform all monitoring functions within this clinical study.  AXIS’ monitors will 
work in accordance with sponsor or AXIS’ SOPs and have the same rights and responsibilities as 
monitors from the sponsor organization. Monitors will establish and maintain regular contact 
between the PI and the sponsor. 
Monitors will evaluate the competence of the study site, informing the sponsor about any 
problems relating to facilities, technical equipment or medical staff.  During the study, monitors 


 
 
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will check that written informed consent has been obtained from all subjects correctly and that 
data are recorded correctly and completely.  Monitors are also entitled to compare entries in 
CRF/eCRF with corresponding source data and to inform the PI of any errors or additions.  
Monitors will also direct adherence to the protocol at the investigator site. They will liaise with 
the sponsor for supply of study drugs and ensure appropriate storage conditions are maintained at 
investigator site. 
Monitoring visits will be conducted according to the, ICH E6 Guideline for GCP, Monitoring 
plan and applicable local regulations. The monitor will visit the site while subjects are enrolled in 
the study at regular intervals according to the monitoring plan.  The monitor will make written 
reports to the Sponsor on each occasion when contact with the PI is made, regardless of whether 
it is by phone or in person. 
During monitoring visits, entries in the CRFs/ eCRFs will be compared with the original source 
documents (source data verification).   
During the monitoring visit, the following items must be accessible for review but not limited to: 
• Source documents, including ICFs, for all screened subjects (Monitor will conduct 100% 
source document verification) 
• CRFs/ eCRFs for all subjects 
• Investigational Product Accountability  
• Site Master File 
• Drug supply and clinical supply cabinets 
• Storage of lab samples and study medication 
All study staff will also need to make themselves available for review of monitoring issues. 
11.2. Data Management/ Coding 
Data generated within this clinical study will be handled according to relevant SOPs of the 
Clinical Data Management department of AXIS. In addition, inconsistency in data identified 
during the data cleaning process is resolved by issuing queries to site. The AE terms reported in 
the study will be coded using MedDRA. 
11.3. Quality Assurance Audit 
Investigator sites, the study database and study documentation may be subject to Quality 
Assurance audit during the course of the study by the Sponsor or AXIS. In addition, inspections 
may be conducted by regulatory bodies at their discretion. 


 
 
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The PI must notify Sponsor or AXIS promptly of any inspections scheduled by regulatory 
authorities. 
11.4. Data Collection 
Entries in CRF/eCRFs legible entries will be made. Any correction to the entered data will be 
made as per the CRF/ eCRF filling instructions. All corrections shall be authenticated with 
proper audit trail. Accuracy of the data will be attested by signatures off investigator. For 
laboratory values, Laboratory reports will be considered as source document. 
For laboratory values, laboratory reports will be considered as source document. 
 
 


 
 
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12.0 
ETHICS 
12.1. Ethics Committee 
Ethics committee (EC) approval will be obtained from an EC registered with CDSCO. PI will 
provide the Sponsor or AXIS with documentation of Institutional Ethics Committee (IEC) 
approval of the protocol, ICF and all documents required as per applicable regulations before the 
study may begin at the study sites.  EC shall maintain all the study records for not less than 5 
years from the date of study completion or termination of the trial. PI will supply documentation 
to the Sponsor or AXIS of required EC’s annual renewal of the protocol, and any approvals of 
revisions to the informed consent document or amendments to the protocol. 
The PI will report promptly to the EC, any new information that may adversely affect the safety 
of subjects or the conduct of the study.  Similarly, the PI will submit written summaries of the 
study status to the EC annually, or more frequently if requested by the EC.  Upon completion of 
the study, the PI will provide the EC with a brief report of the outcome of the study, if required. 
12.2. Ethical Conduct of the Study 
This study will be conducted and the informed consent will be obtained according to the ethical 
principles stated in the Declaration of Helsinki (2013), the applicable guidelines for GCP and/ or 
the applicable local drug and data protection laws and regulations. 
12.3. Regulatory Approval 
Study will be initiated only after obtaining approval from DCGI. 
12.4. Subject Information and Informed Consent 
A freely given informed consent will be obtained from all the subjects prior to any study specific 
procedures being carried out. In obtaining ICF investigator will comply with all applicable 
regulatory requirements, GCP and Ethical principles that have their origin in declaration of 
Helsinki. Investigator /designee shall fully inform the subject about all pertinent aspects of study 
including written informed consent. Subject will be given ample time to read informed consent 
and investigator shall address all the queries raised by the subject. Investigator/ designee shall 
also sign the ICF. A copy of completed signed ICF shall be given to subject. Subject shall be 
made aware of all the risks and benefits involved in the study. Subjects will also be made aware 
that in case of trial related injury/death, free medical management and financial compensation 
will be provided to subject/ nominee. 


 
 
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Subject will also be informed that they are free to withdraw at any point of time during the study.  
Written consent must be given by the subject and/or legal representative, only after the receipt of 
detailed information on the study. 
Investigator is responsible for ensuring that informed consent is obtained from each subject or 
legal representative and for obtaining the appropriate signatures and dates on the informed 
consent document prior to the performance of any protocol procedures and prior to the 
administration of study drug. 
 
 


 
 
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13.0 
STUDY ADMINISTRATION 
13.1. Administrative Structure 
The following table provides a list of key individuals and their roles from the Sponsor and AXIS 
who will contribute to this study. 
Table X: Study Administration Structure 
Sponsor 
CRO 
Aurobindo Pharma Research  
Center-II 
Survey No -71&72, Indrakaran Village,
Kandi Mandal, 
Sangareddy Dist -500 090, Telangana, 
India, 
Tel. no: +91-40-23040262, 
AXIS Clinicals Limited  
1-121/1, Miyapur  
Hyderabad-500049, INDIA 
Direct: +91-40-40408064  
Fax: +91-40-40408060  
E-mail: subhra.l@axisclinicals.com 
IP Supplies  
Medical Monitoring and Support 
 
Aurolife, a subsidiary of Aurobindo 
Pharma, USA, Inc.  
2929 Weck Dr., Durham, NC 27709 
Dr. Mohammed Sajid 
Medical Manager-Clinical Research 
AXIS Clinicals Limited, 1-121/1, 
Miyapur, Hyderabad 500049, INDIA. 
Tel: +91 40 4040 8270 
Email: Sajid.m@Axisclinicals.com 
Statistical Analysis 
Drug Safety Reporting 
Mandar Oak,
1002, Siddhivinayaka, Plot No-03, 
Sector 14, New Panvel (W), Navi 
Mumbai, Maharashtra-410206, India 
 AND/ OR 
Nadamuni Naidu.K 
Head of Biostatistics  
Inductive Quotient, Cavery’s City 
Plaza, 2nd Floor, 
Sundar Nagar, Andhra Bank Building,  
Hyderabad-500038. 
Telephone: +91 40 23722238 
Email id: 
naidu.adusumalli@inductivequotient.co
m 
 
AXIS Clinicals Ltd, 1-121/1, Miyapur 
Hyderabad 500049, INDIA 


 
 
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Clinical Monitoring 
Quality Assurance 
AXIS Clinicals Ltd 
1-121/1, Miyapur 
Hyderabad 500049,  
INDIA 
AXIS Clinicals Ltd 
1-121/1, Miyapur 
Hyderabad 500049,  
INDIA 
 
 
Data Management and CDISC Facility 
Medical Writing 
AXIS Clinicals Ltd 
1-121/1, Miyapur 
Hyderabad 500049,  
INDIA 
AXIS Clinicals Ltd 
1-121/1, Miyapur 
Hyderabad 500049,  
INDIA 
Laboratory Services 
Any Designated Laboratory 
 
13.2. Data Handling and Record Keeping 
The PI must maintain essential study documents (protocol and protocol amendments, completed 
CRF/eCRF, signed ICFs, relevant correspondence, and all other supporting documentation) until 
at least 20 years after completion of all regulatory activity.  These documents should be retained 
for a longer period if required by the applicable regulatory requirements and/ or the hospital/ 
institution in which the study is being conducted.  Subject identification codes (subject names 
and corresponding study numbers) will be retained for this same period of time.  These 
documents may be transferred to another responsible party, acceptable to Sponsor, who agrees to 
abide by the retention policies.  Written notification of transfer must be submitted to sponsor.  
The PI must contact sponsor prior to disposing of any study records.  
13.3. Investigator Information 
13.3.1. Investigator Obligations 
This study will be conducted in accordance with the ICH-GCP, Nov 2016; and the applicable 
regulatory requirements inclusive of the GCP, Schedule Y- Drugs and Cosmetics (2nd 
Amendment) Rules, 2005 of Central Drugs Standard Control Organization (CDSCO) and ICMR 
Ethical Guidelines for Biomedical Research on Human Subjects (2017); and the ethical 
principles that have their origin in the Declaration of Helsinki. 
 
 
 


 
 
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13.3.2. Protocol Deviations and Protocol Waivers 
Investigator will conduct this study in accordance with protocol approved by IEC and DCGI. 
Under no circumstances, investigator shall deviate from protocol without prior permission from 
sponsor and EC.  
In case of all deviations, investigator shall document all the deviations and notify same to EC 
which accorded approval for the study. 
In case of Pre planned protocol deviation i.e., protocol waivers, approval from Axis Clinicals 
shall be obtained. 
13.3.3. Publication Policy 
The rights of publication lie solely with sponsor. 
13.3.4. Data Ownership 
The data collected in this study are the sole property of Aurobindo Pharma, but not the hospital 
subject’s record.  
13.4. Financing and Insurance 
Aurobindo Pharma is funding this study. In the event of study-related injury or death, insurance 
for the subjects and indemnity of the investigators and those of their employees, servants or 
agents, whose participation in this study has been documented, will be provided by Aurobindo 
Pharma, USA Inc. Insurance and liability will be in accordance with applicable law and GCP 
(ICH, November 2016). In case of SAEs occurring to clinical trial subject, Aurobindo Pharma 
will provide free medical management as long as required along with financial compensation in 
case of trial related injury and death.  
 
 


 
 
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14.0 
REFERENCES 
1. Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma 
(GINA), 2006. Available from www.ginasthma.org Date last updated. 2006. 
2. Gupta RS, Weiss KB. The 2007 national asthma education and prevention program 
asthma guidelines: accelerating their implementation and facilitating their impact on 
children with asthma. Pediatrics. 2009;123(Suppl 3):S193–8. 
3. Gupta RS, Weiss KB. The 2007 national asthma education and prevention program 
asthma guidelines: accelerating their implementation and facilitating their impact on 
children with asthma. Pediatrics. 2009;123(Suppl 3):S193–8. 
4. Busse WW, Lemanske RF. Asthma. N Engl J Med 2001;344(5): 350–362. 
5. Leung DY, Bloom JW. Update on glucocorticoid action and resistance. J Allergy Clin 
Immunol 2003;111(1):3–22. 
6. Cerasoli F Jr. Developing the ideal inhaled corticosteroid. Chest 2006; 130(1 
Suppl):54S–64S. 
7. National Institutes of Health, author. National Asthma Education and Prevention Program 
Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 2007.  
8. Draft Guidance on Beclomethasone  
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM481768.pdf 
9. HIGHLIGHTS OF PRESCRIBING INFORMATION: QVAR® (beclomethasone 
dipropionate HFA), inhalation aerosol, for oral inhalation use 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020911s029s030lbl.pdf 
10. Instructions for Use QVAR (Kyü-vär) (beclomethasone dipropionate HFA) Inhalation 
Aerosol 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020911s025lbl.pdf 
11. GINA guidelines 2018  
12. An Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric Oxide 
Levels (FENO) for Clinical Applications 
 
 


 
 
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APPENDIX 1:  SPONSOR PROTOCOL AGREEMENT 
PROTOCOL TITLE:  
A randomized, multiple-dose, double blind, placebo controlled, parallel group, multicentric study 
to evaluate Efficacy and Safety of Beclomethasone Dipropionate Metered Dose Inhaler (Inhalat-
ion Aerosol) (0.04 mg/ INH) in male and/ or female subjects with Asthma [GroupI (Test): Beclo-
methasone Dipropionate 0.04 mg/ INH; Group II (Reference): QVAR® 40 mcg (Beclomethasone 
dipropionate HFA); and Group III: Placebo]. 
PROTOCOL NO: CR176-17 
I, on behalf of Aurobindo Pharma have read reviewed and understood this protocol and thus 
approve it. I agree to comply with the applicable regulatory requirements of ICH – Good Clinical 
Practice, Schedule Y, Declaration of Helsinki, 21 CFR 312.120 and 21 CFR 320 regarding the 
obligations and role as a Sponsor of this study. 
 
Signature Sponsor:  __________________________                      Date:  ________ 
Printed Name:  
Dr. M. Joseph  
Sponsor Title:            Associate Vice President-Clinical Affairs 
                                   Specialty Products 
 
             
 
Address of Sponsor:  APL Research Centre-II, 
                       Aurobindo Pharma Limited, 
                       Survey No. 71 & 72, Indrakaran Village, 
 
                       Kandi Mandal, Sangareddy dist – 502329, India. 
                       Telephone:  
+91-8455223700, Ext: 1516 
                       Mobile no:  
+91-9765800454. 
 


 
 
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APPENDIX 2:  INVESTIGATOR PROTOCOL AGREEMENT  
PROTOCOL TITLE:   
A randomized, multiple-dose, double blind, placebo controlled, parallel group, multicentric study 
to evaluate Efficacy and Safety of Beclomethasone Dipropionate Metered Dose Inhaler (Inhalat-
ion Aerosol) (0.04 mg/ INH) in male and/ or female subjects with Asthma [GroupI (Test): Beclo-
methasone Dipropionate 0.04 mg/ INH; Group II (Reference): QVAR® 40 mcg (Beclomethasone 
dipropionate HFA); and Group III: Placebo]. 
PROTOCOL NO: 
CR176-17 
 I confirm agreement to conduct the study in compliance with the protocol. 
 I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described clinical study. 
 I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that 
site staffs receive the appropriate information throughout the study. 
 
Name: 
 
Address: 
 
Phone Number: 
 
 
 
 
Signature 
 
Date 
 
 


 
 
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APPENDIX 3: Investigator’s Global Evaluation (Assessed by Investigators) 
An investigator-rated test measured on a 7-point scale, with scores ranging from 1 (very much 
improved) to 7 (very much worse); used to rate change in subject's condition over the course of 
the study. 
 
Rate total improvement whether or not in your judgement it is due entirely to drug treatment. 
 
Compared to his/her condition at Visit 3, how much has he/she changed? 
 
1. Very Much Improved 
2. Much Improved 
3. Minimally Improved 
4. No Change 
5. Minimally Worse 
6. Much Worse 
7. Very Much Worse. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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APPENDIX 4: ASTHMA CONTROL QUESTIONNAIRE TEST 
 
 
 
 
 
 


 
 
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APPENDIX 5: NATIONAL ASTHMA EDUCATION AND PREVENTION PROGRAM-
ASTHMA DIAGNOSIS CRITERIA 
 
i) Wheezing (high-pitched whistling sounds when breathing out)           Yes           No 
(A lack of wheezing and a normal chest examination do not exclude asthma) 
ii) History of any of the following: 
 Cough (worse particularly at night)        Yes           No 
 Recurrent wheeze      Yes           No 
 Recurrent difficulty in breathing      Yes           No 
 Recurrent chest tightness      Yes           No 
iii) Symptoms occur or worsen in the presence of (any one of the following or more):  
 Exercise      Yes           No 
 Viral infection       Yes           No 
 Inhalant allergens (e.g., animals with fur or hair, house-dust mites, mold, pollen)             
Yes       No 
 Irritants (tobacco or wood smoke, airborne chemicals)      Yes           No 
 Changes in weather     Yes           No 
 Strong emotional expression (laughing or crying hard)      Yes           No 
 Stress       Yes           No 
 Menstrual cycles      Yes           No 
iv)  Symptoms occur or worsen at night, awakening the patient      Yes           No 
v) Episodic symptoms of airflow obstruction or airway hyperresponsiveness are present              
     Yes           No 
vi)  Airflow obstruction is at least partially reversible, measured by spirometry     Yes      No 
(Reversibility is determined by an increase in FEV1 of >200 mL and ≥12 percent from baseline 
measure after inhalation of short-acting beta2-agonist)       
 
 


 
 
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APPENDIX 6: ESCAPE CRITERIA FOR ASTHMA 
Escape Criteria for Asthma 
 
Assessing exacerbation severity  
A brief focused history and relevant physical examination should be conducted concurrently with 
the prompt initiation of therapy, and findings documented in the notes. If the subject shows signs 
of severe life-threatening exacerbation, treatment with SABA, controlled oxygen and systemic 
corticosteroids should be initiated while arranging for the subject’s urgent transfer to an acute 
care facility where monitoring and expertise are more readily available. Milder exacerbation can 
usually be treat in a primary care setting, depending on resources and expertise. 
History  
The history should include 
 Timing of onset and cause of the present exacerbation  
 Severity of asthma symptoms including any limiting exercise or disturbing sleep 
 Any symptoms of anaphylaxis  
 Risk factors for asthma related death 
 
Physical examination  
 
Physical examination should assess  
 Signs of exacerbations severity including vital signs 
 Complicating factors (eg. Pneumonia, pneumothorax etc) 
 Signs of alternative conditions that could explain acute breathlessness (eg. Cardiac 
failure, pulmonary embolism etc) 
 
Objective assessment 
 Pulse oximetry, saturation level if <90% aggressive therapy would be needed 
 Pulmonary function test (PEF/FEV1) 
 
Treating Exacerbations 
 
The main initial therapies include repetitive administration of SABA, early introduction of 
systemic corticosteroids and controlled flow oxygen supplementation. The aim is to rapidly 
relieve airflow obstruction and hypoxemia.  
 
 


 
 
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Inhaled short acting Beta2 agonists 
 
For mild to moderate exacerbations, repeated administration of inhaled SABA (up to 4-10 puffs 
every 20 minutes for the first hour) is usually the most effective and efficient way to achieve 
rapid reversal airflow limitation. After the first hour, the dose of SABA required varies from 4-
10 puffs every 3-4 hours up to 6-10 puffs every 1-2 hours or more often. No additional SABA is 
needed if there is a good response to initial treatment. 
 
Delivery of SABA by spacer device would be more beneficial. 
 
Controlled oxygen Therapy (If available) 
 
Oxygen therapy should be titrated against pulse oximetry (if available) to maintain oxygen 
saturation at 93-95%. 
 
Systemic corticosteroids 
 
Oral corticosteroids (OCS) should be given promptly, especially if the condition of subject 
deteriorating or had already increased his/her reliever and controller medication before 
presenting. The recommended dose of prednisolone is 1mg/kg body weight or maximum of 
50mg/day. OCS should usually be continued for 5-7 days. 
 
Controlled medication 
 
The dose of controller medications should be increased for period of 2-4 weeks. 
 
Antibiotics  
Use of antibiotics generally not recommended unless there is strong evidence of lung infections. 
 
Reviewing of responses 
During treatment, subjects should be closely monitored and treatment titrated according to their 
response. Subjects who presents with signs of severe life-threatening exacerbations should be 
transferred immediately to an acute care facility. 
 
Follow up 
Discharge medications should include as needed reliever medications, short course of OCS and 
for more subject’s regular controller treatment. Inhaler technique and adherence should be 
reviewed before discharge. 
 
 


 
 
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Management of asthma exacerbations & severe asthma exacerbations 
 
 
Patient presents with acute or sub-acute 
asthma exacerbations 
MILD OR MODERATE
Talks in phrases
Prefers sitting to lying, not agitated 
Respiratory rate increased
Accessory muscles not used 
Pulse rate 100-120 bpm
O2 saturation 90-95 %
PEF > 50 % predicted or best
START TREATMENT
SABA 4-10 puffs by pMDI + spacer, 
repeated every 20 minutes for 1 
hour
Prednisolone: adults 1mg/kg
Controlled oxygen: target saturation 
93-95%
CONTINUE TREATMENT with SABA as 
needed
Assess response at 1 hour (or earlier)
ASSES FOR DISCHARGE based on improvement in symptoms, 
requirement of SABA, PFT, O2 saturation
Discharge
Worsening
SEVERE
Talks in words
Sits hunched forwards, agitated
Respiratory rate  >30/min
Accessory muscles in use
Pulse rate > 120 bpm
O2 saturation  < 90%
PEF ≤50% predicted or best
TRANSFER TO ACUTE CARE CARE 
FACILITY
While waiting : give SABA, O2 , 
systemic corticosteroids
LIFE THREATENING
Drowsy, confused or 
silent chest
Assess the 
patient
SEVERITY OF ASTHMA
Is it asthma?
Risk factor for asthma related 
death

SAP_001.pdf: 
AXIS CLINICALS 
Protocol CR 176-17 
Statistical Analysis Plan: Final 1.0 
 
Page 1 of 24 
 
                       STATISTICAL ANALYSIS PLAN 
 
SAP VERSION:                              Final 1.0 
SPONSOR:                                    
Aurobindo Pharma Research Center-II 
Survey No -71 & 72, Indrakaran Village, 
Kandi Mandal, Sangareddy, 
Dt Telangana -502329, India, 
Tel. no: +91-40-8455223700 Ext-1516 
 
STUDY TITLE: 
A randomized, multiple -dose, double blind, placebo 
controlled, parallel group, multicentric study to evaluate 
Efficacy and Safety of Beclomethasone Dipropionate 
Metered Dose Inhaler (Inhalation aerosol) (0.04mg/INH) in 
male and /or female subjects with Asthma 
• Group I (Test): Beclomethasone Dipropionate 0.04 
mg/INH;  
• Group II (Reference): QVAR® 40 mcg 
(Beclomethasone dipropionate HFA); and  
• Group III: Placebo 
 
Investigational Product: 
Beclomethasone Dipropionate Metered Dose Inhaler 
(Inhalation Aerosol) (0.04 mg/ INH);  
Manufactured by: Aurolife, a subsidiary of Aurobindo 
Pharma, USA, Inc., 2929 Weck Dr., Durham, NC 27709. 
 
Reference Product: 
QVAR® 40 mcg (Beclomethasone dipropionate HFA), 
Inhalation Aerosol;  
Marketed by: Teva Pharmaceuticals LLC Frazer, PA 19355.  
NDC code: 59310-202-12 
 
Placebo Product: 
 
 
 
Study Phase: 
Placebo Metered Dose Inhaler;  
Manufactured by: Aurolife, a subsidiary of Aurobindo 
Pharma, USA, Inc., 2929 Weck Dr., Durham, NC 27709. 
 
Clinical Pharmacodynamic BE Study  
 
PROTOCOL NUMBER: 
 
CR176-17 
PROTOCOL VERSION/DATE:    
Version 1.0 Amendment 02 Dated 07.08.2019 


AXIS CLINICALS 
Protocol CR 176-17 
Statistical Analysis Plan: Final 1.0 
 
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CRO: 
AXIS Clinicals Ltd  
1-121/1, Miyapur Hyderabad 500049, India  
Telephone: +91 40 4040 8064 
FAX – 91-40-4040 8060. 
 
 
 
 
 
                                                             
 
 




AXIS CLINICALS 
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Statistical Analysis Plan: Final 1.0 
 
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TABLE OF CONTENTS 
 
1. 
ABBREVIATIONS ................................................................................... 6 
2. 
INTRODUCTION ..................................................................................... 8 
2.1.  
Responsibilities .......................................................................................... 8 
2.2. 
Timing of Analyses .................................................................................... 8 
3.  
STUDY RATIONALE .............................................................................. 8 
4.  
STUDY OBJECTIVES AND ENDPOINTS ............................................. 9 
4.1. 
Primary Objective ...................................................................................... 9 
4.2. 
Secondary Objective .................................................................................. 9 
4.3. 
End points .................................................................................................. 9 
4.3.1. 
Efficacy ...................................................................................................... 9 
4.3.2. 
Safety ......................................................................................................... 9 
5. 
STUDY DESIGN .................................................................................... 10 
5.1. 
Schedule of Assessments (Table I) .......................................................... 12 
6. 
INCLUSION & EXCLUSION CRITERIA ............................................. 13 
7. 
STUDY TREATMENTS......................................................................... 15 
7.1.  
Method of Assigning Subjects to Treatment Groups .............................. 15 
7.2. 
Blinding ................................................................................................... 15 
8. 
SAMPLE SIZE JUSTIFICATION .......................................................... 16 
9. 
DATA COLLECTION ............................................................................ 16 
10. 
ANALYSIS POPULATIONS ................................................................. 16 
10.1. 
Safety ....................................................................................................... 16 
10.2. 
ITT Population ......................................................................................... 17 
10.3. 
mITT Population ...................................................................................... 17 
10.4. 
Per Protocol Population ........................................................................... 17 
10.5. 
Procedure for Accounting for Missing Data ............................................ 17 
11. 
GENERAL ASPECTS OF THE STATISTICAL ANALYSIS............... 18 
12. 
STATISTICAL ANALYSIS ................................................................... 19 
12.1. 
Subject Disposition .................................................................................. 19 
12.2. 
Demographic and Baseline Characteristics ............................................. 19 
12.3. 
Protocol Deviations and Protocol Waivers .............................................. 19 
12.4. 
Analysis of Efficacy Data ........................................................................ 19 
12.4.1. 
Primary Efficacy ...................................................................................... 19 
12.4.2. 
Secondary Efficacy Variables .................................................................. 21 


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Statistical Analysis Plan: Final 1.0 
 
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12.5. 
Safety Analysis ........................................................................................ 21 
12.5.1. 
Adverse Events ........................................................................................ 21 
12.6. 
General and Systemic Examination ......................................................... 22 
12.7. 
Medical History ....................................................................................... 22 
12.8. 
Vital Signs ............................................................................................... 22 
12.9. 
Prior and Concomitant Medication .......................................................... 22 
12.10. 
 12 Lead electrocardiogram & Chest X-Ray (PA View) ......................... 22 
12.11. 
Laboratory Investigations: Hematology and Serum Chemistry Panel .... 22 
12.12. 
Treatment Compliance ............................................................................. 22 
13. 
DEFINITIONS ........................................................................................ 23 
14. 
TITLES OF MOCK SHELLS ................................................................. 24 
15.  
APPENDIX: ANALYSIS PRESENTATION CONVENTIONS ........... 24 
16. 
REFERENCES ........................................................................................ 24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan: Final 1.0 
 
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1. ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ANCOVA  
Analysis of Covariance 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BDP 
Beclomethasone dipropionate 
BMI 
Basal Metabolic Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
EOS 
End of Study 
ECRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FeNO 
Exhaled Nitric Oxide 
FEV1 
Forced expiratory volume in 1 second 
HBsAg 
Hepatitis B Surface Antigen 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
ICS’S 
Inhaled corticosteroids 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LDL 
Low-density lipoprotein 
LOCF 
Last Observation Carried Forward 
MDI 
Metered-Dose Inhaler 
MedDRA 
Medical Dictionary for Regulatory Affairs 
mITT 
modified Intent-to-Treat 
mL 
Milliliter 
PEF 
Peak expiratory flow 
PFT 
Pulmonary Function Test 
PI 
Principal Investigator 
PP 
Per Protocol 
RBC 
Red blood cell count 
RLD 
Reference listed drug 


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Statistical Analysis Plan: Final 1.0 
 
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SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
US/USA  
United States of America 
UAE 
Unexpected Adverse Events 
WBC 
White blood cell count 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. INTRODUCTION 
 
The purpose of this statistical analysis plan (SAP) is to outline in detail the statistical methods, 
data derivations, and presentations of data so that valid conclusions can be reached to address 
the study objectives outlined in the CR176-17 Protocol Amendment 02 Dated 07.08.2019. 
 
This SAP is being written with due consideration of the recommendations outlined in the most 
recent International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for 
Industry: Statistical Principles for Clinical Trials and the most recent ICH E3 Guideline entitled 
Guidance for Industry: Structure and Content of Clinical Study Reports (CSR).  
 
The planned analyses identified in this statistical analysis plan (SAP) may be included in 
regulatory submissions and/or future manuscripts. Exploratory analyses, not identified in this 
SAP, may be performed to support the clinical development program. The statistical analysis 
methods presented in this document will supersede the statistical analysis methods described 
in the protocol. Any post-hoc or unplanned analyses that are performed but not identified in 
this SAP will be clearly identified in the clinical study report (CSR). 
 
2.1.  Responsibilities 
Inductive Quotient will perform the statistical analyses for all clinical data collected.  
Inductive Quotient is responsible for production and quality control of all datasets, tables, 
figures, and listings. 
2.2. Timing of Analyses 
Final analysis will be done by Inductive Quotient after receipt of the final data from AXIS. 
Any additional tables required by the regulatory or sponsor also will be undertaken in this 
SAP. 
 
3.  STUDY RATIONALE 
 
Aurobindo Pharma, India, is seeking marketing approval for Beclomethasone Dipropionate 
Metered Dose Inhaler (0.04 mg/INH) in USA, for which demonstration of equivalence in 
efficacy to a reference QVAR® 40 mcg (Beclomethasone dipropionate hydrofluoroalkane) is 
required; therefore an appropriate comparability exercise is required to demonstrate that the 
similar therapeutic benefit with that of reference medicinal products in terms of quality, safety 
and efficacy is achieved and superiority in efficacy to that of placebo. 
 
 
 
 


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Statistical Analysis Plan: Final 1.0 
 
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4.  
STUDY OBJECTIVES AND ENDPOINTS 
 
4.1. Primary Objective   
 
• To compare the therapeutic equivalence of Beclomethasone Dipropionate MDI 
(Inhalation Aerosol) 0.04 mg/ INH, with the marketed QVAR® 40 mcg 
(Beclomethasone dipropionate hydrofluoroalkane (HFA) and to demonstrate 
the superiority of both active treatments compared to placebo.  
 
4.2. Secondary Objective   
 
• To assess the safety and tolerability of Beclomethasone Dipropionate Metered 
Dose Inhaler (Inhalation Aerosol) (0.04 mg/ INH). 
 
4.3. 
End points 
 
4.3.1. Efficacy 
 
• Primary Endpoint: Mean change in Forced Expiratory volume in 1 second (FEV 1) 
from baseline (visit 3) to end of study visit (visit 5).  
 
 
            
• Secondary Endpoints: 
o Mean change in FeNO value from baseline (visit 1 and visit 3) to end of study 
visit (visit 5) 
o Percentage of subjects with reduction of FeNO from Baseline (visit 1 and visit 
3) to End of Study (Visit 5)  
 
4.3.2. Safety 
• Safety will be assessed on the basis of reported adverse events, serious adverse events 
and laboratory assessments. 
 
 
 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan: Final 1.0 
 
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5. STUDY DESIGN  
This is a randomized, multiple dose, double blind, placebo-controlled, parallel group, 
multicentric study to evaluate the Efficacy and Safety of Beclomethasone Dipropionate (0.04 
mg/ INH) Metered Dose Inhaler in male and/ or female subjects with Asthma [Group I (Test): 
Beclomethasone Dipropionate 0.04 mg/ INH; Group II (Reference): QVAR® 40 mcg 
(Beclomethasone dipropionate HFA), Inhalation Aerosol; and Group III: Placebo].  
 
A total of five visits are scheduled in this study.   
• Visit 1 Screening (Day -7 to Day -1),  
• Visit 2.  Day 0 
• Visit 3.  Randomization (Day 15 + 1),  
• Visit 4.  On-treatment visit (Day 21 ± 1)  
• Visit 5.  End of Study visit (Day 42 ± 2).  
 
All subjects will be reported to the study site for screening.  Subjects with asthma diagnosed 
as per National Asthma Education and Prevention Program at least 12 months prior will be 
briefed about the study and Informed Consent Form will be obtained. An exhaled nitric oxide 
(FeNO) test will be performed. If FeNO is < 25 ppb, those subjects will not be screened further. 
Pulmonary function test (PFT) by spirometer will be performed. After completion of the 
required screening tests and procedures, subjects meeting all the inclusion criteria and none of 
the exclusion criteria will be asked to visit the study site for run-in period. Subjects will be 
provided with placebo metered dose inhaler in the run-in period and will be advised to take one 
inhalation twice daily for two weeks. Subjects will be provided with subject diary and rescue 
medication (Salbutamol) with detail instructions regarding filling of subject diary and usage of 
rescue medication (Salbutamol).  
 
Subjects will be required to visit on Day 15 + 1 and those subjects who completed the placebo 
run period and met the applicable eligible criteria will be randomized. An exhaled nitric oxide 
(FeNO) test will be performed on day 15 + 1. Pulmonary function test (PFT) by spirometer 
will be performed. Airway reversibility will be checked. According to the randomization 
scheme, subjects will be supplied with the study medication (either Test or Reference or 
Placebo in 2:2:1 ratio as per the randomization schedule) along with diary card with 
instructions regarding filling of subject diary.  
 
Subjects will be advised to take one inhalation twice daily for 4 weeks in the morning and 
evening, preferably on the same time period during the entire treatment period. Subjects need 
to report to the Investigator site on day 21 ± 1 and 42 ± 2. At these visits (Visit  4 and Visit 5), 
efficacy and safety evaluation will be done. At the EOS visit (Visit 5), subjects will go through 
all the end of study evaluation procedures, as outlined in the Table of Events (Table I). They 
will be clinically evaluated for the assessment of the efficacy parameters and Investigator’s 
Global Evaluation Score.  
 


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Statistical Analysis Plan: Final 1.0 
 
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At every study visit, all the procedures mentioned in the Table of events (Table I) will be carried 
out. Safety assessments (reporting of adverse events and serious adverse events if any, clinical 
laboratory measures and vital sign parameters) will be performed and any change in 
concomitant medications will be noted at all the scheduled visits. 
 
 
 
 
Note: After Placebo Run-in Period, subjects will be randomized either to test/ reference/ 
placebo if they fulfil the eligibility. 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan: Final 1.0 
 
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5.1. Schedule of Assessments (Table I) 
 
Procedure  
Screening 
Period 
 
Run-in 
Period 
Treatment Period 
End of 
Study 
-7 days 
 Day 0 
 Day 1 to 
Day 14 
 Day 15 + 1  Day 21±1  Day 42±2 
Visit  
1 
2 
-- 
3 
4 
5 
Informed consent 
X 
-- 
-- 
-- 
-- 
-- 
Eligibility criteria 
X 
-- 
-- 
X 
-- 
-- 
Demography 
X 
-- 
-- 
-- 
-- 
-- 
Medical and Medication 
History1 
X 
-- 
-- 
-- 
-- 
-- 
General & Systemic 
Examination2 
X 
X 
-- 
X 
X 
X 
Vital signs3 
X 
X 
-- 
X 
X 
X 
Serum Pregnancy Test  (for 
females of child bearing 
potential) 
X 
-- 
-- 
-- 
-- 
-- 
Urine Pregnancy Test (for 
females of child bearing 
potential) 
-- 
-- 
-- 
X 
-- 
X 
Clinical Laboratory Test4 
X 
-- 
-- 
-- 
-- 
X 
12 lead ECG 
X 
-- 
-- 
-- 
-- 
-- 
Chest X-Ray (PA view) 
X 
-- 
-- 
-- 
-- 
-- 
FeNO Estimation 
X 
-- 
-- 
X 
-- 
X 
FEV1 value recording 
(through Spirometry)  
X 
X 
-- 
X 
X 
X 
Bronchodilator/ Reversibility 
test  
-- 
-- 
-- 
X 
-- 
-- 
Placebo Canister Dispensing  
(for Run-in period) 
-- 
X 
-- 
-- 
-- 
-- 
Collection of Placebo 
Canister given in run-in 
Period 
-- 
-- 
-- 
X 
-- 
-- 
Rescue Medication 
Dispensing 
-- 
X 
-- 
X 
-- 
-- 
Collection of rescue 
medication canister 
-- 
-- 
-- 
X 
-- 
X 
Subject Diary Card 
Dispensing  
-- 
X 
-- 
-- 
-- 
-- 
Placebo Administration 
(in Run-in Period) 
-- 
-- 
One 
inhalation 
two times 
daily from 
Day 1  to 
Day 14 
-- 
-- 
-- 
Subject Diary Card 
Compliance  
-- 
-- 
-- 
X 
X 
X 
Placebo administration 
compliance (Run-in- Period) 
-- 
-- 
-- 
X 
-- 
-- 
Randomization 
-- 
-- 
-- 
X 
-- 
-- 
Study Drug Dispensing  
(for Treatment period) 
-- 
-- 
-- 
X 
-- 
-- 
Study Drug Administration 
-- 
-- 
-- 
One inhalation two times daily from 
Day 15  to Day 42 


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Statistical Analysis Plan: Final 1.0 
 
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Procedure  
Screening 
Period 
 
Run-in 
Period 
Treatment Period 
End of 
Study 
-7 days 
 Day 0 
 Day 1 to 
Day 14 
 Day 15 + 1  Day 21±1  Day 42±2 
Visit  
1 
2 
-- 
3 
4 
5 
Collection of Study Drug 
Canister 
-- 
-- 
-- 
-- 
-- 
X 
Collection of Subject Diary  
-- 
-- 
-- 
-- 
-- 
X 
 
Concomitant  Medication 
Check  
X 
X 
X 
X 
X 
X 
Adverse event recording 
X 
X 
X 
X 
X 
X 
Asthma Control Test 
Questionnaire 
-- 
-- 
-- 
X 
-- 
X 
Investigator’s Global 
Evaluation 
-- 
-- 
-- 
X 
-- 
X 
 
1Medical and medication history will be performed at screening visit only. 
2General and Systemic examination includes head, neck, eye, ear, nose, throat, skin & appendages, renal, 
cardiovascular, pulmonary, reproductive, endocrine, gastrointestinal, nervous system, musculo-skeletal, 
peripheral vascular and psychiatric. 
3Vital signs include: blood pressure (supine), respiration rate, pulse rate and body temperature in 0F/0C. 
4 Haematology panel includes haemoglobin, haematocrit, white blood cell count with differential cell count, red 
blood cell count and platelets. Serum chemistry panel will include blood urea nitrogen, creatinine, albumin, 
alkaline phosphatase, total bilirubin, aspartate aminotransferase, alanine aminotransferase random blood sugar, 
sodium, potassium, and chloride. Serum pregnancy test (for females of child bearing potential) will be done at 
screening only.   
  
6. INCLUSION & EXCLUSION CRITERIA 
 
Inclusion criteria  
 
1. Adult male or female subjects of aged ≥18 to ≤ 65 years inclusive.  
2. Diagnosis of asthma as defined by the National Asthma Education and Prevention Program 
at least 12 months prior to screening.  
3. Pre-bronchodilator FEV1 of ≥ 45% and ≤ 85% of predicted value during the screening visit 
and on the first day of treatment visit.  
4. ≥15% and > 0.20 L reversibility of FEV1 within 30 minutes following 360 mcg of 
Salbutamol inhalation (pMDI) on the first day of treatment visit.  
5. Subjects with FeNO > 25 ppb at screening and on the first day of treatment visit.  
6. Subjects stable on their chronic asthma treatment regimen for at least four weeks prior to 
enrollment.  
7. Subject should able to replace current SABAs with Salbutamol inhaler for use as needed 
for the duration of the study.  
8. Subject should be able to withhold all inhaled SABAs for at least six hours prior to lung 
function assessments on study visits.  


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Statistical Analysis Plan: Final 1.0 
 
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9. Ability to discontinue their asthma medications (inhaled corticosteroids and long-acting β 
agonists) during the run-in period and for remainder of the study.  
10. Asthma patients who are stable on low dose ICS or low dose ICS+LABA or who would be 
stable with low dose ICS as per Investigator’s clinical judgement.  
11. Currently non-smoking; had not used tobacco products (i.e., cigarettes, cigars, pipe 
tobacco) within the past year, and having had ≤ 10 pack-years of historical use.  
12. Willingness to give their written informed consent to participate in the study.  
13. Subjects willing to perform all study related procedures including the use of study inhalers, 
Spirometry and willing to complete the Subject diary.  
14. Female of child-bearing potential, agreed to use a reliable method of contraception during 
study (e.g., condom + spermicide, IUD, oral, transdermal, injected or implanted hormonal 
contraceptives).   
Exclusion criteria  
 
1. Life-threatening asthma, a history of asthma episodes(s) requiring intubation, and/or 
associated with hypercapnia, respiratory arrest or hypoxic seizures, asthma related 
syncopal episode(s).  
2. Hospitalizations within the past year prior to the screening for the conditions mentioned 
in exclusion criteria No.01 or during the run-in period.  
3. Significant respiratory disease other than asthma (COPD, interstitial lung disease, etc.)  
4. Evidence or history of clinically significant disease or abnormality including congestive 
heart failure, uncontrolled hypertension  
5. Evidence or history of clinically significant disease or abnormality including 
uncontrolled coronary artery disease, myocardial infarction, or cardiac dysrhythmia.  
6. Historical or current evidence of significant hematologic, hepatic, neurologic, 
psychiatric, renal, or other diseases that, in the opinion of the investigator, would put 
the subject at risk through study participation, or would affect the study analyses if the 
disease exacerbates during the study.  
7. Viral or bacterial, upper or lower respiratory tract infection, or sinus, or middle ear 
infection within four weeks prior to the screening, during the run-in period, or on the 
day of treatment.  
8. Hypersensitivity to Beclomethasone or any of the ingredients of the formulation and 
any sympathomimetic drug (e.g., Salbutamol) or any inhaled, intranasal, or systemic 
corticosteroid therapy.  
9. Subjects receiving β2-blockers, anti-arrhythmics, anti-depressants, and monoamine 
oxidase inhibitors within 4 weeks prior to the screening.  
10. Subjects who required systemic corticosteroids (for any reason) within the past 2 
months.  
11. Clinically significant abnormalities in ECG at screening as per investigators discretion.  
12. Female subjects who are pregnant, nursing or planning a pregnancy during the study. 
13. Subjects who have participated in another investigational drug or device research study 
within 30 days of screening. 


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Statistical Analysis Plan: Final 1.0 
 
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14. Subjects who are using any medication or has any disease which in the judgment of the 
Investigator will interfere with the conduct or interpretation of the study. 
7. 
STUDY TREATMENTS 
 
• 
Group I: Investigational Product:  Beclomethasone Dipropionate Metered Dose 
Inhaler (Inhalation Aerosol) (0.04 mg/ INH); Manufactured by: Aurolife, a subsidiary 
of Aurobindo Pharma, USA, Inc., 2929 Weck Dr., Durham, NC 27709.  
 
• 
Group II: Reference Product: QVAR® 40 mcg (Beclomethasone dipropionate HFA), 
Inhalation Aerosol; Marketed by: Teva Pharmaceuticals LLC Frazer, PA 19355.  NDC 
code: 59310-202-12  
 
• 
GROUP III: PLACEBO – Manufactured by: Aurolife, a subsidiary of Aurobindo 
Pharma, USA, Inc.2929 Weck Dr., Durham, NC 27709 
 
Subjects will receive one inhalation of Study medication (either Test/ Reference/ 
Placebo) twice daily. 
 
 
7.1.  Method of Assigning Subjects to Treatment Groups 
 
This study will be double blind randomized parallel group study with three arms: Reference 
Formulation, Test Formulation, Placebo formulation. Randomization will be in 2:2:1 
proportion. The potential total enrolled sample size will be 1550 subjects [(620 (Test): 620 
(Reference): 310 (Placebo)]. The subjects will be assigned to the placebo or active groups as 
per a predetermined randomization schedule. The actual treatment given to individual subject 
will be determined by a randomization scheme prepared by third party. Randomization will be 
done after completion of placebo run in period. 
 
An IWRS (Interactive Web Response System) will be used to administer the randomization 
schedule. The programming, validation and monitoring of the randomization process by IWRS 
will be guided by the applicable SOPs of the IWRS vendor. In practice, the investigator or 
designee will use the IWRS system to receive the dosing formulation (test/reference/ placebo) 
for the subject. 
 
7.2. 
Blinding 
 
This study is double-blinded. The treatment allocation information was concealed from the 
study personnel (Principal Investigator, sponsor, and laboratory staff) and the subjects.   
 


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Statistical Analysis Plan: Final 1.0 
 
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8. Sample Size Justification 
 
Computer simulations (100,000 trials/subject number evaluated) were performed using 
Statistics101: Resampling Simulator Version 4.6 (John Grosberg, stats101@statistics101.net) 
assuming that approximately 80% of ITT subjects would also qualify as PP. The proportion of 
the trials where the 90% confidence interval on the Test-to-Reference ratio was within the 
interval 0.80 to 1.25 in the PP population was considered the power for Bioequivalence for the 
subject number evaluated. Likewise, the proportion of trials where both the Test and Reference 
means were greater than, and statistically different from (p < 0.05, 2-sided), that of the placebo 
in the mITT population was considered the power for Superiority for the subject number. The 
proportion of the trials that demonstrated both Bioequivalence in the PP population and 
Superiority in the mITT population was considered the power for study success. The results of 
these simulations are provided in the following table. Change from baseline in FEV1 for Test, 
Reference and Placebo was considered to be 0.24 L, 0.24 L and 0.05 L respectively. These 
considerations are based upon results of study 1081 mentioned in the Summary Basis of 
Approvals for QVAR®. Coefficient of Variation for Mean change from baseline in FEV1 value 
was assumed to be 115.5% of the Reference Mean. 
 
mITT subjects 
(Test: RLD: 
Placebo)  
PP Subjects**  
(Test: RLD: 
Placebo)  
Power  
Bioequivalence  
Power 
Superiority  
Power  
Study Success  
588:588:294  
(1470)  
470:470:235  
(1175)  
0.80  
>0.99  
0.80  
 
Based upon calculations shown in table above, a sample size of 1470 subjects in mITT 
population (588:588:294 subjects in Test: RLD: Placebo respectively) with 1175 in the PP 
population (470:470:235) will have 80 % power to demonstrate both bioequivalence between 
the two active treatments and to show that each of these are superior to placebo. 
Randomization schedule will be generated using appropriate software package. 
 
9. DATA COLLECTION 
 
All subject data will be captured in the subject source documents which will be transcribed to 
the eCRFs. The investigator is responsible for ensuring that study data is completely and 
accurately recorded on each subject’s eCRF, source documents, and all study-related materials. 
10. ANALYSIS POPULATIONS 
 
10.1. Safety 
  
The Safety population will include all randomized subjects who received at least one dose of 
investigational study treatment during the double blind treatment period.   
 


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Statistical Analysis Plan: Final 1.0 
 
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10.2. ITT Population 
 
All the randomized patients will be included in intent to treat population (ITT). 
 
10.3. mITT Population  
 
The mITT population will include all randomized subjects who met all inclusion/exclusion 
criteria, and received study treatment, and having at least one post baseline efficacy assessment.  
Missing efficacy results in the mITT population will be imputed using last observation carried 
forward (LOCF). The mITT population will be used to compare both test and reference 
products for superiority over placebo. 
 
10.4. Per Protocol Population  
 
The PP population will include all randomized subjects who meet all inclusion/exclusion 
criteria and are found to be compliant with the assigned study treatment, who return to the 
study site for the primary endpoint visit at 4 weeks (+/- 7 days) OR discontinue from the study 
as a treatment failure, or no clinical benefit and do not have any major protocol deviation 
impacting efficacy outcome. The PP population will be used for the bioequivalence evaluation 
of test vs. reference. Subjects who used at least 75% and no more than 125% of study treatment 
doses will be considered be compliant to study medication. Compliance will be assessed based 
upon diary data for study drug administration. Protocol deviations will be classified as major 
(impacting efficacy assessment) or minor, prior to database lock using blinded study data by 
study personnel who are not aware of treatment assignments.  
Protocol deviation classification and individual subject’s assignment to analysis population 
will be finalized before un-blinding of data. Summary of subjects with Major vs minor Protocol 
deviations will be provided along with listing.  
 
10.5. Procedure for Accounting for Missing Data 
 
Missing efficacy results in the mITT population will be imputed using last observation carried 
forward (LOCF). The mITT population will be used to compare both test and reference 
products for superiority over placebo. 
 
If subject discontinued due to lack of efficacy and does not have a post baseline value, then 
subject will be included in mITT population with baseline value carried forward.  
 
Subjects discontinued early for reasons other than lack of efficacy will be excluded from the 
PP population but included in the mITT population. Subjects discontinued early for lack of 
efficacy will be included in the PP population, using LOCF imputation for missing efficacy 
results. The PP population will be used to compare test and reference products for equivalence. 
 


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11.  GENERAL ASPECTS OF THE STATISTICAL ANALYSIS  
 
The following general rules will be followed for the analysis specified in this SAP.  
 
Quantitative variables will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, SD, median, minimum value (min), and maximum 
value (max) and coefficient of variation (CV).  
 
Qualitative variables will be summarized using counts and percentages.  
Baseline value will be defined as the last non-missing measurement (scheduled or unscheduled) 
prior to the initiation of randomized study treatment. In most cases, this will be data from  
Visit 1. 
 
Unscheduled visits: Subject data obtained during unscheduled visits/assessments will not be 
summarized but will be included in subject data listings only; except for the analysis of 
maximum values and maximum changes from baseline. Unscheduled visit values will not be 
used to impute missing scheduled visit values, except for baseline calculation.  
 
Coding: For summarization, medical history, concurrent therapies, and AEs will be coded to 
the latest versions of MedDRA and WHO Drug dictionaries, as appropriate. 
 
 
 
 
 
 
 
 
 
 


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12. STATISTICAL ANALYSIS 
 
12.1. Subject Disposition 
 
The total number of randomized subjects, subjects who completed the study, subjects who 
discontinued from the study with reason of discontinuation will be summarized by treatments 
and overall.  
Inclusion and Exclusion criteria will be presented in listing format for all subjects. 
 
12.2. Demographic and Baseline Characteristics 
 
Demographic information collected at screening will be summarized descriptively for the 
randomized population, including Box plots and frequency distributions.    
 
Variables summaries (for all data collected) will be presented. Demographic and baseline 
characteristics will also be presented by site. 
 
12.3. Protocol Deviations and Protocol Waivers 
 
Investigator will conduct this study in accordance with protocol approved by IEC and DCGI. 
 
In case of all deviations, investigator shall document all the deviations and notify same to EC 
which accorded approval for the study. 
 
 The Protocol violations list will be finalized. 
 
12.4. Analysis of Efficacy Data  
 
12.4.1. Primary Efficacy  
 
Analysis will be carried out with FEV1 original values as given below 
 
1. FEV1 values at baseline, and FEV1 EOS values will be used in the analysis 
 
Mean change in Forced Expiratory volume in 1 second (FEV 1) from baseline (visit 3) to end 
of study visit (visit 5), will be analyzed as primary end value point.  
 
Note: “Baseline morning FEV1 readings at visit 3 will be the average of pre dose highest FEV1 
values at two time points (i.e., Patient needs to perform one baseline Spirometry session with 
minimum of 3 acceptable readings and then after a gap of minimum 30 minutes, one more 
baseline session will be performed with minimum of 3 acceptable readings. Highest value from 
both the sessions will be noted. Average of both the highest readings will be considered as 
baseline FEV1 value). Sampling need to be taken on the same time (with a window period of 


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± 30 min) of day as used for first day of a 4 week treatment on the last day of a 4-week 
treatment. 
 
First 76 patients who enrolled into the study prior to protocol waiver dated 17/04/19 will not 
be considered for efficacy conclusion. Data with inclusion of 76 subjects will be provided as 
an additional information. This data will not be considered for PP population and will be 
considered in mITT population. 
 
Primary Analysis 
The primary endpoint is the change from baseline to week 4 for FEV1. The statistical 
evaluations for this endpoint are described below.  
 
Equivalence  
 
Compound Hypothesis to be tested is H0: μT / μR ≤ 0.80 or μT / μR ≥ 1.25 versus  
HA: 0.80< μT / μR< 1.25  
                                         (or) 
H01: μT - μR < -0.20 Versus HA1: -0.20 ≤   μT – μR (The lower tail)  
H02: μT - μR > 0.20 Versus   HA2:  μT – μR  ≤  0.20  (The upper tail)  
 
Where μT = mean of test treatment, and μR = mean of reference treatment  
 
Analysis of covariance (ANCOVA) will be used to evaluate the mean change in FEV1 at week 4, 
for the test and reference treatments using baseline FEV1 as a covariate and treatment and clinical 
site as factors. The 90% confidence interval will be computed based on the results from the 
ANCOVA. The 90 % confidence interval on the test-to-reference ratio must contain within the 
interval 80.00% to 125.00% for the test product to be considered equivalent to the reference 
product. 
1. When the null hypothesis H0 is rejected at 5 % level of significance bioequivalence will be 
claimed by the 90% C.I lies between 0.8 to 1.25 (for ratio) 
2.When the null Hypothesis H01 and H02 are rejected at 5% level of significance, 
bioequivalence will be claimed by the 90% C.I lies between -0.2 to 0.20 (Change Mean 
difference). 
 
Superiority  
 
Hypothesis is to be tested is 
 
H0:  μT – μP ≤ 0   
HA: μT – μP > 0 
and 
H0:  μR – μP ≤ 0   
HA: μR – μP > 0 


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where 
 μT = mean of test treatment  
μR == mean of reference treatment 
μP = mean of placebo treatment.         
 
Analysis of Covariance will be used to compare each active(test/reference) treatment with 
placebo using Baseline FEV1 as covariate and clinical site and treatment as factor. If the active 
treatment shows a greater increase in FEV1 from baseline than that for the placebo, and the 
difference between it and the placebo is statistically significant (p<0.05), and the lower limit 
of the difference should be greater than 0, then the active treatment will be considered superior 
to placebo. Superiority must be shown for both active treatments over placebo for the 
equivalence evaluation between the test and reference treatments to be considered valid.  
 
 
12.4.2. Secondary Efficacy Variables  
 
• Mean change in FeNO value from baseline (visit 1 and visit 3) to end of study visit 
(visit 5)  
• Percentage of subjects with reduction of FeNO from Baseline (visit 1 and visit 3) to 
End of Study (Visit 5)  
Descriptive Summary statistics will be presented for all secondary endpoints for active 
treatment groups. Number and percentage of subjects meeting the criteria for reduction 
(at least 20 % for FeNO ≥ 50 ppb values and at least 10 % for FeNO < 50 ppb) in FeNO 
will be presented. 
 
 
12.5. Safety Analysis  
 
All safety analysis will be run on the safety population as described in section 10.1(Safety).  
 
12.5.1. 
Adverse Events 
 
Number of events and numbers and proportions of study subjects experiencing AEs will be 
tabulated by treatment arm received and overall. AEs and SAEs will be classified according to 
the MedDRA [22.0] or upgraded version (Medical Dictionary for Regulatory Activities) 
system and summarized by system organ class and preferred term. SAEs and drug related AEs 
will also be tabulated separately by treatment arm. 
 
The proportions of subjects experiencing at least one adverse event will be compared between 
treatment arms using a Chi-square or Fisher exact test. 
AEs will be summarized for different time period:  Immediate AEs 


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o AEs will also be summarized by site. Inferential statistics will be used to compare 
proportions between treatment arms only for treatment period but not for baseline day 
0 and run in period. 
  
 
12.6. General and Systemic Examination 
 
A subject wise listing displaying abnormal results of general and systemic examination will be 
provided, displaying body system, the abnormality for the safety population. 
 
12.7. Medical History 
 
Medical history will be classified by System Organ Class (SOC) and Preferred Term (PT) for 
the mITT population and will be summarized using counts and percentages. A subject-wise 
listing of medical history will be presented. 
 
12.8. Vital Signs 
 
Descriptive statistics will be displayed for all the vital signs for the respective visits. Vital signs 
data will be summarized by presenting summary statistics of actual values and change from 
baseline values by visit. A subject-wise listing displaying results of vital signs assessments will 
also be provided. 
12.9. Prior and Concomitant Medication 
 
Subject wise Listings will be provided for Prior and concomitant medications. 
 
12.10. 12 Lead electrocardiogram & Chest X-Ray (PA View) 
A subject wise listing will be provided for abnormal 12 Lead ECG and Chest X Ray results. 
12.11. Laboratory Investigations: Hematology and Serum Chemistry Panel 
Descriptive statistics will be displayed for all the laboratory parameters for the respective visits. 
A subject wise listing will be provided for normal and abnormal laboratory parameters. 
12.12. Treatment Compliance 
 
Compliance will be assessed by the data obtained from subject diary. This will be recorded in 
the eCRF. 
 
Treatment compliance will be assessed on the basis of diary cards with following formula 
 


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Compliance will be presented as subjects who have taken approximately 75% to 125% of the 
doses of the assigned study drug. 
 
13. 
DEFINITIONS   
 
For this study, the following definitions are used: 
 
1.Screen Failures: Patients entered into the study are those from whom informed consent for 
the study has been obtained. Patients entered into the study but not assigned to a treatment 
group are considered to be screen failures.  
 
2.Randomized: Patients who are enrolled in the study are those who have been assigned to a 
treatment group.  
 
3.Multiple Comparisons and Multiplicity: 
 
There is one primary efficacy endpoint in this study, will be tested at a significance level of 
0.05. Covariate adjustments for primary endpoints will be made. 
Nominal 2-sided p-values will be reported for primary efficacy endpoint.    
 
4. Data Handling Conventions 
 
“End of treatment” will refer to the subject’s last dose visit or early termination visit. 
“End of study” will refer to the subject’s visit 5 or early termination visit. 
 
 
4.1. Early Termination and Missing Data: 
 
If possible, data for subjects who terminated the study early will be collected at the scheduled 
visit. 
 
Missing post baseline efficacy values will be imputed using last observation carried forward 
(LOCF). Missing baseline values and missing safety data will not be imputed 
 
 


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14. 
TITLES OF MOCK SHELLS            
Attached document PDF: Beclomethasone_ Mock TLFs v1 1 23-10-2019.pdf 
                                                 WORD: Beclomethasone_ Mock TLFs v1 1 23-10-2019.docx 
 
15.  
APPENDIX: ANALYSIS PRESENTATION CONVENTIONS 
 
Post-text tables and listings will be prepared in accordance with the current ICH Guidelines.  
The information and explanatory notes to be provided in the “footer” or bottom of each table 
and listing will include the following information: 
 
1. 
Date and time of output generation; 
2. 
SAS® program name, including the path that generates the output; 
3. 
Any other output specific details that require further elaboration. 
 
In general, row entries in tables are made only if data exists for at least one subject (i.e., a row 
with all zeros will not appear). The only exception to this rule applies to tables that list the 
termination status of subjects (e.g., reasons for not completing the study). In this case, zeros 
will appear for study termination reasons that no subject satisfied. The summary tables clearly 
indicate the number of subjects to which the data apply and unknown or not performed are 
distinguished from missing data. 
The treatment and subject number will be included in all data listings. All listings will be sorted 
by study treatment, subject number, and visit date, as applicable. Subject listings will also 
include the number of days relative to the initial exposure to the study drug, if applicable.   
This section details general conventions to be used for the statistical analyses. The following 
conventions will be applied to all data presentations and analyses. 
 
• The number and percentage of responses will be presented in the form XX (XX.X%). 
• All summary tables will include the analysis population sample size (ie, number of subjects). 
• Date variables will be formatted as DDMMMYYYY for presentation. 
• SAS® Version 9.4 or higher will be the statistical software package used for all data analyses, 
except for the interim analysis where SAS Version 9.1.3 or higher will be used.   
 
16. REFERENCES 
 
1. SAS Institute Inc., SAS® Version 9.4 software, Cary, NC. 
2. Protocol: CR176-17 Version 1.0, Version 1.0 Amendment 02 Dated 07.08.2019