Clinical trial NCT03015259
Conditions: Asthma
Keywords: bioequivalence
Sponsor: Kindeva Drug Delivery
Start date: 2016-12-29; Completion date: 2018-02-08
Enrollment: 1762 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized multiple-dose, placebo-controlled, parallel group design consisting of a 2-week run-in period followed by a 6-week treatment period of the placebo, Test product (Budesonide 80 mcg / Formoterol fumarate dihydrate 4.5 mcg), or Reference product Symbicort® inhalation aerosol.

Detailed description:
This is a pivotal trial that will examine therapeutic equivalence of a new generic fixed-dose combination product containing Budesonide 80 mcg / Formoterol fumarate dihydrate 4.5 mcg and reference listed drug (RLD) Symbicort® inhalation aerosol in adult patients with chronic but stable asthma as defined in National Asthma Education and Prevention Program Expert Panel Report 3 (NAEPP 3) guidelines. To ensure adequate study sensitivity the test and reference products should both be statistically superior to placebo (p\<0.05) with regard to the bioequivalent study primary endpoints.

A secondary study objective is the safety and tolerability of the test compound.

Arms: arm 1: Generic Budesonide/Formoterol Fumarate Dihydrate (80mcg/4.5mcg) Inhalation Aerosol, two inhalation twice daily, consisting of a 2-week run-in period followed by a 6-week treatment period arm 2: Symbicort (Budesonide/Formoterol Fumarate Dihydrate) Inhalation Aerosol, two inhalation twice daily, consisting of a 2-week run-in period followed by a 6-week treatment period arm 3: Placebo Inhalation Aerosol, two inhalation twice daily, consisting of a 2-week run-in period followed by a 6-week treatment period
Interventions: intervention 1: Budesonide/Formoterol fumarate dihydrate intervention 2: Symbicort intervention 3: Placebo
Intervention descriptions: intervention 1: Experimental: Treatment 1 intervention 2: Active Comparator: Treatment 2 intervention 3: Placebo Comparator: Treatment 3

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Randomized, Single-Blind, Parallel-Group, Placebo-Controlled, 
Multidose Study Comparing the Therapeutic Equivalence of a 3M Inhaler 
and a Symbicort® Reference Inhaler, Each Delivering 
Budesonide/Formoterol Fumarate (80 µg/4.5 µg) in Adult Subjects With 
Asthma 
 
Sponsor: 
3M Health Care Ltd 
xxxxx  
United Kingdom 
 
Sponsor Contact: 
xxxxx 
xxxxx 
 
Medical Monitor: 
xxxxx 
 
xxxxx 
 
24-Hour Safety Hotline 
(North America): 
 
SAE Fax Number 
(North America): 
xxxxx 
 
 
xxxxx
 
Protocol Number: 
CSP-07-000034 
Study Phase: 
Clinical Endpoint Bioequivalence Study 
Version of Protocol: 
Protocol Amendment 1, Version 2.0 
 
Date of Protocol: 
31 Oct 2016 
 
Authors: 
xxxxx 
 
IND Number: 
Not applicable 
 
 
 
         xxxxx 
 


3M 
Protocol CSP-07-000034: Amendment 1
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Declaration of Investigator 
 
I have read and understood all sections of the protocol CSP-07-000034 entitled “A 
Randomized, Single-Blind, Parallel-Group, Placebo-Controlled, Multidose Study Comparing 
the Therapeutic Equivalence of a 3M Inhaler and a Symbicort® Reference Inhaler, Each 
Delivering Budesonide/Formoterol Fumarate (80 µg/4.5 µg) in Adult Subjects With Asthma.” 
 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with Protocol Amendment 1, dated 31 Oct 2016, the International Council for 
Harmonisation guideline E6: Good Clinical Practice, and all applicable government 
regulations. I will not make changes to the protocol before consulting with 3M or implement 
protocol changes without institutional review board approval except to eliminate an 
immediate risk to subjects. I agree to administer study medication only to subjects under my 
personal supervision or the supervision of a subinvestigator. 
 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from 3M. 
 
 
 
Signature of Investigator 
Date 
 
 
 
 
 
 
Printed Name of Investigator 


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Table of Contents 
Table of Contents ....................................................................................................................... 4 
List of Tables .............................................................................................................................. 7 
Protocol Synopsis ....................................................................................................................... 8 
List of Abbreviations ................................................................................................................ 11 
1 
Introduction ....................................................................................................................... 12 
2 
Study Objectives and Endpoints ....................................................................................... 14 
3 
Investigational Plan .......................................................................................................... 15 
3.1 
Schedule of Events .................................................................................................. 15 
3.2 
Study Design ........................................................................................................... 16 
3.2.1 
Screening Visit ..........................................................................................16 
3.2.2 
Run-In Period ........................................................................................... 17 
3.2.3 
Baseline Visit ............................................................................................ 17 
3.2.4 
Telephone Contacts (Week 2 and Week 4) ............................................... 18 
3.2.5 
End-of-Treatment Visit (Week 6) ............................................................. 19 
4 
Subject Selection and Withdrawal Criteria ....................................................................... 21 
4.1 
Selection of Study Population ................................................................................. 21 
4.1.1 
Inclusion Criteria ...................................................................................... 21 
4.1.2 
Exclusion Criteria .................................................................................... 22 
4.2 
Withdrawal of Subjects From the Study.................................................................. 24 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................. 24 
4.2.2 
Handling of Withdrawals ......................................................................... 25 
5 
Study Treatments .............................................................................................................. 27 
5.1 
Method of Assigning Subjects to Treatment Groups ............................................... 27 
5.2 
Treatments Administered ......................................................................................... 27 
5.2.1 
Administration of Study Medication ........................................................ 28 
5.2.2 
Rescue Therapy ........................................................................................ 29 
5.2.3 
Inhaler Functionality ................................................................................ 29 
5.3 
Identity of Investigational Product .......................................................................... 30 
5.4 
Management of Clinical Supplies ........................................................................... 30 


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5.4.1 
Study Medication Packaging and Storage ................................................ 30 
5.4.1.1 Priming the Inhalers ................................................................................. 31 
5.4.2 
Study Medication Accountability ............................................................. 31 
5.4.3 
Retention Samples .................................................................................... 31 
5.5 
Overdose Management ............................................................................................ 32 
5.6 
Blinding ................................................................................................................... 32 
5.7 
Treatment Compliance ............................................................................................. 32 
6 
Study Assessments and Procedures .................................................................................. 33 
6.1 
Efficacy Assessments .............................................................................................. 33 
6.2 
Safety Assessments .................................................................................................. 35 
6.2.1 
Handheld Device for Home Use .............................................................. 35 
6.2.2 
Asthma Exacerbation ............................................................................... 36 
6.2.3 
Adverse Events ......................................................................................... 37 
6.2.3.1 Definitions of Adverse Events .................................................................. 37 
6.2.3.2 Eliciting and Documenting Adverse Events ............................................ 39 
6.2.3.3 Reporting Adverse Events ........................................................................ 39 
6.2.3.4 Assessment of Severity ............................................................................ 40 
6.2.3.5 Assessment of Causality .......................................................................... 40 
6.2.3.6 Follow-Up of Subjects Reporting Adverse Events ................................... 41 
6.2.4 
Concomitant Medications ........................................................................ 42 
6.2.5 
Physical Examination and Vital Signs ..................................................... 42 
6.2.6 
Electrocardiogram .................................................................................... 42 
6.3 
Laboratory Analyses ................................................................................................. 43 
6.4 
Pregnancy ................................................................................................................ 44 
7 
Statistical Considerations .................................................................................................. 45 
7.1 
Endpoints ................................................................................................................. 45 
7.1.1 
Primary Efficacy Endpoints ..................................................................... 45 
7.1.2 
Safety Endpoint ........................................................................................ 45 
7.2 
Sample Size Calculations ......................................................................................... 46 
7.2.1 
Equivalence .............................................................................................. 46 
7.2.2 
Superiority ................................................................................................ 47 
7.3 
Analysis Sets ........................................................................................................... 48 
7.4 
Description of Subgroups to be Analyzed ............................................................... 49 


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7.5 
Statistical Analysis Methodology ............................................................................ 49 
7.5.1 
Analysis of Primary Efficacy Endpoint.................................................... 49 
7.5.1.1 Equivalence .............................................................................................. 49 
7.5.1.2 Superiority ................................................................................................ 50 
7.5.2 
Safety Analyses ........................................................................................ 51 
7.5.3 
Other Analyses ......................................................................................... 51 
7.5.4 
Blinded Sample Size Re-estimation ......................................................... 51 
7.5.5 
Interim Analysis ....................................................................................... 52 
7.6 
Data Quality Assurance ........................................................................................... 52 
7.6.1 
Data Management .................................................................................... 52 
8 
Ethics ................................................................................................................................ 53 
8.1 
Independent Ethics Committee or Institutional Review Board ............................... 53 
8.2 
Ethical Conduct of the Study .................................................................................. 53 
8.3 
Subject Information and Consent ............................................................................ 54 
9 
Investigator’s Obligations ................................................................................................. 55 
9.1 
Confidentiality ......................................................................................................... 55 
9.2 
Financial Disclosure and Obligations ...................................................................... 55 
9.3 
Investigator Documentation .................................................................................... 56 
9.4 
Study Conduct ......................................................................................................... 56 
9.5 
Adherence to Protocol ............................................................................................. 57 
9.6 
Adverse Events and Study Report Requirements .................................................... 57 
9.7 
Investigator’s Final Report. ..................................................................................... 57 
9.8 
Records Retention ................................................................................................... 57 
9.9 
Publications ............................................................................................................. 57 
10 Study Management ........................................................................................................... 59 
10.1 Monitoring ............................................................................................................... 59 
10.1.1 
Monitoring of the Study ........................................................................... 59 
10.1.2 
Inspection of Records ............................................................................... 59 
10.2 Management of Protocol Amendments and Deviations .......................................... 59 
10.2.1 
Modification of the Protocol .................................................................... 59 
10.2.2 
Protocol Deviations .................................................................................. 60 


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10.3 Study Termination ................................................................................................... 60 
10.4 Final Report ............................................................................................................. 61 
11 References ......................................................................................................................... 62 
12 Appendices ....................................................................................................................... 63 
12.1 Appendix 1: Allowed and Disallowed Medications ................................................ 63 
12.2 Appendix 2: Contraception ...................................................................................... 64 
12.2.1 
Females of Non-childbearing Potential .................................................... 64 
12.2.2 
Females of Childbearing Potential ........................................................... 65 
12.3 Protocol Amendments ............................................................................................. 66 
12.3.1 
Protocol Amendment 1 Summary of Changes ......................................... 66 
 
 
List of Tables 
Table 6–1 
Laboratory Assessments .................................................................................. 44 
 
Table 7–1 
Sample Size Calculations for Equivalence ...................................................... 47 
Table 7–2 
Sample Size Calculations for Superiority ....................................................... 48 


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Protocol Synopsis 
Protocol Number: 
CSP-07-000034 
Title: 
A 
Randomized, 
Single-Blind, 
Parallel-Group, 
Placebo-Controlled, Multidose Study Comparing the 
Therapeutic Equivalence of a 3M Inhaler and a Symbicort® 
Reference Inhaler, Each Delivering Budesonide/Formoterol 
Fumarate (80 µg/4.5 µg) in Adult Subjects With Asthma 
Sponsor: 
3M Health Care Ltd (3M) 
Study Phase: 
Clinical Endpoint Bioequivalence Study 
Study Centers Planned: 
Approximately xxx study centers in the United States 
Number of Subjects 
Planned: 
Estimated Study 
Duration: 
Approximately 1470 adult subjects with asthma 
 
Each subject is expected to be in the study for approximately 8 
to 10 weeks, which includes screening, a 2-week run-in period, 
and a 6-week treatment period. It is expected that the total 
duration of the study will be approximately 9 to 12 months. 
Rationale: 
The 3M Inhaler is being developed as a generic equivalent of the 
Symbicort® Reference Inhaler (80 µg /4.5 µg in order to provide 
a choice for patients, prescribers, and payers. 
Objectives: 
The primary objectives of this study are as follows: 
 To demonstrate the equivalence of the 3M Inhaler compared 
with a Symbicort Reference Inhaler in delivering 
budesonide/formoterol fumarate (80 µg/4.5 µg) 
 To demonstrate the superiority of the 3M Inhaler and the 
Symbicort Reference Inhaler compared with placebo 
 
 
The safety object of this study is as follows: 
 To assess the safety of the 3M Inhaler compared with a 
Symbicort Reference Inhaler in delivering 
budesonide/formoterol fumarate (80 µg/4.5 µg) and 
compared with placebo 


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Efficacy Endpoints: 
 
Change from baseline in the area under the concentration-time 
curve of forced expiratory volume in 1 second (FEV1) from zero up 
to 12 hours (AUC0-12) at Day 1 
 Change from baseline in FEV1 measured in the morning at the 
end-of-treatment visit 
Safety Endpoints: 
 
Number (percent), severity, and relatedness of adverse 
events (AEs) and serious adverse events 
Subject Population: 
Adult male or female subjects ≥18 years of age with a diagnosis of 
asthma, as defined by the National Asthma Education and Prevention 
Program, for at least 6 months. Subjects will have moderate-to-severe 
asthma with a pre-bronchodilator FEV1 of ≥45% and ≤85% of predicted 
normal at least 6 hours after receiving a short-acting β2 agonist (SABA), 
as well as ≥15% reversibility of FEV1 (14.5% to 14.99% will be rounded 
to 15%) and ≥0.20 L increase within 30 minutes following the 
administration of albuterol 360 µg. Chronic medications must be stable 
and subjects must be currently nonsmoking. Subjects must also be able 
and willing to perform peak expiratory flow assessments and enter diary 
information. 
Study Design: 
This is a randomized, single-blind, parallel-group, placebo-
controlled, multidose study consisting of a 2-week run-in period 
followed by a 6-week treatment period using budesonide/formoterol 
delivered by the 3M Inhaler or the Symbicort Reference Inhaler and 
compared with placebo. Subjects will visit the study center at a 
screening, baseline, and end-of-treatment visits, and they will receive 
telephone contacts after 2 weeks and after 4 weeks of study treatment. 
Efficacy Assessment: 
Efficacy will be assessed via spirometry. Each subject will  
undergo spirometry assessments at the screening, baseline, and 
end-of-treatment/Week 6 visits. 
Safety Assessment: 
Safety will be assessed via AEs (seriousness, number [percent], 
severity, and relatedness). 


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Study Medication, 
Dosage, and Route of 
Administration: 
During the run-in period, study medication will consist of a run- 
in (placebo) inhaler. During the treatment period, study 
medication will include randomized treatment with either a 
metered-dose inhaler containing a combination of budesonide 
(80 µg) and formoterol (4.5 µg) using the 3M Inhaler or the 
Symbicort Reference Inhaler, or a metered-dose inhaler 
containing placebo. Regardless of treatment, study medication 
will be administered as 2 inhalations each given twice daily 
(morning and evening, approximately 12 hours apart). 
Statistical Methods: 
Statistical analysis will be performed using SAS® software 
Version 9.2 or later. 
Summary statistics of the data collected will be provided by 
treatment (3M Inhaler, Symbicort Reference Inhaler, and 
placebo). Continuous variables will be summarized using the 
mean, SD, coefficient of variance, median, minimum value, and 
maximum value. Categorical variables will be summarized using 
frequency counts and percentages. Data will be listed in data 
listings. 
Details of the statistical analyses, methods, and data conventions 
will be further described in the statistical analysis plan. 
Date of Protocol: 
31 Oct 2016 


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Abbreviation 
Definition 
List of Abbreviations 
 
 
3M 
3M Health Care Ltd 
AE 
adverse event 
AUC0-12 
area under the concentration-time curve from zero up to 12 hours 
CFR 
Code of Federal Regulations 
CV 
coefficient of variance 
CYP 
cytochrome P450 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
HFA 
hydrofluoroalkane 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IRB 
institutional review board 
xxx 
LABA 
long-acting  agonist 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAEPP 
 National Asthma Education and Prevention Program 
xxx 
xxx 
 
pMDI 
pressurized metered-dose inhaler 
PPS 
per-protocol set 
SABA 
short-acting 2 agonist 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


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1 
Introduction 
Asthma is a common respiratory disease. It is characterized by chronic airway inflammation 
leading to airflow obstruction with symptoms such as breathlessness, cough, impairment of 
physical activity, and potentially death. Prevalence data in the United States between 2001 
and 2010 indicated an overall increase in asthma during the period [Akinbami, 2012], and by 
2014, there were 24 million people with asthma [CDC, 2016]. 
 
Inhaled corticosteroids have been widely used as a safe and effective anti-inflammatory 
therapy for the treatment of persistent asthma for many years. Inhaled corticosteroids are 
recommended as the maintenance treatment of choice in treatment guidelines (ie, Global 
Initiative for Asthma [GINA] and the National Heart, Lung, and Blood Institute National 
Asthma Education and Prevention Program [NAEPP]) in all but patients with mild 
intermittent asthma whose symptoms are adequately maintained on short-acting β2 agonists 
(SABAs) alone [GINA, 2016; NAEPP, 2007]. 
 
Long-acting β agonists (LABAs) have also been widely used as safe and effective 
bronchodilator therapy for the treatment of persistent asthma for many years, and they are 
also recommended as a maintenance therapy in conjunction with inhaled corticosteroids 
[GINA, 2016; NAEPP, 2007] for patients with moderate to severe asthma who remain 
symptomatic despite low-dose inhaled corticosteroids and SABAs (as needed). 
 
Symbicort® is approved by the US Food and Drug Administration (FDA) as a combination 
product containing a corticosteroid and a LABA and is indicated for the treatment of asthma 
patients 12 years of age and older and for the maintenance treatment of airflow obstruction in 
patients with chronic obstructive pulmonary disease including chronic bronchitis and 
emphysema. It is not indicated for the relief of acute bronchospasm. It is available as a 
pressurized metered-dose inhaler (pMDI) containing a combination of budesonide (80 or 
160 µg) and formoterol (4.5 µg) as an inhalation aerosol and is administered as 2 inhalations 
twice daily (morning and evening, approximately 12 hours apart) [Symbicort, 2016]. 
 
3M Health Care Ltd (3M) is developing a drug product (3M Inhaler) that is a pMDI 
containing a combination of budesonide (80 µg) and formoterol (4.5 µg) as an inhalation 
aerosol. The 3M Inhaler is expected to be equivalent to the currently available Symbicort 
(referred to in this protocol as Symbicort Reference Inhaler) in terms of reproducibility of 
delivery of both emitted and respirable dose of medication. The 3M Inhaler is being 


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developed as a generic equivalent of the Symbicort Reference Inhaler in order to provide a 
choice for patients, prescribers, and payers. 
 
This study was designed in accordance with the FDA guidance on budesonide/formoterol 
fumarate dihydrate [FDA, 2015], and this clinical endpoint study is intended to establish 
bioequivalence between the 3M Inhaler and the Symbicort Reference Inhaler. 


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2 
Study Objectives and Endpoints 
 
Objectives 
Endpoints 
The primary objectives of this study are as 
follows: 
 
 To demonstrate the equivalence of the 
3M Inhaler compared with a Symbicort 
Reference Inhaler in delivering 
budesonide/formoterol fumarate 
(80 µg/4.5 µg) 
 
 To demonstrate the superiority of the 3M 
Inhaler and the Symbicort Reference 
Inhaler compared with placebo 
 
 
 
 
Change from baseline in the area under 
the concentration-time curve of forced 
expiratory volume in 1 second (FEV1) 
from zero up to 12 hours (AUC0-12) at 
Day 1 
 
 
Change from baseline in FEV1 measured 
in the morning at the end-of-treatment 
visit 
The safety object of this study is as follows: 
 
 To assess the safety of the 3M Inhaler 
compared with a Symbicort Reference 
Inhaler in delivering 
budesonide/formoterol fumarate 
(80 µg/4.5 µg) and compared with 
placebo 
 
 
 
Number (percent), severity, and 
relatedness of adverse events (AEs) and 
serious adverse events (SAEs) 


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3 
Investigational Plan 
3.1 
Schedule of Events 
 
 
Procedure 
Screening 
Visit1 
Baseline 
Visit 
Telephone 
Contacts 
End of 
Treatment 
 
Visit Day/Window 
-21 days to 
-14 days 
Day 1 
(12-hour visit) 
Day 14
2 days 
Day 282
2 days 
Day 42
2 days 
Informed consent
X
 
 
 
 
Medical history
X
 
 
 
 
Demographics
X
 
 
 
 
Electrocardiogram
X
 
 
 
 
Safety laboratory assessment 
(obtained locally)
X 
 
 
 
X 
Physical examination (with height 
[screening only] and weight)
X 
 
 
 
X 
Pregnancy test3
X
X
 
 
X
Vital sign (blood pressure and 
heart rate) assessments
X 
X 
 
 
X 
Spirometry assessments4
X
X
 
 
X
Inclusion/exclusion criteria 
review
X 
X 
 
 
 
Randomization xxx
 
X
 
 
 
Inhaler training
X
X
 
 
 
Dispense run-in period inhaler
X
 
 
 
 
Dispense rescue therapy inhaler5
X
X
 
 
 
Dispense study medication
 
X
 
 
 
Concomitant medications
X
X
X
X
X
Adverse event monitoring
X
X
X
X
X
Training xxx 
X 
 
 
 
 
Study medication compliance and 
diary monitoring (retraining, as 
needed) 
 
X 
X 
X 
 
Diary collection
 
 
 
 
X
1 Following the screening visit, there will be 14- to 21-day run-in period. If needed, subjects can also rescreen. 
See Section 3.2 for additional details on the run-in period and on rescreening. 
2 At the Day 28 (Week 4) visit, subjects will be instructed to switch to the second inhaler beginning with the 
evening dose on the day of the telephone visit. Subjects will be reminded not to take study medication 
within 12 hours (±2 hours) of the start time of their end-of-treatment visit. 
3 For females of childbearing potential only, a urine pregnancy test must be conducted at the screening and 
baseline visits, and a serum pregnancy test must be obtained at the screening and end-of-treatment visits. 
See Appendix 2 for a definition of childbearing potential. 
4 See Section 6.1 for details on each spirometry assessment. 
5 Ensure that the subject has enough rescue therapy (see Section 5.2.2) for the remainder of the study. 


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3.2 
Study Design 
This is a randomized, single-blind, parallel-group, placebo-controlled, multidose study 
consisting of a 2-week run-in period followed by a 6-week treatment period using 
budesonide/formoterol delivered by the 3M Inhaler or the Symbicort Reference Inhaler and 
compared with placebo. Subjects will visit the study center at a screening, baseline, and 
end-of-treatment visits, and they will receive telephone contacts after 2 weeks and after 
4 weeks of study treatment. 
 
3.2.1 Screening Visit 
Subjects will undergo the procedures outlined in the Schedule of Events (Section 3.1). 
 
Two spirometry assessments will occur at the screening visit and must be conducted between 
0400 and 1100 (ie, 4:00 AM and 11:00 AM) (see Section 6.1). Subjects cannot have taken a 
LABA within 24 hours of the spirometry assessment and they cannot have taken rescue 
medication within 6 hours of the spirometry assessment; if these requirements are not met, 
the visit must be rescheduled. If a subject does not meet the spirometry assessment criteria 
outlined in the inclusion criteria (see Section 4.1.1), a repeat spirometry assessment may 
occur within 7 days. The repeat assessment must be conducted at the same time of day 
(±1 hour) as the original spirometry screening assessment. Subjects who meet the spirometry 
requirements upon repeat testing can enter the run-in period (provided they meet all other 
inclusion criteria and none of the exclusion criteria). Additional screening assessments 
outlined in the Schedule of Events do not need to be repeated if they were performed within 
the past 7 days. 
 
Subjects who consent to participate and who meet the entry criteria will enter the run-in 
period. This run-in period will be used to washout prestudy medications and to establish an 
FEV1 baseline value. See Appendix 1 for a complete list of washout medications and the 
required washout period for each. Some medications (such as immunosuppressive therapy) 
require more than 14 days of washout. If more than 21 days of washout are needed, subjects 
will be considered a screen failure. However, subjects who have failed screening due to the 
need for an extended medication washout may be subsequently rescreened 1 additional time. 
 
During the screening visit, subjects will be given instructions on how to use the run-in period 
inhaler, and subjects will be informed that compliance to the run-in period inhaler schedule 


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will be checked at the baseline visit. Subjects will also be observed and trained until they are 
able to use the run-in medication properly. Subjects will take home a run-in period inhaler for 
use during the run-in period. 
 
Subjects will be given a SABA inhaler (see Section 5.2.2) to be used throughout the study as 
rescue therapy for the treatment of acute episodes of bronchospasm or shortness of breath. In 
addition, xxx collect diary information twice daily (at home), in the morning and in the 
evening, approximately 12 hours apart, throughout the study (see 
Section 6.2.1). Subjects will be observed to ensure that they are able to use the device 
properly. 
 
3.2.2 Run-In Period 
The run-in period will be 14 to 21 days in duration, depending on the washout needs of each 
subject. During the run-in period, subjects will receive a run-in period (placebo) inhaler from 
which they will administer 2 inhalations twice daily (morning and evening, approximately 
12 hours apart). They will xxx collect diary information twice daily throughout the run-in 
period. 
 
3.2.3 Baseline Visit 
Following the run-in period, subjects will come to the clinic for a baseline visit that will 
include 12 hours of serial spirometry assessments; the first predose baseline assessment (ie, 
30 minutes before dosing) must begin between 0400 and 1100 (ie, 4:00 AM and 11:00 AM). 
Note: When setting the start time for the baseline visit, consider that not only does the 
baseline visit include 12 hours of serial spirometry testing but also that the spirometry 
assessment during the end-of-treatment visit must occur within 1 hour from the first predose 
baseline spirometry assessment (ie, 30 minutes before initial dosing). 
 
Subjects will be instructed to not use the run-in period inhaler on the day of the baseline visit 
and, if possible, to not take rescue medication within 6 hours of the start of the baseline visit; 
if a subject is unable to withhold rescue medication, the visit must be rescheduled. 
 
Prior to randomization, study center personnel will calculate compliance with the run-in 
period inhaler schedule using xxx  number of run-in period inhalations used as well as the 
number of rescue therapy inhalations xxx  Study medication, diary, and  


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compliance re-education should be provided as needed. xxxxx 
 
Prior to randomization, the study center personnel must review the inclusion and exclusion 
criteria, as appropriate, to confirm that each subject qualifies to continue in the study. This 
includes performing 2 pulmonary function tests 30 minutes apart to assess FEV1 (see 
Section 6.1). 
 
Qualified subjects will be randomized xxx in a 3:3:1 ratio to receive the 3M Inhaler, the 
Symbicort Reference Inhaler, or placebo, respectively. Following randomization, subjects 
will undergo the procedures outlined in the Schedule of Events (Section 3.1). 
 
Subjects will be given instructions on how to use the treatment period inhalers, xxx. Subjects 
will also be observed to ensure that they are able to use the study medication properly, and 
re-education will be provided as necessary. 
 
3.2.4 Telephone Contacts (Week 2 and Week 4) 
There will be 2 separate telephone contacts during this study to assess safety and determine if 
the subject has had any new AEs, changes to ongoing AEs (including discontinuation or 
exacerbation of an AE), or changes to their concomitant medications, whether or not the 
changes were recorded in the diary. If a subject indicates that changes occurred but were not 
recorded in the diary, the study center personnel will re-educate the subject on capturing 
information in the diary. 
 
The first telephone contact will occur at Week 2 (Day 14 ± 2 days), and the second telephone 
contact will occur at Week 4 (Day 28 ± 2 days). At the baseline visit, subjects will be given 2 
canisters of study medication, clearly labeled as Canister 1 and Canister 2, based on their 
randomized treatment (3M Inhaler, Symbicort Reference Inhaler, or placebo). Subjects will use 
Canister 1 until the Week 4 telephone call visit. At the Week 4 telephone visit, subjects will be 
instructed to switch to Canister 2 beginning with the evening dose on the day of the telephone 
visit and use that canister for the remainder of the study. (If a subject needs to switch to 
Canister 2 for any reason prior to the Week 4 telephone contact, the subject must notify study 
center personnel so that study medication compliance can be calculated correctly.) 
 
Subjects will also be reminded that no study medication should be taken within 12 hours 
(±2 hours) of the start time of their end-of-treatment visit. 


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3.2.5 End-of-Treatment Visit (Week 6) 
Following 6 weeks of treatment, subjects will come into the clinic for an end-of-treatment 
visit (Day 42 ± 2 days). At the end-of-treatment visit, subjects will have 2 spirometry 
assessments. The first spirometry assessment will be conducted at the same time of day 
(±1 hour) as the first predose baseline spirometry assessment (ie, 30 minutes before initial 
dosing); the second spirometry assessment will be performed 30 minutes (±5 minutes) later. 
 
Subjects will be instructed not to take study medication within 12 hours of the start of their 
end-of-treatment visit and not to take rescue medication within 6 hours of the start of the 
visit. If a subject is unable to withhold rescue medication or inadvertently took study 
medication within 12 hours of the start of their end-of-treatment visit, the visit must be 
rescheduled. Subjects will undergo the procedures outlined in the Schedule of Events 
(Section 3.1). 
 
Subjects must bring both canisters of study medication so that study center personnel can 
confirm study medication compliance. Study center personnel will also review the diary 
information and speak with the subject to determine if the subject has had any new AEs, 
changes to ongoing AEs (including discontinuation or exacerbation of an AE), or changes to 
their concomitant medications, whether or not the changes were recorded in the diary. 
 
Subjects who discontinue the study early will attend the end-of-treatment visit upon 
termination. Any ongoing SAE or AE that led to study discontinuation will continue to be 
followed up after the end-of-treatment visit until satisfactory resolution, the investigator 
deems the event to be chronic or not clinically significant, or the subject is considered to 
be stable. 
 
This study will be considered complete when the last subject has completed the last 
end-of-treatment visit or additional AE follow-up as necessary. 


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4 
Subject Selection and Withdrawal Criteria 
 
4.1 
Selection of Study Population 
Approximately 1470 adult subjects with asthma will be enrolled at approximately xxx study 
centers in the United States. Subjects will be assigned to study treatment only if they meet all 
of the inclusion criteria and none of the exclusion criteria. Deviations from the inclusion and 
exclusion criteria are not allowed because they can potentially jeopardize the scientific 
integrity of the study, regulatory acceptability, or subject safety. Therefore, adherence to the 
criteria as specified in the protocol is essential. 
 
Each subject is expected to be in the study for approximately 8 to 10 weeks, which includes 
screening, a 2-week run-in period, and a 6-week treatment period. It is expected that the total 
duration of the study will be approximately 9 to 12 months. 
 
4.1.1 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
 
1. Is capable of understanding the written informed consent, provides signed and witnessed 
written informed consent, and agrees to comply with protocol requirements 
 
2. Is a male or female 18 years of age 
 
3. If female, is of non-childbearing potential or of childbearing potential and committed to 
consistent and correct use of an acceptable method of birth control (see Appendix 2 for 
additional information on contraception) 
 
4. Has been diagnosed by a physician to have asthma, as defined by the NAEPP [NAEPP, 
2007] at least 6 months prior to screening for study participation 
 
5. Has moderate-to-severe asthma with a prebronchodilator FEV1 of ≥45% and ≤85% of 
predicted normal, measured at least 6 hours after receiving a SABA and at least 24 hours 
after the last dose of a LABA, at the screening and baseline visits 
 
6. Has ≥15% reversibility of FEV1 (14.5% to 14.99% will be rounded to 15%) and ≥0.20 L 
increase within 30 minutes following the administration of albuterol 360 µg delivered via 
a pMDI with a spacer (see Section 6.1) 
 
 


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7. Has stable asthma control on a chronic asthma treatment regimen (mono- or combination 
therapy) for at least 4 weeks prior to the screening visit 
 
8. Is currently nonsmoking; has not used tobacco products (ie, cigarettes, cigars, pipe 
tobacco, E-cigarettes, other inhaled nicotine) within the past year, and has less than 10 
pack-years of historical use 
 
9. Is able to replace current regularly scheduled SABA with albuterol hydrofluoroalkane 
(HFA) pMDI 90 µg for use only on an as-needed basis for the duration of the study 
(subjects should be able to withhold all inhaled SABAs for at least 6 hours prior to lung 
function assessments on study visit days) 
 
10. Is willing to discontinue current asthma medications (inhaled corticosteroids and 
LABAs), as well as the prohibited medications listed in Appendix 1, during the run-in 
period and for the remainder of the study 
 
11. Is able and willing to xxx enter diary information twice daily (at home) with a handheld 
device. 
 
4.1.2 
Exclusion Criteria 
A subject meeting any of the following criteria will be excluded from the study: 
 
1. If female, is pregnant or lactating/breastfeeding, as well as those not postmenopausal 
(no menses for the previous 24 months), surgically sterile, or practicing an effective 
method of birth control (see Appendix 2 for additional information on contraception) 
 
2. Has life-threatening asthma, defined as a history of asthma episode(s) requiring 
intubation, and/or associated with hypercapnoea, respiratory arrest or hypoxic 
seizures, asthma-related syncopal episode(s), emergency room/urgent care clinic visit, 
or hospitalizations within the past year or during the run-in period 
3. Has significant respiratory disease other than asthma (eg, chronic obstructive 
pulmonary disease, interstitial lung disease, etc.) 
 
4. Has evidence or history of a clinically significant cardiovascular disease or 
abnormality, including congestive heart failure, uncontrolled hypertension, 
uncontrolled coronary artery disease, myocardial infarction, or cardiac dysrhythmia 
 
5. Has historical or current evidence of clinically significant hematologic, hepatic, 
neurologic, psychiatric, renal, or other diseases that, in the opinion of the investigator, 


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would put the subject at risk through study participation, or would affect the study 
analyses if the disease exacerbated during the study 
 
6. Has required systemic corticosteroids (for any reason) within the past 4 weeks or 
during the run-in period 
 
7. Is hypersensitive to any sympathomimetic drug (eg, formoterol or albuterol); any 
inhaled, intranasal, or systemic corticosteroid therapy; or any excipients in the study 
medication (including HFA, povidone, and polyethylene glycol) 
 
8. Is currently receiving  blockers 
 
9. Has a current diagnosis or history of hepatitis B, hepatitis C, or human 
immunodeficiency virus as determine by laboratory testing at Screening, or active 
tuberculosis as determined by medical history and physical examination 
 
10. Is currently smoking, has had tobacco products within the last year, or has a tobacco 
smoking history of 10 pack-years or more 
 
11. Currently smokes marijuana or has used marijuana within the previous 30 days prior 
to screening 
 
12. Has evidence of a viral or bacterial upper or lower respiratory tract infection, or sinus 
or middle ear infection within 4 weeks of screening 
 
13. Has untreated oropharyngeal candidiasis at the screening visit 
 
14. Has a history of alcohol or drug abuse within the year prior to screening 
 
15. Has had treatment with any other investigational drug within 5 half-lives (if known), 
otherwise a minimum of 30 days prior to screening, or has any plans to participate in 
another investigational drug study at any time during this study 
 
16. Has been treated with any known strong cytochrome P450 (CYP) 3A4 inhibitors (eg, 
ketoconazole, ritonavir, clarithromycin) within 30 days before the screening visit, or 
plans to be treated with any strong CYP3A4 inhibitor during study participation 
 
17. Is an employee or family member of the investigator or study center personnel 


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18. Has any condition or other factor that in the investigator’s opinion may limit 
compliance to study procedures, dosing intervals, or study visits 
 
19. Has previously been randomized in 3M study CSP-07-000034 
 
4.2 
Withdrawal of Subjects From the Study 
The duration of the study is defined for each subject as the date signed written informed 
consent is provided through the end-of-treatment visit (or the last follow-up visit if the 
subject is withdrawn due to an AE; see Section 6.2.3.6). If a subject is withdrawn from the 
study due to an AE, the event will be followed up after the end-of-treatment visit until 
satisfactory resolution, the investigator deems the event to be chronic or not clinically 
significant, or the subject is considered to be stable; this follow-up is also required for SAEs. 
 
4.2.1 
Reasons for Withdrawal/Discontinuation 
Subjects may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study center. Every effort should be 
made to keep subjects in the study. The reasons for subjects not completing the study will be 
recorded. A subject may be withdrawn from the study for any of the following reasons: 
 
1. The subject does not meet the protocol inclusion or exclusion criteria 
 
2. The subject demonstrates noncompliance to the protocol, including during the run-in 
period 
3. A serious or intolerable AE that in the investigator’s opinion requires withdrawal from 
the study. (Upon the occurrence of a serious or intolerable AE, the investigator must 
confer with the medical monitor) 
 
4. Symptoms or an intercurrent illness not consistent with the protocol requirements or 
that justifies withdrawal, including significant respiratory tract infection or 
exacerbation of asthma symptoms severe enough to warrant additional medications 
 
5. The subject is lost to follow-up 
 
6. Other (eg, pregnancy, development of contraindications of use of study medication) 
 


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7. The subject withdraws consent or the investigator or sponsor decides to discontinue 
the subject’s participation in the study 
 
8. 3M terminates the study 
 
4.2.2 
Handling of Withdrawals 
Subjects are free to withdraw from the study at any time upon request. Subject participation 
in the study may be stopped at any time at the discretion of the investigator or at the request 
of the sponsor. If study medication is permanently stopped by the subject or investigator (ie, 
no additional study medication will be taken by the subject), the subject will be removed 
from the study. 
 
When a subject withdraws from the study, the reason(s) for withdrawal must be recorded in 
the electronic case report form (eCRF). Whenever possible, all subjects who withdraw from 
the study prematurely will undergo all end-of-treatment assessments (see Section 3.1). 
Subjects who fail to return for final assessments will be contacted by the study center in an 
attempt to have them comply with the protocol. 
 
If a subject does not return for a scheduled visit, every effort will be made to contact the 
subject. This follow-up will include 2 documented telephone calls from the study center 
personnel to the subject, followed by 1 registered letter requesting that the subject contact the 
study center to complete all follow-up procedures. 
The investigator will inquire about the reason for withdrawal, request that the subject return 
all study medication, request that the subject return for a final visit, and subsequently follow 
up with the subject on any unresolved AE. It is vital to obtain follow-up data on any subject 
withdrawn because of an AE. 


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5 
Study Treatments 
 
5.1 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomly assigned to receive budesonide/formoterol fumarate 
(80 µg/4.5 µg) via a 3M Inhaler, budesonide/formoterol fumarate (80 µg/4.5 µg) via a 
Symbicort Reference Inhaler, or placebo using a 3:3:1 allocation ratio. xxx. 
 
5.2 
Treatments Administered 
The 3M Inhaler, the Symbicort Reference Inhaler, and placebo inhalers (for both the run-in 
and treatment periods) will be supplied by 3M or its designee. The run-in period inhalers will 
be shipped in a separate box clearly labeled for use during the run-in period. Study center 
personnel must not dispense placebo inhalers from the treatment box in place of the run-in 
period inhalers and must not dispense the run-in period inhalers during the treatment period. 
 
The following treatments will be administered during the study: 
 
 Placebo via a placebo inhaler (over the 2-week run-in period, 2 inhalations twice 
daily) 
 
 Budesonide/formoterol fumarate (80 µg/4.5 µg) via the 3M Inhaler (over the 6-week 
treatment period, 2 inhalations twice daily) 
 
 Budesonide/formoterol fumarate (80 µg/4.5 µg) via the Symbicort Reference Inhaler 
(over the 6-week treatment period, 2 inhalations twice daily) 
 
 Placebo via a placebo inhaler (over the 6-week treatment period, 2 inhalations twice 
daily) 
 
Subjects will be instructed to rinse their mouths with water without swallowing after study 
medication administration in the morning and in the evening. 
Of note, the 3M Inhaler and the Symbicort Reference Inhaler include formoterol, a LABA, as 
an active ingredient. Clinical studies have shown that LABA medicines such as formoterol 
increase the risk of death from asthma complications. It is not known whether budesonide, 
the other active ingredient in the 3M Inhaler and the Symbicort Reference Inhaler, reduces 
the risk of death from asthma complications seen with formoterol. 


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5.2.1 
Administration of Study Medication 
Symbicort is an FDA-approved medication, and administration information can be found in 
the package insert [Symbicort, 2016]. 
 
At the screening visit, subjects will be provided with detailed instructions on how to 
administer the study medication. They will demonstrate to study center personnel their ability 
to correctly use the product. During the 2-week run-in period, subjects will use a run-in 
(placebo) inhaler. The first run-in dose will be administered at the study center at the end of 
the screening visit. 
 
For the day of the baseline visit, subjects will be instructed not to take their morning dose 
from the run-in (placebo) inhaler prior to attending the visit. At the baseline visit, eligible 
subjects will receive 2 canisters of study medication, clearly labeled as Canister 1 and 
Canister 2, with randomized treatment after the first (predose) spirometry assessment. 
Subjects will take their morning dose on the first day of treatment in the presence of study 
center personnel. The evening dose of study medication on the day of the baseline visit will 
be taken 12 hours after the morning dose. 
 
All subsequent doses of study medication will be taken in the morning and evening during 
the 6-week study period. Subjects will be instructed to take their medication around the same 
time each day with approximately 12 hours between doses. If a subject misses a dose, the 
dose may be taken late if it is within 6 hours of the target time of the missed dose and at least 
6 hours from the target time of the next dose (ie, doses cannot be taken less than 6 hours 
apart). 
 
Subjects will take study medication as directed from Canister 1 until the telephone contact 
visit at Week 4, at which point they will be instructed to switch to Canister 2, beginning with 
the evening dose on the day of the telephone visit, and they will use Canister 2 for the 
remainder of the study. (If a subject needs to switch to Canister 2 for any reason prior to the 


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Week 4 telephone contact, the subject must notify study center personnel so that study 
medication compliance can be calculated correctly.) 
 
The last dose of study medication will be the day before the end-of-treatment visit. When 
subjects are contacted for the Week 4 telephone visit, they will be reminded that no study 
medication should be taken within 12 hours (±2 hours) of the start time of their 
end-of-treatment visit and to bring back both canisters to the study center for their visit. 
 
5.2.2 
Rescue Therapy 
A SABA inhaler (albuterol HFA pMDI 90 µg) will be provided to subjects by the study 
center for use as rescue medication during the study. 
 
Subjects will record the number of inhalations (puffs used) of rescue medication (albuterol 
HFA pMDI 90 µg) each morning and evening in the diary. The average number of daily 
inhalations over the 7 days before the baseline visit will be the baseline value and will be 
compared with the rescue medication use during the 6-week treatment period. Rescue-free 
days are defined as 24-hour periods with no rescue medication usage. 
 
Subjects who experience an asthma exacerbation, including excessive SABA use (see 
Section 6.2.2) should be reassessed by the investigator for potential worsening asthma and to 
determine if the subject should be withdrawn from the study. 
 
If a subject requires rescue medication during the postdose serial spirometry assessment 
period of the baseline visit, the event will be recorded as an AE and the medication used will 
be recorded as a concomitant medication in the eCRF; the date and time of administration as 
well as the number of puffs will be recorded. These subjects may continue in the study. 
 
5.2.3 
Inhaler Functionality 
If a subject suspects that an inhaler is not working properly, the subject should immediately 
contact study center personnel. All inhalers suspected of not working properly will be sent 
back to 3M for further evaluation. 


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5.3 
Identity of Investigational Product 
The 3M Inhaler is a pMDI containing a combination of budesonide (80 µg) and formoterol 
(4.5 µg) as an inhalation aerosol. The 3M Inhaler also contains the following inactive 
excipients: xxx. Each inhaler contains 120 actuations per canister. 
 
The Symbicort Reference Inhaler is a pMDI containing a combination of budesonide (80 µg) 
and formoterol (4.5 µg) as an inhalation aerosol. The Symbicort Reference Inhaler contains 
the following inactive excipients: xxx. Each inhaler contains 120 actuations per canister. 
 
The placebo inhaler is identical in appearance to the 3M Inhaler. It is a pMDI containing 
placebo as an inhalation aerosol. The placebo inhaler contains xxx. Each inhaler contains 120 
actuations per canister. 
 
The sponsor (3M) or its designee will provide adequate supplies of study medication to the 
study centers. 
 
5.4 
Management of Clinical Supplies 
 
5.4.1 
Study Medication Packaging and Storage 
Budesonide/formoterol (80 µg/4.5 µg) to be used with the 3M Inhaler and the Symbicort 
Reference Inhaler, along with placebo, will be prepared and shipped by 3M or its designee. 
 
Each budesonide/formoterol kit xxx 
 
All study medication must be stored in a secure area, protected from moisture, and kept at a 
controlled room temperature between 68F and 77°F (20C and 25°C). 


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5.4.1.1 
Priming the Inhalers 
Each inhaler should be primed before the first use xxx. To prime an inhaler, 2 test sprays 
should be released into the air away from the face, with the inhaler shaken well for 5 seconds 
before each spray. 
 
5.4.2 
Study Medication Accountability 
The investigator will maintain accurate records of receipt of all study medication, including 
dates of receipt. In addition, accurate records will be kept regarding when and how much 
study medication is dispensed and used by each subject in the study. Reasons for departure 
from the expected dispensing regimen must also be recorded. At the completion of the study, 
to satisfy regulatory requirements regarding study medication accountability, all study 
medication will be reconciled and retained or destroyed according to applicable regulations. 
 
5.4.3 
Retention Samples 
Per the FDA Guidance for Industry [DHHS, 2004], study centers must maintain retention 
samples that may be accessed by the FDA. 
 
xxxxx 
 
 
5.5 
Overdose Management 
An overdose is any dose of study medication given to a subject or taken by a subject that 
exceeds the dose described in the protocol. Any overdose, with or without associated AEs, 
must be promptly reported to the medical monitor. Overdoses without signs or symptoms do 
not need to be recorded as AEs; in case of any AEs associated with the overdose, these will 
be reported on the relevant AE or SAE sections, as applicable, in the eCRF. 
 
5.6 
Blinding 
This is a single-blind study. xxxxx 
 
5.7 
Treatment Compliance 
Subject compliance will be assessed at the baseline visit (for the run-in period inhaler) and at 
the end-of-treatment visit (for the study medication inhaler) using the dose counter on each 


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inhaler. The diaries will also be used as a source for subject compliance, particularly when 
the study medications are not returned. xxxxx 


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6 
Study Assessments and Procedures 
Before performing any study procedures, all potential subjects will sign an informed consent 
form (ICF). Subjects will have the opportunity to have any questions answered before 
signing the ICF. The investigator must address all questions raised by the subject. The 
investigator and a witness will also sign the ICF. 
 
As shown in the Schedule of Events (Section 3.1), subjects will have evaluations at 
screening, baseline, Week 2, Week 4, and end-of-treatment (Week 6) visits. The Week 2 and 
Week 4 evaluations are telephone contacts from the study center personnel, during which 
subjects will be queried regarding changes to their concomitant medications and AE 
experiences (new AEs or changes to ongoing AEs [including discontinuation or exacerbation 
of AEs]), whether or not the changes were recorded in the diary. If a subject indicates that 
changes occurred but were not recorded in the diary, the study center personnel will 
re-educate the subject on capturing information in the diary. 
 
At the Week 4 telephone contact, subjects will also be reminded to switch to Canister 2 and 
to not take study medication within 12 hours of their end-of-treatment visit. 
 
6.1 
Efficacy Assessments 
The primary efficacy endpoints are described in Section 7.1.1. 
 
Lung function will be assessed using spirometry xxx. Each subject will undergo lung function 
assessments at the screening, baseline, and end-of-treatment visits. At the screening visit, 
subjects cannot have taken a LABA within 24 hours of the first spirometry assessment; at the 
end-of-treatment visit, subjects cannot have taken study medication within 12 hours before 
the first spirometry assessment. In addition, for all visits where lung function is tested, 
subjects cannot have taken rescue medication within 6 hours of the first spirometry 
assessment of each visit; if these requirements are not met, the spirometry assessments must 
be rescheduled. 
 
At the screening visit, subjects will have 2 spirometry assessments. The screening 
assessments will be completed in the morning. The first spirometry assessment will be 
conducted to assess the subject’s FEV1 value. To meet the entry criteria, subjects must 
demonstrate an FEV1 of ≥45% and ≤85% of predicted normal. Those who fail to meet this 


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criterion may present for repeat spirometry testing within 7 days. 
 
Subjects who demonstrate an FEV1 of ≥45% and ≤85% of predicted normal will then be 
administered albuterol 360 µg delivered via a pMDI with a spacer. The reversibility of FEV1 
will be assessed with a second spirometry assessment 30 minutes (±5 minutes) later. To meet 
the entry criteria, subjects must demonstrate ≥15% reversibility of FEV1 (reversibility of 
14.50% to 14.99% will be rounded to 15%) and a ≥0.2 L increase within 30 minutes 
(±5 minutes) following the administration of 360 µg albuterol delivered via a pMDI. Subjects 
who demonstrate reversibility of FEV1 ≥10% and <14.5% or those who fail to show an 
increase of >0.20 L within 30 minutes (±5 minutes) of 360 µg albuterol may present for 
repeat spirometry and reversibility testing within 7 days. 
 
xxxxx 
 
At the baseline visit on Day 1 (following the run-in period), the subjects will have a predose 
(30 minutes before initial dosing) spirometry assessment, have a time point 0 spirometry 
assessment (which will be averaged with the first spirometry assessment for a baseline 
value), receive their first morning dose of study medication, and have subsequent serial 
spirometry assessments as follows: 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after dosing. A 
window of ±5 minutes will be applied through the 3-hour assessment, and a window of 
±10 minutes will be applied for the assessments at Hours 4 through 12. 
 
If a subject requires rescue medication during the postdose serial spirometry assessment 
period of the baseline visit, the event will be recorded as an AE and the medication used will 
be recorded as a concomitant medication in the eCRF; the date and time of administration as 
well as the number of puffs will be recorded. These subjects may continue in the study. 
At the end-of-treatment visit, subjects will have 2 spirometry assessments. Study medication 
must not have been taken within 12 hours (±2 hours) and rescue medication must not have 
been taken within 6 hours of the first spirometry assessment. The first spirometry assessment 
will be conducted at the same time of day (±1 hour) as the first predose baseline spirometry 
assessment (ie, 30 minutes before initial dosing), and the second spirometry assessment will 
be performed 30 minutes (±5 minutes) later; the end-of-treatment FEV1 value will be the 
average of the 2 assessments. 
 
 
 


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6.2 
Safety Assessments 
Safety assessments in this study include evaluation of all AEs noted during study 
participation (including exacerbation of preexisting conditions), changes in concomitant 
medication during study participation (including change in dose), and changes from baseline 
in vital signs.  
 
4.1.1 
Handheld Device for Home Use 
At the screening visit, subjects will be provided with and trained on the proper use of the 
handheld device that will xxx collect diary information. Subjects will be asked to xxx answer 
diary questions twice daily (at home), in the morning and in the evening, approximately 12 
hours apart. xxxxx 
 
Diary information collected may include, but is not limited to, the following: 
 xxxxx 
 Time of dosing of study medication in the morning and canister used (ie, Canister 1 or 
Canister 2). 
 
 Time of dosing of study medication in the evening and canister used (ie, Canister 1 or 
Canister 2). 
 xxxxx 
In addition, subjects will be asked to indicate if any AEs or changes in concomitant 
medications occurred. 
 
Study center personnel will review the data xxx. Study medication, diary, and compliance re-
education will be provided as needed. xxxxx 
 
Data from the handheld device will not be electronically entered into the analysis database or 
statistically analyzed. xxxxx 
 
6.2.1 
Asthma Exacerbation 
Alert criteria for individual subjects with worsening asthma have been designed to ensure 
subject safety. If any of the following criteria are met, the subject will be instructed to come 
into the study center for evaluation so that the investigator can determine whether the 
subject’s overall clinical picture is consistent with worsening asthma or if the subject will be 


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withdrawn from the study: 
 
 xxxxx 
 
 The subject experiences any of the following during a 7-day period:  
o Three or more days in which 12 or more inhalations per day of rescue 
medication were used 
 
o Three or more nights in which the subject was awoken with nighttime 
asthma exacerbation requiring rescue medication 
 
o Persistent worsening of asthma symptoms 
Clinical asthma exacerbation: Subjects who do not meet the alert criteria but who 
experience a clinically meaningful worsening of their asthma warranting a change in their 
asthma treatment will be removed from the study. The investigator should offer alternative 
treatment consistent with the policies and procedures at the study center. xxxxx 
 
6.2.2 
Adverse Events 
 
6.2.3.1 
Definitions of Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study medication or their clinical significance. 
 
An AE is defined as any untoward medical occurrence in a subject that is associated with the 
use of a study medication in humans, whether or not considered related to the study 
medication. Subjects will be instructed to contact the investigator at any time after 
randomization if any symptoms develop. 
 
A treatment-emergent AE is defined as any event not present before exposure to study 
medication or any event already present that worsens in either intensity or frequency after 
exposure to study medication.  
 
A life-threatening AE or life-threatening suspected adverse reaction is defined as an event that, 
in the view of the investigator or the sponsor, places the subject at immediate risk of death; it 
does not include an event that had it occurred in a more severe form might have caused death. 
 


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An SAE or serious suspected adverse reaction is defined as any event that, in the view of the 
investigator or the sponsor, results in any of the following outcomes: death, a life-threatening 
AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, 
or a congenital anomaly/birth defect. Important medical events that may not result in death, 
be life threatening, or require hospitalization may be considered SAEs when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
study medication caused the AE. For the purposes of FDA safety reporting, "reasonable 
possibility" means there is evidence to suggest a causal relationship between the study 
medication and the AE. Suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction, which means any AE caused by the study medication. 
 
An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the 
Investigator’s brochure or is not listed at the specificity or severity that has been observed; or, 
if an Investigator’s 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’s 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’s brochure 
listed only cerebral vascular accidents. "Unexpected," as used in this definition, also refers to 
AEs or suspected adverse reactions that are mentioned in the Investigator’s 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. 
 
6.2.3.2 
Eliciting and Documenting Adverse Events  
Adverse events will be assessed beginning at enrollment (date of signed informed consent) 
and up to the end-of-treatment visit. Even though the Investigator does not need to actively 


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monitor subjects for AEs once the study has ended, SAEs occurring to a subject within 
30 days after the last dose of study medication should be reported if the Investigator becomes 
aware of them. 
 
At each visit, subjects will be asked a standard nonleading question (such as “How have you 
felt since your last visit”) to elicit any medically related changes in their well-being. They 
will also be asked if they have visited an emergency room/urgent care clinic or have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (see Section 6.2.4). 
 
In addition to subject observations, AEs identified from any study data (eg, vital sign data, 
laboratory values, physical examination findings) or identified from review of other 
documents (eg, subject diaries) that are relevant to subject safety will be documented on the 
AE page in the eCRF. 
 
6.2.3.3 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes date of onset, description of AE, investigator-specified 
severity and relationship to study medication, action taken, and date of resolution. Adverse 
events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported. All AEs will 
be followed up to adequate resolution. The Medical Dictionary for Regulatory Activities 
(MedDRA) will be used to code all AEs. 
 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate will not be reported as an AE. However, if it deteriorates at any time during the 
study, it will be recorded as an AE. 
Any AE that meets SAE criteria (Section 6.2.3.1) must be immediately (ie, within 24 hours 
after the time study center personnel first learn about the event) reported on the SAE page in 
the eCRF. The 24-hour safety hotline telephone number and the SAE fax number are located 
on the cover page. 
 
6.2.3.4 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s 


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daily activities. The intensity of the AE will be rated as mild, moderate, or severe using the 
following criteria: 
 
Mild: 
These events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
Moderate: 
These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
normal functioning. 
Severe: 
These events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent do not require documentation of onset and duration of each episode. 
 
6.2.3.5 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study medication is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
 
The relationship or association of the test article in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Unrelated: 
This relationship suggests that there is no association between the study 
medication and the reported event. 
 
Possible: 
This relationship suggests that treatment with the study medication caused or 
contributed to the AE, ie, the event follows a reasonable temporal sequence 
from the time of drug administration or follows a known response pattern to the 
study medication, but could also have been produced by other factors. 
 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with drug administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the drug 
or class of drugs, or judgment based on the investigator’s clinical experience, 
the association of the event with the study medication seems likely. The event 
disappears or decreases on cessation or reduction of the dose of study 


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medication. 
 
Definite: 
This relationship suggests that a definite causal relationship exists between drug 
administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do 
not appear to explain the event. 
 
6.2.3.6 
Follow-Up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF. 
 
For SAEs, follow-up information to an initial safety report must be provided by the 
Investigator as soon as the relevant information is available. Relevant information such as 
discharge summaries, autopsy reports, and medical consultations will be reviewed in detail 
by the Investigator and discussed with the medical monitor as appropriate. 
 
All SAEs or AEs that lead to discontinuation of study medication will be followed up until 
satisfactory resolution, the investigator deems the event to be chronic or not clinically 
significant, or the subject is considered to be stable. 
6.2.3 
Concomitant Medications 
Use of all concomitant medications will be recorded in the subject’s eCRF. The minimum 
requirement is that the drug name, dose, and dates of administration are to be recorded (start 
and stop dates). This will include all prescription drugs, herbal products, vitamins, minerals, 
and over-the-counter medications. Any changes in concomitant medications (including 
discontinuations of drugs, changes in dose, and initiation of new medications) will also be 
recorded in the subject’s eCRF. 
 
The run-in period will be used to washout prestudy medications and to establish FEV1 
baseline values. See Appendix 1 for a complete list of washout medications and the required 
washout period for each; these medications are excluded throughout the study unless 
otherwise noted. Throughout the study, any concomitant medication deemed necessary for 
the welfare of the subject during the study may be given at the discretion of the investigator. 
However, it is the responsibility of the investigator to ensure that details regarding the 
medication, and as necessary withdrawal (see Section 4.2), are recorded in full in the eCRF. 
 
 


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6.2.4 
Physical Examination and Vital Signs 
A complete physical examination, including height and weight, will be performed at the 
screening visit and the end-of-treatment visit; height only needs to be collected at the 
screening visit. Vital sign assessments, including blood pressure and heart rate, will be 
collected at screening, baseline, and at the end-of-treatment visits. 
 
All data collected from the physical examinations and vital sign assessments must be 
available in the source documents but will not be added to the analysis database. An 
abnormal vital sign value or physical examination finding at the screening visit will be 
captured in the medical history. An abnormal vital sign value or physical examination finding 
at the end-of-treatment visit that has worsened since the screening visit will be captured as an 
AE. 
 
6.2.5 
Electrocardiogram 
A standard 12-lead electrocardiogram assessment will be performed locally at the study 
center during the screening visit and following standard procedures at the study center. If 
spirometry has been performed, the subject should rest for at least 10 minutes prior to the 
electrocardiogram assessment. Data collected from the electrocardiogram assessments 
must be available in the source documents but will not be added to the analysis database. 
 
6.3 
Laboratory Analyses 
Laboratory testing will be performed at local laboratories only at the screening and 
end-of-treatment visits. Laboratory assessments will be obtained per standard of care at each 
study center, with the laboratory assessments in Table 6–1 collected at a minimum. The 
volume of blood drawn throughout the study will vary based on each study center’s standard 
of care but is expected to be approximately 50 mL per subject during the course of the study. 
Additional blood draws may be needed if clinically indicated, as determined by the 
investigator. 
 
Any data collected from the laboratory testing must be available in the source documents but 
will not be added to the analysis database. An abnormal laboratory value at the screening 
visit will be captured in the medical history. An abnormal laboratory value at the 
end-of-treatment visit that has worsened since the screening visit will be captured as an AE. 
 


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A urine pregnancy test will be used at the screening and baseline visits to screen potential 
subjects for eligibility to participate in the study. A serum pregnancy test must be obtained at 
the screening and end-of-treatment visits. If a pregnancy occurs, refer to Section 6.4. 
Table 6–1 
Laboratory Assessments 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Urea 
pH 
Hepatitis B (Screening only) 
Hematocrit 
Creatinine 
Glucose (qualitative) 
Hepatitis C (Screening only) 
RBC count 
Glucose 
Protein (qualitative) 
Human immunodeficiency 
Platelet count 
Calcium 
Blood (qualitative) 
virus (Screening only) 
WBC count 
Sodium 
Ketones 
Pregnancy test (urine and/or 
Total neutrophils 
Potassium 
Nitrites 
serum) 
(absolute) 
Chloride 
Leukocyte esterase 
 
Eosinophils (absolute) 
Monocytes (absolute) 
Total CO2 (bicarbonate) 
Alanine aminotransferase 
 
 
Basophils (absolute) 
Aspartate aminotransferase  
 
Lymphocytes (absolute) 
Total bilirubin 
 
 
 
Alkaline phosphatase 
 
 
 
Uric acid 
 
 
 
Albumin 
 
 
 
Total protein 
 
 
 
6.4 
Pregnancy 
Subjects who become pregnant during the study will be withdrawn as outlined in Section 4.2. 
 
Pregnancy is not regarded as an AE unless there is a suspicion that an investigational product 
may have interfered with the effectiveness of a contraceptive medication. Any pregnancy that 
occurs during study participation must be reported in the eCRF. To ensure subject safety, 
each pregnancy must be reported to 3M or its designee within 2 weeks of learning of its 
occurrence. The pregnancy must be followed up to determine the outcome (including 
spontaneous miscarriage, elective termination, normal birth, or congenital abnormality) and 
status of mother and child, even if the subject was discontinued from the study. Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or 
SAE. Spontaneous miscarriages must be reported as an SAE. 
 
Any SAE occurring in association with a pregnancy brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as possibly 
related to the study medication must be promptly reported to 3M or its designee. 


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7 
Statistical Considerations 
Detailed methodologies for the summary and statistical analyses of the data collected in this 
study will be documented in a separate document, the statistical analysis plan (SAP). The 
SAP may modify the statistical plans outlined in this protocol; however, major modifications 
of the primary endpoint definition and/or its analyses will also be reflected in a protocol 
amendment. 
 
7.1 
Endpoints 
 
7.1.1 
Primary Efficacy Endpoints 
The primary efficacy endpoints are as follows: 
 
 Change from baseline in FEV1AUC0-12 at Day 1 
 
FEV1 will be measured on Day 1 before dosing (30 minutes before initial dosing), at 
time point 0, and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after dosing for the calculation 
of FEV1AUC0-12. Details on the calculations of this endpoint will be provided in the 
SAP. 
 
 Change from baseline to the end-of-treatment in FEV1 
 
The baseline FEV1 is defined as the average of the 2 predose FEV1 values measured in 
the morning of the first day of treatment. The end-of-treatment FEV1 is defined as the 
average of the 2 FEV1 values measured in the morning on the last day of treatment and 
within 1 hour of the first predose assessment on the first day of treatment. 
 
7.1.2 
Safety Endpoint 
Safety will be evaluated by assessing number (percent), severity, and relatedness of AEs and 
SAEs between treatment groups. 
7.2 
Sample Size Calculations 
Approximately 1470 adult subjects (18 years of age or older) with asthma are proposed to be 
randomized to the 3 treatment groups in a 3:3:1 ratio (630 subjects per active treatment group 
and 210 in the placebo group). 


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7.2.1 
Equivalence 
xxxxx. Sample size calculations are mainly driven by demonstrating equivalence for the 
change from baseline in FEV1 at Week 6. Equivalence will be defined as the 90% CIs for the 
ratio (test/reference) falling within the (0.80, 1.25) target ratio. The sample size of 567 
subjects in each active treatment group will provide approximately 87.1% power at the 5% 
significance level for the equivalence test of means using two 1-sided tests and assuming a 
true ratio of the means equal to 0.95, coefficient of variance (CV) of 1.00, and equivalence 
limits of the mean ratio of 0.80 and 1.25. 
 
Similarly for the change from baseline in FEV1AUC0-12 at Day 1 endpoint, using an SD of 
xxx the sample size of 567 subjects in each active treatment group will provide 90.1% power 
at the 5% significance level for the equivalence test of means using two 1-sided tests and 
assuming a true ratio of the means equal to 0.95, CV of 0.95, and equivalence limits of the 
mean ratio of 0.80 and 1.25. 
 
The sample size will be based on the per-protocol set (PPS). Therefore, accounting for an 
approximate 10% dropout rate from the PPS, a sample size of 1470 subjects (630 subjects per 
active treatment group and 210 in the placebo group) is proposed. 
 
Sample size calculations were performed xxx 
 
7.2.2 
Superiority 
xxxxx For the change from baseline in FEV1, the sample size of 630 in the active treatment 
group and 210 subjects in the placebo group will provide more than 99% power to reject the 
hypothesis of equal means at the 5% significance level using a 2-sided 2-sample equal-
variance t test, assuming that the population mean difference xxx 
 
Similarly, for FEV1AUC0-12, the sample size of 630 in the active treatment group and 
210 subjects in the placebo group will provide more than 99% power to reject the hypothesis 
of equal means at the 5% significance level using a 2-sided 2-sample equal-variance t test 
and using the population mean difference xxx for both treatments. 
 
Power was calculated using xxx for a 2-sample t test assuming equal variance. xxxxx 


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7.3 
Analysis Sets 
The following analysis sets will be used in the statistical analyses: 
 
Full-analysis set (FAS): The FAS will consist of all subjects who were randomly assigned to 
receive single-blind study medication. All analyses using the FAS will group subjects 
according to randomized treatment. This analysis set will be used to assess the assay 
sensitivity of each active treatment (3M Inhaler and Symbicort Reference Inhaler) compared 
with placebo. 
 
Per-protocol set (PPS): The PPS will consist of all FAS subjects who fulfill all 
inclusion/exclusion criteria, are compliant to the study medication schedule (see Section 5.7), 
have not taken any prohibited medications, and have no significant protocol deviations. 
 
Per definition, the PPS will only include subjects who received the study medication to 
which they were randomly assigned. This analysis set will be used to assess the therapeutic 
equivalence of 3M Inhaler compared with Symbicort Reference Inhaler. 
Safety set: The safety set will consist of all subjects who received any study medication. All 
analyses using the safety set will group subjects according to treatment actually received. All 
safety endpoints will be analyzed based on the safety set. 
 
7.4 
Description of Subgroups to be Analyzed 
No subgroup analyses are planned. 
 
7.5 
Statistical Analysis Methodology 
Statistical analysis will be performed using SAS software Version 9.2 or later. 
 
Summary statistics of the data collected will be provided by treatment (3M Inhaler, 
Symbicort Reference Inhaler, and placebo). Continuous variables will be summarized using 
the mean, SD, CV, median, minimum value, and maximum value. Categorical variables will 
be summarized using frequency counts and percentages. 
 
Details of the statistical analyses, methods, and data conventions will be further described in 
the SAP. 
 


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7.5.1 
Analysis of Primary Efficacy Endpoint 
In order to claim therapeutic (overall) equivalence of the 3M Inhaler and the Symbicort 
Reference Inhaler, the following results should be demonstrated for both primary endpoints: 
 
 Equivalence of the active treatments means using ratio. The 90% CI for the ratio 
should fall within 80.00% and 125.00% 
 
 Assay sensitivity of each active treatment compared with placebo will be established if 
both active treatment groups are statistically superior to placebo (P<0.05) 
 
7.5.1.1 
Equivalence 
For each primary endpoint, the equivalence analysis of 3M Inhaler compared with the 
Symbicort Reference Inhaler will be performed using an analysis of covariance. Factors will 
be treatment (3M Inhaler and Symbicort Reference Inhaler) and the appropriate baseline for 
the endpoint. From the least-squares (LS) mean estimates obtained for each treatment group, 
the ratio (3M Inhaler/Symbicort Reference Inhaler) will be calculated. Fieller’s theorem 
[Hirschberg, 2010] will then be used to generate 2-sided CIs for each ratio. This analysis will 
be based on the PPS. 
 
The mean of the 2 predose FEV1 measurements taken at Day 1 will be used as the baseline 
for the FEV1AUC0-12 assessment. 
The baseline for the FEV1 endpoint will be calculated by taking the mean of the 2 predose 
FEV1 measurements taken at the baseline visit (Day 1). 
The first FEV1 assessment on the last day of the 6-week treatment period should correspond 
to the same time of day as that used for the baseline measurements (see Section 6.1). 
 
The 90% CI for the 2 active treatments (3M Inhaler and Symbicort Reference Inhaler) for the 
primary endpoint should fall within the limits of 80.00% to 125.00% for equivalence to be 
concluded [FDA, 2015]. 
 
7.5.1.2 
Superiority 
Assay sensitivity will be shown if the 3M Inhaler and Symbicort Reference Inhaler are both 
statistically superior to placebo (P<0.05) with regards to both study primary endpoints. 


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For the superiority test, the analysis will be performed using an analysis of covariance model 
fitted to each primary endpoint. Treatment (3M Inhaler, Symbicort Reference Inhaler, and 
placebo) will be included as a fixed effect. Baseline FEV1 will also be included as a 
continuous covariate (using the definition appropriate for each endpoint). The LS means will 
be derived for each treatment, and LS mean differences will be calculated by comparing each 
active treatment group (3M Inhaler and Symbicort Reference Inhaler) with placebo for each 
primary endpoint. Standard errors and 2-sided 95% CIs will be calculated for LS means and 
LS mean differences. In addition, 2-sided P values will be presented for the LS mean 
differences. The superiority of each active treatment compared with placebo will have been 
demonstrated if the P value for the pairwise comparison is statistically significant at the 
5% level. 
Assay sensitivity will be achieved if both pairwise comparisons (3M Inhaler compared with 
Symbicort Reference Inhaler compared with placebo) are statistically significant at the 
P<0.05 significance level for both primary endpoints. 
 
No adjustment for multiplicity is required because the primary endpoints are expected to be 
highly correlated and because equivalence on the basis of both endpoints is required before 
equivalence of the 2 inhalers can be claimed. 
 
These analyses will be based on the FAS. 
 
Additional sensitivity analyses may be carried out as described in the SAP, as appropriate, 
which may include accounting for FEV1 missing values in the FAS. 
 
7.5.2 
Safety Analyses 
All AEs will be reported, whether or not they are considered to be related to the treatment. 
The report of each AE will include date of onset, description of AE, investigator-specified 
severity and relationship to study medication, action taken, and date of resolution. This 
information will assist in determining whether the incidence and severity of adverse reactions 
are different among the 3 treatment groups. 
 
7.5.3 
Other Analyses 
Summary statistical analyses will be provided for demographics, medical history, risk factor 
variables at baseline, and study medication compliance. 


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7.5.4 
Blinded Sample Size Re-estimation 
A blinded sample size re-estimation may be performed after 30% of the subjects are enrolled 
to check for the sample size assumptions and, if necessary, increase the sample size. 
However, if a sample size re-estimation was to be performed, details would be prespecified in 
a protocol amendment prior to any statistical analysis of the data. 
7.5.5 
Interim Analysis 
There is no interim analysis planned for this study. However, if an interim analysis was to be 
performed, details would be prespecified in a protocol amendment prior to any statistical 
analysis of the data. 
 
7.6 
Data Quality Assurance 
Data will be entered into an electronic data capture system. Management of clinical data will 
be performed in accordance with applicable 3M or its designee’s standards and data cleaning 
procedures to ensure the integrity of the data (eg, removing errors and inconsistencies in the 
data). 
 
7.6.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents include but are not limited to diary cards, 
laboratory reports, physical examination records, and spirometry assessments. 
 
Study center personnel will enter subject data into eCRFs. The analysis data sets will be a 
combination of these data and data from other sources (eg, spirometry data). 
 
Clinical data management will be performed in accordance with applicable 3M or its 
designee’s standards and data cleaning procedures to ensure the integrity of the data, eg, 
removing errors and inconsistencies in the data. Adverse events and concomitant medication 
terms will be coded using MedDRA. 


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8 
Ethics 
 
8.1 
Independent Ethics Committee or Institutional Review Board 
Federal regulations and the International Council for Harmonisation (ICH) guidelines require 
that approval be obtained from an institutional review board (IRB) before participation of 
human subjects in research studies. Before study onset, the protocol, informed consent, 
advertisements to be used for the recruitment of study subjects, and any other written 
information regarding this study to be provided to the subject or the subject’s legal guardian 
must be approved by the IRB. Documentation of all IRB approvals and of the IRB 
compliance with ICH harmonised tripartite guideline E6: Good Clinical Practice (GCP) will 
be maintained by the study center and will be available for review by the sponsor or its 
designee. 
 
All IRB approvals should be signed by the IRB chairman or designee and must identify the 
IRB name and address, the clinical protocol by title or protocol number or both, and the date 
approval or a favorable opinion was granted. 
 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB. The 
investigator must promptly supply the sponsor or its designee, the IRB, and where applicable, 
the institution, with written reports on any changes significantly affecting the conduct of the 
study or increasing the risk to subjects. 
 
8.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, and all applicable regulations. 
 
If a serious breach is detected, the sponsor or its designee will take appropriate corrective and 
preventative actions in response. These actions will be documented and the FDA will be 
notified as appropriate. 
 
The investigator is responsible to take appropriate action to protect a subject’s life but must 
notify the sponsor or its designee and the medical monitor after any such event. 
3M or its designee will comply with all FDA requirements when reporting SAEs and urgent 


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safety issues. 
 
8.3 
Subject Information and Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 shall be obtained from each subject before entering the study or performing 
any unusual or nonroutine procedure that involves risk to the subject. An informed consent 
template may be provided by the sponsor or its designee to the study center. If any 
institution-specific modifications to study-related procedures are proposed or made by the 
study center, the consent should be reviewed by the sponsor or its designee or both before 
IRB submission. Once reviewed, the consent will be submitted by the investigator to his or 
her IRB for review and approval before the start of the study. If the ICF is revised during the 
course of the study, all active participating subjects must sign the revised form. 
 
Before recruitment and enrollment, each prospective subject or his or her legal guardian will 
be given a full explanation of the study and be allowed to read the approved ICF. Once the 
investigator is assured that the subject or legal guardian understands the implications of 
participating in the study, the subject or legal guardian will be asked to give consent to 
participate in the study by signing the ICF. 
 
The investigator shall retain the signed original ICF and give a copy of the signed original 
form to the subject or legal guardian. 


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9 
Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB 
but will not result in protocol amendments. 
 
9.1 
Confidentiality 
All evaluation forms, reports, and other records will be identified in a manner designed to 
maintain subject confidentiality. All records will be kept in a secure storage area with limited 
access. Clinical information will not be released without the written permission of the subject 
(or the subject’s legal guardian), except as necessary for monitoring and auditing by the 
sponsor, its designee, the FDA, or the IRB. 
 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
 
9.2 
Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor or 
its designee to submit the complete and accurate certification or disclosure statements 
required under 21 CFR 54. In addition, the investigator must provide to the sponsor or its 
designee a commitment to promptly update this information if any relevant changes occur 
during the course of the investigation and for 1 year after the completion of the study. 
 
The sponsor or its designee are not financially responsible for further testing or treatment of 
any medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, the sponsor or its designee are not financially responsible 
for further treatment of the subject’s disease. 


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9.3 
Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R1) 8.2 
and Title 21 of the CFR by providing the following essential documents, including but not 
limited to the following: 
 
 IRB approval 
 
 Original investigator-signed investigator agreement page of the protocol 
 
 Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572 
 
 Curriculum vitae for the investigator and each subinvestigator listed on Form 
FDA 1572 
 
 Financial disclosure information to allow the sponsor or its designee to submit 
complete and accurate certification or disclosure statements required under 
21 CFR 54. In addition, the investigators must provide to the sponsor or its designee a 
commitment to promptly update this information if any relevant changes occur during 
the course of the investigation and for 1 year after the completion of the study 
 
 IRB-approved informed consent, samples of study center advertisements for 
recruitment for this study, and any other written information regarding this study that 
is to be provided to the subject or legal guardian 
 
 Laboratory certifications and normal ranges for any local laboratories used by the 
study center, in accordance with 42 CFR 493 
 
9.4 
Study Conduct 
The investigator agrees that the study will be conducted according to the principles of 
ICH E6. The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of subjects begins. 
 


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9.5 
Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6 and all applicable guidelines and regulations. 
 
9.6 
Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in the protocol (see Section 6.2.3.3 and Section 6.2.3.6). In 
addition, the investigator agrees to submit annual reports to the study center’s IRB as 
appropriate. 
 
9.7 
Investigator’s Final Report 
Upon completion of the study, the investigator, or where applicable the institution, should 
provide the IRB with a summary of the study’s outcome at the study center (eg, total number 
of subjects enrolled, study duration) and provide the sponsor or its designee with any reports 
required. 
 
9.8 
Records Retention 
xxxxx 
 
9.9 
Publications 
 
xxxxx


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10 Study Management 
 
10.1 Monitoring 
 
10.1.1 
Monitoring of the Study 
The clinical monitor, as a representative of the sponsor or its designee, has the obligation to 
follow the study closely. In doing so, the monitor will visit the investigator and study center 
at periodic intervals, in addition to maintaining necessary telephone and letter contact. The 
monitor will maintain current personal knowledge of the study through observation, review 
of study records and source documentation, and discussion of the conduct of the study with 
the investigator and study center personnel. 
 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
 
10.1.2 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 
In the event of an audit, the investigator agrees to allow the sponsor, representatives of the 
sponsor, or a regulatory agency (eg, FDA or other regulatory agency) access to all study 
records. 
 
The investigator should promptly notify the sponsor or its designee of any audits scheduled 
by any regulatory authorities and promptly forward copies of any audit reports received to 
the sponsor or its designee. 
 
10.2 Management of Protocol Amendments and Deviations 
 
10.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the sponsor or its 


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designee. Amendments to the protocol must be submitted in writing to the investigator’s IRB 
for approval before subjects can be enrolled into an amended protocol. 
 
10.2.2 
Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB for review and approval, to the sponsor or its designee for 
agreement, and to the regulatory authorities, if required. 
 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor or its designee and the IRB and agreed to 
by the investigator. A significant deviation occurs when there is nonadherence to the protocol 
by the subject or investigator that results in a significant, additional risk to the subject. 
Significant deviations can include nonadherence to inclusion or exclusion criteria, enrollment 
of the subject without prior sponsor approval, or nonadherence to FDA regulations or ICH 
GCP guidelines, and will lead to the subject being withdrawn from the study (Section 4.2). 
 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Investigators will be notified in writing by the monitor of deviations. The 
IRB should be notified of all protocol deviations in a timely manner. 
 
10.3 Study Termination 
Although 3M has every intention of completing the study, 3M reserves the right to 
discontinue the study at any time for clinical or administrative reasons. 
 
The end of the study is defined as the date on which the last subject completes the last visit 
(ie, end-of-treatment visit or follow-up visit for subjects who have an SAE or those who 
withdraw due to an AE). 
 
10.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor or its designee will 


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ensure that the clinical study reports are prepared and provided to the regulatory agency as 
required by the applicable regulatory requirements. The sponsor or its designee will also 
ensure that the clinical study reports in marketing applications meet the standards of the ICH 
harmonised tripartite guideline E3: Structure and content of clinical study reports. 
 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
 
Upon completion of the clinical study report, the sponsor or its designee will provide the 
investigator with the full summary of the study results. The investigator is encouraged to 
share the summary results with the study subjects, as appropriate. The study results will be 
posted on publicly available clinical trial registers. 


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11 References 
Akinbami LJ, Moorman JE, Bailey C, et al. Trends in asthma prevalence, health care use, and 
mortality in the United States, 2001-2010. NCHS Data Brief. 2012;(94):1-8. 
 
Centers for Disease Control and Prevention (CDC). Asthma data, statistics, and surveillance: 
Most recent asthma data [Internet]. March 2016 [cited 2016 Sep 11]. Available from: 
http://www.cdc.gov/asthma/most_recent_data.htm. 
 
Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (US). Guidance for industry: Handling and retention of 
BA and BE testing samples. May 2004 [cited 2016 Sep 11] [15 screens]. Available from: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126836.pdf. 
 
Food and Drug Administration (US FDA). Draft guidance for on budesonide; formoterol 
fumarate dihydrate. June 2015 [cited 2016 Sep 11] [7 screens]. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance 
s/UCM452690.pdf. 
 
Global Initiative for Asthma (GINA). Global strategy for asthma management and 
prevention. 2016 [cited 2016 Sep 11] [151 screens]. Available from: 
http://www.ginasthma.org. 
 
Hirschberg J, Lye J. A geometric comparison of the delta and Fieller confidence intervals. 
Am Stat. 2010;64(3):234-41. 
 
National Asthma Education and Prevention Program (NAEPP). Expert panel report 3: 
Guidelines for the diagnosis and management of asthma. Bethesda (MD): National Heart, 
Lung, and Blood Institute, National Institutes of Health (US); 2007 [cited 2016 Sep 11] 
[440 screens]. Available from: http://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln.pdf. 
 
Symbicort® (budesonide and formoterol fumarate dihydrate) [package insert]. AstraZeneca 
LP. Wilmington (DE); 2016 [cited 2016 Sep 28] [15 screens]. Available from: 
http://www.azpicentral.com/symbicort/symbicort.pdf. 


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12 Appendices 
 
12.1 Appendix 1: Allowed and Disallowed Medications 
All medications used in the treatment of asthma (inhaled corticosteroids, long-acting  
agonists, noncorticosteroids) are to be discontinued at the screening visit. The subject will be 
supplied with a short-acting β2 agonist (SABA) for use to relieve asthma symptoms as 
required during the entire study (see Section 5.2.2). The subject’s routine SABA will be 
discontinued at the screening visit. 
 
The following drugs are prohibited or restricted during the study: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.2 Appendix 2: Contraception 
 
12.2.1 
Females of Non-childbearing Potential 
Female subjects of non-childbearing potential must meet and have documentation of at least 
one of the following criteria: 
           xxxxx 
 
 
Postmenopausal, defined as amenorrheic for at least 2 years OR have been 
amenorrheic for less than 2 years but have a serum follicle-stimulating hormone level 
>30 IU/L in the absence of hormone replacement therapy 
 
 
Surgically sterile, which includes hysterectomy or bilateral oophorectomy 
All other females will be considered to be of childbearing potential. 
 
12.2.2 
Females of Childbearing Potential 
Female subjects of childbearing potential must use an acceptable method of contraception 
starting from the screening visit through the end-of-treatment visit. 
 
xxxxx 
 
12.3 Protocol Amendments 
 
12.3.1 
Protocol Amendment 1 Summary of Changes 
The original protocol was amended to provide additional clarity around the baseline 
spirometry testing and exclusion criterion #9. 
 
Following is a summary of the changes. Additions are indicated in bold and underlined font, 
and deletions are indicated using strikethrough text. 
 
Global Change 
 
Reference to the protocol was changed from “Original Protocol” to “Protocol Amendment 1” 
and the date was changed to 31 Oct 2016. 


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Exclusion Criteria #9: 
 
Has a current diagnosis or history of hepatitis B, hepatitis C, or human immunodeficiency 
virus as determined by laboratory testing at Screening, or active tuberculosis as 
determined by medical history and physical examination 
 
6.1 Efficacy Assessments 
 
At the screening visit, subjects will have 2 spirometry assessments. The screening 
assessments will be completed in the morning. The first spirometry assessment will be 
conducted to assess the subject’s FEV1 value. To meet the entry criteria, subjects must 
demonstrate an FEV1 of ≥45% and ≤85% of predicted normal. Those who fail to meet this 
criterion may present for repeat spirometry testing within 7 days. 
 
Subjects who demonstrate an FEV1 of ≥45% and ≤85% of predicted normal will then be 
administered albuterol 360 µg delivered via a pMDI with a spacer. The reversibility of FEV1 
will be assessed with a second spirometry assessment 30 minutes (±5 minutes) later. To meet 
the entry criteria, subjects must demonstrate ≥15% reversibility of FEV1 (reversibility of 
14.50% to 14.99% will be rounded to 15%) and a ≥0.2 L increase within 30 minutes 
(±5 minutes) following the administration of 360 µg albuterol delivered via a pMDI. 
Subjects who demonstrate reversibility of FEV1 ≥10% and <14.5% or those who fail to 
how an increase of >0.20 L within 30 minutes (±5 minutes) of 360 µg albuterol may 
present for repeat spirometry and reversibility testing within 7 days. 
 
The repeat spirometry assessment must be conducted at the same time of day (±1 hour) as the 
original screening assessment. Subjects who meet the spirometry requirements upon repeat 
testing can enter the run-in period (provided they meet all other inclusion criteria and none of 
the exclusion criteria). Subjects who required repeat spirometry testing will have the baseline 
visit up to 21 days after the initial screening visit (versus approximately 14 days after the 
initial screening visit for subjects who do not require repeat testing). If the subject fails to 
meet all of the spirometry assessment criteria outlined in the inclusion criteria (see 
Section 4.1.1) upon repeat testing, the subject will be considered to have failed screening. 
 
 
 
 


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Table 6-1 Laboratory Assessments 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Urea 
pH 
Hepatitis B (Screening only) 
Hematocrit 
Creatinine 
Glucose (qualitative) 
Hepatitis C (Screening only) 
RBC count 
Glucose 
Protein (qualitative) 
Human immunodeficiency 
Platelet count 
Calcium 
Blood (qualitative) 
virus (Screening only) 
WBC count 
Sodium 
Ketones 
Tuberculosis (Screening 
Total neutrophils 
Potassium 
Nitrites 
only) 
(absolute) 
Chloride 
Leukocyte esterase 
Pregnancy test (urine and/or 
Eosinophils (absolute) 
Monocytes (absolute) 
Total CO2 (bicarbonate) 
Alanine aminotransferase 
 
serum) 
Basophils (absolute) 
Aspartate aminotransferase  
 
Lymphocytes (absolute) 
Total bilirubin 
 
 
 
Alkaline phosphatase 
 
 
 
Uric acid 
 
 
 
Albumin 
 
 
 
Total protein 
 
 
 

SAP_001.pdf: 
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CSP-07-000034 
Final Version 2.0 23Mar2018 
Statistical Analysis Plan 
1 
 
 
 
 
 
 
 
3M Health Care Ltd 
CSP-07-000034 
 
 
A RANDOMIZED, SINGLE-BLIND, PARALLEL-GROUP, 
PLACEBO-CONTROLLED, MULTIDOSE STUDY COMPARING THE 
THERAPEUTIC EQUIVALENCE OF A 3M INHALER AND A 
SYMBICORT® REFERENCE INHALER, EACH DELIVERING 
BUDESONIDE/FORMOTEROL FUMARATE (80 µg/4.5 µg) IN ADULT 
SUBJECTS WITH ASTHMA 
 
 
 
 
Statistical Analysis Plan, Final Version 2.0 
23 Mar 2018 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS .......................................................................................................  
1. 
INTRODUCTION .............................................................................................................  
2. 
OBJECTIVES ...................................................................................................................  
3. 
INVESTIGATIONAL PLAN ...........................................................................................  
3.1. OVERALL STUDY DESIGN AND PLAN ........................................................................................................  
3.2. STUDY ENDPOINTS .......................................................................................................................................  
3.3. TREATMENTS .................................................................................................................................................  
3.4. DOSE ADJUSTMENT/MODIFICATIONS .....................................................................................................  
4. GENERAL STATISTICAL CONSIDERATIONS ......................................................... 
4.1. SAMPLE SIZE ..................................................................................................................................................  
4.1.1 Equivalence ...................................................................................................................  
4.1.2 Superiority .....................................................................................................................  
4.2. RANDOMIZATION AND BLINDING ............................................................................................................  
4.3. TREATMENT PERIODS ..................................................................................................................................  
4.4. ANALYSIS SETS .............................................................................................................................................  
4.4.1. 
Screened Set ..............................................................................................................  
4.4.2. 
Enrolled Set ...............................................................................................................  
4.4.3. 
Randomized Set .........................................................................................................  
4.4.4. 
Full Analysis Set ........................................................................................................  
4.4.5. 
Per Protocol Set ........................................................................................................  
4.4.6. 
Safety Set ...................................................................................................................  
4.5. SPIROMETRY DATA HANDLING CONVENTIONS ..................................................................................  
4.5.1 
Handling Spirometry Measurements with Unacceptable PFT Grade .......................  
4.5.2 
Handling Spirometry Data from Rescheduled Visits.................................................  
4.5.3 
Handling Optional Spirometry Measurements ................................................... 
4.5.4 
Handling Missing Co-primary Endpoint Data ..........................................................  
5. 
SUBJECT DISPOSITION ..............................................................................................  
5.1. DISPOSITION ...................................................................................................................................................  
5.2. PROTOCOL DEVIATIONS .............................................................................................................................  
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ...................................  
6.1. DEMOGRAPHICS ............................................................................................................................................  
6.2. BASELINE DISEASE CHARACTERISTICS .................................................................................................  
6.3. MEDICAL HISTORY ......................................................................................................................................  
6.3.1. 
General Medical History ...........................................................................................  
6.3.2. 
Disease-Specific History ...........................................................................................  
6.4. INCLUSION AND EXCLUSION CRITERIA ..................................................................................................  
7. 
TREATMENTS AND MEDICATIONS .......................................................................  
7.1. CONCOMITANT MEDICATIONS .................................................................................................................  


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7.2. STUDY TREATMENTS ...................................................................................................................................  
7.2.1. 
Treatment Compliance ..............................................................................................  
7.2.2. 
Extent of Exposure ....................................................................................................  
8. 
EFFICACY ANALYSIS .................................................................................................  
8.1. PRIMARY EFFICACY ENDPOINTS ..............................................................................................................  
8.1.1. 
Primary Analysis .......................................................................................................  
8.1.2. 
Assumption Testing ....................................................................................................  
8.1.3. 
Sensitivity Analyses ...................................................................................................  
8.1.4. 
Covariate Analysis ....................................................................................................  
9. 
SAFETY ANALYSIS ......................................................................................................  
9.1. ADVERSE EVENTS.........................................................................................................................................  
9.2. CLINICAL LABORATORY EVALUATIONS ...............................................................................................  
9.3. PHYSICAL EXAMINATION AND VITAL SIGNS .......................................................................................  
9.4. ELECTROCARDIOGRAM ...............................................................................................................................  
9.5. PREGNANCY ...................................................................................................................................................  
10. 
INTERIM ANALYSIS .....................................................................................................  
11. 
BLINDED SAMPLE SIZE RE-ESTIMATION ...............................................................  
12. 
REFERENCES ..................................................................................................................  
13. 
APPENDICES ...................................................................................................................  
13.1. 
SCHEDULE OF STUDY PROCEDURES ...................................................................................................  


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List of Abbreviations 
 
ADaM
Analysis Data Model (ADaM)
AE
Adverse event
AIC
Akaike information criterion
ANCOVA
Analysis of Covariance
ATS
American Thoracic Society
AUC
Area Under the Curve
AUC0-12 
Area Under the Concentration-Time Curve from Zero up to 12 Hours
BMI
Body Mass Index
BP
Blood pressure
CI
Confidence Interval
CMD
Concomitant Medication
CRF
Case report form
CTMS
Clinical Trial Management System
CT
Clinical Trial
CV
Coefficient of Variation
DBL
Database Lock
ECG
Electrocardiogram
eCRF 
Electronic Case Report Form 
xxx
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEV1 
Forced Expiratory Volume in 1 Second
GINA
Global Initiative for Asthma
ICF
Informed Consent Form
ICS
Inhaled corticosteroid
xxx
LABA
Long Acting β2 Agonist
LS
Least Squares
mcg
Microgram
MedDRA
Medical Dictionary for Regulatory Activities
NAEPP
National Asthma Education and Prevention Program
xxx
PD 
Protocol Deviation 
xxx
pMDI
Pressurized Metered-Dose Inhaler
PFT
Pulmonary Function Test
pMDI
Pressurized Metered Dose Inhaler
PPS
Per-Protocol Set
PT
Preferred Term
SABA
Short Acting β2 Agonist
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan


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SB
Single-Blind
SD
Standard Deviation
SDTM
Standard Data Tabulation Model
SID
Subject Identification
SOC
System organ class
SS
Sum of Squares
USA
United States of America
WHO
World Health Organization
 
1. Introduction 
 
Asthma is a common respiratory disease. It is characterized by chronic airway inflammation 
leading to airflow obstruction with symptoms such as breathlessness, cough, impairment of 
physical activity, and potentially death. Prevalence data in the United States between 2001 and 
2010 indicated an overall increase in asthma during the period [Akinbami, 2012], and by 2014, 
there were 24 million people with asthma [CDC, 2016]. 
 
Inhaled corticosteroids have been widely used as a safe and effective anti-inflammatory therapy 
for the treatment of persistent asthma for many years. Inhaled corticosteroids are recommended 
as the maintenance treatment of choice in treatment guidelines (ie, Global Initiative for Asthma 
[GINA] and the National Heart, Lung, and Blood Institute National Asthma Education and 
Prevention Program [NAEPP]) in all but patients with mild intermittent asthma whose symptoms 
are adequately maintained on short-acting β2 agonists (SABAs) alone. 
 
Long-acting β agonists (LABAs) have also been widely used as safe and effective bronchodilator 
therapy for the treatment of persistent asthma for many years, and they are also recommended as 
a maintenance therapy in conjunction with inhaled corticosteroids xxx for patients with moderate 
to severe asthma who remain symptomatic despite low-dose inhaled corticosteroids and SABAs 
(as needed). 
 
Symbicort® is approved by the US Food and Drug Administration (FDA) as a combination 
product containing a corticosteroid and a LABA and is indicated for the treatment of asthma 
patients 12 years of age and older and for the maintenance treatment of airflow obstruction in 
patients with chronic obstructive pulmonary disease including chronic bronchitis and 
emphysema. It is not indicated for the relief of acute bronchospasm. It is available as a 
pressurized metered-dose inhaler (pMDI) containing a combination of budesonide (80 or 160 µg) 
and formoterol (4.5 µg) as an inhalation aerosol and is administered as 2 inhalations twice daily 
(morning and evening, approximately 12 hours apart) [Symbicort, 2016]. 
 
3M Health Care Ltd (3M) is developing a drug product (3M Inhaler) that is a pMDI containing a 
combination of budesonide (80 µg) and formoterol (4.5 µg) as an inhalation aerosol. The 3M 
Inhaler is expected to be equivalent to the currently available Symbicort (referred to in this 
protocol as Symbicort Reference Inhaler) in terms of reproducibility of delivery of both emitted 
and respirable dose of medication. The 3M Inhaler is being developed as a generic equivalent of 
the Symbicort Reference Inhaler in order to provide a choice for patients, prescribers, and 
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2. Objectives 
 
CSP-07-000034 will investigate the effect of pMDI on FEV1 AUC0-12 after the first dose on 
Day 1 of the study and on FEV1 at the End-of-Treatment Visit (Week 6) to assess the 
equivalence of the 3M Inhaler compared with a Symbicort Reference Inhaler in delivering 
budesonide/formoterol fumarate (80 µg/4.5 µg). 
 
The primary objectives of this study are as follows: 
 To demonstrate the equivalence of the 3M Inhaler compared with a Symbicort Reference 
Inhaler in delivering budesonide/formoterol fumarate (80 µg/4.5 µg)
 
 To demonstrate the superiority of the 3M Inhaler and the Symbicort Reference Inhaler 
compared with placebo.
 
The safety objectives of this study are as follows: 
 
To assess the safety of the 3M Inhaler compared with a Symbicort Reference Inhaler in 
delivering budesonide/formoterol fumarate (80 μg/4.5 μg) and compared with placebo.
 
3. Investigational Plan 
 
3.1. Overall Study Design and Plan 
 
This is a randomized, single-blind, parallel-group, placebo-controlled, multidose study designed 
to evaluate local equivalence of 3M Inhaler vs. Symbicort Reference Inhaler. Specifically, 
equivalence of 3M Inhaler budesonide/formoterol fumarate (80 µg/4.5 µg) to Symbicort 
Reference Inhaler budesonide/formoterol fumarate (80 µg/4.5 µg) will be evaluated. Assay 
sensitivity analysis is also planned by comparing 3M Inhaler and Symbicort Reference Inhaler to 
Placebo inhalers. The co-primary endpoints for these analyses are AUC0-12 of the change from 
baseline in FEV1 at Day 1 and change from baseline in trough FEV1 (L) at the End-of-Treatment 
Visit (Week 6).  
 
Approximately 1470 adult subjects with asthma will be enrolled at approximately 100 study 
centers in the United States. Subjects will be assigned to study treatment only if they meet all of 
the inclusion criteria and none of the exclusion criteria. Each subject is expected to be in the 
study for approximately 8 to 10 weeks, which includes screening, a 2-week placebo run-in 
period, and a 6-week treatment period. It is expected that the total duration of the study will be 
approximately 9 to 12 months.  
During the screening visit, subjects will be given instructions on how to use the placebo run-in 
period inhaler, and subjects will be informed that compliance to the placebo run-in period inhaler 
schedule will be checked at the baseline visit. The first placebo run-in dose will be administered 
at the study center at the end of the screening visit. Compliance should be 75-125% of per 
protocol dosing for subjects to be eligible to enter the single-blind treatment phase of the study; 
timing of dosing will be captured in a subject diary and assessment of dose counters on inhalers 
will be made at study visits. The primary assessment of compliance will be the dose counter. 
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The study will incorporate: 
 
 A Screening visit (approximately 14-21 days prior to randomization), followed by a 14-21 
days placebo run-in period. 
 
 A 6-week study treatment period, encompassing the following visits: 
 
 Baseline Visit: Day 1 (Baseline) 
 The first telephone contact: Day 14 ± 2 days (Week 2) 
 The second telephone contact: Day 28 ± 2 days (Week 4) 
 End-of-Treatment Visit: Day 42 ± 2 days (Week 6). 
 
Screening to discharge will be approximately 2 months in duration. 
 
At the baseline visit, subjects will be given 2 inhalers of study medication, clearly labeled as 
Inhaler 1 and Inhaler 2, based on their randomized treatment (3M Inhaler, Symbicort Reference 
Inhaler, or placebo). Subjects will use Inhaler 1 until the Week 4 telephone call visit. At the 
Week 4 telephone visit, subjects will be instructed to switch to Inhaler 2 beginning with the 
evening dose on the day of the telephone visit and use that inhaler for the remainder of the study. 
 
The first dose of randomized treatment will be administered in the clinic on Day 1 with 
pulmonary function tests being performed up to 12 hours post dose. The FEV1 measurements 
from this visit are key to assessing the FEV1 AUC0-12 primary endpoint. The visit to assess 
change from baseline to the end-of-treatment in FEV1 is on the End-of-Treatment Visit (Week 
6). 
 
A complete overview of study activities is shown in the schedule of study procedures included in 
Appendix 13.1. 
 
3.2. Study Endpoints 
 
The following are the co-primary endpoints: 
 
 
Area under the concentration-time curve of the change from baseline in forced expiratory 
volume in 1 second (FEV1) from zero up to 12 hours (AUC0-12) at Day 1  
 
Change from baseline in trough FEV1 measured in the morning at the End-of-Treatment 
Visit (Week 6)
 
Safety will be evaluated by assessing number (percent), severity, and relatedness of AEs and 
SAEs between treatment groups. 
 
3.3. Treatments 
 
The following treatments will be administered during the study: 
 
 Run-in placebo via placebo inhaler (over the 2-week placebo run-in period, 2 inhalations 


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twice daily)
 Budesonide/formoterol fumarate (80 µg/4.5 µg) via the 3M Inhaler (over the 6-week 
treatment period, 2 inhalations twice daily)
 Budesonide/formoterol fumarate (80 µg/4.5 µg) via the Symbicort Reference Inhaler 
(over the 6-week treatment period, 2 inhalations twice daily)
 Placebo via a placebo inhaler (over the 6-week treatment period, 2 inhalations twice 
daily)
 
The 3M Inhaler is a pMDI containing a combination of budesonide (80 µg) and formoterol 
(4.5 µg) as an inhalation aerosol. The 3M Inhaler also contains the following inactive excipients: 
xxx. 
 
The Symbicort Reference Inhaler is a pMDI containing a combination of budesonide (80 µg) and 
formoterol (4.5 µg) as an inhalation aerosol. The Symbicort Reference Inhaler contains the 
following inactive excipients: xxx. The placebo inhaler is identical in appearance to the 3M 
Inhaler. It is a pMDI containing placebo as an inhalation aerosol. The placebo inhaler contains 
the same inactive excipients as the 3M Inhaler (without the active compounds). 
 
Each inhaler contains 120 actuations. 
 
3.4. Dose Adjustment/Modifications 
 
No dose adjustments or modifications are allowed for this study. 
 
4. General Statistical Considerations 
 
In general, descriptive statistics will be presented by treatment group and by visit, as applicable. 
For continuous variables, summary statistics for the raw value and change from baseline at each 
time-point will include the number of subjects (n), arithmetic mean, standard deviation (SD), 
median, minimum and maximum. 
Categorical variables will be summarized using subject counts and percentages. Percentages will 
be calculated using the total subjects per treatment unless otherwise specified. 
 
Baseline demographic data are those collected at Screening. Baseline spirometry data for the 
primary endpoints are defined in Section 8. No baseline testing will be performed for this study. 
 
The analysis set for assay sensitivity will be the Full Analysis Set and the analysis set for 
equivalence testing will be the Per Protocol Set. Analyses that are performed on the Full 
Analysis Set will use the planned treatment while analyses using the Per Protocol Set will use the 
actual treatment the subject received. See Section 4.4 for the Full Analysis Set and Per Protocol 
Set definitions. 
 
The safety analysis will be conducted on the Safety Set using the actual treatment the subject 
received. See Section 4.4 for the Safety Set definition. 
 
Listings will be presented by subject identifier and treatment group. In general, all listings will 
present all data for the Enrolled Set unless otherwise specified. 


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All statistical tests will be 2-sided and will be conducted at the 5% significance level, unless 
otherwise specified. P-values will be reported to 4 decimal places, with p-values less than 0.0001 
reported as “<0.0001”. 
 
SAS® version 9.2 or higher will be used to perform all statistical analyses or procedures. 
 
4.1. Sample Size 
 
Approximately 1470 adult subjects (18 years of age or older) with asthma are proposed to be 
randomized to the 3 treatment groups in a 3:3:1 ratio (630 subjects per active treatment group 
and 210 in the placebo group). 
 
4.1.1 Equivalence 
 
The sample size calculations for equivalence are mainly driven by demonstrating equivalence for 
the change from baseline in trough FEV1 (L) at the End-of-Treatment Visit (Week 6). 
Equivalence will be defined as the 90% CIs for the ratio (test/reference) falling within the (0.80, 
1.25) target ratio. The sample size of 567 subjects in each active treatment group will provide 
approximately 87.1% power at the 5% significance level for the equivalence test of means using 
two 1-sided tests and assuming a true ratio of the means equal to 0.95, coefficient of variance 
(CV) of 1.00, and equivalence limits of the mean ratio of 0.80 and 1.25. Similarly, for AUC0-12 
of the change from baseline in FEV1at Day 1 endpoint, using an SD of xxx the sample size of 
567 subjects in each active treatment group will provide 90.1% power at the 5% significance 
level for the equivalence test of means using two 1-sided tests and assuming a true ratio of the 
means equal to 0.95, CV of 0.95, and equivalence limits of the mean ratio of 0.80 and 1.25. The 
sample size will be based on the per-protocol set (PPS). Therefore, accounting for an 
approximate 10% dropout rate from the PPS, a sample size of 1470 subjects (630 subjects per 
active treatment group and 210 in the placebo group) is proposed. 
 
 
      xxxxx 
 
4.1.2 Superiority 
 
For the change from baseline in trough FEV1, the sample size of 630 in the active treatment 
group and 210 subjects in the placebo group will provide more than 99% power to reject the 
hypothesis of equal means at the 5% significance level using a 2-sided 2-sample equal-variance t 
test, assuming that the population mean difference xxx. 
 
Similarly, for FEV1AUC0-12, the sample size of 630 in the active treatment group and 
210 subjects in the placebo group will provide more than 99% power to reject the hypothesis of 
equal means at the 5% significance level using a 2-sided 2-sample equal-variance t test and using 
a population mean difference xxx. 
 
xxxxx 


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4.2. Randomization and Blinding 
 
Subjects will be randomly assigned to receive budesonide/formoterol fumarate (80 µg/4.5 µg) 
via a 3M Inhaler, budesonide/formoterol fumarate (80 µg/4.5 µg) via a Symbicort Reference 
Inhaler, or placebo using a 3:3:1 allocation ratio. xxx. Each qualified subject who is randomly 
assigned to study treatment will receive 1 kit xxx. As each inhaler holds sufficient medication 
for 30 days of twice-daily dosing, 2 inhalers are required for the subject to have sufficient study 
medication for the 6-week treatment period. Each inhaler will be clearly labeled as Inhaler 1 and 
Inhaler 2. 
 
This is a single-blind study. Subjects will not be informed of the study treatment to which they 
are randomly assigned. The appearance of the 3M Inhaler and the Symbicort Reference Inhaler 
are not identical so some subjects may be able to infer whether or not they have a Symbicort 
Reference Inhaler. 
 
4.3. Treatment Periods 
Placebo run-in period 
The placebo run-in period is defined as the period between the date of the first dose of run-in 
placebo and the day prior to the date of the first dose of single-blind study drug, inclusive. 
 
xxxxx 
 
Single-blind treatment period 
 
For efficacy data, the single-blind treatment period is defined as the period between the date of 
first dose of single-blind study drug and the End-of-Treatment Visit (Week 6) date ± 2 day, 
inclusive. 
 
Adverse events will be assessed beginning at enrollment (date of signed informed consent) and 
up to the End-of-Treatment Visit (Week 6). Even though the Investigator does not need to 
actively monitor subjects for AEs once the study has ended, SAEs occurring to a subject within 
30 days after the last dose of study medication should be reported if the Investigator becomes 
aware of them. 
 
xxxxx 
 
4.4. Analysis Sets 
 
Data will be analyzed and summarized using the analysis sets defined below. 
 
 


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4.4.1. Screened Set 
 
All subjects who signed the informed consent form (ICF). Screen failures are defined as subjects 
who never received placebo during the placebo run-in period and were not randomized in the 
study. 
 
4.4.2. Enrolled Set 
 
All subjects who took at least one dose of placebo run-in medication during the placebo run-in 
period. Run-in failures are defined as subjects who received the placebo study drug during the 
placebo run-in period but were not randomized in the study. 
 
4.4.3. Randomized Set 
 
All subjects randomly assigned to receive single-blind study treatment regardless of whether or 
not they received a dose of single-blind study medication. Mis-randomized subjects will be 
excluded. 
 
 
4.4.4. Full Analysis Set 
 
All randomized subjects who have taken at least one dose of single-blind study medication and 
have provided data for either the FEV1AUC0-12 endpoint measured on Day 1 or the endpoint for 
change from baseline in trough FEV1 at the End-of-Treatment (Week 6), including the baseline 
FEV1 value. All analyses using the FAS will group subjects according to randomized treatment. 
This analysis set will be used to assess the assay sensitivity of each active treatment (3M Inhaler 
and Symbicort Reference Inhaler) compared with placebo. 
 
4.4.5. Per Protocol Set 
 
All subjects in the Full Analysis Set who have not deviated from the protocol in such a way that 
could affect the outcome of the FEV1 assessments for both primary endpoints. 
Per definition, the PPS will only include subjects who received the single-blind study medication 
to which they were randomly assigned. This analysis set will be used to assess the therapeutic 
equivalence of 3M Inhaler compared with Symbicort Reference Inhaler. 
 
4.4.6. Safety Set 
 
All subjects who received any single-blind study medication. All analyses using the safety set 
will group subjects according to treatment actually received. All safety endpoints will be 
analyzed based on the Safety Set. 
 
 
 


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4.5. 
Spirometry Data Handling Conventions 
 
4.5.1 Handling Spirometry Measurements with Unacceptable PFT Grade 
FEV1 measurements with a PFT grade of ‘Unacceptable’ after best test review (BTR) will be 
excluded from the ADaM dataset. However, all data will be retained in the SDTM dataset. 
 
4.5.2 Handling Spirometry Data from Rescheduled Visits 
 
Per protocol Section 6.1, subjects may present for repeat spirometry and reversibility testing 
7 days (±1 day) after the Screening visit if they did not satisfy the FEV1 acceptability criteria. 
Spirometry data resulting from the repeat visits will be included in summary tables, listings 
and statistical analyses. However, all data, including those from the original visits will be 
retained in the ADaM and SDTM datasets. 
 
4.5.3 Handling Optional Spirometry Measurements 
 
xxxxx 
 
4.5.4 Handling Missing Co-primary Endpoint Data 
 
xxxxx 
 
5. Subject Disposition 
 
5.1. Disposition 
 
The number of subjects included in each analysis set will be presented by treatment group and 
overall. Three summary tables will be provided; one table for the Screened Set, a second table 
for the Enrolled Set and a third table for the Randomized Set.  
 
xxxxx 
 
5.2. Protocol Deviations 
 
Protocol deviations will be recorded within the xxx Clinical Trial Management System (CTMS) 
and will undergo a blinded review prior to database lock and unblinding. The 3M CSP-07- 
000034 Study Deviation Rules document contains potential protocol deviations, classified by 
CTMS subtype and whether the deviation is significant or not. xxx severity codes xxx will be 
assigned in order to identify significant deviations from the protocol that could affect 
inclusion/exclusion of subject data into the analysis sets or one of the sensitivity analyses. 
 
xxxxx 
 
 
 


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6. Demographics and Baseline Characteristics 
 
6.1. Demographics 
 
Demographic variables such as age, sex, race, ethnicity, height, weight, and body mass index 
(BMI) at baseline will be summarized. Continuous variables, such as age (years), body mass 
index, weight, height, asthma duration (years) and whether subject was on Short Acting β2 
Agonist (SABA) only at screening will be summarized using descriptive statistics for each 
treatment group. Categorical variables such as sex, ethnicity, and race will be summarized by 
reporting the number and percentage of subjects in each category for each treatment group. 
Summaries will be performed using the Full Analysis Set and Per Protocol Set. 
 
xxxxx 
 
Demographic data will be listed using the Screened Set. 
 
6.2. Baseline Disease Characteristics 
 
Spirometry data at Screening visit will be summarized using the Full Analysis Set. These 
parameters will include FEV1 (recorded as absolute volume in liters), both actual values and 
percent of predicted values; improvement and percent improvement in FEV1 (reversibility); FVC 
actual values; FEV1/FVC ratios. Baseline pre-dose spirometry measurements will also be 
summarized by time point, and treatment group using the Full Analysis Set. 
 
Spirometry data during the Screening visit will be listed using the Full Analysis Set. 
 
6.3. Medical History 
 
6.3.1. General Medical History 
 
Medical history of subjects will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The MedDRA version used for reporting the study will be documented in the 
summary table footnotes. The number and percentage of subjects in each primary system organ 
class (SOC) and each preferred term (PT) will be summarized by treatment group using the 
Safety Set. 
 
Each subject’s medical history will be listed by SOC and PT using the Safety Set. 
 
6.3.2. Disease-Specific History 
 
No disease-specific history summary tables or listings will be presented. 
 
6.4. Inclusion and Exclusion Criteria 
 
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criteria will be listed for the Screened set. 
 
7. Treatments and Medications 
 
7.1. Concomitant Medications 
 
Any prior and concomitant medication used during the study will be recorded and coded using 
WHODRUG. The WHODRUG version used for reporting the study will be documented in the 
summary table footnotes. Summaries of all medications by drug class (ATC Level 2 coding), 
preferred term and treatment group will be provided separately for prior medications and 
concomitant medications. xxxxx 
 
All prior and concomitant medications will be listed for the Enrolled Set using verbatim and 
preferred terms. 
 
7.2. Study Treatments 
 
7.2.1. Treatment Compliance 
 
Subject compliance will be assessed at the baseline visit (for the placebo run-in period inhaler) 
and at the End-of-Treatment Visit (Week 6) (for the single-blind study medication inhaler) using 
the dose counter on each inhaler. The diaries may also be used as a source for subject 
compliance, particularly when the study medications are not returned. 
 
Subjects are expected to take two inhalations twice daily for a total of 4 doses daily. Subjects 
will be defined as compliant if at least 75% and no more than 125% of study medication doses 
are used. Subjects who are deemed noncompliant (ie, <75% and >125% of study medication 
doses are used) after the run-in period will be removed from the study. 
 
xxxxx 
 
7.2.2. Extent of Exposure 
 
Descriptive summary statistics including the number of subjects, mean, standard deviation, 
median, minimum, and maximum for the duration of study drug exposure (days) will be 
presented by treatment group. Single-blind study drug duration of exposure will be categorized 
and summarized as follows: 1 day, >1 to ≤7 days, >7 to ≤14 days, >14 to ≤21 days, >21 to ≤28 
days, >28 to ≤35 days, >35 to ≤42days, >42 to ≤49 days and >49 days. Single-blind study drug 
exposure will be calculated as the number of days from first to last dose date of single-blind 
study drug. 
 
xxxxx 
 
 
 


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8. Efficacy Analysis 
 
8.1. Primary Efficacy Endpoints 
 
The co-primary endpoints for this study will be the AUC0-12 of the change from baseline in 
FEV1 measured on Day 1 (Baseline visit) and change from baseline in trough FEV1 (L) at the 
End-of- Treatment Visit (Week 6). FEV1AUC0-12 on Day 1 will be calculated from FEV1 
measurements collected 30 minutes prior to initial dose, at time point 0, and 0.5, 1, 2, 3, 4, 6, 8, 
10, and 12 hours after dosing for the calculation of FEV1AUC0-12. The baseline for the FEV1 
AUC0-12 endpoint is the mean of the 2 pre-dose FEV1 measures. In the unlikely event that 
either the 30 minute or 0 hour pre-dose FEV1 value is missing, the mean will be set to the non-
missing pre- dose measure for the Full Analysis set. However, for the Per Protocol set, such 
situation will result in a protocol deviation that removes the subject from the Per Protocol 
analysis. If both pre- dose values are missing then the baseline value will be missing. 
 
FEV1 AUC0-12 on Day 1 (Baseline visit) will be calculated as the area under the FEV1 effect 
curve over 12 hours post dose on Day 1 (Baseline visit), estimated by the linear trapezoidal rule 
and corrected for the appropriate baseline FEV1 value. The AUC formula by the trapezoidal rule 
is defined as: 
 
 
 
i=n  
FEV1AUC0-12 =

i=1 
ci + ci-1  (ti – ti-1)
2 
 
here n = number of non-missing time points for that subject 
i = sample number post-dose (ith FEV1 measurement on Day 1) 
t0 = clock time at dose administration 
ti = clock time at i 
c0 = 0, no change in FEV1 from baseline at baseline time point 
ci = change in FEV1 at ti from baseline 
xxxxx 
The second co-primary endpoint, change from baseline in trough FEV1 (L) at the End-of- 
Treatment Visit (Week 6) is based on two FEV1 assessments performed 30 minutes apart on Day 
42 (Week 6) or at the time of early discontinuation if subject terminates early from the study. 
The first spirometry assessment will be conducted at approximately the same time of day as the 
first pre-dose baseline spirometry assessment (ie, 30 minutes before initial dosing), and the 
second spirometry assessment will be performed at approximately 30 minutes later; the end-of- 
treatment FEV1 value will be the average of the 2 assessments. If either of the 2 spirometry 
values is missing, then FEV1 will be set to the non-missing value. The baseline FEV1 is defined 
as the average of the 2 pre-dose FEV1 values measured in the morning of the first day of 
treatment on Day 1. In the unlikely event that either the 30 minute or 0 hour pre-dose FEV1 value 
is missing, the mean will be set to the non-missing pre-dose measure for the Full Analysis set. 
However, for the Per Protocol analysis, such situation will result in a protocol deviation that 
removes the subject from the Per Protocol Set. 
 


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xxxxx 
 
8.1.1. Primary Analysis 
 
In order to show local equivalence, 3M Inhaler will be compared with the effect of Symbicort 
Reference Inhaler in delivering budesonide/formoterol fumarate (80 µg/4.5 µg) in a parallel 
group design; a placebo group will also be studied in order to show assay sensitivity for both 
primary endpoints. Assay sensitivity will be concluded if the p-value is less than 0.05 for the 3M 
Inhaler versus placebo and Symbicort Reference Inhaler versus placebo comparisons for both 
primary endpoints. It is anticipated that if the 2-sided 90% CI for the Least Squares (LS) mean 
ratios for both primary endpoints (3M Inhaler vs. Symbicort Reference Inhaler) are wholly 
contained within 80.00-125.00% limits, then this would be sufficient to show local equivalence 
[FDA, 2015]. 
The primary efficacy analysis will be performed to establish local equivalence of the 3M Inhaler 
vs. Symbicort Reference Inhaler.  xxxxx 
 
Equivalence Testing 
 
Separate linear ANCOVA models will be fit for each primary endpoint. Treatment (3M Inhaler 
and Symbicort Reference Inhaler) will be included as a fixed effect. Baseline FEV1 will be 
included as a continuous covariate. 
 
Least Squares (LS) means will be derived for each treatment (3M Inhaler and Symbicort 
Reference Inhaler) for each primary endpoint. To establish equivalence, LS means from the 
ANCOVA models for each endpoint will be used to generate ratios (3M Inhaler/Symbicort 
Reference Inhaler). Fieller’s theorem [Fieller E.,1954; Locke CS., 1984] will then be used to 
generate 2-sided CIs for the ratios for each endpoint. If the 2-sided 90% confidence intervals 
(CIs) for the ratios (3M Inhaler vs. Symbicort Reference Inhaler for each primary endpoint) are 
wholly contained within the interval 80.00-125.00% then we can conclude equivalence of 3M 
Inhaler to Symbicort Reference Inhaler. 
 
Assay sensitivity 
 
In order for the equivalence results to hold, assay sensitivity has to be established. For assay 
sensitivity the following comparisons need to be performed for each co-primary endpoint: 
 
1) 3M Inhaler versus placebo 
2) Symbicort Reference Inhaler versus placebo 
 
A linear ANCOVA model will be fitted for each co-primary endpoint. All three treatments (3M 
Inhaler, Symbicort Reference Inhaler and placebo) will be included as fixed effects. Baseline 
FEV1 will be included as a continuous covariate. LS means will be derived for each of the three 
treatments and LS mean differences will be calculated for 3M Inhaler versus placebo and 
Symbicort Reference Inhaler versus placebo for each primary endpoint. 
 


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Assay sensitivity will have been demonstrated if the p-values for all four comparisons are <0.05. 
No adjustment for multiplicity (i.e. potential loss of power due to making 4 comparisons) will be 
made because the primary endpoints are expected to be highly correlated. 
 
8.1.2. Assumption Testing 
 
The assumption of homogeneity of variances for the ANCOVA and Fieller’s confidence 
intervals will be evaluated using a combination of several methods, including significance 
testing, Akaike information criterion (AIC) criteria and diagnostic statistics and plots. To 
evaluate homogeneity of variance using the AIC criteria, two models will be fitted: one model 
assuming equal variances and another model assuming unequal variances. If the model assuming 
equal variances has a significantly smaller AIC then this provides evidence towards potential 
homogeneity of variance among treatment groups. xxxxx 
 
The same procedure for assessing homogeneity of variance will be applied to each of the 
sensitivity analyses of equivalence for the Per Protocol Set (see section 8.1.3). xxxxx 
 
The normality assumption for the FEV1 AUC0-12 endpoint and the change from baseline in trough 
FEV1 (L) at the End-of-Treatment Visit (Week 6) endpoint data will be checked using residual 
plots. xxxxx 
 
8.1.3. Sensitivity Analyses 
 
As defined in Section 4.4.5, the Per Protocol Set will exclude subjects who have deviated from 
the protocol in such a way that could affect the outcome of both primary endpoints. However, 
the primary endpoints for this study are measured at different occasions. The FEV1 AUC0-12 
endpoint is measured on Day 1 (Baseline Visit) and the change from baseline in trough FEV1 (L) 
at the End-of-Treatment Visit (Week 6) endpoint is measured at the End-of-Treatment Visit 
(Week 6). Therefore, it is entirely possible for a protocol deviation to affect one primary 
endpoint but not the other. xxxxx 
 
Sensitivity analyses will be carried out for both assay sensitivity and equivalence, for both 
primary endpoints, using the Per Protocol Set as a reference. Subjects will be excluded based on 
significant adverse events, significant protocol deviations, compliance, missing data and 
procedural issues that are considered relevant to the outcome of the primary endpoint under 
consideration.  
 
8.1.4. Covariate Analysis 
 
A covariate analysis based on the PP Set for both the AUC0-12 of the change from baseline in FEV1 
measured on Day 1 endpoint and the change from baseline in trough FEV1 (L) at the End-of- 
Treatment Visit (Week 6) endpoint assessing equivalence will be conducted to determine 
whether subjects who are on SABA only at Screening have a consistent treatment effect as all 
other subjects. ANCOVA models will be fit for each primary endpoint with treatment (3M 
Inhaler and Symbicort Reference Inhaler) included as a fixed effect, baseline FEV1 and SABA 
only at Screening indicator as covariates, and SABA only at Screening indicator by treatment 


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interaction term. If the interaction term is significant, subgroup tables will be produced for 
SABA only subjects vs. all other subjects.  
 
9. Safety Analysis 
 
Safety will be assessed by all AEs noted during study participation (including exacerbation of 
preexisting conditions), changes in concomitant medication during study participation (including 
change in dose), and changes from baseline in vital signs, ECGs or laboratory results. 
 
Adverse events will be assessed beginning at enrollment (date of signed informed consent) and 
up to the End-of-Treatment Visit (Week 6). Even though the Investigator does not need to 
actively monitor subjects for AEs once the study has ended, SAEs occurring to a subject within 
30 days after the last dose of study medication should be reported if the Investigator becomes 
aware of them. A treatment-emergent AE is defined as any event not present before exposure to 
single-blind study medication or any event already present that worsens in either intensity or 
frequency after exposure to study medication. 
 
All analyses of safety will be conducted using the Safety Set. 
 
9.1. Adverse Events 
 
A subject with multiple adverse events within a primary SOC or preferred term is only counted 
once towards the total for that SOC and/or preferred term. For the AE severity and relationship 
summaries, if a subject reported more than one adverse event with the same preferred term, the 
adverse event with the greatest severity or relationship will be presented. If a subject reported 
more than one adverse event within the same primary system organ class, then the subject will be 
counted only once with the greatest severity or relationship at the system organ class level. For 
table summaries, if severity is missing then ‘severe’ is assumed. If relationship is missing, 
relationship to study drug is assumed to be ‘related’. 
The number and percentage of subjects with treatment emergent adverse events as well as the 
number of events will be summarized in the following ways: 
 by primary system organ class, preferred term and treatment group 
 by primary system organ class, preferred term, maximum severity and treatment group 
 by primary system organ class, preferred term, relationship to study drug and treatment 
group 
The most common adverse events reported will be presented by preferred term in descending 
frequency starting from the most common event. 
The number and proportion of subjects as well as the number of events with the following types 
of events will be summarized by primary system organ class, preferred term and treatment: 
 Adverse events leading to treatment discontinuation 
 Serious Adverse Events (SAEs) 
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All adverse events, regardless of study period, will be included in a listing using the Screened 
Set. In addition the following select adverse events will be displayed in separate listings: 
 Deaths 
 Serious adverse events 
 Adverse events leading to dose interruption 
 Adverse events leading to treatment discontinuation 
 Adverse events requiring concomitant or additional treatment 
 
The above listings will use the Enrolled Set except for serious adverse events which will be listed 
for the Screened Set. 
 
9.2. Clinical Laboratory Evaluations 
 
Any data collected from the laboratory testing must be available in the source documents but will 
not be added to the analysis database. An abnormal laboratory value at the screening visit will be 
captured in the medical history. An abnormal laboratory value at the End-of-Treatment Visit 
(Week 6) that has worsened since the screening visit will be captured as an AE. 
 
9.3. Physical Examination and Vital Signs 
 
All data collected from the physical examinations and vital sign assessments must be available in 
the source documents but will not be added to the analysis database. An abnormal vital sign 
value or physical examination finding at the screening visit will be captured in the medical 
history. An abnormal vital sign value or physical examination finding at the End-of-Treatment 
Visit (Week 6) that has worsened since the screening visit will be captured as an AE. 
 
9.4. Electrocardiogram 
 
No ECG summary tables or listings will be presented. Data collected from the electrocardiogram 
assessments must be available in the source documents but will not be added to the analysis 
database. 
 
9.5. Pregnancy 
 
For females of childbearing potential only, a urine pregnancy test must be conducted at the 
screening and baseline visits, and a serum pregnancy test must be obtained at the screening and 
end-of-treatment visits. Both urine and serum pregnancy results will be included in the data 
listing. 
 
 
 


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10. Interim Analysis 
 
There is no interim analysis planned for this study. 
 
11. Blinded Sample Size Re-estimation 
 
A blinded sample size re-estimation may be performed after 30% of the subjects are enrolled to 
check for the sample size assumptions and, if necessary, increase the sample size. However, if a 
sample size re-estimation was to be performed, details would be prespecified in a protocol 
amendment prior to any statistical analysis of the data. 
 
12. References 
 
Akinbami L. Asthma Prevalence, Health Care Use and Mortality: United States, 2003-05 [cited]. 
 
Centers for Disease Control and Prevention (CDC). Asthma data, statistics, and surveillance: 
Most recent asthma data [Internet]. March 2016 [cited 2016 Sep 11]. Available from: 
http://www.cdc.gov/asthma/most_recent_data.htm. 
 
Chow, SC, Liu, JP. Design and Analysis of Bioavailability and Bioequivalence Studies, 3rd 
Edition. Chapman & Hall/CRC (2009). 
 
Food and Drug Administration (US FDA). Draft guidance for on budesonide; formoterol 
fumarate dihydrate. June 2015 [cited 2016 Sep 11] [7 screens]. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U 
CM452690.pdf. 
 
Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. 
2016 [cited 2016 Sep 11] [151 screens]. Available from: http://www.ginasthma.org. 
 
Hirschberg J, Lye J. A geometric comparison of the delta and Fieller confidence intervals. Am 
Stat. 2010;64(3):234-41. 
 
Fieller E. Some problems in interval estimation. J. Roy. Statist. Soc. B 16:175-185 (1954). 
 
Lee, JC, Lin, SH. Generalized confidence intervals for the ratio of means of two normal 
populations. Journal of Statistical Planning and Inference, 123, 49-60 (2004). 
 
Locke CS. An Exact Confidence Interval from Untransformed Data for the Ratio of Two 
Formulation Means. Journal of Pharmacokinetics and Biopharmaceutics, Vol. 12, No. 6:649- 
655(1984). 
 
National Asthma Education and Prevention Program (NAEPP) Expert panel report 3: Guidelines 
for the diagnosis and management of asthma. National Institutes of Health (NIH) publication No. 
07-4051. Bethesda, MD; US Department of Health and Human Services; NIH; National Heart, 
Lung, and Blood Institute, 2007. Available at: 
http://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln.pdf 


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Symbicort® (budesonide and formoterol fumarate dihydrate) [package insert]. AstraZeneca LP. 
Wilmington (DE); 2016 [cited 2016 Sep 28] [15 screens]. Available from: 
http://www.azpicentral.com/symbicort/symbicort.pdf. 
 
Wu, J, Jiang, G. Small sample likelihood inference for the ratio of means. Computational 
Statistics & Data Analysis, 38, 181-190 (2001). 


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13. Appendices 


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13.1. Schedule of Study Procedures 
This table provides an overview of the protocol visits and procedures in the Schedule of Events 
Section of the study protocol. 
 
Procedure 
Screening 
Visit1 
Baseline 
Visit 
Telephone 
Contacts 
End of 
Treatment 
 
 
Visit Day/Window 
-21 days 
to 
-14 days 
 
Day 1 
(12-hour visit) 
 
Day 14 
2 days 
 
Day 282
2 days 
 
Day 42 
2 days 
Informed consent
X
 
 
 
 
Medical history
X
 
 
 
 
Demographics
X
 
 
 
 
Electrocardiogram
X
 
 
 
 
Safety laboratory assessment (obtained 
locally)
X 
 
 
 
X 
Physical examination (with height 
[screening only] and weight)
X 
 
 
 
X 
Pregnancy test3
X
X
 
 
X
Vital sign (blood pressure and heart rate) 
assessments
X 
X 
 
 
X 
Spirometry assessments4
X
X
 
 
X
Inclusion/exclusion criteria review
X
X
 
 
 
Randomization using IWRS
 
X
 
 
 
Inhaler training
X
X
 
 
 
Dispense placebo run-in period inhaler
X
 
 
 
 
Dispense rescue therapy inhaler5
X
X
 
 
 
Dispense study medication
 
X
 
 
 
Concomitant medications
X
X
X
X
X
Adverse event monitoring
X
X
X
X
X
Training and dispensing of handheld 
device to collect xxx diary 
information 
X 
 
 
 
 
Study medication compliance and diary 
monitoring (retraining, as needed)
 
X 
X 
X 
 
Diary collection
 
 
 
 
X
1 Following the screening visit, there will be 14- to 21-day run-in period. If needed, subjects can also 
rescreen. See Section 3.2 for additional details on the run-in period and on rescreening. 
2 At the Day 28 (Week 4) visit, subjects will be instructed to switch to the second inhaler beginning with the 
evening dose on the day of the telephone visit. Subjects will be reminded not to take study medication 
within 12 hours (±2 hours) of the start time of their end-of-treatment visit. 
3 For females of childbearing potential only, a urine pregnancy test must be conducted at the screening and 
baseline visits, and a serum pregnancy test must be obtained at the screening and end-of-treatment visits. 
See Appendix 2 for a definition of childbearing potential. 
4 See Section 6.1 for details on each spirometry assessment. 
5 Ensure that the subject has enough rescue therapy (see Section 5.2.2) for the remainder of the study.