A Randomized Clinical Study to Assess the Impact of Symbicort® pMDI Medication Reminders on Adherence in COPD Patients
Phase: PHASE4
Conditions: Chronic Obstructive Pulmonary Disease (COPD
Sponsor: AstraZeneca

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Clinical Study Protocol 
Drug Substance
Symbicort 
Study Code
D589CL00003
Edition Number
3.0
Date
03 October 2016
A randomized clinical study to assess the impact of Symbicort® pMDI 
medication reminders on adherence in COPD patients 
Sponsor: AstraZeneca Pharmaceuticals LP
The following Amendment(s) and Administrative Changes have been made to this protocol since the date of 
preparation:
Amendment No.
Date of Amendment
Local Amendment No:
Date of Local Amendment
1
29 June 2016
2
03 October 2016
Administrative 
Change No.
Date of Administrative 
Change
Local Administrative 
Change No.
Date of Local 
Administrative Change
This submission document contains confidential commercial information, disclosure of which is prohibited 
without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 

Clinical Study Protocol Synopsis
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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PROTOCOL SYNOPSIS
A randomized clinical study to assess the impact of Symbicort® pMDI 
medication reminders on adherence in COPD patients
Study site(s) and number of subjects planned
Approximately six study sites within the United States (US) will enroll approximately
487 subjects in order to randomize a total of 414 adult subjects with chronic obstructive 
pulmonary disease (COPD).
Study period
Phase of development
Estimated date of first subject enrolled
Q3 2016
Phase IV
Estimated date of last subject completed
Q3 2017
Phase IV
Study design
This is a 26-week, 2-arm, randomized, multicenter, phase IV study to evaluate the impact of 
medication reminders on adherence to Symbicort pressurized metered-dose inhaler (pMDI),
budesonide/formoterol, 1ȝJx 2 actuations twice daily (bid) in subjects with COPD.  
This study will randomize approximately 414 subjects.
At the enrollment visit (Visit 1) entry criteria will be confirmed.  Subjects who are already on 
Symbicort and have met all eligibility criteria will be randomized at Visit 1 and will directly 
enter a 26-week treatment period (no run-in period).  Subjects who are taking another inhaled 
corticosteroid/long-DFWLQJȕ-agonist (ICS/LABA) combination at a dose approved for COPD 
at Visit 1 will be converted to Symbicort pMDI and will enter a 25-day run-in period after 
which they will attend Visit 2.  Subjects who still meet the eligibility criteria will be 
randomized at Visit 2 to the 26-week treatment period.  Subjects who entered the study on 
Symbicort will not participate in Visit 2.
Subjects will be randomized (1:1) to receive current care and a medication usage monitoring 
device (control group) or current care, a medication usage monitoring device and a supportive
service (intervention group). The service known as ‘BreatheMate’ includes a BreatheMate 
bluetooth device that monitors daily Symbicort inhaler use and a cellular phone application 
that provides support for subjects in the intervention group who are using Symbicort as part of 
their COPD maintenance therapy.  All subjects will receive a BreatheMate bluetooth 
monitoring device that will monitor daily Symbicort inhaler use, as well as a study-supplied 
cellular phone that is paired with the BreatheMate device and used to transmit data regarding 

Clinical Study Protocol Synopsis
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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Symbicort usage. Subjects in the intervention group will also receive audio-visual daily 
reminders (beeps and flashes) on the BreatheMate bluetooth monitoring device to take their 
Symbicort, and medication reminders from the cellular phone application. Subjects in the 
control group will not receive any reminders.
Subjects will be provided with a helpline phone number should they have any questions 
regarding use of the BreatheMate device or application. All subjects will also receive a 
telephone call from the study site coordinator 4 days after randomization to help resolve any 
issues they may have using the BreatheMate device or using the application (intervention 
group only).  In addition, 14 days after the randomization visit, all subjects’ data will be 
checked by the study coordinator.  If it appears that there is a technical issue (i.e., no data has 
been received from subjects following the enrollment visit), subjects will be contacted to 
assess if there are any potential technical issues, for example low signal (poor communication 
of phone signal) or issues due to removing the inhaler from the device.  Subjects may be asked 
to return to the clinic to receive additional training as required.  All subjects will receive a 
telephone call 90 days after randomization, to assess any adverse events (AEs) experienced, 
along with concomitant medication use.  There will be a final clinic visit (Visit 3) for all 
subjects at the end of the 26-week/6-month treatment period, as well as a follow-up phone call 
30 days thereafter.  The follow-up phone call will assess any AEs experienced since Visit 3,
along with concomitant medication use.
Objectives
Primary Objective:
Outcome Measure:
Demonstrate the impact of the BreatheMate 
medication reminders on adherence to 
Symbicort in COPD patients.
Adherence measured as mean number of sets of 
puffs/day for the entire 6 month study period.
Example: Mean of 2.00 would be equal to 100% 
adherence (2 sets of 2 puffs). To constitute as a set, 2
puffs must be taken within 60 minutes.
Secondary Objectives:
Outcome Measure:
Demonstrate improved symptom control from 
baseline with use of medication reminders.
Mean Clinical COPD Questionnaire (CCQ) symptom 
score (total, symptom, mental, and function score) in 
the control vs. intervention group at baseline, end of 
study, and change over the 6 month period.
Mean total and domain weekly CCQ scores for each 
2 month study interval (intervention group only).

Clinical Study Protocol Synopsis
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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Demonstrate the impact of the BreatheMate 
medication reminders on additional adherence 
measures.
Mean number of sets of puffs/day for each 2-month 
study interval.
Mean and total number of adherent days (2 sets of 2
puffs per day) per subject.
Mean number of prescription refills at pharmacy 
Target subject population
The target population includes patients (men or womeQ\HDUVRIDJH, who are current or 
past smokers with at least a 10 pack-year cigarette smoking history and a diagnosis of 
moderate to very severe COPD. COPD must be confirmed by a spirometry-verified post-
bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio 
of <0.70 at any time in the last 3 years. Most recent post-bronchodilator FEV1 should be 
<80% of predicted. Patients must be on an ICS/LABA indicated for COPD, and are already 
being treated with or are willing to convert to Symbicort at a dose labelled for COPD.  
Patients are required to have been on a stable dose of ICS/LABA combination products 
approved for COPD for at least 3 months prior to Visit 1. Additional medications for the 
treatment of COPD are allowed, if usage has been stable for at least 3 months. Patients are not 
eligible for study enrollment if they have had an acute exacerbation of COPD that required 
hospitalization or urgent ER visit, or treatment with systemic steroids or antibiotics, or both
during the 28 day period prior to Visit 1, or if they have a known malignancy, clinical disease, 
or disorder which in the Investigator’s opinion may put them at risk because of their 
participation.  At Visit 2, patients who convert to Symbicort will be asked if they have had a 
COPD exacerbation during the run-in period.  Should a COPD exacerbation have occurred 
during run-in, these patients will be considered to have failed screening, and will not be 
randomized at this time, but are eligible for a re-screen 28 days after the exacerbation.
Patients who failed screening at Visit 1 or Visit 2 due to a COPD exacerbation may be 
re-screened once.  Re-screening can occur no earlier than 28 days from the last dose of 
systemic steroid and/or antibiotics and/or hospitalization, whichever is later.  For patients who 
fail screening at Visit 1, re-screening shall include completion of a new Visit 1, and if the 
patient meets all eligibility criteria at the time of the new Visit 1, the patient can then proceed 
to the treatment period (for those who were on Symbicort at study entry) or enter the run-in 
period (for those who were not on Symbicort at study entry). For patients who fail screening 
at Visit 2, re-screening shall include completion of a new Visit 1; patients would be required 
to go through the run-in period again, and patients would also be required to attend Visit 2 
screening prior to being randomized.
Duration of treatment
Subjects who enter the study already on a stable dose of Symbicort will be enrolled and 
randomized at Visit 1 followed by a 26-week treatment period.  Subjects who are converted to 
Symbicort will be enrolled at Visit 1 and enter a 25-day run-in period after which they will be 
randomized at Visit 2, followed by a 26 week treatment period.  All subjects will receive a 

Clinical Study Protocol Synopsis
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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phone call at 90 days after randomization to check on AEs and concomitant medications, will
return to the clinic at week 26 for Visit 3 at the end of treatment, and will also participate in a 
follow-up telephone call 4 weeks after Visit 3.
The total planned study duration is 30 to 34 weeks (depending on whether the subject 
participates in a run-in period).
Investigational product, dosage and mode of administration
There is no pharmaceutical investigational product.  Symbicort pMDI will be the ICS/LABA 
utilized in this study as the BreatheMate bluetooth monitoring device has been designed and 
built to fit onto this specific inhaler.
All subjects will be taking Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations 
bid, for oral inhalation.
Outcome Measures:
Primary Outcome Measure:
x
Adherence measured as mean number of sets of puffs/day for the entire 6 
month study period
Secondary Outcome Measures:
x
Mean Clinical COPD Questionnaire (CCQ) symptom score (total, 
symptom, mental, and function score) in the control vs. intervention 
group at baseline, end of study, and change over the 6 month period
x
Mean total and domain weekly CCQ scores for each 2 month study 
interval (intervention group only)
x
Mean number of sets of puffs/day for each 2 month study interval
x
Mean and total number of adherent days (2 sets of 2 puffs per day) per 
subject
x
Mean number of prescription refills at pharmacy
Statistical methods
x
Analyses to address primary and secondary endpoints will be based on 
the full analysis set. The full analysis set will consist of all enrolled 
subjects who meet eligibility criteria and received at least 1 dose of 
Symbicort. This analysis set will be used for primary and secondary 
endpoints.

Clinical Study Protocol Synopsis
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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x
In general, summaries of continuous variables will be provided using 
number, mean, median, standard deviation, minimum, and maximum 
values. Summaries of categorical variables will be provided using 
number and percentage of subjects. The comparison of mean values 
between the intervention and control groups will be performed using a t-
test. An Analysis of Covariance (ANCOVA) model with the individual 
secondary continuous outcome measure as a dependent variable and 
potential covariates as independent variables will be used to estimate and 
compare means between the control and intervention groups. To select 
the best fit model, the backward elimination method will be used for the
ANCOVA model. Details of the methodology will be explained in the
statistical analysis plan (SAP).
x
The possible covariates that may affect adherence include: age, gender, 
race, smoking status, severity of COPD (Moderate, Severe + Very 
Severe), number of COPD exacerbations during the past 12 months at 
baseline, prior exposure to Symbicort at baseline (Symbicort naïve, 
Symbicort pre-treated), time on ICS/LABA medications in months at 
baseline (<6 months, PRQWKV New covariates and/or interactions may 
be added to the model if the real data exploration suggests that they are 
required.
x
Demographics, baseline disease characteristics, and vital signs will be 
summarized by treatment arm, and overall. Baseline vital signs and 
physical examinations will be summarized descriptively or categorically 
as applicable.  
x
Safety analyses will include an analysis of concomitant medication use.  
Concomitant medications will be analyzed by preferred medication terms 
and Anatomical Therapeutic Chemical classification using number and 
percentage of subjects. AEs will be presented in data listings using
standard Medical Dictionary for Regulatory Activities (MedDRA) terms. 
x
Subgroup analyses will be performed for the secondary outcome 
measures of interest. A 2-step approach will be followed for performing 
subgroup analyses. First, for a covariate to be qualified for the subgroup 
analyses a statistically significant association is to be established through 
a multivariable ANCOVA model for the continuous outcome variables.
The backward elimination method will be used to select the best model
and covariates. Second, a t-test comparison between the treatment arms 
for continuous secondary outcome measures stratified by individual
covariates will be performed. The second step will be followed for all 
eligible covariates which have a statistically significant association with 
the outcome variable in step one.

Clinical Study Protocol Synopsis
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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x
In general, missing data will not be imputed and the data will be analyzed 
as recorded on the study electronic case report forms (eCRFs).
Sample Size Determination
A total sample size of 352 subjects will be required for this study to achieve ~80% power to 
reject the null hypothesis of equal means of daily sets of Symbicort puffs per day when mean 
difference is μ1 - μ2 = 0.18, with a standard deviation for both groups of 0.6 and with a 
significance level Į of 0.05 using a 2-sided 2 sample equal-variance t-test. A dropout rate of 
15% will give rise to the total sample size of approximately 414 subjects. Therefore, the study 
will randomize approximately 207 subjects into each individual group. 

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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TABLE OF CONTENTS
PAGE
TITLE PAGE .......................................................................................................... 1 
PROTOCOL SYNOPSIS........................................................................................ 2 
TABLE OF CONTENTS........................................................................................ 8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................... 13 
1. 
INTRODUCTION................................................................................................. 15 
1.1 
Background and rationale for conducting this study............................................. 15 
1.2 
Rationale for study design, doses and control groups........................................... 15 
1.3 
Benefit/risk and ethical assessment....................................................................... 17 
1.4 
Study Design ......................................................................................................... 17 
2. 
STUDY OBJECTIVES......................................................................................... 20 
2.1 
Primary objective .................................................................................................. 20 
2.2 
Secondary objectives............................................................................................. 20 
3. 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ..................... 20 
3.1 
Inclusion criteria.................................................................................................... 20 
3.2 
Exclusion criteria................................................................................................... 21 
3.3 
Subject enrollment and randomization.................................................................. 23 
3.4 
Procedures for handling incorrectly enrolled or randomized subjects.................. 24 
3.5 
Methods for assigning treatment groups ............................................................... 24 
3.6 
Methods for ensuring blinding .............................................................................. 24 
3.7 
Methods for unblinding......................................................................................... 24 
3.8 
Restrictions............................................................................................................ 25 
3.9 
Discontinuation of use of the BreatheMate device ............................................... 25 
3.9.1 
Procedures for discontinuation of a subject .......................................................... 25 
3.10 
Criteria for withdrawal .......................................................................................... 25 
3.10.1 
Screen failures ....................................................................................................... 26 
3.10.2 
Withdrawal of the informed consent..................................................................... 26 
3.11 
Discontinuation of the study.................................................................................. 26 
4. 
STUDY PLAN AND TIMING OF PROCEDURES............................................ 27 
4.1 
Enrollment/screening period ................................................................................. 29 

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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4.1.1 
Screening Visit (Visit 1)........................................................................................ 29 
4.1.2 
Run-in Period and Visit 2...................................................................................... 29 
4.1.3 
Re-screen............................................................................................................... 30 
4.2 
Treatment period ................................................................................................... 30 
4.2.1 
Telephone contacts during the treatment period ................................................... 30 
4.3 
Follow-up period................................................................................................... 31 
5. 
STUDY ASSESSMENTS..................................................................................... 31 
5.1 
Efficacy assessments ............................................................................................. 31 
5.1.1 
Primary efficacy endpoints.................................................................................... 32 
5.1.1.1 
Adherence.............................................................................................................. 32 
5.1.2 
Secondary efficacy endpoints................................................................................ 32 
5.1.2.1 
Mean CCQ domain and total scores...................................................................... 32 
5.1.2.2 
Additional adherence measures............................................................................. 33 
5.2 
Safety assessments ................................................................................................ 33 
5.2.1 
Laboratory safety assessments .............................................................................. 33 
5.2.2 
Physical examination............................................................................................. 33 
5.2.3 
Vital signs.............................................................................................................. 33 
5.2.3.1 
Pulse and blood pressure....................................................................................... 33 
5.2.3.2 
Respiratory rate ..................................................................................................... 33 
5.2.3.3 
Body temperature .................................................................................................. 34 
5.2.4 
Diagnosis of COPD............................................................................................... 34 
5.2.4.1 
Level of COPD severity by airflow limitation...................................................... 34 
5.2.5 
COPD exacerbation assessment............................................................................ 34 
5.2.6 
Other safety assessments....................................................................................... 34 
5.3 
Other assessments.................................................................................................. 34 
5.3.1 
Patient reported outcomes ..................................................................................... 34 
5.3.1.1 
BreatheMate User Satisfaction Survey (Intervention group only)........................ 34 
5.3.1.2 
CCQ....................................................................................................................... 35 
5.4 
Pharmacokinetics................................................................................................... 35 
5.5 
Pharmacodynamics................................................................................................ 35 
5.6 
Pharmacogenetics.................................................................................................. 35 
5.7 
Biomarker analysis................................................................................................ 35 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT.............................. 35 
6.1 
Definition of adverse events.................................................................................. 35 
6.2 
Definitions of serious adverse event ..................................................................... 35 
6.3 
Recording of adverse events.................................................................................. 36 
6.3.1 
Time period for collection of adverse events ........................................................ 36 
6.3.2 
Follow-up of unresolved adverse events............................................................... 36 
6.3.3 
Variables................................................................................................................ 36 

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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6.3.4 
Causality collection............................................................................................... 38 
6.3.5 
Adverse events based on signs and symptoms...................................................... 38 
6.3.6 
Adverse events based on examinations and tests.................................................. 38 
6.3.7 
Malfunctions based on electronic devices used in the study................................. 39 
6.3.8 
Disease progression............................................................................................... 39 
6.3.9 
Concomitant medications...................................................................................... 39 
6.4 
Reporting of serious adverse events...................................................................... 39 
6.5 
Overdose................................................................................................................ 40 
6.6 
Pregnancy.............................................................................................................. 41 
6.6.1 
Maternal exposure................................................................................................. 41 
6.6.2 
Paternal exposure .................................................................................................. 42 
6.7 
Management of IP related toxicities...................................................................... 42 
6.8 
Study governance and oversight............................................................................ 42 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS.................... 42 
7.1 
Identity of investigational product(s) .................................................................... 42 
7.2 
Dose and treatment regimens ................................................................................ 42 
7.3 
Labelling................................................................................................................ 43 
7.4 
Storage................................................................................................................... 43 
7.5 
Compliance............................................................................................................ 43 
7.6 
Accountability ....................................................................................................... 44 
7.7 
Concomitant and other treatments......................................................................... 44 
7.8 
Post Study Access to Study Treatment.................................................................. 44 
8. 
STATISTICAL ANALYSES................................................................................ 44 
8.1 
Statistical considerations....................................................................................... 44 
8.2 
Sample size estimate ............................................................................................. 45 
8.3 
Definitions of analysis sets.................................................................................... 46 
8.3.1 
Full analysis set ..................................................................................................... 46 
8.4 
Outcome measures for analyses ............................................................................ 46 
8.4.1 
Primary outcome measure:.................................................................................... 46 
8.4.2 
Secondary outcome measures: .............................................................................. 46 
8.5 
Methods for statistical analyses............................................................................. 46 
8.5.1 
Demographic and baseline characteristics ............................................................ 46 
8.5.2 
Analysis of the primary variable (s)...................................................................... 47 
8.5.2.1 
Mean number of sets of Symbicort puffs/day over an average of 6 months......... 47 
8.5.3 
Analysis of the secondary variable(s) ................................................................... 47 
8.5.3.1 
Mean CCQ scores.................................................................................................. 47 

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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8.5.3.2 
Change in weekly total and domain CCQ scores in the intervention group 
for each 2 month interval....................................................................................... 47 
8.5.3.3 
Mean number of sets of Symbicort puffs per day at every 2 month interval........ 48 
8.5.3.4 
Mean and total number of adherent days .............................................................. 48 
8.5.3.5 
Mean number of Symbicort prescription refills .................................................... 48 
8.5.4 
Potential Covariates............................................................................................... 48 
8.5.5 
Subgroup analysis (if applicable).......................................................................... 49 
8.5.6 
Safety analysis....................................................................................................... 50 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA.......................... 50 
9.1 
Training of study site personnel............................................................................ 50 
9.2 
Monitoring of the study......................................................................................... 50 
9.2.1 
Source data ............................................................................................................ 51 
9.2.2 
Study agreements .................................................................................................. 51 
9.2.3 
Archiving of study documents .............................................................................. 51 
9.3 
Study timetable and end of study .......................................................................... 51 
9.4 
Data management by Quintiles ............................................................................. 51 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ........................................ 52 
10.1 
Ethical conduct of the study.................................................................................. 52 
10.2 
Subject data protection .......................................................................................... 52 
10.3 
Ethics and regulatory review................................................................................. 53 
10.4 
Informed consent................................................................................................... 53 
10.5 
Changes to the protocol and informed consent form ............................................ 54 
10.6 
Audits and inspections........................................................................................... 54 
11. 
LIST OF REFERENCES ...................................................................................... 54 
LIST OF TABLES
Table 1
Study Plan................................................................................................ 27 
LIST OF FIGURES
Figure 1
Study flow chart....................................................................................... 19 

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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LIST OF APPENDICES
Appendix A
Signatures
Appendix B
Additional Safety Information 
Appendix C
Clinical COPD Questionnaire
Appendix D
User Satisfaction Survey

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol
(CSP).
Abbreviation or 
special term
Explanation
AE
Adverse event
ANCOVA
Analysis of Covariance
bid
Twice daily
CCQ
Clinical COPD Questionnaire
COPD
Chronic obstructive pulmonary disease
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
eCRF
electronic case report form
EOT
End of treatment
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GCP
Good Clinical Practice
ICF
Informed consent form
ICH
International Council for Harmonization
ICS/LABA
,QKDOHGFRUWLFRVWHURLGORQJDFWLQJȕ-agonist
IRB
Institutional Review Board
IVRS
Interactive voice response system
IWRS
Interactive web response system
MedDRA
Medical Dictionary for Regulatory Activities
PI
Principal Investigator 
pMDI
Pressurized metered dose inhaler
SAE
Serious adverse event 
SAP
Statistical analysis plan
US
United States

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Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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Abbreviation or 
special term
Explanation
WBDC
Web based data capture
WOCBP
Women of child-bearing potential

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Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Chronic obstructive pulmonary disease (COPD) is a common disease with substantial 
associated morbidity and mortality.  COPD is the third-leading cause of death in the United 
States (US) and claimed 133,965 US lives in 2009 (Murphy et al 2013).  In 2011, 12.7 million 
US adults were estimated to have COPD (NHLBI 2012).  However, approximately 24 million 
US adults have evidence of impaired lung function, indicating an under diagnosis of COPD 
(Mannino et al 2002, van den Boom et al 1998).  COPD also has a potentially harmful 
economic impact. In 2010, COPD resulted in over 10 million office visits, nearly 1.5 million 
emergency department visits, 700,000 hospitalizations, and 133,575 deaths in the US (Ford et 
al 2013). In 2010, US total medical treatment costs attributed solely to COPD (i.e., excluding 
comorbidities) were estimated to be $32.1 billion, with an additional $3.9 billion in COPD 
costs resulting from worker absenteeism (Ford et al 2015). Even in industrialized countries 
such as the US where anti-smoking initiatives have been relatively successful, the legacy of 
past smoking behavior in aging populations ensures that the COPD burden will—
unavoidably—continue to climb over the next 20 to 30 years (Feenstra et al 2001).
Adherence rates for inhaled combination therapy is poor (average 3.9 refills per year) (Kern et 
al 2015). COPD patients with lower adherence tend to have higher overall healthcare costs, as 
demonstrated in a 24-month study of 33,816 patients in the US (Simoni-Wastila et al 2012),
which found:
x
Patients continuing therapy had lower costs of care by $3764 compared 
with patients who had ceased to take their maintenance therapy
x
COPD patients with higher adherence to prescribed regimens experienced 
fewer hospitalizations and lower Medicare costs (-$2185) than those who 
exhibited lower adherence behaviors
Given the poor adherence with inhaled combination therapy seen in patients with COPD, and 
associated morbidity/mortality and economic costs, the present study is being conducted to see 
if medication reminders can be used to improve adherence in this population.
1.2
Rationale for study design, doses and control groups
Note: In this CSP, the term “intervention group” refers to subjects who receive the 
BreatheMate bluetooth device (including audio-visual medication reminders) and a supportive 
BreatheMate cellular phone application.  The term “control group” refers to subjects who 
receive the BreatheMate bluetooth device with no audio-visual medication reminders, and a 
cellular phone but no supportive BreatheMate cellular phone application.  The term 
“BreatheMate service” refers to the BreatheMate bluetooth device and the BreathMate 
cellular phone application.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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The primary objective of this study is to determine the impact of medication reminders on 
adherence to Symbicort pressurized metered dose inhaler (pMDI) ȝJ x 2 actuations
twice daily (bid) in patients with COPD, as measured by mean number of sets of puffs/day 
over the entire 6 month study period.
The BreatheMate bluetooth device is attached to subjects’ Symbicort pMDI inhaler and 
automatically detects and logs their maintenance medication use.  The bluetooth device 
transmits this data to a cellular phone that is provided to all subjects in the study.
In addition, for subjects in the intervention group only, BreatheMate also includes a cellular
phone application that delivers: 1) daily reminder messages (pre-emptively) and alerts 
(following missed doses) to prompt subjects to take their medication as prescribed by their 
physician; 2) weekly reminders to fill out the Clinical COPD Questionnaire (CCQ); and 
3) monthly reminders to obtain Symbicort refills and attach them to the BreatheMate device.  
Subjects in the intervention group will also be able to receive feedback regarding their 
medication compliance over the previous 7-day period and will receive a notification from the 
application if no record of Symbicort use has been received over a 7-day period.
Subjects will have access to the BreatheMate device and application for a 6-month period. 
The primary outcome under investigation is the adherence to Symbicort among subjects in the
intervention group versus the control group throughout the treatment period.  Secondary 
outcomes to be investigated include:  1) mean total and domain CCQ scores (total, symptom, 
mental, and function score) at baseline, end of study, and change over the 6 month study 
period in the intervention vs. control group, 2) change in total and domain CCQ scores for
each 2-month study interval (intervention group only), 3) mean number of sets of puffs/day 
for each 2-month study interval, 4) mean and total number of adherent days and 5) mean 
number of prescription refills from the pharmacy.
A control group is included in this study in order to have a basis for comparison of adherence 
rates with and without the BreatheMate device audio-visual notifications and application
messaging reminders. Subjects in the control group will receive treatment with the same 
medication and dose as subjects in the intervention group6\PELFRUWS0',ȝJ
x 2 actuations bid was chosen because it is Food and Drug Administration (FDA)-approved as 
standard-of-care treatment for COPD and because the BreatheMate device is specifically 
engineered to fit the Symbicort pMDI.
Allocation of subjects to the intervention or control groups will be unblinded.  Sites will need 
to know how to instruct subjects in use of the device and cellular phone.  To avoid potential 
unintended differences in how subjects are treated, interaction with site staff will be kept to a 
minimum following randomization (1 phone call 4 days after randomization to answer 
questions, 1 phone call 14 days after randomization to subjects whose Symbicort bluetooth 
data seen from the server are low [i.e., no data received since enrollment visit], 1 phone call 
90 days after randomization to assess for adverse events [AEs] and concomitant medications,
1 visit at the end of the 26-week treatment period, and 1 follow-up phone call to assess for 
AEs and concomitant medications 30 days post-treatment period).

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
17(56)
Subjects who had an exacerbation of COPD symptoms within 28 days before randomization 
are excluded so that an accurate symptom baseline may be captured.
1.3
Benefit/risk and ethical assessment
The efficacy and safety profiles of SymELFRUWS0',ȝJx 2 actuations bid is well 
established for the maintenance treatment of COPD.  There are no known risks to general 
health or COPD symptoms associated with the BreatheMate service (device and application), 
and thus the service is considered to be of low risk to the subject. If the service malfunctions 
(no reminders are sent) the subjects’ COPD treatment will be no different from standard 
medical practice.  The risk/benefit profile is considered to be acceptable.
In addition, risks to study subjects have been minimized in the following ways:
x
All subjects will be screened and those with any chronic condition that 
could, in the judgment of the Investigator, represent a risk to safe 
participation, will be excluded.
x
Subjects will be routinely monitored for AEs during telephone contacts 
and clinic visits.
Each participating site will obtain Institutional Review Board (IRB) approval.
1.4
Study Design 
Figure 1 presents the overall design of the study.
This is a 26-week, 2-arm, randomized, multicenter phase IV study to evaluate the impact of 
PHGLFDWLRQUHPLQGHUVRQDGKHUHQFHWR6\PELFRUWS0',ȝJx 2 actuations bid in 
subjects with COPD.  This study will randomize approximately 414 subjects.
At the enrollment visit (Visit 1), entry criteria will be confirmed.  Subjects who are already on 
Symbicort and have met all eligibility criteria will be randomized at Visit 1 and will directly 
enter a 26-week treatment period (no run-in period).  Subjects who are taking another inhaled 
corticosteroid/long-DFWLQJȕ-agonist (ICS/LABA) combination at a dose approved for COPD 
at Visit 1 will be converted to Symbicort pMDI and will enter a 25-day run-in period after 
which they will attend Visit 2.  Subjects who still meet the eligibility criteria will be 
randomized at Visit 2 to the 26-week treatment period.  Subjects who entered the study on 
Symbicort will not participate in Visit 2. At the point of randomization, subjects in the control 
group will fill out a paper-based CCQ and subjects in the intervention group will fill out the 
CCQ using the study-supplied cellular phone.
Subjects will be randomized (1:1) to receive current care and a medication usage monitoring 
device (control group) or current care and a supportive service (intervention group).  All 
subjects will receive a BreatheMate bluetooth device that is attached to subjects’ Symbicort 
pMDI inhaler and automatically detects and logs their maintenance medication use.  All 

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
18(56)
subjects will also receive a study-supplied cellular phone that is paired with the BreatheMate 
device and used to transmit data regarding Symbicort usage.  All subjects will be required to 
place the cellular phone near the BreatheMate device on a daily basis so that data regarding 
Symbicort usage can be transmitted to the study site through the cellular phone.  
Subjects in the intervention group will receive audio-visual daily reminders (beeps and 
flashes) on the BreatheMate bluetooth device to take their medication.  In addition, for 
subjects in the intervention group only, BreatheMate also includes a cellular phone application 
that delivers: 1) daily reminder messages (pre-emptively) and alerts (following missed doses) 
to prompt subjects to take their medication as prescribed by their physician; 2) weekly 
reminders to fill out the CCQ; and 3) monthly reminders to obtain Symbicort refills and attach 
them to the BreatheMate device.  Subjects in the intervention group will also be able to 
receive feedback regarding their medication compliance over the previous 7-day period and 
will receive a notification from the application if no record of Symbicort use has been 
received over a 7-day period.
Subjects in the control group will receive treatment with the same medication and dose as 
VXEMHFWVLQWKHLQWHUYHQWLRQJURXS6\PELFRUWS0',ȝJ[DFWXDWLRQVELGZDVFKRVHQ
because it is FDA-approved as standard-of-care treatment for COPD and because the 
BreatheMate device is specifically engineered to fit the Symbicort pMDI.
Subjects will be provided with a helpline phone number should they have any questions 
regarding use of the BreatheMate device or application. All subjects will also receive a
telephone call from the study site coordinator 4 days after randomization to help resolve any 
issues they may have using the BreatheMate device or using the application (intervention 
group only).  In addition, 14 days after the randomization visit, all subjects’ data will be 
checked by the study coordinator.  If it appears that there is a technical issue (i.e., no data has 
been received from subjects following the enrollment visit), subjects will be contacted to 
assess if there are any potential technical issues, for example low signal (poor communication 
of phone signal) or issues due to removing the inhaler from the device.  Subjects may be asked 
to return to the clinic to receive additional training as required.  All subjects will receive a 
telephone call 90 days after randomization, to assess any AEs experienced, along with 
concomitant medication use.  There will be a final clinic visit (Visit 3) for all subjects at the 
end of the 26-week treatment period, at which time all subjects will fill out a paper-based 
CCQ. All subjects will receive a follow-up phone call 30 days thereafter.  The follow-up
phone call will assess any AEs experienced since Visit 3, along with concomitant medication
use.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
19(56)
Figure 1
Study flow chart
App=application
(a) Treatment Phase lasts 26 weeks. During the Treatment Phase all subjects will 
self-administer Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations 
bid, for oral inhalation. All patients will be contacted via phone 90 days after 
randomization to assess AEs and concomitant medications. Subjects in the intervention 
group will record their COPD symptoms on a weekly basis through the use of the CCQ 
on a study cellular phone.  Subjects in the intervention group will receive daily audio-
visual reminders through the BreatheMate device and application messages through 
the cellular phone to take the Symbicort inhaler as prescribed by their physician, a
notification from the application if no record of Symbicort use has been received over 
a 7-day period, weekly reminders to fill out the CCQ, and monthly reminders to obtain 
Symbicort refills and attach them to the BreatheMate device. All subjects will be 
instructed at randomization about how and when to prime their Symbicort Inhaler and 
that the priming should be done when the inhaler is not connected to the BreatheMate 
device.
(b) The Follow-up phone call will occur 30 days after the Treatment Phase ends. 

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
20(56)
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
Demonstrate the impact of the BreatheMate 
medication reminders on adherence to 
Symbicort in COPD patients.
Adherence measured as mean number of sets of 
puffs/day for the entire 6 month study period.
Example: Mean of 2.00 would be equal to 100% 
adherence (2 sets of 2 puffs). To constitute as a set, 2
puffs must be taken within 60 minutes.
2.2
Secondary objectives
Secondary Objective:
Outcome Measure :
Demonstrate improved symptom control from 
baseline with use of medication reminders.
Mean CCQ symptom score (total, symptom, mental, 
and function score) in the control vs. intervention 
group at baseline, end of study, and change over the 6 
month period.
Mean total and domain weekly CCQ scores over each 
2 month study interval (intervention group only).
Demonstrate the impact of the BreatheMate 
medication reminders on additional adherence 
measures.
Mean number of sets of puffs/day for each 2-month 
study interval
Mean and total number of adherent days (2 sets of 2 
puffs per day) per subject.
Mean prescription refills at pharmacy 
3.
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study subjects should fulfill the following criteria:
1.
Signed informed consent at Visit 1 prior to any study specific procedures.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
21(56)
2.
Outpatient adults 40 years and older.
3.
A diagnosis of COPD confirmed by a post-bronchodilator Forced Expiratory 
Volume in 1 second/Forced Vital Capacity (FEV1/FVC) <0.70 at some point in the 
past 3 years.
4.
Moderate to Very Severe COPD as defined by a post-bronchodilator FEV1 <80% of 
predicted on most recent spirometry.
5.
Had been on an ICS/LABA combination therapy of a brand and dose approved for 
COPD, for at least 3 months prior to screening.
6.
Current or previous smoker with a smoking history equivalent to 10 or more pack 
years (1 pack year = 20 cigarettes smoked per day for 1 year).
7.
Willing to discontinue all medications containing both a LABA and an ICS and to 
begin Symbicort 160/4.5 μg, 2 inhalations bid.
8.
Must be willing to make a return visit, and complete all study assessments for the 
duration of study.
9.
Life expectancy >12 months.
10.
Must be willing to comply with all study procedures including being able to remove 
and attach device to the inhaler.
11.
Must be able and willing to read and write/respond using the electronic device
provided.
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).
2.
Previous randomization in the present study.
3.
Patients who have been randomized in a clinical study and received an
investigational product within 30 days of Visit 1 (participation is defined as the 
completion of a treatment related visit).
4.
Current diagnosis of asthma.
5.
Known history of drug or alcohol abuse which, in the opinion of the Investigator, 
may interfere with subject’s ability to participate or comply with the study.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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6.
An acute exacerbation of COPD that required hospitalization or emergency room
visit or treatment with systemic steroids and/or antibiotics during the 28 days before 
Visit 1.
Patients who had a COPD exacerbation within 28 days of Visit 1 can be re-screened 
once. Re-screening can occur no earlier than 28 days from the last dose of systemic 
steroids and/or antibiotics and/or hospitalization, whichever is later.
7.
Enrolled patients that have a COPD exacerbation during the run-in period, defined 
as worsening symptoms which in the judgment of the Investigator requires 
treatment with systemic steroids and/or antibiotics and/or hospitalization.
Patients who had a COPD exacerbation during the run-in period can be re-screened 
once. Re-screening can occur no earlier than 28 days from the last dose of systemic 
steroid and/or antibiotics and/or hospitalization, whichever is later. 
8.
Any hospital admissions due to ischemic heart disease or heart failure within 
3 months of study enrollment.
9.
Any significant disease or disorder (e.g., gastrointestinal, liver, renal, neurologic, 
musculoskeletal, endocrine, metabolic, infectious, psychiatric, major physical 
impairment) which, in the opinion of the Investigator, may either put the patient at 
risk because of participation in the study, or may influence the results of the study, 
or the patient's ability to participate in the study.
10.
History of lung or upper airway cancer and any other malignancy not in remission 
for 5 years or more, except for patients who have had basal cell carcinoma, or in 
situ carcinoma of the cervix provided that the patient is in remission and curative 
therapy was completed at least 12 months prior to the date informed consent was 
obtained.
11.
Use or planned use of systemic corticosteroids as a maintenance treatment (defined 
as daily or every other day treatment for 21 or more days) for inflammatory or 
immunologic conditions unrelated to their COPD.
12.
Planned hospitalization or surgical procedure requiring inpatient stay during the 
study.
13.
Pregnancy, breast-feeding or planned pregnancy during the study; fertile women not 
using acceptable contraceptive measures, as judged by the Investigator. Female 
subjects who are not post-menopausal or surgically sterile must have a negative 
urine pregnancy test (urine dipstick test only) prior to randomization and must 
comply with contraceptive methods. 

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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14.
Any clinically relevant abnormal findings in physical examination or vital signs, 
which in the opinion of the Investigator, may put the patient at risk because of 
his/her participation in the study.
15.
Known or suspected hypersensitivity to the study therapy (Symbicort).
16.
Patients who are unable or unwilling to use mobile communication devices, or 
patients who plan to be away from home for a significant part of the study without 
access to cellular connectivity are excluded because of the challenges of collecting 
data and providing information to these patients who are unable to use the service.
17.
Patients with thoracic surgery within 6 months of Visit 1.
18.
Patients who have received a lung transplant or are currently active on the lung 
transplant waiting list.
Procedures for withdrawal of incorrectly enrolled subjects are described in Section 3.4.
3.3
Subject enrollment and randomization
Investigator(s) should keep a record, the subject screening log, of subjects who entered 
pre-study screening.
The Investigator(s) will:
1.
Obtain signed informed consent from the potential subject before any study specific 
procedures are performed.
2.
Assign potential subject a unique enrollment number, beginning with ‘E#’.
3.
Determine subject eligibility. See Section 3.1 and 3.2.
4.
Assign eligible subject a unique randomization code via an interactive voice 
response system (IVRS)/interactive web response system (IWRS).
If a subject withdraws from participation in the study, then his/her enrollment/randomization 
code cannot be reused.
Randomization codes will be assigned strictly sequentially as subjects become eligible for 
randomization.
If any patient reports symptoms of a COPD exacerbation within 28 days before Visit 1 or 
during the run-in period between Visit 1 and Visit 2, the patient shall not proceed to the 
treatment period, but may be re-screened once.  This is the only condition during which re-
screening is permitted in the study (see Section 4.1.3).

Clinical Study Protocol
Drug Substance Symbicort  
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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3.4
Procedures for handling incorrectly enrolled or randomized 
subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled at Visit 1 or enter the study treatment period.  There can be no exceptions to this rule.  
Subjects who are enrolled, but subsequently found not to meet all the eligibility criteria must 
not be randomized or initiated on treatment, and must be withdrawn from the study.
Where a subject does not meet all the eligibility criteria or meets any of the exclusion criteria
but is randomized in error, or incorrectly started on treatment, the Investigator should inform 
the AstraZeneca study physician immediately, and a discussion should occur between the 
AstraZeneca study physician and the Investigator regarding whether to continue or 
discontinue the subject from treatment. The AstraZeneca study physician must ensure all 
decisions are appropriately documented. 
3.5
Methods for assigning treatment groups
Subjects who meet all inclusion criteria and none of the exclusion criteria for this study will 
be randomized at Visit 1 (if they enter the study already on Symbicort) or Visit 2 (if they 
require conversion to Symbicort). 
After the subject eligibility (based on inclusion/exclusion criteria) is confirmed, the subject 
will be randomly assigned either to the intervention group or the control group.  Enrollment 
and randomization will be implemented using an IVRS/IWRS, which will be built and 
managed by
.  Using the randomization schedule the system will assign the next 
randomization record including randomization number.  Treatment assignment will be 
performed manually at the site.
The lead study statistician at 
 will be responsible for generating randomization 
schedules complying with the protocol and IVRS/IWRS specifications.  The randomization 
schedules will be developed based on the specifications provided in the IVRS/IWRS
requirements and design specification document.  There will be no stratification by site or any 
other parameters.  The list will be generated using SAS version 9.2 or higher in a permuted 
block design.  The block size will be balanced within each block and will maintain a 1:1 ratio 
between the intervention group and the control group.  Details of the format and generation of 
the randomization schedule will be provided in the statistical analysis plan (SAP).
3.6
Methods for ensuring blinding
Not applicable.  
3.7
Methods for unblinding 
Not applicable.
d

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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3.8
Restrictions
Refer to Exclusion Criteria in Section 3.2.
3.9
Discontinuation of use of the BreatheMate device
Subjects may be discontinued from using the BreatheMate device in the following situations:
x
Subject decision.  The subject is free to discontinue treatment at any time,
without prejudice to further treatment;
x
Safety reasons as judged by the Investigator and/or AstraZeneca.
Subjects who are discontinued will attend an end of treatment (EOT) visit.
3.9.1
Procedures for discontinuation of a subject 
At any time, subjects are free to discontinue use of the BreatheMate device or withdraw from 
the study (i.e., BreatheMate device and assessments – see Section 3.10), without prejudice to 
further treatment.  A subject that decides to discontinue use of the BreatheMate device will 
always be asked about the reason(s) for discontinuation and the presence of any AEs.  If 
possible, they will be seen and assessed by an Investigator(s).  Adverse events will be 
followed up (see Section 6); the BreatheMate device and cellular phone, as well as all study 
drugs and vouchers should be returned by the subject.
If a subject is withdrawn from the study, see Section 3.10.
3.10
Criteria for withdrawal 
Subject participation in this trial may be discontinued for any of the following reasons:
1.
Occurrence of any medical condition or circumstance that exposes the subject to 
substantial risk and/or does not allow the subject to adhere to the requirements of 
the protocol.
2.
Pregnancy.
3.
Any serious adverse event (SAE), clinically significant AE, intercurrent illness, or 
other medical condition where the Investigator or the Sponsor determines that 
continued participation is not in the best interest of the subject.
4.
Subject's decision to withdraw.
5.
Subject failure to comply with protocol requirements or study related procedures 
per Principal Investigator (PI) discretion. Low adherence to BreatheMate is not a 
criteria for withdrawal.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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6.
Termination of the study by the Investigator, Sponsor, FDA, or other regulatory 
authorities.
The clinical study report (CSR) will include reason(s) for subject withdrawals as well as 
details relevant to the subject withdrawal. If a subject is withdrawn from the trial prior to 
study completion, the subject will undergo all procedures scheduled for study completion 
(EOT evaluations) as the situation allows. Subjects who do not withdraw consent will receive 
a follow-up phone call 30 days after treatment ends.  Any subject withdrawn due to an AE 
(whether serious or non-serious) will be evaluated by the Investigator and will be treated 
and/or followed up until the symptoms return to normal or acceptable levels, as judged by the 
Investigator.
3.10.1
Screen failures 
Screening failures are patients who do not fulfill the eligibility criteria for the study, and 
therefore must not be randomized.
Patients who are screen failures due to an exacerbation of COPD during the 28 days prior to 
Visit 1, or during the run-in period between Visit 1 and Visit 2, may be re-screened once.  
This is the only provision for re-screening of screen failures in this study (see Section 4.1.3).
3.10.2
Withdrawal of the informed consent
Subjects are free to withdraw from the study at any time without prejudice to further 
treatment.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs.  The Investigator will follow up AEs outside of the clinical study. The subject will 
return the BreatheMate device, the study-provided cellular phone and prescription vouchers.
If a subject withdraws from participation in the study, then his/her enrollment/randomization 
code cannot be reused. Withdrawn subjects will not be replaced.
If possible, subjects should complete the EOT visit at the time of withdrawal of consent.
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that are not considered to be consistent 
with continuation of the study.
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the electronic Case Report Form (eCRF).
All reasons for discontinuation of treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
27(56)
4.
STUDY PLAN AND TIMING OF PROCEDURES
Table 1
Study Plan
Assessment
Screening
Treatment
Follow-up
Visit
1
2a
Phone Callsb
3c
(EOT)
Phone Call
Days
0
-25a
Day 
4
Day 
14
Day 
90
Day 
180
30 days 
after Visit 3
Visit Window (days)
±3
±1
±3
±7
±7
±3
Informed consent
X
Review of inclusion/exclusion criteria with 
documentation of post-bronchodilator FEV1/FVC ratio 
and FEV1% predicted
X
X
Demography and review of prior medications/therapies
X
Medical/surgical history 
X
COPD exacerbation history
Xd
COPD exacerbation assessment
Xd
X
Smoking history
X
Height and weight 
X
Physical examination
X
X
Randomization
Xe
Xf
Vital signs (pulse rate, blood pressure, respiratory rate, 
body temperature)
X
X
X
Pregnancy testingg
X
X
X
Distribute Symbicort pMDIh
X
Provide Symbicort pMDI training
X
Distribute prescription voucher cardsi
X
X
BreatheMate device and phone trainingj
Xe
Xf
BreatheMate device and phone dispensedk
Xe
Xf
Check-in on use of BreatheMate device/cellular phone 
application
Xb
Xb
Device and phone returnedl
X
Control only: paper-based CCQm
X
X
Intervention only: app-based CCQn
X
X
Both Intervention and Control: paper-based CCQo
X
User Satisfaction Surveyp
X
Concomitant medication/therapy review
X
X
X
X
X
Adverse event collection(AEs and SAEs)
X
X
X
X
CCQ: Clinical COPD Questionnaire, COPD: chronic obstructive pulmonary disease, EOT: end of treatment, pMDI:
pressurized metered-dose inhaler, SAE: serious adverse event.
a
Only subjects who are not already on Symbicort at study entry will be required to attend Visit 2.
b
There will be up to 3 phone calls during the Treatment Phase.  The first phone call will occur 4 days after start of the 
treatment intervention, to answer any questions the subject may have regarding use of the BreatheMate device or 
cellular phone application.  Fourteen days after subjects start the treatment intervention, the study site coordinator will 
check the subject’s Symbicort bluetooth data from the server. If it appears that there is a technical issue (i.e., no data 
has been received from subjects following the enrollment visit), subjects will be contacted to assess if there are any 

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
28(56)
potential technical issues. Subjects whose bluetooth data are being received by the server will not receive a phone call 
on Day 14.  All subjects will receive a phone call 90 days after the start of the treatment intervention to collect 
information regarding AEs and concomitant medication use.
c
Visit 3 will occur 180 days after the start of the treatment intervention.
d
Subjects who had an exacerbation of COPD during the 28 days prior to Visit 1 or during the run-in period between 
Visit 1 and Visit 2 will be considered to have failed screening and will not be randomized. However, re-screening is 
permitted once.
e
For subjects taking Symbicort at study entry and randomized at Visit 1.
f
For subjects who are converted to Symbicort and are randomized at Visit 2.
g
For women of child-bearing potential (WOCBP).  Pregnancy testing will be performed using a urine dipstick.
h
Subjects who agree to convert to Symbicort at Visit 1 will receive a Symbicort pMDI at Visit 1.  Subjects who convert 
to Symbicort will be asked to bring the inhaler with them to Visit 2 to be collected
i
Subjects who are randomized at Visit 1 will receive a 30-day prescription voucher that can be re-used each month at 
Visit 1.  Subjects who are randomized at Visit 2 will receive prescription vouchers at Visit 2.
j
Timing of reminders will be set at this visit for subjects in the intervention group.
k
All subjects will receive a starter pack which will include the BreatheMate device, cellular phone, cellular phone 
charger, and patient information leaflet (instructions on how to use the BreatheMate device and for subjects in the 
intervention group, instructions on using the cellular phone application).  The starter pack will also include contact 
information should subjects have questions on using the BreatheMate device or application.
l
At Visit 3, the site should confirm that the BreatheMate device and the phone are paired and connecting to ensure that 
all possible data has been transferred from the device to the application.
m
Completed on paper at Visit 1 for subjects randomized at Visit 1, and at Visit 2 for subjects randomized at Visit 2.
n
Completed weekly throughout the trial using the BreatheMate app, starting at Visit 1 for subjects randomized at Visit 1, 
and Visit 2 for subjects randomized at Visit 2.
o
Completed on paper at Visit 3 (EOT) for all subjects.
p
Completed by subjects in the intervention group only.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
29(56)
4.1
Enrollment/screening period
4.1.1
Screening Visit (Visit 1)
Procedures will be performed according to the Study Plan (Table 1). Informed consent will 
be signed prior to performing any protocol-required procedures.  Of note, the following will 
be performed during this visit:
x
Subjects who are randomized at Visit 1 will be trained in the use of the 
Symbicort inhaler, including priming procedures. Subjects who agree to 
convert to Symbicort at Visit 1 will receive a Symbicort inhaler and
training in use of the inhaler, including priming procedures at Visit 1.
x
Subjects who are randomized at Visit 1 will be dispensed a 30-day 
prescription voucher card which must be used each month during the 
study to obtain their Symbicort.
x
For subjects who are randomized at Visit 1: Device and cellular phone 
will be dispensed.
x
For subjects who are randomized at Visit 1: Device and phone training 
will occur for all subjects.  Subjects in the intervention group will also 
receive training on the BreatheMate supportive intervention application,
and the timing of application reminders will be set at Visit 1 for these 
subjects.
x
Subjects in the intervention group will complete the CCQ at 
randomization through the cellular phone application. Subjects 
randomized to the control group will complete the paper version of the 
CCQ.
x
Subjects will also be provided with contact information should they 
have any questions during the study.
4.1.2
Run-in Period and Visit 2
Patients who require conversion to Symbicort (are receiving a different ICS/LABA 
combination approved for COPD at Visit 1) will receive Symbicort pMDI, 
budesonide/formoterol, 160/4.5 μg x 2 actuations bid during a run-in period, and will 
participate in a second screening visit (Visit 2) on Day 25 ( ± 3 days).
Procedures at Visit 2 will be performed according to the Study Plan (Table 1).  Device and 
cellular phone training will be provided as described for Visit 1.  Subjects will be asked to 
bring their Symbicort inhaler with them to Visit 2 to be collected. Reusable 30-day 
prescription vouchers will be dispensed to subjects who meet the inclusion and exclusion 
criteria and are randomized at Visit 2.

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Drug Substance Symbicort
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Edition Number 3.0
Date 03 October 2016
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Subjects who require a run-in period and are randomized to the intervention group will 
complete the CCQ at Visit 2 through the cellular phone application. Subjects who require a 
run-in period and are randomized to the control group will complete the paper version of the 
CCQ at Visit 2.
4.1.3
Re-screen
If any patient reports symptoms of a COPD exacerbation (defined as worsening symptoms 
which in the judgment of the Investigator requires treatment with systemic steroids and/or 
antibiotics and/or hospitalization), within 28 days before Visit 1 or during the run-in period 
between Visit 1 and Visit 2, the patient shall not proceed to the treatment period, but may be 
re-screened.  Re-screening can occur no earlier than 28 days from the last dose of systemic 
steroid and/or antibiotics and/or hospitalization, whichever is later. 
For patients who fail screening at Visit 1, re-screening shall include completion of a new 
Visit 1 and if the patient meets all eligibility criteria at the time of the new Visit 1, the patient 
can then proceed to the treatment period (for those who were on Symbicort at study entry) or 
enter the run-in period (for those who were not on Symbicort at study entry).  For patients 
who fail screening at Visit 2, re-screening shall include completion of a new Visit 1, going 
through the run-in period, and attending Visit 2 screening again prior to being randomized.  
Patients who had a COPD exacerbation during screening can be re-screened only once.
4.2
Treatment period
Descriptions of the procedures for this period are included in the Study Plan with exceptions 
of the following specific requirements for the treatment period.
4.2.1
Telephone contacts during the treatment period
A member of the site staff will contact subjects by phone 4 days following randomization to 
offer support and help resolve any issues the subject may be having with the BreatheMate 
device (all subjects) or with the supportive BreatheMate application (intervention group 
only), or in completing the CCQ (intervention group only).
Fourteen days after the randomization visit, all subjects’ data in the system will be checked 
by the study staff. If it appears that there is a technical issue (i.e., no data has been received 
from subjects following the enrollment visit), subjects will be contacted to resolve possible 
issues such as an area of low signal (poor communication of phone signal), or removal of the 
BreatheMate device from the inhaler, and may be asked to return to the clinic to receive 
additional training as required.  No discussion regarding compliance should occur during this 
call.
All subjects will receive a telephone call 90 days after randomization.  The purpose of this 
phone call will be to collect information regarding AEs and concomitant medication use 
since randomization.

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Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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At Week 26 of the treatment period, subjects will return to the study site for the Visit 3/EOT 
visit. Procedures at the EOT visit will be performed according to the Study Plan (Table 1).
Of note, at Visit 3, the site should confirm that the BreatheMate device and the phone are 
paired and connecting, to ensure that all possible data has been transferred from the device to 
the application.
4.3
Follow-up period
All subjects will be contacted by phone 30 days after Visit 3 as a follow-up for safety.  
Adverse events and concomitant medications will be recorded.
5.
STUDY ASSESSMENTS  
An Inform web based data capture (WBDC) system will be used for data collection and 
query handling. The Investigator will ensure that data are recorded on the eCRFs as 
specified in the study protocol and in accordance with the instructions provided.
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA).
The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be 
archived at the study site.
5.1
Efficacy assessments
Efficacy data are collected using the BreatheMate service.  The service collects medication 
use measured and reported by a paired bluetooth device on a daily basis.
Data reporting for BreatheMate includes the following components: 
x
The web portal provides secure user registration for each study 
coordinator and Investigator for the intervention and control groups.
x
Linked mobile and web portal interfaces.
x
In-application messaging on the importance of taking Symbicort 
including both pre-emptive reminders to take medication as well as 
reminders of missed doses (intervention group only).
x
Reminders to obtain Symbicort refills and attach them to the 
BreatheMate device (intervention group only).
x
Collection of weekly respiratory symptoms through the CCQ via the 
BreatheMate application (intervention group only).
x
Collection of CCQ on paper forms at randomization (control group 
only) and EOT (both control and intervention groups).

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Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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5.1.1
Primary efficacy endpoints
5.1.1.1
Adherence
Adherence will be quantified as mean sets of puffs per day over the 6 month study period. A 
mean of 2.00 sets would be equal to 100% adherence (2 sets of 2 puffs). The 2 puffs that 
constitute a set must be taken within 60 minutes to count as a set.  A patient will not be given 
credit for taking more than 2 sets of 2 puffs a day, and any sets of puffs above 2 per day will 
not be included in calculations of the primary endpoint.
5.1.2
Secondary efficacy endpoints
5.1.2.1
Mean CCQ domain and total scores
The CCQ is a 10-item measure, divided into 3 domains (Symptoms: Items 1, 2, 5 and 6; 
Functional State: Items 7, 8, 9, and 10; and Mental State: Items 3 and 4) (Clinical COPD 
Questionnaire website; van der Molen et al 2003). Individual items within the CCQ are 
equally weighted.  The total score is calculated by adding the scores of the 10 items and 
dividing that number by 10 (=number of items).  In addition, individual domain scores can be 
calculated. The total CCQ score, and the score on each of the 3 domains, varies between 
0 (very good health status) to 6 (extremely poor health status).
In the intervention group, the CCQ is completed at Visit 1 for subjects randomized at Visit 1, 
Visit 2 for subjects randomized at Visit 2 and on a weekly basis, via the BreatheMate app. At 
the EOT visit (Visit 3), the CCQ is completed on paper.
In the control group, the CCQ is completed on paper at Visit 1 for subjects randomized at 
Visit 1, Visit 2 for subjects randomized at Visit 2, and Visit 3/EOT visit for all subjects in the 
control group.
Mean CCQ domain and total scores will be estimated at baseline and at EOT and compared 
between intervention and control groups using Analysis of Covariance (ANCOVA). The 
change in mean CCQ domain and total scores from baseline to EOT will be estimated and 
compared between intervention and control groups using ANCOVA. Additionally, mean 
weekly CCQ domain and total scores over each 2 month study interval will be estimated in 
the intervention group only. The change in mean weekly CCQ domain and total scores 
between the 2 immediate intervals and the first and the last intervals within the intervention 
group will be estimated and compared using ANCOVA. Thus the change in mean weekly
CCQ domain and total scores will be compared within the intervention group between the 
following 2-months intervals.
x
0RQWKV0RQWKIROORZ-up period) and >2 Months - 0onths 
(Month 4 follow-up period)
x
>2 Months - 0RQWKV0RQWKIROORZ-up period)  and >4 Months -
0RQWKV0RQWKIROORZ-up period)

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
33(56)
x
0RQWKs (Month 2 follow-up period) and >4 Months - 0RQWKV
(Month 6 follow-up period)
5.1.2.2
Additional adherence measures
Additional adherence measures include:
x
Mean number of sets of puffs/day for each 2-month study interval.
x
Mean and total number of adherent days (2 sets of 2 puffs per day) per
subject.
x
Mean number of prescription refills at pharmacy
5.2
Safety assessments
5.2.1
Laboratory safety assessments
No laboratory safety assessments will be conducted during the study.
Urine pregnancy testing will be conducted on WOCBP at Screening (Visit 1 and Visit 2 [as 
applicable]) and at Visit 3.  Urine dipsticks will be analyzed by study personnel at the study 
center.
5.2.2
Physical examination
A physical examination will be performed at Visit 1 and Visit 3/EOT and will include an 
assessment of the following:  general appearance, abdomen, cardiovascular and respiratory 
systems, weight and height.
5.2.3
Vital signs
Vital sign measurements in this study will include sitting systolic and diastolic blood 
pressure, pulse rate, respiratory rate, and body temperature.  Vital sign measurements will be 
measured at Visit 1, Visit 2 [as applicable], and Visit 3.
5.2.3.1
Pulse and blood pressure
Pulse rate should be measured before the blood pressure measurement.  An appropriate-sized 
cuff (cuff bladder encircling at least 80% of the group) should be used to ensure accuracy.  
This will be documented in the source documents at the investigative site.  
Blood pressure and pulse rate measurements must be performed while the subject is in a 
seated position.
5.2.3.2
Respiratory rate
Respiratory rate (breaths/min) will be measured.

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Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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5.2.3.3
Body temperature
Body temperature will be recorded in Celsius in accordance with local standards.
5.2.4
Diagnosis of COPD
Clinic Site Investigator will document date of diagnosis and a confirmatory post-
bronchodilator FEV1/FVC ratio <0.70.
5.2.4.1
Level of COPD severity by airflow limitation
Clinic Site Investigator will document most recent post-bronchodilator FEV1 % predicted.
5.2.5
COPD exacerbation assessment
Subjects will be queried at Visit 1, Visit 2 [as applicable], and Visit 3 as to whether they have 
experienced a COPD exacerbation, defined as an acute event characterized by a worsening of 
the subject’s respiratory symptoms that is beyond normal day-to-day variations and leads to a 
change in COPD medications.  In addition, if the study physician responds to calls from the 
subject or elevated symptoms reported by the subject, they may determine that the subject is 
experiencing an exacerbation.  In all cases where an exacerbation of COPD is reported, the 
following definitions will be used to grade the level of the exacerbation.  A moderate 
exacerbation shall be defined as worsening of COPD symptoms which in the judgment of the 
Investigator requires treatment with systemic steroids with or without antibiotics or 
antibiotics alone. A severe exacerbation shall be defined as a worsening of COPD symptoms 
which in the judgment of the Investigator or other healthcare provider requires emergency 
room (ER) stD\IRUKRXUVRUKRVSLWDODGPLVVLRQ
5.2.6
Other safety assessments
Adverse events and information regarding use of concomitant medications will be collected 
throughout the study (see Section 6). Device malfunctions that do not result in an AE will be 
tracked separately.
5.3
Other assessments
5.3.1
Patient reported outcomes
Subjects will complete the following self-administered patient-reported outcome measures at 
Visit 3 (EOT visit).
5.3.1.1
BreatheMate User Satisfaction Survey (Intervention group only)
Subjects in the intervention group will complete a paper-and-pencil user satisfaction survey 
regarding the BreatheMate device concerning ease of use, appearance and feel of the device.  
In addition, these subjects will complete questions regarding the cellular phone application
including ease of use, design, and helpfulness of reminders in improving compliance.
Investigators and study coordinators will fill out similar surveys regarding ease of use, 
accessibility of the BreatheMate web portal, design, patient adherence with daily ICS/LABA 

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Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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medication and medication re-fills, as well as overall usefulness of the BreatheMate device in 
clinical practice.
5.3.1.2
CCQ
Subjects in the intervention group will complete the CCQ using the BreatheMate app at 
randomization and weekly throughout the study. Subjects in the control group will complete 
a paper version of the CCQ according to the Study Plan (see Table 1). At Visit 3, all subjects 
will complete the CCQ on paper.
5.4
Pharmacokinetics
Not applicable.
5.5
Pharmacodynamics
Not applicable.
5.6
Pharmacogenetics
Not applicable.
5.7
Biomarker analysis
Not applicable.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, 
follow-up), that fulfills one or more of the following criteria:

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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x
Results in death;
x
Is immediately life-threatening;
x
Requires in-patient hospitalization or prolongation of existing 
hospitalization;
x
Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions;
x
Is a congenital abnormality or birth defect;
x
Is an important medical event that may jeopardize the subject or may 
require medical intervention to prevent one of the outcomes listed 
above.
For further guidance on the definition of a SAE, see Appendix B to the CSP.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse events will be collected from time of signature of informed consent (Visit 1) 
throughout the treatment period, and including the 30-day follow-up period (last telephone
contact).
SAEs will be recorded from the time of informed consent.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 
eCRF.  AstraZeneca retains the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Variables 
The following variables will be collect for each AE:
x
AE (verbatim)- specify if causally related to device or application;
x
The date (and time) when the AE started and stopped;
x
Maximum intensity of the AE;
x
Whether the AE is serious or not;
x
Investigator causality rating against Symbicort (yes or no);

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Edition Number 3.0
Date 03 October 2016
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x
Action taken with regard to Symbicort;
x
Whether or not AE caused subject’s withdrawal from study (yes or no);
x
Outcome.
In addition, the following variables will be collected for SAEs:
x
Date AE met criteria for SAE;
x
Date Investigator became aware of SAE;
x
Reasons AE is considered serious;
x
Date of hospitalization;
x
Date of discharge;
x
Probable cause of death;
x
Date of death;
x
Autopsy performed;
x
Causality assessment in relation to study procedure(s);
x
Description of AE.
Maximum intensities will be reported for each AE.  Maximum intensity refers to the 
complete course of the AE.  The subjects will be asked to assess the maximum intensity of 
the reported AEs according to the following scale:
x
Mild (awareness of sign or symptoms, but easily tolerated);
x
Moderate (discomfort sufficient to cause interference with normal 
activities);
x
Severe (incapacitating, with inability to perform normal activities).
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.

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Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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6.3.4
Causality collection
The Investigator will assess causal relationship between Symbicort and each AE, and answer 
‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the 
event may have been caused by Symbicort?’.
A guide to the interpretation of the causality question can be found in Appendix B to the 
CSP.
The Investigator will also assess the causal relationship between the device (Bluetooth 
monitoring device or phone) and each AE using the same criteria outlined above. If the 
Investigator feels the AE is related to the device, this should be captured in the AE Verbatim 
term field.
For SAEs, causal relationship will also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure, the causal 
relationship is implied as ‘yes’.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from protocol-mandated assessments and vital signs will be summarized in the
CSR.  Deterioration as compared with baseline in protocol-mandated vital signs or 
assessments should therefore only be reported as AEs if they fulfill any of the SAE criteria or 
are the reason for discontinuation from the study.
If deterioration in a vital sign is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an AE and the associated vital sign will be considered as 
additional information.  Wherever possible the reporting Investigator uses the clinical, rather 
than the laboratory term (e.g., anemia versus low hemoglobin value). In the absence of 
clinical signs or symptoms, clinically relevant deteriorations in non-mandated parameters 
should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical
examination as compared with the baseline assessment will be reported as an AE.

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Edition Number 3.0
Date 03 October 2016
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6.3.7
Malfunctions based on electronic devices used in the study
AEs that are related to the subjects’ use of the devices being tested in the study (BreatheMate 
device or cellular phone) will be collected by AstraZeneca and reported to the companies that 
manufacture those devices. Malfunction means the failure of a device to perform as specified 
or otherwise perform as intended.
6.3.8
Disease progression
Disease progression can be considered as a worsening of a subject’s condition attributable to
COPD.  It may be an increase in the severity of the disease under study and/or increases in 
the symptoms of the disease.  Events that are unequivocally due to disease progression, 
should not be reported as an AE during the study. Exacerbations of COPD that meet SAE 
criteria should be reported as SAEs.
6.3.9
Concomitant medications
All changes to a subject’s concomitant medications must be reported on the concomitant 
medications page of the eCRF and reasons for a change in medication that reflects an AE 
must be recorded on the AE page of the eCRF.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to Symbicort, the 
device (Bluetooth monitoring device or phone), or to the study procedure(s). All SAEs will 
be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the Inform system
(WBDC) an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by facsimile machine.

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Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed. 
6.5
Overdose
For the purposes of this study, an accidental or deliberate intake of more than 10 inhalations 
of Symbicort (1600 μg budesonide/45 μg formoterol) during a 24 hour period is defined as 
an overdose.  All overdoses with Symbicort should be reported to AstraZeneca.
Background
The risks associated with overdosage of Symbicort pMDI are considered to be small, as the 
safety margins for inhaled budesonide and formoterol are substantial.  Administration of a 
Symbicort Turbuhaler dose of 1600/45 ȝg over 1 hour on top of maintenance treatment with 
daily doses of 640 ȝg budesonide and 18 ȝg formoterol in asthmatic patients raised no safety 
concerns, nor did a formoterol dose of 90 ȝg over 3 hours in adult patients with acute 
bronchoconstriction or a budesonide dose of 7200 ȝg in healthy volunteers.
Symptoms
Corticosteroids have a low toxicity and are virtually without harmful effects after a single or 
a few doses, even if the doses are very high.  Thus, acute overdosage with budesonide – even 
in excessive doses – is not a clinical problem.  As with all ICSs, systemic corticosteroid 
effects may appear if used chronically in excessive doses.
There is limited clinical experience regarding overdosage with inhaled formoterol.  An 
overdose would likely lead to effects that are typical of ȕ2-agonists such as tremor, headache, 
and palpitations.  Symptoms and signs reported with formoterol from isolated cases are 
tachycardia, hyperglycemia, hypokalemia, prolonged QTc interval, arrhythmia, nausea, and 
vomiting.
Experience with other ȕ2-agonists has shown that overdoses may also cause restlessness, 
irritability, excitation, somnolence, convulsions, and hyper- or hypotension.  Metabolic 
effects may include acidosis and in serious cases, possibly rhabdomyolysis and renal failure.
Treatment suggestions
Normally, an overdose with Symbicort pMDI should not require any special treatment.  
However, if signs of adrenergic effects occur, these should be counteracted by supportive and 
symptomatic treatment, according to local routines.
Procedures for reporting an overdose
The following information should be provided:
x
Details of the subject who was prescribed the medication allowed in the 
study protocol.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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x
Details of the subject who took the overdose (demographic information, 
was subject a study participant?).
x
Details of the drug overdose (total daily dose, route, formulation, 
overdose start and stop dates).
x
Details of whether the recorded overdose was from actual inhalation of 
the Symbicort or discharge of the inhaler into the environment
x
Was the overdose accidental or intentional?
x
Was the overdose associated with an AE (serious or non-serious)?
x
AE description: provide start and stop dates of the event, or indicate if 
the event is ongoing.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
Pregnancy in itself is not regarded as an AE or SAE. However, Investigator/site staff should 
report pregnancies and their outcomes to AstraZeneca. Congenital abnormalities/birth 
defects and spontaneous miscarriages should be reported and handled as SAEs.  Elective 
abortions without complications should not be handled as AEs. The outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality) should be followed up and documented even if the subject was 
discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.

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Edition Number 3.0
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The same timelines apply when outcome information is available.
6.6.2
Paternal exposure 
The Investigator should also inform AstraZeneca of any paternal exposure pregnancies 
during the course of the study.  The female partner of the subject will be asked to consent to 
allow collection of information and follow-up on the pregnancy.  The outcome of the 
pregnancy should be reported to AstraZeneca.
6.7
Management of IP related toxicities 
Not applicable.
6.8
Study governance and oversight
Not applicable.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Investigational product
Dosage form and strength
Manufacturer
BreatheMate Device and 
Application
Not Applicable
Adherium
7.2
Dose and treatment regimens
There is no pharmaceutical investigational product.  Symbicort pMDI will be the ICS/LABA 
utilized in this study because the BreatheMate bluetooth monitoring device has been 
designed and built to fit onto this specific inhaler.  All subjects will use Symbicort pMDI, 
budesonide/formoterol, 160/4.5 μg x 2 actuations bid, for oral inhalation. Subjects who 
require a run-in period will be provided with a Symbicort inhaler at Visit 1. All subjects will 
obtain Symbicort inhalers, 160/4.5 μg x 2 actuations bid, needed for the treatment period 
through reusable prescription voucher cards provided at randomization.
The service known as ‘BreatheMate’ is a patient support tool that monitors daily Symbicort 
inhaler use.  This service will also provide support for subjects in the intervention group who 
are using Symbicort as part of their COPD maintenance therapy.
BreatheMate service includes: 
x
A bluetooth monitoring device provided to subjects in both the 
intervention and the control groups.  The bluetooth monitoring device is 

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
43(56)
attached to the COPD subjects’ Symbicort pMDI inhaler which 
automatically detects and logs their maintenance medication use.
Subjects in the intervention group will receive audio-visual daily 
reminders (beeps and flashes) on the BreatheMate bluetooth device.
This functionality is deactivated for the control group.
x
A cellular phone application, for subjects in the intervention group only, 
that delivers: 1) daily reminder messages (pre-emptively) and alerts 
(following missed doses) to prompt subjects to take their medication as 
prescribed by their physician; 2) weekly reminders to fill out the CCQ; 
and 3) monthly reminders to obtain Symbicort refills and attach them to 
the BreatheMate device.  Subjects, in the intervention group only, will 
also be able to receive feedback regarding their medication compliance 
over the previous 7-day period and will receive a notification from the 
application if no record of Symbicort use has been received over a 7-day 
period.
Note: Subjects in the control group will receive study cellular phones but they will not be 
equipped with the supportive application. The cellular phone for the control group will 
display whether the bluetooth monitoring device is paired and communicating with the 
cellular phone.  The bluetooth device will transmit data regarding medication usage to the 
cellular phones of all subjects, including those in the control group.  These data will be 
available for access by the study sites, but subjects in the control group will not have access 
to the data. Subjects in the control group will receive treatment with the same medication 
and dose as subjects in the intervention group.  SymbicoUWS0',ȝJ[DFWXDWLRQV
bid was chosen because it is FDA-approved as standard-of-care treatment for COPD and 
because the BreatheMate device is specifically engineered to fit the Symbicort pMDI.
7.3
Labelling
Drugs and devices are labelled according to local regulatory requirements.
7.4
Storage
All study drugs and devices should be kept in a secure place under appropriate storage 
conditions as stated on the labels and described in instructions provided together with the 
study drug/devices.  The study devices (i.e. BreatheMate device, Symbicort inhaler, and 
cellular phone) will be stored at ambient temperature.
7.5
Compliance
Adherence with the BreatheMate device and with the Symbicort medication will be measured 
by the BreatheMate device.

Clinical Study Protocol
Drug Substance Symbicort  
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
44(56) 
7.6
Accountability
The study personnel will account for all items dispensed at the sites including: Symbicort 
pMDI used during run-in period, the training inhaler, the BreatheMate device, and cellular
phone. 
Study personnel will also account for prescription voucher cards dispensed to and returned 
from the subject. 
7.7
Concomitant and other treatments 
Not applicable.  There is no disallowed medication in this study.   
7.8
Post Study Access to Study Treatment
Not applicable.
8.
STATISTICAL ANALYSES
Adherence will be estimated as the mean number of sets of Symbicort puffs per day over the 
6 month study period within the intervention and control groups and compared between the 2
groups using a t-test statistic. 
The mean domain and total CCQ scores at baseline, EOT and the mean change in CCQ 
domain and total scores from baseline to EOT will be compared between intervention and 
control groups using ANCOVA.  The mean change in CCQ domain and total scores between 
every immediate interval and first and last interval (as explained in Section 5.1.2.1) will be 
estimated and compared within intervention group using ANCOVA. Other additional 
adherence measures such as mean numbers of sets of puffs per day between every immediate 
interval and first and last interval, mean and total number of adherent days, and mean number 
of pharmacy refills will be estimated at a respective time points/interval and compared 
between intervention and control group using ANCOVA model.   
Analyses may be stratified by potential confounding variables for the outcome measures of 
interest if the confounding variables are found to be significantly associated with adherence.  
Details of the specific subgroup analyses will be described in the SAP.
8.1
Statistical considerations
Statistical analyses will be performed by 
. Details of the statistical analyses will be 
provided in the SAP. 
Analyses to address primary and secondary endpoints will be based on the full analysis set. 
The full analysis set will consist of all randomized subjects who meet eligibility criteria and 
received at least 1 dose of Symbicort.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
45(56)
In general, summaries of continuous variables will be provided using number, mean, median, 
standard deviation, minimum, and maximum values.  The comparison of mean values 
between the intervention and control groups will be performed using ANCOVA for the 
secondary continuous outcome measures.  The comparison of mean number of sets of 
Symbicort puffs per day will be performed using a t-test for the primary endpoint. 
Summaries of categorical variables will be provided using the number and percentage of 
subjects.  As applicable 2-sided binomial exact confidence intervals for proportions, and 95% 
confidence intervals for means of normally distributed variables will be provided. All 
significance tests will be conducted at the 0.05 significance level.
Demographic, baseline disease characteristics, and vital signs will be summarized by 
intervention group, control group, and overall.  Baseline vital signs and physical 
examinations will be summarized descriptively or categorically as applicable.  
Safety analyses will include an analysis of concomitant medications use.
In general, missing data will not be imputed and the data will be analyzed as recorded on the 
study eCRFs.
8.2
Sample size estimate
The sample size is based on the primary endpoint of an 18% absolute increase in mean 
number of daily sets of Symbicort puffs in COPD subjects receiving reminders compared 
with those who are not receiving reminders.  The null hypothesis is that there is no difference 
in adherence to Symbicort as measured by sets of puffs/day in COPD subjects who receive 
reminders compared with those who do not receive reminders.  The alternate hypothesis is 
that there is a difference in adherence to Symbicort as measured by sets of puffs/day in 
COPD subjects who receive reminders compared with those who do not receive reminders. A
mean of 2 sets of 2 Symbicort puffs per day is defined as 100% adherence to Symbicort. 
Based on the information received from the Health Core Research Environment claims
database, and the Simmons et al 1996 manuscript from the Lung Study, the mean Symbicort 
sets of puffs per day is assumed to be 1.0 (50% adherence) in COPD subjects.  It is assumed 
that the mean Symbicort sets of puffs per day in subjects receiving reminders will be 1.18 
which is an improvement in adherence of 18 percentage points compared with subjects not 
receiving reminders.  Thus a total sample size of 352 achieve ~ 80% power to reject null 
hypothesis of equal means of daily sets of Symbicort puffs per day when mean difference is 
μ1 - μ2 = 0.18 with a standard deviation for both groups of 0.6 and with a significance level 
Į of 0.05 using a two-sided two sample equal-variance t-test.  A dropout rate of 15% will 
give rise to the total sample size of approximately 414 subjects.  Therefore, the study will 
randomize approximately 207 subjects in each individual group.  The sample size was 
calculated using PASS software.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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8.3
Definitions of analysis sets
8.3.1
Full analysis set
The full analysis set will consist of all randomized subjects who meet eligibility criteria and 
received at least 1 dose of Symbicort. This analysis set will be used for both efficacy and 
safety analyses.
8.4
Outcome measures for analyses
8.4.1
Primary outcome measure:
x
Adherence measured as mean number of sets of puffs/day for the entire 
6 month study period
8.4.2
Secondary outcome measures:
x
Mean CCQ symptom score (total, symptom, mental, and function score) 
in the control vs. intervention group at baseline, end of study, and 
change over the 6 month period
x
Mean total and domain weekly CCQ scores over each 2 month study 
interval (intervention group only) 
x
Mean number of sets of puffs/day for each 2 month study interval
x
Mean and total number of adherent days (2 sets of 2 puffs per day) per 
subject
x
Mean number of pharmacy refills
8.5
Methods for statistical analyses
All computations and generation of tables, listings, and figures will be performed using 
SAS version 9.2 or higher.
The SAP will be generated to provide the details of the planned analysis. 
8.5.1
Demographic and baseline characteristics
Demographic and baseline characteristics will be summarized by intervention group, control 
group, and overall. Baseline demographic and clinical characteristics of study subjects will 
be summarized using descriptive statistics (number of subjects, mean, median, standard 
deviation, minimum, and maximum values for continuous variables); and number and 
percentage of subjects for categorical variables. Baseline characteristics will be provided 
with respect to 
x
Age, sex, and race (in countries where legally allowed)

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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x
Baseline vital signs such as height, weight, pulse rate, blood pressure, 
respiratory rate, and temperature
x
Baseline physical examination
x
COPD disease severity via airflow limitation
x
COPD disease via exacerbation history
x
COPD treatment history prior to start of Symbicort
The categorical variables will be compared using a chi-square test and the continuous 
variables will be compared between treatment arms using a t-test.
8.5.2
Analysis of the primary variable (s)
8.5.2.1
Mean number of sets of Symbicort puffs/day over an average of 6 months
The number of sets of Symbicort puffs per day will be estimated using means and compared 
using t-test between the intervention and control groups over an average of 6 months. The 
mean numbers of sets of Symbicort puffs/per day are calculated as explained in Section
8.4.1.
8.5.3
Analysis of the secondary variable(s)
8.5.3.1
Mean CCQ scores
The CCQ domain and total scores will be summarized descriptively.  The mean domain and 
total CCQ scores at baseline and EOT will estimated and compared using ANCOVA 
between the intervention and control groups.
Adjusted (least square) CCQ means may be analyzed for the statistically significant 
confounders. 
8.5.3.2
Change in weekly total and domain CCQ scores in the intervention group for 
each 2 month interval
The change in weekly CCQ domain and total scores will be summarized descriptively. The 
change in mean weekly CCQ domain and total scores from baseline to 6 months will be 
estimated and compared using ANCOVA between the intervention and control groups.  
Additionally, the mean change between 2 immediate intervals and the first and last intervals 
will be estimated within intervention group and compared using ANCOVA. 
The change from baseline to 6 months is calculated as weekly CCQ domain/total scores at 6 
months – weekly CCQ domain/total scores at the baseline 
The change between every 2-month intervals is calculated in intervention group as follows

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
48(56)
Weekly CCQ domain/total scores at the follow-up period 4 months – weekly CCQ 
domain/total scores at the follow-up period 2 months
Weekly CCQ domain/total scores at the follow-up period 6 months –weekly CCQ 
domain/total scores at the follow-up period 4 months
Weekly CCQ domain/total scores at the follow-up period 6 months – weekly CCQ 
domain/total scores at the follow-up period 2 months
Adjusted (least square) means for change in CCQ scores may be provided for the statistical 
significant confounders.
8.5.3.3
Mean number of sets of Symbicort puffs per day at every 2 month interval
Mean number of sets of Symbicort puffs per day are calculated as explained in Section 8.4.2.
The number of sets of Symbicort puffs per day will be summarized descriptively between 
and within treatment arms for every 2 months intervals. The comparisons of mean number of 
sets of Symbicort puffs per day between treatment arms at each interval will be performed 
using ANCOVA. The comparisons between each interval within individual treatment arm 
will be performed using ANCOVA. 
8.5.3.4
Mean and total number of adherent days
The number of adherent days will be calculated as explained in Section 8.4.2.  The number of 
adherent days will be summarized descriptively.  The mean adherent days will be compared 
between the intervention and control groups using ANCOVA.  Adjusted (least square) means 
for adherent days may be provided for the statistically significant covariates.
8.5.3.5
Mean number of Symbicort prescription refills
The mean number of Symbicort prescription refills will be calculated as explained in Section 
8.4.2. The number of prescription refills will be summarized descriptively. The mean number 
of refills will be compared between the intervention and control groups using ANCOVA. 
Adjusted (least square) means for prescription refills may be provided for the statistically 
significant covariates.
8.5.4
Potential Covariates
The following covariates will be evaluated to assess their association with the secondary 
outcome measures of 
x
Demographics (age [continuous], sex [male, female], race [white, 
non-white]) 
x
Smoking status (yes, no)

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
49(56)
x
Severity of COPD disease at baseline via level of airflow limitation-
moderate: post-bronchodilator FEV1 % predicted 50 to 79%, severe + 
very severe : post-bronchodilator FEV% predicted < 50%
x
Number of COPD exacerbations during the past 12 months at baseline 
(continuous)
x
COPD severe exacerbations during past 12 months at baseline (severe 
exacerbations, not severe exacerbations) where severe exacerbation of 
COPD is defined as the hospitalization for COPD during the past 
12 months of the baseline. 
x
Prior Symbicort treatment at baseline (Symbicort naïve, Symbicort 
pre-treated)
x
Time on ICS/LABA medications in months at baseline (<
If the number of subjects in the subcategories is <5, categorical covariates may be dropped or 
merged.
8.5.5
Subgroup analysis (if applicable)
Subgroup analyses will be performed for the secondary outcome measures of interest. Details 
of specific subgroups will be provided in the SAP. A 2- step approach will be followed for 
performing subgroup analyses. The step 1 will be analogous to performing analyses using 
either an ANCOVA for the continuous outcome variable. A backward elimination method 
will be used to select the best model. 
The second step will include a t-test comparison between the treatment arms for the 
continuous secondary outcome measures stratified by individual covariates. The second step 
will be followed for all eligible covariates which have demonstrated statistically significant 
association in the first step.    
The following subgroups are deemed to be of interest 
x
Sex (male, female) 
x
Race (white, non-white) 
x
Smoking status (yes, no)
x
Severity of COPD disease at baseline (moderate, severe + very severe)
x
COPD severe exacerbations during past 12 months at baseline (severe 
exacerbations, not severe exacerbations) where severe exacerbation of 
COPD is defined as the hospitalization for COPD during the past 
12 months of the baseline. 

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
50(56)
x
Prior Symbicort treatment at baseline (Symbicort naïve, Symbicort pre-
treated)
x
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For the binary outcomes, the proportion of subjects, odds ratios, and associated 95% 
confidence intervals will be estimated by the subgroup for intervention group and control. 
For the continuous outcomes the descriptive statistics will be provided. The subgroup 
analysis will only be performed if the number of subjects within each subgroup is at least 5.
8.5.6
Safety analysis
Safety analyses will include an analysis of concomitant medications use. Concomitant 
medications will be analyzed using medication preferred name and Anatomical Therapeutic 
Chemical class. The number and percentage of subjects using concomitant medication will 
be summarized. Adverse events will be presented in data listings.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the CSP and related documents with the investigational staff 
and also train them in any study specific procedures, the BreatheMate service (device and 
application), and any study specific procedures and systems utilized. 
The PI will ensure that appropriate training relevant to the study is given to all of these staff, 
and that any new information relevant to the performance of this study is forwarded to the 
staff involved.
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study 
site, including visits to:
x
Provide information and support to the Investigator(s)
x
Confirm that facilities remain acceptable
x
Confirm that the investigational team is adhering to the protocol, that 
data are being accurately and timely recorded in the eCRFs
x
Perform source data verification (a comparison of the data in the eCRFs 
with the subject’s medical records at the hospital or practice, and other 

Clinical Study Protocol
Drug Substance Symbicort  
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
51(56) 
records relevant to the study) including verification of informed consent 
of participating subjects. This will require direct access to all original 
records for each subject (e.g., clinic charts) 
x
Ensure withdrawal of informed consent to the use of the subject’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the subject. 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the center need information or advice about the study conduct. 
9.2.1
Source data
Refer to the CSA for location of source data. 
9.2.2
Study agreements
The PI at each center should comply with all the terms, conditions, and obligations of the 
CSA, or equivalent, for this study.  In the event of any inconsistency between this CSP and 
the CSA, the terms of CSP shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the CSA shall prevail.
Agreements between AstraZeneca and the PI should be in place before any study-related 
procedures can take place, or subjects are enrolled. 
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the CSA. 
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last subject undergoing the study’.
The end of the study definition is for the entire study, and not for a specific site.
The study is expected to start in Q3 2016 and to end by Q3 2017.  The recruitment period is 
expected to last approximately 6 months. 
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  
AstraZeneca may also terminate the entire study prematurely if concerns for safety arise 
within this study or in any other study with ICS/LABA medications.
9.4
Data management by 
Data management will be performed by 
, according to the Data Management Plan.
Adverse events and medical/surgical history will be classified according to the terminology 

Clinical Study Protocol
Drug Substance Symbicort  
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
52(56) 
of the latest version of the Medical Dictionary for Regulatory Activities.  Medications will be 
classified according to the AstraZeneca Drug Dictionary.  Classification coding will be 
performed by 
.
The data collected through third party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles 
and responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed and locked, clean file will be declared.  
Any treatment revealing data may thereafter be added and the final database will be locked.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.
Data Management of genotype data 
Not applicable. 
Management of external data 
Not applicable. 
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonization 
(ICH)/GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics and 
Human Biological Samples.
10.2
Subject data protection
The informed consent form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
53(56)
10.3
Ethics and regulatory review
An IRB should approve the final study protocol, including the final version of the ICF and 
any other written information and/or materials to be provided to the subjects.  The 
Investigator will ensure the distribution of these documents to the applicable IRB, and to the 
study site staff.
The opinion of the IRB should be given in writing. The Investigator should submit the 
written approval to AstraZeneca before enrollment of any subject into the study. 
The IRB should approve all advertising used to recruit subjects for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the IRB annually.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, IRBs, and PIs with safety updates/reports 
according to local requirements.
10.4
Informed consent
The PI(s) at each center will:
x
Ensure each subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the 
study.
x
Ensure each subject is notified that they are free to discontinue from the 
study at any time.
x
Ensure that each subject is given the opportunity to ask questions and 
allowed time to consider the information provided.
x
Ensure each subject provides signed and dated informed consent before 
conducting any procedure specifically for the study.
x
Ensure the original, signed ICF(s) is/are stored in the Investigator’s 
Study File.
x
Ensure a copy of the signed ICF is given to the subject.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
54(56)
x
Ensure that any incentives for subjects who participate in the study as 
well as any provisions for subjects harmed as a consequence of study 
participation are described in the ICF that is approved by an IRB.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the agreement of AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised CSP).
The amendment is to be approved by the relevant IRB before implementation.  Local 
requirements are to be followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each PI(s). For distribution to IRB see Section 10.3.
If a protocol amendment requires a change to a center’s ICF, AstraZeneca and the center’s 
IRB are to approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each IRB.
10.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an IRB may perform 
audits or inspections at the center, including source data verification.  The purpose of an 
audit or inspection is to systematically and independently examine all study-related activities 
and documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines of the 
ICH, and any applicable regulatory requirements.  The Investigator will contact AstraZeneca
immediately if contacted by a regulatory agency about an inspection at the center.
11.
LIST OF REFERENCES
Clinical COPD Questionnaire website
Clinical COPD Questionnaire website. http://ccq.nl/?page_id=15.  Accessed January 15, 
2016.
Feenstra et al 2001
Feenstra TL, van Genugten ML, Hoogenveen RT, Wouters EF, Rutten-van Mölken MP. 
The impact of aging and smoking on the future burden of chronic obstructive pulmonary 
disease: a model analysis in the Netherlands. Am J Respir Crit Care Med
2001;164(4):590-596.

Clinical Study Protocol
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
55(56)
Ford et al 2013
Ford ES, Croft JB, Mannino DM, Wheaton AG, Zhang X, Giles WH. COPD 
surveillance--United States, 1999-2011. Chest 2013;144(1):284-305.
Ford et al 2015
Ford ES, Murphy LB, Khavjou O, Giles WH, Holt JB, Croft JB. Total and state-specific 
medical and absenteeism costs of chronic obstructive pulmonary disease among adults 
aged 18 years in the United States for 2010 and projections through 2020. Chest 
2015;147(1):31-45.
Kern et al 2015
Kern DM, Davis J, Williams SA, Tunceli O, Wu B, Hollis S, et al. Comparative 
effectiveness of budesonide/formoterol combination and fluticasone/salmeterol 
combination among chronic obstructive pulmonary disease patients new to controller 
treatment: a US administrative claims database study. Respir Res 2015;16:52.
Mannino et al 2002
Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic obstructive 
pulmonary disease surveillance--United States, 1971-2000. Respir Care
2002;47(10):1184-1199.
Murphy et al 2013
Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital Stat Rep 
2013;61(4):1-117.
NHLBI 2012
National Institutes of Health National Heart, Lung, and Blood Institute Fact Book 
Prevalence of Common Cardiovascular and Lung Diseases, U.S., 2007-2011. https://www 
nhlbi nih gov/about/documents/factbook/2012/chapter4 htm#4_5 ;2014.
Simmons et al 1996
Simmons MS, Nides MA, Rand CS, Wise RA, Tashkin DP  Trends in compliance with
bronchodilator inhaler use between follow-up visits in a clinical trial.  Chest 1996: 109:963-
968.
Simoni-Wastila et al 2012
Simoni-Wastila L, Wei YJ, Qian J, Zuckerman IH, Stuart B, Shaffer T, et al. Association
of chronic obstructive pulmonary disease maintenance medication adherence with 
all-cause hospitalization and spending in a Medicare population. Am J Geriatr 
Pharmacother 2012;10(3):201-210.
van den Boom et al 1998
van den Boom G, van Schayck CP, van Mollen MP, Tirimanna PR, den Otter JJ, van 
Grunsven PM, et al. Active detection of chronic obstructive pulmonary disease and 
asthma in the general population. Results and economic consequences of the DIMCA 
program. Am J Respir Crit Care Med 1998;158(6):1730-1738.

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Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
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van der Molen et al 2003
van der Molen T, Willemse BW, Schokker S, ten Hacken, NH, Postma DS, Juniper EF.
Development, validity and responsiveness of the Clinical COPD Questionnaire. Health 
Qual Life Outcomes 2003;1:13. DOI: 10.1186/1477-7525-1-13.

Clinical Study Protocol Appendix A
Drug Substance
Symbicort
Study Code
D589CL00003
Edition Number
3.0
Date
03 October 2016
Protocol Dated
03 October 2016
Appendix A
Signatures

Clinical Study Protocol Appendix B
Drug Substance
Symbicort
Study Code
D589CL00003
Edition Number
3.0
Date
03 October 2016
Appendix B
Additional Safety Information

Clinical Study Protocol Appendix B
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
2 (3)
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
x
Angioedema not severe enough to require intubation but requiring intravenous
hydrocortisone treatment
x
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine
x
Intensive treatment in an emergency room or at home for allergic bronchospasm
x
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization
x
Development of drug dependency or drug abuse

Clinical Study Protocol Appendix B
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
3 (3)
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
x
Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?
x
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
x
De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?
x
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
x
Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AstraZeneca would not normally 
recommend or support a re-challenge.
x
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship.
In difficult cases, other factors could be considered such as:
x
Is this a recognized feature of overdose of the drug?
x
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

Clinical Study Protocol Appendix C
Drug Substance
Symbicort
Study Code
D589CL00003
Edition Number
3.0
Date
03 October 2016
Appendix C
Clinical COPD Questionnaire

Clinical Study Protocol Appendix C
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
2(2)
1.
CLINICAL COPD QUESTIONNAIRE

Clinical Study Protocol Appendix D
Drug Substance
Symbicort
Study Code
D589CL00003
Edition Number
3.0
Date
03 October 2016
Appendix D
User Satisfaction Survey

Clinical Study Protocol Appendix D
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
2(3)
1.
USER SATISFACTION SURVEY
BreatheMate User Satisfaction Survey - Patient
We would like your feedback on the product. We will assess and use your feedback to 
improve the product.
PART 1 – BreatheMate Mobile App
Have you used BreatheMate mobile app? YES/NO [if ‘YES’ selected, continues to 
questions below, ‘NO’ exits part 1]
Statement
1
2
3
4
5
Strongly 
disagree
Disagree
Indifferent
Agree
Strongly 
agree
1
The BreatheMate app is easy to use
2
I did not have any technical 
difficulties in using the app and 
phone
3
The BreatheMate app has a suitable 
number of options to tailor how I 
would like to receive my reminders
4
The BreatheMate app has a clean, 
uncluttered design
5
The medication reminders were 
helpful to ensure I was talking my 
medication as prescribed.
PART 2 – SmartTouch Symbicort Device
Have you used the SmartTouch Symbicort device? YES/NO [YES, continues to questions 
below, NO exits]
Statement
1
2
3
4
5
Strongly 
disagree
Disagree
Indifferent
Agree
Strongly 
agree
1
SmartTouch Symbicort device is 
easy to use
2
SmartTouch Symbicort device has 
all the features I expected it to have
3
The visual and audio reminders on 
the device were helpful to ensure I 
was taking my medication as 
prescribed
4
The SmartTouch Symbicort device 
was easy to take on and off of my 
Symbicort medication 
5
SmartTouch Symbicort device has a 
great look and feel

Clinical Study Protocol Appendix D
Drug Substance Symbicort
Study Code D589CL00003
Edition Number 3.0
Date 03 October 2016
3(3)
BreatheMate User Satisfaction Survey – Investigator and Study 
Coordinator
[Note: Investigators and Study Coordinators will complete separate and identical User 
Satisfaction Surveys at the completion of the study]
Have you used the BreatheMate web portal? YES/NO [YES, continues to questions below, 
NO exits]
Statement
1
2
3
4
5
Strongly 
disagree
Disagree
Indifferent
Agree
Strongly 
agree
1
The BreatheMate web portal is easy 
to use
2
The BreatheMate web portal has all 
the features I expected it to have
3
I could complete/view  tasks in the 
BreatheMate web portal with a 
minimum number of clicks
4
The BreatheMate web portal has a 
clean, uncluttered design
5
The information provided by the 
BreatheMate web portal is easy to 
find and to understand (including 
graphs)
6
The BreatheMate reminders improve 
patient compliance with their daily 
ICS/LABA medication 
7
The BreateMate service improves 
medication refills
8
The BreatheMate service would be 
useful to me in helping patients to 
manage their condition
Thank you very much for completing the survey, your support and feedback are appreciated