Clinical trial NCT01176916
Conditions: Breast Neoplasms
Keywords: breast cancer Aromasin adjuvant chemotherapy endocrine therapy
Sponsor: Pfizer
Start date: 2011-02-09; Completion date: 2018-11-30
Enrollment: 564 participants; Allocation: ; Intervention model: 

Brief summary:
Aromasin® (Exemestane) was approved in China for adjuvant treatment of postmenopausal women with estrogen receptor (ER) positive early invasive breast cancer who have received 2-3 years of tamoxifen \& are switched to Aromasin® for completion of a total of 5 consecutive years of adjuvant hormonal therapy by State Food and Drug Administration (SFDA) with clinical trial waive. While Aromasin® has been used in China for adjuvant therapy of breast cancer since then, there is currently lack of systematic collection and analysis for the efficacy and safety data of Aromasin® adjuvant setting in Chinese population. The Aromasin® Interventional Study is being proposed to collect data systematically and to assess the efficacy and safety of Aromasin® adjuvant setting in Chinese population.

Detailed description:
This is interventional study and single arm study. N/A

Arms: arm 1: None
Interventions: intervention 1: Aromasin (exemestane)
Intervention descriptions: intervention 1: the dosage, frequency and duration base on the LPD approved by SFDA.

Protocol documents:
Prot_001.pdf: 
Aromasin® (Exemestane) 
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Final Protocol Amendment 4, 29-June-2016 
 
 
 
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`
PRAGMATIC CLINICAL TRIAL PROTOCOL  
A PROSPECTIVE PRAGMATIC CLINICAL TRIAL OF CHINA EARLY INVASIVE 
BREAST CANCER PATIENTS RECEIVING ADJUVANT THERAPY WITH 
AROMASIN 
Protocol Number: 
A5991093 
Medicinal product: 
Aromasin® (Exemestane) 
United States (US) Investigational New 
Drug (IND) Number: 
Not applicable (N/A) 
European Clinical Trial Database 
(EudraCT) Number: 
N/A 
Universal Trial Number: 
N/A 
Phase: 
4 
 
 
 


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Document History 
Document 
Version 
Date 
Substantial or 
administrative 
amendment 
Protocol 
section(s) 
changed 
Summary of Changes 
Reason 
Amendment 
4 
29 June 
2016 
Substantial 
Study type 
change 
Requisite changes were made to 
the protocol in light of the change 
from a non-interventional study to 
an interventional study (CT-45); 
no other substantial changes were 
introduced 
Non-
interventional 
study transfer to 
pragmatic study 
type 
Amendment 
3 
20 
March 
2015 
Administrative 
Amendment 
 
The protocol template update 
The protocol 
template update
Administrative 
Amendment 
4 Milestones 
Amend to “End of data collection: 
31/12/2016” 
Modified the 
study timeline 
Administrative 
Amendment 
7.1 Study 
design 
Amend End of data collection to 
31/12/2016 and delete “If accrual 
is less than 550 cases by Dec.31, 
2014, the analysis will be based 
on the actually recruited patients.” 
Modified the 
study timeline 
Administrative 
Amendment 
7.3 Variables 
Amend End of data collection to 
31/12/2016 and delete “If accrual 
is less than 550 cases by Dec.31, 
2014, the analysis will be based 
on the actually recruited patients.” 
Modified the 
study timeline 
Administrative 
Amendment 
9 Management 
and reporting 
of adverse 
events/adverse 
reactions 
Update the safety reporting 
language 
Update the 
safety reporting 
language  
Amendment 
2 
06 Jun 
2013 
Administrative 
Amendment 
 
The protocol template update 
The protocol 
template update
Administrative 
Amendment 
7.2.1 
Inclusion 
criteria 
Amend Inclusion Criteria to 
before or had received Aromasin® 
treatment no more than one week 
from before received Aromasin® 
treatment 
Increase
population who 
had received 
Aromasin®  no 
more than one 
week 


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Administrative 
Amendment 
7.3.1 
screening 
Add “(Due to non-interventional 
study, permit to collect the 
screening procedures prior to 
ICD no more than 2 years)” into 
screening procedures 
Don’t limit the 
time of 
screening data 
collection due 
to Non-
interventional 
study nature 
Administrative 
Amendment 
7.8 Data 
analysis 
Amend to “The first interim 
analysis data cut-off date is Dec 
31, 2013. 
The second interim analysis data 
cut- off date is Dec 31, 2015.” 
From “The first is to occur when 
approximately 50% of subjects 
completed their 1st year of follow 
up. The second is to occur when 
approximately 50% of subjects 
completed the study 
drug treatment or withdrawal 
from the study.” 
Meet the 
timeline of the 
license renewal 
submission 
Amendment 
1 
24 Aug 
2010 
Administrative 
Amendment 
Section 4.1 
To update inclusion criterion 1 
Modify 
postmenopausal 
criteria 
Original 
protocol 
12 May 
2010 
 
 
N/A 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.   
 
 
 
 
 
 
 
 
Abbreviations 


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This is a list of abbreviations used in the protocol template.  All of these 
abbreviations may or may not be used in the protocol. 
Abbreviation 
Definition 
AE 
Adverse Event
AJCC 
American Joint Committee on Cancer
ALT 
Alanine aminotransferase
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen
CFDA 
China Food and Drug Administration
CRF 
Case Report Form
CSA 
Clinical Study Agreement
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCIS 
Ductal Carcinoma In Situ
E2 
Estradiol 
ECOG 
Eastern Cooperative Oncology Group 
EDP 
Exposure during pregnancy
ER 
Estrogen Receptor
FSFV 
First Subject First Visit 
FSH 
Follicle-StimulatingHormone
GCP 
Good Clinical Practices
GGT 
Gamma-Glutamyl Transpeptidase
GPP 
Good Pharmacoepidemiology Practices 
Her2 
Human Epidermal Growth Factor Receptor 2
HDL-C 
High-densitylipoprotein cholesterol
ICD 
Informed consent form
ICH 
International Conference on Harmonisation
IEC 
Independent Ethics Committee
IES 
Intergroup Exemestane Study 
IRB 
Institutional Review Board
LDL-C 
Low density lipoprotein-cholesterol 
LH-RH 
Luteinizing-Hormone-ReleasingHormone
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute
PCD 
Primary completion date
PR 
Progesterone Receptor
PVC  
Polyvinyl chloride polymer
SAE 
Serious Adverse Event
SAP 
Statistical Analysis Plan
SRSD 
Single Reference Safety Document
TNM 
Tumor, Lymph Node and Metastasis


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SCHEDULE OF ACTIVITIES  
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to STUDY PROCEDURES and ASSESSMENTS sections of the protocol for detailed 
information on each procedure and assessment required for compliance with the protocol.  
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect the 
wellbeing of the subject. 
Visit Identifier 
Prior to 
Enrollment/Day 1 
Enrollment/
Day 1 
Between Day 1 and End of 
Treatment/ Early Termination 
Screening 
X 
 
 
Demographic data 
X 
 
 
Performance status at diagnosis 
X 
 
 
Histopathological diagnosis 
X 
 
 
TNM current stage (as per AJCC, 
2002) 
X 
 
 
Hormone receptor status (ER/PR 
status) 
X 
 
 
HER-2 receptor status 
X 
 
 
Treatment history related to 
primary diagnosis 
X 
 
 
Chemotherapy (CT) 
X 
 
 
Radiotherapy 
X 
 
 
History of hormonal therapy 
received before Aromasin® 
X 
 
 
 
X 
 
Laboratory 
X 
 
X 
 
Hematology 
X 
 
X 
 
Blood Chemistry 
X 
 
X 
 
Serum FSH and E2 
X 
 
X 
Lipid Profile 
X 
 
X 
 
Bone mineral density estimations 
X 
 
X 
Abdominal/transvaginal 
ultrasonography 
X 
 
X 
Breast ultrasonography 
X 
 
X 
Breast mammogram 
X 
 
X 
Informed consent 
X 
 
 
Registration/Enrollment 
 
X 
 
Confirm eligibility. 
 
X 
 
Aromasin treatment  
 
X 
X 
Assessments  
 
 
X 
Symptoms 
 
 
X 
Details of Aromasin® treatment 
 
 
X 
Efficacy 
 
 
X 
 
Safety 
 
 
X 
HRQL  
 
 
 
HRU 
 
 
 
Concomitant Treatments 
 
X 
X 
Adverse Events 
 
X 
X 
Abbreviations: E2 = estradiol; FSH = follicle-stimulating hormone HRQL = health-related quality of life; HRU = 
healthcare resource utilization 


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TABLE OF CONTENTS 
 
1. INTRODUCTION .................................................................................................................9 
1.1. Mechanism of Action/Indication ...............................................................................9 
1.2. Background and Rationale ........................................................................................9 
2. STUDY OBJECTIVES AND ENDPOINTS .......................................................................10 
2.1. Objectives ................................................................................................................10 
2.2. Endpoints .................................................................................................................10 
2.2.1. Primary Endpoints ......................................................................................10 
2.2.2. Secondary Endpoints ..................................................................................10 
3. STUDY DESIGN.................................................................................................................11 
4. SUBJECT SELECTION ......................................................................................................11 
4.1. Inclusion Criteria .....................................................................................................11 
4.2. Exclusion Criteria ....................................................................................................13 
4.3. Randomization Criteria ...........................................................................................13 
4.4. Life Style Guidelines ...............................................................................................13 
5. STUDY INTERVENTION ..................................................................................................13 
5.1. Allocation to Intervention/Treatment ......................................................................13 
5.2. Drug Supplies ..........................................................................................................13 
5.2.1. Dosage Form(s) and Packaging ..................................................................13 
5.2.2. Preparation and Dispensing ........................................................................14 
5.3. Administration .........................................................................................................14 
5.4. Drug Storage ...........................................................................................................14 
5.5. Drug Accountability ................................................................................................15 
5.6. Concomitant Treatment(s) .......................................................................................15 
6. STUDY PROCEDURES .....................................................................................................16 
6.1. Screening (within 2 years prior to Day 1) ...............................................................16 
6.2. Day 1 (Enrollment and First Dose of Study Drug) .................................................17 
6.3. Study Period ............................................................................................................18 
6.3.1. Interim Visits between Day 1 and End of Treatment .................................18 
6.3.2. Final Visit ...................................................................................................18 


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6.4. Subject Withdrawal .................................................................................................19 
7. ASSESSMENTS ..................................................................................................................20 
7.1. Efficacy Endpoint ....................................................................................................20 
7.2. Safety Parameters ....................................................................................................21 
7.3. Pregnancy Testing ...................................................................................................21 
8. ADVERSE EVENT REPORTING......................................................................................21 
8.1. Adverse Events ........................................................................................................21 
8.2. Reporting Period .....................................................................................................22 
8.3. Definition of an Adverse Event ...............................................................................22 
8.4. Medication Errors ....................................................................................................23 
8.5. Abnormal Test Findings ..........................................................................................24 
8.6. Serious Adverse Events ...........................................................................................24 
8.6.1. Protocol-Specified Serious Adverse Events ...............................................25 
8.6.2. Potential Cases of Drug-Induced Liver Injury ............................................25 
8.7. Hospitalization ........................................................................................................26 
8.8. Severity Assessment ................................................................................................27 
8.9. Causality Assessment ..............................................................................................28 
8.10. Exposure During Pregnancy ..................................................................................28 
8.11. Withdrawal Due to Adverse Events (See Also Section on Subject 
Withdrawal) ...............................................................................................................29 
8.12. Eliciting Adverse Event Information ....................................................................30 
8.13. Reporting Requirements ........................................................................................30 
8.14. Serious Adverse Event Reporting Requirements ..................................................30 
8.15. Nonserious Adverse Event Reporting Requirements ............................................30 
8.16. Sponsor Reporting Requirements to Regulatory Authorities ................................31 
9. DATA ANALYSIS/STATISTICAL METHODS ...............................................................31 
9.1. Sample Size Determination .....................................................................................31 
9.2. Data Sources ............................................................................................................31 
9.3. Effectiveness Analysis ............................................................................................31 
9.3.1. Analysis of Primary Endpoint ....................................................................31 
9.3.2. Analysis of Secondary Endpoints ...............................................................32 


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9.4. Safety Analysis ........................................................................................................32 
9.5. Interim analysis .......................................................................................................33 
10. QUALITY CONTROL AND QUALITY ASSURANCE .................................................33 
11. DATA HANDLING AND RECORD KEEPING .............................................................33 
11.1. Case Report Forms/Electronic Data Record .........................................................33 
11.2. Record Retention ...................................................................................................34 
12. ETHICS..............................................................................................................................34 
12.1. Institutional Review Board (IRB)/Ethics Committee (EC) ...................................34 
12.2. Ethical Conduct of the Study ................................................................................34 
12.3. Subject Information and Consent ..........................................................................35 
12.4. Subject Recruitment ..............................................................................................36 
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................36 
13. DEFINITION OF END OF STUDY .................................................................................36 
13.1. End of Study in all Participating Countries ...........................................................36 
14. SPONSOR DISCONTINUATION CRITERIA ................................................................36 
15. PUBLICATION OF STUDY RESULTS ..........................................................................36 
15.1. Communication of Results by Pfizer ....................................................................36 
15.2. Publications by Investigators ................................................................................37 
16. REFERENCES ..................................................................................................................38 
 
APPENDICES 
Appendix 1. Eastern Cooperative Oncology Group (ECOG) Performance Status .................39 
Appendix 2. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ....................................................................................39 
 
 
 
 


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1. INTRODUCTION  
1.1. Mechanism of Action/Indication  
Aromasin® (Exemestane) is an irreversible, steroidal aromatase inhibitor that has been 
developed for adjuvant treatment of postmenopausal women with estrogen receptor (ER) 
positive early invasive breast cancer who have received 2-3 years of tamoxifen and are 
switched to Aromasin® for completion of a total of 5 consecutive years of adjuvant hormonal 
therapy . 
1.2. Background and Rationale  
Aromasin® (Exemestane) is an irreversible, steroidal aromatase inhibitor, structurally related 
to the natural substrate androstenedione. In post-menopausal women, oestrogens are 
produced primarily from the conversion of androgens into oestrogens through the aromatase 
enzyme in peripheral tissues. Oestrogen deprivation through aromatase inhibition is an 
effective and selective treatment for hormone dependent breast cancer in postmenopausal 
women. In the year 2002, Aromasin® (Exemestane) was approved in China for the treatment 
of advanced breast cancer in women with natural or induced postmenopausal status whose 
disease has progressed following tamoxifen therapy.  
Aromasin® (Exemestane) was approved in China for adjuvant treatment of postmenopausal 
women with estrogen receptor (ER) positive early invasive breast cancer who have received 
2-3 years of tamoxifen & are switched to Aromasin® for completion of a total of 5 
consecutive years of adjuvant hormonal therapy by China Food and Drug Administration 
(CFDA) with clinical trial waiver in May. 2008.1  The approval was granted in view of the 
significant efficacy and tolerant safety from the Intergroup Exemestane Study (IES), which 
was a phase III randomized controlled trial conducted primarily in Caucasian patients.2,3  
While Aromasin® has been used in China for adjuvant therapy of breast cancer since then, 
there is currently a lack of systematic collection and analysis of the efficacy and safety data 
for Aromasin® in the adjuvant setting in Chinese population.  The Aromasin® pragmatic 
clinical trial is being proposed to collect data systematically and to assess the efficacy and 
safety of Aromasin® in the adjuvant setting in Chinese population.  Generation of such 
information is expected to provide evidence for Chinese physicians to manage clinical 
practice of Aromasin® in the adjuvant setting.  The single reference safety document to be 
used in this study and complete information for this compound may be found in the Single 
Reference Safety Document (SRSD), which for this study is the China Aromasin® Package 
Insert.   
The ex-study number is NRA5990043. 
This study was conceived and initiated as a prospective observational study and all subjects 
were enrolled under that paradigm.  After all subjects had been enrolled, the original design 
was modified to an interventional pragmatic study, primarily for the purpose of allowing the 
study to provide study drug to the subjects, at no cost to the subject. 


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2. STUDY OBJECTIVES AND ENDPOINTS  
2.1. Objectives 
This is a Post-Approval Safety Study (PASS) intended to generate efficacy and safety data 
from patients with early invasive breast cancer treated with Aromasin® in the adjuvant 
setting in China. 
Primary objective: Efficacy of the treatment with Aromasin® in postmenopausal women 
with estrogen receptor positive early invasive breast cancer who have received adjuvant 
Tamoxifen therapy for up to 2-3 years 
Secondary objective: Safety of treatment with Aromasin® in women with postmenopausal 
estrogen receptor positive early invasive breast cancer who have received adjuvant 
Tamoxifen therapy for up to 2-3 years 
2.2. Endpoints 
2.2.1. Primary Endpoints 
The primary endpoint will be time-to-event, where event is defined as the earliest occurrence 
any of the following: 
 Loco-regional/distant recurrence of the primary breast cancer; 
 Appearance of a second primary or contralateral breast cancer; 
 Death due to any cause. 
Loco-regional recurrence is defined as any recurrence in the ipsilateral breast, chest wall or 
axillary lymph nodes. 
2.2.2. Secondary Endpoints 
The proportion of subjects experiencing the events. 
The incidence rate (per annum) is defined as a ratio of the number of events and the total 
exposure times (in years) to Aromasin® therapy. 
The relationship between Human Epidermal Growth Factor Receptor 2 (Her2) 
overexpression level and efficacy endpoint will be analyzed. 
The events define as below: 
Patients who used Aromasin® met the occurrence of any of the following events, whichever 
occurs earliest: 
 Loco-regional/distant recurrence of the primary breast cancer; 
 Appearance of 2nd primary or contralateral breast cancer; 
 Death due to any cause. 


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The incidence of adverse events and discontinuation of Aromasin® due to adverse event will 
be summarized. 
3. STUDY DESIGN 
This is a multicenter, single-arm, and prospective clinical study. This study is transitioned 
from a non-interventional (observational) study to an interventional, pragmatic clinical study. 
The study will collect and analyze efficacy and safety data from approximately 550 
consecutive eligible patients from study beginning to last subject last visit.  
The endpoints of the study include efficacy endpoints and safety endpoints. 
All subjects enrolled must meet all inclusion criteria and none of the exclusion criteria. 
The dose of Aromasin to be used in this study will be as specified in the protocol, which is 
intended to be in accord with the approved dose for this indication in China. 
The subjects will receive 2-3 years of Aromasin® for completion of a total 5 years of 
adjuvant hormonal therapy or until the occurrence of any of the following events that would 
signify the need for treatment termination, whichever occurs earlier: 
 Loco-regional/distant recurrence of the primary breast cancer; 
 Appearance of a second primary breast cancer or contralateral breast cancer; 
 Unacceptable toxicity, protocol deviation, withdrawal of subject consent or other 
reason for termination of treatment; 
 Death due to any cause; 
 Administration of another aromatase inhibitors (ie, not Aromasin®). 
4. SUBJECT SELECTION  
Under Amendment 4, this study transitioned from a non-interventional (observational) study 
to an interventional, pragmatic clinical study.  Approximately 550 patients were planned to 
enroll by or before Dec. 31, 2016.  At the time of the transition to a pragmatic study (May 
2016), enrollment of the study had already completed in December 2015.  The inclusion 
criteria and exclusion criteria applicable to all enrolled subjects were based on the previous 
non-interventional version of the study protocol.  No additional subjects will be enrolled in 
the study following the transition to an interventional pragmatic clinical study design. 
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom the protocol intervention is 
considered appropriate by their health care provider. 
4.1. Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study. 


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Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Early invasive breast cancer (T1-4N0-3M0) confirmed by histology or cytology. 
2. ER positive. 
3. The patient must be postmenopausal woman.  Post-menopause is defined as follows: 
a. Prior bilateral oophorectomy; 
b. Age 60 years; 
c. Age <60 years and amenorrheic for 12 or more months in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression and plasma Follicle-
Stimulating Hormone (FSH) and estradiol in the postmenopausal range; if taking 
tamoxifen or toremifene, and age <60 years, then serial measurement of plasma 
FSH and estradiol are need to ensure in the postmenopausal ranges. 
d. In addition, following situations should be considered: 
• It is not possible to assign menopausal status to women who are receiving an 
Luteinizing-Hormone-Releasing Hormone (LH-RH) agonist or antagonist 
• In women premenopausal at the beginning of adjuvant chemotherapy, 
amenorrhea is not a reliable indicator of menopausal status, because ovarian 
function may still be intact or resume despite anovulation/amenorrhea after 
chemotherapy. 
• For these women with chemotherapy-induced amenorrhea, ovarian 
suppression (oophorectomy or drug suppression) or serial measurement of 
FSH and/or estradiol are needed to ensure postmenopausal status if the use of 
aromatase inhibitors is considered as a component of endocrine therapy. 
4. The patient has received adjuvant Tamoxifen therapy for up to 2-3 years and will 
switch to receive Aromasin® treatment or had received Aromasin® treatment no 
more than one week (The decision to prescribe Aromasin® will necessarily precede 
and will be independent of the decision to enroll patients in the study). 
5. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or legally acceptable representative, parent(s)/legal guardian) has been 
informed of all pertinent aspects of the study. 


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4.2. Exclusion Criteria 
Subjects presenting with any of the following will not be included in the study: 
1. Subjects who are investigational site staff members directly involved in the conduct 
of the study and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are Pfizer employees directly involved in the conduct of 
the study. 
2. Following the adjuvant Tamoxifen therapy for 2-3 years and prior to receiving 
Aromasin® treatment, there is evidence of a local relapse or distant metastasis of 
breast cancer, or a second primary cancer. 
3. Following the adjuvant Tamoxifen therapy for 2-3 years and received other aromatase 
inhibitors (not Aromasin®) 
4.3. Randomization Criteria  
Not applicable as this is a single arm, non-randomized study.   
4.4. Life Style Guidelines  
Not applicable  
5. STUDY INTERVENTION  
5.1. Allocation to Intervention/Treatment 
The investigator will assign subject identification numbers sequentially to the subjects as 
they are screened for the study.  This identifying number will be retained throughout the 
study.  A subject number must never be reassigned or reused for any reason. The investigator 
must maintain a log linking the subject number to the subject’s name. 
5.2. Drug Supplies  
5.2.1. Dosage Form(s) and Packaging  
Aromasin® (study drug) will be provided by Pfizer as round, biconvex, off-white sugar 
coated tablets with a white core for oral administration.  The recommended dose of 
Aromasin® in early and advanced breast cancer is one 25 mg tablet once daily after a meal.  
The label attached to each Aromasin® states the product name and amount, potency (drug 
only), lot number, directions for storage, and name of manufacturer.  Labels may contain 
other information, such as expiry date, as required by local regulatory guidelines. 
The active ingredient is: 6-methylenandrosta-l,4-diene-3,17-dione. 


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Structural formula:  
                                                                                                                                                                    
 
                                           
 
         
       
Molecular formula: C20H24O2 
Molecular weight: 296.41 
TABLET STRENGTH: 25 mg. 
PACKAGING: 
30 tablets in blister packs (Polyvinyl chloride polymer (PVC) /Aluminium foil). 
5.2.2. Preparation and Dispensing 
Pfizer will provide the investigators with a sufficient quantity of study drug.  Once study 
drug is dispensed to a subject it must not be re-dispensed to another subject.  The product 
should be used in accordance with the China Aromasin® Package Insert.  At each visit 
before the End of Treatment/ Early Termination visit, the subject should receive a sufficient 
quantity of study drug in order to last until the next visit. 
5.3. Administration  
The product will be administered in accordance with the China Aromasin® Package Insert. 
5.4. Drug Storage   
The investigator, or an approved representative, eg, a pharmacist, will ensure that all 
investigational products, including any comparative agents and/or marketed products are 
stored in a secured area with controlled access under recommended storage conditions and in 
accordance with applicable regulatory requirements. 
Investigational product should be stored in its original container and in accordance with the 
drug label.  See the China Aromasin® Package Insert for storage conditions of the product.  
Storage conditions stated in the China Aromasin® Package Insert should be followed.  The 
package that contains the study drug must be stored below 30°C. 
O 
 
 
CH 3 
CH 3 O 
CH 
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Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout study, on all business 
days.  Even for continuous monitoring systems, a log or site procedure which ensures active 
daily evaluation for excursions should be available.  The operation of the temperature 
monitoring device and storage unit (for example, refrigerator), as applicable, should be 
regularly inspected to ensure it is maintained in working order.   
Any excursions from the product label storage conditions should be reported upon discovery. 
The site should actively pursue options for returning the product to labeled storage conditions, 
as soon as possible.  Deviations from the storage requirements, including any actions taken, 
must be documented and reported to the sponsor.   
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  
Specific details regarding information the site should report for each excursion will be 
provided to the site.  
Site staff will instruct subjects on the storage requirements for take-home medications 
including how to report temperature excursions.  
5.5. Drug Accountability  
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies.  When investigational product is taken home by the 
subject, any unused products must be returned to the investigator by the subject at the End of 
Treatment/ Early Termination visit. 
The monitor will review drug accountability during routine monitoring visits.  Drug 
accountability will be done at all study visits after Day 1 until End of Treatment/ Early 
Termination visit.  Any discrepancies must be investigated and their resolution documented.  
At the completion or termination of the study, a final drug accountability review and 
reconciliation must be performed.  Any discrepancies that cannot be reconciled must be 
documented in writing in the study file. 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer and all destruction must be adequately documented. 
5.6. Concomitant Treatment(s)  
The use of permitted concomitant medication must be in accordance with the study drug 
label. 


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6. STUDY PROCEDURES   
6.1. Screening (within 2 years prior to Day 1) 
Due to the non-interventional- study design at the time subjects were enrolled, the Informed 
consent form (ICD) permitted the collection of data related to screening procedures up to 2 
years prior to Informed Consent being given.  After the transition from a non-interventional 
study to an interventional, pragmatic study, the ongoing subjects must re-sign the ICD.  
The following screening procedures (to the extent that they are available) must be performed 
prior to the start of treatment on study unless otherwise stated. 
Patient signature on current Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) approved informed consent document. 
Demographic data; 
 Subject date of birth, gender, race. 
Physical examination including examination of major body systems (General, Lungs, Heart, 
Musculoskeletal, Genitourinary, Neurological, Lymph nodes, Skin, Abdomen and Other), 
Easter Cooperative Oncology Group (ECOG) performance status, body weight, height 
(screening only), and vital signs (temperature, blood pressure, heart rate, respiratory rate). 
Breast cancer history: 
 Date of initial diagnosis of breast cancer; 
 Tumor location: Left/right breast. 
Performance status at diagnosis (Easter Cooperative Oncology Group Performance Status). 
Histopathological diagnosis: 
 Tumor, Lymph Node and Metastasis (TNM) current stage (as per AJCC, 2002); 
 Hormone receptor status (ER/PR status); 
 HER-2 receptor status (as per Breast Cancer National Comprehensive Cancer Network 
(NCCN) clinical practice guideline Chinese version v.1.2009). 
Medical history: 
 Concomitant illnesses; 
 Concomitant drug and non-drug treatment (within 21 days prior to the start of 
treatment on study) including supportive therapy (calcium, bisphosphonates, etc). 
Treatment history related to primary diagnosis: 
 Surgery related to primary diagnosis: 
 Date of surgery; 
 Type of surgery; 
 Outcome of surgery. 


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 Chemotherapy (CT): 
 Adjuvant CT: Agent name, date of starting, stop date, number of cycles. 
 Radiotherapy: 
 Site of radiotherapy; 
 Dates started and stopped; 
 Total dose. 
 History of hormonal therapy received before Aromasin®: 
 Agent used; 
 Dosage and duration. 
Baseline investigations (the updated investigation result prior to the start of the treatment on 
study) 
 Hematology: hemoglobin, platelet count, white blood cell count, and differential count 
(percent); 
 Serum Chemistry: total bilirubin, ALT (Alanine Transaminase), AST (Aspartate 
Transaminase), alkaline phosphatase, GGT (Gamma-Glutamyl Transferase), total 
protein, albumin, BUN (Blood Urea Nitrogen), creatinine, uric acid, glucose; 
 Serum FSH (follicle stimulating hormone) and E2 (estradiol); 
 Lipid Profile: Serum HDL-C (high-density lipoprotein cholesterol), LDL-C (low 
density lipoprotein-cholesterol), total cholesterol, triglycerides; 
 Bone mineral density estimations; 
 Abdominal/transvaginal ultrasonography: Uterine hyperplasia, polyps, fibroids; 
 Breast ultrasonography; 
 Breast mammogram. 
Assessment of ongoing symptoms/events (serious adverse events must be recorded from time 
of signed consent). 
6.2. Day 1 (Enrollment and First Dose of Study Drug) 
After the Screening Visit laboratory results are available, the investigator will confirm 
eligibility by ensuring that the laboratory related entry criteria have been fulfilled.  This 
should occur before the date of Day 1. 
The following procedure will be performed: 
 Confirm eligibility. 
Once baseline data has been collected and eligibility has been confirmed, study drug will first 
be dispensed to the subject at this visit.   
Investigator (or designee) will provide the subject with instructions regarding Aromasin® 
dosing, administration and storage. 


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The subject may now commence treatment with study drug.  Subjects will be treated with 
study drug at a dose and frequency prescribed by the subject’s treating physician in 
accordance with the China Aromasin® Package Insert. 
6.3. Study Period 
6.3.1. Interim Visits between Day 1 and End of Treatment 
Patients will receive the study drug (Aromasin®) as outpatients and are generally expected to 
return to the clinic for interim visits at approximately 6 month intervals.  Since this study was 
originally configured as an observational study, patient visits during the course of the study 
may occur at the discretion of the Investigators according to local clinical practice guideline 
and/or the Investigator’s clinical judgment. 
A final End-of-Treatment/Early Termination Visit is required for all study subjects. 
The following data will be collected at each study period visit: 
 
 Symptoms; 
 Physical examination including major body systems, ECOG performance status, body 
weight, and vital signs. 
 Investigations (as available): 
 Serum Chemistry: total bilirubin, ALT, AST, alkaline phosphatase, GGT, total protein, 
albumin, BUN, creatinine, uric acid, glucose; 
 Serum FSH and E2; 
 Lipid Profile: Serum HDL-C, LDL-C, total cholesterol, triglycerides; 
 Bone mineral density estimations; 
 Abdominal/transvaginal ultrasonography:Uterine hyperplasia, polyps, fibroids; 
 Breast ultrasonography; 
 Breast mammogram. 
 Details of Aromasin® treatment: 
 Dose and duration; 
 Reason for dose change or an missed medication. 
 
 Adverse events/ Serious adverse events. 
 
 Concomitant drug and non-drug treatment (study period): 
 Change in concomitant drug and non-drug treatment including any change in 
supportive therapy (calcium, bisphosphonates, etc). 
6.3.2. Final Visit 
For each subject, the final visits will occur at completion the study drug or at the occurrence 
of any of the events signifying treatment termination (refer Section 7.2). 


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Observational Parameters collected at the Final Visit are identical to the Study Period Visits; 
with the addition of recurrence time and location, if the subject has recurrence. 
6.4. Subject Withdrawal 
When subjects are permanently withdrawn from treatment, the primary reason for 
discontinuation must be provided.  Reasons for discontinuation include: 
 Death due to any cause; 
 Unacceptable toxicity; 
 Disease recurrence/ metastases; 
 Appearance of a second primary or contralateral breast cancer; 
 Protocol deviation (eg, subject noncompliance, including the study drug accumulated 
dosage subject taken is less than 70% or more than 130% of the total study drug 
dosage); 
 Receive other aromatase inhibitors (not Aromasin®); 
 Withdrawal of subject consent; 
 Study terminated by sponsor; 
 Other reason. 
 Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator. 
 Withdrawal of Consent: Subjects who request to discontinue study treatment will 
remain in the study and must continue to be followed for protocol specified follow-up 
procedures.  The only exception to this is when a subject specifically withdraws 
consent for any further contact with him/her or persons previously authorized by 
subject to provide this information.  Subjects should notify the investigator, in writing, 
of their decision to withdraw consent from future follow-up, whenever possible.  The 
withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study drug 
only or also from study procedures and/or post treatment study follow-up, and entered 
on the appropriate CRF page.  In the event that vital status (whether the subject is 
alive or dead) is being measured, publicly available information should be used to 
determine vital status only as appropriately directed in accordance with local law. 
 If the patient withdraws consent, no further evaluations should be performed and no 
additional data should be collected.  The sponsor may retain and continue to use any 
data collected before such withdrawal of consent. 


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 Lost to Follow-Up: 
 If a subject does not return for a scheduled visit, every effort should be made to 
contact the subject.  All attempts to contact the subject and information received 
during contact attempts must be documented in the subject’s medical record.  In all 
circumstances, every effort should be made to document subject outcome. The 
investigator should inquire about the reason for withdrawal and follow-up with the 
subject regarding any unresolved adverse events. 
 All reasonable efforts must be made to locate subjects to determine and report their 
ongoing status.  This includes follow-up with persons authorized by the subject as 
noted above.  Lost to follow-up is defined by the inability to reach the subject after a 
minimum of three documented phone calls, faxes, or emails as well as lack of 
response by subject to one registered mail letter.  All attempts should be documented 
in the subject’s medical records.  If it is determined that the subject has died, the site 
will use permissible local methods to obtain the date and cause of death.  If 
investigator’s use of third-party representative to assist in the follow-up portion of the 
study has been included in the subject’s informed consent, then the investigator may 
use a Sponsor retained third-party representative to assist site staff with obtaining 
subject’s contact information or other public vital status data necessary to complete 
the follow-up portion of the study.  The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to 
obtain updated contact information.  If after all attempts, the subject remains lost to 
follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records. 
7. ASSESSMENTS  
Data to be collected on the case report forms must be documented in patient records. 
7.1. Efficacy Endpoint 
The first occurrence of any of the following events constitutes an efficacy endpoint for the 
subject:  
 Loco-regional/distant recurrence of the primary breast cancer;  
 Appearance of a second primary or contralateral breast cancer;  
 Death due to any cause.  
Loco-regional recurrence is defined as any recurrence in the ipsilateral breast, chest wall or 
axillary lymph nodes.  


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7.2. Safety Parameters 
The safety of treatment with Aromasin® will be assessed by Adverse Event reporting in the 
study.  Every adverse event that is observed must be recorded as an adverse event in the CRF, 
whether or not the Investigator suspects a causal relationship with study drug. 
Adverse events of particular interest in this study: 
 Gynaecological: Bleeding ,discharge, uterine dilatation and curettage; 
 Cardiac: myocardial infarction, hypertension; 
 Venous thromboembolic events; 
 Musculoskeletal: Joint stiffness, arthralgia, muscle cramps, fractures; 
 Menopausal symptoms: Hot flushes, anxiety, depression, headaches; 
 Changes in lipids; 
 Changes in bone mineral density. 
Severity of the adverse events reported while on Aromasin® will be graded by the National 
Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE] version 3.0. 
Please refer to the Section 8 for additional details on recording and reporting of adverse 
events. 
7.3. Pregnancy Testing  
Not applicable for this Aromasin® pragmatic clinical trial because the use of Aromasin® for 
this indication is for post-menopausal women.  
8. ADVERSE EVENT REPORTING  
8.1. Adverse Events 
All observed or volunteered Adverse Event (AEs) regardless of treatment group or suspected 
causal relationship to the investigational product(s) will be reported as described in the 
following sections.  
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  


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Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment. 
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.   
8.2. Reporting Period 
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to study drug are to be reported to the sponsor. 
AEs (serious and nonserious) should be recorded on the Case Report Form (CRF) from the 
time the subject has taken at least 1 dose of study treatment through the last subject visit.   
 If a patient begins a new anticancer therapy, the AE reporting period for nonserious 
AEs ends at the time the new treatment is started.  Death must be reported if it occurs 
during the SAE reporting period after the last dose of investigational product, 
irrespective of any intervening treatment. 
8.3. Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  
 Abnormal test findings; 
 Clinically significant symptoms and signs; 
 Changes in physical examination findings; 
 Hypersensitivity; 
 Progression/worsening of underlying disease; 
 Drug abuse; 
 Drug dependency. 


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Additionally, they may include the signs or symptoms resulting from: 
 Drug overdose; 
 Drug withdrawal; 
 Drug misuse;  
 Drug interactions; 
 Extravasation; 
 Exposure during pregnancy (EDP); 
 Exposure via breastfeeding; 
 Medication error; 
 Occupational exposure. 
 Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs. 
8.4. Medication Errors 
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong subject, at the wrong time, or at the wrong dosage strength.  Such 
medication errors occurring to a study participant are to be captured on the adverse event 
(AE) page of the case report forms (CRFs) and on the SAE form when appropriate.  In the 
event of medication dosing error, the sponsor should be notified immediately. 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
 Medication errors involving subject exposure to the investigational product; 
 Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated AE(s) are captured on an 
AE CRF page (refer to the ADVERSE EVENT REPORTING section for further details).   


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8.5. Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows:  
 Test result is associated with accompanying symptoms; and/or 
 Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
 Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or 
 Test result is considered to be an AE by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
8.6. Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose that: 
 Results in death; 
 Is life-threatening (immediate risk of death); 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
 Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
 Results in congenital anomaly/birth defect. 
 Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with Common Terminology Criteria (CTC) 
Grade 5 (see section on Severity Assessment). 
 Lack of efficacy should be reported as an AE when it is associated with an SAE. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  The important medical event should be reported as serious, 
if it is determined that the event may jeopardize the subject or may require intervention to 
prevent one of the other AE outcomes. 


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Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see section on Serious Adverse Event Reporting Requirements). 
8.6.2. Potential Cases of Drug-Induced Liver Injury  
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to run LFTs because of clinical 
sign/symptom presentation in a subject, such LFT results should be handled and followed up 
as described below.  
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) levels 
concurrent with abnormal elevations in total bilirubin level that meet the criteria outlined 
below in the absence of other causes of liver injury are considered potential cases of drug-
induced liver injury (potential Hy’s law cases) and should always be considered important 
medical events.   
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values: 
 Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 X ULN or not available. 
 For subjects with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above: 
 For subjects with preexisting AST or ALT baseline values above the normal range: 
AST or ALT values 2 times the baseline values and 3 X ULN, or 8 X ULN 
(whichever is smaller). 
Concurrent with 
 For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased by 1 X ULN or ≥3 X ULN (whichever is smaller). 


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The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.   
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/ international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted. All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at 
the time, should be considered potential Hy’s law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs. 
8.7. Hospitalization 
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute an 
hospitalization; however, the event leading to the emergency room visit should be assessed 
for medical importance. 
Hospitalization does not include the following: 
 Rehabilitation facilities; 
 Hospice facilities; 
 Respite care (eg, caregiver relief); 
 Skilled nursing facilities; 
 Nursing homes; 
 Same-day surgeries (as outpatient/same-day/ambulatory procedures). 


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Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include:  
 Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality); 
 Social admission (eg, subject has no place to sleep); 
 Administrative admission (eg, for yearly physical examination); 
 Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol); 
 Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery); 
 Hospitalization for observation without a medical AE; 
 Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject; 
 Admission exclusively for the administration of blood products. 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE. 
8.8. Severity Assessment 
GRADE Clinical Description of Severity 
0  
No change from normal or reference range (This grade is not included in the 
Version 4.0 CTC document but may be used in certain circumstances.) 
1 
MILD adverse event 
2 
MODERATE adverse event 
3 
SEVERE adverse event 
4 
LIFE-THREATENING consequences; urgent intervention indicated 
5 
DEATH RELATED TO adverse event 


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Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above. 
8.9. Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious). The investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an AE; 
generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records.   
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable. 
8.10. Exposure During Pregnancy 
For investigational products and for marketed products, an exposure during pregnancy occurs 
if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;  
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products). 
2. A male subject has been exposed (eg, because of treatment or environmental 
exposure) to the investigational product prior to or around the time of conception 
and/or is exposed during his partner’s pregnancy.  
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on a Serious Adverse Event (SAE) Report Form 
and Exposure During Pregnancy (EDP) supplemental form, regardless of whether an SAE 


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has occurred.  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a subject reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EDP 
supplemental form.  This must be done irrespective of whether an AE has occurred and 
within 24 hours of awareness of the exposure.  The information submitted should include the 
anticipated date of delivery (see below for information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion or until pregnancy termination) and notify Pfizer of the outcome as a follow-up to 
the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows:  
 Spontaneous abortion includes miscarriage and missed abortion; 
 Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to investigational product.  
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis (eg, 
follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator will provide the study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The investigator must document in the source 
documents that the subject was given the Pregnant Partner Release of Information Form to 
provide to his partner.  
8.11. Withdrawal Due to Adverse Events (See Also Section on Subject Withdrawal) 
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.   
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below. 


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8.12. Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject/parent/legally acceptable representative.  In addition, each study subject 
/parent/legally acceptable representative will be questioned about AEs. 
8.13. Reporting Requirements 
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate. 
8.14. Serious Adverse Event Reporting Requirements 
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy and exposure via 
breastfeeding cases.   
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE. 
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative.  
8.15. Nonserious Adverse Event Reporting Requirements 
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information. 


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8.16. Sponsor Reporting Requirements to Regulatory Authorities 
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations. 
9. DATA ANALYSIS/STATISTICAL METHODS    
No inferential statistical analyses for primary and secondary endpoints are planned. Analyses 
will consist of descriptive statistics and corresponding 95% 2-sided confidence intervals 
when appropriate.   
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be dated, filed and 
maintained by the sponsor.  The SAP may modify the plans outlined in the protocol; any 
major modifications of primary endpoint definitions or their analyses would be reflected in a 
protocol amendment. 
9.1. Sample Size Determination 
Analyses will be primarily descriptive in nature, and therefore no statistical sample size 
estimation was performed.  
9.2. Data Sources  
This study data will be recorded by a physician/nurse in the medical records, through subject 
interview, and in the Case Report Form (CRF). 
This study will collect and analyze the efficacy and safety data from approximately 550 
eligible consecutive patients. All recruited 550 patients or actually recruited patients will be 
observed until the end of Aromasin® therapy. 
9.3. Effectiveness Analysis 
All summaries of efficacy parameters will be reported within the Full Analysis Set (FAS). 
This is defined as all patients who receive at least one dose of Aromasin® during the 
observation period. 
9.3.1. Analysis of Primary Endpoint  
The primary efficacy variable will be time-to-event, where event is defined as the earliest 
occurrence any of the following:  
 Loco-regional/distant recurrence of the primary breast cancer;  
 
Appearance of a second primary or contralateral breast cancer;  
 
Death due to any cause. 


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Time-to-event will be calculated as the time from date of enrollment to first objective 
documentation of the event defined above. In the analysis of time to event, subjects lost to 
follow-up and subjects who are still being followed at the time of analysis with no documented 
event will be censored at the last date the subject was known to be event-free. 
The Kaplan Meier non-parametric estimate will be used to summarize the survival 
distribution and median for time-to-event. Ninety-five percent confidence intervals for the 
survival distribution will be computed. 
9.3.2. Analysis of Secondary Endpoints 
Loco-regional/distant recurrence, appearance of a second primary or contralateral breast 
cancer, and death will also be summarized as follows: 
x Time to each event; 
x 
The proportion of subjects experiencing the event; 
x 
The incidence rate (per annum) is defined as a ratio of the number of events and the total 
exposure time (in years) to Aromasin® therapy; 
x The relationship between Her2 overexpression level and time-to-event. 
Categorical data will be presented using counts, percentages and 95% confidence intervals 
for percentages.  Continuous data will be reported using n, mean, standard deviation, median 
and range, 95% confidence interval may also be presented where specified.  The Kaplan 
Meier non-parametric estimate will be used to summarize the survival distribution and 
median for time-to-event, 95% confidence intervals for the survival distribution will be 
computed. 
9.4. Safety Analysis 
All safety analyses will be performed on all enrolled subjects who receive at least one dose of 
Aromasin®.  
Severity of the adverse events reported while on Aromasin® will be graded by the National 
Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE] version 
3.0.The reasons for discontinuation of Aromasin® therapy will be described.  
Safety data will be tabulated and listed according to Pfizer’s standard reporting algorithms.  
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9.5. Interim analysis 
Up to 2 early analyses of the data will be performed. The first interim analysis data cut-off 
date is Dec 31, 2013. The second interim analysis data cut-off date is to occur when the study 
has enrolled 550 subjects. The final analysis will be done at the end of treatment. 
10. QUALITY CONTROL AND QUALITY ASSURANCE 
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification. 
The study site may be subject to review by the Institutional Review Board (IRB)/Ethics 
Committee (EC), and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
11. DATA HANDLING AND RECORD KEEPING 
11.1. Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry.  
In most cases, the source documents are the subject’s chart in the hospital or the physician's 
office.  In these cases data collected on the CRFs must match the data in those charts.  
In some cases, the CRF, or part of the CRF, may also serve as source documents.   


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11.2. Record Retention 
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, e.g., CRFs and hospital records), all original signed informed 
consent/assent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
according to local regulations, or as specified in the Clinical Study Agreement (CSA), 
whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.   
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 
12. ETHICS  
12.1. Institutional Review Board (IRB)/Ethics Committee (EC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the Investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer. 
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation. 
12.2. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association  
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws. 


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12.3. Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.  
When study data is compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify study subjects.  The study 
site will maintain a confidential list of subjects who participated in the study linking their 
numerical code to the subject’s actual identity.  In case of data transfer, Pfizer will maintain 
high standards of confidentiality and protection of subject personal data consistent with 
applicable privacy laws. 
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws. 
The informed consent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for inspection.   
The investigator must ensure that each study subject, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation.   
Whenever consent is obtained from a subject’s legally acceptable representative/parent(s) or 
legal guardian, the subject’s assent (affirmative agreement) must subsequently be obtained 
when the subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a subject’s decisional capacity is so limited he/she cannot 
reasonably be consulted, as permitted by the IRB/EC and consistent with local regulatory and 
legal requirements, then the subject’s assent may be waived with source documentation of 
the reason assent was not obtained.  If the study subject does not provide his/her own consent, 
the source documents must record why the subject did not provide consent (eg, minor, 
decisionally impaired adult), how the investigator determined that the person signing the 
consent was the subject’s legally acceptable representative, the consent signer’s relationship 
to the study subject (eg, parent, spouse) and that the subject’s assent was obtained, or waived.  
If assent is obtained verbally it must be documented in the source documents. 
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must be re-consented as adults to remain in the study.  If the 
enrollment of ‘emancipated minors’ is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.    


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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative, parent(s) or legal 
guardian and the subject’s assent, when applicable, before any study-specific activity is 
performed, unless a waiver of informed consent has been granted by an IRB/EC.  The 
investigator will retain the original of each subject's signed consent/assent document. 
12.4. Subject Recruitment 
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures. 
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.   
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
13. DEFINITION OF END OF STUDY  
13.1. End of Study in all Participating Countries  
End of Study in all participating countries (only one country of China for this study) is 
defined as Last Subject Last Visit. 
14. SPONSOR DISCONTINUATION CRITERIA  
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.   
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within a time period set by Pfizer.  As directed by 
Pfizer, all study materials must be collected and all CRFs completed to the greatest extent 
possible. 
15. PUBLICATION OF STUDY RESULTS  
15.1. Communication of Results by Pfizer 
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), www.pfizer.com, and/or the 
European Clinical Trials Database (EudraCT), and other public registries in accordance with 
applicable local laws/regulations.  


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www.clinicaltrials.gov 
Pfizer posts clinical trial Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of a Pfizer product.  
15.2. Publications by Investigators 
Pfizer has no objection to publication by investigator of any information collected or 
generated by investigator, whether or not the results are favorable to the investigational drug.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure before it is submitted or otherwise disclosed. 
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, the investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days. 
The investigator will, on request, remove any previously undisclosed confidential 
information (other than the Study results themselves) before disclosure. 
If the study is part of a multicenterr study, the investigator agrees that the first publication is 
to be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, investigator is free to publish separately, subject to the other requirements 
of this section. 
For all publications relating to the study, institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement. 


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16. REFERENCES 
1. Aromasin® Locally Approved Prescribing Information. Pfizer China. 2008. 
2. Coombes C, Hall E, Gibson L, et al. A randomized trial of Exemestane after two to three 
years of tamoxifen therapy in postmenopausal women with primary breast cancer. N 
Engl J Med 2004; 350: 1081 
3. Coombes C, Kilburn L, Snowdon C, et al. Survival and safety of exemestane versus 
tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): A 
randomised controlled trial. Lancet 2007; 369: 559. 
 
 


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APPENDICES 
Appendix 1. Eastern Cooperative Oncology Group (ECOG) Performance Status 
Grade ECOG 
0 
Fully active, able to carry on all predisease performance without restriction
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair 
5 
Dead
 
Appendix 2. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) 
The NCI CTCAE (version 3.0, dated 09 August 2006) can be reviewed online at the 
following NCI website: 
http://ctep.cancer.gov/reporting/ctc.html 

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Statistical Analysis Plan
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PROTOCOL A5991093
NON-INTERVENTIONAL DRUG STUDY
A PROSPECTIVE NON-INTERVENTIONAL STUDY OF
CHINA EARLY INVASIVE BREAST CANCER PATIENTS 
RECEIVING ADJUVANT THERAPY WITH AROMASIN®
STATISTICAL ANALYSIS PLAN
(SAP)
Version: 1.2
Author: 
, CRDC, 
, China
Date:     21 JUN 2015
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TABLE OF CONTENTS
APPENDICES ...........................................................................................................................3
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................4
2. INTRODUCTION .................................................................................................................6
2.1. Study Design .............................................................................................................6
2.2. Study Objectives .......................................................................................................6
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................7
4. HYPOTHESES AND DECISION RULES...........................................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................7
5. ANALYSIS SETS .................................................................................................................7
5.1. Full Analysis Set .......................................................................................................7
5.2. ‘PER PROTOCOL’ Analysis Set..............................................................................7
5.3. Safety Analysis Set....................................................................................................7
5.4. Other Analysis Sets ...................................................................................................7
5.5. Treatment Misallocations..........................................................................................7
5.6. Protocol Deviations...................................................................................................7
6. ENDPOINTS AND COVARIATES .....................................................................................8
6.1. Primary Efficacy Endpoint........................................................................................8
6.2. SECONDARY EFFICACY Endpoints.....................................................................8
6.3. Safety Endpoints .......................................................................................................8
6.4. Other Endpoints.........................................................................................................9
6.5. PK Endpoints.............................................................................................................9
6.6. PD Endpoints.............................................................................................................9
6.7. Outcomes Research (OR) Endpoints.........................................................................9
6.8. Covariates..................................................................................................................9
7. HANDLING OF MISSING VALUES ..................................................................................9
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ............................9
8.1. Statistical Methods ....................................................................................................9
8.1.1. Analyses for Continuous Data......................................................................9
8.1.2. Analyses for Categorical Data......................................................................9
8.1.3. Time to Event Data.......................................................................................9


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8.2. Statistical Analyses .................................................................................................10
8.2.1. Efficacy Analyses .......................................................................................10
8.2.2. Safety Analyses ..........................................................................................11
9. REFERENCES ....................................................................................................................12
10. APPENDICES ...................................................................................................................13
APPENDICES
Appendix 1. DATA DERIVATION DETAILS ......................................................................13
Appendix 1.1. Derivation of Local, Distant and Locoregional................................................13
Appendix 1.2. Derivation of Appearance of 2nd Primary or Contralateral Breast Cancer.......15
Appendix 1.3. Derivation of HER2 Status...............................................................................16
Appendix 2. SAS PROGRAMMING DETAILS ....................................................................18
Appendix 2.1. Programming Confidence Bands for KM Survival Curve...............................18
Appendix 2.2. Programming Confidence Intervals for KM Median Time to Event...............18
18
 
18
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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
Version 1.2 is amended from version 1.1 based on protocol amendment 3 dated 20 Mar 2015. 
Please see the below table for the detailed amendments from previous versions. 
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
1.0
Jul 8, 
2011
Original SAP
1.1
Nov 5,
2013
Update citation of protocol amendment 1 to protocol 
amendment 2; 
Details:
Section 2
Add targeted data cut-off date for final analysis.
Section 3
V1.0: “The first is to occur when approximately 50% of 
subjects completed their 1st year of follow up. The second is 
to occur when approximately 50% of subjects completed the 
study drug treatment or withdrawal from the study.” 
V1.1: “The first interim analysis data cut-off date is Dec 31, 
2013. The second interim analysis data cut-off date is Dec 31, 
2015.”
Section 5.3
Revised definition of the safety analysis set from “all enrolled 
patients” to “all enrolled patients who take at least one dose of 
the study drug”
Section 8.1.3
Add method of Hall and Wellner.
Section 8.2.1
Add method of Brookmeyer and Crowley.
Delete duplicated sentence.
Section 8.2.2
Delete “history of disease” as it duplicates medical history.
Section 10.2
Add programming details for calculating confidence intervals 
for median time to event.
1.2
Jun 
21, 
2015
Update citation of protocol amendment 2 to amendment 3;
Details:
Section 3
Updated time for interim analyses.
V1.1: “The second interim analysis data cut-off date is Dec 
31, 2015.”
V1.2: “The second interim analysis is to occur when the study 
enrolled 550 subjects.”
Section 8.2.2
Common Technology Criteria for Adverse Events Version 
4.0 was changed to 3.0 to be consistent with the protocol 
amendment 3.
Appendix 1.3
Derivation of HER2 status changed.
V1.1:” HER2 status positive or negative is defined below:
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Version
Date
Author(s)
Summary of Changes/Comments

HER2 positive if HER2 IHC status = 3+, HER2 FISH 
status = positive or HER2 CISH status = positive or 
HER2 mutation = positive.

HER2 positive if HER2 IHC status = 2+ or unknown 
or undone, HER2 FISH status = positive or 
HER2 CISH status = positive or HER2 mutation = 
positive.

HER2 negative if HER2 IHC status = 2+ or unknown 
or undone, HER2 FISH status = negative or 
HER2 CISH status = negative or HER2 mutation = 
negative.

HER2 negative if HER2 IHC status = 0 or 1+, 
HER2 FISH status = negative or HER2 CISH status = 
negative or HER2 mutation = negative.”
V1.2: “HER2 status positive or negative is defined below, 
note that the results from HER2 FISH, CISH and mutation 
should be the same.

If HER2 FISH status = positive or HER2 CISH status 
= positive or HER2 mutation = positive, then HER2 
is positive.

If HER2 FISH status = negative or HER2 CISH
status = negative or HER2 mutation = negative, then 
HER2 is negative.

If HER2 FISH, HER2 CISH and HER2 mutation are 
all undone or unknown, then

If HER2 IHC status = 3+, HER2 is positive.

If HER2 IHC status = 0 or 1+, HER2 is negative.

If HER2 IHC status = 2+ or unknown or undone, 
HER2 is unknown.”
Appendix 2.2: sample SAS code added.
Appendix 2.3 and 2.4 was added for programming cox model 
for HER2 Status and programming Cox model for multiple 
factors with stepwise selection.


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2. INTRODUCTION
Note: in this document any text copied directly from the protocol is italicised.
Aromasin® (Exemestane) is an irreversible, steroidal aromatase inhibitor, structurally 
related to the natural substrate androstenedione. In post-menopausal women, oestrogens 
are produced primarily from the conversion of androgens into oestrogens through the 
aromatase enzyme in peripheral tissues. Oestrogen deprivation through aromatase 
inhibition is an effective and selective treatment for hormone dependent breast cancer in 
postmenopausal women. In the year 2002, Aromasin® (Exemestane) was approved in China 
for the treatment of advanced breast cancer in women with natural or induced 
postmenopausal status whose disease has progressed following tamoxifen therapy.
Aromasin® (Exemestane) was approved in China for adjuvant treatment of postmenopausal
women with estrogen receptor (ER) positive early invasive breast cancer who have received
2-3 years of tamoxifen & are switched to Aromasin® for completion of a total of 
5 consecutive years of adjuvant hormonal therapy by State Food and Drug Administration
(CFDA) with clinical trial waive in May. 2008. The approval was granted in view of the
significant efficacy and tolerant safety from the Intergroup Exemestane Study (IES), which
was a phase III randomized controlled trial conducted primarily in Caucasian patients.
While Aromasin® has been used in China for adjuvant therapy of breast cancer since then,
there is currently lack of systematic collection and analysis for the efficacy and safety data of
Aromasin® adjuvant setting in Chinese population. The Aromasin® Non-Interventional 
Study is being proposed to collect data systematically and to assess the efficacy and safety of
Aromasin® adjuvant setting in Chinese population. Generation of such information is
expected to provide evidence for Chinese physicians to manage clinical practice of
Aromasin® adjuvant setting. The safety document will be used in this study is the 
Aromasin® Local Product Document approved by CFDA.
2.1. Study Design
This is a multicenter, non-interventional, and prospective clinical study. The study will
collect and analyze the efficacy and safety data from consecutive 550 eligible patients from
study beginning to Dec. 31, 2016. If the 550 patient’s recruitment has completed before
Dec.31, 2016, the recruiting will stop.
2.2. Study Objectives 
To generate the efficacy and safety data from patients with early invasive breast cancer
treated with Aromasin® in the adjuvant setting in China.
Primary objective: Efficacy of the treatment with Aromasin® in postmenopausal women with 
estrogen receptor positive early invasive breast cancer who have received adjuvant
Tamoxifen therapy for up to 2-3 years.
Secondary objective: Safety of the treatment with Aromasin® in women with
postmenopausal estrogen receptor positive early invasive breast cancer who have received
adjuvant Tamoxifen therapy for up to 2-3 years.


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3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
Up to 2 early analyses of the data will be performed. The first interim analysis data cut-off
date is Dec 31, 2013. The second interim analysis is to occur when the study enrolled 
550 subjects. The final analysis will be done at the end of treatment.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
This study is non-comparative and no inferential statistical analyses are planned.  Analyses 
will consist of descriptive statistics and corresponding 95% 2-sided confidence intervals 
when appropriate. 
4.2. Statistical Decision Rules
There are no statistical decision rules.
5. ANALYSIS SETS
5.1. Full Analysis Set
The Full Analysis Set (FAS) will be defined as all patients who receive at least one dose of 
Aromasin® during the observation period.  All efficacy analyses will be performed using the 
FAS.  
5.2. ‘PER PROTOCOL’ Analysis Set 
Not applicable.
5.3. Safety Analysis Set
The safety population will be defined as all enrolled patients who take at least one dose of the 
study drug; all summaries of safety will be reported within the safety. 
5.4. Other Analysis Sets
Not applicable.
5.5. Treatment Misallocations 
Not applicable.
5.6. Protocol Deviations
Not applicable.


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6. ENDPOINTS AND COVARIATES
6.1. Primary Efficacy Endpoint
The primary efficacy endpoint is time-to-recurrence, where recurrence is defined as the 
earliest occurrence of any of the following:

Locoregional/distant recurrence of the primary breast cancer.

Appearance of 2nd primary or contralateral breast cancer.

Death due to any cause.
Locoregional recurrence is defined as any recurrence in the ipsilateral breast, chest wall or 
axillary lymph nodes.
6.2. SECONDARY EFFICACY Endpoints
Locoregional/distant recurrence, appearance of 2nd primary or contralateral breast cancer, and 
death will also be summarized as follows:

Time to each event.

The proportion of subjects experiencing each event.

The incidence rate (per annum) is defined as a ratio of the number of events and the 
total exposure time (in years) to Aromasin® therapy.
6.3. Safety Endpoints
Safety endpoints include:

Adverse events of particular interest are as follows:

Gynaecological: Bleeding ,discharge, uterine dilatation and curettage;

Cardiac: myocardial infarction, hypertension;

Venous thromboembolic events;

Musculoskeletal: Joint stiffness, arthralgia, muscle cramps, fractures;

Menopausal symptoms: Hot flushes, anxiety, depression, headaches.

Changes in laboratory parameters, including lipids.

Changes in bone mineral density.

Vital signs.


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
Reasons for discontinuation of Aromasin® therapy.

Duration of Aromasin® therapy.
6.4. Other Endpoints 
Not applicable.
6.5. PK Endpoints 
Not applicable.
6.6. PD Endpoints 
Not applicable.
6.7. Outcomes Research (OR) Endpoints
None.
6.8. Covariates 
The following subgroup is of interest:

HER2 status (binary: positive, negative).
7. HANDLING OF MISSING VALUES
Censoring for time-to-recurrence is defined in Section 8.2.  Subjects with missing value for a 
given efficacy variable will not contribute to the analysis of that variable. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
8.1.1. Analyses for Continuous Data
Continuous variables will be presented using summary statistics: number of observations, 
arithmetic mean, standard deviation, standard error, minimum, maximum, and median 
values.  Additional 2-sided 95% confidence intervals based on Student’s t-distribution will 
also be presented where specified.
8.1.2. Analyses for Categorical Data
For dichotomous variables (proportions, incidences and HER2 status), the number and 
percent of subjects will be presented.  A two-sided 95% confidence interval (Wilson score 
interval) will be presented for the percent. 
8.1.3. Time to Event Data
Time-to-recurrence will be summarized using the Kaplan-Meier (KM) estimates of the 
survival function and presented graphically. KM plots will display months as the unit of time 
(365.25/12 days per month).  If estimable, the median time to event (based on the KM 


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estimate) and its associated 2-sided 95% confidence interval (method of Brookmeyer and 
Crowley 1982) will also be presented.  95% confidence bands for the survival distribution 
(method of Hall and Wellner, 1980) will be computed.  In addition, a Cox regression model 
will also be fit for the purpose of comparing subgroup of HER2 status level, and hazard ratio
estimated along with corresponding 2-sided 95% confidence interval.
8.2. Statistical Analyses 
8.2.1. Efficacy Analyses
All summaries of efficacy parameters will be reported within the FAS population.  Analyses 
will be primarily descriptive in nature, and therefore no statistical sample size estimation was 
performed. 
Primary analysis 
The primary analysis is time-to-recurrence, where recurrence is defined as the earliest 
occurrence any of the following:

Locoregional/distant recurrence of the primary breast cancer.

Appearance of 2nd primary or contralateral breast cancer.

Death due to any cause.
Time-to-recurrence is calculated as the time from date of enrollment to first objective 
documentation of the recurrence defined above.  In the analysis of time to recurrence, 
subjects lost to follow-up and subjects who are still being followed at the time of analysis 
with no documented event will be censored at the last date the subject was known to be 
event-free.  The Kaplan Meier non-parametric estimate will be used to summarize the 
survival distribution and median for time-to-event.  95% confidence interval for median time 
to event (method of Brookmeyer and Crowley 1982) and 95% confidence bands for the 
survival distribution (method of Hall and Wellner, 1980) will be computed.
Secondary analyses
Locoregional/distant recurrence, appearance of 2nd primary or contralateral breast cancer, and 
death will also be summarized as follows:

Time to each event will be summarized similarly as the primary analyses for 
time-to-recurrence (See Section 8.1.3). 

Summary statistics for the proportion of subjects experiencing each event.

Summary statistics for the incidence rate (per annum), defined as a ratio of the number of 
events and the total exposure time (in years) to Aromasin® therapy.


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8.2.2. Safety Analyses
All summaries will use the safety analysis set.
Adverse events which will be graded according to grades of severity specified in the 
Common Technology Criteria for Adverse Events Version 3.0 (CTCAE v3.0).  Pfizer data 
standards (PDS) will be used to summarize all safety data. 
Patient baseline characteristics (demography, breast cancer history, medical history, primary 
diagnosis, lab data, treatment history related to primary diagnosis, history of hormonal 
therapy received before Aromasin, location of primary diagnosis, histopathological 
classification and grade, TNM stage) will also be summarized according to PDS.  Vital signs, 
ECOG status, laboratory data and physical examination will be summarized by visit using 
observed data as well as each patient’s last available value.
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9. REFERENCES 
1.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics 1982; 38:29-41.
2.
Hall, W. J. and Wellner, J. A. (1980), “Confidence Bands for a Survival Curve for 
Censored Data,” Biometrika 69. 


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10. APPENDICES 
Appendix 1. DATA DERIVATION DETAILS
Appendix 1.1. Derivation of Local, Distant and Locoregional
Cancer Event Assessment Case Report Form


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The following types of cancer recurrence will be derived from the Cancer Event Assessment 
CRF:

Local: "Recurrent Disease" is checked on the CRF and “Disease Site” is marked "Breast".

Distant: "Recurrent Disease" is checked on the CRF and “Disease Site” is marked 
something other than breast (brain, lung, bone, lymph node, liver, other).

Time to Locoregional recurrence: Time from inclusion into the study to the date of the
first documentation of locoregional recurrence.  Specifically, time to Locoregional
recurrence is (date of inclusion into the study) – (first date of documented locoregional
recurrence) +1.
Locoregional recurrence is defined as any recurrence in the ipsilateral breast, chest wall or 
axillary lymph nodes.


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Appendix 1.2. Derivation of Appearance of 2nd Primary or Contralateral Breast Cancer

Appearance of 2nd primary or contralateral breast cancer: When “Second Primary 
malignancy of breast cancer" is checked on the CRF. This represents either ipsilateral or 
contralateral breast cancer recurrence.  When “Second Primary malignancy other than 
breast cancer” is checked, a disease site other than breast will not be considered recurrent 
disease.

Time to appearance of 2nd primary or contralateral breast cancer: Time from inclusion 
into the study to the date of the first documentation appearance of 2nd primary
malignancy of breast cancer or contralateral breast cancer.  Specifically, time to 
appearance of 2nd primary or contralateral breast cancer is (date of inclusion into the 
study) – (first date of documented appearance of 2nd primary or contralateral breast 
cancer) +1.


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Appendix 1.3. Derivation of HER2 Status
HER2 status positive or negative is defined below, note that the results from HER2 FISH, 
CISH and mutation should be the same.

If HER2 FISH status = positive or HER2 CISH status = positive or HER2 mutation = 
positive, then HER2 is positive.

If HER2 FISH status = negative or HER2 CISH status = negative or HER2 mutation = 
negative, then HER2 is negative.


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
If HER2 FISH, HER2 CISH and HER2 mutation are all undone or unknown, then

If HER2 IHC status = 3+, HER2 is positive.

If HER2 IHC status = 0 or 1+, HER2 is negative.

If HER2 IHC status = 2+ or unknown or undone, HER2 is unknown.


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Appendix 2. SAS PROGRAMMING DETAILS
Appendix 2.1. Programming Confidence Bands for KM Survival Curve
•
Use of PROC LIFETEST; 
•
Create an OUTPUT dataset containing the survival estimates;
•
Use CONFBAND = HW to produce confidence bands for the method of Hall and 
Wellner in the PROC LIFETEST statement.
Appendix 2.2. Programming Confidence Intervals for KM Median Time to Event
•
Use of PROC LIFETEST; 
•
Use CONFTYPE=LINEAR to produce confidence intervals for the method of 
Brookmeyer and Crowley in the PROC LIFETEST statement;
Sample SAS code:
proc lifetest data=mydata outsurv=estimates confband=HW conftype=linear 
timelist=182;  
time Days*Status(0);
run;
 
   
 
 
  
                            
                              
                          
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